WO2015007206A1 - Afatinib acid addition salts and crystal forms thereof, preparation method and pharmaceutical composition thereof - Google Patents

Afatinib acid addition salts and crystal forms thereof, preparation method and pharmaceutical composition thereof Download PDF

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WO2015007206A1
WO2015007206A1 PCT/CN2014/082252 CN2014082252W WO2015007206A1 WO 2015007206 A1 WO2015007206 A1 WO 2015007206A1 CN 2014082252 W CN2014082252 W CN 2014082252W WO 2015007206 A1 WO2015007206 A1 WO 2015007206A1
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afatinib
solvent
preparation
crystal form
acid
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PCT/CN2014/082252
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Chinese (zh)
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沈涛
盛晓霞
盛晓红
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杭州普晒医药科技有限公司
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Priority to CN201480002096.3A priority Critical patent/CN104540820B/en
Publication of WO2015007206A1 publication Critical patent/WO2015007206A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/34—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfuric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C307/00—Amides of sulfuric acids, i.e. compounds having singly-bound oxygen atoms of sulfate groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C307/02—Monoamides of sulfuric acids or esters thereof, e.g. sulfamic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/05—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing at least two sulfo groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/33—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of six-membered aromatic rings being part of condensed ring systems
    • C07C309/34—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of six-membered aromatic rings being part of condensed ring systems formed by two rings
    • C07C309/35—Naphthalene sulfonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/45—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
    • C07C309/46—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton having the sulfo groups bound to carbon atoms of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/08—Malonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/145—Maleic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/01—Saturated compounds having only one carboxyl group and containing hydroxy or O-metal groups
    • C07C59/06—Glycolic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/01—Saturated compounds having only one carboxyl group and containing hydroxy or O-metal groups
    • C07C59/10—Polyhydroxy carboxylic acids
    • C07C59/105—Polyhydroxy carboxylic acids having five or more carbon atoms, e.g. aldonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention belongs to the technical field of medicinal chemical crystallization, in particular to a novel afatinidine acid addition salt and a crystal form thereof, a preparation method thereof, and a pharmaceutical composition and use thereof.
  • afatinib N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6- Quinazolinyl]-4-(dimethylamino;)-2-butenamide
  • English name is AFATINIB, also known as BIBW 2992, molecular formula C 24 H 25 C1FN 5 03, its structural formula
  • Afatinib is indicated for advanced non-small cell lung cancer (NSCLC) and HER2-positive patients with advanced breast cancer. Oral tablets are given at a standard dose of 40 mg once daily. Now Boehringer Ingelheim is submitting a marketing permit application to the European Medicines Agency and is expected to be listed on Tovok.
  • Afatinib is a potent and selective dual inhibitor of the epidermal growth factor receptor (EGFR also known as ErbBl) and human epidermal growth factor receptor-2 (HER2/neu also known as ErbB2) tyrosine kinase. Unlike the first generation tyrosine kinase inhibitors, afatinib is designed to covalently bind to EGFR and HER2, thereby irreversibly inactivating its bound receptor molecules.
  • EGFR epidermal growth factor receptor
  • HER2/neu human epidermal growth factor receptor-2
  • Patent application WO 2002/50043 A1 discloses afatinib compounds
  • WO2007/054550A1 and WO2007/054551A1 disclose indications for afatinib.
  • WO2012121764 A1 discloses crystal form B of afatinib dimaleate.
  • the DSC chart shows that it has an exothermic peak at 125.9 ° C, indicating that the crystal form is unstable to heat, and crystal transformation or even decomposition occurs.
  • WO2013052157A1 discloses crystal form C, D, E of afatinib dimaleate.
  • the literature indicates that crystal forms C and D may be anhydrate, but there is no direct evidence; the DSC chart of crystal form C is shown at 40 ° C. -95 ° C has an endothermic peak, most likely a solvate; Form E is a hydrate with a water content of 5.9% - 8.1%, and a higher water content is sensitive to humidity.
  • afatinib dimaleate crystal forms 8, C, D, and E have relatively serious hygroscopicity and are not suitable for storage and formulation applications.
  • the patent document WO 2009/147238 A1 discloses that the afatinib dimaleate salt described in WO 2005/037824 A2 is in the form of fine needles, which results in poor fluidity and large differences between batches. The processability is also poor, and it is easy to stick and cannot be pressed directly. Therefore, the patent document WO 2009/147238 A1 employs a roll pressing method to improve the problem of being difficult to process due to the needle-like appearance of the raw material, but the roll pressing method increases the unit operation of the roll crushing, thereby increasing the production cost.
  • the afatinib dimaleate salt described in WO2005/037824 A2 is referred to herein as "the prior art crystalline form of afatinib dimaleate".
  • Patent document WO 2012121764 A1 discloses a process for the preparation of a solid form of afatinidine acid addition salt, comprising a dimaleate salt of afatinib, a diphenyl sulfonate, a fumarate, a disulfate, a disalt. Acid, dioxalate, methanesulfonate, diphosphate, di L-malate, citrate, succinate, L-aspartate and difumarate.
  • This document is only a general reference to the above-mentioned afatinidine acid addition salts having some beneficial properties suitable for tablet applications, but no specific data is provided.
  • the patent document CN1867564B discloses that the prior art crystalline form of afatinib dimaleate has a certain hygroscopicity, but there is no specific data. According to the research of the present inventors, the prior art of afatinib dimaleate The crystal form has a weight change of 2.6% in the range of 10% to 80% relative humidity. Preferably, the pharmaceutically active substance should have only limited hygroscopicity, and higher hygroscopicity often has an adverse effect.
  • the absorption of moisture reduces the content of the pharmaceutically active substance, affects the formulation process, and affects the uniformity of the preparation; moisture storage measures must be taken during storage, such as adding a desiccant or storing it in a moisture-proof environment. Increased costs and the risk of poor long-term storage stability.
  • the present invention provides a novel pharmaceutically acceptable afatinidine acid addition salt and a crystal form thereof, including ethanedisulfonate, 1,5-naphthalene disulfonate, and propylene Acid salt, dimalonate, bis 2-naphthalene sulfonate, diamino sulfonate, di D-gluconate, glycolate, dicyclohexane sulfamate, di 4-aminobenzene sulfonate
  • the acid form, as well as the crystalline form of the above novel salts also include a novel crystalline form of afatinib dimaleate.
  • the afatinidine acid addition salt of the present invention and its crystal form have one or more improved properties compared to the prior art afatinidine acid addition salt or a crystalline form thereof.
  • the present invention further provides a process for the preparation of the afatinidine acid addition salt of the present invention and a crystal form thereof, a pharmaceutical composition thereof and use thereof.
  • One of the contents of the present invention is to provide afatinib ethanedisulfonate and its crystal form, and a process for the preparation thereof.
  • the actual content of afatinib free base in the afatinib ethanedisulfonate was 71.4% (excluding the amount of solvent), and the ratio of afatinib to ethanedisulfonic acid was 1:1 by HPLC.
  • the theoretical content of afatinib in the formed compound is 71.9%. Therefore, the afatinib and ethanedisulfonic acid in the afatinib ethanedisulfonate of the present invention are salted in a molar ratio of 1:1, and the structural formula is as follows: :
  • the preparation method of the afatinib ethanedisulfonate comprises the following steps: respectively forming a solution system of afatinib and ethanedisulfonic acid in a soluble solvent, a molar of afatinib and ethanedisulfonic acid Ratio 1: 1:1:2, the two systems are mixed to form a slurry, and then the soluble solvent is removed.
  • the soluble solvent is a nitrile, an alcohol, a ketone, an ester, an alkane, an ether or a mixture thereof; the soluble solvent is further preferably acetonitrile, methanol, acetone, ethyl acetate, n-heptane or Methyl tert-butyl ether.
  • the soluble solvent is removed by spin-drying.
  • the afatinib ethanedisulfonate is an E1 crystalline form of afatinib ethanedisulfonate, using Cu- ⁇ radiation, and the X-ray powder diffraction pattern has a diffraction angle of 2 ⁇ of 6.3 ⁇ 0.2. , 7.0 ⁇ 0.2. , 17.6 ⁇ 0.2. , 17.8 ⁇ 0.2. , 21.7 ⁇ 0.2. Characteristic peaks at 22.8 ⁇ 0.2° and 24.6 ⁇ 0.2°.
  • the E1 crystal form of afatinib ethanedisulfonate has an X-ray powder diffraction pattern at a diffraction angle of 2 ⁇ of 6.3 ⁇ 0.2. , 7.0 ⁇ 0.2. , 12.6 ⁇ 0.2. , 14.5 ⁇ 0.2. , 17.6 ⁇ 0.2. , 17.8 ⁇ 0.2. , 18.3 ⁇ 0.2. , 19.0 ⁇ 0.2. , 21.7 ⁇ 0.2. , 22.8 ⁇ 0.2. , 24.6 ⁇ 0.2. , 26.3 ⁇ 0.2. And 28.6 ⁇ 0.2. There are characteristic peaks.
  • E1 crystal form of afatinib ethanedisulfonate, the diffraction angle of the X-ray powder diffraction pattern and the relative intensity thereof are as follows:
  • a typical example of the El crystalline form of afatinib ethanedisulfonate has an X-ray powder diffraction pattern as shown in FIG.
  • the E1 crystal form of afatinib ethanedisulfonate has a Fourier transform infrared spectrum having characteristic peaks at wave numbers of 1501, 1454, 1227, 1206, 1168, 1023 and 767 cm" 1 .
  • the E1 crystal form of afatinib ethanedisulfonate has a characteristic peak at a wave number of 1661, 1610, 1551, 1406, 1379, 1297 and 1207 cm" 1 .
  • a preparation method of the E1 crystal form afatinib ethanedisulfonate comprises the following steps: respectively forming a solution system of afatinib and ethanedisulfonic acid in a soluble solvent, afatinib and B
  • the molar ratio of disulfonic acid is 1:1-1:2, the two systems are mixed to form a slurry and stirred, and maintained at -10 to 50 ° C for 1 to 48 hours, and then the solvent is removed, wherein the soluble solvent is selected from C 2 -C 4 nitrile, dC 4 alcohol, C 3 -C 5 ketone, C 4 -C 5 ester, C 6 -C 9 alkane, C 4 -C 6 ether or a mixture thereof.
  • the C 2 -C 4 nitrile includes, but is not limited to, acetonitrile
  • the dC 4 alcohol includes, but is not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, and sec-butanol
  • the C 3 -C 5 ketone including but not limited to, acetone and methyl ethyl ketone
  • the C 4 -C 5 esters include, but are not limited to ethyl acetate and isopropyl acetate
  • a C 6 -C 9 alkanes include but are not limited to, n-hexane, n-heptane and a
  • the cyclohexane, the C 4 -C 6 ether includes but is not limited to diethyl ether, methyl tert-butyl ether and diisopropyl ether; preferably the soluble solvent is acetonitrile, m
  • the concentration of afatinib in a soluble solvent is 10 mg/ml to a saturated solution of afatinib in the solvent.
  • the molar ratio of afatinib and ethanedisulfonic acid is from 1:1 to 1:2.
  • the operating temperature of the preparation method is room temperature.
  • the preparation method of the E1 crystal form afatinib ethanedisulfonate comprises the following steps: the afatinib ethanedisulfonate prepared by the above method is slurried in an organic solvent and stirred, and the slurry is slurried.
  • the solvent is removed by maintaining at -10-50 ° C for 1 to 72 hours, wherein the organic solvent is selected from the group consisting of acetonitrile, methanol, acetone, ethyl acetate, n-heptane, methyl t-butyl ether or a mixture thereof.
  • the operating temperature of the preparation method is room temperature.
  • afatinib dimaleate or its crystal form afatinib ethanedisulfonate or E1 crystal form afatinib ethanedisulfonate has One or more improved properties, such as: higher crystallinity, better solubility, dissolution rate, preferred crystalline morphology, better thermal stability and storage stability, lower hygroscopicity, better Flowability and advantageous processing and handling characteristics.
  • the E1 crystalline form of afatinib ethanedisulfonate has the following beneficial properties:
  • the decomposition temperature is 261.8 ° C, and the decomposition temperature of the prior art crystal form of afatinib dimaleate is 164.1 ° C, which has higher thermal stability;
  • afatinib ethanedisulfonate or the E1 crystal form afatinib ethanedisulfonic acid of the present invention is compared with the prior art afatinib dimaleate or a crystal form thereof.
  • Salt has many advantages and performance, and the application effect is better. It is suitable as a medicine.
  • the active ingredient of the preparation is compared with the prior art afatinib dimaleate or a crystal form thereof.
  • the higher solubility of the active ingredient is beneficial to improve the bioavailability of the drug, and thus has a positive effect on the efficacy;
  • the crystalline component of the active ingredient has good morphology, has better fluidity, compressibility and processability, and the preparation process
  • the suitability is good;
  • the active ingredient has lower hygroscopicity and higher thermal stability, and can better resist the uneven content of active ingredients caused by environmental temperature, humidity and the like in the process of drug manufacture and/or storage, Problems such as reduced purity and increased impurities reduce the risk of reduced efficacy and safety risks, and facilitate accurate quantification in drug manufacturing, improve formulation uniformity, and later storage and transportation.
  • a second aspect of the present invention provides afatinib 1,5-naphthalene disulfonate and a crystalline form thereof, and a process for the preparation thereof.
  • the actual content of afatinib free base in the afatinib 1,5-naphthalene disulfonate was 63.3% (excluding the amount of solvent), afatinib and 1,5-naphthalene by HPLC.
  • afatinib 1,5-naphthalene disulfonate of the present invention is afatinib and 1,5 - Naphthalene disulfonic acid is salted in a molar ratio of 1:1, and its structural formula is as follows:
  • the preparation method of the afatinib 1,5-naphthalenedisulfonate comprises the following steps: respectively forming a solution system of afatinib and 1,5-naphthalene disulfonic acid in a soluble solvent, Alfati
  • the molar ratio of nitrile to 1,5-naphthalene disulfonic acid was 1:1-1:2, and the two systems were mixed to form a slurry, and then the soluble solvent was removed.
  • the soluble solvent is a nitrile, an alcohol, a ketone, an ester, an alkane, an ether or a mixture thereof; the soluble solvent is further preferably acetonitrile, methanol, acetone, ethyl acetate, n-heptane or Methyl tert-butyl ether.
  • the soluble solvent is removed by spin-drying.
  • the afatinib 1,5-naphthalenedisulfonate is an N1 crystalline form of afatinib 1,5-naphthalenedisulfonate, using Cu-Ka radiation, and its X-ray powder diffraction pattern is diffracted.
  • the angle 2 ⁇ is 6.6 ⁇ 0.2 ° and 13.4 ⁇ 0.2. , 16.6 ⁇ 0.2. , 17.5 ⁇ 0.2. , 20.8 ⁇ 0.2. And 24.2 ⁇ 0.2. There are characteristic peaks.
  • the N1 crystal form of afatinib 1,5-naphthalenedisulfonate has an X-ray powder diffraction pattern at a diffraction angle of 2 ⁇ of 6.6 ⁇ 0.2. , 8.1 ⁇ 0.2. , 13.4 ⁇ 0.2. , 14.8 ⁇ 0.2. , 16.3 ⁇ 0.2. , 16.6 ⁇ 0.2. , 17.5 ⁇ 0.2. , 18.3 ⁇ 0.2. , 20.8 ⁇ 0.2. , 22.0 ⁇ 0.2. , 22.7 ⁇ 0.2. And 24.2 ⁇ 0.2. There are characteristic peaks.
  • the N1 crystal form afatinib 1,5-naphthalenedisulfonate, the diffraction peak 2 ⁇ characteristic peak of the X-ray powder diffraction pattern and its relative intensity are as follows:
  • Nl crystal form afatinib 1,5-naphthalene disulfonate has an X-ray powder diffraction pattern as shown in Fig. 13.
  • the N1 crystal form of afatinib 1,5-naphthalene disulfonate has a Fourier transform infrared spectrum with characteristic peaks at wave numbers of 1639, 1577, 1524, 1500, 1452, 1216, 1155, 1028 and 765 cm _1 .
  • the N1 crystalline form of afatinib 1,5-naphthalene disulfonate has a Raman spectrum with characteristic peaks at wavenumbers of 1704, 1661, 1613, 1543, 1403, 1365, 1205, 1068, 999 and 780 cm. .
  • a preparation method of the N1 crystal form afatinib 1,5-naphthalene disulfonate comprises the following steps: respectively forming a solution of afatinib and 1,5-naphthalene disulfonic acid in a soluble solvent The molar ratio of afatinib to 1,5-naphthalenedisulfonic acid is 1:1-1:2, the two systems are mixed to form a slurry and stirred, and maintained at -10 to 50 ° C for 1-48 hours.
  • the soluble solvent is selected from the group consisting of C 2 -C 4 nitriles, dC 4 alcohols, C 3 -C 5 ketones, C 4 -C 5 esters, C 6 -C 9 alkanes, C 4 -C 6 ethers Or a mixture thereof.
  • the C 2 -C 4 nitrile includes, but is not limited to, acetonitrile
  • the dC 4 alcohol includes, but is not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, and sec-butanol
  • the C 3 -C 5 ketone including but not limited to, acetone and methyl ethyl ketone
  • the C 4 -C 5 esters include, but are not limited to ethyl acetate and isopropyl acetate
  • a C 6 -C 9 alkanes include but are not limited to, n-hexane, n-heptane and a
  • the cyclohexane, the C 4 -C 6 ether includes but is not limited to diethyl ether, methyl tert-butyl ether and isopropyl ether; preferably the soluble solvent is acetonitrile, methanol
  • the concentration of afatinib in a soluble solvent is 10 mg/ml to a saturated solution of afatinib in the solvent.
  • the molar ratio of afatinib to 1,5-naphthalene disulfonic acid is 1:1-1:1.5.
  • the operating temperature of the preparation method is room temperature.
  • Another preparation method of the N1 crystal form afatinib 1,5-naphthalene disulfonate comprises the following steps: afatinib 1,5-naphthalene disulfonate prepared according to the aforementioned preparation method
  • the slurry is formed in an organic solvent and stirred, and the slurry is kept at -10 to 50 ° C for 1 to 72 hours to remove the solvent, wherein the organic solvent is selected from the group consisting of methanol, ethanol, acetonitrile, acetone, ethyl acetate, and n-glycol. Alkane, methyl tert-butyl ether or a mixture thereof.
  • the operating temperature of the preparation method is room temperature.
  • the afatinib 1,5-naphthalene disulfonate is an N2 crystal form afatinib 1,5-naphthalene disulfonic acid salt hydrate.
  • the X-ray powder diffraction pattern of the N2 crystal form afatinib 1,5-naphthalenedisulfonic acid salt hydrate was 6.7 ⁇ 0.2 at a diffraction angle of 2 ⁇ . , 8.1 ⁇ 0.2. , 9.3 ⁇ 0.2. , 14.9 ⁇ 0.2. Characteristic peaks at 20.9 ⁇ 0.2° and 23.0 ⁇ 0.2°.
  • the N2 crystal form afatinib 1,5-naphthalene disulfonic acid salt hydrate has an X-ray powder diffraction pattern at a diffraction angle of 2 ⁇ of 6.7 ⁇ 0.2. , 8.1 ⁇ 0.2. , 9.3 ⁇ 0.2. , 13.9 ⁇ 0.2. , 14.9 ⁇ 0.2 °, 15.8 ⁇ 0.2. , 16.7 ⁇ 0.2. , 17.5 ⁇ 0.2. , 20.5 ⁇ 0.2. , 20.9 ⁇ 0.2. , 21.7 ⁇ 0.2. , 23.0 ⁇ 0.2. Characteristic peaks at 24.1 ⁇ 0.2° and 24.3 ⁇ 0.2°.
  • N2 crystal form afatinib 1,5-naphthalene disulfonic acid salt hydrate, the X-ray powder diffraction pattern of the diffraction angle 2 ⁇ characteristic peak and its relative intensity are as follows:
  • a typical example of the N2 crystal form afatinib 1,5-naphthalenedisulfonic acid salt hydrate has an X-ray powder diffraction pattern as shown in Fig. 20.
  • thermogravimetric analysis (TGA) pattern of the N2 crystal form afatinib 1,5-naphthalenedisulfonic acid salt hydrate showed a weight loss of 5.97% before 100 ° C, which was about trihydrate.
  • the N2 crystal form afatinib 1,5-naphthalenedisulfonic acid salt hydrate has a Fourier transform infrared spectrum having characteristic peaks at wave numbers of 1641, 1578, 1500, 1451, 1219, 1155, 1028 and 764 cm.
  • the preparation method of the N2 crystal form afatinib 1,5-naphthalene disulfonic acid salt hydrate comprises the following steps: placing the N1 type afatinib 1,5-naphthalene disulfonate at 75%-100 % room temperature in a relative humidity environment, set the time 1 to 7 days. It is preferably placed in a room temperature environment of 75%-85% relative humidity for 1 to 3 days.
  • afatinib dimaleate or its crystal form afatinib 1,5-naphthalene disulfonate or N1 crystal form afatinib 1
  • 5-naphthalene disulfonate or N2 crystal form afatinib 1,5-naphthalenedisulfonic acid salt hydrate has one or more improved properties, such as: higher crystallinity, better solubility, Dissolution speed, preferred crystalline morphology, better thermal stability and storage stability, lower moisture absorption, better flowability, and advantageous processing and handling characteristics.
  • N1 crystalline form of afatinib 1,5-naphthalenedisulfonate has the following beneficial properties:
  • the decomposition temperature is 276.3 ° C, and the decomposition temperature of the prior art crystal form of afatinib dimaleate is 164.1 ° C, which has higher thermal stability;
  • N2 crystal form afatinib 1,5-naphthalenedisulfonic acid salt hydrate has the following beneficial properties:
  • the decomposition temperature is 275.4 ° C, and the decomposition temperature of the prior art crystal form of afatinib dimaleate is 164.1 ° C, which has higher thermal stability;
  • afatinib 1,5-naphthalene disulfonate or the N1 crystal form afatinib of the present invention is compared with the prior art afatinib dimaleate or a crystal form thereof.
  • 1,5-naphthalene disulfonate or N2 crystal form afatinib 1,5-naphthalenedisulfonic acid salt hydrate has a plurality of advantageous properties, and the application effect is better, and is suitable as an active ingredient of a pharmaceutical preparation.
  • the active ingredient has good crystal morphology, better fluidity, compressibility and processability, and is suitable for the preparation process; the active ingredient has lower hygroscopicity and higher thermal stability, and can be better.
  • a third aspect of the present invention is to provide afatinib monomalonate and a crystal form thereof, and a process for the preparation thereof.
  • the actual content of afatinib free base in the afatinib monomalonate was 83.0% (excluding the amount of solvent), and afatinib and malonic acid were formed in a molar ratio of 1:1 by HPLC.
  • the theoretical content of afatinib in the compound is 82.4%, so that afatinib and malonic acid in the afatinib-malonate of the present invention are salted in a molar ratio of 1:1, and the structural formula is as follows :
  • the preparation method of the afatinib monomalonate comprises the following steps: respectively forming a solution system of afatinib and malonic acid in a soluble solvent, a molar ratio of afatinib to malonic acid 1 : 1-1 : 1.5, the two systems were mixed to form a slurry, and then the solvent was removed.
  • the solvent is soluble ether solvent; more preferably, C 4 -C 5 ethers, the C 4 -C 5 ethers include, but are not limited to, diethyl ether, methyl tert-butyl ether and isopropyl ether; and most preferably A Tert-butyl ether.
  • the solvent is preferably removed by spin-drying.
  • the afatinib monomalonate is a crystalline form of afatinib monomalonate, using Cu- ⁇ radiation, and the X-ray powder diffraction pattern has a diffraction angle of 2 ⁇ of 6.6 ⁇ 0.2°. , 7.2 ⁇ 0.2. , 13.2 ⁇ 0.2. , 13.4 ⁇ 0.2. , 17.3 ⁇ 0.2. Characteristic peaks at 20.8 ⁇ 0.2° and 25.1 ⁇ 0.2°.
  • the M1 crystal form afatinib monomalonate has an X-ray powder diffraction pattern at a diffraction angle of 2 ⁇ of 6.6 ⁇ 0.2. , 7.2 ⁇ 0.2. , 8.7 ⁇ 0.2. , 13.2 ⁇ 0.2. , 13.4 ⁇ 0.2. , 14.3 ⁇ 0.2. , 17.3 ⁇ 0.2. , 18.0 ⁇ 0.2. , 19.7 ⁇ 0.2. , 20.8 ⁇ 0.2. , 21.4 ⁇ 0.2. Characteristic peaks at 25.1 ⁇ 0.2° and 26.1 ⁇ 0.2°.
  • the M1 crystal form afatinib monomalonate has a diffraction angle 2 ⁇ characteristic peak and its relative intensity in an X-ray powder diffraction pattern as follows:
  • a typical example of the Ml crystal form afatinib monomalonate has an X-ray powder diffraction pattern as shown in Fig. 25.
  • the M1 crystalline form of afatinib monomalonate has a Fourier infrared spectrum with characteristic peaks at wavenumbers of 1693, 1628, 1499, 1454, 1363, 1213, 1155, 1063 and 749 cm _1 .
  • the M1 crystal form afatinib monomalonate has a Raman spectrum with characteristic peaks at wave numbers of 1657, 1609, 1544, 1397, 1369, 1343, 1301, 1204 and 780 cm.
  • a preparation method of the M1 crystal form afatinib monomalonate comprises the following steps: respectively forming a solution system of afatinib and malonic acid in C 4 -C 5 ether, afatinib The molar ratio to malonic acid 1: 1-1 : 1.5, the two systems were mixed to form a slurry and stirred, maintained at -10 to 50 ° C for 1-48 hours, and then the solvent was removed.
  • the C 4 -C 5 ethers include, but are not limited to, diethyl ether, methyl tert-butyl ether, and isopropyl ether, preferably methyl tert-butyl ether.
  • the concentration of afatinib in the C 4 -C 5 ether is 10 mg/ml to a saturated solution of afatinib in the solvent.
  • the preparation method has an operating temperature of room temperature.
  • the preparation method of the M1 crystal form afatinib monomalonate comprises the following steps: preparing the afatinib monomalonate prepared by the foregoing method into a slurry in an organic solvent and stirring, The slurry is maintained at -10 to 50 ° C for 1 to 72 hours to further remove the solvent, wherein the organic solvent is selected from the group consisting of methanol, acetone, acetonitrile, methyl tert-butyl ether, ethyl acetate, n-heptane or a mixture thereof.
  • the operating temperature of the preparation method is room temperature.
  • afatinib monomalonate or Ml crystal form afetinib-malonate has One or more improved properties, such as: higher crystallinity, better solubility, dissolution rate, preferred crystalline morphology, better thermal stability and storage stability, lower hygroscopicity, better Flowability and advantageous processing and handling characteristics.
  • the M1 crystalline form of afatinib monomalonate has the following beneficial properties:
  • solubility in water at room temperature is 40.8 mg/ml, which has higher solubility than the prior art crystalline form of afatinib dimaleate under the same conditions of 7.5 mg/ml;
  • the needle crystals of the prior art crystal form of afatinib dimaleate have better fluidity, compressibility and processability.
  • afatinib monomalonate or Ml crystal form afatinib malonate of the present invention is compared to the prior art afatinib dimaleate or a crystalline form thereof.
  • Salt has a variety of advantageous properties, and the application effect is better, and it is suitable as an active ingredient of a pharmaceutical preparation.
  • the higher solubility of the active ingredient is beneficial to improve the bioavailability of the drug, and thus has a positive effect on the drug effect;
  • the crystalline component of the active ingredient has good morphology, has better fluidity, compressibility and processability, and the preparation process The suitability is good.
  • a fourth aspect of the present invention provides afatinib dimalonate and a crystalline form thereof, and a process for the preparation thereof.
  • afatinib free base in the afatinib dimalonate was 70.2% (excluding the amount of solvent), and afatinib and malonic acid were formed in a 1:2 molar ratio.
  • the theoretical content of afatinib in the compound is 70.0%, so the afar salt of the present invention has the following structural formula:
  • the preparation method of the afatinib dimalonate comprises the following steps: respectively forming a solution system of afatinib and malonic acid in a soluble solvent, a molar ratio of afatinib to malonic acid 1 :2-1 : 4, the two systems were mixed to form a slurry, and then the solvent was removed.
  • the soluble solvent is an ester solvent; further preferably, the soluble solvent is a C 4 -C 5 ester, and the C 4 -C 5 ester includes but is not limited to ethyl acetate or isopropyl acetate; more preferably Ethyl acetate.
  • the solvent is preferably removed by spin-drying.
  • the afatinib dipropanedionate is an M2 crystalline form of afatinib dipropanedionate, using Cu- ⁇ radiation, and having an X-ray powder diffraction pattern at a diffraction angle of 2 ⁇ of 6.5 ⁇ 0.2. , 8.1 ⁇ 0.2. , 13.1 ⁇ 0.2. , 16.1 ⁇ 0.2. , 20.8 ⁇ 0.2. And characteristic peaks at 25.8 ⁇ 0.2°.
  • the M2 crystal form afatinib dipropane acid salt has an X-ray powder diffraction pattern at a diffraction angle of 2 ⁇ of 6.5 ⁇ 0.2. , 8.1 ⁇ 0.2. , 9.7 ⁇ 0.2. , 10.9 ⁇ 0.2. , 13.1 ⁇ 0.2. , 14.0 ⁇ 0.2. , 16.1 ⁇ 0.2. , 18.3 ⁇ 0.2. , 19.0 ⁇ 0.2. , 20.8 ⁇ 0.2. , 25.8 ⁇ 0.2. And 27.0 ⁇ 0.2. There are characteristic peaks. Further, the M2 crystal form afatinib dipropanedionate, the X-ray powder diffraction pattern has a diffraction angle 2 ⁇ characteristic peak and its relative intensity as follows:
  • a typical example of the M2 crystalline form of afatinib dipropanedionate has an X-ray powder diffraction pattern as shown in FIG.
  • the M2 crystal form of afatinib dipropaneate has a Fourier transform infrared spectrum having characteristic peaks at wave numbers of 1694, 1630, 1501, 1455, 1364, 1262, 1214, 1064, 892 and 749 cm -1 .
  • the M2 crystal form of afatinib dipropanedionate has a Raman spectrum with characteristic peaks at wave numbers of 1658, 1621, 1607, 1545, 1491, 1397, 1301, 1205 and 781 cm.
  • a preparation method of the M2 crystal form afatinib dipropanedionate comprises the following steps: respectively forming a solution system of afatinib and malonic acid in a C 4 -C 5 ester, afatinib a molar ratio of 1:2:4 to malonic acid, mixing the two systems to form a slurry and stirring, maintaining at -10 to 50 ° C for 1 to 48 hours, and then removing the solvent; or, respectively, forming afatinib a suspension system malonate and malonic acid in the C 4 -C 5 ester of a solution system in C 4 -C 5 ester, a method a molar ratio of imatinib malonate and malonic acid For 1: 1:1:2, the two systems were mixed to form a slurry and stirred, maintained at -10 to 50 ° C for 1-48 hours, and then the solvent was removed.
  • the C 4 -C 5 ester includes, but is not limited to, ethyl acetate, isopropyl acetate, and preferably the C 4 -C 5 ester is ethyl acetate.
  • a concentration of 10 mg/ml of afatinib in the C 4 -C 5 ester to a saturated solution of afatinib in the solvent is preferred.
  • the molar ratio of afatinib to malonic acid is 1:2-1:3.
  • the molar ratio of afatinib monomalonate to malonic acid is 1:1-1:1.5.
  • the operating temperature of the preparation method is room temperature.
  • the preparation method of the M2 crystal form afatinib dipropane acid salt comprises the following steps: the aftinib dimalonate obtained by the above preparation method is slurried in an organic solvent and stirred. The slurry is maintained at -10 to 50 ° C for 1 to 72 hours to remove the solvent, and the organic solvent is selected from the group consisting of methanol, acetone, acetonitrile, methyl tert-butyl ether, ethyl acetate, n-heptane or a mixture thereof.
  • the operating temperature of the preparation method is room temperature.
  • afatinib dimaleate or its crystal form Compared with the prior art, in particular, compared with the prior art afatinib dimaleate or its crystal form, afatinib dimalonate or M2 crystal form afotinib dipropanedioate Has one or more improved properties, such as: higher crystallinity, better solubility, dissolution rate, better crystalline morphology, better thermal stability and storage stability, lower moisture absorption, Good flowability and favorable processing and handling characteristics.
  • M2 crystalline form of afatinib dipropionate has the following beneficial properties:
  • solubility in water at room temperature is 26.2 mg/ml, which has higher solubility than the prior art crystalline form of afatinib dimaleate under the same conditions of 7.5 mg/ml.
  • the above beneficial properties indicate that the afatinib dimalonate or M2 crystal form afatinib dimalonic acid of the present invention is compared to the prior art afatinib dimaleate or a crystal form thereof.
  • Salt has a variety of advantageous properties, and the application effect is better, and it is suitable as an active ingredient of a pharmaceutical preparation.
  • the higher solubility of the active ingredient is beneficial to improve the bioavailability of the drug, which in turn has a positive effect on the efficacy; the active ingredient has a lower hygroscopicity and is better able to resist the environmental humidity during the manufacture and/or storage of the drug.
  • the problems caused by uneven content of active ingredients, decreased purity and increased impurities reduce the risk and safety risks of the resulting therapeutic effects, and facilitate accurate quantification in drug manufacturing, improve uniformity of the preparation, and later storage and transportation.
  • a fifth aspect of the present invention provides afatinib di 2-naphthalenesulfonate and a crystal form thereof, and a process for the preparation thereof.
  • the actual content of afatinib free base in the afatinib di 2-naphthalene sulfonate was 55.0% (excluding the amount of solvent), and afatinib and 2-naphthalenesulfonic acid were as follows:
  • the theoretical content of afatinib in the compound formed by 2 molar ratio is 53.9%, so the afatinib di 2-naphthalene sulfonate of the present invention has a 1:2 mole of afatinib and 2-naphthalenesulfonic acid.
  • its structural formula is as follows:
  • the preparation method of the afatinib bis 2-naphthalene sulfonate comprises the following steps: respectively forming a solution system of afatinib and 2-naphthalenesulfonic acid in a soluble solvent, afatinib and 2-naphthalene
  • the molar ratio of the sulfonic acid was 1:2-1:4, and the two systems were mixed to form a slurry, and then the solvent was removed.
  • the soluble solvent is an alcohol, a ketone, an ester, an alkane, an ether or a mixture thereof; more preferably methanol, acetone, ethyl acetate, n-heptane or methyl tert-butyl ether.
  • the solvent is preferably removed by spin-drying.
  • the afatinib bis 2-naphthalene sulfonate is an Nsl crystal form afatinib di 2-naphthalene sulfonate, using Cu-Ka radiation, and the X-ray powder diffraction pattern is at a diffraction angle of 2 ⁇ Characteristic peaks at 5.6 ⁇ 0.2 °, 24.0 ⁇ 0.2 °, and 26.8 ⁇ 0.2 °.
  • Nsl crystal form afatinib di 2-naphthalene sulfonate has a diffraction angle 2 ⁇ characteristic peak and its relative intensity in an X-ray powder diffraction pattern as follows:
  • a typical example of the Nsl crystal form afatinib di 2-naphthalenesulfonate has an X-ray powder diffraction pattern as shown in Fig. 37.
  • the Nsl crystal form afatinib di 2-naphthalenesulfonate has a Fourier infrared spectrum having characteristic peaks at wave numbers of 1627, 1536, 1498, 1427, 1211, 1090, 1030 and 675 cm -1 .
  • the Nsl crystal form afatinib di 2-naphthalene sulfonate has a Raman spectrum with characteristic peaks at wave numbers of 1650, 1628, 1610, 1581, 1501, 1386, 1355, 1211, 1021 and 771 cm _1 .
  • the preparation method of the Nsl crystal form afatinib bis 2-naphthalene sulfonate comprises the following steps: respectively forming a solution system of afatinib and 2-naphthalenesulfonic acid in a soluble solvent, Afati
  • the molar ratio of nitrile to 2-naphthalenesulfonic acid is 1:2-1:4, mixing the two systems to form a slurry and stirring, maintaining at -10 to 50 ° C for 1-48 hours, and then removing the solvent, wherein the The solvent is selected from the group consisting of dC 4 alcohols, C 3 -C 5 ketones, C 4 -C 5 esters, C 6 -C 9 alkanes, C 4 -C 6 ethers or mixtures thereof.
  • the dC 4 alcohol includes, but is not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, and sec-butanol
  • the C 3 -C 5 ketone includes, but is not limited to, acetone and methyl ethyl ketone
  • the C 4 - C 5 esters include, but are not limited to ethyl acetate and isopropyl acetate
  • a C 6 -C 9 alkanes include but are not limited to, n-hexane, n-heptane and methylcyclohexane
  • a C 4 -C 6 ethers comprising But not limited to diethyl ether, diisopropyl ether and methyl tert-butyl ether
  • the solvent is methanol, acetone, ethyl acetate, n-heptane, methyl tert-butyl ether or
  • the concentration of afatinib in a soluble solvent is 10 mg/ml to a saturated solution of afatinib in the solvent.
  • the molar ratio of afatinib to 2-naphthalenesulfonic acid is 1:2-1:3.
  • the operating temperature of the preparation method is room temperature.
  • the preparation method of the Nsl crystal form afatinib bis 2-naphthalene sulfonate comprises the following steps: preparing the afatinib di 2-naphthalene sulfonate obtained by the above preparation method into a slurry in an organic solvent And stirring, the slurry is maintained at -10 to 50 ° C for 1 to 72 hours, thereby removing the solvent, wherein the organic solvent is selected from the group consisting of methanol, acetone, acetonitrile, ethyl acetate, n-heptane, methyl tert-butyl ether Or a mixture thereof.
  • the operating temperature of the preparation method is room temperature.
  • afatinib dimaleate or its crystal form afatinib di 2-naphthoate or Nsl crystal form afatinib II 2 Naphthalene acid salts have one or more improved properties such as higher crystallinity, better solubility, dissolution rate, preferred crystalline morphology, better thermal stability and storage stability, lower Hygroscopicity, good flowability and advantageous processing and handling characteristics.
  • the Nsl crystal form afatinib bis 2-naphthalene sulfonic acid has the following beneficial properties: its decomposition temperature is 249.1 ° C, and the decomposition temperature of the prior art crystal form relative to afatinib dimaleate is 164.1 ° C. , with higher thermal stability.
  • the above beneficial properties indicate that the afatinib di 2-naphthalenesulfonic acid or the Nsl crystalline form of afatinib ii-2 of the present invention is compared with the prior art afatinib dimaleate or a crystalline form thereof.
  • Naphthalene sulfonic acid has a variety of advantageous properties, and the application effect is better, and is suitable as an active ingredient of a pharmaceutical preparation.
  • the active ingredient has higher thermal stability, and can better prevent problems such as uneven content of active ingredients, decrease in purity, and increase in impurities caused by factors such as ambient temperature during the manufacture and/or storage of the drug, thereby reducing the The efficacy reduces risk and safety risks, and facilitates accurate quantification in drug manufacturing, improved formulation uniformity, and later storage and transportation.
  • a sixth aspect of the present invention provides afatinib diamino sulfonate and a crystalline form thereof, and a process for the preparation thereof.
  • the afatinib diaminosulphonate of the present invention has a salt of afatinib and sulfamic acid in a molar ratio of 1:2, and the structural formula is as follows:
  • the preparation method of the afatinib diamino sulfonate comprises the following steps: respectively forming a solution system in a fatinib soluble solvent and a suspension system of sulfamic acid in an organic solvent, afatinib
  • the molar ratio to the amino acid was 1:2-1:4, and the two systems were mixed to form a slurry, and then the solvent was removed.
  • the soluble solvent or organic solvent is a nitrile, an alcohol, a ketone, an ester, an alkane, an ether or a mixture thereof; further preferably acetonitrile, methanol, acetone, ethyl acetate, n-heptane or methyl Tert-butyl ether.
  • the solvent is preferably removed by spin-drying.
  • the afatinib diamino sulfonate is an alfatinib diamino sulfonate of the S1 crystal form, using Cu-Ka radiation, and the X-ray powder diffraction pattern has a diffraction angle of 2 ⁇ of 5.3 ⁇ 0.2. . , 10.7 ⁇ 0.2. , 13.2 ⁇ 0.2. , 21.5 ⁇ 0.2 °, 22.3 ⁇ 0.2. , 25.5 ⁇ 0.2. And 26.1 ⁇ 0.2. There are characteristic peaks.
  • the S1 crystal form afatinib diamino sulfonate has an X-ray powder diffraction pattern at a diffraction angle of 2 ⁇ of 5.3 ⁇ 0.2. , 10.7 ⁇ 0.2. , 11.0 ⁇ 0.2. , 12.3 ⁇ 0.2. , 13.2 ⁇ 0.2. , 13.6 ⁇ 0.2. , 17.1 ⁇ 0.2. , 20.2 ⁇ 0.2. , 21.5 ⁇ 0.2. , 22.3 ⁇ 0.2. Characteristic peaks at 25.5 ⁇ 0.2° and 26.1 ⁇ 0.2°.
  • the S1 crystal form afatinib diamino sulfonate, the diffraction angle 2 ⁇ characteristic peak of the X-ray powder diffraction pattern and its relative intensity are as follows:
  • a typical example of the S I crystalline form of afatinib diamino sulfonate has an X-ray powder diffraction pattern as shown in FIG.
  • the S 1 crystal form afatinib diamino sulfonate has a Fourier transform infrared spectrum having characteristic peaks at wave numbers of 1640, 1575, 1528, 1497, 1450, 1233, 1159, 1042 and 776 cm _1 .
  • the S 1 crystal form afatinib diamino sulfonate has a Raman spectrum having characteristic peaks at wave numbers of 1656, 1606, 1548, 1490, 1401, 1374, 1297, 1215 and 782 cm -1 .
  • a preparation method of the S 1 crystal form afatinib diamino sulfonate comprises the following steps: respectively forming a solution system of afatinib in a soluble solvent and suspending the sulfamic acid in an organic solvent
  • the liquid system, the molar ratio of afatinib to sulfamic acid is 1:2-1:4, the two systems are mixed to form a slurry and stirred, and kept at -10 to 50 ° C for 1-48 hours, thereby removing the solvent.
  • the soluble solvent or organic solvent is selected from the group consisting of C 2 -C 4 nitriles, dC 4 alcohols, C 3 -C 5 ketones, C 4 -C 5 esters, C 6 -C 9 alkanes, C 4 -C 6 ethers or Its mixture.
  • the C 2 -C 4 nitrile includes, but is not limited to, acetonitrile
  • the dC 4 alcohol includes, but is not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, and sec-butanol
  • the C 3 -C 5 ketone including but not limited to, acetone and methyl ethyl ketone
  • the C 4 -C 5 esters include, but are not limited to ethyl acetate and isopropyl acetate
  • a C 6 -C 9 alkanes include but are not limited to, n-hexane, n-heptane and a
  • the cyclohexane, the C 4 -C 6 ether includes, but is not limited to, diethyl ether, isopropyl ether and methyl tert-butyl ether; preferably the soluble solvent or organic solvent is acetonit
  • the concentration of afatinib in a soluble solvent is 10 mg/ml to a saturated solution of afatinib in the solvent.
  • the molar ratio of afatinib to sulfamic acid is 1:2-1:3.
  • the operating temperature of the preparation method is room temperature.
  • Another preparation method of the S 1 crystal form afatinib diamino sulfonate comprises the following steps: preparing the afatinib diamino sulfonate prepared by the foregoing method into a slurry in an organic solvent and stirring, The slurry is maintained at -10 to 50 ° C for 1 to 72 hours to further remove the solvent, wherein the organic solvent is selected from the group consisting of methanol, acetone, acetonitrile, ethyl acetate, n-heptane, methyl t-butyl ether or a mixture thereof .
  • the operating temperature of the preparation method is room temperature.
  • afatinib diamino sulfonate or S 1 crystal form afatinib diamino sulfonate Has one or more improved properties, such as: higher crystallinity, better solubility, dissolution rate, better crystalline morphology, better thermal stability and storage stability, lower hygroscopicity, Good flowability and favorable processing and handling characteristics.
  • the S 1 crystalline form of afatinib diamino sulfonate has the following beneficial properties:
  • the decomposition temperature is 246.3 °C, which has better thermal stability than the decomposition temperature of the prior art crystal form of afatinib dimaleate 164.1 °C.
  • afatinib diamino sulfonate or the S 1 crystalline form of afatinib diamino sulfonic acid of the present invention is compared to the prior art afatinib dimaleate or a crystalline form thereof.
  • Salt has a variety of advantageous properties, and the application effect is better, and it is suitable as an active ingredient of a pharmaceutical preparation.
  • the higher solubility of the active ingredient is beneficial to improve the bioavailability of the drug, and thus has a positive effect on the efficacy; the active ingredient has higher thermal stability and can better resist the process of manufacturing and/or storage of the drug by the environment.
  • Seventh aspect of the present invention provides afatinib di D-gluconate and a crystal form thereof, and a process for the preparation thereof.
  • the actual content of afatinib free base in the afatinib di D-gluconate was 54.4% (excluding the amount of solvent) by HPLC, and 1 : 2 moles of afatinib and D-gluconic acid.
  • afatinib di D-gluconate in the afatinib di D-gluconate of the present invention forms a salt in a molar ratio of 1:2.
  • Its structural formula is as follows:
  • the preparation method of the afatinib di D-gluconate comprises the following steps: forming a solution of afatinib in a soluble solvent, the molar ratio of afatinib to D-gluconic acid is 1:2- 1 : 4, a solution of afatinib in a soluble solvent and an aqueous D-gluconic acid solution were mixed to form a slurry, and then the solvent was removed.
  • the soluble solvent is a nitrile, an alcohol, a ketone, an ester, an alkane, an ether or a mixture thereof; further preferably acetonitrile, methanol, acetone, ethyl acetate, n-heptane or methyl t-butyl ether.
  • the solvent is preferably removed by spin-drying.
  • the concentration of the aqueous D-gluconic acid solution is 50%.
  • the afatinib di D-gluconate is a G1 crystal form of afatinib di D-gluconate, using Cu- ⁇ radiation, and the X-ray powder diffraction pattern is 4.9 at a diffraction angle of 2 ⁇ ⁇ 0.2. , 5.5 ⁇ 0.2. , 10.0 ⁇ 0.2. , 13.0 ⁇ 0.2. , 25.3 ⁇ 0.2. And 25.9 ⁇ 0.2. There are characteristic peaks.
  • the G1 crystal form of afatinib di D-gluconate has an X-ray powder diffraction pattern at a diffraction angle of 2 ⁇ of 4.9 ⁇ 0.2. , 5.5 ⁇ 0.2. , 6.1 ⁇ 0.2. , 9.6 ⁇ 0.2. , 10.0 ⁇ 0.2. , 13.0 ⁇ 0.2. , 17.1 ⁇ 0.2. , 19.6 ⁇ 0.2. , 20.0 ⁇ 0.2. , 20.3 ⁇ 0.2. , 25.3 ⁇ 0.2. And 25.9 ⁇ 0.2. There are characteristic peaks.
  • the G1 crystal form of afatinib di D-gluconate, the diffraction angle of the X-ray powder diffraction pattern 2 ⁇ characteristic peak and its relative intensity are as follows:
  • a typical example of the G1 crystal form afatinib di D-gluconate has an X-ray powder diffraction pattern as shown in FIG.
  • the Gl crystal form afatinib di D-gluconate has a Fourier transform infrared spectrum having characteristic peaks at wave numbers of 1626, 1578, 1538, 1497, 1453, 1237, 1209, 1050 and 777 cm -1 .
  • the G1 crystal form of afatinib di D-gluconate has a Raman spectrum with characteristic peaks at wavenumbers of 1656, 1608, 1546, 1400, 1370, 1300, 1215 and ⁇ ⁇ 1 .
  • a preparation method of the G1 crystal form afatinib di D-gluconate comprises the following steps: forming a solution of afatinib in a soluble solvent, a molar ratio of afatinib to D-gluconic acid For 1:2-1:4, a solution of afatinib in a soluble solvent and a D-gluconic acid aqueous solution are mixed to form a slurry and stirred, and kept at -10 to 50 ° C for 1-48 hours, thereby removing the solvent.
  • the soluble solvent is selected from the group consisting of C 2 -C 4 nitriles, dC 4 alcohols, C 3 -C 5 ketones, C 4 -C 5 esters, C 6 -C 9 alkanes, nitro-substituted dC 3 alkanes, C 4- C 6 ether or a mixture thereof.
  • the C 2 -C 4 nitrile includes, but is not limited to, acetonitrile
  • the dC 4 alcohol includes, but is not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, and sec-butanol
  • the C 3 -C 5 ketone including but not limited to, acetone and methyl ethyl ketone
  • the C 4 -C 5 esters include, but are not limited to ethyl acetate and isopropyl acetate
  • a C 6 -C 9 alkanes include but are not limited to, n-hexane, n-heptane and a
  • the cyclohexane, the nitro-substituted dC 3 alkane includes, but is not limited to, nitromethane
  • the C 4 -C 6 ether includes, but is not limited to, diethyl ether, isopropy
  • the concentration of afatinib in a soluble solvent is 10 mg/ml to a saturated solution of afatinib in the solvent.
  • the molar ratio of afatinib to D-gluconic acid is 1:2-1:3.
  • the operating temperature of the preparation method is room temperature.
  • the concentration of the D-gluconic acid aqueous solution is 50%.
  • Another preparation method of the G1 crystal form afatinib di D-gluconate comprises the following steps: the aftinib di D-gluconate obtained by the above preparation method is slurried and stirred in an organic solvent. The slurry is maintained at -10 to 50 ° C for 1 to 72 hours to further remove the solvent, wherein the organic solvent is selected from the group consisting of methanol, acetonitrile, ethyl acetate, nitromethane, acetone, n-heptane, methyl tert-butyl Ether or a mixture thereof.
  • the operating temperature of the preparation method is room temperature.
  • the acid salt has one or more improved properties such as: higher crystallinity, better solubility, dissolution rate, better crystalline morphology, better thermal and storage stability, lower moisture absorption. , good flowability and favorable processing and processing characteristics.
  • the G1 crystalline form of afatinib di D-gluconate has the following beneficial properties:
  • D-gluconic acid has lower toxicity than maleic acid.
  • afatinib di D-gluconate or the G1 crystal form afatinib di D- of the present invention is compared to the prior art afatinib dimaleate or a crystal form thereof.
  • Gluconate has a variety of advantageous properties, and the application effect is better, and it is suitable as an active ingredient of a pharmaceutical preparation.
  • the higher solubility of the active ingredient is beneficial to improve the bioavailability of the drug, which in turn has a positive effect on the efficacy; the active ingredient has lower toxicity, making the preparation process and the clinical application of the drug safer.
  • Eighth of the present invention provides afatinib dicyclohexylamino stearate and a crystal form thereof, and a process for the preparation thereof.
  • the actual content of afatinib free base in the afatinib dicyclohexyl sulfamate was 58.3% (excluding the amount of solvent), and afatinib and cyclohexane sulfamic acid were detected by HPLC.
  • the theoretical content of afatinib in the compound formed by a molar ratio of 1 : 2 is 57.6%, and thus the afatinib dicyclohexyl sulfamate of the present invention has afatinib and cyclohexane sulfamic acid.
  • the 1:2 molar ratio is salt, and its structural formula is as follows:
  • the preparation method of the afatinib dicyclohexyl sulfamate comprises the following steps: respectively forming a solution system of afatinib in a soluble solvent and a suspension liquid of cyclohexanesulfamic acid in an organic solvent
  • the molar ratio of afatinib to cyclohexanesulfamic acid was 1:2-1:4, and the two systems were mixed to form a slurry, and then the solvent was removed.
  • the soluble solvent or organic solvent is a nitrile, an alcohol, a ketone, an ester, an alkane, an ether or a mixture thereof; further preferably acetonitrile, methanol, acetone, ethyl acetate, n-heptane or methyl Tert-butyl ether.
  • the solvent is preferably removed by spin-drying.
  • the afatinib dicyclohexyl sulfamate is a crystalline form of afatinib dicyclohexyl sulfamate, using Cu- ⁇ radiation, the X-ray powder diffraction pattern of the diffraction angle 2 ⁇ is 5.0 ⁇ 0.2. , 6.0 ⁇ 0.2. , 16.5 ⁇ 0.2. , 17.9 ⁇ 0.2. , 18.6 ⁇ 0.2. And 20.2 ⁇ 0.2. There are characteristic peaks.
  • the C1 crystal form of afatinib dicyclohexyl sulfamate has an X-ray powder diffraction pattern at a diffraction angle of 2 ⁇ of 5.0 ⁇ 0.2. , 6.0 ⁇ 0.2. , 12.5 ⁇ 0.2. , 14.9 ⁇ 0.2. , 16.5 ⁇ 0.2. , 17.9 ⁇ 0.2. , 18.4 ⁇ 0.2. , 18.6 ⁇ 0.2. , 20.2 ⁇ 0.2. , 21.3 ⁇ 0.2. , 21.6 ⁇ 0.2. And 24.2 ⁇ 0.2. There are characteristic peaks.
  • the C1 crystal form afatinib dicyclohexyl sulfamate
  • the X-ray powder diffraction pattern has a diffraction angle 2 ⁇ characteristic peak and its relative intensity as follows:
  • a typical example of the C1 crystal form afatinib dicyclohexyl sulfamate has an X-ray powder diffraction pattern as shown in FIG.
  • the C1 crystal form of afatinib dicyclohexyl sulfamate has a Raman spectrum having characteristic peaks at wave numbers of 1662, 1609, 1543, 1401, 1372, 1291, 1209 and 778 cm.
  • a preparation method of the C1 crystal form afatinib dicyclohexyl sulfamate comprises the following steps: respectively forming a solution system of afatinib in a soluble solvent and cyclohexane sulfamic acid in an organic Solvent suspension system, the molar ratio of afatinib to cyclohexane sulfamic acid is 1:2-1:4, mixing the two systems to form a slurry and stirring, maintaining 1-48 at -10-50 °C And then removing the solvent, wherein the soluble solvent or organic solvent is selected from the group consisting of C 2 -C 4 nitriles, dC 4 alcohols, C 3 -C 5 ketones, C 4 -C 5 esters, C 6 -C 9 alkanes, C 4- C 6 ether or a mixture thereof.
  • the C 2 -C 4 nitrile includes, but is not limited to, acetonitrile
  • the dC 4 alcohol includes, but is not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, and sec-butanol
  • the C 3 -C 5 ketone including but not limited to, acetone and methyl ethyl ketone
  • the C 4 -C 5 esters include, but are not limited to ethyl acetate and isopropyl acetate
  • a C 6 -C 9 alkanes include but are not limited to, n-hexane, n-heptane and a
  • the cyclohexane, the C 4 -C 6 ether includes, but is not limited to, diethyl ether, isopropyl ether and methyl tert-butyl ether; preferably the soluble solvent or organic solvent is acetonit
  • the concentration of afatinib in a soluble solvent is 10 mg/ml to a saturated solution of afatinib in the solvent.
  • the molar ratio of afatinib to cyclohexane amino acid is 1:2-1:3.
  • the operating temperature of the preparation method is room temperature.
  • Another preparation method of the C1 crystal form afatinib dicyclohexyl sulfamate comprises the following steps: the afatinib dicyclohexane amino stearate obtained by the above preparation method is in an organic solvent Forming a slurry and stirring, the slurry is maintained at -10 to 50 ° C for 1 to 72 hours, thereby removing the solvent, wherein the organic solvent is selected from the group consisting of methanol, acetone, acetonitrile, ethyl acetate, n-heptane, Methyl tert-butyl ether or a mixture thereof.
  • the operating temperature of the preparation method is room temperature.
  • afatinib dimaleate or its crystal form afatinib dicyclohexyl sulfamate or C1 crystal form afatinib bicyclic
  • the hexane amino acid salt has one or more improved properties such as higher crystallinity, better solubility, dissolution rate, better crystal morphology, better thermal stability and storage stability, Low hygroscopicity, good flowability and favorable processing and handling characteristics.
  • the C1 crystalline form of afatinib dicyclohexyl sulfamate has the following beneficial properties:
  • the decomposition temperature is 246.1 °C, which has higher thermal stability than the decomposition temperature of the prior art crystal form of afatinib dimaleate 164.1 °C.
  • afatinib dicyclohexyl sulfamate or the C1 crystal form of the afetidine ring of the present invention is compared with the prior art afatinib dimaleate or a crystal form thereof.
  • Hexane amino acid salt has a variety of advantageous properties, and the application effect is better, and is suitable as an active ingredient of a pharmaceutical preparation.
  • the higher solubility of the active ingredient is beneficial to improve the bioavailability of the drug, and thus has a positive effect on the efficacy; the active ingredient has higher thermal stability and can better resist the process of manufacturing and/or storage by the environment. Problems such as uneven content of active ingredients, decreased purity and increased impurities caused by factors such as temperature, reducing the risk and safety risks of the resulting therapeutic effects, and facilitating accurate quantification in drug manufacturing, improving uniformity of preparations, and later storage And transportation.
  • a ninth aspect of the present invention provides afatinib di 4-aminobenzenesulfonate and a crystal form thereof, and a process for the preparation thereof.
  • the actual content of afatinib free base in the afatinib di 4-aminobenzenesulfonate was 59.1% (excluding the amount of solvent), and afatinib and 4-aminobenzenesulfonic acid were detected by HPLC.
  • the theoretical content of afatinib in the compound formed by the molar ratio of 1 : 2 is 58.4%, and thus the afatinib di 4-aminobenzenesulfonate of the present invention is obtained by using afatinib and 4-aminobenzenesulfonic acid.
  • the preparation method of the afatinib di 4-aminobenzenesulfonate comprises the following steps: respectively forming a solution system of afatinib in a soluble solvent and a suspension liquid of 4-aminobenzenesulfonic acid in an organic solvent;
  • the molar ratio of afatinib to 4-aminobenzenesulfonic acid was 1:2-1:4, and the two systems were mixed to form a slurry, and then the solvent was removed.
  • the soluble solvent or organic solvent is a nitrile, an alcohol, a ketone, an alkane, an ether or a mixture thereof; further preferably acetonitrile, methanol, acetone, ethyl acetate, n-heptane or methyl t-butyl ether.
  • the solvent is preferably removed by spin-drying.
  • the afatinib di 4-aminobenzenesulfonate is A1 crystal form afatinib di 4-aminobenzenesulfonate, using Cu- ⁇ radiation, and its X-ray powder diffraction pattern is at diffraction angle 2
  • the ⁇ is 12.9 ⁇ 0.2. , 17.1 ⁇ 0.2. , 18.2 ⁇ 0.2. 23.8 ⁇ 0.2. , 24.5 ⁇ 0.2. And 25.7 ⁇ 0.2.
  • the A1 crystal form of afatinib di 4-aminobenzenesulfonate has an X-ray powder diffraction pattern at a diffraction angle of 2 ⁇ of 5.6 ⁇ 0.2. , 12.9 ⁇ 0.2. , 17.1 ⁇ 0.2. , 18.2 ⁇ 0.2. , 21.3 ⁇ 0.2 °, 23.8 ⁇ 0.2. , 24.5 ⁇ 0.2. , 25.7 ⁇ 0.2. Characteristic peaks at 27.6 ⁇ 0.2° and 34.3 ⁇ 0.2°.
  • the A1 crystal form of afatinib di 4-aminobenzenesulfonate has a diffraction angle 2 ⁇ characteristic peak and its relative intensity in an X-ray powder diffraction pattern as follows:
  • a typical example of the Al crystalline form of afatinib di 4-aminobenzenesulfonate has an X-ray powder diffraction pattern as shown in Fig. 58.
  • the A1 crystalline form of afatinib di 4-aminobenzenesulfonate has a Fourier transform infrared spectrum with characteristic peaks at wavenumbers of 1637, 1599, 1525, 1498, 1451, 1206, 1158, 1118, 1027 and 694 cm. .
  • the A1 crystalline form of afatinib di 4-aminobenzenesulfonate has a Raman spectrum having characteristic peaks at wavenumbers of 1657, 1644, 1546, 1499, 1400, 1371, 1297, 1208, 1122 and 781 cm.
  • a preparation method of the A1 crystal form afatinib di 4-aminobenzenesulfonate comprises the following steps: respectively forming a solution system of afatinib in a soluble solvent and 4-aminobenzenesulfonic acid in an organic
  • the suspension system in the solvent, the molar ratio of afatinib to 4-aminobenzenesulfonic acid is 1:2-1:4, mixing the two systems to form a slurry and stirring, maintaining 1- at -10-50 °C
  • the solvent is then removed, wherein the soluble solvent or organic solvent is selected from the group consisting of C 2 -C 4 nitriles, dC 4 alcohols, C 3 -C 5 ketones, C 6 -C 9 alkanes, C 4 -C 6 ethers or Its mixture.
  • the C 2 -C 4 nitrile includes, but is not limited to, acetonitrile
  • the dC 4 alcohol includes, but is not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, and sec-butanol
  • the C 3 -C 5 ketone Including but not limited to acetone and methyl ethyl ketone
  • the C 6 -C 9 alkane includes, but is not limited to, n-hexane, n-heptane and methylcyclohexane
  • the C 4 -C 6 ether includes, but is not limited to, diethyl ether, isopropyl ether.
  • the soluble solvent or organic solvent is acetonitrile, methanol, acetone, n-heptane, methyl t-butyl ether or a mixture thereof; more preferably acetonitrile.
  • the concentration of afatinib in a soluble solvent is 10 mg/ml to a saturated solution of afatinib in the solvent.
  • the molar ratio of afatinib to 4-aminobenzenesulfonic acid is 1:2-1:3.
  • the operating temperature of the preparation method is room temperature.
  • Another preparation method of the A1 crystal form afatinib di 4-aminobenzenesulfonate comprises the following steps: the afatinib di 4-aminobenzenesulfonate obtained by the above preparation method is in an organic solvent Forming a slurry and stirring, the slurry is maintained at -10 to 50 ° C for 1 to 72 hours, thereby removing the solvent, wherein the organic solvent is selected from the group consisting of methanol, acetone, acetonitrile, ethyl acetate, n-heptane, methyl tert-butyl Ether or a mixture thereof.
  • the operating temperature of the preparation method is room temperature.
  • afatinib dimaleate or its crystal form afatinib di 4-aminobenzene succinate or A1 crystal form afatinib 2-4
  • the aminobenzate salt has one or more improved properties such as: higher crystallinity, better solubility, dissolution rate, better crystalline morphology, better thermal stability and storage stability, lower Hygroscopicity, good flowability and advantageous processing and handling characteristics.
  • A1 crystalline form of afatinib di 4-aminobenzenesulfonate has the following beneficial properties:
  • solubility in water at room temperature is 123.8 mg/ml, which has a higher solubility than the prior art crystalline form of afatinib dimaleate under the same conditions of 7.5 mg/ml.
  • the decomposition temperature is 261.7 ° C, which has higher thermal stability than the decomposition temperature of the prior art crystal form of afatinib dimaleate of 164.1 °C.
  • afatinib dicyclohexylamino stearate or the C1 crystal form afatinib bifuran of the present invention is compared with the prior art afatinib dimaleate or its crystal form.
  • Hexane amino acid salt has a variety of advantageous properties, and the application effect is better, and is suitable as an active ingredient of a pharmaceutical preparation.
  • the higher solubility of the active ingredient is beneficial to improve the bioavailability of the drug, and thus has a positive effect on the efficacy; the active ingredient has higher thermal stability and can better resist the process of manufacturing and/or storage by the environment. Temperature and other factors caused by uneven content of active ingredients, decreased purity and increased impurities, reduce the risk of reduced efficacy and safety risks, and facilitate accurate quantification in drug manufacturing, improve formulation uniformity and post-storage And transportation.
  • a tenth aspect of the present invention provides afatinibanoate and a crystal form thereof, and a process for the preparation thereof.
  • the actual content of afatinib free base in the afatinibane glycolate was 85.4% (excluding the amount of solvent), and the afatinib and glycolic acid were formed in a 1:1 molar ratio.
  • the theoretical content of afatinib in the compound is 86.5%, so that the afatinib and the glycolic acid in the afatinibane glycolate are salted in a molar ratio of 1:1, and the structural formula is as follows:
  • the preparation method of the afatinibane glycolate comprises the following steps: respectively forming a solution system of afatinib and glycolic acid in a soluble solvent, and the molar ratio of afatinib to glycolic acid is 1 : 1-1 : 2, mixing the two systems to form a slurry, and then removing the solvent.
  • the soluble solvent is an alcohol, a ketone, an ester, an alkane, an ether or a mixture thereof; more preferably methanol, acetone, ethyl acetate, n-heptane or methyl tert-butyl ether.
  • the solvent is preferably removed by spin-drying.
  • the afatinibane glycolate is a G1-1 crystal form of afatinibane glycolate using Cu- ⁇ radiation, and the X-ray powder diffraction pattern has a diffraction angle of 2 ⁇ of 5.1 ⁇ 0.2. °, 6.4 ⁇ 0.2. , 13.0 ⁇ 0.2. 13.3 ⁇ 0.2. Characteristic peaks at 20.8 ⁇ 0.2° and 25.0 ⁇ 0.2°.
  • the G1-1 crystal form afatinibanoate has an X-ray powder diffraction pattern of 5.1 ⁇ 0.2 at a diffraction angle of 2 ⁇ . , 6.4 ⁇ 0.2. , 7.0 ⁇ 0.2. , 13.0 ⁇ 0.2. 13.3 ⁇ 0.2. , 17.2 ⁇ 0.2. , 17.9 ⁇ 0.2. , 19.7 ⁇ 0.2. , 20.8 ⁇ 0.2. Characteristic peaks at 22.4 ⁇ 0.2°, 25.0 ⁇ 0.2° and 25.9 ⁇ 0.2°.
  • the G1-1 crystalline form of afatinibane carbonate has a diffraction angle 2 ⁇ characteristic peak and its relative intensity in an X-ray powder diffraction pattern as follows:
  • a typical example of the G1-1 crystalline form of afatinibane has an X-ray powder diffraction pattern as shown in FIG.
  • the G1-1 crystalline afatinibane glycolate has a Fourier transform infrared spectrum with characteristic peaks at wave numbers of 1625, 1577, 1536, 1497, 1452, 1427, 1234, 1212, 1081 and 777 cm -1 .
  • the G1-1 crystalline afatinibanoate has a Raman spectrum with characteristic peaks at wave numbers of 1650, 1629, 1610, 1536, 1398, 1344, 1304, 1215 and ⁇ ⁇ 1 .
  • a preparation method of the G1-1 crystal form afatinibane glycolate comprises the following steps: respectively forming a solution system of afatinib and glycolic acid in a soluble solvent, afatinib and glycine
  • the molar ratio of alkyd is 1:1-1:2, the two systems are mixed to form a slurry and stirred, and maintained at -1050 ° C for 1-48 hours, thereby removing the solvent, wherein the soluble solvent is selected from dC 4 alcohol, C 3 -C 5 ketone, C 4 -C 5 ester, C 6 -C 9 alkane, nitro-substituted dC 3 alkane, C 4 -C 6 ether or a mixture thereof.
  • the dC 4 alcohol includes, but is not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, and sec-butanol
  • the C 3 -C 5 ketone includes, but is not limited to, acetone and methyl ethyl ketone
  • the C 4 - C 5 esters include, but are not limited to ethyl acetate and isopropyl acetate
  • a C 6 -C 9 alkanes include but are not limited to, n-hexane, n-heptane and methylcyclohexane
  • a nitro-substituted alkanes dC 3 Including but not limited to nitromethane
  • the C 4 -C 6 ethers include, but are not limited to, diethyl ether, diisopropyl ether and methyl tert-butyl ether; preferably the soluble solvent is eth
  • the concentration of afatinib in a soluble solvent is 10 mg/ml to a saturated solution of afatinib in the solvent.
  • the molar ratio of afatinib to glycolic acid is 1:1-1:1.5.
  • the operating temperature of the preparation method is room temperature.
  • the preparation method of the G1- 1 crystal form afatinibane glycolate comprises the steps of: forming the slurry of the afatinibane glycolate obtained by the above preparation method in an organic solvent and stirring, The slurry is maintained at -10 to 50 ° C for 1 to 72 hours to remove the solvent, wherein the organic solvent is selected from the group consisting of methanol, acetone, acetonitrile, ethyl acetate, nitromethane, n-heptane, and methyl t-butyl ether. Or a mixture thereof.
  • the operating temperature of the preparation method is room temperature.
  • afatinib dimaleate or its crystal form afatinibane glycolate or G1- 1 crystal form afatinibane glycolate Has one or more improved properties, such as: higher crystallinity, better solubility, dissolution rate, better crystalline morphology, better thermal stability and storage stability, lower moisture absorption, Good flowability and favorable processing and handling characteristics.
  • G1- 1 crystal form afatinibanoate has the following beneficial properties:
  • the melting point is 83.5 ° C, lower than the melting point of the prior art crystal form of afatinib dimaleate of 166.2 ° C, the amorphous substance can be prepared at a very low temperature, and the amorphous substance has a better Solubility.
  • glycolic acid has lower toxicity than maleic acid.
  • afatinibane glycolate or G1-1 crystal form afatinibanoic acid of the present invention is compared to the prior art afatinib dimaleate or a crystal form thereof.
  • Salt has a variety of advantageous properties, and the application effect is better, and it is suitable as an active ingredient of a pharmaceutical preparation.
  • the higher solubility of the active ingredient is beneficial to improve the bioavailability of the drug, which in turn has a positive effect on the efficacy; the active ingredient has lower toxicity, making the preparation process and the clinical application of the drug safer.
  • An eleventh aspect of the present invention provides a novel form of afatinib dimaleate form N and a process for the preparation thereof.
  • the X-ray powder diffraction pattern of the crystalline form N of the afatinib dimaleate salt was 4.8 ⁇ 0.2 at a diffraction angle of 2 ⁇ . , 9.7 ⁇ 0.2. , 14.5 ⁇ 0.2. , 17.0 ⁇ 0.2. , 19.5 ⁇ 0.2. , 20.1 ⁇ 0.2, 25.6 ⁇ 0.2.
  • the diffraction peak 2 ⁇ characteristic peak and relative intensity of the X-ray powder diffraction pattern of the afatinib dimaleate salt form N are as follows:
  • a typical example of the crystalline form N of the afatinib dimaleate salt has an X-ray powder diffraction pattern as shown in FIG.
  • the afatinib dimaleate crystal form N has a Fourier transform infrared spectrum having characteristic peaks at wave numbers of 1684, 1576, 1542, 1496, 1449, 1351, 1088, 891 and 859 cm.
  • the afatinib dimaleate salt form N has a Raman spectrum with characteristic peaks at wavenumbers of 1657, 1607, 1546, 1494, 1404, 1374, 1302, 1217 and 783 cm.
  • the preparation method of the afatinib dimaleate salt form N comprises the following steps: respectively forming a solution system of afatinib and maleic acid in nitromethane, afatinib and maleic acid
  • the molar ratio was 1:2-1:4, and the two systems were mixed to form a slurry and stirred, and maintained at -10 to 50 ° C for 1 to 48 hours, and then the solvent was removed.
  • the concentration of afatinib in nitromethane is from 10 mg/ml to a saturated solution of afatinib in nitromethane; preferably the molar ratio of afatinib to maleic acid is 1:2-1: 3;
  • the operating temperature of the preparation method is room temperature.
  • the afatinib dimaleate crystal form N of the present invention has one or more improved properties compared to the prior art, particularly in comparison to the prior art crystalline form of afatinib dimaleate. For example: higher crystallinity, better solubility, dissolution Speed, preferred crystalline morphology, better thermal and storage stability, lower moisture absorption, better flowability and advantageous processing and handling characteristics.
  • the afatinib dimaleate salt form N has the following beneficial properties: its solubility in water at room temperature is 12.7 mg/ml, which is the same as the prior art crystal form of afatinib dimaleate.
  • the solubility under conditions is 7.5 mg/ml, which has higher solubility.
  • the above beneficial properties indicate that the afatinib dimaleate crystal form N of the present invention has superior performance and better application effect than the prior art crystal form of afatinib dimaleate.
  • the active ingredient of a pharmaceutical preparation. The higher solubility of the active ingredient is beneficial to increase the bioavailability of the drug, which in turn has a positive effect on the efficacy.
  • the mixing method of the solution system of the afatinib with the acid solution system or the suspension system is: i) the solution system of the afatinib solution to the acid solution system. Or adding to the suspension system; or ii) adding an acid solution or suspension system to the solution system of afatinib; or iii) simultaneously applying the solution system of afatinib to the acid solution system or suspension system Add to the reaction vessel.
  • the "stirring" described in any of the above preparation methods of the present invention can be accomplished by conventional techniques such as magnetic stirring and mechanical stirring.
  • the agitation speed is 50 1800 rpm, preferably 300 900 rpm.
  • the "solvent removal” step described in any of the above preparation methods of the present invention can be carried out by conventional techniques such as filtration, centrifugation, drying or evaporation.
  • the specific operation of the rotary steaming is: placing the container containing the solution in a rotary evaporator at a temperature of from room temperature to the boiling point of the solvent (preferably 30 to 50 ° C), less than atmospheric pressure (preferably, the pressure is less than 0.08 MPa).
  • the solvent is removed at a rotation speed of 10 180 rpm (preferably 50 to 100 rpm).
  • the afatinidine acid addition salt obtained by any of the above production methods of the present invention and its crystal form can be further dried by a conventional technique.
  • the drying is carried out under reduced pressure or without a reduced pressure, preferably at a pressure of less than 0.09 MPa, a drying temperature of about 30 to 50 ° C, and a drying time of 10 to 72 hours, preferably 10 to 48 hours, more preferably 10 to 24 hours. Drying can be carried out in a fume hood, a forced air oven or a vacuum oven.
  • the starting material afatinib can be prepared according to the method disclosed in Example 1 of the document CN1867564B, which is incorporated herein by reference.
  • room temperature means 10-25 ° Cc
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of one or more of the afatinidine acid addition salts of the present invention or a crystal thereof An albininic acid addition salt or a crystalline form thereof prepared by the process of the invention, and at least one pharmaceutically acceptable excipient.
  • the afartinic acid addition salt of the present invention or a crystal form thereof is selected from the group consisting of ethanedisulfonate of afatinib, E1 crystal form ethanedisulfonate, 1,5-naphthalene disulfonate , N1 crystal form 1,5-naphthalene disulfonate, N2 crystal form 1,5-naphthalenedisulfonic acid salt hydrate, malonate, Ml crystal malonate, dipropionate, M2 crystal Dimalonate, bis 2-naphthalene sulfonate, Nsl bis 2-naphthalene sulfonate, diamino sulfonate, S1 crystalline diamino sulfonate, di D-gluconate, G1 crystal Type di D-gluconate, dicyclohexyl sulfamate, C1 crystalline dicyclohexane sulfamate, di 4-aminobenzenesulf
  • Excipients in the pharmaceutical composition include sugars, cellulose and derivatives thereof, starch or modified starch, solid inorganic substances such as calcium phosphate, dicalcium phosphate, hydroxyapatite, calcium sulfate, calcium carbonate, Semi-solids such as lipids or paraffins, binders such as microcrystalline cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, glidants such as colloidal dioxide Silicon, light anhydrous silicic acid, crystalline cellulose, talc or stearic acid, disintegrating agents such as sodium starch glycolate, crospovidone, croscarmellose, sodium carboxymethylcellulose, Dry corn starch, lubricants such as stearic acid, magnesium stearate, sodium stearyl fumarate, polyethylene glycol.
  • solid inorganic substances such as calcium phosphate, dicalcium phosphate, hydroxyapatite, calcium sulf
  • the pharmaceutical composition may be in a solid or liquid form, and the administration route includes oral, intravenous, subcutaneous, intra-tissue, transdermal, rectal, intranasal, and the like.
  • solid oral dosage forms including tablets, granules, capsules, powders, pills, and lozenges, may be conventional, dispersible, chewable, orally dissolved or rapidly melted formulations; liquid oral dosage forms, including Solution, syrup, suspension, dispersant and emulsion; injectable preparations, including solutions, dispersions and lyophilizates; aerosol formulations suitable for inhalation; suppositories suitable for rectal administration.
  • the formulation may be adapted for immediate release, sustained release or modified release of the active ingredient.
  • the pharmaceutical composition can be prepared using methods well known to those skilled in the art.
  • the afatinidine acid addition salt of the invention or a crystalline form thereof is admixed with one or more pharmaceutically acceptable excipients, optionally with pharmaceutically acceptable afatinib
  • the crystalline form, or amorphous form of the other salt is optionally mixed with one or more other pharmaceutically active ingredients.
  • the solid preparation can be prepared by a process such as direct mixing, granulation, or the like.
  • the afatinidine acid addition salt of the present invention or a crystal form thereof is suitable for the treatment of benign or malignant tumors, for the prevention and treatment of respiratory and pulmonary diseases, and for the treatment of gastrointestinal, bile duct and gallbladder diseases.
  • the present invention provides the aforementioned afatinidine acid addition salt of the present invention or a crystal form thereof for use in the preparation of a medicament for treating and/or preventing advanced non-small cell lung cancer (NSCLC) and HER2-positive advanced breast cancer diseases. the use of.
  • NSCLC non-small cell lung cancer
  • HER2-positive advanced breast cancer diseases the use of.
  • the present invention provides a method of treating and/or preventing advanced non-small cell lung cancer (NSCLC) and HER2-positive advanced breast cancer, the method comprising administering to a patient in need thereof a therapeutically and/or prophylactically effective amount of the aforementioned An afatinidine acid addition salt or a crystalline form thereof or a pharmaceutical composition comprising the afatinidine acid addition salt of the present invention or a crystalline form thereof.
  • the patient is typically a warm blood ridge pusher, particularly a human.
  • the dose used as a medicine is 0.01 100 mg / kg body weight, preferably 0.1 15 mg / kg body weight.
  • Figure 1 is an XRPD pattern of a prior art crystal form of afatinib dimaleate disclosed in CN1867564B.
  • Figure 3 is a TGA diagram of the prior art crystal form of afatinib dimaleate prepared in Preparation Example 1.
  • Figure 4 is a DSC chart of the prior art crystal form of afatinib dimaleate prepared in Preparation Example 1.
  • Figure 5 is a DVS diagram of a prior art crystal form of afatinib dimaleate prepared in Preparation Example 1.
  • Figure 6 is an XRPD pattern of the E1 crystal form of afatinib ethanedisulfonate prepared in Example 3.
  • Figure 7 is a PLM diagram of the E1 crystal form of afatinib ethanedisulfonate prepared in Example 3.
  • Figure 8 is a TGA diagram of the E1 crystal form of afatinib ethanedisulfonate prepared in Example 3.
  • Figure 9 is a DVS diagram of the E1 crystal form of afatinib ethanedisulfonate prepared in Example 3.
  • Figure 10 is an IR chart of the E1 crystal form of afatinib ethanedisulfonate prepared in Example 3.
  • Figure 11 is a Raman diagram of the E1 crystal form of afatinib ethanedisulfonate prepared in Example 3.
  • Figure 12 is an NMR chart of the E1 crystal form of afatinib ethanedisulfonate prepared in Example 3.
  • Figure 13 is an XRPD pattern of the N1 crystal form of afatinib 1,5-naphthalenedisulfonate prepared in Example 12.
  • Figure 14 is a PLM diagram of the N1 crystal form of afatinib 1,5-naphthalenedisulfonate prepared in Example 12.
  • Figure 15 is a TGA diagram of the N1 crystal form of afatinib 1,5-naphthalenedisulfonate prepared in Example 12.
  • Figure 16 is a DVS diagram of the N1 crystal form of afatinib 1,5-naphthalenedisulfonate prepared in Example 12.
  • Figure 17 is an IR chart of the N1 crystal form of afatinib 1,5-naphthalenedisulfonate prepared in Example 12.
  • Figure 18 is a Raman diagram of the N1 crystal form of afatinib 1,5-naphthalenedisulfonate prepared in Example 12.
  • Figure 19 is an NMR chart of the N1 crystal form of afatinib 1,5-naphthalenedisulfonate prepared in Example 12.
  • Figure 20 is an XRPD pattern of the N2 crystal form of afatinib 1,5-naphthalenedisulfonic acid salt hydrate prepared in Example 20.
  • Figure 21 is a PLM diagram of the N2 crystal form of afatinib 1,5-naphthalene disulfonic acid salt hydrate prepared in Example 20.
  • Figure 22 is a TGA diagram of the N2 crystal form of afatinib 1,5-naphthalenedisulfonic acid salt hydrate prepared in Example 20.
  • Figure 23 is an IR chart of the N2 crystal form of afatinib 1,5-naphthalene disulfonic acid salt hydrate prepared in Example 20.
  • Figure 24 is a Raman diagram of the N2 crystal form of afatinib 1,5-naphthalenedisulfonic acid salt hydrate prepared in Example 20.
  • Figure 25 is an XRPD pattern of the M1 crystal form of afatinib monomalonate prepared in Example 24.
  • Figure 26 is a PLM diagram of the M1 crystal form of afatinib monomalonate prepared in Example 24.
  • Figure 27 is a TGA diagram of the M1 crystal form of afatinib monomalonate prepared in Example 24.
  • Figure 28 is an IR chart of the M1 crystal form of afatinib monomalonate prepared in Example 24.
  • Figure 29 is a Raman diagram of the M1 crystal form of afatinib monomalonate prepared in Example 24.
  • Figure 30 is an NMR chart of the M1 crystal form of afatinib monomalonate prepared in Example 24.
  • Figure 31 is an XRPD pattern of the M2 crystalline form of afatinib dipropanedioate prepared in Example 31.
  • Figure 32 is a TGA diagram of the M2 crystalline form of afatinib dipropanedioate prepared in Example 31.
  • Figure 33 is an embodiment 31
  • Figure 34 is an embodiment 31
  • Figure 35 is an embodiment 31
  • Figure 36 is an embodiment 31
  • Figure 37 is an embodiment 38
  • Figure 38 is an embodiment 38
  • Figure 39 is an embodiment 38
  • Figure 40 is an embodiment 38
  • Figure 41 is an embodiment 38
  • Figure 42 is an embodiment 46
  • Figure 43 is an embodiment 46
  • Figure 44 is an embodiment 46
  • Figure 45 is an embodiment 46
  • Figure 46 is an embodiment 46
  • Figure 47 is an embodiment 54
  • Figure 48 is an embodiment 54
  • Figure 49 is an embodiment 54
  • Figure 50 is an embodiment 54
  • Figure 51 is an embodiment 54
  • Figure 52 is an embodiment 54
  • Figure 53 is an embodiment 63
  • Figure 54 is an embodiment 63
  • Figure 55 is an embodiment 63
  • Figure 56 is an embodiment 63
  • Figure 57 is an embodiment 63
  • Figure 58 is an embodiment 72
  • Figure 59 is an embodiment 72
  • Figure 60 is an embodiment 72
  • Figure 61 is an embodiment 72
  • Figure 62 is an embodiment 72
  • Figure 63 is an embodiment 81
  • Figure 64 is an embodiment 81
  • Figure 65 is an embodiment 81
  • Figure 66 is an embodiment 81
  • Figure 67 is an embodiment 81
  • Figure 68 is an embodiment 81
  • Figure 69 is an embodiment 88
  • Figure 70 is an embodiment 88
  • Figure 71 is an embodiment 88
  • Figure 72 is an embodiment 88
  • the instrument used for X-ray powder diffraction is the Bruker D8 Advance diffractometer, which uses a copper target wave. ⁇ X-rays with a length of 1.54 nm, operating conditions of 40 kV and 40 mA, ⁇ -2 ⁇ goniometer, Mo monochromator, Lynxeye detector. The instrument is used to correct the peak position with the standard sample supplied with the instrument before use.
  • the acquisition software was a Diffrac Plus XRD Commander sample tested at room temperature and the sample was placed on an organic slide. Detection conditions: Angle range: 3 ⁇ 4. 2 ⁇ ; Step size: 0.02°2 ⁇ ; Speed: 0.2s/step.
  • the polarized light microscope (PLM) spectrum was taken from an XP-500E polarized light microscope (Shanghai Changfang Optical Instrument Co., Ltd.). Take a small amount of powder sample on the glass slide, add a small amount of mineral oil to better disperse the powder sample, cover the cover glass, and then place the sample on the stage of the XP-500E polarized light microscope, select the appropriate magnification Multiply observe the morphology of the sample and shoot it.
  • Thermogravimetric analysis (TGA) data was obtained from TA Instruments Q500 TGA, instrument control software Thermal Advantage, and analysis software Universal Analysis usually took 5 ⁇ 15mg samples in platinum crucible, using segmented high-resolution detection method, at 10 °C / The temperature of min was raised from room temperature to 300 ° C under the protection of dry N 2 at 50 mL/min, while the TA software recorded the change in weight during the temperature rise of the sample.
  • Dynamic moisture adsorption analysis (DVS) data was taken from the TA Instruments Q5000 TGA, the instrument control software was Thermal Advantage, and the analysis software was Universal Analysis. Usually 1 to 10 mg of the sample is placed in a platinum crucible, and the TA software records the change in weight of the sample during the relative humidity change from 0% to 80% to 0%. Depending on the specifics of the sample, different adsorption and desorption steps are also applied to the sample.
  • Infrared spectroscopy (IR) data was taken from Bruker Tensor 27, and instrument control software and data analysis software were OPUS.
  • the ATR device is usually used to collect the infrared absorption spectrum in the range of ⁇ ⁇ - 1 .
  • the scanning time of the sample and the blank background is 16 seconds, and the resolution of the instrument is 4 cm- 1 .
  • Raman spectroscopy (Raman) data was taken from the Nikola DXR 780, and instrument control software and data analysis software were onmic 8.2.
  • the Raman spectra were collected on a sample under a 10x mirror, in the wave number SO ⁇ Ocm, 8 exposures, and 1 second exposure time.
  • Nuclear magnetic analysis (NMR) data was taken from Bruker Ascend Tm 500. Usually use full-frequency excitation, spectral width 30PPM, single pulse, 30° angle excitation, 16 scans, digital orthogonal detection, temperature control 298K.
  • the HPLC data was taken from the Agilent 1260, the instrument control software was Agilent ChemStation Rev. B.04 online, and the analysis software was Agilent ChemStation Rev. B.04 offline.
  • the mobile phase A was water containing 0.01% trifluoroacetic acid
  • the mobile phase B was acetonitrile containing 0.01% trifluoroacetic acid.
  • the gradient is shown in Table 1:
  • the tablet hardness test data was obtained from the YD-1 tablet hardness tester of Tianjin Xintianguang Analytical Instrument Technology Co., Ltd. Place the tablet in the test stand and turn the rotating disk clockwise until the value of the tablet is crushed and broken.
  • afatinib free base 50 mg was added to 1 mL of ethyl acetate and stirred to dissolve. 19.6 mg of ethanedisulfonic acid was added to 2 mL of ethyl acetate and stirred to dissolve. The ethyl acetate solution of ethanedisulfonic acid was slowly added dropwise to the afatinib free. The slurry was slurried in a solution of the base in ethyl acetate. After stirring at room temperature overnight, a solid was precipitated and dried at 40 ° C under vacuum to give 68 mg of afatinib ethanedisulfonate in a yield of 97.7%.
  • afatinib free base 50 mg was added to 1 mL of acetonitrile and stirred to dissolve. 19.6 mg of ethanedisulfonic acid was added to 2 mL of acetonitrile and stirred to dissolve. The acetonitrile solution of ethanedisulfonic acid was slowly added dropwise to the acetonitrile solution of afatinib free base. The slurry was stirred, and reacted at room temperature overnight to precipitate a solid. The mixture was filtered and dried under vacuum at 40 ° C overnight to give 62 mg of the crystals of the crystals of the form of s.
  • Example 2 "slowly add acetonitrile solution of ethanedisulfonic acid to acetonitrile solution of afatinib free base” was replaced with “slow addition of acetonitrile solution of afatinib free base to ethanedisulfonate.
  • the other operation was the same as in Example 2 to obtain 63.6 mg of the crystalline form of afatinib ethanedisulfonate. The yield was 91.5%.
  • the PLM map is shown in Figure 7. It is shown that the salt is a granular crystal and has better fluidity and processability than the needle crystal of the prior art crystal form of afatinib dimaleate.
  • the TGA map is shown in Figure 8. It shows: The salt has a weight loss of 3.4% before 150 °C, is a hydrate, contains 1.5 moles of water, and has a decomposition temperature of 261.1 °C, which is higher than the decomposition temperature of the prior art crystal form of afatinib dimaleate. 164.1 ° C, showing better thermal stability.
  • the DVS isotherm adsorption curve is shown in Figure 9. It is shown that the salt has a weight change of 1.4% in the range of 10%-80% relative humidity, and the prior art crystal form of afatinib dimaleate has a lower weight change of 2.6% under the same conditions. Hygroscopicity.
  • the MR spectrum is shown in Figure 12. Display: Afatinib and ethanedisulfonic acid have been salted.
  • Example 2 30 mg of afatinib ethanedisulfonate prepared in Example 1 was placed in a 50 ml flask, and 2 ml of methanol was added to form a slurry, which was stirred at room temperature for 72 hours, filtered, and dried under vacuum at 40 ° C overnight to obtain E1 crystal form. Fatinib ethanedisulfonate.
  • Example 5 The "methanol” in Example 5 was replaced with "methyl tert-butyl ether", and the other operation was the same as in Example 5 to obtain a crystalline form E1 type of afatinib ethanedisulfonate.
  • Example 5 The "methanol” in Example 5 was replaced with “acetone”, and the other operation was the same as in Example 5 to obtain the E1 crystal form of afatinib ethanedisulfonate.
  • Example 5 The "methanol” in Example 5 was replaced with “n-heptane", and the other operation was the same as in Example 5 to obtain the E1 crystal form of afatinibethane disulfonate.
  • Example 5 The "methanol” in Example 5 was replaced with “ethyl acetate", and the other operation was the same as in Example 5 to obtain the E1 crystal form of alfatinib ethanedisulfonate.
  • the PLM map is shown in Figure 14. It shows: The salt is a granular crystal, which is more regular and has better fluidity and processability than the needle-like crystal of the prior art crystal form of afatinib dimaleate.
  • the TGA map is shown in Figure 15. Show: The sample is anhydrate with a decomposition temperature of 276.3 ° C, which has better thermal stability than the 164.1 ° C decomposition temperature of the prior art crystal form of afatinib dimaleate.
  • N1 crystal form afatinib 1,5-naphthalene disulfonate is stable below 50% relative humidity, starting to form N2 crystal form afatinib 1,5-naphthalene disulfonate above 50% relative humidity Hydrate, forming N2 crystal form afatinib 1,5-naphthalene disulfonic acid salt hydrate to 80% relative humidity, water absorption weight change is 1.8%; N2 crystal form afatinib 1,5-naphthalene The sulfonic acid salt hydrate is stable above 30% relative humidity, and de-crystallization water is started to be removed below 30% relative humidity.
  • the MR spectrum is shown in Figure 19.
  • Example 11 30 mg of afatinib 1,5 naphthalenedisulfonate prepared in Example 11 was placed in a 50 ml flask, and 2 ml of methanol was added to form a slurry, which was stirred at room temperature for 72 hours, filtered, and vacuum dried at 40 ° C to obtain N1 crystal form. Fatinib 1,5 naphthalene disulfonate.
  • Example 14 The "methanol” in Example 14 was replaced with "methyl tert-butyl ether”, and the other operation was the same as in Example 14, to obtain the N1 crystal form of afatinib 1,5-naphthalene disulfonate.
  • Example 14 The "methanol” in Example 14 was replaced with “acetone”, and the other operation was the same as in Example 14, to obtain the N1 crystal form of afatinib 1,5-naphthalenedisulfonate.
  • Example 14 The "methanol” in Example 14 was replaced with “n-heptane”, and the other operation was the same as in Example 14, to obtain the N1 crystal form of favertinib 1,5-naphthalene disulfonate.
  • Example 14 The "methanol” in Example 14 was replaced with “ethyl acetate", and the other operation was the same as in Example 14 to obtain the N1 crystal form of afatinib 1,5-naphthalenedisulfonate.
  • Example 19 Preparation of Nl Form Afatinib 1,5-Naphthalene Disulfonate
  • Example 12 The "37.1 mg 1,5-naphthalene disulfonic acid tetrahydrate" in Example 12 was replaced with "74.2 mgl, 5-naphthalene disulfonic acid tetrahydrate", and the other operation was the same as in Example 12 to obtain the N1 crystal form. Fatinib 1,5-naphthalene disulfonate.
  • Example 12 50 mg of the N1 crystal form afatinib 1,5-naphthalene disulfonate prepared in Example 12 was placed in a humidifier having a relative humidity of 75% at room temperature for 24 hours to obtain N2 crystal form afatinib 1,5. - Naphthalene disulfonic acid salt hydrate.
  • the PLM map is shown in Figure 21. It shows: The salt is a granular crystal, which is more regular and has better fluidity and processability than the needle-like crystal of the prior art crystal form of afatinib dimaleate.
  • the TGA map is shown in Figure 22.
  • the DVS isotherm adsorption curve is shown in Figure 16. It is shown that: N1 crystal form afatinib 1,5-naphthalene disulfonate starts to form N2 crystal form afatinib 1,5-naphthalenedisulfonic acid salt hydrate at 50% relative humidity to form N2 crystal form. After fatinib 1,5-naphthalene disulfonic acid salt hydrate to 80% relative humidity, the weight change of water absorption is 1.8%, and the N2 crystal form afatinib 1,5-naphthalene disulfonic acid salt hydrate is 30%. It is stable above the relative humidity, and starts to remove the crystal water below 30% relative humidity.
  • Example 20 The "humidifier with relative humidity of 75%" in Example 20 was replaced with “humidifier with relative humidity of 85%”, and the other operation was the same as in Example 20 to obtain N2 crystal form afatinib 1,5-naphthalene disulfonic acid. Salt hydrate.
  • Example 20 The "24 hours” in Example 20 was replaced with "3 days", and the other operation was the same as in Example 20 to obtain an N2 crystal form of afatinib 1,5-naphthalene disulfonic acid salt hydrate.
  • afatinib free base 50 mg was added to 4 mL of methyl tert-butyl ether and stirred to dissolve. 15.9 mg of malonic acid was added to 4 mL of methyl t-butyl ether and stirred to dissolve. The methyl tert-butyl ether solution of malonic acid was slowly dropped. Adding to a solution of afatinib free base in methyl tert-butyl ether to form a slurry and stirring, stirring at room temperature overnight, solid precipitation, filtration, vacuum drying at 40 ° C overnight, to obtain Ml crystal form afatinib-propane The acid salt was 55 mg, and the yield was 90.6%.
  • the PLM map is shown in Figure 26. It shows: The salt is a granular crystal, which is more regular and has better fluidity and processability than the needle-like crystal of the prior art crystal form of afatinib dimaleate.
  • the TGA map is shown in Figure 27. Display: The decomposition temperature of this salt is 108.3 °C.
  • the MR spectrum is shown in Figure 30. Display: Afatinib and malonic acid have been salted.
  • Example 19 30 mg of afatinib monomalonate prepared in Example 19 was placed in a 50 ml flask and 2 ml of methanol was added to form The slurry was stirred at room temperature for 72 hours, filtered, and dried under vacuum at 40 ° C to obtain M1 crystal form afatinib monopropionate.
  • Example 25 The "methanol” in Example 25 was replaced with “ethyl acetate", and the other operation was the same as in Example 25 to obtain the M1 crystal form afatinib monomalonate.
  • Example 25 The “methanol” in Example 25 was replaced with “acetone”, and the other operation was the same as in Example 25 to obtain the M1 crystal form of afatinib monomalonate.
  • Example 25 The "methanol” in Example 25 was replaced with “n-heptane", and the other operation was the same as in Example 25 to obtain the M1 crystal form of favertinib-malonate.
  • afatinib free base 50 mg was added to 1.5 mL of acetonitrile and stirred to dissolve. 21.4 mg of malonic acid was added to 4 mL of acetonitrile and stirred to dissolve. The acetonitrile solution of afatinib free base was slowly added dropwise to the solution of malonic acid in acetonitrile. The slurry was stirred, and the solid was precipitated at room temperature, stirred overnight, and dried under vacuum at 40 ° C to give 69 mg of Adjustidin dimalonate, yield 96.6%.
  • afatinib monomalonate prepared in Example 23 50 mg was added to 1 mL of ethyl acetate to prepare a suspension and stirred, and 8.81 mg of malonic acid was added to 2 mL of ethyl acetate to stir and dissolve, and acetic acid of malonic acid was added.
  • the ethyl ester solution was slowly added dropwise to an ethyl acetate suspension of afatinib monomalonate to form a slurry, stirred at room temperature overnight, filtered, and dried under vacuum at 40 ° C overnight to obtain M2 crystal form afatinib dipropyl
  • the diacid salt was 52.5 mg, and the yield was 89.3%.
  • afatinib free base 50 mg was added to 1.5 mL of ethyl acetate and stirred to dissolve. 21.4 mg of malonic acid was added to 4 mL of ethyl acetate and stirred to dissolve. The ethyl acetate solution of afatinib free base was slowly added dropwise to C. A slurry of the acid in ethyl acetate was formed and stirred, and the solid was precipitated at room temperature, stirred overnight, filtered, and dried under vacuum at 40 ° C overnight to yield 66 mg of the M2 crystal form afatinib dimalonate in a yield of 92.4%.
  • the TGA map is shown in Figure 32. Display: The decomposition temperature of this salt is 105.7 °C.
  • the DVS isotherm adsorption curve is shown in Figure 33. It shows: The salt has a weight change of 1.1% in the range of 10%-80% relative humidity, and has a lower hygroscopicity than the 2.6% weight change of the prior art crystal form of afatinib dimaleate.
  • the MR spectrum is shown in Figure 36. Display: Afatinib and malonic acid have been salted.
  • Example 29 30 mg of afatinib dipropanedicarboxylate prepared in Example 29 was placed in a 50 ml flask, and 2 ml of methanol was added to form a slurry, which was stirred at room temperature for 72 hours, filtered, and dried under vacuum at 40 ° C to obtain M2 crystal form Afate. Nitradipropionate.
  • Example 32 The "methanol” in Example 32 was replaced with “ethyl acetate", and the other operation was the same as in Example 32 to obtain the M2 crystal form of afatinib dimalonate.
  • Example 32 The “methanol” in Example 32 was replaced with “acetone”, and the other operation was the same as in Example 32 to obtain the M2 crystal form of afatinib dipropanedioate.
  • Example 32 The "methanol” in Example 32 was replaced with “n-heptane", and the other operation was the same as in Example 32 to obtain the M2 crystal form of favertinibdipropane.
  • Example 36 Preparation of M2 Crystal Form Afatinib Dipropionate
  • the "21.4 mg of malonic acid” in Example 31 was replaced with "42.8 mg of malonic acid”, and the other operation was the same as in Example 31 to obtain the M2 crystal form of afatinib dipropanedioate.
  • afatinib free base 50 mg was added to 1.5 mL of ethyl acetate, 42.8 mg of 2-naphthalene acid was added to 3 mL of ethyl acetate and stirred to dissolve, and the ethyl acetate solution of 2-naphthalenesulfonic acid was slowly added dropwise to the afatinib.
  • the slurry was slurried in a solution of the free base in ethyl acetate. Stirring was carried out. After solid precipitation at room temperature, the mixture was stirred overnight, and dried under vacuum at 40 ° C overnight to obtain 85 mg of Nsl crystal form afatinib di 2-naphthoate, yield 91.7. %.
  • the TGA map is shown in Figure 38. It shows: The decomposition temperature of this salt is 249.1 ° C, which has better thermal stability than the 164.1 ° C decomposition temperature of the prior art crystal form of afatinib dimaleate.
  • the MR spectrum is shown in Figure 41. Display: Afatinib and 2-naphthalenesulfonic acid have been salted.
  • Example 37 30 mg of afatinib di 2-naphthalenesulfonate prepared in Example 37 was placed in a 50 ml flask, and 0.2 ml of methanol was added to form a slurry, which was stirred at room temperature for 72 hours, filtered, and dried under vacuum at 40 ° C to obtain Nsl crystal form. Fatinib di 2-naphthalene sulfonate.
  • Example 40 The "methanol” in Example 40 was replaced with "methyl tert-butyl ether", and the other operation was the same as in Example 40 to obtain Nsl crystal form afatinib di 2-naphthalenesulfonate.
  • Example 40 The "methanol” in Example 40 was replaced with “acetone”, and the other operation was the same as in Example 40 to obtain the Nsl crystal form of afatinib di 2-naphthalenesulfonate.
  • Example 40 The "methanol” in Example 40 was replaced with “n-heptane", and the other operation was the same as in Example 40 to obtain the Nsl crystal form of favertinib 2-naphthalenesulfonate.
  • Example 38 The "42.8 mg of 2-naphthalenesulfonic acid" in Example 38 was replaced with "64.2 mg of 2-naphthalenesulfonic acid", and the other operation was the same as in Example 38 to obtain Nsl crystal form afatinib di 2-naphthalenesulfonate.
  • afatinib free base 50 mg was added to 1.5 mL of ethyl acetate to dissolve, 20 mg of sulfamic acid was added to 2 mL of ethyl acetate to prepare a suspension and stirred, and the ethyl acetate solution of afatinib free base was slowly added dropwise to A slurry was formed in an ethyl acetate suspension of sulfamic acid, stirred at room temperature for 4 hours, and vacuum-dried at 40 ° C to obtain 67.5 mg of afatinib diaminosulphonate in a yield of 96.4%.
  • the TGA map is shown in Figure 43. It shows: The decomposition temperature of this salt is 246.3 ° C, which has better thermal stability than the 164.1 ° C decomposition temperature of the prior art crystal form of afatinib dimaleate.
  • the MR spectrum is shown in Figure 46. Display: Afatinib and sulfamic acid have been salted.
  • Example 45 30 mg of afatinib diamino sulfonate prepared in Example 45 was placed in a 50 ml flask, and 2 ml of methanol was added to form a slurry, which was stirred at room temperature for 72 hours, filtered, and dried under vacuum at 40 ° C to obtain S1 crystal form Afate. Nitrosamine salt.
  • Example 48 The "methanol” in Example 48 was replaced with "methyl tert-butyl ether”, and the other operation was the same as in Example 48 to obtain the S1 crystal form afatinib diamino sulfonate.
  • Example 48 The "methanol” in Example 48 was replaced with “acetone”, and the other operation was the same as in Example 48 to obtain the S1 crystal form afatinib diamino sulfonate.
  • Example 48 The "methanol” in Example 48 was replaced with “n-heptane", and the other operation was the same as in Example 48 to obtain the S1 crystal form of afatinib diamino sulfonate.
  • Example 46 The "20 mg amino acid” in Example 46 was replaced with "40 mg amino acid", and the other operation was the same as in Example 46 to obtain the S1 crystal form afatinib diamino sulfonate.
  • afatinib free base 50 mg was added to 1.5 mL of ethyl acetate to dissolve, and 88% of a 50% aqueous solution of D-gluconic acid was directly added dropwise to the ethyl acetate solution of afatinib free base and stirred, and after the oily substance was precipitated, The supernatant liquid was taken out, and 1 mL of acetonitrile was added to the oil, and the mixture was stirred at room temperature overnight, filtered, and dried under vacuum overnight at 40 ° C to obtain a G1 crystal form of afatinib di D-gluconate 59 mg, yield 65.3%.
  • the TGA map is shown in Figure 48. Display: The decomposition temperature of this salt is 129.4 °C.
  • the DSC spectrum is shown in Figure 49. Show: The salt has a melting point of 101.3 °C.
  • the MR spectrum is shown in Figure 52.
  • afatinib free base 10 mg was added to 0.5 mL of nitromethane to dissolve, and 8.1 mg of 50% D-gluconic acid aqueous solution was directly added dropwise to the nitromethane solution of afatinib free base and stirred, and oily substance was precipitated. After the supernatant was taken out, 1 mL of acetonitrile was added to the oil, and the mixture was stirred overnight to obtain a white solid afatinib-D-gluconate.
  • Example 53 30 mg of afatinib di D-gluconate prepared in Example 53 was placed in a 50 ml flask, and 2 ml of methanol was added to form a slurry, which was stirred at room temperature for 72 hours, filtered, and dried under vacuum at 40 ° C to obtain G1 crystal form Afate. Nitra D-gluconate.
  • Example 56 The "methanol” in Example 56 was replaced with "methyl tert-butyl ether”, and the other operation was the same as in Example 56 to obtain the G1 crystal form afatinib di D-gluconate.
  • Example 56 The "methanol” in Example 56 was replaced with “ethyl acetate", and the other operation was the same as in Example 56 to obtain the G1 crystal form afatinib di D-gluconate.
  • Example 56 The "methanol” in Example 56 was replaced with “acetone”, and the other operation was the same as in Example 56 to obtain the G1 crystal form of afatinib di D-gluconate.
  • Example 56 The "methanol” in Example 56 was replaced with “n-heptane", and the other operation was the same as in Example 56 to obtain the G1 crystal form of favertinibdi D-gluconate.
  • Example 54 The "D-gluconic acid aqueous solution 88 mg" in Example 54 was replaced with “D-gluconic acid aqueous solution 160 mg", and the other operation was the same as in Example 52 to obtain G1 crystal form afatinib di D-gluconate.
  • afatinib free base 50 mg was added to 1 mL of acetonitrile to dissolve, 40.6 mg of cyclohexane sulfamic acid was added to 3 mL of acetonitrile to prepare a suspension and stirred, and the acetonitrile solution of afatinib free base was slowly added dropwise to cyclohexane.
  • the suspension of sulfamic acid in acetonitrile was stirred at room temperature overnight, and dried under vacuum at 40 ° C overnight to obtain 74.6 mg of C1 crystal form afatinib dicyclohexane sulfamate, yield 85.9%.
  • the TGA map is shown in Figure 54. It shows: The decomposition temperature of this salt is 246.1 °C, which has better thermal stability than the 164.1 °C decomposition temperature of the prior art crystal form of afatinib dimaleate.
  • afatinib free base 10 mg was added to 0.5 mL of acetonitrile to dissolve, 4.1 mg of cyclohexane amino acid was added to 1 mL of acetonitrile to prepare a suspension and stirred, and the acetonitrile solution of afatinib free base was slowly added dropwise to the ring.
  • a suspension of alkylsulfonic acid in acetonitrile stirred at room temperature overnight, filtered, dried under vacuum at 40 ° C overnight to give a white solid afatinib-cyclohexanesulfamic acid Salt.
  • Example 62 Take 30 mg of afatinib dicyclohexyl sulfamate prepared in Example 62, place it in a 50 ml flask, add 2 ml of methanol to form a slurry, stir at room temperature for 72 hours, filter, and dry at 40 ° C to obtain C1. Crystalline afatinib dicyclohexyl sulfamate.
  • Example 65 The "methanol” in Example 65 was replaced with “ethyl acetate", and the other operation was carried out in the same manner as in Example 65 to give the crystals of s.
  • Example 65 The "methanol” in Example 65 was replaced with "methyl tert-butyl ether”, and the other operation was the same as in Example 65 to give C1 crystal form of afatinib dicyclohexane sulfamate.
  • Example 65 The "methanol” in Example 65 was replaced with “acetone”, and the other operation was the same as in Example 65 to give the C1 crystal form of the af- s.
  • Example 65 The "methanol” in Example 65 was replaced with “n-heptane", and the other operation was carried out in the same manner as in Example 65 to give the crystals of the crystals of the form of s.
  • Example 63 The "40.6 mg of cyclohexanesulfamic acid" in Example 63 was replaced with "73 mg of cyclohexanesulfamic acid", and the other operation was the same as in Example 63 to obtain a crystalline form of afatinib dicyclohexylsulfamic acid. salt.
  • afatinib free base 50 mg was added to 1 mL of acetonitrile to dissolve, 39.2 mg of 4-aminobenzenesulfonic acid was added to 3 mL of acetonitrile to prepare a suspension and stirred, and the acetonitrile solution of afatinib free base was slowly added dropwise to 4-aminobenzene.
  • the sulfonic acid in acetonitrile suspension was stirred at room temperature overnight, filtered and dried overnight at 40 ° C to obtain 65 mg of A1 crystal form afatinib di 4-aminobenzenesulfonate, yield 75.9%.
  • the TGA map is shown in Figure 59. It shows: The decomposition temperature of this salt is 261.7 ° C, which has better thermal stability than the 164.1 ° C decomposition temperature of the prior art crystal form of afatinib dimaleate.
  • Example 71 30 mg of afatinib di 4-aminobenzenesulfonate prepared in Example 71 was placed in a 50 ml flask, and 2 ml of methanol was added to form a slurry, which was stirred at room temperature for 72 hours, filtered, and dried under vacuum at 40 ° C to obtain A1 crystal form.
  • Alfatinib di 4-aminobenzenesulfonate was placed in a 50 ml flask, and 2 ml of methanol was added to form a slurry, which was stirred at room temperature for 72 hours, filtered, and dried under vacuum at 40 ° C to obtain A1 crystal form.
  • Example 75 Preparation of A1 Form Afatinib Di 4-Aminobenzenesulfonate
  • the "methanol” in Example 74 was replaced with “ethyl acetate”, and the other operation was the same as in Example 74 to obtain the A1 crystal form afatinib di 4-aminobenzenesulfonate.
  • Example 74 The "methanol” in Example 74 was replaced with "methyl tert-butyl ether", and the other operation was the same as in Example 74 to give the crystals of the A1 crystal form afatinib di 4-aminobenzenesulfonate.
  • Example 74 The "methanol” in Example 74 was replaced with “acetone”, and the other operation was the same as in Example 74 to obtain the A1 crystal form of afatinib di 4-aminobenzenesulfonate.
  • Example 74 The "methanol” in Example 74 was replaced with “n-heptane", and the other operation was carried out in the same manner as in Example 74 to obtain a crystal form of fafinidin di 4-aminobenzenesulfonate.
  • Example 72 The "39.2 mg 4-aminobenzenesulfonic acid" in Example 72 was replaced with "70 mg 4-aminobenzenesulfonic acid", and the other operation was the same as in Example 72 to obtain the A1 crystal form of afatinib di 4-aminobenzenesulfonic acid. salt.
  • afatinib free base 50 mg was added to 1.5 mL of ethyl acetate and stirred to dissolve. 8.6 mg of glycolic acid was added to 1.5 mL of ethyl acetate and stirred to dissolve. The ethyl acetate solution of glycolic acid was slowly added dropwise to the afatinib free. A slurry of the base was slurried and stirred, and a solid precipitated during the dropwise addition. The mixture was stirred overnight at room temperature, and then dried at 40 ° C under vacuum to give 54.4 mg of afatinibane.
  • the TGA map is shown in Figure 64. Display: The decomposition temperature of this salt is 1 12.4 °C.
  • the DSC spectrum is shown in Figure 65. Show: The salt has a melting point of 83.5 °C.
  • Raman spectroscopy is shown in Figure 67.
  • the MR spectrum is shown in Figure 68. Display: Afatinib and glycolic acid have been salted.
  • Example 80 30 mg of afatinibane glycolate prepared in Example 80 was placed in a 50 ml flask, and 2 ml of methanol was added to form a slurry, which was stirred at room temperature for 72 hours, filtered, and dried under vacuum at 40 ° C to obtain G1-1 crystal form Afati Niganoate.
  • Example 83 The "methanol” in Example 83 was replaced with "methyl tert-butyl ether", and the other operation was carried out in the same manner as in Example 83 to give the G1-1 crystal form of afatinibane.
  • Example 83 The "methanol” in Example 83 was replaced with “acetone”, and the other operation was the same as in Example 83 to obtain the G1-1 crystal form of afatinibane.
  • Example 86 Preparation of Gl-1 crystal form afatinibane glycolate
  • Example 83 The "methanol” in Example 83 was replaced with “n-heptane”, and the other operation was carried out in the same manner as in Example 83 to obtain the G1-1 crystal form of eptatinib.
  • Example 81 The procedure of "8.6 mg of glycolic acid" in Example 81 was replaced with "15. 5 mg of glycolic acid”, and the same operation as in Example 81 gave G1-1 crystal form of afatinibane.
  • the TGA map is shown in Figure 70. Display: The decomposition temperature of this salt is 133.7 °C.
  • Example 88 The "26.5 mg maleic acid” in Example 88 was replaced with "39.8 mg maleic acid", and the other operation was the same as in Example 88 to obtain the crystalline form N of afatinib dimaleate.
  • the tablet was prepared by passing microcrystalline cellulose, crospovidone, unmilled, afatinib dimaleate salt form N prepared in Example 88 through a #30 mesh screen (about 430 ⁇ to about 655 ⁇ ). ).
  • the sieved crospovidone was placed in a 3 cubic foot double-shell tumble mixer, and the sieved microcrystalline cellulose and lactose monohydrate were added and mixed for about 5 minutes; the sieved afatinib was added.
  • the maleate salt crystal form is mixed and mixed for another 25 minutes.
  • the premix is passed through a roller compactor with a hammer mill at the discharge and moved back into the tumbling mixer. Magnesium stearate and anhydrous colloidal silica were added to a tumble mixer and mixed for about 3 minutes. The final mixture was pressed on a rotary tablet press to produce 200,000 tablets in batches.
  • Example 88 The afatinib dimaleate salt form ⁇ (Example 88) of Example 90 was replaced with the Alphatin E1 crystal form ethanedisulfonic acid according to the formulation of Table 2 and the preparation method of Example 90, respectively.
  • Example 31 Nsl crystalline di-2-naphthalenesulfonate (Example 38), S1 crystalline diaminosulfonate (Example 46), G1 crystalline di D-gluconate (Example 54), C1 Crystalline dicyclohexane sulfamate (Example 63), A1 crystalline di 4-aminobenzenesulfonate (Example 72
  • Capsules containing the afatinib dimaleate salt form N (Example 88) of the present invention were prepared, and Table 3 lists the single dose formulations and batch formulations.
  • the capsules were prepared by: passing lactose monohydrate, microcrystalline cellulose, and afatinib dimaleate salt form N prepared in Example 88 through a 710 ⁇ sieve, and then loading the diffusion with baffle insertion. Mix in the mixer for 15 minutes. Magnesium stearate was passed through a 210 ⁇ m sieve and added to the diffusion mixer. The mixture was then filled into capsule #0, 500 mg/capsule using a Dosator capsule filling machine to produce 84,000 capsules.
  • Example 88 The afatinib dimaleate salt form N (Example 88) of Example 102 was replaced with the Alphatinib E1 crystal form afatinib according to the formulation of Table 3 and the preparation method of Example 102, respectively.
  • Ethylene disulfonate (Example 3), N1 crystal form 1,5-naphthalene disulfonate (Example 12), N2 crystal form 1,5 naphthalenedisulfonic acid salt hydrate (Example 20), Ml crystal Type monomalonate (Example 24), M2 crystalline dimalonate (Example 31), Nsl crystalline bis 2-naphthalene sulfonate (Example 38), S1 crystalline diamino sulfonate (Example 46), G1 crystalline di D-gluconate (Example 54), C1 crystalline dicyclohexanesulfonate (Example 63), A1 crystalline di 4-aminobenzenesulfonate
  • the fatinib dimaleate prepared in Comparative Example 2 is a good tablet of the prior art crystal form and the E1 crystal form afatinib ethanedisulfonate, the N1 crystal form afatinib 1,5-naphthalene A hardness test was carried out on each of 20 tablets of disulfonate, N2 crystal form 1,5-naphthalenedisulfonic acid salt hydrate, and Ml crystal form afatinib monomalonate.

Abstract

The present invention relates to novel afatinib acid addition salts and crystal forms thereof. Compared with the prior art, the afatinib acid addition salts and crystal forms thereof of the present invention have one or more improved properties. The present invention also relates to a preparation method of the novel afatinib acid addition salts and crystal forms thereof, a pharmaceutical composition thereof, and the use thereof in preparing drugs for treating and/or preventing advanced non-small cell lung cancer and HER2-positive advanced breast cancer.

Description

阿法替尼酸加成盐及其晶型、 其制备方法及药物組合物 技术领域  Afatinidine acid addition salt and crystal form thereof, preparation method thereof and pharmaceutical composition thereof
本发明属于药物化学结晶技术领域，具体而言，涉及新型的阿法替尼酸加成盐及其晶型、 其制备方法， 以及其药物組合物和用途。  The invention belongs to the technical field of medicinal chemical crystallization, in particular to a novel afatinidine acid addition salt and a crystal form thereof, a preparation method thereof, and a pharmaceutical composition and use thereof.
背景技术 Background technique
阿法替尼的化学名称为 N-[4-[(3-氯 -4-氟苯基)氨基] -7-[[(3S)-四氫 -3-呋喃基]氧基] -6-喹唑 啉基]—4- (二甲基氨基； )-2-丁烯酰胺， 英文名称为 AFATINIB , 又称为 BIBW 2992, 分子式 C24H25C1FN503， 其结构式如 The chemical name of afatinib is N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6- Quinazolinyl]-4-(dimethylamino;)-2-butenamide, English name is AFATINIB, also known as BIBW 2992, molecular formula C 24 H 25 C1FN 5 03, its structural formula
Figure imgf000002_0001
Figure imgf000002_0001
阿法替尼由德国勃林格殷格翰公司研发， 适用于晚期非小细胞肺癌 （NSCLC) 及 HER2 阳性的晚期乳腺癌患者， 口服片剂， 标准剂量为每日一次 40mg。 现勃林格殷格翰公司正向 欧洲药品管理局提交上市许可申请，有望以 Tovok上市。阿法替尼为表皮生长因子受体（EGFR 亦称 ErbBl) 和人表皮生长因子受体 -2 (HER2/neu 亦称 ErbB2) 酪氨酸激酶的强效且选择 性双重抑制剂。 不同于第一代酪氨酸激酶抑制剂的是， 阿法替尼设计为与 EGFR及 HER2共 价结合， 从而使其结合的受体分子不可逆失活。  Developed by Boehringer Ingelheim, Germany, afatinib is indicated for advanced non-small cell lung cancer (NSCLC) and HER2-positive patients with advanced breast cancer. Oral tablets are given at a standard dose of 40 mg once daily. Now Boehringer Ingelheim is submitting a marketing permit application to the European Medicines Agency and is expected to be listed on Tovok. Afatinib is a potent and selective dual inhibitor of the epidermal growth factor receptor (EGFR also known as ErbBl) and human epidermal growth factor receptor-2 (HER2/neu also known as ErbB2) tyrosine kinase. Unlike the first generation tyrosine kinase inhibitors, afatinib is designed to covalently bind to EGFR and HER2, thereby irreversibly inactivating its bound receptor molecules.
专利文献 WO2002/50043A1 公开了 阿法替尼化合物， WO2007/054550A1 及 WO2007/054551A1公开了阿法替尼的适应症。  Patent application WO 2002/50043 A1 discloses afatinib compounds, WO2007/054550A1 and WO2007/054551A1 disclose indications for afatinib.
专利文献 WO2005/037824A2 (同族专利文献 CN1867564B) 公开了晶态的阿法替尼二马 来酸盐的制备方法。  A method for preparing a crystalline form of afatinib dimaleate is disclosed in the patent document WO2005/037824A2 (the same family patent document CN1867564B).
WO2012121764 A1公开了阿法替尼二马来酸盐晶型 B， DSC图显示其在 125.9°C即有放热 峰， 说明该晶型对热不稳定， 会发生转晶甚至分解。  WO2012121764 A1 discloses crystal form B of afatinib dimaleate. The DSC chart shows that it has an exothermic peak at 125.9 ° C, indicating that the crystal form is unstable to heat, and crystal transformation or even decomposition occurs.
WO2013052157A1 公开了阿法替尼二马来酸盐晶型 C、 D、 E， 该文献称晶型 C、 D可能是 无水物， 但无直接证据； 晶型 C的 DSC图显示在 40°C-95°C有吸热峰， 很可能为溶剂化物； 晶 型 E为水合物， 含水 5.9%-8.1%， 较高的水含量对湿度敏感。  WO2013052157A1 discloses crystal form C, D, E of afatinib dimaleate. The literature indicates that crystal forms C and D may be anhydrate, but there is no direct evidence; the DSC chart of crystal form C is shown at 40 ° C. -95 ° C has an endothermic peak, most likely a solvate; Form E is a hydrate with a water content of 5.9% - 8.1%, and a higher water content is sensitive to humidity.
经本发明人研究显示， 上述阿法替尼二马来酸盐晶型8、 C、 D、 E均有较为严重的吸湿性， 不适于储存和制剂应用。  According to the study by the present inventors, the above-mentioned afatinib dimaleate crystal forms 8, C, D, and E have relatively serious hygroscopicity and are not suitable for storage and formulation applications.
专利文献 WO2009/147238 A1公开了 WO2005/037824 A2中所述的阿法替尼二马来酸盐 是细针状形态， 这样会使其流动性较差， 不同批次间的差异较大， 可加工性也较差， 且容易 粘冲， 不可直压。 故专利文献 WO2009/147238 A1采用辊压法来改善由于原料的针状形貌而 带来的难以加工的问题， 但采用辊压法会增加辊压粉碎的单元操作， 从而增加生产成本。 为 了方便， 在本申请中将 WO2005/037824 A2中所述的阿法替尼二马来酸盐称为 "阿法替尼二 马来酸盐现有技术晶型"。  The patent document WO 2009/147238 A1 discloses that the afatinib dimaleate salt described in WO 2005/037824 A2 is in the form of fine needles, which results in poor fluidity and large differences between batches. The processability is also poor, and it is easy to stick and cannot be pressed directly. Therefore, the patent document WO 2009/147238 A1 employs a roll pressing method to improve the problem of being difficult to process due to the needle-like appearance of the raw material, but the roll pressing method increases the unit operation of the roll crushing, thereby increasing the production cost. For convenience, the afatinib dimaleate salt described in WO2005/037824 A2 is referred to herein as "the prior art crystalline form of afatinib dimaleate".
专利文献 WO 2012121764A1公开了固态形式的阿法替尼酸加成盐的制备方法， 包括阿 法替尼的二马来酸盐、 二苯磺酸盐、 富马酸盐、 二硫酸盐、 二盐酸盐、 二草酸盐、 甲磺酸盐、 二磷酸盐、 二 L-苹果酸盐、 柠檬酸盐、 二丁二酸盐、 L-天冬氨酸盐和二反丁烯二酸盐。 该文 献只是泛泛提及上述阿法替尼酸加成盐具有适合片剂应用的一些有益性质， 但没有提供具体 数据。  Patent document WO 2012121764 A1 discloses a process for the preparation of a solid form of afatinidine acid addition salt, comprising a dimaleate salt of afatinib, a diphenyl sulfonate, a fumarate, a disulfate, a disalt. Acid, dioxalate, methanesulfonate, diphosphate, di L-malate, citrate, succinate, L-aspartate and difumarate. This document is only a general reference to the above-mentioned afatinidine acid addition salts having some beneficial properties suitable for tablet applications, but no specific data is provided.
专利文献 CN1867564B公开了阿法替尼二马来酸盐现有技术晶型有一定的吸湿性， 但没有 具体数据， 经本发明人的研究显示， 阿法替尼二马来酸盐现有技术晶型晶型在 10%-80%相对湿 度范围内重量变化为 2.6%。 较佳地， 医药活性物质应该仅具有有限的吸湿性， 较高的吸湿性往 往带来不利的影响。 例如， 在制造期间， 水分的吸收降低了药物活性物质的含量， 影响制剂工 艺， 影响制剂的均一性； 在储藏时必须采取防潮措施， 例如加入干燥剂或者储存在防潮环境中， 增加了成本， 还有长期储存稳定性变差的风险。 The patent document CN1867564B discloses that the prior art crystalline form of afatinib dimaleate has a certain hygroscopicity, but there is no specific data. According to the research of the present inventors, the prior art of afatinib dimaleate The crystal form has a weight change of 2.6% in the range of 10% to 80% relative humidity. Preferably, the pharmaceutically active substance should have only limited hygroscopicity, and higher hygroscopicity often has an adverse effect. For example, during the manufacturing process, the absorption of moisture reduces the content of the pharmaceutically active substance, affects the formulation process, and affects the uniformity of the preparation; moisture storage measures must be taken during storage, such as adding a desiccant or storing it in a moisture-proof environment. Increased costs and the risk of poor long-term storage stability.
因此， 需开发具有更多优越性能的， 尤其是可采用粉末直压法和不易吸湿的阿法替尼酸 加成盐及其晶型。  Therefore, it is necessary to develop a more advantageous performance, in particular, a powder direct pressure method and a fat-free addition of afatinibic acid and a crystal form thereof.
发明内容  Summary of the invention
针对现有技术的不足， 本发明提供了新型的可药用的阿法替尼酸加成盐及其晶型， 包括 其乙二磺酸盐、 1,5-萘二磺酸盐、 丙二酸盐、 二丙二酸盐、 二 2-萘磺酸盐、 二氨基磺酸盐、 二 D-葡萄糖酸盐、 甘醇酸盐、 二环己烷氨基磺酸盐、 二 4-氨基苯磺酸盐、 以及上述新型的盐 的晶型， 还包括了阿法替尼二马来酸盐的一种新晶型。 与现有技术的阿法替尼酸加成盐或其 晶型相比， 本发明的阿法替尼酸加成盐及其晶型具有一种或多种的改进性能。 本发明进一步 提供了本发明的阿法替尼酸加成盐及其晶型的制备方法、 其药物組合物和用途。  In view of the deficiencies of the prior art, the present invention provides a novel pharmaceutically acceptable afatinidine acid addition salt and a crystal form thereof, including ethanedisulfonate, 1,5-naphthalene disulfonate, and propylene Acid salt, dimalonate, bis 2-naphthalene sulfonate, diamino sulfonate, di D-gluconate, glycolate, dicyclohexane sulfamate, di 4-aminobenzene sulfonate The acid form, as well as the crystalline form of the above novel salts, also include a novel crystalline form of afatinib dimaleate. The afatinidine acid addition salt of the present invention and its crystal form have one or more improved properties compared to the prior art afatinidine acid addition salt or a crystalline form thereof. The present invention further provides a process for the preparation of the afatinidine acid addition salt of the present invention and a crystal form thereof, a pharmaceutical composition thereof and use thereof.
本发明的内容之一是提供阿法替尼乙二磺酸盐及其晶型、 以及它们的制备方法。  One of the contents of the present invention is to provide afatinib ethanedisulfonate and its crystal form, and a process for the preparation thereof.
经 HPLC检测， 所述阿法替尼乙二磺酸盐中阿法替尼游离碱的实际含量为 71.4% (不计 溶剂的量）， 阿法替尼和乙二磺酸以 1 : 1摩尔比形成的化合物中阿法替尼的理论含量 71.9%， 因此本发明所述阿法替尼乙二磺酸盐中阿法替尼和乙二磺酸以 1 : 1摩尔比成盐， 其结构式如 下：  The actual content of afatinib free base in the afatinib ethanedisulfonate was 71.4% (excluding the amount of solvent), and the ratio of afatinib to ethanedisulfonic acid was 1:1 by HPLC. The theoretical content of afatinib in the formed compound is 71.9%. Therefore, the afatinib and ethanedisulfonic acid in the afatinib ethanedisulfonate of the present invention are salted in a molar ratio of 1:1, and the structural formula is as follows: :
Figure imgf000003_0001
Figure imgf000003_0001
所述阿法替尼乙二磺酸盐的制备方法， 包括以下步骤： 分别形成阿法替尼和乙二磺酸在 可溶溶剂中的溶液体系， 阿法替尼和乙二磺酸的摩尔比 1 : 1-1 :2， 混合两个体系形成浆液， 然 后除去可溶溶剂。 优选所述可溶溶剂为腈类、 醇类、 酮类、 酯类、 烷烃类、 醚类或其混合物； 所述可溶溶剂进一步优选为乙腈、 甲醇、 丙酮、 乙酸乙酯、 正庚烷或甲基叔丁基醚。 优选采 用旋干法除去可溶溶剂。  The preparation method of the afatinib ethanedisulfonate comprises the following steps: respectively forming a solution system of afatinib and ethanedisulfonic acid in a soluble solvent, a molar of afatinib and ethanedisulfonic acid Ratio 1: 1:1:2, the two systems are mixed to form a slurry, and then the soluble solvent is removed. Preferably, the soluble solvent is a nitrile, an alcohol, a ketone, an ester, an alkane, an ether or a mixture thereof; the soluble solvent is further preferably acetonitrile, methanol, acetone, ethyl acetate, n-heptane or Methyl tert-butyl ether. Preferably, the soluble solvent is removed by spin-drying.
优选地， 所述阿法替尼乙二磺酸盐为 E1晶型阿法替尼乙二磺酸盐， 使用 Cu-Κα辐射， 其 X射线粉末衍射图谱在衍射角 2 Θ为 6.3±0.2。、 7.0±0.2。、 17.6±0.2。、 17.8±0.2。、 21.7±0.2。、 22.8±0.2°和 24.6±0.2°处具有特征峰。  Preferably, the afatinib ethanedisulfonate is an E1 crystalline form of afatinib ethanedisulfonate, using Cu-Κα radiation, and the X-ray powder diffraction pattern has a diffraction angle of 2 Θ of 6.3 ± 0.2. , 7.0 ± 0.2. , 17.6 ± 0.2. , 17.8 ± 0.2. , 21.7 ± 0.2. Characteristic peaks at 22.8±0.2° and 24.6±0.2°.
进一步地， 所述 E1晶型阿法替尼乙二磺酸盐， 其 X射线粉末衍射图谱在衍射角 2 Θ为 6.3±0.2。、7.0±0.2。、 12.6±0.2。、 14.5±0.2。、 17.6±0.2。、 17.8±0.2。、 18.3±0.2。、 19.0±0.2。、 21.7±0.2。、 22.8±0.2。、 24.6±0.2。、 26.3±0.2。和 28.6±0.2。处具有特征峰。  Further, the E1 crystal form of afatinib ethanedisulfonate has an X-ray powder diffraction pattern at a diffraction angle of 2 Θ of 6.3 ± 0.2. , 7.0 ± 0.2. , 12.6 ± 0.2. , 14.5 ± 0.2. , 17.6 ± 0.2. , 17.8 ± 0.2. , 18.3 ± 0.2. , 19.0 ± 0.2. , 21.7 ± 0.2. , 22.8 ± 0.2. , 24.6 ± 0.2. , 26.3 ± 0.2. And 28.6 ± 0.2. There are characteristic peaks.
更进一步地， 所述 E1晶型阿法替尼乙二磺酸盐， 其 X射线粉末衍射图的衍射角 2 Θ特 征峰及其相对强度如下：  Further, the E1 crystal form of afatinib ethanedisulfonate, the diffraction angle of the X-ray powder diffraction pattern and the relative intensity thereof are as follows:
衍射角 2Θ 相对强度％  Diffraction angle 2Θ relative intensity%
6.3±0.2° 26.9  6.3±0.2° 26.9
7.0±0.2° 47.3  7.0±0.2° 47.3
12.6±0.2° 16.8  12.6±0.2° 16.8
14.1±0.2° 10.2  14.1±0.2° 10.2
14.5±0.2° 15.2  14.5±0.2° 15.2
16.4±0.2° 10.8  16.4±0.2° 10.8
17.6±0.2° 62.8  17.6±0.2° 62.8
17.8±0.2° 100.0  17.8±0.2° 100.0
18.3±0.2° 21.8  18.3±0.2° 21.8
19.0±0.2° 23.9  19.0±0.2° 23.9
21.3±0.2° 12.7  21.3 ± 0.2 ° 12.7
21.7±0.2° 49.9  21.7±0.2° 49.9
22.5±0.2° 17.8 22.8±0.2° 65.3 22.5 ± 0.2 ° 17.8 22.8 ± 0.2 ° 65.3
23.0±0.2° 40.5  23.0±0.2° 40.5
24.1±0.2° 18.0  24.1±0.2° 18.0
24.6±0.2° 91.5  24.6 ± 0.2 ° 91.5
25.4±0.2° 13.6  25.4±0.2° 13.6
26.3±0.2° 16.9  26.3±0.2° 16.9
27.6±0.2° 15.8  27.6 ± 0.2 ° 15.8
28.6±0.2° 39.8  28.6±0.2° 39.8
29.0±0.2° 17.5  29.0±0.2° 17.5
29.4±0.2° 10.9  29.4±0.2° 10.9
36.7±0.2° 13.0  36.7±0.2° 13.0
非限制性地， 所述 El晶型阿法替尼乙二磺酸盐的一个典型实例具有如图 6所示的 X射 线粉末衍射图谱。  Without limitation, a typical example of the El crystalline form of afatinib ethanedisulfonate has an X-ray powder diffraction pattern as shown in FIG.
所述 E1晶型阿法替尼乙二磺酸盐，其傅里叶红外光谱在波数为 1501、 1454、 1227、 1206、 1168、 1023和 767cm"1处具有特征峰。 The E1 crystal form of afatinib ethanedisulfonate has a Fourier transform infrared spectrum having characteristic peaks at wave numbers of 1501, 1454, 1227, 1206, 1168, 1023 and 767 cm" 1 .
所述 E1晶型阿法替尼乙二磺酸盐，其拉曼光谱在波数为 1661、 1610、 1551、 1406、 1379、 1297和 1207 cm"1处具有特征峰。 The E1 crystal form of afatinib ethanedisulfonate has a characteristic peak at a wave number of 1661, 1610, 1551, 1406, 1379, 1297 and 1207 cm" 1 .
所述 E1晶型阿法替尼乙二磺酸盐的一种制备方法， 包括以下步骤： 分别形成阿法替尼和 乙二磺酸在可溶溶剂中的溶液体系， 阿法替尼和乙二磺酸的摩尔比 1 :1-1 :2， 混合两个体系形 成浆液并搅拌，在 -10-50°C下保持 1-48小时， 然后除去溶剂， 其中所述可溶溶剂选自 C2-C4腈、 d-C4醇、 C3-C5酮、 C4-C5酯、 C6-C9烷烃、 C4-C6醚或其混合物。 所述 C2-C4腈包括但不限于 乙腈，所述 d-C4醇包括但不限于甲醇、 乙醇、正丙醇、异丙醇、正丁醇和仲丁醇，所述 C3-C5 酮包括但不限于丙酮和丁酮， 所述 C4-C5酯包括但不限于乙酸乙酯和乙酸异丙酯， 所述 C6-C9 烷烃包括但不限于正己烷、 正庚烷和甲基环己烷， 所述 C4-C6醚包括但不限于乙醚、 甲基叔 丁基醚和异丙醚； 优选所述可溶溶剂为乙腈、 甲醇、 丙酮、 乙酸乙酯、 正庚烷、 甲基叔丁基 醚或其混合物，更优选为乙腈。优选阿法替尼在可溶溶剂中的浓度为 10毫克 /毫升至该溶剂下 阿法替尼的饱和溶液。 优选阿法替尼和乙二磺酸的摩尔为 1 :1-1:2。 优选所述制备方法的操作 温度为室温。 A preparation method of the E1 crystal form afatinib ethanedisulfonate comprises the following steps: respectively forming a solution system of afatinib and ethanedisulfonic acid in a soluble solvent, afatinib and B The molar ratio of disulfonic acid is 1:1-1:2, the two systems are mixed to form a slurry and stirred, and maintained at -10 to 50 ° C for 1 to 48 hours, and then the solvent is removed, wherein the soluble solvent is selected from C 2 -C 4 nitrile, dC 4 alcohol, C 3 -C 5 ketone, C 4 -C 5 ester, C 6 -C 9 alkane, C 4 -C 6 ether or a mixture thereof. The C 2 -C 4 nitrile includes, but is not limited to, acetonitrile, and the dC 4 alcohol includes, but is not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, and sec-butanol, the C 3 -C 5 ketone including but not limited to, acetone and methyl ethyl ketone, the C 4 -C 5 esters include, but are not limited to ethyl acetate and isopropyl acetate, a C 6 -C 9 alkanes include but are not limited to, n-hexane, n-heptane and a The cyclohexane, the C 4 -C 6 ether includes but is not limited to diethyl ether, methyl tert-butyl ether and diisopropyl ether; preferably the soluble solvent is acetonitrile, methanol, acetone, ethyl acetate, n-heptane Methyl tert-butyl ether or a mixture thereof, more preferably acetonitrile. Preferably, the concentration of afatinib in a soluble solvent is 10 mg/ml to a saturated solution of afatinib in the solvent. Preferably, the molar ratio of afatinib and ethanedisulfonic acid is from 1:1 to 1:2. Preferably, the operating temperature of the preparation method is room temperature.
所述 E1 晶型阿法替尼乙二磺酸盐的另一种制备方法， 包括以下步骤： 将前述方法制备得到 的阿法替尼乙二磺酸盐在有机溶剂中形成浆液并搅拌， 浆液在 -10-50°C下保持 1〜72 小时， 进而 除去溶剂， 其中所述有机溶剂选自乙腈、 甲醇、 丙酮、 乙酸乙酯、 正庚烷、 甲基叔丁基醚或其混 合物。 优选所述制备方法的操作温度为室温。  The preparation method of the E1 crystal form afatinib ethanedisulfonate comprises the following steps: the afatinib ethanedisulfonate prepared by the above method is slurried in an organic solvent and stirred, and the slurry is slurried. The solvent is removed by maintaining at -10-50 ° C for 1 to 72 hours, wherein the organic solvent is selected from the group consisting of acetonitrile, methanol, acetone, ethyl acetate, n-heptane, methyl t-butyl ether or a mixture thereof. Preferably, the operating temperature of the preparation method is room temperature.
与现有技术比较， 尤其与现有技术的阿法替尼二马来酸盐或其晶型比较， 阿法替尼乙二磺 酸盐或 E1晶型阿法替尼乙二磺酸盐具有一种或多种改进的特性， 例如： 更高的结晶度、 较好 的溶解度、 溶解速度、 较佳的结晶形态、 较好的热稳定性和贮存稳定性、 较低的吸湿性、 较好 的可流动性和有利的加工与处理特性。  Compared with the prior art, in particular, compared with the prior art afatinib dimaleate or its crystal form, afatinib ethanedisulfonate or E1 crystal form afatinib ethanedisulfonate has One or more improved properties, such as: higher crystallinity, better solubility, dissolution rate, preferred crystalline morphology, better thermal stability and storage stability, lower hygroscopicity, better Flowability and advantageous processing and handling characteristics.
特别是 E1晶型阿法替尼乙二磺酸盐具有以下有益性质：  In particular, the E1 crystalline form of afatinib ethanedisulfonate has the following beneficial properties:
1 ) 室温下水中溶解度为 55.7mg/ml，相对于阿法替尼二马来酸盐现有技术晶型在相同 条件下的溶解度 7.5 mg/ml, 具有更高的溶解性；  1) The solubility in water at room temperature is 55.7 mg/ml, and the solubility of the prior art crystal form of afatinib dimaleate under the same conditions is 7.5 mg/ml, which has higher solubility;
2) 室温下 10%-80%相对湿度范围内吸湿 1.4%，相对于阿法替尼二马来酸盐现有技术 晶型在相同条件下吸湿 2.6%， 具有更小的吸湿性；  2) moisture absorption of 1.4% at room temperature in the range of 10%-80% relative humidity, relative to the base of afatinib dimaleate. The crystal form absorbs 2.6% under the same conditions, and has less hygroscopicity;
3 ) 分解温度为 261.8°C， 相对于阿法替尼二马来酸盐现有技术晶型的分解温度 164.1 °C， 具有更高的热稳定性；  3) The decomposition temperature is 261.8 ° C, and the decomposition temperature of the prior art crystal form of afatinib dimaleate is 164.1 ° C, which has higher thermal stability;
4) 为颗粒状晶体， 相对于阿法替尼二马来酸盐现有技术晶型为针状晶体， 具有更好 的流动性、 可压性和可加工性。  4) It is a granular crystal, and the prior art crystal form is needle-like crystal with respect to afatinib dimaleate, which has better fluidity, compressibility and processability.
上述有益性质表明， 与现有技术的阿法替尼二马来酸盐或其晶型相比， 本发明的阿法替尼 乙二磺酸盐或 E1晶型阿法替尼乙二磺酸盐具有多种优势性能， 应用效果可更好， 适合作为药 物制剂的活性成分。活性成分更高的溶解性有利于提高药物的生物利用度，进而对药效产生积 极影响； 活性成分的结晶形貌佳， 具有更好的流动性、 可压性和可加工性， 对制剂工艺的适 宜性好； 活性成分具有更低的吸湿性和更高的热稳定性， 能够更好地对抗药物制造和 /或存储 等过程中由环境温度、 湿度等因素引起的活性成分含量不均 、 纯度降低和杂质增加等问题， 降低由此带来的疗效下降风险和安全风险，并有利于药物制造中的准确定量、提高制剂均一性 以及后期的储存和运输。 The above beneficial properties indicate that the afatinib ethanedisulfonate or the E1 crystal form afatinib ethanedisulfonic acid of the present invention is compared with the prior art afatinib dimaleate or a crystal form thereof. Salt has many advantages and performance, and the application effect is better. It is suitable as a medicine. The active ingredient of the preparation. The higher solubility of the active ingredient is beneficial to improve the bioavailability of the drug, and thus has a positive effect on the efficacy; the crystalline component of the active ingredient has good morphology, has better fluidity, compressibility and processability, and the preparation process The suitability is good; the active ingredient has lower hygroscopicity and higher thermal stability, and can better resist the uneven content of active ingredients caused by environmental temperature, humidity and the like in the process of drug manufacture and/or storage, Problems such as reduced purity and increased impurities reduce the risk of reduced efficacy and safety risks, and facilitate accurate quantification in drug manufacturing, improve formulation uniformity, and later storage and transportation.
本发明的内容之二是提供阿法替尼 1,5-萘二磺酸盐及其晶型、 以及它们的制备方法。 经 HPLC检测，所述阿法替尼 1,5-萘二磺酸盐中阿法替尼游离碱的实际含量为 63.3% (不 计溶剂的量）， 阿法替尼和 1,5-萘二磺酸以 1 : 1摩尔比形成的化合物中阿法替尼的理论含量为 62.8%, 因此本发明所述阿法替尼 1,5-萘二磺酸盐中阿法替尼和 1,5-萘二磺酸以 1 : 1摩尔比成 盐， 其结构式如下：  A second aspect of the present invention provides afatinib 1,5-naphthalene disulfonate and a crystalline form thereof, and a process for the preparation thereof. The actual content of afatinib free base in the afatinib 1,5-naphthalene disulfonate was 63.3% (excluding the amount of solvent), afatinib and 1,5-naphthalene by HPLC. The theoretical content of afatinib in the compound formed by the sulfonic acid in a molar ratio of 1:1 is 62.8%, and thus the afatinib 1,5-naphthalene disulfonate of the present invention is afatinib and 1,5 - Naphthalene disulfonic acid is salted in a molar ratio of 1:1, and its structural formula is as follows:
Figure imgf000005_0001
Figure imgf000005_0001
所述阿法替尼 1,5-萘二磺酸盐的制备方法， 包括以下步骤：分别形成阿法替尼和 1,5-萘二磺 酸在可溶溶剂中的溶液体系， 阿法替尼和 1,5-萘二磺酸的摩尔比为 1 : 1-1 :2， 混合两个体系形成 浆液， 然后除去可溶溶剂。 优选所述可溶溶剂为腈类、 醇类、 酮类、 酯类、 烷烃类、 醚类或其 混合物； 所述可溶溶剂进一步优选为乙腈、 甲醇、 丙酮、 乙酸乙酯、 正庚烷或甲基叔丁基醚。 优选采用旋干法除去可溶溶剂。  The preparation method of the afatinib 1,5-naphthalenedisulfonate comprises the following steps: respectively forming a solution system of afatinib and 1,5-naphthalene disulfonic acid in a soluble solvent, Alfati The molar ratio of nitrile to 1,5-naphthalene disulfonic acid was 1:1-1:2, and the two systems were mixed to form a slurry, and then the soluble solvent was removed. Preferably, the soluble solvent is a nitrile, an alcohol, a ketone, an ester, an alkane, an ether or a mixture thereof; the soluble solvent is further preferably acetonitrile, methanol, acetone, ethyl acetate, n-heptane or Methyl tert-butyl ether. Preferably, the soluble solvent is removed by spin-drying.
优选地，所述阿法替尼 1,5-萘二磺酸盐为 N1晶型阿法替尼 1,5-萘二磺酸盐，使用 Cu-Ka 辐射， 其 X射线粉末衍射图谱在衍射角 2 Θ为 6.6±0.2°、 13.4±0.2。、 16.6±0.2。、 17.5±0.2。、 20.8±0.2。和 24.2±0.2。处具有特征峰。  Preferably, the afatinib 1,5-naphthalenedisulfonate is an N1 crystalline form of afatinib 1,5-naphthalenedisulfonate, using Cu-Ka radiation, and its X-ray powder diffraction pattern is diffracted. The angle 2 Θ is 6.6 ± 0.2 ° and 13.4 ± 0.2. , 16.6 ± 0.2. , 17.5 ± 0.2. , 20.8 ± 0.2. And 24.2 ± 0.2. There are characteristic peaks.
进一步地， 所述 N1晶型阿法替尼 1,5-萘二磺酸盐， 其 X射线粉末衍射图谱在衍射角 2 Θ 为 6.6±0.2。、8.1±0.2。、 13.4±0.2。、 14.8±0.2。、 16.3±0.2。、 16.6±0.2。、 17.5±0.2。、 18.3±0.2。、20.8±0.2。、 22.0±0.2。、 22.7±0.2。和 24.2±0.2。处具有特征峰。  Further, the N1 crystal form of afatinib 1,5-naphthalenedisulfonate has an X-ray powder diffraction pattern at a diffraction angle of 2 Θ of 6.6 ± 0.2. , 8.1 ± 0.2. , 13.4 ± 0.2. , 14.8 ± 0.2. , 16.3 ± 0.2. , 16.6 ± 0.2. , 17.5 ± 0.2. , 18.3 ± 0.2. , 20.8 ± 0.2. , 22.0 ± 0.2. , 22.7 ± 0.2. And 24.2 ± 0.2. There are characteristic peaks.
更进一步地， 所述 N1晶型阿法替尼 1,5-萘二磺酸盐， 其 X射线粉末衍射图的衍射角 2 Θ特征峰及其相对强度如下：  Further, the N1 crystal form afatinib 1,5-naphthalenedisulfonate, the diffraction peak 2 Θ characteristic peak of the X-ray powder diffraction pattern and its relative intensity are as follows:
衍射角 2Θ 相对强度％  Diffraction angle 2Θ relative intensity%
6.6±0.2° 100.0  6.6±0.2° 100.0
8.1±0.2° 16.1  8.1±0.2° 16.1
1 1. .2±0. .2° 12.2  1 1. .2±0. .2° 12.2
13. .4±0. .2° 75.6  13. .4±0. .2° 75.6
14. .8±0. .2° 21.2  14. .8±0. .2° 21.2
16. .3±0. .2° 13.4  16. .3±0. .2° 13.4
16. .6±0. .2° 53.5  16. .6±0. .2° 53.5
17. .5±0. .2° 27.1  17. .5±0. .2° 27.1
17. .9±0. .2° 13.0  17. .9±0. .2° 13.0
18. .3±0. .2° 23.1  18. .3±0. .2° 23.1
19. .2±0. .2° 20.7  19. .2±0. .2° 20.7
19. .5±0. .2° 22.5  19. .5±0. .2° 22.5
20. .5±0. .2° 29.9  20. .5±0. .2° 29.9
20. .8±0. .2° 38.0  20. .8±0. .2° 38.0
21. .8±0. .2° 24.5  21. .8±0. .2° 24.5
22. .0±0. .2° 24.8  22. .0±0. .2° 24.8
22. .4±0. .2° 26.4 22.7±0.2° 28.9 22. .4±0. .2° 26.4 22.7 ± 0.2 ° 28.9
23.2±0.2° 14.3  23.2±0.2° 14.3
23.5±0.2° 15.4  23.5±0.2° 15.4
24.2±0.2° 62.3  24.2±0.2° 62.3
24.7±0.2° 15.6  24.7±0.2° 15.6
26.5±0.2° 15.3  26.5 ± 0.2 ° 15.3
30.2±0.2° 19.5  30.2±0.2° 19.5
非限制性地， 所述 Nl晶型阿法替尼 1,5-萘二磺酸盐的一个典型实例具有如图 13所示的 X射线粉末衍射图谱。  Without limitation, a typical example of the Nl crystal form afatinib 1,5-naphthalene disulfonate has an X-ray powder diffraction pattern as shown in Fig. 13.
所述 N1晶型阿法替尼 1,5-萘二磺酸盐， 其傅里叶红外光谱在波数为 1639、 1577、 1524、 1500、 1452、 1216、 1155、 1028和 765cm_1处具有特征峰。 The N1 crystal form of afatinib 1,5-naphthalene disulfonate has a Fourier transform infrared spectrum with characteristic peaks at wave numbers of 1639, 1577, 1524, 1500, 1452, 1216, 1155, 1028 and 765 cm _1 .
所述 N1晶型阿法替尼 1,5-萘二磺酸盐， 其拉曼光谱在波数为 1704、 1661、 1613、 1543、 1403、 1365、 1205、 1068、 999和 780 cm 处具有特征峰。  The N1 crystalline form of afatinib 1,5-naphthalene disulfonate has a Raman spectrum with characteristic peaks at wavenumbers of 1704, 1661, 1613, 1543, 1403, 1365, 1205, 1068, 999 and 780 cm. .
所述 N1晶型阿法替尼 1,5-萘二磺酸盐的一种制备方法， 包括以下步骤： 分别形成阿法替 尼和 1,5-萘二磺酸在可溶溶剂中的溶液体系， 阿法替尼和 1,5-萘二磺酸的摩尔比为 1 : 1-1 :2， 混 合两个体系形成浆液并搅拌， 在 -10-50°C下保持 1-48小时， 然后除去溶剂， 其中所述可溶溶剂 选自 C2-C4腈、 d-C4醇、 C3-C5酮、 C4-C5酯、 C6-C9烷烃、 C4-C6醚或其混合物。 所述 C2-C4 腈包括但不限于乙腈， 所述 d-C4醇包括但不限于甲醇、 乙醇、 正丙醇、 异丙醇、 正丁醇和仲 丁醇， 所述 C3-C5酮包括但不限于丙酮和丁酮， 所述 C4-C5酯包括但不限于乙酸乙酯和乙酸异 丙酯， 所述 C6-C9烷烃包括但不限于正己烷、 正庚烷和甲基环己烷， 所述 C4-C6醚包括但不限 于乙醚、 甲基叔丁基醚和异丙醚； 优选所述可溶溶剂为乙腈、 甲醇、 乙醇、 丙酮、 乙酸乙酯、 正庚烷、 甲基叔丁基醚或其混合物； 更优选分别形成阿法替尼的乙腈溶液和 1,5-萘二磺酸的乙 醇溶液。 优选阿法替尼在可溶溶剂中的浓度为 10毫克 /毫升至该溶剂下阿法替尼的饱和溶液。 优选阿法替尼和 1,5-萘二磺酸的摩尔比为 1 : 1-1 : 1.5。 优选所述制备方法的操作温度为室温。 A preparation method of the N1 crystal form afatinib 1,5-naphthalene disulfonate comprises the following steps: respectively forming a solution of afatinib and 1,5-naphthalene disulfonic acid in a soluble solvent The molar ratio of afatinib to 1,5-naphthalenedisulfonic acid is 1:1-1:2, the two systems are mixed to form a slurry and stirred, and maintained at -10 to 50 ° C for 1-48 hours. The solvent is then removed, wherein the soluble solvent is selected from the group consisting of C 2 -C 4 nitriles, dC 4 alcohols, C 3 -C 5 ketones, C 4 -C 5 esters, C 6 -C 9 alkanes, C 4 -C 6 ethers Or a mixture thereof. The C 2 -C 4 nitrile includes, but is not limited to, acetonitrile, and the dC 4 alcohol includes, but is not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, and sec-butanol, the C 3 -C 5 ketone including but not limited to, acetone and methyl ethyl ketone, the C 4 -C 5 esters include, but are not limited to ethyl acetate and isopropyl acetate, a C 6 -C 9 alkanes include but are not limited to, n-hexane, n-heptane and a The cyclohexane, the C 4 -C 6 ether includes but is not limited to diethyl ether, methyl tert-butyl ether and isopropyl ether; preferably the soluble solvent is acetonitrile, methanol, ethanol, acetone, ethyl acetate, positive Heptane, methyl tert-butyl ether or a mixture thereof; more preferably an acetonitrile solution of afatinib and an ethanol solution of 1,5-naphthalenedisulfonic acid, respectively. Preferably, the concentration of afatinib in a soluble solvent is 10 mg/ml to a saturated solution of afatinib in the solvent. Preferably, the molar ratio of afatinib to 1,5-naphthalene disulfonic acid is 1:1-1:1.5. Preferably, the operating temperature of the preparation method is room temperature.
所述 N1 晶型阿法替尼 1,5-萘二磺酸盐的另一种制备方法， 包括以下步骤： 将按照前述 制备方法制得的阿法替尼 1,5-萘二磺酸盐在有机溶剂中形成浆液并搅拌， 该浆液在 -10-50°C 下保持 1〜72小时， 进而除去溶剂， 其中所述有机溶剂选自甲醇、 乙醇、 乙腈、 丙酮、 乙酸 乙酯、 正庚烷、 甲基叔丁基醚或其混合物。 优选所述制备方法的操作温度为室温。  Another preparation method of the N1 crystal form afatinib 1,5-naphthalene disulfonate comprises the following steps: afatinib 1,5-naphthalene disulfonate prepared according to the aforementioned preparation method The slurry is formed in an organic solvent and stirred, and the slurry is kept at -10 to 50 ° C for 1 to 72 hours to remove the solvent, wherein the organic solvent is selected from the group consisting of methanol, ethanol, acetonitrile, acetone, ethyl acetate, and n-glycol. Alkane, methyl tert-butyl ether or a mixture thereof. Preferably, the operating temperature of the preparation method is room temperature.
优选地， 所述阿法替尼 1,5-萘二磺酸盐为 N2晶型阿法替尼 1,5-萘二磺酸盐水合物。 使用 Cu-Κα辐射， 所述 N2晶型阿法替尼 1,5-萘二磺酸盐水合物的 X射线粉末衍射图谱 在衍射角 2 Θ为 6.7±0.2。、 8.1±0.2。、 9.3±0.2。、 14.9±0.2。、 20.9±0.2°和 23.0±0.2°处具有特征峰。  Preferably, the afatinib 1,5-naphthalene disulfonate is an N2 crystal form afatinib 1,5-naphthalene disulfonic acid salt hydrate. Using Cu-Κα radiation, the X-ray powder diffraction pattern of the N2 crystal form afatinib 1,5-naphthalenedisulfonic acid salt hydrate was 6.7 ± 0.2 at a diffraction angle of 2 Θ. , 8.1 ± 0.2. , 9.3 ± 0.2. , 14.9 ± 0.2. Characteristic peaks at 20.9±0.2° and 23.0±0.2°.
进一步地， 所述 N2晶型阿法替尼 1,5-萘二磺酸盐水合物， 其 X射线粉末衍射图谱在衍 射角 2 Θ为 6.7±0.2。、 8.1±0.2。、 9.3±0.2。、 13.9±0.2。、 14.9±0.2°、 15.8±0.2。、 16.7±0.2。、 17.5±0.2。、 20.5±0.2。、 20.9±0.2。、 21.7±0.2。、 23.0±0.2。、 24.1±0.2°和 24.3±0.2°处具有特征峰。  Further, the N2 crystal form afatinib 1,5-naphthalene disulfonic acid salt hydrate has an X-ray powder diffraction pattern at a diffraction angle of 2 Θ of 6.7 ± 0.2. , 8.1 ± 0.2. , 9.3 ± 0.2. , 13.9 ± 0.2. , 14.9 ± 0.2 °, 15.8 ± 0.2. , 16.7 ± 0.2. , 17.5 ± 0.2. , 20.5 ± 0.2. , 20.9 ± 0.2. , 21.7 ± 0.2. , 23.0 ± 0.2. Characteristic peaks at 24.1±0.2° and 24.3±0.2°.
更进一步地， 所述 N2晶型阿法替尼 1,5-萘二磺酸盐水合物， 其 X射线粉末衍射图的衍 射角 2 Θ特征峰及其相对强度如下：  Further, the N2 crystal form afatinib 1,5-naphthalene disulfonic acid salt hydrate, the X-ray powder diffraction pattern of the diffraction angle 2 Θ characteristic peak and its relative intensity are as follows:
衍射角 2Θ 相对强度％  Diffraction angle 2Θ relative intensity%
5.9±0.2° 12.1  5.9±0.2° 12.1
6.7±0.2° 25.2  6.7±0.2° 25.2
8.1±0.2° 36.7  8.1±0.2° 36.7
9.3±0.2° 27.4  9.3±0.2° 27.4
12.0±0.2° 13.9  12.0±0.2° 13.9
13.5±0.2。 12.6  13.5 ± 0.2. 12.6
13.9±0.2° 26.8  13.9 ± 0.2 ° 26.8
14.9±0.2° 93.0  14.9±0.2° 93.0
15.8±0.2° 39.0  15.8±0.2° 39.0
16.3±0.2° 14.7  16.3±0.2° 14.7
16.7±0.2° 28.6 17 5±0 2° 26.8 16.7±0.2° 28.6 17 5±0 2° 26.8
18 1±0 2° 19.8  18 1±0 2° 19.8
19 4±0 2° 12.1  19 4±0 2° 12.1
20 0±0 2° 30.1  20 0±0 2° 30.1
20 5±0 2° 47.9  20 5±0 2° 47.9
20 9±0 2° 53.1  20 9±0 2° 53.1
21 7±0 2° 45.9  21 7±0 2° 45.9
22 2±0 2° 15.3  22 2±0 2° 15.3
23 0±0 2° 100.0  23 0±0 2° 100.0
24 1±0 2° 43.3  24 1±0 2° 43.3
24 3±0 2° 47.5  24 3±0 2° 47.5
24 8±0 2° 18.9  24 8±0 2° 18.9
25 7±0 2° 15.9  25 7±0 2° 15.9
26 1±0 2° 28.0  26 1±0 2° 28.0
27 6±0 2° 26.6  27 6±0 2° 26.6
非限制性地， 所述 N2晶型阿法替尼 1,5-萘二磺酸盐水合物的一个典型实例具有如图 20 所示的 X射线粉末衍射图谱。  Without limitation, a typical example of the N2 crystal form afatinib 1,5-naphthalenedisulfonic acid salt hydrate has an X-ray powder diffraction pattern as shown in Fig. 20.
所述 N2晶型阿法替尼 1,5-萘二磺酸盐水合物， 其热重分析（TGA) 图谱显示 100°C之前 有 5.97%的失重， 约合为三水合物。  The thermogravimetric analysis (TGA) pattern of the N2 crystal form afatinib 1,5-naphthalenedisulfonic acid salt hydrate showed a weight loss of 5.97% before 100 ° C, which was about trihydrate.
所述 N2晶型阿法替尼 1,5-萘二磺酸盐水合物， 其傅里叶红外光谱在波数为 1641、 1578、 1500、 1451、 1219、 1155、 1028和 764cm 处具有特征峰。  The N2 crystal form afatinib 1,5-naphthalenedisulfonic acid salt hydrate has a Fourier transform infrared spectrum having characteristic peaks at wave numbers of 1641, 1578, 1500, 1451, 1219, 1155, 1028 and 764 cm.
所述 N2晶型阿法替尼 1,5-萘二磺酸盐水合物， 其拉曼光谱在波数为 1654、 1610、 1549、 1400、 1371、 1297、 1216、 997和 781cm-1处具有特征峰。 The N2 crystal form afatinib 1,5-naphthalenedisulfonic acid salt hydrate having Raman spectra with characteristics at wave numbers of 1654, 1610, 1549, 1400, 1371, 1297, 1216, 997 and 781 cm -1 peak.
所述 N2晶型阿法替尼 1,5-萘二磺酸盐水合物的制备方法， 包括以下步骤：将 N1型阿法 替尼 1,5-萘二磺酸盐放置在 75%-100%相对湿度的室温环境中， 放置时间 1〜7天。 优选放置 在 75%-85%相对湿度的室温环境中， 放置时间 1〜3天。  The preparation method of the N2 crystal form afatinib 1,5-naphthalene disulfonic acid salt hydrate comprises the following steps: placing the N1 type afatinib 1,5-naphthalene disulfonate at 75%-100 % room temperature in a relative humidity environment, set the time 1 to 7 days. It is preferably placed in a room temperature environment of 75%-85% relative humidity for 1 to 3 days.
与现有技术比较，尤其是与现有技术的阿法替尼二马来酸盐或其晶型比较，阿法替尼 1,5- 萘二磺酸盐或 N1晶型阿法替尼 1,5-萘二磺酸盐或 N2晶型阿法替尼 1,5-萘二磺酸盐水合物具 有一种或多种改进的特性， 例如： 更高的结晶度、 较好的溶解度、 溶解速度、 较佳的结晶形 态、 较好的热稳定性和贮存稳定性、 较低的吸湿性、 较好的可流动性和有利的加工与处理特 性。  Compared with the prior art, in particular, compared with the prior art afatinib dimaleate or its crystal form, afatinib 1,5-naphthalene disulfonate or N1 crystal form afatinib 1 , 5-naphthalene disulfonate or N2 crystal form afatinib 1,5-naphthalenedisulfonic acid salt hydrate has one or more improved properties, such as: higher crystallinity, better solubility, Dissolution speed, preferred crystalline morphology, better thermal stability and storage stability, lower moisture absorption, better flowability, and advantageous processing and handling characteristics.
特别是 N1晶型阿法替尼 1,5-萘二磺酸盐具有以下有益性质：  In particular, the N1 crystalline form of afatinib 1,5-naphthalenedisulfonate has the following beneficial properties:
1 ) 分解温度为 276.3°C， 相对于阿法替尼二马来酸盐现有技术晶型的分解温度 164.1 °C， 具有更高的热稳定性；  1) The decomposition temperature is 276.3 ° C, and the decomposition temperature of the prior art crystal form of afatinib dimaleate is 164.1 ° C, which has higher thermal stability;
2) 为较为规则的颗粒状晶体， 相对于阿法替尼二马来酸盐现有技术晶型的针状晶 体， 具有更好的流动性、 可压性和可加工性；  2) For relatively regular granular crystals, it has better fluidity, compressibility and processability than the needle-like crystals of the prior art crystal form of afatinib dimaleate;
特别是 N2晶型阿法替尼 1,5-萘二磺酸盐水合物具有以下有益性质：  In particular, the N2 crystal form afatinib 1,5-naphthalenedisulfonic acid salt hydrate has the following beneficial properties:
1 ) 室温下在 30-80%相对湿度下吸湿 1.80%， 相对于阿法替尼二马来酸盐现有技术 晶型在相同条件下吸湿 2.2%， 具有更低的吸湿性；  1) moisture absorption at room temperature at 30-80% relative humidity 1.80%, relative to afatinib dimaleate. The crystal form absorbs 2.2% under the same conditions and has lower hygroscopicity;
2) 分解温度为 275.4°C， 相对于阿法替尼二马来酸盐现有技术晶型的分解温度 164.1 °C， 具有更高的热稳定性；  2) The decomposition temperature is 275.4 ° C, and the decomposition temperature of the prior art crystal form of afatinib dimaleate is 164.1 ° C, which has higher thermal stability;
3 ) 为较为规则的颗粒状晶体， 相对于阿法替尼二马来酸盐现有技术晶型的针状晶 体， 具有更好的流动性、 可压性和可加工性。  3) For the more regular granular crystals, it has better fluidity, compressibility and processability than the needle-like crystals of the prior art crystal form of afatinib dimaleate.
上述有益性质表明， 与现有技术的阿法替尼二马来酸盐或其晶型相比， 本发明的阿法替尼 1,5-萘二磺酸盐或 N1晶型阿法替尼 1,5-萘二磺酸盐或 N2晶型阿法替尼 1,5-萘二磺酸盐水合物 具有多种优势性能，应用效果可更好，适合作为药物制剂的活性成分。活性成分的结晶形貌佳， 具有更好的流动性、 可压性和可加工性， 对制剂工艺的适宜性好； 活性成分具有更低的吸湿性 和更高的热稳定性， 能够更好地对抗药物制造和 /或存储等过程中由环境温度、 湿度等因素引 起的活性成分含量不均 、纯度降低和杂质增加等问题， 降低由此带来的疗效下降风险和安全 风险， 并有利于药物制造中的准确定量、 提高制剂均一性以及后期的储存和运输。 The above beneficial properties indicate that the afatinib 1,5-naphthalene disulfonate or the N1 crystal form afatinib of the present invention is compared with the prior art afatinib dimaleate or a crystal form thereof. 1,5-naphthalene disulfonate or N2 crystal form afatinib 1,5-naphthalenedisulfonic acid salt hydrate has a plurality of advantageous properties, and the application effect is better, and is suitable as an active ingredient of a pharmaceutical preparation. The active ingredient has good crystal morphology, better fluidity, compressibility and processability, and is suitable for the preparation process; the active ingredient has lower hygroscopicity and higher thermal stability, and can be better. In the process of manufacturing and/or storing drugs, it is caused by factors such as ambient temperature and humidity. Problems such as uneven content of active ingredients, reduced purity and increased impurities reduce the risk and safety risks of the resulting therapeutic effects, and facilitate accurate quantification in drug manufacturing, improve formulation uniformity, and later storage and transportation.
本发明的内容之三是提供阿法替尼一丙二酸盐及其晶型、 以及它们的制备方法。  A third aspect of the present invention is to provide afatinib monomalonate and a crystal form thereof, and a process for the preparation thereof.
经 HPLC检测， 所述阿法替尼一丙二酸盐中阿法替尼游离碱的实际含量为 83.0% (不计 溶剂的量）， 阿法替尼和丙二酸以 1 : 1摩尔比形成的化合物中阿法替尼的理论含量为 82.4%， 因此本发明所述阿法替尼一丙二酸盐中阿法替尼和丙二酸是以 1 : 1摩尔比成盐， 其结构式如 下：  The actual content of afatinib free base in the afatinib monomalonate was 83.0% (excluding the amount of solvent), and afatinib and malonic acid were formed in a molar ratio of 1:1 by HPLC. The theoretical content of afatinib in the compound is 82.4%, so that afatinib and malonic acid in the afatinib-malonate of the present invention are salted in a molar ratio of 1:1, and the structural formula is as follows :
HOOCCH COOH
Figure imgf000008_0001
HOOCCH COOH
Figure imgf000008_0001
所述阿法替尼一丙二酸盐的制备方法， 包括以下步骤： 分别形成阿法替尼和丙二酸在可 溶溶剂中的溶液体系， 阿法替尼和丙二酸的摩尔比 1 : 1-1 : 1.5， 混合两个体系形成浆液， 然后 除去溶剂。 优选所述可溶溶剂为醚类溶剂； 更优选为 C4-C5醚， 所述 C4-C5醚包括但不限于 乙醚、 甲基叔丁基醚和异丙醚； 最优选为甲基叔丁基醚。 优选采用旋干法除去溶剂。 The preparation method of the afatinib monomalonate comprises the following steps: respectively forming a solution system of afatinib and malonic acid in a soluble solvent, a molar ratio of afatinib to malonic acid 1 : 1-1 : 1.5, the two systems were mixed to form a slurry, and then the solvent was removed. Preferably, the solvent is soluble ether solvent; more preferably, C 4 -C 5 ethers, the C 4 -C 5 ethers include, but are not limited to, diethyl ether, methyl tert-butyl ether and isopropyl ether; and most preferably A Tert-butyl ether. The solvent is preferably removed by spin-drying.
优选地， 所述阿法替尼一丙二酸盐为 Ml晶型阿法替尼一丙二酸盐， 使用 Cu-Κα辐射， 其 X射线粉末衍射图谱在衍射角 2 Θ为 6.6±0.2°、 7.2±0.2。、 13.2±0.2。、 13.4±0.2。、 17.3±0.2。、 20.8±0.2°和 25.1±0.2°处具有特征峰。  Preferably, the afatinib monomalonate is a crystalline form of afatinib monomalonate, using Cu-Κα radiation, and the X-ray powder diffraction pattern has a diffraction angle of 2 Θ of 6.6±0.2°. , 7.2 ± 0.2. , 13.2 ± 0.2. , 13.4 ± 0.2. , 17.3 ± 0.2. Characteristic peaks at 20.8±0.2° and 25.1±0.2°.
进一步地， 所述 Ml晶型阿法替尼一丙二酸盐， 其 X射线粉末衍射图谱在衍射角 2 Θ为 6.6±0.2。、 7.2±0.2。、 8.7±0.2。、 13.2±0.2。、 13.4±0.2。、 14.3±0.2。、 17.3±0.2。、 18.0±0.2。、 19.7±0.2。、 20.8±0.2。、 21.4±0.2。、 25.1±0.2°和 26.1±0.2°处具有特征峰。  Further, the M1 crystal form afatinib monomalonate has an X-ray powder diffraction pattern at a diffraction angle of 2 Θ of 6.6 ± 0.2. , 7.2 ± 0.2. , 8.7 ± 0.2. , 13.2 ± 0.2. , 13.4 ± 0.2. , 14.3 ± 0.2. , 17.3 ± 0.2. , 18.0 ± 0.2. , 19.7 ± 0.2. , 20.8 ± 0.2. , 21.4 ± 0.2. Characteristic peaks at 25.1±0.2° and 26.1±0.2°.
更进一步地， 所述 Ml晶型阿法替尼一丙二酸盐， 其 X射线粉末衍射图的衍射角 2 Θ特 征峰及其相对强度如下：  Further, the M1 crystal form afatinib monomalonate has a diffraction angle 2 Θ characteristic peak and its relative intensity in an X-ray powder diffraction pattern as follows:
衍射角 2Θ 相对强度％  Diffraction angle 2Θ relative intensity%
6.6±0.2° 92.8  6.6±0.2° 92.8
7.2±0.2° 31.1  7.2±0.2° 31.1
8.7±0.2° 12.4  8.7±0.2° 12.4
13. .2±0. .2° 29.7  13. .2±0. .2° 29.7
13. .4±0. .2° 32.2  13. .4±0. .2° 32.2
14. .3±0. .2° 15.0  14. .3±0. .2° 15.0
17. .3±0. .2° 30.8  17. .3±0. .2° 30.8
18. .0±0. .2° 25.5  18. .0±0. .2° 25.5
19. .3±0. .2° 15.7  19. .3±0. .2° 15.7
19. .7±0. .2° 22.2  19. .7±0. .2° 22.2
20. .8±0. .2° 42.1  20. .8±0. .2° 42.1
21. .4±0. .2° 18.7  21. .4±0. .2° 18.7
22. .3±0. .2° 10.7  22. .3±0. .2° 10.7
22. .7±0. .2° 16.6  22. .7±0. .2° 16.6
23. .6±0. .2° 18.5  23. .6±0. .2° 18.5
25. .1±0. .2° 100.0  25. .1±0. .2° 100.0
26. .0±0. .2° 32.2  26. .0±0. .2° 32.2
非限制性地， 所述 Ml 晶型阿法替尼一丙二酸盐的一个典型实例具有如图 25所示的 X 射线粉末衍射图谱。  Without limitation, a typical example of the Ml crystal form afatinib monomalonate has an X-ray powder diffraction pattern as shown in Fig. 25.
所述 Ml晶型阿法替尼一丙二酸盐，其傅里叶红外光谱在波数为 1693、 1628、 1499、 1454、 1363、 1213、 1155、 1063和 749cm_1处具有特征峰。 所述 Ml晶型阿法替尼一丙二酸盐，其拉曼光谱在波数为 1657、 1609、 1544、 1397、 1369、 1343、 1301、 1204和 780 cm 处具有特征峰。 The M1 crystalline form of afatinib monomalonate has a Fourier infrared spectrum with characteristic peaks at wavenumbers of 1693, 1628, 1499, 1454, 1363, 1213, 1155, 1063 and 749 cm _1 . The M1 crystal form afatinib monomalonate has a Raman spectrum with characteristic peaks at wave numbers of 1657, 1609, 1544, 1397, 1369, 1343, 1301, 1204 and 780 cm.
所述 Ml晶型阿法替尼一丙二酸盐的一种制备方法， 包括以下步骤： 分别形成阿法替尼 和丙二酸在 C4-C5醚中的溶液体系， 阿法替尼和丙二酸的摩尔比 1 : 1-1 : 1.5， 混合两个体系形 成浆液并搅拌， 在 -10-50°C下保持 1-48小时， 然后除去溶剂。 所述 C4-C5醚包括但不限于乙 醚、 甲基叔丁基醚和异丙醚， 优选为甲基叔丁基醚。 优选阿法替尼在 C4-C5醚中的浓度为 10 毫克 /毫升至该溶剂下阿法替尼的饱和溶液。 优选所述制备方法的操作温度为室温， A preparation method of the M1 crystal form afatinib monomalonate comprises the following steps: respectively forming a solution system of afatinib and malonic acid in C 4 -C 5 ether, afatinib The molar ratio to malonic acid 1: 1-1 : 1.5, the two systems were mixed to form a slurry and stirred, maintained at -10 to 50 ° C for 1-48 hours, and then the solvent was removed. The C 4 -C 5 ethers include, but are not limited to, diethyl ether, methyl tert-butyl ether, and isopropyl ether, preferably methyl tert-butyl ether. Preferably, the concentration of afatinib in the C 4 -C 5 ether is 10 mg/ml to a saturated solution of afatinib in the solvent. Preferably, the preparation method has an operating temperature of room temperature.
所述 Ml晶型阿法替尼一丙二酸盐的另一种制备方法， 包括以下步骤： 将前述方法制成 的阿法替尼一丙二酸盐在有机溶剂中形成浆液并搅拌，该浆液在 -10-50°C下保持 1〜72小时， 进而除去该溶剂， 其中所述有机溶剂选自甲醇、 丙酮、 乙腈、 甲基叔丁基醚、 乙酸乙酯、 正 庚烷或其混合物。 优选所述制备方法的操作温度为室温。  The preparation method of the M1 crystal form afatinib monomalonate comprises the following steps: preparing the afatinib monomalonate prepared by the foregoing method into a slurry in an organic solvent and stirring, The slurry is maintained at -10 to 50 ° C for 1 to 72 hours to further remove the solvent, wherein the organic solvent is selected from the group consisting of methanol, acetone, acetonitrile, methyl tert-butyl ether, ethyl acetate, n-heptane or a mixture thereof. . Preferably, the operating temperature of the preparation method is room temperature.
与现有技术比较， 尤其是与已知的阿法替尼二马来酸盐或其晶型比较， 阿法替尼一丙二酸 盐或 Ml 晶型阿法替尼一丙二酸盐具有一种或多种改进的特性， 例如： 更高的结晶度、 较好的 溶解度、 溶解速度、 较佳的结晶形态、 较好的热稳定性和贮存稳定性、 较低的吸湿性、 较好的 可流动性和有利的加工与处理特性。  Compared with the prior art, in particular, compared with the known afatinib dimaleate or its crystal form, afatinib monomalonate or Ml crystal form afetinib-malonate has One or more improved properties, such as: higher crystallinity, better solubility, dissolution rate, preferred crystalline morphology, better thermal stability and storage stability, lower hygroscopicity, better Flowability and advantageous processing and handling characteristics.
特别是 Ml晶型阿法替尼一丙二酸盐具有以下有益性质：  In particular, the M1 crystalline form of afatinib monomalonate has the following beneficial properties:
1 ) 室温下水中的溶解度为 40.8mg/ml， 相对于阿法替尼二马来酸盐现有技术晶型在相 同条件下的溶解度 7.5mg/ml， 具有更高的溶解性；  1) The solubility in water at room temperature is 40.8 mg/ml, which has higher solubility than the prior art crystalline form of afatinib dimaleate under the same conditions of 7.5 mg/ml;
2) 为较为规则的颗粒状， 相对于阿法替尼二马来酸盐现有技术晶型的针状晶体， 具 有更好的流动性、 可压性和可加工性。  2) For the more regular granules, the needle crystals of the prior art crystal form of afatinib dimaleate have better fluidity, compressibility and processability.
上述有益性质表明， 与现有技术的阿法替尼二马来酸盐或其晶型相比， 本发明的阿法替尼 一丙二酸盐或 Ml 晶型阿法替尼一丙二酸盐具有多种优势性能， 应用效果可更好， 适合作为药 物制剂的活性成分。 活性成分更高的溶解性有利于提高药物的生物利用度， 进而对药效产生积 极影响； 活性成分的结晶形貌佳， 具有更好的流动性、 可压性和可加工性， 对制剂工艺的适宜 性好。  The above beneficial properties indicate that the afatinib monomalonate or Ml crystal form afatinib malonate of the present invention is compared to the prior art afatinib dimaleate or a crystalline form thereof. Salt has a variety of advantageous properties, and the application effect is better, and it is suitable as an active ingredient of a pharmaceutical preparation. The higher solubility of the active ingredient is beneficial to improve the bioavailability of the drug, and thus has a positive effect on the drug effect; the crystalline component of the active ingredient has good morphology, has better fluidity, compressibility and processability, and the preparation process The suitability is good.
本发明的内容之四是提供阿法替尼二丙二酸盐及其晶型、 以及它们的制备方法。  A fourth aspect of the present invention provides afatinib dimalonate and a crystalline form thereof, and a process for the preparation thereof.
经 HPLC检测， 所述阿法替尼二丙二酸盐中阿法替尼游离碱的实际含量为 70.2% (不计 溶剂的量）， 阿法替尼和丙二酸以 1 :2摩尔比形成的化合物中阿法替尼的理论含量为 70.0%， 因此本发明所述阿法 成盐， 其结构式如下：  The actual content of afatinib free base in the afatinib dimalonate was 70.2% (excluding the amount of solvent), and afatinib and malonic acid were formed in a 1:2 molar ratio. The theoretical content of afatinib in the compound is 70.0%, so the afar salt of the present invention has the following structural formula:
Figure imgf000009_0001
Figure imgf000009_0001
所述阿法替尼二丙二酸盐的制备方法， 包括以下步骤： 分别形成阿法替尼和丙二酸在可 溶溶剂中的溶液体系， 阿法替尼和丙二酸的摩尔比 1 :2-1 :4， 混合两个体系形成浆液， 然后除 去溶剂。 优选所述可溶溶剂为酯类溶剂； 进一步优选所述可溶溶剂为 C4-C5酯， 所述 C4-C5 酯包括但不限于乙酸乙酯、 乙酸异丙酯； 更优选为乙酸乙酯。 优选采用旋干法除去溶剂。 The preparation method of the afatinib dimalonate comprises the following steps: respectively forming a solution system of afatinib and malonic acid in a soluble solvent, a molar ratio of afatinib to malonic acid 1 :2-1 : 4, the two systems were mixed to form a slurry, and then the solvent was removed. Preferably, the soluble solvent is an ester solvent; further preferably, the soluble solvent is a C 4 -C 5 ester, and the C 4 -C 5 ester includes but is not limited to ethyl acetate or isopropyl acetate; more preferably Ethyl acetate. The solvent is preferably removed by spin-drying.
优选地， 所述阿法替尼二丙二酸盐为 M2晶型阿法替尼二丙二酸盐， 使用 Cu-Κα辐射， 其 X射线粉末衍射图谱在衍射角 2 Θ为 6.5±0.2。、 8.1±0.2。、 13.1±0.2。、 16.1±0.2。、 20.8±0.2。 和 25.8±0.2°处具有特征峰。  Preferably, the afatinib dipropanedionate is an M2 crystalline form of afatinib dipropanedionate, using Cu-Κα radiation, and having an X-ray powder diffraction pattern at a diffraction angle of 2 Θ of 6.5 ± 0.2. , 8.1 ± 0.2. , 13.1 ± 0.2. , 16.1 ± 0.2. , 20.8 ± 0.2. And characteristic peaks at 25.8 ± 0.2°.
进一步地， 所述 M2晶型阿法替尼二丙二酸盐， 其 X射线粉末衍射图谱在衍射角 2 Θ为 6.5±0.2。、 8.1±0.2。、 9.7±0.2。、 10.9±0.2。、 13.1±0.2。、 14.0±0.2。、 16.1±0.2。、 18.3±0.2。、 19.0±0.2。、 20.8±0.2。、 25.8±0.2。和 27.0±0.2。处具有特征峰。 更进一步地， 所述 M2晶型阿法替尼二丙二酸盐， 其 X射线粉末衍射图的衍射角 2 Θ特 征峰及其相对强度如下： Further, the M2 crystal form afatinib dipropane acid salt has an X-ray powder diffraction pattern at a diffraction angle of 2 Θ of 6.5 ± 0.2. , 8.1 ± 0.2. , 9.7 ± 0.2. , 10.9 ± 0.2. , 13.1 ± 0.2. , 14.0 ± 0.2. , 16.1 ± 0.2. , 18.3 ± 0.2. , 19.0 ± 0.2. , 20.8 ± 0.2. , 25.8 ± 0.2. And 27.0 ± 0.2. There are characteristic peaks. Further, the M2 crystal form afatinib dipropanedionate, the X-ray powder diffraction pattern has a diffraction angle 2 Θ characteristic peak and its relative intensity as follows:
衍射角 2Θ 相对强度％  Diffraction angle 2Θ relative intensity%
5.8±0.2° 12.3  5.8±0.2° 12.3
6.5±0.2° 58.7  6.5±0.2° 58.7
8.1±0.2° 24.1  8.1±0.2° 24.1
9.7±0.2° 14.2  9.7±0.2° 14.2
10. .9±0. .2° 14.9  10. .9±0. .2° 14.9
13. .1±0. .2° 42.9  13. .1±0. .2° 42.9
13. .6±0. .2° 16.0  13. .6±0. .2° 16.0
14. .0±0. .2° 31.9  14. .0±0. .2° 31.9
15. .1±0. .2° 14.7  15. .1±0. .2° 14.7
16. .1±0. .2° 35.0  16. .1±0. .2° 35.0
16. .4±0. .2° 18.8  16. .4±0. .2° 18.8
18. .3±0. .2° 15.9  18. .3±0. .2° 15.9
19. .0±0. .2° 19.9  19. .0±0. .2° 19.9
19. .8±0. .2° 18.0  19. .8±0. .2° 18.0
20. .4±0. .2° 14.7  20. .4±0. .2° 14.7
20. .8±0. .2° 41.7  20. .8±0. .2° 41.7
21. .5±0. .2° 10.5  21. .5±0. .2° 10.5
22. .2±0. .2° 19.9  22. .2±0. .2° 19.9
23. .6±0. .2° 1 1.3  23. .6±0. .2° 1 1.3
25. .8±0. .2° 100.0  25. .8±0. .2° 100.0
26. .5±0. .2° 13.3  26. .5±0. .2° 13.3
27. .0±0. .2° 39.3  27. .0±0. .2° 39.3
27. .7±0. .2° 1 1.8  27. .7±0. .2° 1 1.8
29. .3±0. .2° 12.0  29. .3±0. .2° 12.0
非限制性地， 所述 M2晶型阿法替尼二丙二酸盐的一个典型实例具有如图 31所示的 X 射线粉末衍射图谱。  Without limitation, a typical example of the M2 crystalline form of afatinib dipropanedionate has an X-ray powder diffraction pattern as shown in FIG.
所述 M2晶型阿法替尼二丙二酸盐，其傅里叶红外光谱在波数为 1694、 1630、 1501、 1455、 1364、 1262、 1214、 1064、 892和 749cm-1处具有特征峰。 The M2 crystal form of afatinib dipropaneate has a Fourier transform infrared spectrum having characteristic peaks at wave numbers of 1694, 1630, 1501, 1455, 1364, 1262, 1214, 1064, 892 and 749 cm -1 .
所述 M2晶型阿法替尼二丙二酸盐，其拉曼光谱在波数为 1658、 1621、 1607、 1545、 1491、 1397、 1301、 1205和 781 cm 处具有特征峰。  The M2 crystal form of afatinib dipropanedionate has a Raman spectrum with characteristic peaks at wave numbers of 1658, 1621, 1607, 1545, 1491, 1397, 1301, 1205 and 781 cm.
所述 M2晶型阿法替尼二丙二酸盐的一种制备方法， 包括以下步骤： 分别形成阿法替尼 和丙二酸在 C4-C5酯中的溶液体系， 阿法替尼和丙二酸的摩尔比 1 :2-1 :4， 混合两个体系形成 浆液并搅拌， 在 -10-50°C下保持 1-48 小时， 然后除去溶剂； 或者， 分别形成阿法替尼一丙二 酸盐在 C4-C5酯中的混悬液体系和丙二酸在 C4-C5酯中的溶液体系， 阿法替尼一丙二酸盐和丙 二酸的摩尔比为 1 : 1-1 :2， 混合两个体系形成浆液并搅拌， 在 -10-50°C下保持 1-48小时， 然后除 去溶剂。 所述 C4-C5酯包括但不限于乙酸乙酯、 乙酸异丙酯， 优选所述 C4-C5酯为乙酸乙酯。 优选阿法替尼在 C4-C5酯中的浓度 10毫克 /毫升至该溶剂下阿法替尼的饱和溶液。 优选阿法 替尼和丙二酸的摩尔比为 1 :2-1 :3。优选阿法替尼一丙二酸盐和丙二酸的摩尔比为 1 : 1-1 : 1.5。优 选所述制备方法的操作温度为室温。 A preparation method of the M2 crystal form afatinib dipropanedionate comprises the following steps: respectively forming a solution system of afatinib and malonic acid in a C 4 -C 5 ester, afatinib a molar ratio of 1:2:4 to malonic acid, mixing the two systems to form a slurry and stirring, maintaining at -10 to 50 ° C for 1 to 48 hours, and then removing the solvent; or, respectively, forming afatinib a suspension system malonate and malonic acid in the C 4 -C 5 ester of a solution system in C 4 -C 5 ester, a method a molar ratio of imatinib malonate and malonic acid For 1: 1:1:2, the two systems were mixed to form a slurry and stirred, maintained at -10 to 50 ° C for 1-48 hours, and then the solvent was removed. The C 4 -C 5 ester includes, but is not limited to, ethyl acetate, isopropyl acetate, and preferably the C 4 -C 5 ester is ethyl acetate. A concentration of 10 mg/ml of afatinib in the C 4 -C 5 ester to a saturated solution of afatinib in the solvent is preferred. Preferably, the molar ratio of afatinib to malonic acid is 1:2-1:3. Preferably, the molar ratio of afatinib monomalonate to malonic acid is 1:1-1:1.5. Preferably, the operating temperature of the preparation method is room temperature.
所述 M2晶型阿法替尼二丙二酸盐的另一种制备方法， 包括以下步骤： 将前述制备方法 得到的阿法替尼二丙二酸酸盐在有机溶剂形成浆液并搅拌， 该浆液在 - 10-50°C下保持 1〜72 小时， 进而除去溶剂， 所述有机溶剂选自甲醇、 丙酮、 乙腈、 甲基叔丁基醚、 乙酸乙酯、 正 庚烷或其混合物。 优选所述制备方法的操作温度为室温。  The preparation method of the M2 crystal form afatinib dipropane acid salt comprises the following steps: the aftinib dimalonate obtained by the above preparation method is slurried in an organic solvent and stirred. The slurry is maintained at -10 to 50 ° C for 1 to 72 hours to remove the solvent, and the organic solvent is selected from the group consisting of methanol, acetone, acetonitrile, methyl tert-butyl ether, ethyl acetate, n-heptane or a mixture thereof. Preferably, the operating temperature of the preparation method is room temperature.
与现有技术比较， 尤其是与现有技术的阿法替尼二马来酸盐或其晶型比较， 阿法替尼二丙 二酸盐或 M2晶型阿法替尼二丙二酸盐具有一种或多种改进的特性， 例如： 更高的结晶度、较 好的溶解度、 溶解速度、 较佳的结晶形态、 较好的热稳定性和贮存稳定性、 较低的吸湿性、 较 好的可流动性和有利的加工与处理特性。 Compared with the prior art, in particular, compared with the prior art afatinib dimaleate or its crystal form, afatinib dimalonate or M2 crystal form afotinib dipropanedioate Has one or more improved properties, such as: higher crystallinity, better solubility, dissolution rate, better crystalline morphology, better thermal stability and storage stability, lower moisture absorption, Good flowability and favorable processing and handling characteristics.
特别是 M2晶型阿法替尼二丙二酸盐具有以下有益性质：  In particular, the M2 crystalline form of afatinib dipropionate has the following beneficial properties:
1 ) 室温下水中的溶解度为 26.2mg/ml， 相对于阿法替尼二马来酸盐现有技术晶型在 相同条件下的溶解度 7.5 mg/ml, 具有更高的溶解性。  1) The solubility in water at room temperature is 26.2 mg/ml, which has higher solubility than the prior art crystalline form of afatinib dimaleate under the same conditions of 7.5 mg/ml.
2) 室温、 10-80%相对湿度下的吸湿为 1.1%， 相对于阿法替尼二马来酸盐现有技术 晶型在相同条件下吸湿 2.6%， 具有更低的吸湿性。  2) The moisture absorption at room temperature and 10-80% relative humidity is 1.1%, compared with the prior art of afatinib dimaleate. The crystal form absorbs 2.6% under the same conditions and has lower hygroscopicity.
上述有益性质表明， 与现有技术的阿法替尼二马来酸盐或其晶型相比， 本发明的阿法替尼 二丙二酸盐或 M2 晶型阿法替尼二丙二酸盐具有多种优势性能， 应用效果可更好， 适合作为 药物制剂的活性成分。活性成分更高的溶解性有利于提高药物的生物利用度，进而对药效产生 积极影响； 活性成分具有更低的吸湿性， 能够更好地对抗药物制造和 /或存储等过程中由环境 湿度引起的活性成分含量不均 、纯度降低和杂质增加等问题， 降低由此带来的疗效下降风险 和安全风险， 并有利于药物制造中的准确定量、 提高制剂均一性以及后期的储存和运输。  The above beneficial properties indicate that the afatinib dimalonate or M2 crystal form afatinib dimalonic acid of the present invention is compared to the prior art afatinib dimaleate or a crystal form thereof. Salt has a variety of advantageous properties, and the application effect is better, and it is suitable as an active ingredient of a pharmaceutical preparation. The higher solubility of the active ingredient is beneficial to improve the bioavailability of the drug, which in turn has a positive effect on the efficacy; the active ingredient has a lower hygroscopicity and is better able to resist the environmental humidity during the manufacture and/or storage of the drug. The problems caused by uneven content of active ingredients, decreased purity and increased impurities reduce the risk and safety risks of the resulting therapeutic effects, and facilitate accurate quantification in drug manufacturing, improve uniformity of the preparation, and later storage and transportation.
本发明的内容之五是提供阿法替尼二 2-萘磺酸盐及其晶型、 以及它们的制备方法。 经 HPLC检测， 所述阿法替尼二 2-萘磺酸盐中阿法替尼游离碱的实际含量为 55.0% (不 计溶剂的量）， 阿法替尼和 2-萘磺酸以 1 :2 摩尔比形成的化合物中阿法替尼的理论含量为 53.9%, 因此本发明所述阿法替尼二 2-萘磺酸盐中阿法替尼和 2-萘磺酸以 1 :2摩尔比成盐， 其结构式如下：  A fifth aspect of the present invention provides afatinib di 2-naphthalenesulfonate and a crystal form thereof, and a process for the preparation thereof. The actual content of afatinib free base in the afatinib di 2-naphthalene sulfonate was 55.0% (excluding the amount of solvent), and afatinib and 2-naphthalenesulfonic acid were as follows: The theoretical content of afatinib in the compound formed by 2 molar ratio is 53.9%, so the afatinib di 2-naphthalene sulfonate of the present invention has a 1:2 mole of afatinib and 2-naphthalenesulfonic acid. Compared to salt, its structural formula is as follows:
Figure imgf000011_0001
Figure imgf000011_0001
所述阿法替尼二 2-萘磺酸盐的制备方法， 包括以下步骤： 分别形成阿法替尼和 2-萘磺酸 在可溶溶剂中的溶液体系，阿法替尼和 2-萘磺酸的摩尔比为 1 :2-1 :4，混合两个体系形成浆液， 然后除去溶剂。 优选所述可溶溶剂为醇类、 酮类、 酯类、 烷烃类、 醚类或其混合物； 进一步 优选为甲醇、 丙酮、 乙酸乙酯、 正庚烷或甲基叔丁基醚。 优选采用旋干法除去溶剂。  The preparation method of the afatinib bis 2-naphthalene sulfonate comprises the following steps: respectively forming a solution system of afatinib and 2-naphthalenesulfonic acid in a soluble solvent, afatinib and 2-naphthalene The molar ratio of the sulfonic acid was 1:2-1:4, and the two systems were mixed to form a slurry, and then the solvent was removed. Preferably, the soluble solvent is an alcohol, a ketone, an ester, an alkane, an ether or a mixture thereof; more preferably methanol, acetone, ethyl acetate, n-heptane or methyl tert-butyl ether. The solvent is preferably removed by spin-drying.
优选地， 所述阿法替尼二 2-萘磺酸盐为 Nsl 晶型阿法替尼二 2-萘磺酸盐， 使用 Cu-Ka 辐射， 其 X射线粉末衍射图谱在衍射角 2 Θ为 5.6±0.2°、 24.0±0.2°和 26.8±0.2°处具有特征峰。  Preferably, the afatinib bis 2-naphthalene sulfonate is an Nsl crystal form afatinib di 2-naphthalene sulfonate, using Cu-Ka radiation, and the X-ray powder diffraction pattern is at a diffraction angle of 2 Θ Characteristic peaks at 5.6 ± 0.2 °, 24.0 ± 0.2 °, and 26.8 ± 0.2 °.
进一步地， 所述 Nsl晶型阿法替尼二 2-萘磺酸盐， 其 X射线粉末衍射图的衍射角 2 Θ特 征峰及其相对强度如下：  Further, the Nsl crystal form afatinib di 2-naphthalene sulfonate has a diffraction angle 2 Θ characteristic peak and its relative intensity in an X-ray powder diffraction pattern as follows:
衍射角 2Θ 相对强度％  Diffraction angle 2Θ relative intensity%
5.6±0.2° 26.0  5.6±0.2° 26.0
24.0±0.2° 100.0  24.0±0.2° 100.0
26.8±0.2° 54.3  26.8 ± 0.2 ° 54.3
非限制性地， 所述 Nsl晶型阿法替尼二 2-萘磺酸盐的一个典型实例具有如图 37所示的 X射线粉末衍射图谱。  Without limitation, a typical example of the Nsl crystal form afatinib di 2-naphthalenesulfonate has an X-ray powder diffraction pattern as shown in Fig. 37.
所述 Nsl晶型阿法替尼二 2-萘磺酸盐， 其傅里叶红外光谱在波数为 1627、 1536、 1498、 1427、 1211、 1090、 1030和 675cm-1处具有特征峰。 The Nsl crystal form afatinib di 2-naphthalenesulfonate has a Fourier infrared spectrum having characteristic peaks at wave numbers of 1627, 1536, 1498, 1427, 1211, 1090, 1030 and 675 cm -1 .
所述 Nsl晶型阿法替尼二 2-萘磺酸盐， 其拉曼光谱在波数为 1650、 1628、 1610、 1581、 1501、 1386、 1355、 1211、 1021和 771 cm_1处具有特征峰。 The Nsl crystal form afatinib di 2-naphthalene sulfonate has a Raman spectrum with characteristic peaks at wave numbers of 1650, 1628, 1610, 1581, 1501, 1386, 1355, 1211, 1021 and 771 cm _1 .
所述 Nsl晶型阿法替尼二 2-萘磺酸盐的一种制备方法， 包括以下步骤： 分别形成阿法替 尼和 2-萘磺酸在可溶溶剂中的溶液体系， 阿法替尼和 2-萘磺酸的摩尔比为 1 :2-1 :4， 混合两个 体系形成浆液并搅拌， 在 -10-50°C下保持 1-48小时， 然后除去溶剂， 其中所述可溶溶剂选自 d-C4醇、 C3-C5酮、 C4-C5酯、 C6-C9烷烃、 C4-C6醚或其混合物。 所述 d-C4醇包括但不限于 甲醇、 乙醇、 正丙醇、 异丙醇、 正丁醇和仲丁醇， 所述 C3-C5酮包括但不限于丙酮和丁酮， 所述 C4-C5酯包括但不限于乙酸乙酯和乙酸异丙酯，所述 C6-C9烷烃包括但不限于正己烷、正 庚烷和甲基环己烷， 所述 C4-C6醚包括但不限于乙醚、 异丙醚和甲基叔丁基醚； 优选所述可 溶溶剂为甲醇、 丙酮、 乙酸乙酯、 正庚烷、 甲基叔丁基醚或其混合物； 更优选为乙酸乙酯。 优选阿法替尼在可溶溶剂中的浓度为 10毫克 /毫升至该溶剂下阿法替尼的饱和溶液。 优选阿 法替尼和 2-萘磺酸的摩尔比为 1 :2-1 :3。 优选所述制备方法的操作温度为室温。 The preparation method of the Nsl crystal form afatinib bis 2-naphthalene sulfonate comprises the following steps: respectively forming a solution system of afatinib and 2-naphthalenesulfonic acid in a soluble solvent, Afati The molar ratio of nitrile to 2-naphthalenesulfonic acid is 1:2-1:4, mixing the two systems to form a slurry and stirring, maintaining at -10 to 50 ° C for 1-48 hours, and then removing the solvent, wherein the The solvent is selected from the group consisting of dC 4 alcohols, C 3 -C 5 ketones, C 4 -C 5 esters, C 6 -C 9 alkanes, C 4 -C 6 ethers or mixtures thereof. The dC 4 alcohol includes, but is not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, and sec-butanol, and the C 3 -C 5 ketone includes, but is not limited to, acetone and methyl ethyl ketone, the C 4 - C 5 esters include, but are not limited to ethyl acetate and isopropyl acetate, a C 6 -C 9 alkanes include but are not limited to, n-hexane, n-heptane and methylcyclohexane, a C 4 -C 6 ethers comprising But not limited to diethyl ether, diisopropyl ether and methyl tert-butyl ether; The solvent is methanol, acetone, ethyl acetate, n-heptane, methyl tert-butyl ether or a mixture thereof; more preferably ethyl acetate. Preferably, the concentration of afatinib in a soluble solvent is 10 mg/ml to a saturated solution of afatinib in the solvent. Preferably, the molar ratio of afatinib to 2-naphthalenesulfonic acid is 1:2-1:3. Preferably, the operating temperature of the preparation method is room temperature.
所述 Nsl晶型阿法替尼二 2-萘磺酸盐的另一种制备方法， 包括以下步骤： 将前述制备方 法得到的阿法替尼二 2-萘磺酸盐在有机溶剂中形成浆液并搅拌，该浆液在 -10-50°C下保持 1〜 72小时， 进而除去溶剂， 其中所述有机溶剂选自甲醇、 丙酮、 乙腈、 乙酸乙酯、 正庚烷、 甲 基叔丁基醚或其混合物。 优选所述制备方法的操作温度为室温。  The preparation method of the Nsl crystal form afatinib bis 2-naphthalene sulfonate comprises the following steps: preparing the afatinib di 2-naphthalene sulfonate obtained by the above preparation method into a slurry in an organic solvent And stirring, the slurry is maintained at -10 to 50 ° C for 1 to 72 hours, thereby removing the solvent, wherein the organic solvent is selected from the group consisting of methanol, acetone, acetonitrile, ethyl acetate, n-heptane, methyl tert-butyl ether Or a mixture thereof. Preferably, the operating temperature of the preparation method is room temperature.
与现有技术比较， 尤其是与现有技术的阿法替尼二马来酸盐或其晶型比较， 阿法替尼二 2- 萘碩酸盐或 Nsl晶型阿法替尼二 2-萘碩酸盐具有一种或多种改进的特性，例如：更高的结晶度、 较好的溶解度、 溶解速度、 较佳的结晶形态、 较好的热稳定性和贮存稳定性、 较低的吸湿性、 较好的可流动性和有利的加工与处理特性。  Compared with the prior art, in particular, compared with the prior art afatinib dimaleate or its crystal form, afatinib di 2-naphthoate or Nsl crystal form afatinib II 2 Naphthalene acid salts have one or more improved properties such as higher crystallinity, better solubility, dissolution rate, preferred crystalline morphology, better thermal stability and storage stability, lower Hygroscopicity, good flowability and advantageous processing and handling characteristics.
特别是 Nsl晶型阿法替尼二 2-萘磺酸具有以下有益性质： 其分解温度为 249.1 °C， 相对于 阿法替尼二马来酸盐现有技术晶型的分解温度 164.1°C， 具有更高的热稳定性。 上述有益性质 表明， 与现有技术的阿法替尼二马来酸盐或其晶型相比， 本发明的阿法替尼二 2-萘磺酸或 Nsl 晶型阿法替尼二 2-萘磺酸具有多种优势性能，应用效果可更好，适合作为药物制剂的活性成分。 活性成分具有更高的热稳定性， 能够更好地对抗药物制造和 /或存储等过程中由环境温度等因 素引起的活性成分含量不均 、纯度降低和杂质增加等问题， 降低由此带来的疗效下降风险和 安全风险， 并有利于药物制造中的准确定量、 提高制剂均一性以及后期的储存和运输。  In particular, the Nsl crystal form afatinib bis 2-naphthalene sulfonic acid has the following beneficial properties: its decomposition temperature is 249.1 ° C, and the decomposition temperature of the prior art crystal form relative to afatinib dimaleate is 164.1 ° C. , with higher thermal stability. The above beneficial properties indicate that the afatinib di 2-naphthalenesulfonic acid or the Nsl crystalline form of afatinib ii-2 of the present invention is compared with the prior art afatinib dimaleate or a crystalline form thereof. Naphthalene sulfonic acid has a variety of advantageous properties, and the application effect is better, and is suitable as an active ingredient of a pharmaceutical preparation. The active ingredient has higher thermal stability, and can better prevent problems such as uneven content of active ingredients, decrease in purity, and increase in impurities caused by factors such as ambient temperature during the manufacture and/or storage of the drug, thereby reducing the The efficacy reduces risk and safety risks, and facilitates accurate quantification in drug manufacturing, improved formulation uniformity, and later storage and transportation.
本发明的内容之六是提供阿法替尼二氨基磺酸盐及其晶型、 以及它们的制备方法。  A sixth aspect of the present invention provides afatinib diamino sulfonate and a crystalline form thereof, and a process for the preparation thereof.
经 HPLC检测， 所述阿法替尼二氨基磺酸盐中阿法替尼游离碱的实际含量为 70.9% (不 计溶剂的量）， 阿法替尼和氨基磺酸以 1 :2 摩尔比形成的化合物中阿法替尼的理论含量为 71.5%, 因此本发明所述阿法替尼二氨基磺酸盐中阿法替尼和氨基磺酸以 1 :2摩尔比成盐， 其 结构式如下：  The actual content of afatinib free base in the afatinib diamino sulfonate was 70.9% (excluding the amount of solvent), and the afatinib and sulfamic acid were formed in a 1:2 molar ratio. The theoretical content of afatinib in the compound is 71.5%. Therefore, the afatinib diaminosulphonate of the present invention has a salt of afatinib and sulfamic acid in a molar ratio of 1:2, and the structural formula is as follows:
Figure imgf000012_0001
Figure imgf000012_0001
所述阿法替尼二氨基磺酸盐的制备方法， 包括以下步骤： 分别形成阿法替尼可溶溶剂中的 溶液体系和氨基磺酸在有机溶剂中的混悬液体系， 阿法替尼和氨基碩酸的摩尔比为 1 :2-1 :4， 混 合两个体系形成浆液， 然后除去溶剂。 优选所述可溶溶剂或有机溶剂为腈类、 醇类、 酮类、 酯 类、 烷烃类、 醚类或其混合物； 进一步优选为乙腈、 甲醇、 丙酮、 乙酸乙酯、 正庚烷或甲基叔 丁基醚。 优选采用旋干法除去溶剂。  The preparation method of the afatinib diamino sulfonate comprises the following steps: respectively forming a solution system in a fatinib soluble solvent and a suspension system of sulfamic acid in an organic solvent, afatinib The molar ratio to the amino acid was 1:2-1:4, and the two systems were mixed to form a slurry, and then the solvent was removed. Preferably, the soluble solvent or organic solvent is a nitrile, an alcohol, a ketone, an ester, an alkane, an ether or a mixture thereof; further preferably acetonitrile, methanol, acetone, ethyl acetate, n-heptane or methyl Tert-butyl ether. The solvent is preferably removed by spin-drying.
优选地， 所述阿法替尼二氨基磺酸盐为 S1 晶型的阿法替尼二氨基磺酸盐， 使用 Cu-Ka 辐射， 其 X射线粉末衍射图谱在衍射角 2 Θ为 5.3±0.2。、 10.7±0.2。、 13.2±0.2。、 21.5±0.2°、 22.3±0.2。、 25.5±0.2。和 26.1±0.2。处具有特征峰。  Preferably, the afatinib diamino sulfonate is an alfatinib diamino sulfonate of the S1 crystal form, using Cu-Ka radiation, and the X-ray powder diffraction pattern has a diffraction angle of 2 Θ of 5.3 ± 0.2. . , 10.7 ± 0.2. , 13.2 ± 0.2. , 21.5 ± 0.2 °, 22.3 ± 0.2. , 25.5 ± 0.2. And 26.1 ± 0.2. There are characteristic peaks.
进一步地， 所述 S1 晶型阿法替尼二氨基磺酸盐， 其 X射线粉末衍射图谱在衍射角 2 Θ 为 5.3±0.2。、 10.7±0.2。、 11.0±0.2。、 12.3±0.2。、 13.2±0.2。、 13.6±0.2。、 17.1±0.2。、 20.2±0.2。、 21.5±0.2。、 22.3±0.2。、 25.5±0.2°和 26.1±0.2°处具有特征峰。  Further, the S1 crystal form afatinib diamino sulfonate has an X-ray powder diffraction pattern at a diffraction angle of 2 Θ of 5.3 ± 0.2. , 10.7 ± 0.2. , 11.0 ± 0.2. , 12.3 ± 0.2. , 13.2 ± 0.2. , 13.6 ± 0.2. , 17.1 ± 0.2. , 20.2 ± 0.2. , 21.5 ± 0.2. , 22.3 ± 0.2. Characteristic peaks at 25.5±0.2° and 26.1±0.2°.
更进一步地， 所述 S1 晶型阿法替尼二氨基磺酸盐， 其 X射线粉末衍射图的衍射角 2 Θ 特征峰及其相对强度如下：  Further, the S1 crystal form afatinib diamino sulfonate, the diffraction angle 2 Θ characteristic peak of the X-ray powder diffraction pattern and its relative intensity are as follows:
衍射角 2Θ 相对强度％  Diffraction angle 2Θ relative intensity%
5.3±0.2° 65.4  5.3 ± 0.2 ° 65.4
10.7±0.2° 42.4  10.7±0.2° 42.4
1 1.0±0.2° 15.7  1 1.0±0.2° 15.7
12.3±0.2° 13.5  12.3±0.2° 13.5
12.9±0.2° 10.1 13.2±0.2° 26. 1 12.9±0.2° 10.1 13.2±0.2° 26. 1
13.6±0.2° 12.0  13.6 ± 0.2 ° 12.0
17. 1±0.2° 17.0  17. 1±0.2° 17.0
19.0±0.2° 10. 1  19.0±0.2° 10. 1
20.2±0.2° 19.3  20.2 ± 0.2 ° 19.3
21.5±0.2° 22.4  21.5±0.2° 22.4
22.3±0.2° 22.2  22.3 ± 0.2 ° 22.2
23.0±0.2° 1 1.2  23.0±0.2° 1 1.2
25.5±0.2° 100.0  25.5 ± 0.2 ° 100.0
26. 1±0.2° 53.2  26. 1±0.2° 53.2
非限制性地， 所述 S I晶型阿法替尼二氨基磺酸盐的一个典型实例具有如图 42所示的 X 射线粉末衍射图谱。  Without limitation, a typical example of the S I crystalline form of afatinib diamino sulfonate has an X-ray powder diffraction pattern as shown in FIG.
所述 S 1晶型阿法替尼二氨基磺酸盐， 其傅里叶红外光谱在波数为 1640、 1575、 1528、 1497、 1450、 1233、 1159、 1042和 776cm_1处具有特征峰。 The S 1 crystal form afatinib diamino sulfonate has a Fourier transform infrared spectrum having characteristic peaks at wave numbers of 1640, 1575, 1528, 1497, 1450, 1233, 1159, 1042 and 776 cm _1 .
所述 S 1晶型阿法替尼二氨基磺酸盐， 其拉曼光谱在波数为 1656、 1606、 1548、 1490、 1401、 1374、 1297、 1215和 782cm-1处具有特征峰。 The S 1 crystal form afatinib diamino sulfonate has a Raman spectrum having characteristic peaks at wave numbers of 1656, 1606, 1548, 1490, 1401, 1374, 1297, 1215 and 782 cm -1 .
所述 S 1 晶型阿法替尼二氨基磺酸盐的一种制备方法， 包括以下步骤： 分别形成阿法替 尼在可溶溶剂中的溶液体系和氨基磺酸在有机溶剂中的混悬液体系， 阿法替尼和氨基磺酸的 摩尔比为 1 :2-1 :4， 混合两个体系形成浆液并搅拌， 在 -10-50°C下保持 1-48小时， 进而除去溶 剂， 其中所述可溶溶剂或有机溶剂选自 C2-C4腈、 d-C4醇、 C3-C5酮、 C4-C5酯、 C6-C9烷烃、 C4-C6醚或其混合物。 所述 C2-C4腈包括但不限于乙腈， 所述 d-C4醇包括但不限于甲醇、 乙 醇、 正丙醇、 异丙醇、 正丁醇和仲丁醇， 所述 C3-C5酮包括但不限于丙酮和丁酮， 所述 C4-C5 酯包括但不限于乙酸乙酯和乙酸异丙酯， 所述 C6-C9烷烃包括但不限于正己烷、 正庚烷和甲 基环己烷， 所述 C4-C6醚包括但不限于乙醚、 异丙醚和甲基叔丁基醚； 优选所述可溶溶剂或 有机溶剂为乙腈、 甲醇、 丙酮、 乙酸乙酯、 正庚烷、 甲基叔丁基醚或其混合物； 更优选为乙 腈或乙酸乙酯。 优选阿法替尼在可溶溶剂中的浓度为 10毫克 /毫升至该溶剂下阿法替尼的饱 和溶液。优选阿法替尼和氨基磺酸的摩尔比为 1 :2-1 :3。优选所述制备方法的操作温度为室温。 A preparation method of the S 1 crystal form afatinib diamino sulfonate comprises the following steps: respectively forming a solution system of afatinib in a soluble solvent and suspending the sulfamic acid in an organic solvent The liquid system, the molar ratio of afatinib to sulfamic acid is 1:2-1:4, the two systems are mixed to form a slurry and stirred, and kept at -10 to 50 ° C for 1-48 hours, thereby removing the solvent. Wherein the soluble solvent or organic solvent is selected from the group consisting of C 2 -C 4 nitriles, dC 4 alcohols, C 3 -C 5 ketones, C 4 -C 5 esters, C 6 -C 9 alkanes, C 4 -C 6 ethers or Its mixture. The C 2 -C 4 nitrile includes, but is not limited to, acetonitrile, and the dC 4 alcohol includes, but is not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, and sec-butanol, the C 3 -C 5 ketone including but not limited to, acetone and methyl ethyl ketone, the C 4 -C 5 esters include, but are not limited to ethyl acetate and isopropyl acetate, a C 6 -C 9 alkanes include but are not limited to, n-hexane, n-heptane and a The cyclohexane, the C 4 -C 6 ether includes, but is not limited to, diethyl ether, isopropyl ether and methyl tert-butyl ether; preferably the soluble solvent or organic solvent is acetonitrile, methanol, acetone, ethyl acetate, n-Heptane, methyl tert-butyl ether or a mixture thereof; more preferably acetonitrile or ethyl acetate. Preferably, the concentration of afatinib in a soluble solvent is 10 mg/ml to a saturated solution of afatinib in the solvent. Preferably, the molar ratio of afatinib to sulfamic acid is 1:2-1:3. Preferably, the operating temperature of the preparation method is room temperature.
所述 S 1 晶型阿法替尼二氨基磺酸盐的另一种制备方法， 包括以下步骤： 将前述方法制 成的阿法替尼二氨基磺酸盐在有机溶剂中形成浆液并搅拌， 该浆液在 -10-50°C下保持 1〜72 小时， 进而除去溶剂， 其中所述有机溶剂选自甲醇、 丙酮、 乙腈、 乙酸乙酯、 正庚烷、 甲基 叔丁基醚或其混合物。 优选所述制备方法的操作温度为室温。  Another preparation method of the S 1 crystal form afatinib diamino sulfonate comprises the following steps: preparing the afatinib diamino sulfonate prepared by the foregoing method into a slurry in an organic solvent and stirring, The slurry is maintained at -10 to 50 ° C for 1 to 72 hours to further remove the solvent, wherein the organic solvent is selected from the group consisting of methanol, acetone, acetonitrile, ethyl acetate, n-heptane, methyl t-butyl ether or a mixture thereof . Preferably, the operating temperature of the preparation method is room temperature.
与现有技术比较， 尤其是与已知的阿法替尼二马来酸盐或其晶型比较， 阿法替尼二氨基 磺酸盐或 S 1晶型阿法替尼二氨基磺酸盐具有一种或多种改进的特性， 例如： 更高的结晶度、 较好的溶解度、 溶解速度、较佳的结晶形态、较好的热稳定性和贮存稳定性、较低的吸湿性、 较好的可流动性和有利的加工与处理特性。  Compared with the prior art, in particular, compared with the known afatinib dimaleate or its crystal form, afatinib diamino sulfonate or S 1 crystal form afatinib diamino sulfonate Has one or more improved properties, such as: higher crystallinity, better solubility, dissolution rate, better crystalline morphology, better thermal stability and storage stability, lower hygroscopicity, Good flowability and favorable processing and handling characteristics.
特别是 S 1晶型阿法替尼二氨基磺酸盐具有以下有益性质：  In particular, the S 1 crystalline form of afatinib diamino sulfonate has the following beneficial properties:
1 ) 室温下水中的溶解度为 138.3mg/ml，相对于阿法替尼二马来酸盐现有技术晶型在 相同条件下的溶解度 7.5mg/ml， 具有更高的溶解性；  1) The solubility in water at room temperature is 138.3 mg/ml, and the solubility of the prior art crystal form of afatinib dimaleate under the same conditions is 7.5 mg/ml, which has higher solubility;
2) 分解温度为 246.3 °C，相对于阿法替尼二马来酸盐现有技术晶型的分解温度 164.1 °C， 具有更好的热稳定性。  2) The decomposition temperature is 246.3 °C, which has better thermal stability than the decomposition temperature of the prior art crystal form of afatinib dimaleate 164.1 °C.
上述有益性质表明， 与现有技术阿法替尼二马来酸盐或其晶型相比， 本发明的阿法替尼二 氨基磺酸盐或 S 1晶型阿法替尼二氨基磺酸盐具有多种优势性能， 应用效果可更好， 适合作为 药物制剂的活性成分。活性成分更高的溶解性有利于提高药物的生物利用度，进而对药效产生 积极影响； 活性成分具有更高的热稳定性， 能够更好地对抗药物制造和 /或存储等过程中由环 境温度等因素引起的活性成分含量不均 、纯度降低和杂质增加等问题， 降低由此带来的疗效 下降风险和安全风险，并有利于药物制造中的准确定量、提高制剂均一性以及后期的储存和运 输。 本发明的内容之七是提供阿法替尼二 D-葡萄糖酸盐及其晶型、 以及它们的制备方法。 经 HPLC检测，所述阿法替尼二 D-葡萄糖酸盐中阿法替尼游离碱的实际含量为 54.4% (不 计溶剂的量）， 阿法替尼和 D-葡萄糖酸以 1 :2摩尔比形成的化合物中阿法替尼的理论含量为 55.3%, 因此本发明所述阿法替尼二 D-葡萄糖酸盐中阿法替尼和 D-葡萄糖酸以 1 :2摩尔比成 盐， 其结构式如下： The above beneficial properties indicate that the afatinib diamino sulfonate or the S 1 crystalline form of afatinib diamino sulfonic acid of the present invention is compared to the prior art afatinib dimaleate or a crystalline form thereof. Salt has a variety of advantageous properties, and the application effect is better, and it is suitable as an active ingredient of a pharmaceutical preparation. The higher solubility of the active ingredient is beneficial to improve the bioavailability of the drug, and thus has a positive effect on the efficacy; the active ingredient has higher thermal stability and can better resist the process of manufacturing and/or storage of the drug by the environment. Problems such as uneven content of active ingredients, decreased purity and increased impurities caused by temperature and other factors, reducing the risk and safety risks of the resulting therapeutic effects, and facilitating accurate quantification in drug manufacturing, improving formulation uniformity and later storage. And transportation. Seventh aspect of the present invention provides afatinib di D-gluconate and a crystal form thereof, and a process for the preparation thereof. The actual content of afatinib free base in the afatinib di D-gluconate was 54.4% (excluding the amount of solvent) by HPLC, and 1 : 2 moles of afatinib and D-gluconic acid. The theoretical content of afatinib in the formed compound is 55.3%, so that the afatinib di D-gluconate in the afatinib di D-gluconate of the present invention forms a salt in a molar ratio of 1:2. Its structural formula is as follows:
Figure imgf000014_0001
Figure imgf000014_0001
所述阿法替尼二 D-葡萄糖酸盐的制备方法， 包括以下步骤： 形成阿法替尼在可溶溶剂中 的溶液， 阿法替尼和 D-葡萄糖酸的摩尔比为 1 :2-1 :4， 将阿法替尼在可溶溶剂中的溶液和 D- 葡萄糖酸水溶液混合形成浆液， 然后除去溶剂。 优选所述可溶溶剂为腈类、 醇类、 酮类、 酯 类、 烷烃类、 醚类或其混合物； 进一步优选为乙腈、 甲醇、 丙酮、 乙酸乙酯、 正庚烷或甲基 叔丁基醚。 优选采用旋干法除去溶剂。 优选 D-葡萄糖酸水溶液的浓度为 50%。  The preparation method of the afatinib di D-gluconate comprises the following steps: forming a solution of afatinib in a soluble solvent, the molar ratio of afatinib to D-gluconic acid is 1:2- 1 : 4, a solution of afatinib in a soluble solvent and an aqueous D-gluconic acid solution were mixed to form a slurry, and then the solvent was removed. Preferably, the soluble solvent is a nitrile, an alcohol, a ketone, an ester, an alkane, an ether or a mixture thereof; further preferably acetonitrile, methanol, acetone, ethyl acetate, n-heptane or methyl t-butyl ether. The solvent is preferably removed by spin-drying. Preferably, the concentration of the aqueous D-gluconic acid solution is 50%.
优选地， 所述阿法替尼二 D-葡萄糖酸盐为 G1 晶型的阿法替尼二 D-葡萄糖酸盐， 使用 Cu-Κα辐射，其 X射线粉末衍射图谱在衍射角 2 Θ为 4.9±0.2。、 5.5±0.2。、 10.0±0.2。、 13.0±0.2。、 25.3±0.2。和 25.9±0.2。处具有特征峰。  Preferably, the afatinib di D-gluconate is a G1 crystal form of afatinib di D-gluconate, using Cu-Κα radiation, and the X-ray powder diffraction pattern is 4.9 at a diffraction angle of 2 Θ ±0.2. , 5.5 ± 0.2. , 10.0 ± 0.2. , 13.0 ± 0.2. , 25.3 ± 0.2. And 25.9 ± 0.2. There are characteristic peaks.
进一步地， 所述 G1晶型阿法替尼二 D-葡萄糖酸盐， 其 X射线粉末衍射图谱在衍射角 2 Θ为 4.9±0.2。、 5.5±0.2。、 6.1±0.2。、 9.6±0.2。、 10.0±0.2。、 13.0±0.2。、 17.1±0.2。、 19.6±0.2。、 20.0±0.2。、 20.3±0.2。、 25.3±0.2。和 25.9±0.2。处具有特征峰。  Further, the G1 crystal form of afatinib di D-gluconate has an X-ray powder diffraction pattern at a diffraction angle of 2 Θ of 4.9 ± 0.2. , 5.5 ± 0.2. , 6.1 ± 0.2. , 9.6 ± 0.2. , 10.0 ± 0.2. , 13.0 ± 0.2. , 17.1 ± 0.2. , 19.6 ± 0.2. , 20.0 ± 0.2. , 20.3 ± 0.2. , 25.3 ± 0.2. And 25.9 ± 0.2. There are characteristic peaks.
更进一步地， 所述 G1晶型阿法替尼二 D-葡萄糖酸盐， 其 X射线粉末衍射图的衍射角 2 Θ 特征峰及其相对强度如下：  Further, the G1 crystal form of afatinib di D-gluconate, the diffraction angle of the X-ray powder diffraction pattern 2 Θ characteristic peak and its relative intensity are as follows:
衍射角 2Θ 相对强度％  Diffraction angle 2Θ relative intensity%
4.9±0.2° 60.6  4.9±0.2° 60.6
5.5±0.2° 23.8  5.5±0.2° 23.8
6. 1±0.2° 17.4  6. 1±0.2° 17.4
8.5±0.2° 14. 1  8.5±0.2° 14. 1
9.6±0.2° 18.5  9.6±0.2° 18.5
10. .0±0. .2° 44.4  10. .0±0. .2° 44.4
12. . 1±0. .2° 14.7  12. 1±0. .2° 14.7
13. .0±0. .2° 26.8  13. .0±0. .2° 26.8
15. .2±0. .2° 10.3  15. .2±0. .2° 10.3
17. . 1±0. .2° 29.4  17. .1±0. .2° 29.4
18. .8±0. .2° 15.6  18. .8±0. .2° 15.6
19. .6±0. .2° 21.8  19. .6±0. .2° 21.8
20. .0±0. .2° 33.5  20. .0±0. .2° 33.5
20. .3±0. .2° 33.8  20. .3±0. .2° 33.8
22. .3±0. .2° 1 1.2  22. .3±0. .2° 1 1.2
25. .3±0. .2° 100.0  25. .3±0. .2° 100.0
25. .9±0. .2° 53.2  25. .9±0. .2° 53.2
26. .6±0. .2° 1 1.8  26. .6±0. .2° 1 1.8
27. .3±0. .2° 13.8  27. .3±0. .2° 13.8
27. .7±0. .2° 1 1.8  27. .7±0. .2° 1 1.8
非限制性地， 所述 G1 晶型阿法替尼二 D-葡萄糖酸盐的一个典型实例具有如图 47所示 的 X射线粉末衍射图谱。 所述 Gl晶型阿法替尼二 D-葡萄糖酸盐，其傅里叶红外光谱在波数为 1626、 1578、 1538、 1497、 1453、 1237、 1209、 1050和 777cm-1处具有特征峰。 Without limitation, a typical example of the G1 crystal form afatinib di D-gluconate has an X-ray powder diffraction pattern as shown in FIG. The Gl crystal form afatinib di D-gluconate has a Fourier transform infrared spectrum having characteristic peaks at wave numbers of 1626, 1578, 1538, 1497, 1453, 1237, 1209, 1050 and 777 cm -1 .
所述 G1晶型阿法替尼二 D-葡萄糖酸盐， 其拉曼光谱在波数为 1656、 1608、 1546、 1400、 1370、 1300、 1215和 δΐ η·1处具有特征峰。 The G1 crystal form of afatinib di D-gluconate has a Raman spectrum with characteristic peaks at wavenumbers of 1656, 1608, 1546, 1400, 1370, 1300, 1215 and δΐ η· 1 .
所述 G1晶型阿法替尼二 D-葡萄糖酸盐的一种制备方法， 包括以下步骤： 形成阿法替尼在 可溶溶剂中的溶液， 阿法替尼和 D-葡萄糖酸的摩尔比为 1:2-1:4， 将阿法替尼在可溶溶剂中的 溶液和 D-葡萄糖酸水溶液混合形成浆液并搅拌， 在 -10-50°C下保持 1-48小时， 进而除去溶剂， 其中所述可溶溶剂选自 C2-C4腈、 d-C4醇、 C3-C5酮、 C4-C5酯、 C6-C9烷烃、 硝基取代的 d-C3 烷烃、 C4-C6醚或其混合物。 所述 C2-C4腈包括但不限于乙腈， 所述 d-C4醇包括但不限于甲醇、 乙醇、 正丙醇、 异丙醇、 正丁醇和仲丁醇， 所述 C3-C5酮包括但不限于丙酮和丁酮， 所述 C4-C5 酯包括但不限于乙酸乙酯和乙酸异丙酯，所述 C6-C9烷烃包括但不限于正己烷、正庚烷和甲基环 己烷， 所述硝基取代的 d-C3烷烃包括但不限于硝基甲烷， 所述 C4-C6醚包括但不限于乙醚、 异 丙醚和甲基叔丁基醚； 优选所述可溶溶剂为乙酸乙酯、 乙腈、 硝基甲烷、 甲醇、 丙酮、 正庚烷、 甲基叔丁基醚或其混合物； 更优选为乙酸乙酯。 优选阿法替尼在可溶溶剂中的浓度为 10 毫克 / 毫升至该溶剂下阿法替尼的饱和溶液。 优选阿法替尼和 D-葡萄糖酸的摩尔比为 1:2-1:3。 优选所 述制备方法的操作温度为室温。 优选 D-葡萄糖酸水溶液的浓度为 50%。 A preparation method of the G1 crystal form afatinib di D-gluconate comprises the following steps: forming a solution of afatinib in a soluble solvent, a molar ratio of afatinib to D-gluconic acid For 1:2-1:4, a solution of afatinib in a soluble solvent and a D-gluconic acid aqueous solution are mixed to form a slurry and stirred, and kept at -10 to 50 ° C for 1-48 hours, thereby removing the solvent. Wherein the soluble solvent is selected from the group consisting of C 2 -C 4 nitriles, dC 4 alcohols, C 3 -C 5 ketones, C 4 -C 5 esters, C 6 -C 9 alkanes, nitro-substituted dC 3 alkanes, C 4- C 6 ether or a mixture thereof. The C 2 -C 4 nitrile includes, but is not limited to, acetonitrile, and the dC 4 alcohol includes, but is not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, and sec-butanol, the C 3 -C 5 ketone including but not limited to, acetone and methyl ethyl ketone, the C 4 -C 5 esters include, but are not limited to ethyl acetate and isopropyl acetate, a C 6 -C 9 alkanes include but are not limited to, n-hexane, n-heptane and a The cyclohexane, the nitro-substituted dC 3 alkane includes, but is not limited to, nitromethane, and the C 4 -C 6 ether includes, but is not limited to, diethyl ether, isopropyl ether, and methyl tert-butyl ether; The soluble solvent is ethyl acetate, acetonitrile, nitromethane, methanol, acetone, n-heptane, methyl t-butyl ether or a mixture thereof; more preferably ethyl acetate. Preferably, the concentration of afatinib in a soluble solvent is 10 mg/ml to a saturated solution of afatinib in the solvent. Preferably, the molar ratio of afatinib to D-gluconic acid is 1:2-1:3. Preferably, the operating temperature of the preparation method is room temperature. Preferably, the concentration of the D-gluconic acid aqueous solution is 50%.
所述 G1晶型阿法替尼二 D-葡萄糖酸盐的另一种制备方法， 包括以下步骤： 将前述制备 方法得到的阿法替尼二 D-葡萄糖酸盐在有机溶剂中形成浆液并搅拌， 该浆液在 -10-50°C下保 持 1〜72小时， 进而除去溶剂， 其中所述有机溶剂选自甲醇、 乙腈、 乙酸乙酯、 硝基甲烷、 丙酮、 正庚烷、 甲基叔丁基醚或其混合物。 优选所述制备方法的操作温度为室温。  Another preparation method of the G1 crystal form afatinib di D-gluconate comprises the following steps: the aftinib di D-gluconate obtained by the above preparation method is slurried and stirred in an organic solvent. The slurry is maintained at -10 to 50 ° C for 1 to 72 hours to further remove the solvent, wherein the organic solvent is selected from the group consisting of methanol, acetonitrile, ethyl acetate, nitromethane, acetone, n-heptane, methyl tert-butyl Ether or a mixture thereof. Preferably, the operating temperature of the preparation method is room temperature.
与现有技术比较， 尤其是与现有技术的阿法替尼二马来酸盐或其晶型比较， 阿法替尼二 D- 葡萄糖酸盐或 G1晶型阿法替尼二 D-葡萄糖酸盐具有一种或多种改进的特性， 例如： 更高的结 晶度、 较好的溶解度、 溶解速度、 较佳的结晶形态、 较好的热稳定性和贮存稳定性、 较低的吸 湿性、 较好的可流动性和有利的加工与处理特性。  Compared with the prior art, especially compared with the prior art afatinib dimaleate or its crystal form, afatinib di D-gluconate or G1 crystal form afatinib di D-glucose The acid salt has one or more improved properties such as: higher crystallinity, better solubility, dissolution rate, better crystalline morphology, better thermal and storage stability, lower moisture absorption. , good flowability and favorable processing and processing characteristics.
特别是 G1晶型阿法替尼二 D-葡萄糖酸盐具有以下有益性质：  In particular, the G1 crystalline form of afatinib di D-gluconate has the following beneficial properties:
1 ) 其熔点为 101.3°C， 低于阿法替尼二马来酸盐现有技术晶型的熔点 166.2°C， 可在很 低的温度下制备无定形物， 而无定形物有着较好的溶解性；  1) Its melting point is 101.3 ° C, lower than the melting point of the prior art crystal form of afatinib dimaleate 166.2 ° C, can prepare amorphous at very low temperature, and amorphous is better Solubility;
2) 根据文献《Handbook of Pharmaceutical Salts properties, Selection,and use》介绍， D- 葡萄糖酸与马来酸相比有着更低的毒性。  2) According to the literature "Handbook of Pharmaceutical Salts properties, Selection, and use", D-gluconic acid has lower toxicity than maleic acid.
上述有益性质表明， 与现有技术的阿法替尼二马来酸盐或其晶型相比， 本发明的阿法替尼 二 D-葡萄糖酸盐或 G1晶型阿法替尼二 D-葡萄糖酸盐具有多种优势性能， 应用效果可更好， 适合作为药物制剂的活性成分。活性成分更高的溶解性有利于提高药物的生物利用度，进而对 药效产生积极影响； 活性成分具有更低的毒性， 使得制剂的制造过程和药物的临床应用更安 全。  The above beneficial properties indicate that the afatinib di D-gluconate or the G1 crystal form afatinib di D- of the present invention is compared to the prior art afatinib dimaleate or a crystal form thereof. Gluconate has a variety of advantageous properties, and the application effect is better, and it is suitable as an active ingredient of a pharmaceutical preparation. The higher solubility of the active ingredient is beneficial to improve the bioavailability of the drug, which in turn has a positive effect on the efficacy; the active ingredient has lower toxicity, making the preparation process and the clinical application of the drug safer.
本发明的内容之八是提供阿法替尼二环己烷氨基碩酸盐及其晶型、 以及它们的制备方法。 经 HPLC检测，所述阿法替尼二环己烷氨基磺酸盐中阿法替尼游离碱的实际含量为 58.3% (不计溶剂的量）， 阿法替尼和环己烷氨基磺酸以 1 :2摩尔比形成的化合物中阿法替尼的理论 含量为 57.6%， 因此本发明所述阿法替尼二环己烷氨基磺酸盐中阿法替尼和环己烷氨基磺酸 以 1 :2摩尔比成盐， 其结构式如下：  Eighth of the present invention provides afatinib dicyclohexylamino stearate and a crystal form thereof, and a process for the preparation thereof. The actual content of afatinib free base in the afatinib dicyclohexyl sulfamate was 58.3% (excluding the amount of solvent), and afatinib and cyclohexane sulfamic acid were detected by HPLC. The theoretical content of afatinib in the compound formed by a molar ratio of 1 : 2 is 57.6%, and thus the afatinib dicyclohexyl sulfamate of the present invention has afatinib and cyclohexane sulfamic acid. The 1:2 molar ratio is salt, and its structural formula is as follows:
Figure imgf000015_0001
所述阿法替尼二环己烷氨基磺酸盐的制备方法， 包括以下步骤： 分别形成阿法替尼在可 溶溶剂中的溶液体系和环己烷氨基磺酸在有机溶剂中的悬浮液体系， 阿法替尼和环己烷氨基 磺酸的摩尔比为 1 :2-1 :4， 混合两个体系形成浆液， 然后除去溶剂。 优选所述可溶溶剂或有机 溶剂为腈类、 醇类、 酮类、 酯类、 烷烃类、 醚类或其混合物； 进一步优选为乙腈、 甲醇、 丙 酮、 乙酸乙酯、 正庚烷或甲基叔丁基醚。 优选采用旋干法除去溶剂。
Figure imgf000015_0001
The preparation method of the afatinib dicyclohexyl sulfamate comprises the following steps: respectively forming a solution system of afatinib in a soluble solvent and a suspension liquid of cyclohexanesulfamic acid in an organic solvent The molar ratio of afatinib to cyclohexanesulfamic acid was 1:2-1:4, and the two systems were mixed to form a slurry, and then the solvent was removed. Preferably, the soluble solvent or organic solvent is a nitrile, an alcohol, a ketone, an ester, an alkane, an ether or a mixture thereof; further preferably acetonitrile, methanol, acetone, ethyl acetate, n-heptane or methyl Tert-butyl ether. The solvent is preferably removed by spin-drying.
优选地，所述阿法替尼二环己烷氨基磺酸盐为 C1晶型的阿法替尼二环己烷氨基磺酸盐， 使用 Cu-Κα辐射， 其 X射线粉末衍射图谱在衍射角 2 Θ为 5.0±0.2。、 6.0±0.2。、 16.5±0.2。、 17.9±0.2。、 18.6±0.2。和 20.2±0.2。处具有特征峰。  Preferably, the afatinib dicyclohexyl sulfamate is a crystalline form of afatinib dicyclohexyl sulfamate, using Cu-Κα radiation, the X-ray powder diffraction pattern of the diffraction angle 2 Θ is 5.0±0.2. , 6.0 ± 0.2. , 16.5 ± 0.2. , 17.9 ± 0.2. , 18.6 ± 0.2. And 20.2 ± 0.2. There are characteristic peaks.
进一步地， 所述 C1晶型阿法替尼二环己烷氨基磺酸盐， 其 X射线粉末衍射图谱在衍射 角 2 Θ为 5.0±0.2。、 6.0±0.2。、 12.5±0.2。、 14.9±0.2。、 16.5±0.2。、 17.9±0.2。、 18.4±0.2。、 18.6±0.2。、 20.2±0.2。、 21.3±0.2。、 21.6±0.2。和 24.2±0.2。处具有特征峰。  Further, the C1 crystal form of afatinib dicyclohexyl sulfamate has an X-ray powder diffraction pattern at a diffraction angle of 2 Θ of 5.0 ± 0.2. , 6.0 ± 0.2. , 12.5 ± 0.2. , 14.9 ± 0.2. , 16.5 ± 0.2. , 17.9 ± 0.2. , 18.4 ± 0.2. , 18.6 ± 0.2. , 20.2 ± 0.2. , 21.3 ± 0.2. , 21.6 ± 0.2. And 24.2 ± 0.2. There are characteristic peaks.
更进一步地， 所述 C1晶型阿法替尼二环己烷氨基磺酸盐， 其 X射线粉末衍射图的衍射 角 2 Θ特征峰及其相对强度如下：  Further, the C1 crystal form afatinib dicyclohexyl sulfamate, the X-ray powder diffraction pattern has a diffraction angle 2 Θ characteristic peak and its relative intensity as follows:
衍射角 2Θ 相对强度％  Diffraction angle 2Θ relative intensity%
5.0±0.2° 100.0  5.0±0.2° 100.0
6.0±0.2° 27.1  6.0±0.2° 27.1
12.5±0.2° 9.6  12.5 ± 0.2 ° 9.6
14.9±0.2° 9.9  14.9±0.2° 9.9
16.5±0.2° 13.6  16.5±0.2° 13.6
17.9±0.2° 15.3  17.9±0.2° 15.3
18.4±0.2° 17.6  18.4±0.2° 17.6
18.6±0.2° 31.3  18.6±0.2° 31.3
19.5±0.2° 9.6  19.5±0.2° 9.6
20.2±0.2° 27.9  20.2 ± 0.2 ° 27.9
21.3±0.2° 12.2  21.3±0.2° 12.2
21.6±0.2° 13.1  21.6±0.2° 13.1
24.2±0.2° 12.9  24.2±0.2° 12.9
27.8±0.2° 10.2  27.8 ± 0.2 ° 10.2
非限制性地，所述 C1晶型阿法替尼二环己烷氨基磺酸盐的一个典型实例具有如图 53所 示的 X射线粉末衍射图谱。  Without limitation, a typical example of the C1 crystal form afatinib dicyclohexyl sulfamate has an X-ray powder diffraction pattern as shown in FIG.
所述 C1晶型阿法替尼二环己烷氨基磺酸盐，其傅里叶红外光谱在波数为 1637、 1577、 1540、 1498、 1453、 1204、 1157、 1029、 866和 775cm_1处具有特征峰。 The C1 crystalline form of afatinib dicyclohexyl sulfamate having a Fourier transform infrared spectrum having characteristics at wave numbers of 1637, 1577, 1540, 1498, 1453, 1204, 1157, 1029, 866 and 775 cm _1 peak.
所述 C1晶型阿法替尼二环己烷氨基磺酸盐， 其拉曼光谱在波数为 1662、 1609、 1543、 1401、 1372、 1291、 1209和 778cm 处具有特征峰。  The C1 crystal form of afatinib dicyclohexyl sulfamate has a Raman spectrum having characteristic peaks at wave numbers of 1662, 1609, 1543, 1401, 1372, 1291, 1209 and 778 cm.
所述 C1晶型阿法替尼二环己烷氨基磺酸盐的一种制备方法， 包括以下步骤：分别形成阿法 替尼在可溶溶剂中的溶液体系和环己烷氨基磺酸在有机溶剂的悬浮液体系， 阿法替尼和环己烷 氨基磺酸的摩尔比为 1 :2-1 :4， 混合两个体系形成浆液并搅拌， 在 -10-50°C下保持 1-48小时， 然 后除去溶剂， 其中所述可溶溶剂或有机溶剂选自 C2-C4腈、 d-C4醇、 C3-C5酮、 C4-C5酯、 C6-C9 烷烃、 C4-C6醚或其混合物。 所述 C2-C4腈包括但不限于乙腈， 所述 d-C4醇包括但不限于甲醇、 乙醇、 正丙醇、 异丙醇、 正丁醇和仲丁醇， 所述 C3-C5酮包括但不限于丙酮和丁酮， 所述 C4-C5 酯包括但不限于乙酸乙酯和乙酸异丙酯，所述 C6-C9烷烃包括但不限于正己烷、正庚烷和甲基环 己烷， 所述 C4-C6醚包括但不限于乙醚、 异丙醚和甲基叔丁基醚； 优选所述可溶溶剂或有机溶 剂为乙腈、 甲醇、 丙酮、 乙酸乙酯、 正庚烷、 甲基叔丁基醚或其混合物； 更优选为乙腈。 优选 阿法替尼在可溶溶剂中的浓度为 10毫克 /毫升至该溶剂下阿法替尼的饱和溶液。优选阿法替尼和 环己烷氨基碩酸的摩尔比为 1 :2-1 :3。 优选所述制备方法的操作温度为室温。 A preparation method of the C1 crystal form afatinib dicyclohexyl sulfamate comprises the following steps: respectively forming a solution system of afatinib in a soluble solvent and cyclohexane sulfamic acid in an organic Solvent suspension system, the molar ratio of afatinib to cyclohexane sulfamic acid is 1:2-1:4, mixing the two systems to form a slurry and stirring, maintaining 1-48 at -10-50 °C And then removing the solvent, wherein the soluble solvent or organic solvent is selected from the group consisting of C 2 -C 4 nitriles, dC 4 alcohols, C 3 -C 5 ketones, C 4 -C 5 esters, C 6 -C 9 alkanes, C 4- C 6 ether or a mixture thereof. The C 2 -C 4 nitrile includes, but is not limited to, acetonitrile, and the dC 4 alcohol includes, but is not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, and sec-butanol, the C 3 -C 5 ketone including but not limited to, acetone and methyl ethyl ketone, the C 4 -C 5 esters include, but are not limited to ethyl acetate and isopropyl acetate, a C 6 -C 9 alkanes include but are not limited to, n-hexane, n-heptane and a The cyclohexane, the C 4 -C 6 ether includes, but is not limited to, diethyl ether, isopropyl ether and methyl tert-butyl ether; preferably the soluble solvent or organic solvent is acetonitrile, methanol, acetone, ethyl acetate, n-Heptane, methyl tert-butyl ether or a mixture thereof; more preferably acetonitrile. Preferably, the concentration of afatinib in a soluble solvent is 10 mg/ml to a saturated solution of afatinib in the solvent. Preferably, the molar ratio of afatinib to cyclohexane amino acid is 1:2-1:3. Preferably, the operating temperature of the preparation method is room temperature.
所述 C1晶型阿法替尼二环己烷氨基磺酸盐的另一种制备方法， 包括以下步骤：将前述制备 方法得到的阿法替尼二环己烷氨基碩酸盐在有机溶剂中形成浆液并搅拌，该浆液在 -10-50°C下保 持 1〜72小时， 进而除去溶剂， 其中所述有机溶剂选自甲醇、 丙酮、 乙腈、 乙酸乙酯、 正庚烷、 甲基叔丁基醚或其混合物。 优选所述制备方法的操作温度为室温。 Another preparation method of the C1 crystal form afatinib dicyclohexyl sulfamate comprises the following steps: the afatinib dicyclohexane amino stearate obtained by the above preparation method is in an organic solvent Forming a slurry and stirring, the slurry is maintained at -10 to 50 ° C for 1 to 72 hours, thereby removing the solvent, wherein the organic solvent is selected from the group consisting of methanol, acetone, acetonitrile, ethyl acetate, n-heptane, Methyl tert-butyl ether or a mixture thereof. Preferably, the operating temperature of the preparation method is room temperature.
与现有技术比较， 尤其是与现有技术的阿法替尼二马来酸盐或其晶型比较， 阿法替尼二环 己烷氨基磺酸盐或 C1晶型阿法替尼二环己烷氨基碩酸盐具有一种或多种改进的特性，例如：更 高的结晶度、 较好的溶解度、 溶解速度、 较佳的结晶形态、 较好的热稳定性和贮存稳定性、 较 低的吸湿性、 较好的可流动性和有利的加工与处理特性。  Compared with the prior art, in particular, compared with the prior art afatinib dimaleate or its crystal form, afatinib dicyclohexyl sulfamate or C1 crystal form afatinib bicyclic The hexane amino acid salt has one or more improved properties such as higher crystallinity, better solubility, dissolution rate, better crystal morphology, better thermal stability and storage stability, Low hygroscopicity, good flowability and favorable processing and handling characteristics.
特别是 C1晶型阿法替尼二环己烷氨基磺酸盐具有以下有益性质：  In particular, the C1 crystalline form of afatinib dicyclohexyl sulfamate has the following beneficial properties:
1 ) 在室温下水中的溶解度为 63.1mg/ml， 相对于阿法替尼二马来酸盐现有技术晶型在相 同条件下的溶解度 7.5 mg/ml, 具有更高的溶解性；  1) The solubility in water at room temperature is 63.1 mg/ml, and the solubility of the prior art crystal form of afatinib dimaleate under the same conditions is 7.5 mg/ml, which has higher solubility;
2) 分解温度为 246.1 °C， 相对于阿法替尼二马来酸盐现有技术晶型的分解温度 164.1 °C， 具有更高的热稳定性。  2) The decomposition temperature is 246.1 °C, which has higher thermal stability than the decomposition temperature of the prior art crystal form of afatinib dimaleate 164.1 °C.
上述有益性质表明， 与现有技术阿法替尼二马来酸盐或其晶型相比， 本发明的阿法替尼二 环己烷氨基磺酸盐或 C1 晶型阿法替尼二环己烷氨基碩酸盐具有多种优势性能， 应用效果可更 好， 适合作为药物制剂的活性成分。 活性成分更高的溶解性有利于提高药物的生物利用度， 进 而对药效产生积极影响； 活性成分具有更高的热稳定性， 能够更好地对抗药物制造和 /或存储等 过程中由环境温度等因素引起的活性成分含量不均 、 纯度降低和杂质增加等问题， 降低由此 带来的疗效下降风险和安全风险， 并有利于药物制造中的准确定量、 提高制剂均一性以及后期 的储存和运输。  The above beneficial properties indicate that the afatinib dicyclohexyl sulfamate or the C1 crystal form of the afetidine ring of the present invention is compared with the prior art afatinib dimaleate or a crystal form thereof. Hexane amino acid salt has a variety of advantageous properties, and the application effect is better, and is suitable as an active ingredient of a pharmaceutical preparation. The higher solubility of the active ingredient is beneficial to improve the bioavailability of the drug, and thus has a positive effect on the efficacy; the active ingredient has higher thermal stability and can better resist the process of manufacturing and/or storage by the environment. Problems such as uneven content of active ingredients, decreased purity and increased impurities caused by factors such as temperature, reducing the risk and safety risks of the resulting therapeutic effects, and facilitating accurate quantification in drug manufacturing, improving uniformity of preparations, and later storage And transportation.
本发明的内容之九是提供阿法替尼二 4-氨基苯磺酸盐及其晶型、 以及它们的制备方法。 经 HPLC检测， 所述阿法替尼二 4-氨基苯磺酸盐中阿法替尼游离碱的实际含量为 59.1% (不计溶剂的量）， 阿法替尼和 4-氨基苯磺酸以 1 :2摩尔比形成的化合物中阿法替尼的理论含 量为 58.4%， 因此本发明所述阿法替尼二 4-氨基苯磺酸盐中阿法替尼和 4-氨基苯磺酸以 1 :2 摩尔比成盐， 其结构式  A ninth aspect of the present invention provides afatinib di 4-aminobenzenesulfonate and a crystal form thereof, and a process for the preparation thereof. The actual content of afatinib free base in the afatinib di 4-aminobenzenesulfonate was 59.1% (excluding the amount of solvent), and afatinib and 4-aminobenzenesulfonic acid were detected by HPLC. The theoretical content of afatinib in the compound formed by the molar ratio of 1 : 2 is 58.4%, and thus the afatinib di 4-aminobenzenesulfonate of the present invention is obtained by using afatinib and 4-aminobenzenesulfonic acid. 1 : 2 molar ratio to salt, its structural formula
Figure imgf000017_0001
Figure imgf000017_0001
所述阿法替尼二 4-氨基苯磺酸盐的制备方法， 包括以下步骤： 分别形成阿法替尼在可溶 溶剂中的溶液体系和 4-氨基苯磺酸在有机溶剂中的悬浮液体系， 阿法替尼和 4-氨基苯磺酸的 摩尔比为 1 :2-1 :4， 混合两个体系形成浆液， 然后除去溶剂。 优选所述可溶溶剂或有机溶剂为 腈类、 醇类、 酮类、 烷烃类、 醚类或其混合物； 进一步优选为乙腈、 甲醇、 丙酮、 乙酸乙酯、 正庚烷或甲基叔丁基醚。 优选采用旋干法除去溶剂。  The preparation method of the afatinib di 4-aminobenzenesulfonate comprises the following steps: respectively forming a solution system of afatinib in a soluble solvent and a suspension liquid of 4-aminobenzenesulfonic acid in an organic solvent; The molar ratio of afatinib to 4-aminobenzenesulfonic acid was 1:2-1:4, and the two systems were mixed to form a slurry, and then the solvent was removed. Preferably, the soluble solvent or organic solvent is a nitrile, an alcohol, a ketone, an alkane, an ether or a mixture thereof; further preferably acetonitrile, methanol, acetone, ethyl acetate, n-heptane or methyl t-butyl ether. The solvent is preferably removed by spin-drying.
优选地， 所述阿法替尼二 4-氨基苯磺酸盐为 A1晶型阿法替尼二 4-氨基苯磺酸盐， 使用 Cu-Κα辐射，其 X射线粉末衍射图谱在衍射角 2 Θ为 12.9±0.2。、17.1±0.2。、18.2±0.2。、23.8±0.2。、 24.5±0.2。和 25.7±0.2。处具有特征峰。  Preferably, the afatinib di 4-aminobenzenesulfonate is A1 crystal form afatinib di 4-aminobenzenesulfonate, using Cu-Κα radiation, and its X-ray powder diffraction pattern is at diffraction angle 2 The Θ is 12.9 ± 0.2. , 17.1 ± 0.2. , 18.2 ± 0.2. 23.8 ± 0.2. , 24.5 ± 0.2. And 25.7 ± 0.2. There are characteristic peaks.
进一步地， 所述 A1晶型阿法替尼二 4-氨基苯磺酸盐， 其 X射线粉末衍射图谱在衍射角 2 Θ为 5.6±0.2。、 12.9±0.2。、 17.1±0.2。、 18.2±0.2。、 21.3±0.2°、 23.8±0.2。、 24.5±0.2。、 25.7±0.2。、 27.6±0.2°和 34.3±0.2°处具有特征峰。  Further, the A1 crystal form of afatinib di 4-aminobenzenesulfonate has an X-ray powder diffraction pattern at a diffraction angle of 2 Θ of 5.6 ± 0.2. , 12.9 ± 0.2. , 17.1 ± 0.2. , 18.2 ± 0.2. , 21.3 ± 0.2 °, 23.8 ± 0.2. , 24.5 ± 0.2. , 25.7 ± 0.2. Characteristic peaks at 27.6±0.2° and 34.3±0.2°.
更进一步地， 所述 A1晶型阿法替尼二 4-氨基苯磺酸盐， 其 X射线粉末衍射图的衍射角 2 Θ特征峰及其相对强度如下：  Further, the A1 crystal form of afatinib di 4-aminobenzenesulfonate has a diffraction angle 2 Θ characteristic peak and its relative intensity in an X-ray powder diffraction pattern as follows:
衍射角 2Θ 相对强度％  Diffraction angle 2Θ relative intensity%
5.6±0.2° 10.5  5.6 ± 0.2 ° 10.5
12.9±0.2° 23.9  12.9±0.2° 23.9
17.1±0.2° 1 1.9  17.1±0.2° 1 1.9
18.2±0.2° 100.0 21.3±0.2° 12.9 18.2±0.2° 100.0 21.3±0.2° 12.9
23.8±0.2° 19.1  23.8±0.2° 19.1
24.5±0.2° 29.6  24.5 ± 0.2 ° 29.6
25.7±0.2° 23.1  25.7±0.2° 23.1
27.6±0.2° 18.3  27.6±0.2° 18.3
34.3±0.2° 16.1  34.3±0.2° 16.1
非限制性地，所述 Al晶型阿法替尼二 4-氨基苯磺酸盐的一个典型实例具有如图 58所示 的 X射线粉末衍射图谱。  Without limitation, a typical example of the Al crystalline form of afatinib di 4-aminobenzenesulfonate has an X-ray powder diffraction pattern as shown in Fig. 58.
所述 A1晶型阿法替尼二 4-氨基苯磺酸盐，其傅里叶红外光谱在波数为 1637、 1599、 1525、 1498、 1451、 1206、 1158、 1118、 1027和 694cm 处具有特征峰。  The A1 crystalline form of afatinib di 4-aminobenzenesulfonate has a Fourier transform infrared spectrum with characteristic peaks at wavenumbers of 1637, 1599, 1525, 1498, 1451, 1206, 1158, 1118, 1027 and 694 cm. .
所述 A1晶型阿法替尼二 4-氨基苯磺酸盐，其拉曼光谱在波数为 1657、 1644、 1546、 1499、 1400、 1371、 1297、 1208、 1122和 781cm 处具有特征峰。  The A1 crystalline form of afatinib di 4-aminobenzenesulfonate has a Raman spectrum having characteristic peaks at wavenumbers of 1657, 1644, 1546, 1499, 1400, 1371, 1297, 1208, 1122 and 781 cm.
所述 A1晶型阿法替尼二 4-氨基苯磺酸盐的一种制备方法， 包括以下步骤： 分别形成阿法 替尼在可溶溶剂中的溶液体系和 4-氨基苯磺酸在有机溶剂中的悬浮液体系， 阿法替尼和 4-氨 基苯磺酸的摩尔比为 1 :2-1 :4， 混合两个体系形成浆液并搅拌， 在 -10-50°C下保持 1-48 小时， 然后除去溶剂， 其中所述可溶溶剂或有机溶剂选自 C2-C4腈、 d-C4醇、 C3-C5酮、 C6-C9烷烃、 C4-C6醚或其混合物。所述 C2-C4腈包括但不限于乙腈，所述 d-C4醇包括但不限于甲醇、乙醇、 正丙醇、 异丙醇、 正丁醇和仲丁醇， 所述 C3-C5酮包括但不限于丙酮和丁酮， 所述 C6-C9烷烃 包括但不限于正己烷、 正庚烷和甲基环己烷， 所述 C4-C6醚包括但不限于乙醚、 异丙醚和甲基 叔丁基醚； 优选所述可溶溶剂或有机溶剂为乙腈、 甲醇、 丙酮、 正庚烷、 甲基叔丁基醚或其混 合物； 更优选为乙腈。 优选阿法替尼在可溶溶剂中的浓度为 10毫克 /毫升至该溶剂下阿法替尼 的饱和溶液。 优选阿法替尼和 4-氨基苯磺酸的摩尔比为 1 :2-1 :3。 优选所述制备方法的操作温 度为室温。 A preparation method of the A1 crystal form afatinib di 4-aminobenzenesulfonate comprises the following steps: respectively forming a solution system of afatinib in a soluble solvent and 4-aminobenzenesulfonic acid in an organic The suspension system in the solvent, the molar ratio of afatinib to 4-aminobenzenesulfonic acid is 1:2-1:4, mixing the two systems to form a slurry and stirring, maintaining 1- at -10-50 °C After 48 hours, the solvent is then removed, wherein the soluble solvent or organic solvent is selected from the group consisting of C 2 -C 4 nitriles, dC 4 alcohols, C 3 -C 5 ketones, C 6 -C 9 alkanes, C 4 -C 6 ethers or Its mixture. The C 2 -C 4 nitrile includes, but is not limited to, acetonitrile, and the dC 4 alcohol includes, but is not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, and sec-butanol, the C 3 -C 5 ketone Including but not limited to acetone and methyl ethyl ketone, the C 6 -C 9 alkane includes, but is not limited to, n-hexane, n-heptane and methylcyclohexane, and the C 4 -C 6 ether includes, but is not limited to, diethyl ether, isopropyl ether. Ether and methyl tert-butyl ether; preferably the soluble solvent or organic solvent is acetonitrile, methanol, acetone, n-heptane, methyl t-butyl ether or a mixture thereof; more preferably acetonitrile. Preferably, the concentration of afatinib in a soluble solvent is 10 mg/ml to a saturated solution of afatinib in the solvent. Preferably, the molar ratio of afatinib to 4-aminobenzenesulfonic acid is 1:2-1:3. Preferably, the operating temperature of the preparation method is room temperature.
所述 A1晶型阿法替尼二 4-氨基苯磺酸盐的另一种制备方法， 包括以下步骤： 将前述制 备方法得到的阿法替尼二 4-氨基苯磺酸盐在有机溶剂中形成浆液并搅拌， 该浆液在 -10-50°C 下保持 1〜72小时， 进而除去溶剂， 其中所述有机溶剂选自甲醇、 丙酮、 乙腈、 乙酸乙酯、 正庚烷、 甲基叔丁基醚或其混合物。 优选所述制备方法的操作温度为室温。  Another preparation method of the A1 crystal form afatinib di 4-aminobenzenesulfonate comprises the following steps: the afatinib di 4-aminobenzenesulfonate obtained by the above preparation method is in an organic solvent Forming a slurry and stirring, the slurry is maintained at -10 to 50 ° C for 1 to 72 hours, thereby removing the solvent, wherein the organic solvent is selected from the group consisting of methanol, acetone, acetonitrile, ethyl acetate, n-heptane, methyl tert-butyl Ether or a mixture thereof. Preferably, the operating temperature of the preparation method is room temperature.
与现有技术比较， 尤其是与现有技术阿法替尼二马来酸盐或其晶型比较， 阿法替尼二 4-氨基 苯碩酸盐或 A1晶型阿法替尼二 4-氨基苯碩酸盐具有一种或多种改进的特性， 例如： 更高的结晶 度、较好的溶解度、 溶解速度、较佳的结晶形态、较好的热稳定性和贮存稳定性、较低的吸湿性、 较好的可流动性和有利的加工与处理特性。  Compared with the prior art, especially compared with the prior art afatinib dimaleate or its crystal form, afatinib di 4-aminobenzene succinate or A1 crystal form afatinib 2-4 The aminobenzate salt has one or more improved properties such as: higher crystallinity, better solubility, dissolution rate, better crystalline morphology, better thermal stability and storage stability, lower Hygroscopicity, good flowability and advantageous processing and handling characteristics.
特别是 A1晶型阿法替尼二 4-氨基苯磺酸盐具有以下有益性质：  In particular, the A1 crystalline form of afatinib di 4-aminobenzenesulfonate has the following beneficial properties:
1 ) 在室温下水中的溶解度为 123.8mg/ml，相对于阿法替尼二马来酸盐现有技术晶型 在相同条件下的溶解度 7.5 mg/ml, 具有更高的溶解性。  1) The solubility in water at room temperature is 123.8 mg/ml, which has a higher solubility than the prior art crystalline form of afatinib dimaleate under the same conditions of 7.5 mg/ml.
2) 分解温度为 261.7°C，相对于阿法替尼二马来酸盐现有技术晶型的分解温度 164.1 °C， 具有更高的热稳定性。  2) The decomposition temperature is 261.7 ° C, which has higher thermal stability than the decomposition temperature of the prior art crystal form of afatinib dimaleate of 164.1 °C.
上述有益性质表明， 与现有技术阿法替尼二马来酸盐或其晶型相比， 本发明的阿法替尼二环 己烷氨基碩酸盐或 C1 晶型阿法替尼二环己烷氨基碩酸盐具有多种优势性能， 应用效果可更好， 适合作为药物制剂的活性成分。 活性成分更高的溶解性有利于提高药物的生物利用度， 进而对药 效产生积极影响； 活性成分具有更高的热稳定性， 能够更好地对抗药物制造和 /或存储等过程中由 环境温度等因素引起的活性成分含量不均匀、 纯度降低和杂质增加等问题， 降低由此带来的疗效 下降风险和安全风险，并有利于药物制造中的准确定量、提高制剂均一性以及后期的储存和运输。  The above beneficial properties indicate that the afatinib dicyclohexylamino stearate or the C1 crystal form afatinib bifuran of the present invention is compared with the prior art afatinib dimaleate or its crystal form. Hexane amino acid salt has a variety of advantageous properties, and the application effect is better, and is suitable as an active ingredient of a pharmaceutical preparation. The higher solubility of the active ingredient is beneficial to improve the bioavailability of the drug, and thus has a positive effect on the efficacy; the active ingredient has higher thermal stability and can better resist the process of manufacturing and/or storage by the environment. Temperature and other factors caused by uneven content of active ingredients, decreased purity and increased impurities, reduce the risk of reduced efficacy and safety risks, and facilitate accurate quantification in drug manufacturing, improve formulation uniformity and post-storage And transportation.
本发明的内容之十是提供阿法替尼甘醇酸盐及其晶型、 以及它们的制备方法。  A tenth aspect of the present invention provides afatinibanoate and a crystal form thereof, and a process for the preparation thereof.
经 HPLC检测， 所述阿法替尼甘醇酸盐中阿法替尼游离碱的实际含量为 85.4% (不计溶 剂的量）， 阿法替尼和甘醇酸以 1： 1摩尔比形成的化合物中阿法替尼的理论含量为 86.5%， 因 此所述阿法替尼甘醇酸盐中阿法替尼和甘醇酸以 1 :1摩尔比成盐， 其结构式如下：
Figure imgf000019_0001
The actual content of afatinib free base in the afatinibane glycolate was 85.4% (excluding the amount of solvent), and the afatinib and glycolic acid were formed in a 1:1 molar ratio. The theoretical content of afatinib in the compound is 86.5%, so that the afatinib and the glycolic acid in the afatinibane glycolate are salted in a molar ratio of 1:1, and the structural formula is as follows:
Figure imgf000019_0001
所述阿法替尼甘醇酸盐的制备方法， 包括以下步骤： 分别形成阿法替尼和甘醇酸在可溶 溶剂中的溶液体系， 阿法替尼和甘醇酸的摩尔比为 1 : 1-1 :2， 混合两个体系形成浆液， 然后除 去溶剂。 优选所述可溶溶剂为醇类、 酮类、 酯类、 烷烃类、 醚类或其混合物； 进一步优选为 甲醇、 丙酮、 乙酸乙酯、 正庚烷或甲基叔丁基醚。 优选采用旋干法除去溶剂。  The preparation method of the afatinibane glycolate comprises the following steps: respectively forming a solution system of afatinib and glycolic acid in a soluble solvent, and the molar ratio of afatinib to glycolic acid is 1 : 1-1 : 2, mixing the two systems to form a slurry, and then removing the solvent. Preferably, the soluble solvent is an alcohol, a ketone, an ester, an alkane, an ether or a mixture thereof; more preferably methanol, acetone, ethyl acetate, n-heptane or methyl tert-butyl ether. The solvent is preferably removed by spin-drying.
优选地， 所述阿法替尼甘醇酸盐为 G1-1 晶型的阿法替尼甘醇酸盐， 使用 Cu-Κα辐射， 其 X射线粉末衍射图谱在衍射角 2 Θ为 5.1±0.2°、 6.4±0.2。、 13.0±0.2。、 13.3±0.2。、 20.8±0.2° 和 25.0±0.2°处具有特征峰。  Preferably, the afatinibane glycolate is a G1-1 crystal form of afatinibane glycolate using Cu-Κα radiation, and the X-ray powder diffraction pattern has a diffraction angle of 2 Θ of 5.1±0.2. °, 6.4 ± 0.2. , 13.0 ± 0.2. 13.3±0.2. Characteristic peaks at 20.8±0.2° and 25.0±0.2°.
进一步地， 所述 G1-1 晶型阿法替尼甘醇酸盐， 其 X射线粉末衍射图谱在衍射角 2 Θ为 5.1±0.2。、 6.4±0.2。、 7.0±0.2。、 13.0±0.2。、 13.3±0.2。、 17.2±0.2。、 17.9±0.2。、 19.7±0.2。、 20.8±0.2。、 22.4±0.2°、 25.0±0.2°和 25.9±0.2°处具有特征峰。  Further, the G1-1 crystal form afatinibanoate has an X-ray powder diffraction pattern of 5.1 ± 0.2 at a diffraction angle of 2 Θ. , 6.4 ± 0.2. , 7.0 ± 0.2. , 13.0 ± 0.2. 13.3±0.2. , 17.2 ± 0.2. , 17.9 ± 0.2. , 19.7 ± 0.2. , 20.8 ± 0.2. Characteristic peaks at 22.4±0.2°, 25.0±0.2° and 25.9±0.2°.
更进一步地， 所述 G1-1晶型阿法替尼甘醇酸盐， 其 X射线粉末衍射图的衍射角 2 Θ特征 峰及其相对强度如下：  Further, the G1-1 crystalline form of afatinibane carbonate has a diffraction angle 2 Θ characteristic peak and its relative intensity in an X-ray powder diffraction pattern as follows:
衍射角 2Θ 相对强度％  Diffraction angle 2Θ relative intensity%
5.1±0.2° 28.9  5.1±0.2° 28.9
6.4±0.2° 100.0  6.4±0.2° 100.0
7.0±0.2° 1 1.5  7.0±0.2° 1 1.5
13.0±0.2° 21.7  13.0±0.2° 21.7
13.3±0.2° 19.0  13.3±0.2° 19.0
17.2±0.2° 14.7  17.2±0.2° 14.7
17.9±0.2° 13.9  17.9±0.2° 13.9
19.0±0.2° 1 1.2  19.0±0.2° 1 1.2
19.7±0.2° 1 1.5  19.7±0.2° 1 1.5
20.8±0.2° 24.7  20.8±0.2° 24.7
21.2±0.2° 12.0  21.2 ± 0.2 ° 12.0
22.4±0.2° 14.8  22.4±0.2° 14.8
23.5±0.2° 12.6  23.5±0.2° 12.6
25.0±0.2° 67.5  25.0±0.2° 67.5
25.9±0.2° 20.1  25.9 ± 0.2 ° 20.1
非限制性地， 所述 G1-1晶型阿法替尼甘醇酸盐的一个典型实例具有如图 63所示的 X射 线粉末衍射图谱。  Without limitation, a typical example of the G1-1 crystalline form of afatinibane has an X-ray powder diffraction pattern as shown in FIG.
所述 G1-1晶型阿法替尼甘醇酸盐，其傅里叶红外光谱在波数为 1625、 1577、 1536、 1497、 1452、 1427、 1234、 1212、 1081和 777cm-1处具有特征峰。 The G1-1 crystalline afatinibane glycolate has a Fourier transform infrared spectrum with characteristic peaks at wave numbers of 1625, 1577, 1536, 1497, 1452, 1427, 1234, 1212, 1081 and 777 cm -1 .
所述 G1-1晶型阿法替尼甘醇酸盐，其拉曼光谱在波数为 1650、 1629、 1610、 1536、 1398、 1344、 1304、 1215和 δΐ η·1处具有特征峰。 The G1-1 crystalline afatinibanoate has a Raman spectrum with characteristic peaks at wave numbers of 1650, 1629, 1610, 1536, 1398, 1344, 1304, 1215 and δΐ η· 1 .
所述 G1-1 晶型阿法替尼甘醇酸盐的一种制备方法， 包括以下步骤： 分别形成阿法替尼和 甘醇酸在可溶溶剂中的溶液体系， 阿法替尼和甘醇酸的摩尔比为 1 : 1-1 :2， 混合两个体系形成 浆液并搅拌， 在 -10-50°C下保持 1-48小时， 进而除去溶剂， 其中所述可溶溶剂选自 d-C4醇、 C3-C5酮、 C4-C5酯、 C6-C9烷烃、 硝基取代的 d-C3烷烃、 C4-C6醚或其混合物。 所述 d-C4醇 包括但不限于甲醇、 乙醇、 正丙醇、 异丙醇、 正丁醇和仲丁醇， 所述 C3-C5酮包括但不限于 丙酮和丁酮，所述 C4-C5酯包括但不限于乙酸乙酯和乙酸异丙酯，所述 C6-C9烷烃包括但不限 于正己烷、 正庚烷和甲基环己烷， 所述硝基取代的 d-C3烷烃包括但不限于硝基甲烷， 所述 C4-C6醚包括但不限于乙醚、 异丙醚和甲基叔丁基醚； 优选所述可溶溶剂为乙酸乙酯或硝基甲 烷。 优选阿法替尼在可溶溶剂中的浓度为 10毫克 /毫升至该溶剂下阿法替尼的饱和溶液。 优 选阿法替尼和甘醇酸的摩尔比为 1 : 1-1 : 1.5。 优选所述制备方法的操作温度为室温。 A preparation method of the G1-1 crystal form afatinibane glycolate comprises the following steps: respectively forming a solution system of afatinib and glycolic acid in a soluble solvent, afatinib and glycine The molar ratio of alkyd is 1:1-1:2, the two systems are mixed to form a slurry and stirred, and maintained at -1050 ° C for 1-48 hours, thereby removing the solvent, wherein the soluble solvent is selected from dC 4 alcohol, C 3 -C 5 ketone, C 4 -C 5 ester, C 6 -C 9 alkane, nitro-substituted dC 3 alkane, C 4 -C 6 ether or a mixture thereof. The dC 4 alcohol includes, but is not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, and sec-butanol, and the C 3 -C 5 ketone includes, but is not limited to, acetone and methyl ethyl ketone, the C 4 - C 5 esters include, but are not limited to ethyl acetate and isopropyl acetate, a C 6 -C 9 alkanes include but are not limited to, n-hexane, n-heptane and methylcyclohexane, a nitro-substituted alkanes dC 3 Including but not limited to nitromethane, The C 4 -C 6 ethers include, but are not limited to, diethyl ether, diisopropyl ether and methyl tert-butyl ether; preferably the soluble solvent is ethyl acetate or nitromethane. Preferably, the concentration of afatinib in a soluble solvent is 10 mg/ml to a saturated solution of afatinib in the solvent. Preferably, the molar ratio of afatinib to glycolic acid is 1:1-1:1.5. Preferably, the operating temperature of the preparation method is room temperature.
所述 G1- 1晶型阿法替尼甘醇酸盐的另一种制备方法， 包括以下步骤：将前述制备方法得 到的阿法替尼甘醇酸盐在有机溶剂中形成浆液并搅拌，该浆液在 -10-50°C下保持 1〜72小时， 进而除去溶剂， 其中所述有机溶剂选自甲醇、 丙酮、 乙腈、 乙酸乙酯、 硝基甲烷、 正庚烷、 甲基叔丁基醚或其混合物。 优选所述制备方法的操作温度为室温。  The preparation method of the G1- 1 crystal form afatinibane glycolate comprises the steps of: forming the slurry of the afatinibane glycolate obtained by the above preparation method in an organic solvent and stirring, The slurry is maintained at -10 to 50 ° C for 1 to 72 hours to remove the solvent, wherein the organic solvent is selected from the group consisting of methanol, acetone, acetonitrile, ethyl acetate, nitromethane, n-heptane, and methyl t-butyl ether. Or a mixture thereof. Preferably, the operating temperature of the preparation method is room temperature.
与现有技术比较， 尤其是与现有技术的阿法替尼二马来酸盐或其晶型比较， 阿法替尼甘 醇酸盐或 G1- 1晶型阿法替尼甘醇酸盐具有一种或多种改进的特性， 例如： 更高的结晶度、较 好的溶解度、 溶解速度、 较佳的结晶形态、 较好的热稳定性和贮存稳定性、 较低的吸湿性、 较好的可流动性和有利的加工与处理特性。  Compared with the prior art, in particular, compared with the prior art afatinib dimaleate or its crystal form, afatinibane glycolate or G1- 1 crystal form afatinibane glycolate Has one or more improved properties, such as: higher crystallinity, better solubility, dissolution rate, better crystalline morphology, better thermal stability and storage stability, lower moisture absorption, Good flowability and favorable processing and handling characteristics.
特别是 G1- 1晶型阿法替尼甘醇酸盐具有以下有益性质：  In particular, G1- 1 crystal form afatinibanoate has the following beneficial properties:
1 ) 熔点为 83.5°C， 低于阿法替尼二马来酸盐现有技术晶型的熔点 166.2°C， 可在很低的 温度下制备无定形物， 而无定形物有着较好的溶解性。  1) The melting point is 83.5 ° C, lower than the melting point of the prior art crystal form of afatinib dimaleate of 166.2 ° C, the amorphous substance can be prepared at a very low temperature, and the amorphous substance has a better Solubility.
2) 根据文献《Handbook of Pharmaceutical Salts properties,selection,and use》介绍， 甘醇 酸与马来酸相比有着更低的毒性。  2) According to the literature "Handbook of Pharmaceutical Salts properties, selection, and use", glycolic acid has lower toxicity than maleic acid.
上述有益性质表明， 与现有技术的阿法替尼二马来酸盐或其晶型相比， 本发明的阿法替 尼甘醇酸盐或 G1-1晶型阿法替尼甘醇酸盐具有多种优势性能， 应用效果可更好， 适合作为药 物制剂的活性成分。活性成分更高的溶解性有利于提高药物的生物利用度，进而对药效产生积 极影响； 活性成分具有更低的毒性， 使得制剂的制造过程和药物的临床应用更安全。  The above beneficial properties indicate that the afatinibane glycolate or G1-1 crystal form afatinibanoic acid of the present invention is compared to the prior art afatinib dimaleate or a crystal form thereof. Salt has a variety of advantageous properties, and the application effect is better, and it is suitable as an active ingredient of a pharmaceutical preparation. The higher solubility of the active ingredient is beneficial to improve the bioavailability of the drug, which in turn has a positive effect on the efficacy; the active ingredient has lower toxicity, making the preparation process and the clinical application of the drug safer.
本发明的内容之十一是提供一种新型的阿法替尼二马来酸盐晶型 N及其制备方法。 使用 Cu-Κα辐射， 所述阿法替尼二马来酸盐晶型 N的 X射线粉末衍射图谱在衍射角 2 Θ为 4.8±0.2。、 9.7±0.2。、 14.5±0.2。、 17.0±0.2。、 19.5±0.2。、 20.1±0.2、 25.6±0.2。处具有特征 峰。  An eleventh aspect of the present invention provides a novel form of afatinib dimaleate form N and a process for the preparation thereof. Using Cu-Κα radiation, the X-ray powder diffraction pattern of the crystalline form N of the afatinib dimaleate salt was 4.8 ± 0.2 at a diffraction angle of 2 Θ. , 9.7 ± 0.2. , 14.5 ± 0.2. , 17.0 ± 0.2. , 19.5 ± 0.2. , 20.1 ± 0.2, 25.6 ± 0.2. There are characteristic peaks.
进一步地， 所述阿法替尼二马来酸盐晶型 N， 其 X射线粉末衍射图的衍射角 2 Θ特征峰 及其相对强度如下：  Further, the diffraction peak 2 Θ characteristic peak and relative intensity of the X-ray powder diffraction pattern of the afatinib dimaleate salt form N are as follows:
衍射角 2Θ 相对强度％  Diffraction angle 2Θ relative intensity%
4.8±0.2° 100.0  4.8±0.2° 100.0
9.7±0.2° 7.5  9.7±0.2° 7.5
14.5±0.2° 3.6  14.5±0.2° 3.6
17.0±0.2° 2.2  17.0±0.2° 2.2
19.5±0.2° 5.7  19.5±0.2° 5.7
20. 1±0.2° 2.3  20. 1±0.2° 2.3
25.5±0.2° 5.0 。  25.5 ± 0.2 ° 5.0.
非限制性地， 所述阿法替尼二马来酸盐晶型 N的一个典型实例具有如图 69所示的 X射 线粉末衍射图谱。  Without limitation, a typical example of the crystalline form N of the afatinib dimaleate salt has an X-ray powder diffraction pattern as shown in FIG.
所述阿法替尼二马来酸盐晶型 N， 其傅里叶红外光谱在波数为 1684、 1576、 1542、 1496、 1449、 1351、 1088、 891和 859cm 处具有特征峰。  The afatinib dimaleate crystal form N has a Fourier transform infrared spectrum having characteristic peaks at wave numbers of 1684, 1576, 1542, 1496, 1449, 1351, 1088, 891 and 859 cm.
所述阿法替尼二马来酸盐晶型 N， 其拉曼光谱在波数为 1657、 1607、 1546、 1494、 1404、 1374、 1302、 1217和 783cm 处具有特征峰。  The afatinib dimaleate salt form N has a Raman spectrum with characteristic peaks at wavenumbers of 1657, 1607, 1546, 1494, 1404, 1374, 1302, 1217 and 783 cm.
所述阿法替尼二马来酸盐晶型 N的制备方法， 包括以下步骤： 分别形成阿法替尼和马来酸 在硝基甲烷中的溶液体系， 阿法替尼和马来酸的摩尔比为 1 :2-1 :4， 混合两个体系形成浆液并搅 拌， 在 -10-50°C下保持 1-48小时， 然后除去溶剂。优选阿法替尼在硝基甲烷中的浓度为 10 毫克 /毫升至阿法替尼在硝基甲烷中的饱和溶液； 优选阿法替尼和马来酸的摩尔比为 1 :2-1 :3 ; 优选所 述制备方法的操作温度为室温。  The preparation method of the afatinib dimaleate salt form N comprises the following steps: respectively forming a solution system of afatinib and maleic acid in nitromethane, afatinib and maleic acid The molar ratio was 1:2-1:4, and the two systems were mixed to form a slurry and stirred, and maintained at -10 to 50 ° C for 1 to 48 hours, and then the solvent was removed. Preferably, the concentration of afatinib in nitromethane is from 10 mg/ml to a saturated solution of afatinib in nitromethane; preferably the molar ratio of afatinib to maleic acid is 1:2-1: 3; Preferably, the operating temperature of the preparation method is room temperature.
与现有技术比较， 尤其是与阿法替尼二马来酸盐现有技术晶型比较， 本发明的阿法替尼 二马来酸盐晶型 N具有一种或多种改进的特性， 例如： 更高的结晶度、 较好的溶解度、 溶解 速度、 较佳的结晶形态、 较好的热稳定性和贮存稳定性、 较低的吸湿性、 较好的可流动性和 有利的加工与处理特性。 The afatinib dimaleate crystal form N of the present invention has one or more improved properties compared to the prior art, particularly in comparison to the prior art crystalline form of afatinib dimaleate. For example: higher crystallinity, better solubility, dissolution Speed, preferred crystalline morphology, better thermal and storage stability, lower moisture absorption, better flowability and advantageous processing and handling characteristics.
特别是阿法替尼二马来酸盐晶型 N 具有以下有益性质： 其在室温下水中的溶解度为 12.7mg/ml, 相对于阿法替尼二马来酸盐现有技术晶型在相同条件下的溶解度 7.5 mg/ml, 具 有更高的溶解性。 上述有益性质表明， 与阿法替尼二马来酸盐现有技术晶型相比， 本发明的 阿法替尼二马来酸盐晶型 N具有优势性能， 应用效果可更好， 适合作为药物制剂的活性成分。 活性成分更高的溶解性有利于提高药物的生物利用度， 进而对药效产生积极影响。  In particular, the afatinib dimaleate salt form N has the following beneficial properties: its solubility in water at room temperature is 12.7 mg/ml, which is the same as the prior art crystal form of afatinib dimaleate. The solubility under conditions is 7.5 mg/ml, which has higher solubility. The above beneficial properties indicate that the afatinib dimaleate crystal form N of the present invention has superior performance and better application effect than the prior art crystal form of afatinib dimaleate. The active ingredient of a pharmaceutical preparation. The higher solubility of the active ingredient is beneficial to increase the bioavailability of the drug, which in turn has a positive effect on the efficacy.
本发明上述任何制备方法中， 可选地， 所述阿法替尼的溶液体系与酸的溶液体系或悬浮液 体系的混合方式为： i)将阿法替尼的溶液体系向酸的溶液体系或悬浮液体系中添加；或 ii) 向阿 法替尼的溶液体系中添加酸的溶液体系或悬浮液体系； 或 iii)将阿法替尼的溶液体系与酸的溶液 体系或悬浮液体系同时向反应容器中添加。  In any of the above preparation methods of the present invention, optionally, the mixing method of the solution system of the afatinib with the acid solution system or the suspension system is: i) the solution system of the afatinib solution to the acid solution system. Or adding to the suspension system; or ii) adding an acid solution or suspension system to the solution system of afatinib; or iii) simultaneously applying the solution system of afatinib to the acid solution system or suspension system Add to the reaction vessel.
本发明上述任何制备方法中描述的 "搅拌" 可用常规技术完成， 例如磁力搅拌和机械 搅拌。 搅拌速度为 50 1800转 /分， 优选 300 900转 /分。  The "stirring" described in any of the above preparation methods of the present invention can be accomplished by conventional techniques such as magnetic stirring and mechanical stirring. The agitation speed is 50 1800 rpm, preferably 300 900 rpm.
本发明上述任何制备方法中描述的 "去除溶剂" 步骤可以用常规技术完成， 例如过 滤、 离心、 干燥或蒸发。 旋蒸的具体操作为： 将装有溶液的容器置于旋蒸仪中， 在室温 至溶剂沸点的水浴温度下 （优选 30~50 °C ) ， 小于大气压的压力下 （优选压力小于 0.08MPa) ， 以 10 180转 /分的旋转速度 （优选 50~100转 /分） ， 将溶剂除尽。  The "solvent removal" step described in any of the above preparation methods of the present invention can be carried out by conventional techniques such as filtration, centrifugation, drying or evaporation. The specific operation of the rotary steaming is: placing the container containing the solution in a rotary evaporator at a temperature of from room temperature to the boiling point of the solvent (preferably 30 to 50 ° C), less than atmospheric pressure (preferably, the pressure is less than 0.08 MPa). The solvent is removed at a rotation speed of 10 180 rpm (preferably 50 to 100 rpm).
本发明上述任何制备方法得到的阿法替尼酸加成盐及其晶型， 可以采用常规技术进一步 干燥。 干燥在减压或不减压下进行， 优选压力小于 0.09MPa， 干燥温度约 30-50°C， 干燥时 间 10-72小时， 优选 10-48小时， 更优选 10-24小时。 干燥可以在通风橱、 鼓风烘箱或真空 烘箱里进行。  The afatinidine acid addition salt obtained by any of the above production methods of the present invention and its crystal form can be further dried by a conventional technique. The drying is carried out under reduced pressure or without a reduced pressure, preferably at a pressure of less than 0.09 MPa, a drying temperature of about 30 to 50 ° C, and a drying time of 10 to 72 hours, preferably 10 to 48 hours, more preferably 10 to 24 hours. Drying can be carried out in a fume hood, a forced air oven or a vacuum oven.
本发明中，起始原料阿法替尼可按照文献 CN1867564B中实施例 1公开的方法制备得到， 该文献通过引用其全文的方式并入到本申请中。  In the present invention, the starting material afatinib can be prepared according to the method disclosed in Example 1 of the document CN1867564B, which is incorporated herein by reference.
本发明中， "室温"指 10-25°Cc  In the present invention, "room temperature" means 10-25 ° Cc
根据本发明的目的， 本发明提供一种药物組合物， 所述药物組合物包含治疗和 /或预防有 效量的一种或多种本发明所述的阿法替尼酸加成盐或其晶型或者由本发明方法制备得到的阿 法替尼酸加成盐或其晶型， 以及至少一种药学上可接受的赋形剂。 其中， 本发明所述的阿法替 尼酸加成盐或其晶型选自阿法替尼的乙二磺酸盐、 E1 晶型乙二磺酸盐、 1,5-萘二磺酸盐、 N1 晶型 1,5-萘二磺酸盐、 N2晶型 1,5-萘二磺酸盐水合物、 丙二酸盐、 Ml晶型丙二酸盐、 二丙二 酸盐、 M2晶型二丙二酸盐、 二 2-萘磺酸盐、 Nsl晶型二 2-萘磺酸盐、 二氨基磺酸盐、 S1晶型 二氨基磺酸盐、 二 D-葡萄糖酸盐、 G1晶型二 D-葡萄糖酸盐、 二环己烷氨基磺酸盐、 C1晶型 二环己烷氨基磺酸盐、 二 4-氨基苯磺酸盐、 A1晶型二 4-氨基苯磺酸盐、 甘醇酸盐、 G1-1晶型 甘醇酸盐或二马来酸盐晶型 N， 此外， 所述药物組合物还可以包含阿法替尼或其可药用的其它 盐、 以及它们的晶型或无定形物。  According to an object of the present invention, the present invention provides a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of one or more of the afatinidine acid addition salts of the present invention or a crystal thereof An albininic acid addition salt or a crystalline form thereof prepared by the process of the invention, and at least one pharmaceutically acceptable excipient. Wherein the afartinic acid addition salt of the present invention or a crystal form thereof is selected from the group consisting of ethanedisulfonate of afatinib, E1 crystal form ethanedisulfonate, 1,5-naphthalene disulfonate , N1 crystal form 1,5-naphthalene disulfonate, N2 crystal form 1,5-naphthalenedisulfonic acid salt hydrate, malonate, Ml crystal malonate, dipropionate, M2 crystal Dimalonate, bis 2-naphthalene sulfonate, Nsl bis 2-naphthalene sulfonate, diamino sulfonate, S1 crystalline diamino sulfonate, di D-gluconate, G1 crystal Type di D-gluconate, dicyclohexyl sulfamate, C1 crystalline dicyclohexane sulfamate, di 4-aminobenzenesulfonate, A1 crystalline di 4-aminobenzenesulfonate, a glycolate, a G1-1 crystalline glycolate or a dimaleate salt form N, further, the pharmaceutical composition may further comprise afatinib or a pharmaceutically acceptable other salt thereof, and Crystal or amorphous.
所述药物組合物中的赋形剂包括糖类， 纤維素及其衍生物， 淀粉或改性淀粉， 固体无机物 如磷酸钙、 磷酸氫二钙、 羟基磷灰石、 硫酸钙、 碳酸钙， 半固体如脂质或石蜡， 粘合剂如微晶 纤維素、 乙基纤維素、 羟甲基纤維素、 羟丙基甲基纤維素、 羟乙基纤維素， 助流剂如胶态二氧 化硅、 轻质无水硅酸、 结晶纤維素、 滑石粉或硬脂酸镇， 崩解剂如乙醇酸淀粉钠、 交聚維酮、 交联羧甲基纤維素、 羧甲基纤維素钠、 干玉米淀粉， 润滑剂如硬脂酸、 硬脂酸镁、 硬脂酰富马 酸钠、 聚乙二醇。  Excipients in the pharmaceutical composition include sugars, cellulose and derivatives thereof, starch or modified starch, solid inorganic substances such as calcium phosphate, dicalcium phosphate, hydroxyapatite, calcium sulfate, calcium carbonate, Semi-solids such as lipids or paraffins, binders such as microcrystalline cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, glidants such as colloidal dioxide Silicon, light anhydrous silicic acid, crystalline cellulose, talc or stearic acid, disintegrating agents such as sodium starch glycolate, crospovidone, croscarmellose, sodium carboxymethylcellulose, Dry corn starch, lubricants such as stearic acid, magnesium stearate, sodium stearyl fumarate, polyethylene glycol.
所述药物組合物可为固态或液态， 给药途径包括口服、 静脉注射、 皮下注射、 組织内给 药、 透皮给药、 直肠给药、 鼻内给药等。 例如， 固体口服剂型， 包括片剂、 颗粒剂、 胶囊剂、 散剂、 丸剂和锭剂， 可以是常规的、 可分散的、 可咀嚼的、 口腔溶解的或快速熔化的制剂； 液体口服剂型， 包括溶液剂、 糖浆剂、 混悬剂、 分散剂和乳剂； 可注射制剂， 包括溶液剂、 分散剂和冻干剂； 适于吸入用的气溶胶制剂； 适于直肠给药的栓剂。 配方可适于活性成分的 速释、 緩释或调节释放。 所述药物組合物可以使用本领域技术人员公知的方法来制备。 制备药物組合物时， 本发明 的阿法替尼酸加成盐或其晶型与一种或多种药学上可接受的赋形剂相混合， 任选地与可药用的 阿法替尼其它盐的晶型、 或无定形物相混合， 任选地与一种或多种其他的药物活性成分相混合。 固体制剂可通过直接混合、 制粒等工艺来制备。 The pharmaceutical composition may be in a solid or liquid form, and the administration route includes oral, intravenous, subcutaneous, intra-tissue, transdermal, rectal, intranasal, and the like. For example, solid oral dosage forms, including tablets, granules, capsules, powders, pills, and lozenges, may be conventional, dispersible, chewable, orally dissolved or rapidly melted formulations; liquid oral dosage forms, including Solution, syrup, suspension, dispersant and emulsion; injectable preparations, including solutions, dispersions and lyophilizates; aerosol formulations suitable for inhalation; suppositories suitable for rectal administration. The formulation may be adapted for immediate release, sustained release or modified release of the active ingredient. The pharmaceutical composition can be prepared using methods well known to those skilled in the art. In the preparation of a pharmaceutical composition, the afatinidine acid addition salt of the invention or a crystalline form thereof is admixed with one or more pharmaceutically acceptable excipients, optionally with pharmaceutically acceptable afatinib The crystalline form, or amorphous form of the other salt, is optionally mixed with one or more other pharmaceutically active ingredients. The solid preparation can be prepared by a process such as direct mixing, granulation, or the like.
本发明的阿法替尼酸加成盐或其晶型适用于治疗良性或恶性肿瘤， 用于预防和治疗呼吸 道和肺部疾病， 以及用于治疗胃肠道、 胆管以及胆囊疾病。  The afatinidine acid addition salt of the present invention or a crystal form thereof is suitable for the treatment of benign or malignant tumors, for the prevention and treatment of respiratory and pulmonary diseases, and for the treatment of gastrointestinal, bile duct and gallbladder diseases.
进一步地，本发明提供了本发明前述的阿法替尼酸加成盐或其晶型用于制备治疗和 /或预 防晚期非小细胞肺癌 （NSCLC) 及 HER2阳性的晚期乳腺癌疾病的药物中的用途。  Further, the present invention provides the aforementioned afatinidine acid addition salt of the present invention or a crystal form thereof for use in the preparation of a medicament for treating and/or preventing advanced non-small cell lung cancer (NSCLC) and HER2-positive advanced breast cancer diseases. the use of.
进一步地， 本发明提供一种治疗和 /或预防晚期非小细胞肺癌 （NSCLC) 及 HER2阳性的 晚期乳腺癌的方法， 所述方法包括给予需要的患者治疗和 /或预防有效量的本发明前述的阿法 替尼酸加成盐或其晶型或包含本发明前述的阿法替尼酸加成盐或其晶型的药物組合物。 所述 患者一般是温血脊推动物， 特别是人。 作为医药使用的剂量为 0.01 100毫克 /公斤体重， 优选 为 0.1 15毫克 /公斤体重。  Further, the present invention provides a method of treating and/or preventing advanced non-small cell lung cancer (NSCLC) and HER2-positive advanced breast cancer, the method comprising administering to a patient in need thereof a therapeutically and/or prophylactically effective amount of the aforementioned An afatinidine acid addition salt or a crystalline form thereof or a pharmaceutical composition comprising the afatinidine acid addition salt of the present invention or a crystalline form thereof. The patient is typically a warm blood ridge pusher, particularly a human. The dose used as a medicine is 0.01 100 mg / kg body weight, preferably 0.1 15 mg / kg body weight.
附图说明 DRAWINGS
图 1 是 CN1867564B公开的阿法替尼二马来酸盐现有技术晶型的 XRPD图  Figure 1 is an XRPD pattern of a prior art crystal form of afatinib dimaleate disclosed in CN1867564B.
图 2是制备例 1制备的阿法替尼二马来酸盐现有技术晶型的 XRPD图  2 is an XRPD pattern of a prior art crystal form of afatinib dimaleate prepared in Preparation Example 1.
图 3是制备例 1制备的阿法替尼二马来酸盐现有技术晶型的 TGA图  Figure 3 is a TGA diagram of the prior art crystal form of afatinib dimaleate prepared in Preparation Example 1.
图 4是制备例 1制备的阿法替尼二马来酸盐现有技术晶型的 DSC图  Figure 4 is a DSC chart of the prior art crystal form of afatinib dimaleate prepared in Preparation Example 1.
图 5是制备例 1制备的阿法替尼二马来酸盐现有技术晶型的 DVS图  Figure 5 is a DVS diagram of a prior art crystal form of afatinib dimaleate prepared in Preparation Example 1.
图 6是实施例 3制备的 E1晶型阿法替尼乙二磺酸盐的 XRPD图  Figure 6 is an XRPD pattern of the E1 crystal form of afatinib ethanedisulfonate prepared in Example 3.
图 7是实施例 3制备的 E1晶型阿法替尼乙二磺酸盐的 PLM图  Figure 7 is a PLM diagram of the E1 crystal form of afatinib ethanedisulfonate prepared in Example 3.
图 8是实施例 3制备的 E1晶型阿法替尼乙二磺酸盐的 TGA图  Figure 8 is a TGA diagram of the E1 crystal form of afatinib ethanedisulfonate prepared in Example 3.
图 9是实施例 3制备的 E1晶型阿法替尼乙二磺酸盐的 DVS图  Figure 9 is a DVS diagram of the E1 crystal form of afatinib ethanedisulfonate prepared in Example 3.
图 10是实施例 3制备的 E1晶型阿法替尼乙二磺酸盐的 IR图  Figure 10 is an IR chart of the E1 crystal form of afatinib ethanedisulfonate prepared in Example 3.
图 11是实施例 3制备的 E1晶型阿法替尼乙二磺酸盐的 Raman图  Figure 11 is a Raman diagram of the E1 crystal form of afatinib ethanedisulfonate prepared in Example 3.
图 12是实施例 3制备的 E1晶型阿法替尼乙二磺酸盐的 NMR图  Figure 12 is an NMR chart of the E1 crystal form of afatinib ethanedisulfonate prepared in Example 3.
图 13是实施例 12制备的 N1晶型阿法替尼 1,5-萘二磺酸盐的 XRPD图  Figure 13 is an XRPD pattern of the N1 crystal form of afatinib 1,5-naphthalenedisulfonate prepared in Example 12.
图 14是实施例 12制备的 N1晶型阿法替尼 1,5-萘二磺酸盐的 PLM图  Figure 14 is a PLM diagram of the N1 crystal form of afatinib 1,5-naphthalenedisulfonate prepared in Example 12.
图 15是实施例 12制备的 N1晶型阿法替尼 1,5-萘二磺酸盐的 TGA图  Figure 15 is a TGA diagram of the N1 crystal form of afatinib 1,5-naphthalenedisulfonate prepared in Example 12.
图 16是实施例 12制备的 N1晶型阿法替尼 1,5-萘二磺酸盐的 DVS图  Figure 16 is a DVS diagram of the N1 crystal form of afatinib 1,5-naphthalenedisulfonate prepared in Example 12.
图 17是实施例 12制备的 N1晶型阿法替尼 1,5-萘二磺酸盐的 IR图  Figure 17 is an IR chart of the N1 crystal form of afatinib 1,5-naphthalenedisulfonate prepared in Example 12.
图 18是实施例 12制备的 N1晶型阿法替尼 1,5-萘二磺酸盐的 Raman图  Figure 18 is a Raman diagram of the N1 crystal form of afatinib 1,5-naphthalenedisulfonate prepared in Example 12.
图 19是实施例 12制备的 N1晶型阿法替尼 1,5-萘二磺酸盐的 NMR图  Figure 19 is an NMR chart of the N1 crystal form of afatinib 1,5-naphthalenedisulfonate prepared in Example 12.
图 20是实施例 20制备的 N2晶型阿法替尼 1,5-萘二磺酸盐水合物的 XRPD图  Figure 20 is an XRPD pattern of the N2 crystal form of afatinib 1,5-naphthalenedisulfonic acid salt hydrate prepared in Example 20.
图 21是实施例 20制备的 N2晶型阿法替尼 1,5-萘二磺酸盐水合物的 PLM图  Figure 21 is a PLM diagram of the N2 crystal form of afatinib 1,5-naphthalene disulfonic acid salt hydrate prepared in Example 20.
图 22是实施例 20制备的 N2晶型阿法替尼 1,5-萘二磺酸盐水合物的 TGA图  Figure 22 is a TGA diagram of the N2 crystal form of afatinib 1,5-naphthalenedisulfonic acid salt hydrate prepared in Example 20.
图 23是实施例 20制备的 N2晶型阿法替尼 1,5-萘二磺酸盐水合物的 IR图  Figure 23 is an IR chart of the N2 crystal form of afatinib 1,5-naphthalene disulfonic acid salt hydrate prepared in Example 20.
图 24是实施例 20制备的 N2晶型阿法替尼 1,5-萘二磺酸盐水合物的 Raman图  Figure 24 is a Raman diagram of the N2 crystal form of afatinib 1,5-naphthalenedisulfonic acid salt hydrate prepared in Example 20.
图 25是实施例 24制备的 Ml晶型阿法替尼一丙二酸盐的 XRPD图  Figure 25 is an XRPD pattern of the M1 crystal form of afatinib monomalonate prepared in Example 24.
图 26是实施例 24制备的 Ml晶型阿法替尼一丙二酸盐的 PLM图  Figure 26 is a PLM diagram of the M1 crystal form of afatinib monomalonate prepared in Example 24.
图 27是实施例 24制备的 Ml晶型阿法替尼一丙二酸盐的 TGA图  Figure 27 is a TGA diagram of the M1 crystal form of afatinib monomalonate prepared in Example 24.
图 28是实施例 24制备的 Ml晶型阿法替尼一丙二酸盐的 IR图  Figure 28 is an IR chart of the M1 crystal form of afatinib monomalonate prepared in Example 24.
图 29是实施例 24制备的 Ml晶型阿法替尼一丙二酸盐的 Raman图  Figure 29 is a Raman diagram of the M1 crystal form of afatinib monomalonate prepared in Example 24.
图 30是实施例 24制备的 Ml晶型阿法替尼一丙二酸盐的 NMR图  Figure 30 is an NMR chart of the M1 crystal form of afatinib monomalonate prepared in Example 24.
图 31是实施例 31制备的 M2晶型阿法替尼二丙二酸盐的 XRPD图  Figure 31 is an XRPD pattern of the M2 crystalline form of afatinib dipropanedioate prepared in Example 31.
图 32是实施例 31制备的 M2晶型阿法替尼二丙二酸盐的 TGA图 图 33是实施例 31 Figure 32 is a TGA diagram of the M2 crystalline form of afatinib dipropanedioate prepared in Example 31. Figure 33 is an embodiment 31
图 34是实施例 31  Figure 34 is an embodiment 31
图 35是实施例 31  Figure 35 is an embodiment 31
图 36是实施例 31  Figure 36 is an embodiment 31
图 37是实施例 38  Figure 37 is an embodiment 38
图 38是实施例 38  Figure 38 is an embodiment 38
图 39是实施例 38  Figure 39 is an embodiment 38
图 40是实施例 38  Figure 40 is an embodiment 38
图 41是实施例 38  Figure 41 is an embodiment 38
图 42是实施例 46  Figure 42 is an embodiment 46
图 43是实施例 46  Figure 43 is an embodiment 46
图 44是实施例 46  Figure 44 is an embodiment 46
图 45是实施例 46  Figure 45 is an embodiment 46
图 46是实施例 46  Figure 46 is an embodiment 46
图 47是实施例 54  Figure 47 is an embodiment 54
图 48是实施例 54  Figure 48 is an embodiment 54
图 49是实施例 54  Figure 49 is an embodiment 54
图 50是实施例 54  Figure 50 is an embodiment 54
图 51是实施例 54  Figure 51 is an embodiment 54
图 52是实施例 54  Figure 52 is an embodiment 54
图 53是实施例 63  Figure 53 is an embodiment 63
图 54是实施例 63  Figure 54 is an embodiment 63
图 55是实施例 63  Figure 55 is an embodiment 63
图 56是实施例 63  Figure 56 is an embodiment 63
图 57是实施例 63  Figure 57 is an embodiment 63
图 58是实施例 72  Figure 58 is an embodiment 72
图 59是实施例 72  Figure 59 is an embodiment 72
图 60是实施例 72  Figure 60 is an embodiment 72
图 61是实施例 72  Figure 61 is an embodiment 72
图 62是实施例 72  Figure 62 is an embodiment 72
图 63是实施例 81  Figure 63 is an embodiment 81
图 64是实施例 81  Figure 64 is an embodiment 81
图 65是实施例 81  Figure 65 is an embodiment 81
图 66是实施例 81  Figure 66 is an embodiment 81
图 67是实施例 81  Figure 67 is an embodiment 81
图 68是实施例 81  Figure 68 is an embodiment 81
图 69是实施例 88  Figure 69 is an embodiment 88
图 70是实施例 88  Figure 70 is an embodiment 88
图 71是实施例 88  Figure 71 is an embodiment 88
图 72是实施例 88  Figure 72 is an embodiment 88
具体实施方式 detailed description
本发明进一步参考以下实施例， 所述实施例详细描述本发明的盐及晶型的制备和应用。 对本领域技术人员显而易见的是， 对于材料和方法两者其中的许多改变可在不脱离本发明范 围的情况下实施。  The invention is further directed to the following examples which describe in detail the preparation and use of the salts and crystalline forms of the invention. It will be apparent to those skilled in the art that many changes in the materials and methods can be practiced without departing from the scope of the invention.
检测仪器及方法：  Testing equipment and methods:
X射线粉末衍射 （XPRD) 所用的仪器为 Bruker D8 Advance diffractometer, 采用铜靶波 长为 1.54nm的 Κα X-射线，在 40kV和 40mA的操作条件下、 Θ-2Θ测角仪、 Mo单色仪、 Lynxeye 探测器。 仪器在使用前用仪器自带的标准样品校正峰位。 采集软件是 Diffrac Plus XRD Commander 样品在室温下测试， 把样品放在有机玻片上。 检测条件： 角度范围： 3~4。2Θ ; 步长： 0.02°2Θ ; 速度： 0.2s/步。 The instrument used for X-ray powder diffraction (XPRD) is the Bruker D8 Advance diffractometer, which uses a copper target wave. Κα X-rays with a length of 1.54 nm, operating conditions of 40 kV and 40 mA, Θ-2Θ goniometer, Mo monochromator, Lynxeye detector. The instrument is used to correct the peak position with the standard sample supplied with the instrument before use. The acquisition software was a Diffrac Plus XRD Commander sample tested at room temperature and the sample was placed on an organic slide. Detection conditions: Angle range: 3~4. 2Θ; Step size: 0.02°2Θ; Speed: 0.2s/step.
偏正光显微镜（PLM)图谱采自于 XP-500E偏振光显微镜（上海长方光学仪器有限公司）。 取少量粉末样品置于载玻片上， 滴加少量矿物油以更好地分散粉末样品， 盖上盖玻片， 然后 将样品放置在 XP-500E偏振光显微镜的载物台上，选择合适的放大倍数观测样品的形貌并拍 昭、  The polarized light microscope (PLM) spectrum was taken from an XP-500E polarized light microscope (Shanghai Changfang Optical Instrument Co., Ltd.). Take a small amount of powder sample on the glass slide, add a small amount of mineral oil to better disperse the powder sample, cover the cover glass, and then place the sample on the stage of the XP-500E polarized light microscope, select the appropriate magnification Multiply observe the morphology of the sample and shoot it.
热重分析（TGA)数据采自于 TA Instruments Q500 TGA，仪器控制软件 Thermal Advantage, 分析软件 Universal Analysis 通常取 5~15mg样品置于白金坩埚内，采用分段高分辨检测方式， 以 10°C/min升温速度在 50mL/min干燥 N2的保护下将样品从室温升至 300°C， 同时 TA软件 记录样品升温过程中的重量变化。 Thermogravimetric analysis (TGA) data was obtained from TA Instruments Q500 TGA, instrument control software Thermal Advantage, and analysis software Universal Analysis usually took 5~15mg samples in platinum crucible, using segmented high-resolution detection method, at 10 °C / The temperature of min was raised from room temperature to 300 ° C under the protection of dry N 2 at 50 mL/min, while the TA software recorded the change in weight during the temperature rise of the sample.
动态水份吸附分析 （DVS) 数据采自于 TA Instruments Q5000 TGA, 仪器控制软件是 Thermal Advantage,分析软件是 Universal Analysis。通常取 1~10 mg样品放置于白金坩埚内， TA软件记录样品在相对湿度从 0%到 80%到 0%变化过程中的重量变化。 根据样品的具体情 况， 也会对样品采用不同的吸附和脱吸附步骤。  Dynamic moisture adsorption analysis (DVS) data was taken from the TA Instruments Q5000 TGA, the instrument control software was Thermal Advantage, and the analysis software was Universal Analysis. Usually 1 to 10 mg of the sample is placed in a platinum crucible, and the TA software records the change in weight of the sample during the relative humidity change from 0% to 80% to 0%. Depending on the specifics of the sample, different adsorption and desorption steps are also applied to the sample.
红外光谱分析 (IR) 数据采自于 Bruker Tensor 27， 仪器控制软件和数据分析软件都是 OPUS。 通常采用 ATR设备， 在 όΟΟ^ΟΟΟ η-1范围内， 采集红外吸收光谱， 样品和空白背景 的扫描时间均为 16秒， 仪器分辨率 4cm—1。 Infrared spectroscopy (IR) data was taken from Bruker Tensor 27, and instrument control software and data analysis software were OPUS. The ATR device is usually used to collect the infrared absorption spectrum in the range of όΟΟ^ΟΟΟ η- 1 . The scanning time of the sample and the blank background is 16 seconds, and the resolution of the instrument is 4 cm- 1 .
拉曼光谱分析 （Raman) 数据采自于尼高力 DXR 780， 仪器控制软件和数据分析软件都 是 onmic 8.2。通常在 10倍镜下，在波数 SO ^Ocm 范围内， 曝光次数 8次， 曝光时间 1秒， 对样品进行拉曼光谱采集。  Raman spectroscopy (Raman) data was taken from the Nikola DXR 780, and instrument control software and data analysis software were onmic 8.2. The Raman spectra were collected on a sample under a 10x mirror, in the wave number SO ^Ocm, 8 exposures, and 1 second exposure time.
核磁分析（NMR)数据采自于 Bruker Ascend Tm 500。通常使用全频激发， 谱宽 30PPM, 单脉冲， 30° 角激发， 扫描 16次， 数字化正交检测， 控温 298K。  Nuclear magnetic analysis (NMR) data was taken from Bruker Ascend Tm 500. Usually use full-frequency excitation, spectral width 30PPM, single pulse, 30° angle excitation, 16 scans, digital orthogonal detection, temperature control 298K.
高效液相分析 （HPLC) 数据采自于 Agilent 1260， 仪器控制软件是 Agilent化学工作站 B.04 版 online , 分析软件是 Agilent 化学工作站 B.04 版 offline。 采用 C18 色谱柱， 150mmx4.6mm， 柱温 40°C， 波长 254nm， 流速 0.3ml/min， 进样量 50 μ 1， 运行时间 30min。 流动相 A为含 0.01%三氟乙酸的水， 流动相 B为含 0.01%三氟乙酸的乙腈， 梯度见表 1：  The HPLC data was taken from the Agilent 1260, the instrument control software was Agilent ChemStation Rev. B.04 online, and the analysis software was Agilent ChemStation Rev. B.04 offline. Using C18 column, 150mm x 4.6mm, column temperature 40 ° C, wavelength 254nm, flow rate 0.3ml / min, injection volume 50 μ 1, running time 30min. The mobile phase A was water containing 0.01% trifluoroacetic acid, and the mobile phase B was acetonitrile containing 0.01% trifluoroacetic acid. The gradient is shown in Table 1:
HPLC中流动相梯度表  Mobile phase gradient table in HPLC
Figure imgf000024_0001
Figure imgf000024_0001
片剂硬度检测数据采自于天津市新天光分析仪器技术有限公司的 YD-1 片剂硬度测试 仪。 将片剂放入测试台中， 顺时针旋转转动圆盘， 至药片被挤压破碎时的数值即为其硬度。  The tablet hardness test data was obtained from the YD-1 tablet hardness tester of Tianjin Xintianguang Analytical Instrument Technology Co., Ltd. Place the tablet in the test stand and turn the rotating disk clockwise until the value of the tablet is crushed and broken.
制备例 1 阿法替尼二马来酸盐现有技术晶型的制备  Preparation 1 Preparation of a prior art crystal form of afatinib dimaleate
取 lOOmg阿法替尼游离碱加入 1.5mL乙醇搅拌溶解， 加热至 70°C， 取 50mg马来酸加入 0.4mL 乙醇搅拌溶解， 将马来酸的乙醇溶液緩慢滴加至阿法替尼游离碱的乙醇溶液中， 搅拌， 析出固体后将反应液降温至室温， 室温搅拌 2-3h， 过滤， 40°C真空干燥过夜得阿法替尼二马来 酸盐。  Take 100 mg of afatinib free base and add 1.5 mL of ethanol to stir and dissolve. Heat to 70 ° C, take 50 mg of maleic acid and add 0.4 mL of ethanol to stir and dissolve. Add the ethanol solution of maleic acid slowly to afatinib free base. The ethanol solution was stirred, and the solid was precipitated. The reaction mixture was cooled to room temperature, stirred at room temperature for 2-3 h, filtered, and dried under vacuum at 40 ° C overnight to obtain afatinib dimaleate.
XRPD分析如图 2所示， 显示与 CN1867564B公开的阿法替尼二马来酸盐现有技术晶型 一致。  The XRPD analysis is shown in Figure 2, which is consistent with the prior art crystal form of afatinib dimaleate disclosed in CN1867564B.
TGA图谱如图 3所示， 显示该盐的分解温度为 164.1°C。  The TGA spectrum is shown in Figure 3, which shows that the decomposition temperature of the salt is 164.1 °C.
DSC图谱如图 4所示， 显示该盐的熔点为 166.2°C。  The DSC spectrum is shown in Figure 4, which shows that the salt has a melting point of 166.2 °C.
DVS等温吸附曲线如图 5所示，显示该盐在 10%-80%相对湿度范围内重量变化为 2.6%。 实施例 1 阿法替尼乙二磺酸盐的制备 The DVS isotherm adsorption curve is shown in Figure 5, which shows that the salt has a weight change of 2.6% in the range of 10% to 80% relative humidity. Example 1 Preparation of afatinib ethanedisulfonate
取 50mg 阿法替尼游离碱加入 lmL乙酸乙酯搅拌溶解，取 19.6mg乙二磺酸加入 2mL乙酸乙 酯搅拌溶解，将乙二磺酸的乙酸乙酯溶液緩慢滴加至阿法替尼游离碱的乙酸乙酯溶液中形成浆液， 搅拌， 室温反应过夜后有固体析出， 40°C真空旋干， 得 68mg阿法替尼乙二磺酸盐， 产率 97.7%。  50 mg of afatinib free base was added to 1 mL of ethyl acetate and stirred to dissolve. 19.6 mg of ethanedisulfonic acid was added to 2 mL of ethyl acetate and stirred to dissolve. The ethyl acetate solution of ethanedisulfonic acid was slowly added dropwise to the afatinib free. The slurry was slurried in a solution of the base in ethyl acetate. After stirring at room temperature overnight, a solid was precipitated and dried at 40 ° C under vacuum to give 68 mg of afatinib ethanedisulfonate in a yield of 97.7%.
实施例 2 E1晶型阿法替尼乙二磺酸盐的制备  Example 2 Preparation of E1 crystal form afatinib ethanedisulfonate
取 50mg 阿法替尼游离碱加入 lmL乙腈搅拌溶解，取 19.6mg乙二磺酸加入 2mL乙腈搅拌溶 解， 将乙二磺酸的乙腈溶液緩慢滴加至阿法替尼游离碱的乙腈溶液中形成浆液， 搅拌， 室温下反 应过夜有固体析出， 过滤， 40°C真空干燥过夜得 62mg El晶型阿法替尼乙二磺酸盐， 产率 89%。  50 mg of afatinib free base was added to 1 mL of acetonitrile and stirred to dissolve. 19.6 mg of ethanedisulfonic acid was added to 2 mL of acetonitrile and stirred to dissolve. The acetonitrile solution of ethanedisulfonic acid was slowly added dropwise to the acetonitrile solution of afatinib free base. The slurry was stirred, and reacted at room temperature overnight to precipitate a solid. The mixture was filtered and dried under vacuum at 40 ° C overnight to give 62 mg of the crystals of the crystals of the form of s.
实施例 3 E1晶型阿法替尼乙二磺酸盐的制备  Example 3 Preparation of E1 crystal form afatinib ethanedisulfonate
将实施例 2 中的 "将乙二磺酸的乙腈溶液緩慢滴加至阿法替尼游离碱的乙腈溶液中"替换 为 "将阿法替尼游离碱的乙腈溶液緩慢滴加至乙二磺酸的乙腈溶液中" ， 其他操作与实施例 2 相同， 得 63.6mg El晶型阿法替尼乙二磺酸盐， 产率 91.5%。  In Example 2, "slowly add acetonitrile solution of ethanedisulfonic acid to acetonitrile solution of afatinib free base" was replaced with "slow addition of acetonitrile solution of afatinib free base to ethanedisulfonate. In the acid acetonitrile solution, the other operation was the same as in Example 2 to obtain 63.6 mg of the crystalline form of afatinib ethanedisulfonate. The yield was 91.5%.
XRPD分析如图 6所示，  The XRPD analysis is shown in Figure 6.
PLM图谱如图 7所示。 显示： 该盐为颗粒状晶体， 和阿法替尼二马来酸盐现有技术晶型 的针状晶体相比有着更好的流动性和可加工性。  The PLM map is shown in Figure 7. It is shown that the salt is a granular crystal and has better fluidity and processability than the needle crystal of the prior art crystal form of afatinib dimaleate.
TGA图谱如图 8所示。 显示： 该盐在 150°C前有 3.4%的失重， 为水合物， 含 1.5摩尔水， 分解温度为 261.1 °C， 高于阿法替尼二马来酸盐现有技术晶型的分解温度 164.1°C，显示出更好 的热稳定性。  The TGA map is shown in Figure 8. It shows: The salt has a weight loss of 3.4% before 150 °C, is a hydrate, contains 1.5 moles of water, and has a decomposition temperature of 261.1 °C, which is higher than the decomposition temperature of the prior art crystal form of afatinib dimaleate. 164.1 ° C, showing better thermal stability.
DVS等温吸附曲线如图 9所示。显示：该盐在 10%-80%相对湿度范围内重量变化为 1.4%， 和阿法替尼二马来酸盐现有技术晶型在相同条件下 2.6%的重量变化相比， 有更低的吸湿性。  The DVS isotherm adsorption curve is shown in Figure 9. It is shown that the salt has a weight change of 1.4% in the range of 10%-80% relative humidity, and the prior art crystal form of afatinib dimaleate has a lower weight change of 2.6% under the same conditions. Hygroscopicity.
红外光谱分析如图 10所示。  Infrared spectroscopy analysis is shown in Figure 10.
拉曼光谱分析如图 11所示。 Raman spectroscopy is shown in Figure 11.
MR图谱如图 12所示。 显示： 阿法替尼和乙二磺酸已经成盐。  The MR spectrum is shown in Figure 12. Display: Afatinib and ethanedisulfonic acid have been salted.
HPLC检测显示该盐中阿法替尼的含量为 71.4%，与阿法替尼和乙二磺酸 1 : 1摩尔比成盐 的理论含量 71.9%接近， 说明阿法替尼和乙二磺酸以 1 : 1摩尔比成盐。  HPLC analysis showed that the content of afatinib in the salt was 71.4%, which was close to the theoretical content of salt of altitudinil and ethanedisulfonic acid of 1:1, which was 71.9%, indicating that afatinib and ethanedisulfonic acid Salt is formed in a molar ratio of 1:1.
实施例 4 E1晶型阿法替尼乙二磺酸盐的制备  Example 4 Preparation of E1 crystal form afatinib ethanedisulfonate
取 30mg 阿法替尼游离碱加入 0.5mL乙腈搅拌溶解， 取 19.6mg乙二碩酸加入 0.5mL乙 腈搅拌溶解， 将乙二磺酸的乙腈溶液緩慢滴加至阿法替尼游离碱的乙腈溶液中形成浆液， 搅 拌， 室温下反应过夜有固体析出， 过滤， 40°C真空干燥过夜得白色固体阿法替尼乙二磺酸盐。  Take 30mg of afatinib free base and add 0.5mL of acetonitrile to stir and dissolve. Take 19.6mg of acetylic acid and add 0.5mL of acetonitrile to stir and dissolve. Add acetonitrile solution of ethanedisulfonic acid slowly to acetonitrile solution of afatinib free base. The slurry was formed, stirred, and reacted at room temperature overnight to precipitate a solid, which was filtered and dried under vacuum at 40 ° C overnight to give a white solid afatinib ethanedisulfonate.
实施例 5 E1晶型阿法替尼乙二磺酸盐的制备  Example 5 Preparation of E1 crystal form afatinib ethanedisulfonate
取实施例 1制备的阿法替尼乙二磺酸盐 30 mg， 置于 50ml烧瓶中， 加入 2 ml甲醇形成 浆液， 室温搅拌 72小时， 过滤， 40°C真空干燥过夜， 得 E1晶型阿法替尼乙二磺酸盐。  30 mg of afatinib ethanedisulfonate prepared in Example 1 was placed in a 50 ml flask, and 2 ml of methanol was added to form a slurry, which was stirred at room temperature for 72 hours, filtered, and dried under vacuum at 40 ° C overnight to obtain E1 crystal form. Fatinib ethanedisulfonate.
实施例 6 E1晶型阿法替尼乙二磺酸盐的制备  Example 6 Preparation of E1 crystal form afatinib ethanedisulfonate
将实施例 5 中的 "甲醇"替换为 "甲基叔丁基醚" ， 其他操作同实施例 5， 得到晶 E1 型阿法替尼乙二磺酸盐。  The "methanol" in Example 5 was replaced with "methyl tert-butyl ether", and the other operation was the same as in Example 5 to obtain a crystalline form E1 type of afatinib ethanedisulfonate.
实施例 7 E1晶型阿法替尼乙二磺酸盐的制备  Example 7 Preparation of E1 crystal form afatinib ethanedisulfonate
将实施例 5中的 "甲醇"替换为 "丙酮"， 其他操作同实施例 5， 得到 E1晶型阿法替尼 乙二磺酸盐。  The "methanol" in Example 5 was replaced with "acetone", and the other operation was the same as in Example 5 to obtain the E1 crystal form of afatinib ethanedisulfonate.
实施例 8 E1晶型阿法替尼乙二磺酸盐的制备  Example 8 Preparation of E1 crystal form afatinib ethanedisulfonate
将实施例 5中的 "甲醇"替换为 "正庚烷"， 其他操作同实施例 5， 得到 E1晶型阿法替 尼乙二磺酸盐。  The "methanol" in Example 5 was replaced with "n-heptane", and the other operation was the same as in Example 5 to obtain the E1 crystal form of afatinibethane disulfonate.
实施例 9 E1晶型阿法替尼乙二磺酸盐的制备  Example 9 Preparation of E1 crystal form afatinib ethanedisulfonate
将实施例 5中的 "甲醇"替换为 "乙酸乙酯"， 其他操作同实施例 5， 得到 E1晶型阿法 替尼乙二磺酸盐。  The "methanol" in Example 5 was replaced with "ethyl acetate", and the other operation was the same as in Example 5 to obtain the E1 crystal form of alfatinib ethanedisulfonate.
实施例 10 E1晶型阿法替尼乙二磺酸盐的制备  Example 10 Preparation of E1 Form Afatinibethanedisulfonate
将实施例 2中的 " 19.6mg乙二磺酸"替换为 "39.1mg乙二磺酸"， 其他操作同实施例 2， 得到 El晶型阿法替尼乙二磺酸盐。 Substituting "19. 6 mg of ethanedisulfonic acid" in Example 2 with "39.1 mg of ethanedisulfonic acid", the other operation is the same as in Example 2. El crystal form afatinib ethanedisulfonate was obtained.
实施例 11 阿法替尼 1,5-萘二磺酸盐的制备  Example 11 Preparation of afatinib 1,5-naphthalenedisulfonate
取 50mg 阿法替尼游离碱加入 lmL丙酮搅拌溶解， 取 37.1mg 1,5-萘二磺酸四水合物加入 2mL丙酮搅拌溶解， 将 1,5-萘二磺酸的丙酮溶液緩慢滴加至阿法替尼游离碱的丙酮溶液中形成 浆液， 搅拌， 室温下固体析出后搅拌过夜， 40°C真空旋干， 得 78mg阿法替尼 1,5-萘二磺酸盐， 产率 98%。  Take 50mg of afatinib free base and add 1mL of acetone to stir and dissolve. Take 37.1mg of 1,5-naphthalene disulfonic acid tetrahydrate and add 2mL of acetone to stir and dissolve. Add acetone solution of 1,5-naphthalene disulfonic acid slowly to A slurry of afatinib free base is formed in acetone, stirred, and the solid is precipitated at room temperature, stirred overnight, and dried at 40 ° C under vacuum to obtain 78 mg of afatinib 1,5-naphthalenedisulfonate, yield 98%. .
实施例 12 N1晶型阿法替尼 1,5-萘二磺酸盐的制备  Example 12 Preparation of N1 crystal form afatinib 1,5-naphthalene disulfonate
取 50mg 阿法替尼游离碱加入 lmL乙腈搅拌溶解， 取 37.1mg 1,5-萘二碩酸四水合物加入 2mL 乙醇搅拌溶解， 将 1,5-萘二磺酸的乙醇溶液緩慢滴加至阿法替尼游离碱的乙腈溶液中形成 浆液， 搅拌， 室温下固体析出后搅拌过夜， 过滤， 40°C真空干燥过夜， 得 71mg Nl晶型阿法替 尼 1,5-萘二磺酸盐， 产率 89.2%。  Take 50mg of afatinib free base and add 1mL of acetonitrile to stir and dissolve. Take 37.1mg of 1,5-naphthalene dioxalate tetrahydrate and add 2mL of ethanol to stir and dissolve. Add 1,5-naphthalenedisulfonic acid in ethanol to the ethanol solution slowly. A slurry of afatinib free base in acetonitrile is stirred, stirred at room temperature, stirred overnight, filtered, and dried under vacuum at 40 ° C overnight to obtain 71 mg of Nl crystal form afatinib 1,5-naphthalenedisulfonate. , the yield was 89.2%.
XRPD分析如图 13所示。  The XRPD analysis is shown in Figure 13.
PLM图谱如图 14所示。 显示： 该盐为颗粒状晶体， 较为规则， 和阿法替尼二马来酸盐 现有技术晶型的针状晶体相比， 有着更好的流动性和可加工性。  The PLM map is shown in Figure 14. It shows: The salt is a granular crystal, which is more regular and has better fluidity and processability than the needle-like crystal of the prior art crystal form of afatinib dimaleate.
TGA图谱如图 15所示。 显示： 样品为无水物， 分解温度为 276.3°C， 和阿法替尼二马来 酸盐现有技术晶型的 164.1°C分解温度相比有着更好的热稳定性。  The TGA map is shown in Figure 15. Show: The sample is anhydrate with a decomposition temperature of 276.3 ° C, which has better thermal stability than the 164.1 ° C decomposition temperature of the prior art crystal form of afatinib dimaleate.
DVS等温吸附曲线如图 16所示。显示： N1晶型阿法替尼 1,5-萘二磺酸盐在 50%相对湿 度以下稳定， 在 50%相对湿度以上开始形成 N2晶型阿法替尼 1,5-萘二磺酸盐水合物， 形成 N2 晶型阿法替尼 1,5-萘二磺酸盐水合物后至 80%相对湿度， 吸水的重量变化为 1.8% ; N2 晶型阿法替尼 1,5-萘二磺酸盐水合物在 30%相对湿度以上稳定，在 30%相对湿度以下开始脱 去结晶水。 和阿法替尼二马来酸盐现有技术晶型在相同条件下 （30%-80%相对湿度下） 吸水 重量变化为 2.2%相比， N2晶型阿法替尼 1,5-萘二磺酸盐水合物有更低的吸湿性。  The DVS isotherm adsorption curve is shown in Figure 16. Display: N1 crystal form afatinib 1,5-naphthalene disulfonate is stable below 50% relative humidity, starting to form N2 crystal form afatinib 1,5-naphthalene disulfonate above 50% relative humidity Hydrate, forming N2 crystal form afatinib 1,5-naphthalene disulfonic acid salt hydrate to 80% relative humidity, water absorption weight change is 1.8%; N2 crystal form afatinib 1,5-naphthalene The sulfonic acid salt hydrate is stable above 30% relative humidity, and de-crystallization water is started to be removed below 30% relative humidity. Compared with the former crystalline form of afatinib dimaleate under the same conditions (30%-80% relative humidity), the water absorption weight change is 2.2%, N2 crystal form afatinib 1,5-naphthalene The disulfonic acid salt hydrate has a lower hygroscopicity.
红外光谱分析如图 17所示。  Infrared spectroscopy analysis is shown in Figure 17.
拉曼光谱分析如图 18所示。 Raman spectroscopy is shown in Figure 18.
MR图谱如图 19所示。 显示： 阿法替尼和 1,5-萘二磺酸已经成盐。  The MR spectrum is shown in Figure 19. Display: Afatinib and 1,5-naphthalene disulfonic acid have been salted.
HPLC检测显示该盐中阿法替尼含量为 63.3%，与阿法替尼和 1,5-萘二磺酸以 1 : 1摩尔比 成盐的理论含量 62.8%接近， 说明阿法替尼和 1,5-萘二磺酸以 1 : 1摩尔比成盐。  HPLC analysis showed that the content of afatinib in the salt was 63.3%, which was close to the theoretical content of salt of afatinib and 1,5-naphthalenedisulfonic acid in a molar ratio of 1:1, which was 62.8%, indicating that afatinib and 1,5-naphthalenedisulfonic acid was salted in a molar ratio of 1:1.
实施例 13 N1晶型阿法替尼 1,5-萘二磺酸盐的制备  Example 13 Preparation of N1 crystal form afatinib 1,5-naphthalene disulfonate
取 15mg阿法替尼游离碱加入 0.5mL乙腈搅拌溶解，取 14.8mg 1,5-萘二碩酸四水合物加入 0.5mL乙醇搅拌溶解， 将 1,5萘二磺酸的乙醇溶液緩慢滴加至阿法替尼游离碱的乙腈溶液中， 搅拌， 固体析出后搅拌过夜， 过滤， 40°C真空干燥过夜得白色固体阿法替尼 1,5-萘二磺酸盐。  Take 15mg of afatinib free base and add 0.5mL of acetonitrile to stir and dissolve. Take 14.8mg of 1,5-naphthalene dioxalate tetrahydrate and add 0.5mL of ethanol to stir and dissolve. Add 1,5 naphthalene disulfonic acid in ethanol solution slowly. To a solution of afatinib free base in acetonitrile, stirred, solid precipitated, stirred overnight, filtered, and dried in vacuo at 40 ° C overnight to give a white solid afatinib 1,5-naphthalene disulfonate.
实施例 14 N1晶型阿法替尼 1,5-萘二磺酸盐的制备  Example 14 Preparation of N1 crystal form afatinib 1,5-naphthalene disulfonate
取实施例 11制备的阿法替尼 1,5萘二磺酸盐 30mg， 置于 50ml烧瓶中，加入 2ml甲醇形 成浆液， 室温下搅拌 72小时， 过滤， 40°C真空干燥得 N1晶型阿法替尼 1,5萘二磺酸盐。  30 mg of afatinib 1,5 naphthalenedisulfonate prepared in Example 11 was placed in a 50 ml flask, and 2 ml of methanol was added to form a slurry, which was stirred at room temperature for 72 hours, filtered, and vacuum dried at 40 ° C to obtain N1 crystal form. Fatinib 1,5 naphthalene disulfonate.
实施例 15 N1晶型阿法替尼 1,5-萘二磺酸盐的制备  Example 15 Preparation of N1 crystal form afatinib 1,5-naphthalene disulfonate
将实施例 14 中的 "甲醇"替换为 "甲基叔丁基醚" ， 其他操作同实施例 14， 得到 N1 晶型阿法替尼 1,5-萘二磺酸盐。  The "methanol" in Example 14 was replaced with "methyl tert-butyl ether", and the other operation was the same as in Example 14, to obtain the N1 crystal form of afatinib 1,5-naphthalene disulfonate.
实施例 16 N1晶型阿法替尼 1,5-萘二磺酸盐的制备  Example 16 Preparation of N1 crystal form afatinib 1,5-naphthalene disulfonate
将实施例 14中的 "甲醇"替换为 "丙酮" ， 其他操作同实施例 14， 得到 N1 晶型阿法 替尼 1,5-萘二磺酸盐。  The "methanol" in Example 14 was replaced with "acetone", and the other operation was the same as in Example 14, to obtain the N1 crystal form of afatinib 1,5-naphthalenedisulfonate.
实施例 17 N1晶型阿法替尼 1,5-萘二磺酸盐的制备  Example 17 Preparation of N1 crystal form afatinib 1,5-naphthalene disulfonate
将实施例 14中的 "甲醇"替换为 "正庚烷" ， 其他操作同实施例 14， 得到 N1 晶型阿 法替尼 1,5-萘二磺酸盐。  The "methanol" in Example 14 was replaced with "n-heptane", and the other operation was the same as in Example 14, to obtain the N1 crystal form of favertinib 1,5-naphthalene disulfonate.
实施例 18 N1晶型阿法替尼 1,5-萘二磺酸盐的制备  Example 18 Preparation of N1 crystal form afatinib 1,5-naphthalene disulfonate
将实施例 14中的 "甲醇"替换为 "乙酸乙酯" ， 其他操作同实施例 14， 得到 N1 晶型 阿法替尼 1,5-萘二磺酸盐。 实施例 19 Nl晶型阿法替尼 1,5-萘二磺酸盐的制备 The "methanol" in Example 14 was replaced with "ethyl acetate", and the other operation was the same as in Example 14 to obtain the N1 crystal form of afatinib 1,5-naphthalenedisulfonate. Example 19 Preparation of Nl Form Afatinib 1,5-Naphthalene Disulfonate
将实施例 12中的 "37.1mg 1,5-萘二磺酸四水合物"替换为 "74.2mgl,5-萘二磺酸四水合 物" ， 其它操作同实施例 12， 得到 N1晶型阿法替尼 1,5-萘二磺酸盐。  The "37.1 mg 1,5-naphthalene disulfonic acid tetrahydrate" in Example 12 was replaced with "74.2 mgl, 5-naphthalene disulfonic acid tetrahydrate", and the other operation was the same as in Example 12 to obtain the N1 crystal form. Fatinib 1,5-naphthalene disulfonate.
实施例 20 N2晶型阿法替尼 1,5-萘二磺酸盐水合物的制备  Example 20 Preparation of N2 crystal form afatinib 1,5-naphthalene disulfonic acid salt hydrate
取 50mg 实施例 12制备的 N1晶型阿法替尼 1,5-萘二磺酸盐，室温下放置于相对湿度 75% 的湿度器中 24小时， 得 N2晶型阿法替尼 1,5-萘二磺酸盐水合物。  50 mg of the N1 crystal form afatinib 1,5-naphthalene disulfonate prepared in Example 12 was placed in a humidifier having a relative humidity of 75% at room temperature for 24 hours to obtain N2 crystal form afatinib 1,5. - Naphthalene disulfonic acid salt hydrate.
XRPD分析如图 20所示。  The XRPD analysis is shown in Figure 20.
PLM图谱如图 21所示。 显示： 该盐为颗粒状晶体， 较为规则， 和阿法替尼二马来酸盐 现有技术晶型的针状晶体相比有着更好的流动性和可加工性。  The PLM map is shown in Figure 21. It shows: The salt is a granular crystal, which is more regular and has better fluidity and processability than the needle-like crystal of the prior art crystal form of afatinib dimaleate.
TGA图谱如图 22所示。 显示： 该样品 100°〇之前有5.97%的失重， 为三水合物， 分解温 度为 275.4°C， 和阿法替尼二马来酸盐现有技术晶型的 164.1 °C分解温度相比有着更好的热稳 定性。  The TGA map is shown in Figure 22. Display: The sample has a weight loss of 5.97% before 100 ° ,, which is a trihydrate with a decomposition temperature of 275.4 ° C. Compared with the decomposition temperature of the 164.1 ° C of the prior art crystal form of afatinib dimaleate Better thermal stability.
DVS等温吸附曲线如图 16所示。显示： N1晶型阿法替尼 1,5-萘二磺酸盐在 50%相对湿 度以上开始形成 N2晶型阿法替尼 1,5-萘二磺酸盐水合物， 形成 N2晶型阿法替尼 1,5-萘二 磺酸盐水合物后至 80%相对湿度， 吸水的重量变化为 1.8%， N2晶型阿法替尼 1,5-萘二磺酸 盐水合物在 30%相对湿度以上稳定， 在 30%相对湿度以下开始脱去结晶水。 和阿法替尼二马 来酸盐现有技术晶型在相同条件下 （30%-80%相对湿度下） 吸水重量变化为 2.2%相比， N2 晶型阿法替尼 1,5-萘二磺酸盐水合物有着更低的吸湿性。  The DVS isotherm adsorption curve is shown in Figure 16. It is shown that: N1 crystal form afatinib 1,5-naphthalene disulfonate starts to form N2 crystal form afatinib 1,5-naphthalenedisulfonic acid salt hydrate at 50% relative humidity to form N2 crystal form. After fatinib 1,5-naphthalene disulfonic acid salt hydrate to 80% relative humidity, the weight change of water absorption is 1.8%, and the N2 crystal form afatinib 1,5-naphthalene disulfonic acid salt hydrate is 30%. It is stable above the relative humidity, and starts to remove the crystal water below 30% relative humidity. Compared with the former crystalline form of afatinib dimaleate under the same conditions (30%-80% relative humidity), the water absorption weight change is 2.2%, N2 crystal form afatinib 1,5-naphthalene Disulfonic acid salt hydrate has a lower hygroscopicity.
红外光谱分析如图 23所示。  Infrared spectroscopy analysis is shown in Figure 23.
拉曼光谱分析如图 24所示。  Raman spectroscopy is shown in Figure 24.
实施例 21 N2晶型阿法替尼 1,5-萘二磺酸盐水合物的制备  Example 21 Preparation of N2 crystal form afatinib 1,5-naphthalene disulfonic acid salt hydrate
将实施例 20中的 "相对湿度 75%的湿度器"替换为 "相对湿度 85%的湿度器" ， 其它 操作同实施例 20， 得到 N2晶型阿法替尼 1,5-萘二磺酸盐水合物。  The "humidifier with relative humidity of 75%" in Example 20 was replaced with "humidifier with relative humidity of 85%", and the other operation was the same as in Example 20 to obtain N2 crystal form afatinib 1,5-naphthalene disulfonic acid. Salt hydrate.
实施例 22 N2晶型阿法替尼 1,5-萘二磺酸盐水合物的制备  Example 22 Preparation of N2 crystal form afatinib 1,5-naphthalene disulfonic acid salt hydrate
将实施例 20中的 "24小时"替换为 "3天" ， 其它操作同实施例 20， 得到 N2晶型阿 法替尼 1,5-萘二磺酸盐水合物。  The "24 hours" in Example 20 was replaced with "3 days", and the other operation was the same as in Example 20 to obtain an N2 crystal form of afatinib 1,5-naphthalene disulfonic acid salt hydrate.
实施例 23 阿法替尼一丙二酸盐的制备  Example 23 Preparation of afatinib monomalonate
取 50mg阿法替尼游离碱加入 4mL乙醇搅拌溶解， 取 15.9mg丙二酸加入 4mL乙醇搅拌 溶解， 将丙二酸的乙醇液緩慢滴加至阿法替尼游离碱的乙醇溶液中形成浆液并搅拌， 室温下 搅拌过夜有固体析出， 40°C真空旋干， 得阿法替尼一丙二酸盐 59.1 mg， 产率 97.3%。  Take 50mg of afatinib free base and add 4mL of ethanol to stir and dissolve. Take 15.9mg of malonic acid and add 4mL of ethanol to stir and dissolve. Add the ethanol solution of malonic acid slowly to the ethanol solution of afatinib free base to form a slurry. After stirring, the mixture was stirred overnight at room temperature to precipitate a solid, which was then evaporated to dryness at 40 ° C to give a fartininin-malonate 59.1 mg, yield 97.3%.
实施例 24 Ml晶型阿法替尼一丙二酸盐的制备  Example 24 Preparation of Ml crystal form afatinib monomalonate
取 50mg阿法替尼游离碱加入 4mL甲基叔丁基醚搅拌溶解， 取 15.9mg丙二酸加入 4mL甲 基叔丁基醚搅拌溶解， 将丙二酸的甲基叔丁基醚溶液緩慢滴加至阿法替尼游离碱的甲基叔丁基 醚溶液中形成浆液并搅拌， 室温下搅拌过夜有固体析出， 过滤， 40°C真空干燥过夜， 得 Ml 晶 型阿法替尼一丙二酸盐 55mg， 产率 90.6%。  50 mg of afatinib free base was added to 4 mL of methyl tert-butyl ether and stirred to dissolve. 15.9 mg of malonic acid was added to 4 mL of methyl t-butyl ether and stirred to dissolve. The methyl tert-butyl ether solution of malonic acid was slowly dropped. Adding to a solution of afatinib free base in methyl tert-butyl ether to form a slurry and stirring, stirring at room temperature overnight, solid precipitation, filtration, vacuum drying at 40 ° C overnight, to obtain Ml crystal form afatinib-propane The acid salt was 55 mg, and the yield was 90.6%.
XRPD分析如图 25所示。  The XRPD analysis is shown in Figure 25.
PLM图谱如图 26所示。 显示： 该盐为颗粒状晶体， 较为规则， 和阿法替尼二马来酸盐 现有技术晶型的针状晶体相比有着更好的流动性和可加工性。  The PLM map is shown in Figure 26. It shows: The salt is a granular crystal, which is more regular and has better fluidity and processability than the needle-like crystal of the prior art crystal form of afatinib dimaleate.
TGA图谱如图 27所示。 显示： 该盐的分解温度为 108.3°C。  The TGA map is shown in Figure 27. Display: The decomposition temperature of this salt is 108.3 °C.
红外光谱分析如图 28所示。  Infrared spectroscopy analysis is shown in Figure 28.
拉曼光谱分析如图 29所示。 Raman spectroscopy is shown in Figure 29.
MR图谱如图 30所示。 显示： 阿法替尼和丙二酸已经成盐。  The MR spectrum is shown in Figure 30. Display: Afatinib and malonic acid have been salted.
HPLC检测显示该盐中阿法替尼含量为 83.0%，与阿法替尼和丙二酸以 1 : 1摩尔比成盐的 理论含量 82.4%接近， 说明阿法替尼和丙二酸以 1 : 1摩尔比成盐。  HPLC analysis showed that the content of afatinib in the salt was 83.0%, which was close to the theoretical content of 82.4% of the salt of afatinib and malonic acid in a molar ratio of 1:1, indicating that alfatinib and malonic acid were 1 : 1 molar ratio to salt.
实施例 25 Ml晶型阿法替尼一丙二酸盐的制备  Example 25 Preparation of Ml crystal form afatinib mono malonate
取实施例 19制备的阿法替尼一丙二酸盐 30mg， 置于 50ml烧瓶中， 加入 2 ml甲醇形成 浆液， 室温下搅拌 72小时， 过滤， 40°C真空干燥得 Ml晶型阿法替尼一丙二酸盐。 30 mg of afatinib monomalonate prepared in Example 19 was placed in a 50 ml flask and 2 ml of methanol was added to form The slurry was stirred at room temperature for 72 hours, filtered, and dried under vacuum at 40 ° C to obtain M1 crystal form afatinib monopropionate.
实施例 26 Ml晶型阿法替尼一丙二酸盐的制备  Example 26 Preparation of Ml crystal form afatinib monomalonate
将实施例 25中的 "甲醇"替换为 "乙酸乙酯" ， 其他操作同实施例 25， 得到 Ml晶型 阿法替尼一丙二酸盐。  The "methanol" in Example 25 was replaced with "ethyl acetate", and the other operation was the same as in Example 25 to obtain the M1 crystal form afatinib monomalonate.
实施例 27 Ml晶型阿法替尼一丙二酸盐的制备  Example 27 Preparation of Ml crystal form afatinib monomalonate
将实施例 25中的 "甲醇"替换为 "丙酮" ， 其他操作同实施例 25， 得到 Ml晶型阿法 替尼一丙二酸盐。  The "methanol" in Example 25 was replaced with "acetone", and the other operation was the same as in Example 25 to obtain the M1 crystal form of afatinib monomalonate.
实施例 28 Ml晶型阿法替尼一丙二酸盐的制备  Example 28 Preparation of Ml crystal form afatinib monomalonate
将实施例 25中的 "甲醇"替换为 "正庚烷" ， 其他操作同实施例 25， 得到 Ml晶型阿 法替尼一丙二酸盐。  The "methanol" in Example 25 was replaced with "n-heptane", and the other operation was the same as in Example 25 to obtain the M1 crystal form of favertinib-malonate.
实施例 29 阿法替尼二丙二酸盐的制备  Example 29 Preparation of afatinib dipropionate
取 50mg 阿法替尼游离碱加入 1.5mL乙腈中搅拌溶解， 取 21.4mg丙二酸加入 4mL乙腈 搅拌溶解， 将阿法替尼游离碱的乙腈溶液緩慢滴加至丙二酸的乙腈溶液中形成浆液， 搅拌， 室温下固体析出后搅拌过夜， 40°C真空旋干， 得阿法替尼二丙二酸盐 69mg， 产率 96.6%。  50 mg of afatinib free base was added to 1.5 mL of acetonitrile and stirred to dissolve. 21.4 mg of malonic acid was added to 4 mL of acetonitrile and stirred to dissolve. The acetonitrile solution of afatinib free base was slowly added dropwise to the solution of malonic acid in acetonitrile. The slurry was stirred, and the solid was precipitated at room temperature, stirred overnight, and dried under vacuum at 40 ° C to give 69 mg of afinidin dimalonate, yield 96.6%.
实施例 30 M2晶型阿法替尼二丙二酸盐的制备  Example 30 Preparation of M2 crystal form afatinib dipropanediate
取实施例 23制备的 50mg 阿法替尼一丙二酸盐加入 lmL乙酸乙酯中配成混悬液并搅拌， 取 8.81mg丙二酸加入 2mL乙酸乙酯搅拌溶解， 将丙二酸的乙酸乙酯溶液緩慢滴加至阿法替尼 一丙二酸盐的乙酸乙酯混悬液中形成浆液， 室温下搅拌过夜， 过滤， 40°C真空干燥过夜得 M2 晶型阿法替尼二丙二酸盐 52.5mg， 产率 89.3%。  50 mg of afatinib monomalonate prepared in Example 23 was added to 1 mL of ethyl acetate to prepare a suspension and stirred, and 8.81 mg of malonic acid was added to 2 mL of ethyl acetate to stir and dissolve, and acetic acid of malonic acid was added. The ethyl ester solution was slowly added dropwise to an ethyl acetate suspension of afatinib monomalonate to form a slurry, stirred at room temperature overnight, filtered, and dried under vacuum at 40 ° C overnight to obtain M2 crystal form afatinib dipropyl The diacid salt was 52.5 mg, and the yield was 89.3%.
实施例 31 M2晶型阿法替尼二丙二酸盐的制备  Example 31 Preparation of M2 crystal form afatinib dipropanediate
取 50mg阿法替尼游离碱加入 1.5mL乙酸乙酯中搅拌溶解， 取 21.4mg丙二酸加入 4mL乙 酸乙酯搅拌溶解， 将阿法替尼游离碱的乙酸乙酯溶液緩慢滴加至丙二酸的乙酸乙酯溶液中形成 浆液并搅拌， 室温下固体析出后搅拌过夜， 过滤， 40°C真空干燥过夜， 得 M2晶型阿法替尼二 丙二酸盐 66mg， 产率 92.4%。  50 mg of afatinib free base was added to 1.5 mL of ethyl acetate and stirred to dissolve. 21.4 mg of malonic acid was added to 4 mL of ethyl acetate and stirred to dissolve. The ethyl acetate solution of afatinib free base was slowly added dropwise to C. A slurry of the acid in ethyl acetate was formed and stirred, and the solid was precipitated at room temperature, stirred overnight, filtered, and dried under vacuum at 40 ° C overnight to yield 66 mg of the M2 crystal form afatinib dimalonate in a yield of 92.4%.
XRPD分析如图 31所示。  The XRPD analysis is shown in Figure 31.
TGA图谱如图 32所示。 显示： 该盐的分解温度为 105.7°C。  The TGA map is shown in Figure 32. Display: The decomposition temperature of this salt is 105.7 °C.
DVS 等温吸附曲线如图 33 所示。 显示： 该盐在 10%-80%相对湿度范围内重量变化为 1.1%, 和阿法替尼二马来酸盐现有技术晶型 2.6%的重量变化相比有着更低的吸湿性。  The DVS isotherm adsorption curve is shown in Figure 33. It shows: The salt has a weight change of 1.1% in the range of 10%-80% relative humidity, and has a lower hygroscopicity than the 2.6% weight change of the prior art crystal form of afatinib dimaleate.
红外光谱分析如图 34所示。  Infrared spectroscopy analysis is shown in Figure 34.
拉曼光谱分析如图 35所示。 Raman spectroscopy is shown in Figure 35.
MR图谱如图 36所示。 显示： 阿法替尼和丙二酸已经成盐。  The MR spectrum is shown in Figure 36. Display: Afatinib and malonic acid have been salted.
HPLC检测显示该盐中阿法替尼含量为 70.2%，与阿法替尼和丙二酸以 1 :2摩尔比成盐的 理论含量 70.0%接近， 说明阿法替尼和丙二酸以 1 :2摩尔比成盐。  HPLC analysis showed that the content of afatinib in the salt was 70.2%, which was close to the theoretical content of 70.0% of the salt of afatinib and malonic acid in a 1:2 molar ratio, indicating that afatinib and malonic acid were 1 : 2 molar ratio to salt.
实施例 32 M2晶型阿法替尼二丙二酸盐的制备  Example 32 Preparation of M2 Crystal Form Afatinib Dipropionate
取实施例 29制备的阿法替尼二丙二酸盐 30mg， 置于 50ml烧瓶中， 加入 2 ml甲醇形成浆 液， 室温下搅拌 72小时， 过滤， 40°C真空干燥得 M2晶型阿法替尼二丙二酸盐。  30 mg of afatinib dipropanedicarboxylate prepared in Example 29 was placed in a 50 ml flask, and 2 ml of methanol was added to form a slurry, which was stirred at room temperature for 72 hours, filtered, and dried under vacuum at 40 ° C to obtain M2 crystal form Afate. Nitradipropionate.
实施例 33 M2晶型阿法替尼二丙二酸盐的制备  Example 33 Preparation of M2 crystal form afatinib dipropanediate
将实施例 32中的 "甲醇"替换为 "乙酸乙酯" ， 其他操作同实施例 32， 得到 M2晶型 阿法替尼二丙二酸盐。  The "methanol" in Example 32 was replaced with "ethyl acetate", and the other operation was the same as in Example 32 to obtain the M2 crystal form of afatinib dimalonate.
实施例 34 M2晶型阿法替尼二丙二酸盐的制备  Example 34 Preparation of M2 crystal form afatinib dipropanedioate
将实施例 32中的 "甲醇"替换为 "丙酮" ， 其他操作同实施例 32， 得到 M2晶型阿法 替尼二丙二酸盐。  The "methanol" in Example 32 was replaced with "acetone", and the other operation was the same as in Example 32 to obtain the M2 crystal form of afatinib dipropanedioate.
实施例 35 M2晶型阿法替尼二丙二酸盐的制备  EXAMPLE 35 Preparation of M2 Formal Afatinib Dipropionate
将实施例 32中的 "甲醇"替换为 "正庚烷" ， 其他操作同实施例 32， 得到 M2晶型阿 法替尼二丙二酸盐。  The "methanol" in Example 32 was replaced with "n-heptane", and the other operation was the same as in Example 32 to obtain the M2 crystal form of favertinibdipropane.
实施例 36 M2晶型阿法替尼二丙二酸盐的制备 将实施例 31中的 "21.4mg丙二酸"替换为 "42.8mg丙二酸"， 其他操作同实施例 31， 得到 M2晶型阿法替尼二丙二酸盐。 Example 36 Preparation of M2 Crystal Form Afatinib Dipropionate The "21.4 mg of malonic acid" in Example 31 was replaced with "42.8 mg of malonic acid", and the other operation was the same as in Example 31 to obtain the M2 crystal form of afatinib dipropanedioate.
实施例 37 阿法替尼二 2-萘磺酸盐的制备  Example 37 Preparation of afatinib di 2-naphthalenesulfonate
取 50mg 阿法替尼游离碱加入 1.5mL丙酮搅拌溶解， 取 42.8mg 2-萘碩酸加入 3mL丙酮 搅拌溶解，将 2-萘磺酸的丙酮溶液緩慢滴加至阿法替尼游离碱的丙酮溶液中形成浆液，搅拌， 室温下有固体析出后搅拌过夜， 40°C真空旋干，得阿法替尼二 2-萘磺酸盐 90mg，产率 97.0%。  Take 50mg of afatinib free base and add 1.5mL of acetone to stir and dissolve. Take 42.8mg of 2-naphthalene acid and add 3mL of acetone to stir and dissolve. Add the acetone solution of 2-naphthalenesulfonic acid slowly to acetone of afatinib free base. A slurry was formed in the solution, stirred, and a solid was precipitated at room temperature, stirred overnight, and then vacuum-dried at 40 ° C to obtain 90 mg of afatinib di 2-naphthalenesulfonate in a yield of 97.0%.
实施例 38 Nsl晶型阿法替尼二 2-萘磺酸盐的制备  Example 38 Preparation of Nsl Form Afatinib Di 2-Naphthalenesulfonate
取 50mg 阿法替尼游离碱加入 1.5mL乙酸乙酯， 取 42.8mg 2-萘碩酸加入 3mL乙酸乙酯 搅拌溶解， 将 2-萘磺酸的乙酸乙酯溶液緩慢滴加至阿法替尼游离碱的乙酸乙酯溶液中形成浆 液， 搅拌， 室温下有固体析出后搅拌过夜， 过滤 40°C真空干燥过夜， 得 Nsl晶型阿法替尼二 2-萘碩酸盐 85mg， 产率 91.7%。  50 mg of afatinib free base was added to 1.5 mL of ethyl acetate, 42.8 mg of 2-naphthalene acid was added to 3 mL of ethyl acetate and stirred to dissolve, and the ethyl acetate solution of 2-naphthalenesulfonic acid was slowly added dropwise to the afatinib. The slurry was slurried in a solution of the free base in ethyl acetate. Stirring was carried out. After solid precipitation at room temperature, the mixture was stirred overnight, and dried under vacuum at 40 ° C overnight to obtain 85 mg of Nsl crystal form afatinib di 2-naphthoate, yield 91.7. %.
XRPD分析如图 37所示。  The XRPD analysis is shown in Figure 37.
TGA图谱如图 38所示。 显示： 该盐的分解温度为 249.1°C， 和阿法替尼二马来酸盐现有 技术晶型的 164.1 °C分解温度相比有着更好的热稳定性。  The TGA map is shown in Figure 38. It shows: The decomposition temperature of this salt is 249.1 ° C, which has better thermal stability than the 164.1 ° C decomposition temperature of the prior art crystal form of afatinib dimaleate.
红外光谱分析如图 39所示。  Infrared spectroscopy analysis is shown in Figure 39.
拉曼光谱分析如图 40所示。 Raman spectroscopy is shown in Figure 40.
MR图谱如图 41所示。 显示： 阿法替尼和 2-萘磺酸已经成盐。  The MR spectrum is shown in Figure 41. Display: Afatinib and 2-naphthalenesulfonic acid have been salted.
HPLC检测显示该盐中阿法替尼含量为 55.0%， 与阿法替尼和 2-萘磺酸以 1 :2摩尔比成 盐的理论含量 53.9%接近， 说明阿法替尼和 2-萘磺酸以 1 :2摩尔比成盐。  HPLC analysis showed that the content of afatinib in the salt was 55.0%, which was close to the theoretical content of salt of afatinib and 2-naphthalenesulfonic acid in a 1:2 molar ratio of 53.9%, indicating that afatinib and 2-naphthalene The sulfonic acid is salted in a 1:2 molar ratio.
实施例 39 阿法替尼一 2-萘磺酸盐的制备  Example 39 Preparation of afatinib 2-naphthalenesulfonate
取 10mg 阿法替尼游离碱加入 0.5mL乙酸乙酯搅拌溶解， 取 4.3mg 2-萘磺酸加入 0.5mL乙 酸乙酯搅拌溶解， 将 2-萘磺酸的乙酸乙酯溶液緩慢滴加至阿法替尼游离碱的乙酸乙酯溶液中， 搅拌， 室温下有固体析出后搅拌过夜， 过滤 40°C真空干燥过夜， 得白色固体阿法替尼一 2-萘碩 酸盐。  Take 10 mg of afatinib free base and add 0.5 mL of ethyl acetate to stir and dissolve. Take 4.3 mg of 2-naphthalenesulfonic acid and add 0.5 mL of ethyl acetate to stir and dissolve. Add 2-ethyl naphthalenesulfonic acid in ethyl acetate slowly. The solution of the pentinib free base in ethyl acetate was stirred, and the solid was precipitated at room temperature, stirred overnight, and dried under vacuum at 40 ° C overnight to give a white solid afatinib- 2-naphthalene acid salt.
实施例 40 Nsl晶型阿法替尼二 2-萘磺酸盐的制备  Example 40 Preparation of Nsl Form Afatinib Di 2-Naphthalenesulfonate
取实施例 37制备的阿法替尼二 2-萘磺酸盐 30mg， 置于 50ml烧瓶中， 加入 0.2ml甲醇 形成浆液， 室温下搅拌 72小时， 过滤， 40°C真空干燥得 Nsl晶型阿法替尼二 2-萘磺酸盐。  30 mg of afatinib di 2-naphthalenesulfonate prepared in Example 37 was placed in a 50 ml flask, and 0.2 ml of methanol was added to form a slurry, which was stirred at room temperature for 72 hours, filtered, and dried under vacuum at 40 ° C to obtain Nsl crystal form. Fatinib di 2-naphthalene sulfonate.
实施例 41 Nsl晶型阿法替尼二 2-萘磺酸盐的制备  Example 41 Preparation of Nsl Form Afatinib Di 2-Naphthalenesulfonate
将实施例 40中的 "甲醇"替换为 "甲基叔丁基醚" ， 其他操作同实施例 40， 得到 Nsl 晶型阿法替尼二 2-萘磺酸盐。  The "methanol" in Example 40 was replaced with "methyl tert-butyl ether", and the other operation was the same as in Example 40 to obtain Nsl crystal form afatinib di 2-naphthalenesulfonate.
实施例 42 Nsl晶型阿法替尼二 2-萘磺酸盐的制备  Example 42 Preparation of Nsl Form Afatinib Di 2-Naphthalenesulfonate
将实施例 40中的 "甲醇"替换为 "丙酮" ， 其他操作同实施例 40， 得到 Nsl晶型阿法 替尼二 2-萘磺酸盐。  The "methanol" in Example 40 was replaced with "acetone", and the other operation was the same as in Example 40 to obtain the Nsl crystal form of afatinib di 2-naphthalenesulfonate.
实施例 43 Nsl晶型阿法替尼二 2-萘磺酸盐的制备  Example 43 Preparation of Nsl crystal form afatinib di 2-naphthalene sulfonate
将实施例 40中的 "甲醇"替换为 "正庚烷" ， 其他操作同实施例 40， 得到 Nsl晶型阿 法替尼二 2-萘磺酸盐。  The "methanol" in Example 40 was replaced with "n-heptane", and the other operation was the same as in Example 40 to obtain the Nsl crystal form of favertinib 2-naphthalenesulfonate.
实施例 44 Nsl晶型阿法替尼二 2-萘磺酸盐的制备  Example 44 Preparation of Nsl Form Afatinib Di 2-Naphthalenesulfonate
将实施例 38中的 "42.8mg 2-萘磺酸"替换为 "64.2mg 2-萘磺酸" ， 其他操作同实施例 38， 得到 Nsl晶型阿法替尼二 2-萘磺酸盐。  The "42.8 mg of 2-naphthalenesulfonic acid" in Example 38 was replaced with "64.2 mg of 2-naphthalenesulfonic acid", and the other operation was the same as in Example 38 to obtain Nsl crystal form afatinib di 2-naphthalenesulfonate.
实施例 45 阿法替尼二氨基磺酸盐的制备  Example 45 Preparation of afatinib diamino sulfonate
取 50mg 阿法替尼游离碱加入 1.5mL乙酸乙酯溶解，取 20mg氨基磺酸加入 2mL乙酸乙 酯配成混悬液并搅拌， 将阿法替尼游离碱的乙酸乙酯溶液緩慢滴加至氨基磺酸的乙酸乙酯混 悬液中形成浆液， 室温下搅拌 4小时， 40°C真空旋干， 得阿法替尼二氨基磺酸盐 67.5mg， 产 率 96.4%。  50 mg of afatinib free base was added to 1.5 mL of ethyl acetate to dissolve, 20 mg of sulfamic acid was added to 2 mL of ethyl acetate to prepare a suspension and stirred, and the ethyl acetate solution of afatinib free base was slowly added dropwise to A slurry was formed in an ethyl acetate suspension of sulfamic acid, stirred at room temperature for 4 hours, and vacuum-dried at 40 ° C to obtain 67.5 mg of afatinib diaminosulphonate in a yield of 96.4%.
实施例 46 S1晶型阿法替尼二氨基磺酸盐的制备  Example 46 Preparation of S1 crystalline form of afatinib diamino sulfonate
取 50mg 阿法替尼游离碱加入 lmL乙腈溶解， 取 20mg氨基碩酸加入 2mL乙腈配成混 悬液并搅拌， 将阿法替尼游离碱的乙腈溶液緩慢滴加至氨基磺酸的乙腈的混悬液中形成浆 液， 室温下搅拌 4小时， 过滤， 40°C真空干燥过夜得 S1晶型阿法替尼二氨基磺酸盐 62mg， 产率 88.6%。 Take 50mg of afatinib free base and add 1mL of acetonitrile to dissolve, take 20mg of amino acid and add 2mL of acetonitrile to mix The suspension was stirred and the acetonitrile solution of afatinib free base was slowly added dropwise to a suspension of sulfamic acid in acetonitrile to form a slurry, which was stirred at room temperature for 4 hours, filtered, and dried under vacuum at 40 ° C overnight to obtain S1 crystal form. Afatinib diamino sulfonate 62 mg, yield 88.6%.
XRPD分析如图 42所示。  The XRPD analysis is shown in Figure 42.
TGA图谱如图 43所示。 显示： 该盐的分解温度为 246.3°C， 和阿法替尼二马来酸盐现有 技术晶型的 164.1 °C分解温度相比有着更好的热稳定性。  The TGA map is shown in Figure 43. It shows: The decomposition temperature of this salt is 246.3 ° C, which has better thermal stability than the 164.1 ° C decomposition temperature of the prior art crystal form of afatinib dimaleate.
红外光谱分析如图 44所示。  Infrared spectroscopy analysis is shown in Figure 44.
拉曼光谱分析如图 45所示。 Raman spectroscopy is shown in Figure 45.
MR图谱如图 46所示。 显示： 阿法替尼和氨基磺酸已经成盐。  The MR spectrum is shown in Figure 46. Display: Afatinib and sulfamic acid have been salted.
HPLC检测显示该盐中阿法替尼含量为 70.9%，与阿法替尼和氨基磺酸以 1 :2摩尔比成盐 的理论含量 71.5%接近， 说明阿法替尼和氨基磺酸以 1 :2摩尔比成盐。  HPLC analysis showed that the content of afatinib in the salt was 70.9%, which was close to the theoretical content of alfatinib and sulfamic acid in a 1:2 molar ratio of 71.5%, indicating that afatinib and sulfamic acid were 1 : 2 molar ratio to salt.
实施例 47 阿法替尼一氨基磺酸盐的制备  Example 47 Preparation of afatinib monosulfamate
取 10mg 阿法替尼游离碱加入 0.5mL乙酸乙酯溶解， 取 2mg氨基碩酸加入 0.5mL乙酸 乙酯配成混悬液并搅拌， 将阿法替尼游离碱的乙酸乙酯溶液緩慢滴加至氨基磺酸的乙酸乙酯 混悬液中， 室温下搅拌 4小时， 过滤 40°C真空干燥过夜得白色固体阿法替尼一氨基磺酸盐。  10 mg of afatinib free base was added to 0.5 mL of ethyl acetate to dissolve, 2 mg of amino acid was added to 0.5 mL of ethyl acetate to prepare a suspension and stirred, and the ethyl acetate solution of afatinib free base was slowly added dropwise. To a suspension of sulfamic acid in ethyl acetate, stirred at room temperature for 4 hours, and filtered at 40 ° C under vacuum overnight to give a white solid afatinib- sulfamic acid salt.
实施例 48 S1晶型阿法替尼二氨基磺酸盐的制备  Example 48 Preparation of S1 crystalline form of afatinib diamino sulfonate
取实施例 45制备的阿法替尼二氨基磺酸盐 30 mg， 置于 50ml烧瓶中， 加入 2ml甲醇形 成浆液， 室温下搅拌 72小时， 过滤， 40°C真空干燥得 S1晶型阿法替尼二氨基磺酸盐。  30 mg of afatinib diamino sulfonate prepared in Example 45 was placed in a 50 ml flask, and 2 ml of methanol was added to form a slurry, which was stirred at room temperature for 72 hours, filtered, and dried under vacuum at 40 ° C to obtain S1 crystal form Afate. Nitrosamine salt.
实施例 49 S1晶型阿法替尼二氨基磺酸盐的制备  Example 49 Preparation of S1 crystalline form of afatinib diamino sulfonate
将实施例 48中的 "甲醇"替换为 "甲基叔丁基醚"， 其他操作同实施例 48， 得到 S1晶 型阿法替尼二氨基磺酸盐。  The "methanol" in Example 48 was replaced with "methyl tert-butyl ether", and the other operation was the same as in Example 48 to obtain the S1 crystal form afatinib diamino sulfonate.
实施例 50 S1晶型阿法替尼二氨基磺酸盐的制备  EXAMPLE 50 Preparation of S1 Formal Afatinib Diamino Sulfonate
将实施例 48中的 "甲醇"替换为 "丙酮"， 其他操作同实施例 48， 得到 S1晶型阿法替 尼二氨基磺酸盐。  The "methanol" in Example 48 was replaced with "acetone", and the other operation was the same as in Example 48 to obtain the S1 crystal form afatinib diamino sulfonate.
实施例 51 S1晶型阿法替尼二氨基磺酸盐的制备  Example 51 Preparation of S1 crystal form afatinib diamino sulfonate
将实施例 48中的 "甲醇"替换为 "正庚烷"， 其他操作同实施例 48， 得到 S1晶型阿法 替尼二氨基磺酸盐。  The "methanol" in Example 48 was replaced with "n-heptane", and the other operation was the same as in Example 48 to obtain the S1 crystal form of afatinib diamino sulfonate.
实施例 52 S1晶型阿法替尼二氨基磺酸盐的制备  Example 52 Preparation of S1 crystalline form of afatinib diamino sulfonate
将实施例 46中的 "20mg氨基碩酸"替换为 "40mg氨基碩酸"， 其他操作同实施例 46， 得到 S1晶型阿法替尼二氨基磺酸盐。  The "20 mg amino acid" in Example 46 was replaced with "40 mg amino acid", and the other operation was the same as in Example 46 to obtain the S1 crystal form afatinib diamino sulfonate.
实施例 53 阿法替尼二 D-葡萄糖酸盐的制备  Example 53 Preparation of afatinib di D-gluconate
取 50mg 阿法替尼游离碱加入 1.5mL硝基甲烷溶解， 取 50%的 D-葡萄糖酸水溶液 88mg 直接滴加至阿法替尼游离碱的硝基甲烷溶液中并搅拌， 有油状物析出后将上层清液取出， 向 油状物加入 lmL乙腈， 室温下搅拌过夜， 得到阿法替尼二 D-葡萄糖酸盐固体， 40°C真空旋 干， 得 88 mg， 产率 97.4%。  Take 50mg of afatinib free base and add 1.5mL of nitromethane to dissolve, take 50% of D-gluconic acid aqueous solution 88mg, directly add to the nitromethane solution of afatinib free base and stir, after oily precipitation The supernatant was taken out, and 1 mL of acetonitrile was added to the oil, and the mixture was stirred at room temperature overnight to obtain a solid of afatinib di D-gluconate, which was dried at 40 ° C under vacuum to give 88 mg, yield 97.4%.
实施例 54 G1晶型阿法替尼二 D-葡萄糖酸盐的制备  Example 54 Preparation of G1 crystalline form afatinib di D-gluconate
取 50mg 阿法替尼游离碱加入 1.5mL乙酸乙酯溶解， 取 50%的 D-葡萄糖酸水溶液 88mg 直接滴加至阿法替尼游离碱的乙酸乙酯溶液中并搅拌， 有油状物析出后将上层清液取出， 向 油状物加入 lmL乙腈， 室温下搅拌过夜， 过滤， 40°C真空干燥过夜， 得 G1晶型阿法替尼二 D-葡萄糖酸盐 59mg， 产率 65.3%。  50 mg of afatinib free base was added to 1.5 mL of ethyl acetate to dissolve, and 88% of a 50% aqueous solution of D-gluconic acid was directly added dropwise to the ethyl acetate solution of afatinib free base and stirred, and after the oily substance was precipitated, The supernatant liquid was taken out, and 1 mL of acetonitrile was added to the oil, and the mixture was stirred at room temperature overnight, filtered, and dried under vacuum overnight at 40 ° C to obtain a G1 crystal form of afatinib di D-gluconate 59 mg, yield 65.3%.
XRPD分析如图 47所示。  The XRPD analysis is shown in Figure 47.
TGA图谱如图 48所示。 显示： 该盐的分解温度为 129.4°C。  The TGA map is shown in Figure 48. Display: The decomposition temperature of this salt is 129.4 °C.
DSC图谱如图 49所示。 显示： 该盐的熔点为 101.3°C。  The DSC spectrum is shown in Figure 49. Show: The salt has a melting point of 101.3 °C.
红外光谱分析如图 50所示。  Infrared spectroscopy analysis is shown in Figure 50.
拉曼光谱分析如图 51所示。 Raman spectroscopy is shown in Figure 51.
MR图谱如图 52所示。 显示： 阿法替尼和 D-葡萄糖酸已经成盐。 HPLC检测显示该盐中阿法替尼含量为 54.4%， 与阿法替尼和 D-葡萄糖酸以 1 :2摩尔比 成盐的理论含量 55.3%接近， 说明阿法替尼和 D-葡萄糖酸以 1 :2摩尔比成盐。 The MR spectrum is shown in Figure 52. Display: Afatinib and D-gluconic acid have been salted. HPLC analysis showed that the content of afatinib in the salt was 54.4%, which was close to the theoretical content of 55.3% of the salt of afatinib and D-gluconic acid in a 1:2 molar ratio, indicating that fatinib and D-gluconic acid. Salt is formed in a 1:2 molar ratio.
实施例 55 阿法替尼一 D-葡萄糖酸盐的制备  Example 55 Preparation of afatinib-D-gluconate
取 10mg 阿法替尼游离碱加入 0.5mL硝基甲烷溶解，取 50%的 D-葡萄糖酸水溶液 8.1mg 直接滴加至阿法替尼游离碱的硝基甲烷溶液中并搅拌， 有油状物析出后将上层清液取出， 向 油状物加入 lmL乙腈， 搅拌过夜， 得到白色固体阿法替尼一 D-葡萄糖酸盐。  10 mg of afatinib free base was added to 0.5 mL of nitromethane to dissolve, and 8.1 mg of 50% D-gluconic acid aqueous solution was directly added dropwise to the nitromethane solution of afatinib free base and stirred, and oily substance was precipitated. After the supernatant was taken out, 1 mL of acetonitrile was added to the oil, and the mixture was stirred overnight to obtain a white solid afatinib-D-gluconate.
实施例 56 G1晶型阿法替尼二 D-葡萄糖酸盐的制备  Example 56 Preparation of G1 crystalline form afatinib di D-gluconate
取实施例 53制备的阿法替尼二 D-葡萄糖酸盐 30mg， 置于 50ml烧瓶中， 加入 2ml甲醇 形成浆液， 室温下搅拌 72小时， 过滤， 40°C真空干燥得 G1晶型阿法替尼二 D-葡萄糖酸盐。  30 mg of afatinib di D-gluconate prepared in Example 53 was placed in a 50 ml flask, and 2 ml of methanol was added to form a slurry, which was stirred at room temperature for 72 hours, filtered, and dried under vacuum at 40 ° C to obtain G1 crystal form Afate. Nitra D-gluconate.
实施例 57 G1晶型阿法替尼二 D-葡萄糖酸盐的制备  Example 57 Preparation of G1 crystalline form afatinib di D-gluconate
将实施例 56 中的 "甲醇"替换为 "甲基叔丁基醚" ， 其他操作同实施例 56， 得到 G1 晶型阿法替尼二 D-葡萄糖酸盐。  The "methanol" in Example 56 was replaced with "methyl tert-butyl ether", and the other operation was the same as in Example 56 to obtain the G1 crystal form afatinib di D-gluconate.
实施例 58 G1晶型阿法替尼二 D-葡萄糖酸盐的制备  Example 58 Preparation of G1 crystalline form afatinib di D-gluconate
将实施例 56中的 "甲醇"替换为 "乙酸乙酯" ， 其他操作同实施例 56， 得到 G1 晶型 阿法替尼二 D-葡萄糖酸盐。  The "methanol" in Example 56 was replaced with "ethyl acetate", and the other operation was the same as in Example 56 to obtain the G1 crystal form afatinib di D-gluconate.
实施例 59 G1晶型阿法替尼二 D-葡萄糖酸盐的制备  Example 59 Preparation of G1 crystalline form afatinib di D-gluconate
将实施例 56中的 "甲醇"替换为 "丙酮" ， 其他操作同实施例 56， 得到 G1 晶型阿法 替尼二 D-葡萄糖酸盐。  The "methanol" in Example 56 was replaced with "acetone", and the other operation was the same as in Example 56 to obtain the G1 crystal form of afatinib di D-gluconate.
实施例 60 G1晶型阿法替尼二 D-葡萄糖酸盐的制备  EXAMPLE 60 Preparation of G1 Formal Alphatinib Di D-Glucurate
将实施例 56中的 "甲醇"替换为 "正庚烷" ， 其他操作同实施例 56， 得到 G1 晶型阿 法替尼二 D-葡萄糖酸盐。  The "methanol" in Example 56 was replaced with "n-heptane", and the other operation was the same as in Example 56 to obtain the G1 crystal form of favertinibdi D-gluconate.
实施例 61 G1晶型阿法替尼二 D-葡萄糖酸盐的制备  Example 61 Preparation of G1 crystalline form afatinib di D-gluconate
将实施例 54中的 "D-葡萄糖酸水溶液 88mg"替换为 "D-葡萄糖酸水溶液 160mg"， 其 他操作同实施例 54， 得到 G1晶型阿法替尼二 D-葡萄糖酸盐。  The "D-gluconic acid aqueous solution 88 mg" in Example 54 was replaced with "D-gluconic acid aqueous solution 160 mg", and the other operation was the same as in Example 52 to obtain G1 crystal form afatinib di D-gluconate.
实施例 62 阿法替尼二环己烷氨基磺酸盐的制备  Example 62 Preparation of afatinib dicyclohexyl sulfamate
取 50mg 阿法替尼游离碱加入 lmL乙酸乙酯溶解， 取 40.6mg环己烷氨基磺酸加入 3mL 乙酸乙酯配成混悬液并搅拌， 将阿法替尼游离碱的乙酸乙酯溶液緩慢滴加至环己烷氨基磺酸 的乙酸乙酯的混悬液中， 室温下搅拌过夜， 40°C真空旋干， 得阿法替尼二环己烷氨基磺酸盐 80mg， 产率 92.2%。  Take 50mg of afatinib free base and add 1mL of ethyl acetate to dissolve. Take 40.6mg of cyclohexane sulfamic acid and add 3mL of ethyl acetate to make a suspension and stir. Slow the ethyl acetate solution of afatinib free base. Add dropwise to a suspension of ethyl sulfasulfamic acid in ethyl acetate, stir at room temperature overnight, and spin dry at 40 ° C to obtain 80 mg of afatinib dicyclohexane sulfamate, yield 92.2%. .
实施例 63 C1晶型阿法替尼二环己烷氨基磺酸盐的制备  Example 63 Preparation of C1 crystalline form afatinib dicyclohexyl sulfamate
取 50mg 阿法替尼游离碱加入 lmL乙腈溶解，取 40.6mg环己烷氨基磺酸加入 3mL乙腈 配成混悬液并搅拌， 将阿法替尼游离碱的乙腈溶液緩慢滴加至环己烷氨基磺酸的乙腈的混悬 液中， 室温下搅拌过夜， 过滤 40°C真空干燥过夜， 得 C1晶型阿法替尼二环己烷氨基磺酸盐 74.6mg， 产率 85.9%。  50 mg of afatinib free base was added to 1 mL of acetonitrile to dissolve, 40.6 mg of cyclohexane sulfamic acid was added to 3 mL of acetonitrile to prepare a suspension and stirred, and the acetonitrile solution of afatinib free base was slowly added dropwise to cyclohexane. The suspension of sulfamic acid in acetonitrile was stirred at room temperature overnight, and dried under vacuum at 40 ° C overnight to obtain 74.6 mg of C1 crystal form afatinib dicyclohexane sulfamate, yield 85.9%.
XRPD分析如图 53所示。  The XRPD analysis is shown in Figure 53.
TGA图谱如图 54所示。 显示： 该盐的分解温度为 246.1 °C， 和阿法替尼二马来酸盐现有 技术晶型的 164.1 °C分解温度相比有着更好的热稳定性。  The TGA map is shown in Figure 54. It shows: The decomposition temperature of this salt is 246.1 °C, which has better thermal stability than the 164.1 °C decomposition temperature of the prior art crystal form of afatinib dimaleate.
红外光谱分析如图 55所示。  Infrared spectroscopy analysis is shown in Figure 55.
拉曼光谱分析如图 56所示。 Raman spectroscopy is shown in Figure 56.
MR图谱如图 57所示。 显示： 阿法替尼和环己烷氨基磺酸已经成盐。  The MR spectrum is shown in Figure 57. Shows: Afatinib and cyclohexane sulfamic acid have been salted.
HPLC检测显示该盐中阿法替尼含量为 58.3%，与阿法替尼和环己烷氨基磺酸以 1 :2摩尔 比成盐的理论含量 57.6%接近， 说明阿法替尼和环己烷氨基磺酸以 1 :2摩尔比成盐。  HPLC analysis showed that the content of afatinib in the salt was 58.3%, which was close to the theoretical content of 57.6% of the salt of afatinib and cyclohexanesulfamic acid in a 1:2 molar ratio, indicating that fatinib and cyclohexyl The alkylsulfamic acid salt is formed in a molar ratio of 1:2.
实施例 64 阿法替尼一环己烷氨基磺酸盐的制备  Example 64 Preparation of afatinib monocyclohexane sulfamate
取 10mg 阿法替尼游离碱加入 0.5mL乙腈溶解， 取 4.1mg环己烷氨基碩酸加入 lmL乙 腈配成混悬液并搅拌， 将阿法替尼游离碱的乙腈溶液緩慢滴加至环己烷氨基磺酸的乙腈的混 悬液中， 室温下搅拌过夜， 过滤， 40°C真空干燥过夜得白色固体阿法替尼一环己烷氨基磺酸 盐。 10 mg of afatinib free base was added to 0.5 mL of acetonitrile to dissolve, 4.1 mg of cyclohexane amino acid was added to 1 mL of acetonitrile to prepare a suspension and stirred, and the acetonitrile solution of afatinib free base was slowly added dropwise to the ring. A suspension of alkylsulfonic acid in acetonitrile, stirred at room temperature overnight, filtered, dried under vacuum at 40 ° C overnight to give a white solid afatinib-cyclohexanesulfamic acid Salt.
实施例 65 CI晶型阿法替尼二环己烷氨基磺酸盐的制备  EXAMPLE 65 Preparation of CI Form Afatinib Dicyclohexylsulfamate
取实施例 62制备的阿法替尼二环己烷氨基磺酸盐 30 mg， 置于 50 ml烧瓶中， 加入 2 ml 甲醇形成浆液， 室温下搅拌 72小时， 过滤， 40°C真空干燥得 C1晶型阿法替尼二环己烷氨基 磺酸盐。  Take 30 mg of afatinib dicyclohexyl sulfamate prepared in Example 62, place it in a 50 ml flask, add 2 ml of methanol to form a slurry, stir at room temperature for 72 hours, filter, and dry at 40 ° C to obtain C1. Crystalline afatinib dicyclohexyl sulfamate.
实施例 66 C1晶型阿法替尼二环己烷氨基磺酸盐的制备  EXAMPLE 66 Preparation of C1 Form Afatinib Dicyclohexylsulfamate
将实施例 65中的 "甲醇"替换为 "乙酸乙酯"， 其他操作同实施例 65， 得到 C1晶型阿 法替尼二环己烷氨基磺酸盐。  The "methanol" in Example 65 was replaced with "ethyl acetate", and the other operation was carried out in the same manner as in Example 65 to give the crystals of s.
实施例 67 C1晶型阿法替尼二环己烷氨基磺酸盐的制备  Example 67 Preparation of C1 crystalline form afatinib dicyclohexyl sulfamate
将实施例 65 中的 "甲醇"替换为 "甲基叔丁基醚" ， 其他操作同实施例 65， 得到 C1 晶型阿法替尼二环己烷氨基磺酸盐。  The "methanol" in Example 65 was replaced with "methyl tert-butyl ether", and the other operation was the same as in Example 65 to give C1 crystal form of afatinib dicyclohexane sulfamate.
实施例 68 C1晶型阿法替尼二环己烷氨基磺酸盐的制备  Example 68 Preparation of C1 crystalline form afatinib dicyclohexyl sulfamate
将实施例 65中的 "甲醇"替换为 "丙酮"， 其他操作同实施例 65， 得到 C1晶型阿法替 尼二环己烷氨基磺酸盐。  The "methanol" in Example 65 was replaced with "acetone", and the other operation was the same as in Example 65 to give the C1 crystal form of the af- s.
实施例 69 C1晶型阿法替尼二环己烷氨基磺酸盐的制备  Example 69 Preparation of C1 crystalline form afatinib dicyclohexyl sulfamate
将实施例 65中的 "甲醇"替换为 "正庚烷"， 其他操作同实施例 65， 得到 C1晶型阿法 替尼二环己烷氨基磺酸盐。  The "methanol" in Example 65 was replaced with "n-heptane", and the other operation was carried out in the same manner as in Example 65 to give the crystals of the crystals of the form of s.
实施例 70 C1晶型阿法替尼二环己烷氨基磺酸盐的制备  Example 70 Preparation of C1 Form Afatinib Dicyclohexane Sulfonate
将实施例 63中的 "40.6mg环己烷氨基磺酸"替换为 "73mg环己烷氨基磺酸"， 其他操 作同实施例 63， 得到 C1晶型阿法替尼二环己烷氨基磺酸盐。  The "40.6 mg of cyclohexanesulfamic acid" in Example 63 was replaced with "73 mg of cyclohexanesulfamic acid", and the other operation was the same as in Example 63 to obtain a crystalline form of afatinib dicyclohexylsulfamic acid. salt.
实施例 71 阿法替尼二 4-氨基苯磺酸盐的制备  Example 71 Preparation of afatinib di 4-aminobenzenesulfonate
取 50mg 阿法替尼游离碱加入 lmL丙酮溶解， 取 39.2mg4-氨基苯磺酸加入 3mL丙酮配 成混悬液并搅拌， 将阿法替尼游离碱的丙酮溶液緩慢滴加至 4-氨基苯磺酸的丙酮混悬液中， 室温下搅拌过夜， 40°C真空旋干， 得阿法替尼二 4-氨基苯磺酸盐 78mg， 产率 91.1%。  Take 50mg of afatinib free base and add 1mL of acetone to dissolve. Take 39.2mg of 4-aminobenzenesulfonic acid and add 3mL of acetone to form a suspension and stir. Slowly add the acetone solution of afatinib free base to 4-aminobenzene. The acetone suspension of the sulfonic acid was stirred at room temperature overnight, and dried under vacuum at 40 ° C to obtain 78 mg of afatinib di 4-aminobenzenesulfonate in a yield of 91.1%.
实施例 72 A1晶型阿法替尼二 4-氨基苯磺酸盐的制备  Example 72 Preparation of Form A1 Alphatinib Di 4-Aminobenzenesulfonate
取 50mg 阿法替尼游离碱加入 lmL乙腈溶解， 取 39.2mg4-氨基苯磺酸加入 3mL乙腈配 成混悬液并搅拌， 将阿法替尼游离碱的乙腈溶液緩慢滴加至 4-氨基苯磺酸的乙腈混悬液中， 室温下搅拌过夜， 过滤并 40°C干燥过夜， 得 A1晶型阿法替尼二 4-氨基苯磺酸盐 65mg， 产 率 75.9%。  50 mg of afatinib free base was added to 1 mL of acetonitrile to dissolve, 39.2 mg of 4-aminobenzenesulfonic acid was added to 3 mL of acetonitrile to prepare a suspension and stirred, and the acetonitrile solution of afatinib free base was slowly added dropwise to 4-aminobenzene. The sulfonic acid in acetonitrile suspension was stirred at room temperature overnight, filtered and dried overnight at 40 ° C to obtain 65 mg of A1 crystal form afatinib di 4-aminobenzenesulfonate, yield 75.9%.
XRPD分析如图 58所示。  The XRPD analysis is shown in Figure 58.
TGA图谱如图 59所示。 显示： 该盐的分解温度为 261.7°C， 和阿法替尼二马来酸盐现有 技术晶型的 164.1 °C分解温度相比有着更好的热稳定性。  The TGA map is shown in Figure 59. It shows: The decomposition temperature of this salt is 261.7 ° C, which has better thermal stability than the 164.1 ° C decomposition temperature of the prior art crystal form of afatinib dimaleate.
红外光谱分析如图 60所示。  Infrared spectroscopy analysis is shown in Figure 60.
拉曼光谱分析如图 61所示。 Raman spectroscopy is shown in Figure 61.
MR图谱如图 62所示。 显示： 阿法替尼和 4-氨基苯磺酸已经成盐。  The MR spectrum is shown in Figure 62. Shows: Afatinib and 4-aminobenzenesulfonic acid have been salted.
HPLC检测显示该盐中阿法替尼含量为 59.1%， 与阿法替尼和 4-氨基苯磺酸以 1 :2摩尔 比成盐的理论含量 58.4%接近， 说明阿法替尼和 4-氨基苯磺酸以 1 :2摩尔比成盐。  HPLC analysis showed that the content of afatinib in the salt was 59.1%, which was close to the theoretical content of 58.4% of the salt of afatinib and 4-aminobenzenesulfonic acid in a 1:2 molar ratio, indicating that afatinib and 4- Aminobenzenesulfonic acid forms a salt in a 1:2 molar ratio.
实施例 73 阿法替尼一 4-氨基苯磺酸盐的制备  Example 73 Preparation of afatinib- 4-aminobenzenesulfonate
取 10mg 阿法替尼游离碱加入 0.5mL乙腈溶解，取 3.9mg 4-氨基苯碩酸加入 lmL乙腈配 成混悬液并搅拌， 将阿法替尼游离碱的乙腈溶液緩慢滴加至 4-氨基苯磺酸的乙腈混悬液中， 室温下搅拌过夜， 过滤并 40°C干燥过夜得白色固体阿法替尼一 4-氨基苯磺酸盐。  Take 10 mg of afatinib free base and add 0.5 mL of acetonitrile to dissolve. Take 3.9 mg of 4-aminobenzene acid and add 1 mL of acetonitrile to prepare a suspension and stir. Slowly add the acetonitrile solution of afatinib free base to 4- The acetonitrile suspension of aminobenzenesulfonic acid was stirred at room temperature overnight, filtered and dried overnight at 40 ° C to give a white solid afatinib- 4-aminobenzenesulfonate.
实施例 74 A1晶型阿法替尼二 4-氨基苯磺酸盐的制备  Example 74 Preparation of Form A1 Alphatinib Di 4-Aminobenzenesulfonate
取实施例 71制备的阿法替尼二 4-氨基苯磺酸盐 30 mg， 置于 50ml烧瓶中， 加入 2ml 甲醇形成浆液， 室温下搅拌 72小时， 过滤， 40°C真空干燥得 A1晶型阿法替尼 二 4-氨基苯 磺酸盐。  30 mg of afatinib di 4-aminobenzenesulfonate prepared in Example 71 was placed in a 50 ml flask, and 2 ml of methanol was added to form a slurry, which was stirred at room temperature for 72 hours, filtered, and dried under vacuum at 40 ° C to obtain A1 crystal form. Alfatinib di 4-aminobenzenesulfonate.
实施例 75 A1晶型阿法替尼二 4-氨基苯磺酸盐的制备 将实施例 74中的 "甲醇"替换为 "乙酸乙酯" ， 其他操作同实施例 74， 得到 A1 晶型 阿法替尼二 4-氨基苯磺酸盐。 Example 75 Preparation of A1 Form Afatinib Di 4-Aminobenzenesulfonate The "methanol" in Example 74 was replaced with "ethyl acetate", and the other operation was the same as in Example 74 to obtain the A1 crystal form afatinib di 4-aminobenzenesulfonate.
实施例 76 A1晶型阿法替尼二 4-氨基苯磺酸盐的制备  Example 76 Preparation of Form A1 Alphatinib Di 4-Aminobenzenesulfonate
将实施例 74 中的 "甲醇"替换为 "甲基叔丁基醚" ， 其他操作同实施例 74， 得到 A1 晶型阿法替尼二 4-氨基苯磺酸盐。  The "methanol" in Example 74 was replaced with "methyl tert-butyl ether", and the other operation was the same as in Example 74 to give the crystals of the A1 crystal form afatinib di 4-aminobenzenesulfonate.
实施例 77 A1晶型阿法替尼二 4-氨基苯磺酸盐的制备  Example 77 Preparation of A1 crystalline form afatinib di 4-aminobenzenesulfonate
将实施例 74中的 "甲醇"替换为 "丙酮" ， 其他操作同实施例 74， 得到 A1 晶型阿法 替尼二 4-氨基苯磺酸盐。  The "methanol" in Example 74 was replaced with "acetone", and the other operation was the same as in Example 74 to obtain the A1 crystal form of afatinib di 4-aminobenzenesulfonate.
实施例 78 A1晶型阿法替尼二 4-氨基苯磺酸盐的制备  Example 78 Preparation of Form A1 Alphatinib Di 4-Aminobenzenesulfonate
将实施例 74中的 "甲醇"替换为 "正庚烷" ， 其他操作同实施例 74， 得到 A1 晶型阿 法替尼二 4-氨基苯磺酸盐。  The "methanol" in Example 74 was replaced with "n-heptane", and the other operation was carried out in the same manner as in Example 74 to obtain a crystal form of fafinidin di 4-aminobenzenesulfonate.
实施例 79 A1晶型阿法替尼二 4-氨基苯磺酸盐的制备  Example 79 Preparation of A1 Form Afatinib Di 4-Aminobenzenesulfonate
将实施例 72中的 " 39.2mg 4-氨基苯磺酸"替换为 " 70mg 4-氨基苯磺酸" ， 其他操作同 实施例 72， 得到 A1晶型阿法替尼二 4-氨基苯磺酸盐。  The "39.2 mg 4-aminobenzenesulfonic acid" in Example 72 was replaced with "70 mg 4-aminobenzenesulfonic acid", and the other operation was the same as in Example 72 to obtain the A1 crystal form of afatinib di 4-aminobenzenesulfonic acid. salt.
实施例 80 阿法替尼甘醇酸盐的制备  Example 80 Preparation of afatinibane glycolate
取 50mg 阿法替尼游离碱加入 1.5mL乙酸乙酯搅拌溶解，取 8.6mg甘醇酸加入 1.5mL乙 酸乙酯搅拌溶解， 将甘醇酸的乙酸乙酯溶液緩慢滴加至阿法替尼游离碱的乙酸乙酯溶液中形 成浆液并搅拌， 滴加过程中有固体析出， 室温下搅拌过夜， 40°C真空旋干， 得阿法替尼甘醇 酸盐 54.4mg， 产率 94.1%。  50 mg of afatinib free base was added to 1.5 mL of ethyl acetate and stirred to dissolve. 8.6 mg of glycolic acid was added to 1.5 mL of ethyl acetate and stirred to dissolve. The ethyl acetate solution of glycolic acid was slowly added dropwise to the afatinib free. A slurry of the base was slurried and stirred, and a solid precipitated during the dropwise addition. The mixture was stirred overnight at room temperature, and then dried at 40 ° C under vacuum to give 54.4 mg of afatinibane.
实施例 81 G1-1晶型阿法替尼甘醇酸盐的制备  Example 81 Preparation of G1-1 crystalline form of afatinibane glycolate
取 50mg 阿法替尼游离碱加入 1.5mL硝基甲烷搅拌溶解， 取 8.6mg甘醇酸加入 3mL硝 基甲烷搅拌溶解， 将甘醇酸的硝基甲烷溶液緩慢滴加至阿法替尼游离碱的硝基甲烷溶液中形 成浆液并搅拌， 室温下搅拌过夜后有固体析出， 过滤并 40°C真空干燥过夜得 G1-1 晶型阿法 替尼甘醇酸盐 50mg， 产率 86.5%。  Take 50mg of afatinib free base and add 1.5mL of nitromethane to stir and dissolve. Take 8.6mg of glycolic acid and add 3mL of nitromethane to stir and dissolve. Add the glycolic acid nitromethane solution slowly to afatinib free base. A slurry was formed in the nitromethane solution and stirred. After stirring at room temperature overnight, a solid precipitated, which was filtered and dried under vacuum at 40 ° C overnight to obtain 50 g of the g-form of the form of the form of the form of the form of the formula
XRPD分析如图 63所示。  The XRPD analysis is shown in Figure 63.
TGA图谱如图 64所示。 显示： 该盐的分解温度为 1 12.4°C。  The TGA map is shown in Figure 64. Display: The decomposition temperature of this salt is 1 12.4 °C.
DSC图谱如图 65所示。 显示： 该盐的熔点为 83.5°C。  The DSC spectrum is shown in Figure 65. Show: The salt has a melting point of 83.5 °C.
红外光谱分析如图 66所示。  Infrared spectroscopy analysis is shown in Figure 66.
拉曼光谱分析如图 67所示。 Raman spectroscopy is shown in Figure 67.
MR图谱如图 68所示。 显示： 阿法替尼和甘醇酸已经成盐。  The MR spectrum is shown in Figure 68. Display: Afatinib and glycolic acid have been salted.
HPLC检测显示该盐中阿法替尼含量为 85.4%，与阿法替尼和甘醇酸以 1 : 1摩尔比成盐理 论含量 86.5%接近， 说明阿法替尼和甘醇酸以 1 : 1摩尔比成盐。  HPLC analysis showed that the content of afatinib in the salt was 85.4%, which was close to the theoretical content of alfatinib and glycolic acid in a molar ratio of 1:1 to 86.5%, indicating that afatinib and glycolic acid were 1: 1 molar ratio to salt.
实施例 82 阿法替尼二甘醇酸盐的制备  Example 82 Preparation of afatinib diglycolate
取 10mg 阿法替尼游离碱加入 0.5mL乙酸乙酯溶解， 取 3.4mg甘醇酸加入 lmL乙酸乙 酯搅拌溶解， 将甘醇酸的乙酸乙酯溶液緩慢滴加至阿法替尼游离碱的乙酸乙酯溶液中并搅 拌， 滴加过程中有固体析出， 室温下搅拌过夜后过滤， 40°C真空干燥过夜得白色固体阿法替 尼二甘醇酸盐。  10 mg of afatinib free base was added to 0.5 mL of ethyl acetate to dissolve, and 3.4 mg of glycolic acid was added to 1 mL of ethyl acetate to stir and dissolve. The ethyl acetate solution of glycolic acid was slowly added dropwise to the afatinib free base. The ethyl acetate solution was stirred and a solid was precipitated during the dropwise addition. After stirring at room temperature overnight, it was filtered and dried under vacuum at 40 ° C overnight to give a white solid afatinidine diglycolate.
实施例 83 G1-1晶型阿法替尼甘醇酸盐的制备  Example 83 Preparation of G1-1 crystalline form of afatinibane glycolate
取实施例 80制备的阿法替尼甘醇酸盐 30mg， 置于 50ml烧瓶中， 加入 2ml甲醇形成浆 液， 室温下搅拌 72小时， 过滤， 40°C真空干燥得 G1- 1晶型阿法替尼甘醇酸盐。  30 mg of afatinibane glycolate prepared in Example 80 was placed in a 50 ml flask, and 2 ml of methanol was added to form a slurry, which was stirred at room temperature for 72 hours, filtered, and dried under vacuum at 40 ° C to obtain G1-1 crystal form Afati Niganoate.
实施例 84 G1-1晶型阿法替尼甘醇酸盐的制备  Example 84 Preparation of G1-1 crystalline form of afatinibane glycolate
将实施例 83中的 "甲醇"替换为 "甲基叔丁基醚" ， 其他操作同实施例 83， 得到 G1-1 晶型阿法替尼甘醇酸盐。  The "methanol" in Example 83 was replaced with "methyl tert-butyl ether", and the other operation was carried out in the same manner as in Example 83 to give the G1-1 crystal form of afatinibane.
实施例 85 G1-1晶型阿法替尼甘醇酸盐的制备  Example 85 Preparation of G1-1 crystalline form of afatinibane glycolate
将实施例 83中的 "甲醇"替换为 "丙酮" ， 其他操作同实施例 83， 得到 G1-1晶型阿法 替尼甘醇酸盐。 实施例 86 Gl-1晶型阿法替尼甘醇酸盐的制备 The "methanol" in Example 83 was replaced with "acetone", and the other operation was the same as in Example 83 to obtain the G1-1 crystal form of afatinibane. Example 86 Preparation of Gl-1 crystal form afatinibane glycolate
将实施例 83中的 "甲醇"替换为 "正庚烷" ， 其他操作同实施例 83， 得到 G1-1晶型阿 法替尼甘醇酸盐。  The "methanol" in Example 83 was replaced with "n-heptane", and the other operation was carried out in the same manner as in Example 83 to obtain the G1-1 crystal form of eptatinib.
实施例 87 G1-1晶型阿法替尼甘醇酸盐的制备  Example 87 Preparation of G1-1 crystalline form of afatinibane glycolate
将实施例 81中的 " 8.6mg甘醇酸"替换为 " 15.5mg甘醇酸" ， 其他操作同实施例 81， 得到 G1-1晶型阿法替尼甘醇酸盐。  The procedure of "8.6 mg of glycolic acid" in Example 81 was replaced with "15. 5 mg of glycolic acid", and the same operation as in Example 81 gave G1-1 crystal form of afatinibane.
实施例 88 阿法替尼二马来酸盐晶型 N的制备  Example 88 Preparation of afatinib dimaleate salt form N
取 50mg 阿法替尼游离碱加入 2mL硝基甲烷搅拌溶解，取 26.5mg马来酸加入 lmL硝基 甲烷搅拌溶解， 将马来酸的硝基甲烷溶液緩慢滴加至阿法替尼游离碱的硝基甲烷溶液中形成 浆液并搅拌， 滴加过程中有固体析出， 室温下搅拌过夜后过滤， 40°C真空干燥过夜得 63mg 阿法替尼二马来酸盐晶型 N， 产率 85.3%。  Take 50mg of afatinib free base and add 2mL of nitromethane to stir and dissolve. Take 26.5mg of maleic acid and add 1mL of nitromethane to stir and dissolve. Add the maleic acid nitromethane solution slowly to the afatinib free base. A slurry was formed in the nitromethane solution and stirred. A solid precipitated during the dropwise addition. After stirring at room temperature overnight, it was filtered, and dried under vacuum at 40 ° C overnight to obtain 63 mg of afatinib dimaleate salt form N, yield 85.3%. .
XRPD分析如图 69所示。  The XRPD analysis is shown in Figure 69.
TGA图谱如图 70所示。 显示： 该盐的分解温度为 133.7°C。  The TGA map is shown in Figure 70. Display: The decomposition temperature of this salt is 133.7 °C.
红外光谱分析如图 71所示。  Infrared spectroscopy analysis is shown in Figure 71.
拉曼光谱分析如图 72所示。  Raman spectroscopy is shown in Figure 72.
HPLC检测显示该盐中阿法替尼含量为 68.1%，与阿法替尼和马来酸以 1 :2摩尔比成盐的 理论含量 67.7%接近， 说明阿法替尼和马来酸以 1 :2摩尔比成盐。  HPLC analysis showed that the content of afatinib in the salt was 68.1%, which was close to the theoretical content of salt of afatinib and maleic acid in a 1:2 molar ratio of 67.7%, indicating that alfatinib and maleic acid were 1 : 2 molar ratio to salt.
实施例 89 阿法替尼二马来酸盐晶型 N的制备  Example 89 Preparation of afatinib dimaleate salt form N
将实施例 88中的 "26.5mg马来酸"替换为 "39.8mg马来酸" ， 其它操作同实施例 88， 得到阿法替尼二马来酸盐晶型 N。  The "26.5 mg maleic acid" in Example 88 was replaced with "39.8 mg maleic acid", and the other operation was the same as in Example 88 to obtain the crystalline form N of afatinib dimaleate.
实施例 90  Example 90
按照表 2处方制备包含不同剂量的本发明阿法替尼二马来酸盐晶型 N C实施例 88)的 A、 B、 C、 D和 E五种片剂。  Five tablets of A, B, C, D and E containing different doses of the afatinib dimaleate salt form of the invention N C Example 88) were prepared according to the formulation of Table 2.
表 2 A、 B、 C、 D、 E五种片剂处方  Table 2 A, B, C, D, E five tablet prescriptions
Figure imgf000034_0001
Figure imgf000034_0001
片剂的制备方法是： 使微晶纤維素、 交聚維酮、 未研磨的实施例 88 制得的阿法替尼二 马来酸盐晶型 N通过 #30 目筛 （约 430μ到约 655μ) 。 将过筛后的交聚維酮装入 3立方英尺 双壳翻滚搅拌机中， 加入过筛后的微晶纤維素和乳糖一水合物， 混合约 5分钟； 加入过筛后 的阿法替尼二马来酸盐晶型 Ν， 再混合 25分钟。 该预混物通过排放处附有锤式粉碎机的滚 筒压实机， 并移回翻滚搅拌机中。 硬脂酸镁和无水胶体二氧化硅加入到翻滚搅拌机中， 混合 约 3分钟。 最终混合物在旋转式压片机上压制， 生产批量 200,000片。  The tablet was prepared by passing microcrystalline cellulose, crospovidone, unmilled, afatinib dimaleate salt form N prepared in Example 88 through a #30 mesh screen (about 430 μ to about 655 μ). ). The sieved crospovidone was placed in a 3 cubic foot double-shell tumble mixer, and the sieved microcrystalline cellulose and lactose monohydrate were added and mixed for about 5 minutes; the sieved afatinib was added. The maleate salt crystal form is mixed and mixed for another 25 minutes. The premix is passed through a roller compactor with a hammer mill at the discharge and moved back into the tumbling mixer. Magnesium stearate and anhydrous colloidal silica were added to a tumble mixer and mixed for about 3 minutes. The final mixture was pressed on a rotary tablet press to produce 200,000 tablets in batches.
实施例 91-101  Example 91-101
按照表 2处方及实施例 90的制备方法，将实施例 90中的阿法替尼二马来酸盐晶型 Ν (实 施例 88) 分别替换为阿法替尼的 E1晶型乙二磺酸盐 （实施例 3 ) 、 N1晶型 1,5-萘二磺酸盐 (实施例 12) 、 N2晶型 1,5-萘二磺酸盐水合物 （实施例 20) 、 Ml晶型一丙二酸盐 （实施例 24) 、 M2晶型二丙二酸盐 （实施例 31 ) 、 Nsl晶型二 2-萘磺酸盐 （实施例 38) 、 S1晶型二 氨基磺酸盐 （实施例 46) 、 G1晶型二 D-葡萄糖酸盐 （实施例 54) 、 C1晶型二环己烷氨基 磺酸盐 （实施例 63 ) 、 A1晶型二 4-氨基苯磺酸盐 （实施例 72) 和 G1-1晶型甘醇酸盐 （实施 例 81 ) ， 分别得到实施例 91-101的片剂。 The afatinib dimaleate salt form Ν (Example 88) of Example 90 was replaced with the Alphatin E1 crystal form ethanedisulfonic acid according to the formulation of Table 2 and the preparation method of Example 90, respectively. Salt (Example 3), N1 crystal form 1,5-naphthalene disulfonate (Example 12), N2 crystal form 1,5-naphthalene disulfonic acid salt hydrate (Example 20), M1 crystal form monomalonate (Example 24), M2 crystal form dimalonate (implementation) Example 31), Nsl crystalline di-2-naphthalenesulfonate (Example 38), S1 crystalline diaminosulfonate (Example 46), G1 crystalline di D-gluconate (Example 54), C1 Crystalline dicyclohexane sulfamate (Example 63), A1 crystalline di 4-aminobenzenesulfonate (Example 72) and G1-1 crystalline glycolate (Example 81), respectively The tablets of Examples 91-101.
实施例 102  Example 102
制备包含本发明阿法替尼二马来酸盐晶型 N (实施例 88) 的胶囊， 表 3列出了其单一剂 量配方和批量配方。  Capsules containing the afatinib dimaleate salt form N (Example 88) of the present invention were prepared, and Table 3 lists the single dose formulations and batch formulations.
表 3 包含阿法替尼二马来酸盐晶型 N的胶囊配方  Table 3 Capsule Formulations Containing Afatinib Dimaleate Form N
Figure imgf000035_0001
Figure imgf000035_0001
胶囊的制备方法是： 使乳糖一水合物、 微晶纤維素和实施例 88 制得的阿法替尼二马来 酸盐晶型 N通过 710 μ ιη筛， 然后装入带挡板插入的扩散混合器中， 混合 15分钟。 使硬脂 酸镁通过 210 μ ιη筛， 添加到扩散混合器中。 然后使用 Dosator型胶囊充填机将混合物装入 0#号胶囊中， 500 mg/胶囊， 生产批量 84000粒胶囊。  The capsules were prepared by: passing lactose monohydrate, microcrystalline cellulose, and afatinib dimaleate salt form N prepared in Example 88 through a 710 μιη sieve, and then loading the diffusion with baffle insertion. Mix in the mixer for 15 minutes. Magnesium stearate was passed through a 210 μm sieve and added to the diffusion mixer. The mixture was then filled into capsule #0, 500 mg/capsule using a Dosator capsule filling machine to produce 84,000 capsules.
实施例 103-113  Example 103-113
按照表 3配方及实施例 102的制备方法， 将实施例 102中的阿法替尼二马来酸盐晶型 N (实施例 88)分别替换为阿法替尼的 E1晶型阿法替尼乙二磺酸盐 （实施例 3 ) 、 N1晶型 1,5- 萘二磺酸盐 （实施例 12) 、 N2晶型 1,5萘二磺酸盐水合物 （实施例 20) 、 Ml晶型一丙二酸 盐 （实施例 24) 、 M2晶型二丙二酸盐 （实施例 31 ) 、 Nsl晶型二 2-萘磺酸盐 （实施例 38) 、 S1晶型二氨基磺酸盐 （实施例 46) 、 G1晶型二 D-葡萄糖酸盐 （实施例 54) 、 C1晶型二环 己烷氨基磺酸盐 （实施例 63 ) 、 A1晶型二 4-氨基苯磺酸盐 （实施例 72) 和 G1-1晶型甘醇酸 盐 （实施例 81 ) ， 分别得到实施例 103-113的胶囊。  The afatinib dimaleate salt form N (Example 88) of Example 102 was replaced with the Alphatinib E1 crystal form afatinib according to the formulation of Table 3 and the preparation method of Example 102, respectively. Ethylene disulfonate (Example 3), N1 crystal form 1,5-naphthalene disulfonate (Example 12), N2 crystal form 1,5 naphthalenedisulfonic acid salt hydrate (Example 20), Ml crystal Type monomalonate (Example 24), M2 crystalline dimalonate (Example 31), Nsl crystalline bis 2-naphthalene sulfonate (Example 38), S1 crystalline diamino sulfonate (Example 46), G1 crystalline di D-gluconate (Example 54), C1 crystalline dicyclohexanesulfonate (Example 63), A1 crystalline di 4-aminobenzenesulfonate ( Example 72) and G1-1 crystalline glycolate (Example 81), the capsules of Examples 103-113 were obtained, respectively.
ϋ于比例 1  Proportion to ratio 1
将制备例 1、 实施例 3、 12、 20、 24、 31、 38、 46、 54、 63、 72、 81和 88的阿法替尼的 酸加成盐各取 5mg， 25°C下逐步向每份样品中添加纯水直至样品全部溶清， 根据样品的实际 重量和水的量计算得样品的溶解度。 结果见表 4， 平行试验表明样品在该检测过程中未发生 转晶。  The acid addition salts of afatinib of Preparation Example 1, Examples 3, 12, 20, 24, 31, 38, 46, 54, 63, 72, 81 and 88 were each taken 5 mg, and gradually introduced at 25 ° C. Pure water was added to each sample until the sample was completely dissolved, and the solubility of the sample was calculated based on the actual weight of the sample and the amount of water. The results are shown in Table 4. Parallel tests indicate that the sample did not undergo crystallisation during the test.
表 4 阿法替尼酸加成盐的溶解度测试结果  Table 4 Solubility test results of afatinib acid addition salt
阿法替尼的盐 溶解度 （mg/ml) 二马来酸盐晶型 （现有技术） （制备例 1 ) 7.5  Salt solubility of afatinib (mg/ml) dimaleate crystal form (prior art) (preparation 1) 7.5
E1晶型乙二磺酸盐 （实施例 3 ) 55.7 E1 crystalline ethanedisulfonate (Example 3) 55.7
N1晶型 1,5-萘二磺酸盐 （实施例 12) 1.4N1 crystal form 1,5-naphthalene disulfonate (Example 12) 1.4
N2晶型 1,5-萘二磺酸盐水合物 （实施例 20) 1.4 N2 crystal form 1,5-naphthalene disulfonic acid salt hydrate (Example 20) 1.4
Ml晶型一丙二酸盐 （实施例 24) 40.8 Ml crystal form monomalonate (Example 24) 40.8
M2晶型二丙二酸盐 （实施例 31 ) 26.2M2 crystalline dimalonate (Example 31) 26.2
Nsl晶型二 2-萘磺酸盐 （实施例 38) 2.0Nsl Formal Di-2-Naphthalenesulfonate (Example 38) 2.0
S1晶型二氨基磺酸盐 （实施例 46) 138.3S1 crystalline diaminosulphonate (Example 46) 138.3
G1晶型二 D-葡萄糖酸盐 （实施例 54) 5.4 G1 Form II D-Gluconate (Example 54) 5.4
C1晶型二环己烷氨基磺酸盐 （实施例 63 ) 63.1  C1 crystalline dicyclohexyl sulfamate (Example 63) 63.1
A1晶型二 4-氨基苯磺酸盐 （实施例 72) 123.8 Gl-1晶型甘醇酸盐 （实施例 81 ) 小于 0.1 二马来酸晶型 N (实施例 88) 12.7 对比例 2 A1 crystalline di 4-aminobenzenesulfonate (Example 72) 123.8 Gl-1 crystalline glycolate (Example 81) less than 0.1 dimaleic acid Form N (Example 88) 12.7 Comparative Example 2
按照实施例 90、 实施例 91-101 中的片剂配方和制备方法， 制备阿法替尼二马来酸盐现 有技术晶型的片剂以及本发明的 E1晶型阿法替尼乙二磺酸盐、 N1晶型阿法替尼 1,5-萘二磺 酸盐、 N2晶型 1,5-萘二磺酸盐水合物、 Ml晶型阿法替尼一丙二酸盐的片剂各 100片， 观察 压片过程及片型。 结果显示： 现有技术阿法替尼二马来酸盐晶型的片剂 23%有粘冲现象， 而 其余片剂则没有。 说明： 在片剂的可加工性方面， 上述本发明阿法替尼酸加成盐晶型的颗粒 状晶体均优于现有技术阿法替尼二马来酸盐晶型的针状晶体。  Preparation of a tablet of the prior art crystalline form of afatinib dimaleate according to the formulation and preparation method of Example 90, Examples 91-101, and the E1 crystal form of the present invention Sulfate, N1 crystal form afatinib 1,5-naphthalene disulfonate, N2 crystal form 1,5-naphthalene disulfonic acid salt hydrate, Ml crystal form afatinib mono malonate tablets Each of the 100 tablets was observed, and the tableting process and sheet type were observed. The results showed that 23% of the tablets of the prior art form of afatinib dimaleate had a sticking phenomenon, while the remaining tablets did not. Description: In terms of processability of the tablet, the above-mentioned granular crystal of the afatinidine acid addition salt crystal form of the present invention is superior to the needle crystal of the prior art afatinib dimaleate crystal form.
对比例 3 Comparative example 3
取对比例 2制备的阿法替尼二马来酸盐现有技术晶型的完好片剂以及 E1晶型阿法替尼 乙二磺酸盐、 N1晶型阿法替尼 1,5-萘二磺酸盐、 N2晶型 1,5-萘二磺酸盐水合物、 Ml晶型阿 法替尼一丙二酸盐的完好片剂各 20片， 进行硬度测试。 结果显示： E1晶型阿法替尼乙二磺 酸盐片剂的硬度平均值 （9.54Kg) 、 N1 晶型阿法替尼 1,5-萘二磺酸盐片剂的硬度平均值 (9.01Kg) 、 N2晶型阿法替尼 1,5-萘二磺酸盐水合物片剂的硬度平均值 （8.55Kg) 、 Ml晶 型阿法替尼一丙二酸盐片剂的硬度平均值 （8.71Kg) 均高于现有技术阿法替尼二马来酸盐晶 型片剂的硬度平均值 （7.10Kg) 。 说明： 在片剂的可压性方面， 上述本发明阿法替尼酸加成 盐晶型的颗粒状晶体均优于现有技术阿法替尼二马来酸盐晶型的针状晶体。  The fatinib dimaleate prepared in Comparative Example 2 is a good tablet of the prior art crystal form and the E1 crystal form afatinib ethanedisulfonate, the N1 crystal form afatinib 1,5-naphthalene A hardness test was carried out on each of 20 tablets of disulfonate, N2 crystal form 1,5-naphthalenedisulfonic acid salt hydrate, and Ml crystal form afatinib monomalonate. The results showed: the average hardness of the E1 crystal form afatinib ethanedisulfonate tablets (9.54Kg), the average hardness of the N1 crystal form afatinib 1,5-naphthalene disulfonate tablets (9.01 Kg), N2 crystal form afatinib 1,5-naphthalene disulfonic acid salt hydrate tablets average hardness (8.55Kg), Ml crystal form afatinib monomalonate tablets hardness average (8.71 Kg) is higher than the average hardness (7.10 Kg) of the prior art afatinib dimaleate tablets. Explanation: In terms of compressibility of the tablet, the above-mentioned granular crystal of the afatinidine acid addition salt crystal form of the present invention is superior to the needle crystal of the prior art afatinib dimaleate crystal form.
以上所述， 仅为本发明的具体实施方式， 但本发明的保护范围并不局限于此， 任何熟悉 本领域的技术人员在本发明所揭露的技术范围内， 可不经过创造性劳动想到的变化或替换， 都应涵盖在本发明的保护范围之内。  The above is only the specific embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can change without thinking of creative work or within the technical scope of the present invention. Alternatives are intended to be covered by the scope of the present invention.

Claims

权 利 要 求 Rights request
1、 阿法替 1. Afatine
Figure imgf000037_0001
Figure imgf000037_0001
2、 权利要求 1 所述的阿法替尼乙二磺酸盐的制备方法， 包含如下步骤： 分别形成阿 法替尼和乙二磺酸在可溶溶剂中的溶 阿法替尼和乙二磺酸的摩尔比为 1 : 1-1 :2， 混 合两个体系形成浆液， 进而除去可溶溶剂； 优选所述可溶溶剂为腈类、 醇类、 酮类、 酯类、 垸烃类、 醚类或其混合物， 更优选所述可溶溶剂为乙腈、 甲醇、 丙酮、 乙酸乙酯、 正庚垸 或甲基叔丁基醚； 优选采用旋干法除去可溶溶剂。 2. The preparation method of afatinib ethanedisulfonate according to claim 1, comprising the steps of: forming afatinib and ethylenedisulfonic acid in a soluble solvent, respectively. The molar ratio of sulfonic acid is 1:1-1:2, mix the two systems to form a slurry, and then remove the soluble solvent; preferably the soluble solvent is nitriles, alcohols, ketones, esters, alkanes, Ethers or mixtures thereof, more preferably the soluble solvent is acetonitrile, methanol, acetone, ethyl acetate, n-heptane or methyl tert-butyl ether; the soluble solvent is preferably removed by spin drying.
3、 根据权利要求 1 所述的阿法替尼乙二磺酸盐， 其特征在于， 所述阿法替尼乙二碩 酸盐为 E1晶型阿法替尼乙二磺酸盐， 使用 Cu-Κα辐射， 其 X射线粉末衍射图在衍射角 2Θ 为 6.3±0.2。、 7.0±0.2。、 17.6±0.2。、 17.8±0.2。、 21.7±0.2。、 22.8±0.2。和 24.6±0.2。处具有特征 3. The afatinib ethanedisulfonate according to claim 1, characterized in that the afatinib ethanedisulfonate is E1 crystalline afatinib ethanedisulfonate, using Cu -Kα radiation, its X-ray powder diffraction pattern at the diffraction angle 2Θ is 6.3±0.2. , 7.0±0.2. , 17.6±0.2. , 17.8±0.2. , 21.7±0.2. , 22.8±0.2. and 24.6±0.2. Characteristic everywhere
4、 根据权利要求 3所述的 E1晶型阿法替尼乙二磺酸盐， 其特征在于： 其 X射线粉末 衍射图在衍射角 2Θ 为 6.3±0.2。、 7.0±0.2。、 12.6±0.2。、 14.5±0.2。、 17.6±0.2。、 17.8±0.2。、 18.3±0.2、 19.0±0.2。、 21.7±0.2。、 22.8±0.2。、 24.6。±0.2、 26.3±0.2。和 28.6±0.2°处具有特征 4. The E1 crystal form afatinib ethanedisulfonate according to claim 3, characterized in that: its X-ray powder diffraction pattern at the diffraction angle 2Θ is 6.3±0.2. , 7.0±0.2. , 12.6±0.2. , 14.5±0.2. , 17.6±0.2. , 17.8±0.2. , 18.3±0.2, 19.0±0.2. , 21.7±0.2. , 22.8±0.2. , 24.6. ±0.2, 26.3±0.2. and 28.6±0.2° are characterized
5、 根据权利要求 4所述的 E1晶型阿法替尼乙二磺酸盐， 其特征在于， 其 X射线粉末 衍射图的衍射角 2Θ特征峰及其相对强度如下： 5. The E1 crystal form afatinib ethanedisulfonate according to claim 4, characterized in that the diffraction angle 2Θ characteristic peak of its X-ray powder diffraction pattern and its relative intensity are as follows:
衍射角 2Θ 相对强度％ Diffraction angle 2Θ Relative intensity %
6.3±0.2° 26.9 6.3±0.2° 26.9
7.0±0.2° 47.3 7.0±0.2° 47.3
12.6±0.2C 16.8 12.6±0.2 C 16.8
14.1±0.2C 10.2 14.1±0.2 C 10.2
14.5±0.2C 15.2 14.5±0.2 C 15.2
16.4±0.2C 10.8 16.4±0.2 C 10.8
17.6±0.2C 62.8 17.6±0.2 C 62.8
17.8±0.2C 100.0 17.8±0.2 C 100.0
18.3±0.2C 21.8 18.3±0.2 C 21.8
19.0±0.2C 23.9 19.0±0.2 C 23.9
21.3±0.2C 12.7 21.3±0.2 C 12.7
21.7±0.2C 49.9 21.7±0.2 C 49.9
22.5±0.2C 17.8 22.5±0.2 C 17.8
22.8±0.2C 65.3 22.8±0.2 C 65.3
23.0±0.2C 40.5 23.0±0.2 C 40.5
24.1±0.2C 18.0 24.1±0.2 C 18.0
24.6±0.2C 91.5 24.6±0.2 C 91.5
25.4±0.2C 13.6 25.4±0.2 C 13.6
26.3±0.2C 16.9 26.3±0.2 C 16.9
27.6±0.2C 15.8 27.6±0.2 C 15.8
28.6±0.2C 39.8 28.6±0.2 C 39.8
29.0±0.2C 17.5 29.0±0.2 C 17.5
29.4±0.2° 10.9 29.4±0.2° 10.9
36.7±0.2° 13.0 36.7±0.2° 13.0
6、 权利要求 3-5中任一项所述的 El晶型阿法替尼乙二磺酸盐的制备方法， 包含如下 步骤： 分别形成阿法替尼和乙二磺酸在可溶溶剂中的溶液体系， 阿法替尼和乙二磺酸的摩 尔比为 1 : 1-1 :2， 混合两个体系形成浆液并搅拌， 在 -10-50°C下保持 1-48小时， 然后除去溶 剂， 其中所述可溶溶剂选自 C2-C4腈、 d-C4醇、 C3-C5酮、 C4-C5酯、 C6-C9烷烃、 C4-C6 醚或其混合物； 优选所述可溶溶剂为乙腈、 甲醇、 丙酮、 乙酸乙酯、 正庚烷、 甲基叔丁基 醚或其混合物； 优选所述制备方法的操作温度为室温。 6. The preparation method of El crystal form afatinib ethanedisulfonate according to any one of claims 3-5, comprising the following steps: forming afatinib and ethanedisulfonic acid in a soluble solvent respectively The solution system, the molar ratio of afatinib and ethanedisulfonic acid is 1:1-1:2, mix the two systems to form a slurry and stir, keep it at -10-50°C for 1-48 hours, and then remove Solvent, wherein the soluble solvent is selected from C 2 -C 4 nitrile, dC 4 alcohol, C 3 -C 5 ketone, C 4 -C 5 ester, C 6 -C 9 alkane, C 4 -C 6 ether or its Mixture; Preferably, the soluble solvent is acetonitrile, methanol, acetone, ethyl acetate, n-heptane, methyl tert-butyl ether or a mixture thereof; Preferably, the operating temperature of the preparation method is room temperature.
7、 权利要求 3-5中任一项所述的 E1晶型阿法替尼乙二磺酸盐的制备方法， 包括以下 步骤： 将按照权利要求 2所述制备方法得到的阿法替尼乙二磺酸盐在有机溶剂中形成浆液 并搅拌， 浆液在 -10-50°C下保持 1〜72小时， 进而除去溶剂， 其中所述有机溶剂选自乙腈、 甲醇、 丙酮、 乙酸乙酯、 正庚烷、 甲基叔丁基醚或其混合物； 优选所述制备方法的操作温 度为室温。 7. The preparation method of the E1 crystal form afatinib ethanedisulfonate according to any one of claims 3 to 5, comprising the following steps: converting the afatinib ethanedisulfonate obtained according to the preparation method of claim 2 The disulfonate is formed into a slurry in an organic solvent and stirred. The slurry is maintained at -10-50°C for 1 to 72 hours, and then the solvent is removed, wherein the organic solvent is selected from acetonitrile, methanol, acetone, ethyl acetate, n- Heptane, methyl tert-butyl ether or mixtures thereof; Preferably, the operating temperature of the preparation method is room temperature.
8、 阿法替尼 8. Afatinib
Figure imgf000038_0001
Figure imgf000038_0001
9、 权利要求 8所述的阿法替尼 1,5-萘二磺酸盐的制备方法， 其特征在于， 包含以下步 骤： 分别形成阿法替尼和 1,5-萘二磺酸在可溶溶剂中的溶液体系， 阿法替尼和 1,5-萘二磺 酸的摩尔比为 1 : 1-1 :2， 混合两个体系形成浆液， 进而除去可溶溶剂； 优选所述可溶溶剂为 腈类、 醇类、 酮类、 酯类、 烷烃类、 醚类或其混合物， 更优选所述可溶溶剂为乙腈、 甲醇、 丙酮、 乙酸乙酯、 正庚烷或甲基叔丁基醚； 优选采用旋干法除去可溶溶剂。 9. The preparation method of afatinib 1,5-naphthalene disulfonate according to claim 8, characterized in that it includes the following steps: forming afatinib and 1,5-naphthalenedisulfonic acid in a In the solution system in the solvent, the molar ratio of afatinib and 1,5-naphthalenedisulfonic acid is 1:1-1:2. Mix the two systems to form a slurry, and then remove the soluble solvent; preferably the soluble The solvent is nitriles, alcohols, ketones, esters, alkanes, ethers or mixtures thereof. More preferably, the soluble solvent is acetonitrile, methanol, acetone, ethyl acetate, n-heptane or methyl tert-butyl. Ether; The soluble solvent is preferably removed by spinning to dryness.
10、 根据权利要求 8所述的阿法替尼 1,5-萘二磺酸盐， 其特征在于： 所述阿法替尼 1,5- 萘二碩酸盐为 N1晶型阿法替尼 1,5-萘二磺酸盐， 使用 Cu-Κα辐射， 其 X射线粉末衍射图在 衍射角 2Θ为 6.6±0.2°、 13.4±0.2。、 16.6±0.2。、 17.5±0.2。、 20.8±0.2°和 24.2±0.2°处具有特征峰。 10. Afatinib 1,5-naphthalene disulfonate according to claim 8, characterized in that: the afatinib 1,5-naphthalene disulfonate is N1 crystal form afatinib 1,5-Naphthalene disulfonate uses Cu-Kα radiation, and its X-ray powder diffraction pattern at the diffraction angle 2Θ is 6.6±0.2° and 13.4±0.2. , 16.6±0.2. , 17.5±0.2. There are characteristic peaks at , 20.8±0.2° and 24.2±0.2°.
11、 根据权利要求 10所述的 N1晶型阿法替尼 1,5-萘二磺酸盐， 其特征在于： 其 X 射线粉末衍射图在衍射角 2Θ 为 6.6。±0.2、 8.1±0.2。、 13.4±0.2。、 14.8±0.2。、 16.3±0.2。、 16.6±0.2。、 17.5±0.2。、 18.3±0.2。、 20.8±0.2。、 22.0±0.2。、 22.7±0.2。和 24.2±0.2。处具有特征 11. The N1 crystal form afatinib 1,5-naphthalene disulfonate according to claim 10, characterized in that: its X-ray powder diffraction pattern at a diffraction angle 2Θ is 6.6. ±0.2, 8.1±0.2. , 13.4±0.2. , 14.8±0.2. , 16.3±0.2. , 16.6±0.2. , 17.5±0.2. , 18.3±0.2. , 20.8±0.2. , 22.0±0.2. , 22.7±0.2. and 24.2±0.2. Characteristic everywhere
12、 根据权利要求 11所述的 N1晶型阿法替尼 1,5-萘二磺酸盐， 其特征在于， 其 X 射线粉末衍射图的衍射角 2Θ特征峰及其相对强度如下： 12. N1 crystal form afatinib 1,5-naphthalene disulfonate according to claim 11, characterized in that the diffraction angle 2Θ characteristic peak of its X-ray powder diffraction pattern and its relative intensity are as follows:
衍射角 2Θ 相对强度％ Diffraction angle 2Θ Relative intensity %
6.6±0.2° 100.0 6.6±0.2° 100.0
8.1±0.2° 16.1 8.1±0.2° 16.1
11.2±0.2° 12.2 11.2±0.2° 12.2
13.4±0.2° 75.6 13.4±0.2° 75.6
14.8±0.2° 21.2 14.8±0.2° 21.2
16.3±0.2° 13.4 16.3±0.2° 13.4
16.6±0.2° 53.5 16.6±0.2° 53.5
17.5±0.2° 27.1 17.5±0.2° 27.1
17.9±0.2° 13.0 17.9±0.2° 13.0
18.3±0.2° 23.1 18.3±0.2° 23.1
19.2±0.2° 20.7 19.2±0.2° 20.7
19.5±0.2° 22.5 19.5±0.2° 22.5
20.5±0.2° 29.9 20.5±0.2° 29.9
20.8±0.2° 38.0 20.8±0.2° 38.0
21.8±0.2° 24.5 21.8±0.2° 24.5
22.0±0.2° 24.8 22.0±0.2° 24.8
22.4±0.2° 26.4 22.4±0.2° 26.4
22.7±0.2° 28.9 22.7±0.2° 28.9
23.2±0.2° 14.3 23.2±0.2° 14.3
23.5±0.2° 15.4 23.5±0.2° 15.4
24.2±0.2° 62.3 24.2±0.2° 62.3
24.7±0.2° 15.6 24.7±0.2° 15.6
26.5±0.2° 15.3 26.5±0.2° 15.3
30.2±0.2° 19.5 30.2±0.2° 19.5
13、 权利要求 10-12中任一项所述的 N1晶型阿法替尼 1,5-萘二磺酸盐的制备方法， 包含以下步骤： 分别形成阿法替尼和 1,5-萘二磺酸在可溶溶剂中的溶液体系， 阿法替尼和 1,5-萘二磺酸的摩尔比为 1 : 1-1 :2， 混合两个体系形成浆液并搅拌， 在 -10-50°C下保持 1-48 小时，进而除去溶剂，其中所述可溶溶剂选自 C2-C4腈、 d-C4醇、 C3-C5酮、 C4-C5酯、 C6-C9 烷烃、 C4-C6醚或其混合物； 优选所述可溶溶剂为乙腈、 甲醇、 乙醇、 丙酮、 乙酸乙酯、 正庚烷、 甲基叔丁基醚或其混合物； 优选所述制备方法的操作温度为室温。 13. The preparation method of N1 crystal form afatinib 1,5-naphthalene disulfonate according to any one of claims 10 to 12, comprising the following steps: forming afatinib and 1,5-naphthalene respectively A solution system of disulfonic acid in a soluble solvent. The molar ratio of afatinib and 1,5-naphthalenedisulfonic acid is 1:1-1:2. Mix the two systems to form a slurry and stir, at -10- Keep it at 50°C for 1-48 hours, and then remove the solvent, wherein the soluble solvent is selected from C 2 -C 4 nitriles, dC 4 alcohols, C 3 -C 5 ketones, C 4 -C 5 esters, C 6 - C 9 alkanes, C 4 -C 6 ethers or mixtures thereof; preferably the soluble solvent is acetonitrile, methanol, ethanol, acetone, ethyl acetate, n-heptane, methyl tert-butyl ether or mixtures thereof; preferably the soluble solvent The operating temperature of the preparation method is room temperature.
14、 权利要求 10-12中任一项所述的 N1晶型阿法替尼 1,5-萘二磺酸盐的制备方法， 包括以下步骤： 将按照权利要求 9所述制备方法得到的阿法替尼 1,5-萘二磺酸盐在有机溶 剂中形成浆液并搅拌， 浆液在 -10-50°C下保持 1〜72 小时， 进而除去溶剂， 其中所述有机 溶剂选自甲醇、 乙醇、 乙腈、 丙酮、 乙酸乙酯、 正庚烷、 甲基叔丁基醚或其混合物； 优选 所述制备方法的操作温度为室温。 14. The preparation method of the N1 crystal form afatinib 1,5-naphthalene disulfonate according to any one of claims 10 to 12, comprising the following steps: converting the afatinib obtained according to the preparation method according to claim 9 Fatinib 1,5-naphthalene disulfonate is formed into a slurry in an organic solvent and stirred. The slurry is maintained at -10-50°C for 1 to 72 hours, and then the solvent is removed, wherein the organic solvent is selected from methanol and ethanol. , acetonitrile, acetone, ethyl acetate, n-heptane, methyl tert-butyl ether or a mixture thereof; preferably, the operating temperature of the preparation method is room temperature.
15、 根据权利要求 8所述的阿法替尼 1,5-萘二磺酸盐， 其特征在于， 所述阿法替尼 1,5-萘二磺酸盐为 N2晶型阿法替尼 1,5-萘二磺酸盐水合物， 使用 Cu-Κα辐射， 其 X射线 粉末衍射图在衍射角 2Θ为 6.7±0.2。、 8.1±0.2。、 9.3±0.2。、 14.9±0.2。、 20.9±0.2。和 23.0±0.2。 处具有特征峰。 15. The afatinib 1,5-naphthalene disulfonate according to claim 8, characterized in that the afatinib 1,5-naphthalene disulfonate is N2 crystalline afatinib The X-ray powder diffraction pattern of 1,5-naphthalenedisulfonate hydrate using Cu-Kα radiation is 6.7±0.2 at the diffraction angle 2Θ. , 8.1±0.2. , 9.3±0.2. , 14.9±0.2. , 20.9±0.2. and 23.0±0.2. There are characteristic peaks.
16、 根据权利要求 15所述的 N2晶型阿法替尼 1,5-萘二磺酸盐水合物，其特征在于， 其 X射线粉末衍射图在衍射角 2Θ为 6.7±0.2°、 8.1±0.2。、 9.3±0.2。、 13.9±0.2。、 14.9±0.2。、 15.8±0.2。、 16.7±0.2。、 17.5±0.2。、 20.5±0.2。、 20.9±0.2。、 21.7±0.2。、 23.0±0.2。、 24.1±0.2。 和 24.3±0.2°处具有特征峰。 16. N2 crystal form afatinib 1,5-naphthalene disulfonate hydrate according to claim 15, characterized in that its X-ray powder diffraction pattern at the diffraction angle 2Θ is 6.7±0.2°, 8.1± 0.2. , 9.3±0.2. , 13.9±0.2. , 14.9±0.2. , 15.8±0.2. , 16.7±0.2. , 17.5±0.2. , 20.5±0.2. , 20.9±0.2. , 21.7±0.2. , 23.0±0.2. , 24.1±0.2. There are characteristic peaks at and 24.3±0.2°.
17、 根据权利要求 16所述的 N2晶型阿法替尼 1,5-萘二磺酸盐水合物，其特征在于， 其 X射线粉末衍射图的衍射角 2Θ特征峰及其相对强度如下： 17. N2 crystal form afatinib 1,5-naphthalene disulfonate hydrate according to claim 16, characterized in that the diffraction angle 2Θ characteristic peak of its X-ray powder diffraction pattern and its relative intensity are as follows:
衍射角 2Θ 相对强度％ Diffraction angle 2Θ Relative intensity %
5.9±0.2° 12.1 5.9±0.2° 12.1
6.7±0.2° 25.2 6.7±0.2° 25.2
8.1±0.2° 36.7 8.1±0.2° 36.7
9.3±0.2° 27.4 9.3±0.2° 27.4
12.0±0.2° 13.9 12.0±0.2° 13.9
13.5±0.2° 12.6 13.5±0.2° 12.6
13.9±0.2° 26.8 13.9±0.2° 26.8
14.9±0.2° 93.0 14.9±0.2° 93.0
15.8±0.2° 39.0 15.8±0.2° 39.0
16.3±0.2° 14.7 16.3±0.2° 14.7
16.7±0.2° 28.6 16.7±0.2° 28.6
17.5±0.2° 26.8 17.5±0.2° 26.8
18.1±0.2° 19.8 18.1±0.2° 19.8
19.4±0.2° 12.1 19.4±0.2° 12.1
20.0±0.2° 30.1 20.0±0.2° 30.1
20.5±0.2° 47.9 20.5±0.2° 47.9
20.9±0.2° 53.1 20.9±0.2° 53.1
21.7±0.2° 45.9 21.7±0.2° 45.9
22.2±0.2° 15.3 22.2±0.2° 15.3
23.0±0.2° 100.0 23.0±0.2° 100.0
24.1±0.2° 43.3 24.1±0.2° 43.3
24.3±0.2。 47.5 24.3±0.2. 47.5
24.8±0.2° 18.9 24.8±0.2° 18.9
25.7±0.2° 15.9 25.7±0.2° 15.9
26.1±0.2° 28.0 26.1±0.2° 28.0
27.6±0.2° 26.6 27.6±0.2° 26.6
18、 权利要求 15-17中任一项所述的 N2晶型阿法替尼 1,5-萘二磺酸盐水合物的制 备方法， 包括以下步骤：将权利要求 10-12中任一项所述的 N1晶型阿法替尼 1,5-萘二磺酸 盐放置在 75%-100%相对湿度的室温环境中， 放置时间 1〜7 天; 优选放置在 75%-85%相 对湿度的室温环境中， 放置时间 1〜3天。 18. The preparation method of N2 crystal form afatinib 1,5-naphthalene disulfonate hydrate according to any one of claims 15-17, comprising the following steps: adding any one of claims 10-12 The N1 crystal form afatinib 1,5-naphthalene disulfonate is placed in a room temperature environment with a relative humidity of 75%-100%, and the placement time is 1 to 7 days; preferably, it is placed in a relative humidity of 75%-85% In a room temperature environment, the storage time is 1 to 3 days.
19、 阿法 19. Alpha
Figure imgf000040_0001
Figure imgf000040_0001
20、 权利要求 19所述的阿法替尼一丙二酸盐的制备方法， 包括以下步骤： 分别形成 阿法替尼和丙二酸在可溶溶剂中的溶液体系， 阿法替尼和丙二酸的摩尔比 1 : 1-1 : 1.5， 混合两 个体系形成浆液， 然后除去溶剂； 优选所述可溶溶剂为醚类溶剂， 更优选所述可溶溶剂为 C4-C5醚； 优选采用旋干法除去溶剂。 20. The preparation method of afatinib-malonate according to claim 19, comprising the following steps: forming a solution system of afatinib and malonate in a soluble solvent, respectively. The molar ratio of the diacid is 1: 1-1: 1.5, mix the two systems to form a slurry, and then remove the solvent; preferably the soluble solvent is an ether solvent, and more preferably the soluble solvent is a C 4 -C 5 ether; The solvent is preferably removed by spinning to dryness.
21、 根据权利要求 19所述的阿法替尼一丙二酸盐， 其特征在于， 所述阿法替尼一 丙二酸盐为 Ml晶型阿法替尼一丙二酸盐， 使用 Cu-Κα辐射， 其 X射线粉末衍射图在衍射 角 2Θ为 6.6±0.2。、 7.2±0.2。、 13.2±0.2。、 13.4±0.2。、 17.3±0.2。、 20.8±0.2。和 25.1±0.2。处具 有特征峰。 21. The afatinib malonate salt according to claim 19, characterized in that the afatinib malonate salt is Ml crystalline afatinib malonate salt, using Cu -Kα radiation, its X-ray powder diffraction pattern is 6.6±0.2 at the diffraction angle 2Θ. , 7.2±0.2. , 13.2±0.2. , 13.4±0.2. , 17.3±0.2. , 20.8±0.2. and 25.1±0.2. There are characteristic peaks everywhere.
22、 根据权利要求 21所述的 Ml晶型阿法替尼一丙二酸盐， 其特征在于： 其 X射 线粉末衍射图在衍射角 2Θ为 6.6±0.2。、 7.2±0.2。、 8.7±0.2。、 13.2±0.2。、 13.4±0.2。、 14.3±0.2。、 17.3±0.2。、 18.0±0.2。、 19.7±0.2。、 20.8±0.2。、 21.4±0.2。、 25.1±0.2。和 26.1±0.2。处具有特征 22. The M1 crystal form afatinib monomalonate according to claim 21, characterized in that: its X-ray powder diffraction pattern at the diffraction angle 2Θ is 6.6±0.2. , 7.2±0.2. , 8.7±0.2. , 13.2±0.2. , 13.4±0.2. , 14.3±0.2. , 17.3±0.2. , 18.0±0.2. , 19.7±0.2. , 20.8±0.2. , 21.4±0.2. , 25.1±0.2. and 26.1±0.2. Characteristic everywhere
23、 根据权利要求 22所述的 Ml晶型阿法替尼一丙二酸盐， 其特征在于， 其 X射 线粉末衍射图的衍射角 2Θ特征峰及其相对强度如下： 23. The M1 crystal form afatinib monomalonate according to claim 22, characterized in that the diffraction angle 2Θ characteristic peak of its X-ray powder diffraction pattern and its relative intensity are as follows:
衍射角 2Θ 相对强度％ Diffraction angle 2Θ Relative intensity %
6.6±0.2° 92.8 6.6±0.2° 92.8
7.2±0.2° 31.1 7.2±0.2° 31.1
8.7±0.2° 12.4 8.7±0.2° 12.4
13.2±0.2° 29.7 13.2±0.2° 29.7
13.4±0.2° 32.2 13.4±0.2° 32.2
14.3±0.2。 15.0 14.3±0.2. 15.0
17.3±0.2° 30.8 17.3±0.2° 30.8
18.0±0.2° 25.5 18.0±0.2° 25.5
19.3±0.2° 15.7 19.3±0.2° 15.7
19.7±0.2° 22.2 19.7±0.2° 22.2
20.8±0.2° 42.1 20.8±0.2° 42.1
21.4±0.2° 18.7 21.4±0.2° 18.7
22.3±0.2。 10.7 22.3±0.2. 10.7
22.7±0.2° 16.6 22.7±0.2° 16.6
23.6±0.2° 18.5 23.6±0.2° 18.5
25.1±0.2° 100.0 25.1±0.2° 100.0
26.0±0.2° 32.2 26.0±0.2° 32.2
24、 权利要求 21-23中任一项所述的 Ml晶型阿法替尼一丙二酸盐的制备方法， 包 括以下步骤： 分别形成阿法替尼和丙二酸在 C4-C5醚中的溶液体系， 阿法替尼和丙二酸的 摩尔比为 1 : 1-1 :2， 混合两个体系形成浆液并搅拌， 在 -10-50°C下保持 1-48小时， 进而除去 溶剂； 优选所述 C4-C5醚为甲基叔丁基醚； 优选所述制备方法的操作温度为室温。 24. The preparation method of M1 crystal form afatinib monomalonate according to any one of claims 21-23, comprising the following steps: forming afatinib and malonate at C 4 -C 5 respectively In the solution system in ether, the molar ratio of afatinib and malonic acid is 1:1-1:2. Mix the two systems to form a slurry and stir, keep it at -10-50°C for 1-48 hours, and then Remove the solvent; Preferably, the C 4 -C 5 ether is methyl tert-butyl ether; Preferably, the operating temperature of the preparation method is room temperature.
25、 权利要求 21-23中任一项所述 Ml晶型阿法替尼一丙二酸盐的制备方法， 包括 以下步骤： 将按照权利要求 20 所述的制备方法得到的阿法替尼一丙二酸盐在有机溶剂中 形成浆液并搅拌， 浆液在 -10-50°C下保持 1〜72 小时， 进而除去溶剂， 其中所述有机溶剂 选自甲醇、 丙酮、 乙腈、 甲基叔丁基醚、 乙酸乙酯、 正庚烷或其混合物； 优选所述制备方 法的操作温度为室温。 25. The preparation method of M1 crystal form afatinib-malonate according to any one of claims 21-23, comprising the following steps: preparing afatinib-malonate obtained according to the preparation method according to claim 20 Malonate is formed into a slurry in an organic solvent and stirred. The slurry is maintained at -10-50°C for 1 to 72 hours, and then the solvent is removed, wherein the organic solvent is selected from methanol, acetone, acetonitrile, and methyl tert-butyl. Ether, ethyl acetate, n-heptane or a mixture thereof; preferably, the operating temperature of the preparation method is room temperature.
26、 阿法 26. Alpha
Figure imgf000041_0001
Figure imgf000041_0001
27、 权利要求 26所述的阿法替尼二丙二酸盐的制备方法， 包括以下步骤： 分别形 成阿法替尼和丙二酸在可溶溶剂中的溶液体系， 阿法替尼和丙二酸的摩尔比 1 :2-1 :4， 混合 两个体系形成浆液， 然后除去溶剂； 优选所述可溶溶剂为酯类溶剂， 更优选为 C4-C5酯； 优选采用旋干法除去溶剂。 27. The preparation method of afatinib dimalonate according to claim 26, comprising the following steps: forming a solution system of afatinib and malonate in a soluble solvent, respectively. The molar ratio of the diacid is 1:2-1:4, mix the two systems to form a slurry, and then remove the solvent; preferably the soluble solvent is an ester solvent, more preferably a C 4 -C 5 ester; the spin-drying method is preferably used Remove solvent.
28、 根据权利要求 26所述的阿法替尼二丙二酸盐， 其特征在于， 所述阿法替尼二丙 二酸盐为 M2晶型阿法替尼二丙二酸盐， 使用 Cu-Κα辐射， 其 X射线粉末衍射图在衍射角 2Θ为 6.5±0.2。、 8.1±0.2。、 13.1±0.2。、 16.1±0.2。、 20.8±0.2°和 25.8±0.2°处具有特征峰。 28. Afatinib dimalonate according to claim 26, characterized in that, the afatinib dimalonate is M2 crystal form afatinib dimalonate, using Cu -Kα radiation, its X-ray powder diffraction pattern is 6.5±0.2 at the diffraction angle 2Θ. , 8.1±0.2. , 13.1±0.2. , 16.1±0.2. There are characteristic peaks at , 20.8±0.2° and 25.8±0.2°.
29、 根据权利要求 28所述的 M2晶型阿法替尼二丙二酸盐， 其特征在于， 其 X射 线粉末衍射图在衍射角 2Θ为 6.5±0.2。、 8.1±0.2。、 9.7±0.2。、 10.9±0.2。、 13.1±0.2。、 14.0±0.2。、 16.1±0.2。、 18.3±0.2。、 19.0±0.2。、 20.8±0.2。、 25.8±0.2°和 27.0±0.2°处具有特征峰。 29. The M2 crystal form afatinib dimalonate according to claim 28, characterized in that its X-ray powder diffraction pattern is 6.5±0.2 at a diffraction angle 2Θ. , 8.1±0.2. , 9.7±0.2. , 10.9±0.2. , 13.1±0.2. , 14.0±0.2. , 16.1±0.2. , 18.3±0.2. , 19.0±0.2. , 20.8±0.2. There are characteristic peaks at , 25.8±0.2° and 27.0±0.2°.
30、 根据权利要求 29所述的 M2晶型阿法替尼二丙二酸盐， 其特征在于， 其 X射 线粉末衍射图的衍射角 2Θ特征峰及其相对强度如下： 30. The M2 crystal form afatinib dimalonate according to claim 29, characterized in that the diffraction angle 2Θ characteristic peak of its X-ray powder diffraction pattern and its relative intensity are as follows:
衍射角 2Θ 相对强度％ Diffraction angle 2Θ Relative intensity %
5.8±0.2° 12.3 5.8±0.2° 12.3
6.5±0.2° 58.7 6.5±0.2° 58.7
8.1±0.2° 24.1 8.1±0.2° 24.1
9.7±0.2° 14.2 9.7±0.2° 14.2
10.9±0.2° 14.9 10.9±0.2° 14.9
13.1±0.2° 42.9 13.1±0.2° 42.9
13.6±0.2° 16.0 13.6±0.2° 16.0
14.0±0.2° 31.9 14.0±0.2° 31.9
15.1±0.2° 14.7 15.1±0.2° 14.7
16.1±0.2° 35.0 16.1±0.2° 35.0
16.4±0.2° 18.8 16.4±0.2° 18.8
18.3±0.2° 15.9 18.3±0.2° 15.9
19.0±0.2° 19.9 19.0±0.2° 19.9
19.8±0.2° 18.0 19.8±0.2° 18.0
20.4±0.2° 14.7 20.4±0.2° 14.7
20.8±0.2° 41.7 20.8±0.2° 41.7
21.5±0.2° 10.5 21.5±0.2° 10.5
22.2±0.2° 19.9 22.2±0.2° 19.9
23.6±0.2° 11.3 23.6±0.2° 11.3
25.8±0.2° 100.0 25.8±0.2° 100.0
26.5±0.2° 13.3 26.5±0.2° 13.3
27.0±0.2° 39.3 27.0±0.2° 39.3
27.7±0.2° 11.8 27.7±0.2° 11.8
29.3±0.2° 12.0 29.3±0.2° 12.0
31、 权利要求 28-30中任一项所述 M2晶型阿法替尼二丙二酸盐的制备方法， 包括 以下步骤： 分别形成阿法替尼和丙二酸在 C4-C5酯中的溶液体系， 阿法替尼和丙二酸的摩 尔比为 1 :2-1 :4， 混合两个体系形成浆液并搅拌， 在 -10-50°C下保持 1-48小时， 进而除去溶 剂， 得到 M2晶型阿法替尼二丙二酸盐； 或者， 分别形成阿法替尼一丙二酸盐在 C4-C5酯 中的混悬液体系和丙二酸在 C4-C5酯中的溶液体系， 阿法替尼一丙二酸盐和丙二酸的摩尔 比为 1 : 1-1 :2， 混合两个体系形成浆液并搅拌，在 -10-50°C下保持 1-48小时，进而除去溶剂， 得到 M2晶型阿法替尼二丙二酸盐； 优选所述 C4-C5酯为乙酸乙酯； 优选所述制备方法的 操作温度为室温。 31. The preparation method of the M2 crystalline afatinib dimalonate salt according to any one of claims 28 to 30, comprising the following steps: forming afatinib and malonic acid esters at C 4 -C 5 respectively In the solution system, the molar ratio of afatinib and malonic acid is 1:2-1:4. Mix the two systems to form a slurry and stir, keep it at -10-50°C for 1-48 hours, and then remove Solvent to obtain the M2 crystal form of afatinib dimalonate; alternatively, form a suspension system of afatinib monomalonate in C 4 -C 5 ester and malonic acid in C 4 - The solution system in C 5 ester, the molar ratio of afatinib monomalonate and malonic acid is 1:1-1:2, mix the two systems to form a slurry and stir, at -10-50°C Keep for 1-48 hours, and then remove the solvent to obtain M2 crystalline afatinib dimalonate; preferably, the C 4 -C 5 ester is ethyl acetate; preferably, the operating temperature of the preparation method is room temperature.
32、 权利要求 28-30中任一项所述 M2晶型阿法替尼二丙二酸盐的制备方法， 包括 以下步骤： 将按照权利要求 27 所述制备方法得到的阿法替尼二丙二酸盐在有机溶剂中形 成浆液并搅拌， 浆液在 -10-50°C下保持 1〜72 小时， 进而除去溶剂， 其中所述有机溶剂选 自甲醇、 丙酮、 乙腈、 甲基叔丁基醚、 乙酸乙酯、 正庚烷或其混合物； 优选所述制备方法 的操作温度为室温。 32. The preparation method of the M2 crystal form afatinib dipropyl salt according to any one of claims 28 to 30, comprising the following steps: converting the afatinib dipropyl salt obtained according to the preparation method of claim 27 The diacid is formed into a slurry in an organic solvent and stirred. The slurry is maintained at -10-50°C for 1 to 72 hours, and then the solvent is removed, wherein the organic solvent is selected from methanol, acetone, acetonitrile, and methyl tert-butyl ether. , ethyl acetate, n-heptane or a mixture thereof; preferably, the operating temperature of the preparation method is room temperature.
33、 阿法 33. Alpha
Figure imgf000042_0001
Figure imgf000042_0001
34、 权利要求 33所述的阿法替尼二 2-萘磺酸盐的制备方法， 包括以下步骤： 分别 形成阿法替尼和 2-萘磺酸在可溶溶剂中的溶液体系， 阿法替尼和 2-萘磺酸的摩尔比为 1 :2-1 :4, 混合两个体系形成浆液， 进而除去溶剂； 优选所述可溶溶剂为醇类、 酮类、 酯类、 烷烃类、 醚类或其混合物， 更优选所述可溶溶剂为甲醇、 丙酮、 乙酸乙酯、 正庚烷或甲基 叔丁基醚； 优选采用旋干法除去溶剂。 34. The preparation method of afatinib di-2-naphthalene sulfonate according to claim 33, comprising the following steps: forming a solution system of afatinib and 2-naphthalene sulfonic acid in a soluble solvent, respectively. The molar ratio of tinib and 2-naphthalenesulfonic acid is 1:2-1:4, mix the two systems to form a slurry, and then remove the solvent; preferably the soluble solvent is alcohols, ketones, esters, alkanes, Ethers or mixtures thereof, more preferably the soluble solvent is methanol, acetone, ethyl acetate, n-heptane or methyl tert-butyl ether; the solvent is preferably removed by spinning to dryness.
35、 根据权利要求 33所述的阿法替尼二 2-萘磺酸盐， 其特征在于， 所述的阿法替 尼二 2-萘磺酸盐为 Nsl晶型阿法替尼二 2-萘磺酸盐， 使用 Cu-Κα辐射， 其 X射线粉末衍 射图在衍射角 2Θ为 5.6±0.2°、 24.0±0.2°和 26.8±0.2°处有特征峰。 35. The afatinib di-2-naphthalene sulfonate according to claim 33, characterized in that the afatinib di-2-naphthalene sulfonate is Nsl crystal form afatinib di-2-naphthalene sulfonate. Naphthalene sulfonate uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2Θ of 5.6±0.2°, 24.0±0.2° and 26.8±0.2°.
36、 根据权利要求 35所述的 Nsl晶型阿法替尼二 2-萘磺酸盐， 其特征在于， 其 X 射线粉末衍射图的衍射角 2Θ特征峰及其相对强度如下： 36. Nsl crystal form afatinib di-2-naphthalene sulfonate according to claim 35, characterized in that the diffraction angle 2Θ characteristic peak of its X-ray powder diffraction pattern and its relative intensity are as follows:
衍射角 2Θ 相对强度％ Diffraction angle 2Θ Relative intensity %
5.6±0.2° 26.0 5.6±0.2° 26.0
24.0±0.2° 100.0 24.0±0.2° 100.0
26.8±0.2° 54.3 26.8±0.2° 54.3
37、 权利要求 35-36中任一项所述 Nsl晶型阿法替尼二 2-萘碩酸盐的制备方法， 包括 以下步骤： 分别形成阿法替尼和 2-萘磺酸在可溶溶剂中的溶液体系， 阿法替尼和 2-萘磺酸的 摩尔比为 1 :2-1 :4， 混合两个体系形成浆液并搅拌， 在 -10-50 °C下保持 1-48小时， 进而除去溶 剂， 其中所述可溶溶剂选自 d-C4醇、 C3-C5酮、 C4-C5酯、 C6-C9烷烃、 C4-C6醚或其混合物; 优选所述可溶溶剂为甲醇、 丙酮、 乙酸乙酯、 正庚烷、 甲基叔丁基醚或其混合物， 更优选为 乙酸乙酯； 优选所述制备方法的操作温度为室温。 37. The preparation method of Nsl crystal form afatinib di-2-naphthalene sulfonic acid salt according to any one of claims 35-36, comprising the following steps: forming afatinib and 2-naphthalene sulfonic acid in soluble The solution system in the solvent, the molar ratio of afatinib and 2-naphthalenesulfonic acid is 1:2-1:4, mix the two systems to form a slurry and stir, keep at -10-50 °C for 1-48 hours , and then remove the solvent, wherein the soluble solvent is selected from dC 4 alcohol, C 3 -C 5 ketone, C 4 -C 5 ester, C 6 -C 9 alkane, C 4 -C 6 ether or a mixture thereof; preferably The soluble solvent is methanol, acetone, ethyl acetate, n-heptane, methyl tert-butyl ether or a mixture thereof, more preferably ethyl acetate; preferably, the operating temperature of the preparation method is room temperature.
38、 权利要求 35-36中任一项所述 Nsl晶型阿法替尼二 2-萘磺酸盐的制备方法，包 括以下步骤： 将按照权利要求 34所述制备方法得到的阿法替尼二 2-萘磺酸盐在有机溶剂 中形成浆液并搅拌， 浆液在 -10-50°C下保持 1〜72小时， 进而除去溶剂， 其中所述有机溶 剂选自甲醇、 丙酮、 乙腈、 乙酸乙酯、 正庚烷、 甲基叔丁基醚或其混合物； 优选所述制备 方法的操作温度为室温。 38. The preparation method of Nsl crystal form afatinib di-2-naphthalene sulfonate according to any one of claims 35-36, comprising the following steps: preparing afatinib obtained according to the preparation method according to claim 34 Di-2-naphthalene sulfonate forms a slurry in an organic solvent and is stirred. The slurry is kept at -10-50°C for 1 to 72 hours, and then the solvent is removed, wherein the organic solvent is selected from methanol, acetone, acetonitrile, and ethyl acetate. ester, n-heptane, methyl tert-butyl ether or a mixture thereof; preferably, the operating temperature of the preparation method is room temperature.
39、 阿 39. Ah
Figure imgf000043_0001
Figure imgf000043_0001
40、 权利要求 39所述的阿法替尼二氨基磺酸盐的制备方法， 包括以下步骤： 分别 形成阿法替尼可溶溶剂中的溶液体系和氨基磺酸在有机溶剂中的混悬液体系， 阿法替尼和 氨基磺酸的摩尔比为 1 :2-1 :4， 混合两个体系形成浆液， 然后除去溶剂； 优选所述可溶溶剂 或有机溶剂为腈类、 醇类、 酮类、 酯类、 烷烃类、 醚类或其混合物， 更优选为乙腈、 甲醇、 丙酮、 乙酸乙酯、 正庚烷或甲基叔丁基醚； 优选采用旋干法除去溶剂。 40. The preparation method of afatinib diasulfamic acid salt according to claim 39, comprising the following steps: forming a solution system of afatinib in a soluble solvent and a suspension of sulfamic acid in an organic solvent respectively. system, the molar ratio of afatinib and sulfamic acid is 1:2-1:4, mix the two systems to form a slurry, and then remove the solvent; preferably the soluble solvent or organic solvent is nitriles, alcohols, ketones esters, alkanes, ethers or mixtures thereof, more preferably acetonitrile, methanol, acetone, ethyl acetate, n-heptane or methyl tert-butyl ether; the solvent is preferably removed by spinning to dryness.
41、 根据权利要求 39所述的阿法替尼二氨基磺酸盐， 其特征在于， 所述阿法替尼 二氨基磺酸盐为 S 1晶型阿法替尼二氨基磺酸盐， 使用 Cu-Κα辐射， 其 X射线粉末衍射图 在衍射角 2Θ为 5.3±0.2。、 10.7±0.2。、 13.2±0.2。、 21.5±0.2。、 22.3±0.2。、 25.5±0.2。和 26.1±0.2。 处具有特征峰。 41. The afatinib diabamate according to claim 39, characterized in that the afatinib diabamate is S1 crystalline afatinib diabamate, using Cu-Kα radiation, its X-ray powder diffraction pattern at the diffraction angle 2Θ is 5.3±0.2. , 10.7±0.2. , 13.2±0.2. , 21.5±0.2. , 22.3±0.2. , 25.5±0.2. and 26.1±0.2. There are characteristic peaks.
42、 根据权利要求 41所述的 S 1 晶型阿法替尼二氨基磺酸盐， 其特征在于： 其 X 射线粉末衍射图在衍射角 2Θ 为 5.3±0.2。、 10.7±0.2。、 1 1.0±0.2。、 12.3±0.2。、 13.2±0.2。、 13.6±0.2。、 17.1±0.2。、 20.2±0.2。、 21.5±0.2。、 22.3±0.2。、 25.5±0.2。和 26.1±0.2。处具有特征 42. The S 1 crystalline afatinib diabamate sulfamate according to claim 41, characterized in that: its X-ray powder diffraction pattern at the diffraction angle 2Θ is 5.3±0.2. , 10.7±0.2. , 1 1.0±0.2. , 12.3±0.2. , 13.2±0.2. , 13.6±0.2. , 17.1±0.2. , 20.2±0.2. , 21.5±0.2. , 22.3±0.2. , 25.5±0.2. and 26.1±0.2. Characteristic everywhere
43、 根据权利要求 42所述的 S1晶型阿法替尼阿法替尼二氨基磺酸盐，其特征在于 其 X射线粉末衍射图的衍射角 2Θ特征峰及其相对强度如下： 43. The S1 crystal form afatinib afatinib diabamate according to claim 42 is characterized in that the diffraction angle 2Θ characteristic peak of its X-ray powder diffraction pattern and its relative intensity are as follows:
衍射角 2Θ 相对强度％ Diffraction angle 2Θ Relative intensity %
5.3±0.2° 65.4 5.3±0.2° 65.4
10.7±0.2° 42.4 10.7±0.2° 42.4
1 1.0±0.2° 15.7 1 1.0±0.2° 15.7
12.3±0.2。 13.5 12.3±0.2. 13.5
12.9±0.2° 10.1 12.9±0.2° 10.1
13.2±0.2° 26.1 13.2±0.2° 26.1
13.6±0.2° 12.0 13.6±0.2° 12.0
17.1±0.2° 17.0 17.1±0.2° 17.0
19.0±0.2° 10.1 19.0±0.2° 10.1
20.2±0.2° 19.3 20.2±0.2° 19.3
21.5±0.2° 22.4 21.5±0.2° 22.4
22.3±0.2。 22.2 22.3±0.2. 22.2
23.0±0.2° 11.2 23.0±0.2° 11.2
25.5±0.2° 100.0 25.5±0.2° 100.0
26.1±0.2° 53.2 26.1±0.2° 53.2
44、 权利要求 41-43 中任一项所述的 SI晶型阿法替尼二氨基磺酸盐的制备方法， 包括以下步骤： 分别形成阿法替尼在可溶溶剂中的溶液体系和氨基磺酸在有机溶剂中的混 悬液体系， 阿法替尼和氨基磺酸的摩尔比为 1 :2-1 :4， 混合两个体系形成浆液并搅拌， 在 -10-50°C下保持 1-48小时， 进而除去溶剂， 得到 S1型阿法替尼二氨基磺酸盐， 其中所述 可溶溶剂或有机溶剂选自 C2-C4腈、 d-C4醇、 C3-C5酮、 C4-C5酯、 C6-C9烷烃、 C4-C6醚或 其混合物； 优选所述可溶溶剂或有机溶剂为乙腈、 甲醇、 丙酮、 乙酸乙酯、 正庚烷、 甲基 叔丁基醚或其混合物； 优选所述制备方法的操作温度为室温。 44. The preparation method of the SI crystal form afatinib diasamic acid salt according to any one of claims 41-43, comprising the following steps: forming a solution system of afatinib in a soluble solvent and an amino acid salt respectively. A suspension system of sulfonic acid in an organic solvent, the molar ratio of afatinib and sulfamic acid is 1:2-1:4, mix the two systems to form a slurry and stir, keep at -10-50°C 1-48 hours, and then remove the solvent to obtain S1 type afatinib diabamate, wherein the soluble solvent or organic solvent is selected from C 2 -C 4 nitrile, dC 4 alcohol, C 3 -C 5 ketone , C 4 -C 5 esters, C 6 -C 9 alkanes, C 4 -C 6 ethers or mixtures thereof; preferably the soluble solvent or organic solvent is acetonitrile, methanol, acetone, ethyl acetate, n-heptane, methane tert-butyl ether or a mixture thereof; preferably, the operating temperature of the preparation method is room temperature.
45、 权利要求 41-43中任一项所述的 S1晶型阿法替尼二氨基碩酸盐的制备方法， 包括 以下步骤：将按照权利要求 40所述制备方法得到的阿法替尼二氨基碩酸盐在有机溶剂中形成浆 液并搅拌， 浆液在 -10-50°C下保持 1〜72 小时， 进而除去溶剂， 其中所述有机溶剂选自甲醇、 丙酮、 乙腈、 乙酸乙酯、 正庚烷、 甲基叔丁基醚或其混合物； 优选所述制备方法的操作温度 为室温。 and The aminosulfate salt is formed into a slurry in an organic solvent and stirred. The slurry is kept at -10-50°C for 1 to 72 hours, and then the solvent is removed, wherein the organic solvent is selected from the group consisting of methanol, acetone, acetonitrile, ethyl acetate, and n-ethyl acetate. Heptane, methyl tert-butyl ether or mixtures thereof; Preferably, the operating temperature of the preparation method is room temperature.
46、 阿法 46. Alpha
Figure imgf000044_0001
Figure imgf000044_0001
47、 权利要求 46所述阿法替尼二 D-葡萄糖酸盐的制备方法， 包括以下步骤： 形成 阿法替尼在可溶溶剂中的溶液， 阿法替尼和 D-葡萄糖酸的摩尔比为 1 :2-1 :4，将阿法替尼在 可溶溶剂中的溶液和 D-葡萄糖酸水溶液混合形成浆液， 进而除去溶剂； 优选所述可溶溶剂 为腈类、 醇类、 酮类、 酯类、 烷烃类、 醚类或其混合物， 更优选所述可溶溶剂为乙腈、 甲 醇、 丙酮、 乙酸乙酯、 正庚烷或甲基叔丁基醚； 优选采用旋干法除去溶剂； 优选 D-葡萄糖 酸水溶液的浓度为 50%。 47. The preparation method of afatinib di-D-gluconate according to claim 46, comprising the following steps: forming a solution of afatinib in a soluble solvent, the molar ratio of afatinib and D-gluconate is 1:2-1:4, mix afatinib solution in a soluble solvent and D-gluconic acid aqueous solution to form a slurry, and then remove the solvent; preferably the soluble solvent is nitriles, alcohols, ketones , esters, alkanes, ethers or mixtures thereof, more preferably the soluble solvent is acetonitrile, methanol, acetone, ethyl acetate, n-heptane or methyl tert-butyl ether; the solvent is preferably removed by spinning to dryness; The preferred concentration of the D-gluconic acid aqueous solution is 50%.
48、 根据权利要求 46所述的阿法替尼二 D-葡萄糖酸盐， 其特征在于， 所述阿法替 尼二 D-葡萄糖酸盐为 G1晶型阿法替尼二 D-葡萄糖酸盐， 使用 Cu-Κα辐射， 其 X射线粉 末衍射图在衍射角 2Θ为 4.9±0.2°、 5.5±0.2°、 10.0±0.2°、 13.0±0.2°、 25.3±0.2°和 25.9±0.2° 处具有特征峰。 48. The afatinib di-D-gluconate according to claim 46, characterized in that the afatinib di-D-gluconate is G1 crystalline afatinib di-D-gluconate. , using Cu-Kα radiation, its X-ray powder diffraction pattern is characterized by diffraction angles 2Θ of 4.9±0.2°, 5.5±0.2°, 10.0±0.2°, 13.0±0.2°, 25.3±0.2° and 25.9±0.2°. peak.
49、 根据权利要求 48所述的 G1晶型阿法替尼二 D-葡萄糖酸盐， 其特征在于， 其 X射线粉末衍射图在衍射角 2Θ为 4.9±0.2°、5.5±0.2°、6.1±0.2°、9.6±0.2°、10.0±0.2°、13.0±0.2°、 17.1±0.2。、 19.6±0.2。、 20.0±0.2。、 20.3±0.2。、 25.3±0.2。和 25.9±0.2。处具有特征峰。 49. The G1 crystal form afatinib diD-gluconate according to claim 48, characterized in that its X-ray powder diffraction pattern at the diffraction angle 2Θ is 4.9±0.2°, 5.5±0.2°, 6.1± 0.2°, 9.6±0.2°, 10.0±0.2°, 13.0±0.2°, 17.1±0.2. , 19.6±0.2. , 20.0±0.2. , 20.3±0.2. , 25.3±0.2. and 25.9±0.2. There are characteristic peaks.
50、 根据权利要求 49所述的 G1晶型阿法替尼二 D-葡萄糖酸盐， 其特征在于， 其 X射线粉末衍射图的衍射角 2Θ特征峰及其相对强度如下： 50. The G1 crystal form afatinib di-D-gluconate according to claim 49, characterized in that the diffraction angle 2Θ characteristic peak of its X-ray powder diffraction pattern and its relative intensity are as follows:
衍射角 2Θ 相对强度％ Diffraction angle 2Θ Relative intensity %
4.9±0.2° 60.6 4.9±0.2° 60.6
5.5±0.2° 23.8 5.5±0.2° 23.8
6.1±0.2° 17.4 6.1±0.2° 17.4
8.5±0.2° 14.1 8.5±0.2° 14.1
9.6±0.2° 18.5 10 0±0.2。 44.4 9.6±0.2° 18.5 10 0±0.2. 44.4
12 1±0.2° 14.7 12 1±0.2° 14.7
13 0±0.2。 26.8 13 0±0.2. 26.8
15 2±0.2。 10.3 15 2±0.2. 10.3
17 1±0.2° 29.4 17 1±0.2° 29.4
18 8±0.2。 15.6 18 8±0.2. 15.6
19 6±0.2。 21.8 19 6±0.2. 21.8
20 0±0.2。 33.5 20 0±0.2. 33.5
20 3±0.2。 33.8 20 3±0.2. 33.8
22 3±0.2。 11.2 22 3±0.2. 11.2
25 3±0.2。 100.0 25 3±0.2. 100.0
25 9±0.2。 53.2 25 9±0.2. 53.2
26 6±0.2。 11.8 26 6±0.2. 11.8
27 3±0.2。 13.8 27 3±0.2. 13.8
27 7±0.2。 11.8 27 7±0.2. 11.8
51、 权利要求 48-50中任一项所述 Gl晶型阿法替尼二 D-葡萄糖酸盐的制备方法， 包括以下步骤： 形成阿法替尼在可溶溶剂中的溶液， 阿法替尼和 D-葡萄糖酸的摩尔比为 1 :2-1 :4, 将阿法替尼在可溶溶剂中的溶液和 D-葡萄糖酸水溶液混合形成浆液并搅拌， 在 -10-50°C下保持 1-48小时，进而除去溶剂，其中所述可溶溶剂选自 C2-C4腈、 d-C4醇、 C3-C5 酮、 C4-C5酯、 C6-C9烷烃、 硝基取代的 C C3烷烃、 C4-C6醚或其混合物； 优选所述可溶溶 剂为乙酸乙酯、 乙腈、 硝基甲烷、 甲醇、 丙酮、 正庚烷、 甲基叔丁基醚或其混合物； 优选 D-葡萄糖酸水溶液的浓度为 50%; 优选所述制备方法的操作温度为室温。 51. The preparation method of G1 crystal form afatinib di-D-gluconate according to any one of claims 48-50, comprising the following steps: forming a solution of afatinib in a soluble solvent, afatinib The molar ratio of afatinib and D-gluconic acid is 1:2-1:4. Mix the solution of afatinib in the soluble solvent and the D-gluconic acid aqueous solution to form a slurry and stir at -10-50°C. Keep for 1-48 hours, and then remove the solvent, wherein the soluble solvent is selected from C 2 -C 4 nitrile, dC 4 alcohol, C 3 -C 5 ketone, C 4 -C 5 ester, C 6 -C 9 alkane, Nitro-substituted CC 3 alkanes, C 4 -C 6 ethers or mixtures thereof; preferably the soluble solvent is ethyl acetate, acetonitrile, nitromethane, methanol, acetone, n-heptane, methyl tert-butyl ether or The mixture thereof; Preferably, the concentration of the D-gluconic acid aqueous solution is 50%; Preferably, the operating temperature of the preparation method is room temperature.
52、 权利要求 48-50中任一项所述 G1晶型阿法替尼二 D-葡萄糖酸盐的制备方法， 包括以下步骤： 将按照权利要求 47所述制备方法得到的阿法替尼二 D-葡萄糖酸盐在有机 溶剂中形成浆液并搅拌， 浆液在 -10-50°C下保持 1〜72 小时， 进而除去溶剂， 其中所述有 机溶剂选自甲醇、 乙腈、 乙酸乙酯、 硝基甲烷、 丙酮、 正庚烷、 甲基叔丁基醚或其混合物； 优选所述制备方法的操作温度为室温。 52. The preparation method of the G1 crystal form afatinib di-D-gluconate according to any one of claims 48 to 50, comprising the following steps: converting the afatinib di-gluconate obtained according to the preparation method of claim 47 D-gluconate is formed into a slurry in an organic solvent and stirred. The slurry is kept at -10-50°C for 1 to 72 hours, and then the solvent is removed, wherein the organic solvent is selected from methanol, acetonitrile, ethyl acetate, nitro Methane, acetone, n-heptane, methyl tert-butyl ether or mixtures thereof; preferably, the operating temperature of the preparation method is room temperature.
53、 阿法替尼 53. Afatinib
Figure imgf000045_0001
Figure imgf000045_0001
54、 权利要求 53所述的阿法替尼二环己烷氨基磺酸盐的制备方法，包括以下步骤： 分别形成阿法替尼在可溶溶剂中的溶液体系和环己烷氨基磺酸在有机溶剂中的悬浮液体 系， 阿法替尼和环己烷氨基磺酸的摩尔比为 1 :2-1 :4， 混合两个体系形成浆液， 进而除去溶 剂； 优选所述可溶溶剂或有机溶剂为腈类、 醇类、 酮类、 酯类、 烷烃类、 醚类或其混合物， 更优选为乙腈、 甲醇、 丙酮、 乙酸乙酯、 正庚烷或甲基叔丁基醚； 优选采用旋干法除去溶 剂。 54. The preparation method of afatinib dicyclohexane sulfamate according to claim 53, comprising the following steps: respectively forming a solution system of afatinib in a soluble solvent and cyclohexane sulfamate in a soluble solvent. For a suspension system in an organic solvent, the molar ratio of afatinib and cyclohexane sulfamic acid is 1:2-1:4. Mix the two systems to form a slurry, and then remove the solvent; preferably the soluble solvent or organic The solvent is nitriles, alcohols, ketones, esters, alkanes, ethers or mixtures thereof, more preferably acetonitrile, methanol, acetone, ethyl acetate, n-heptane or methyl tert-butyl ether; preferably rotary solvents are used. Remove solvent dryly.
55、 根据权利要求 53所述的阿法替尼二环己烷氨基磺酸盐， 其特征在于， 所述阿 法替尼二环己烷氨基磺酸盐为 C1晶型阿法替尼二环己烷氨基磺酸盐， 使用 Cu-Κα辐射， 其 X射线粉末衍射图在衍射角 2Θ为 5.0±0.2°、 6.0±0.2。、 16.5±0.2。、 17.9±0.2。、 18.6±0.2° 和 20.2±0.2。处具有特征峰。 55. The afatinib dicyclohexane sulfamate according to claim 53, characterized in that the afatinib dicyclohexane sulfamate is C1 crystalline afatinib bicyclo Hexane sulfamate uses Cu-Kα radiation, and its X-ray powder diffraction pattern at the diffraction angle 2Θ is 5.0±0.2° and 6.0±0.2. , 16.5±0.2. , 17.9±0.2. , 18.6±0.2° and 20.2±0.2. There are characteristic peaks.
56、 根据权利要求 55所述 C1 晶型阿法替尼二环己烷氨基磺酸盐， 其特征在于， 其 X射线粉末衍射图在衍射角 2Θ为 5.0±0.2°、 6.0±0.2。、 12.5±0.2。、 14.9±0.2。、 16.5±0.2。、 56. The C1 crystalline afatinib dicyclohexane sulfamate according to claim 55, characterized in that its X-ray powder diffraction pattern at the diffraction angle 2Θ is 5.0±0.2° and 6.0±0.2. , 12.5±0.2. , 14.9±0.2. , 16.5±0.2. ,
17.9±0.2。、 18.4±0.2。、 18.6±0.2。、 20.2±0.2。、 21.3±0.2。、 21.6±0.2。和 24.2±0.2。处具有特征 17.9±0.2. , 18.4±0.2. , 18.6±0.2. , 20.2±0.2. , 21.3±0.2. , 21.6±0.2. and 24.2±0.2. Characteristic everywhere
57、 根据权利要求 56所述的 C1晶型阿法替尼二环己烷氨基磺酸盐， 其特征在于 其 X射线粉末衍射图的衍射角 2Θ特征峰及其相对强度如下： 57. The C1 crystal form afatinib dicyclohexane sulfamate according to claim 56, characterized in that the diffraction angle 2Θ characteristic peak of its X-ray powder diffraction pattern and its relative intensity are as follows:
衍射角 2Θ 相对强度％ Diffraction angle 2Θ Relative intensity %
5.0±0.2° 100.0 5.0±0.2° 100.0
6.0±0.2° 27.1 6.0±0.2° 27.1
12.5±0.2。 9.6 12.5±0.2. 9.6
14.9±0.2° 9.9 14.9±0.2° 9.9
16.5±0.2° 13.6 16.5±0.2° 13.6
17.9±0.2° 15.3 17.9±0.2° 15.3
18.4±0.2° 17.6 18.4±0.2° 17.6
18.6±0.2° 31.3 18.6±0.2° 31.3
19.5±0.2° 9.6 19.5±0.2° 9.6
20.2±0.2° 27.9 20.2±0.2° 27.9
21.3±0.2° 12.2 21.3±0.2° 12.2
21.6±0.2° 13.1 21.6±0.2° 13.1
24.2±0.2° 12.9 24.2±0.2° 12.9
27.8±0.2° 10.2 27.8±0.2° 10.2
58、 权利要求 55-57中任一项所述的 C1晶型阿法替尼二环己烷氨基磺酸盐的制备 方法， 包括以下步骤： 分别形成阿法替尼在可溶溶剂中的溶液体系和环己烷氨基磺酸在有 机溶剂中的悬浮液体系， 阿法替尼和环己烷氨基磺酸的摩尔比为 1 :2-1 :4， 混合两个体系形 成浆液并搅拌， 在 -10-50°C下保持 1-48小时， 进而除去溶剂， 其中所述可溶溶剂或有机溶 剂选自 C2-C4腈、 d-C4醇、 C3-C5酮、 C4-C5酯、 C6-C9烷烃、 C4-C6醚或其混合物; 优选所 述可溶溶剂或有机溶剂为乙腈、 甲醇、 丙酮、 乙酸乙酯、 正庚烷、 甲基叔丁基醚或其混合 物； 优选所述制备方法的操作温度为室温。 58. The preparation method of the C1 crystal form afatinib dicyclohexane sulfamate according to any one of claims 55-57, comprising the following steps: forming a solution of afatinib in a soluble solvent respectively system and a suspension system of cyclohexane sulfamate in an organic solvent. The molar ratio of afatinib and cyclohexane sulfamate is 1:2-1:4. Mix the two systems to form a slurry and stir. Keep it at -10-50°C for 1-48 hours, and then remove the solvent, wherein the soluble solvent or organic solvent is selected from C 2 -C 4 nitrile, dC 4 alcohol, C 3 -C 5 ketone, C 4 -C 5 esters, C 6 -C 9 alkanes, C 4 -C 6 ethers or mixtures thereof; preferably the soluble solvent or organic solvent is acetonitrile, methanol, acetone, ethyl acetate, n-heptane, methyl tert-butyl ether Or a mixture thereof; Preferably, the operating temperature of the preparation method is room temperature.
59、 权利要求 55-57 中任一项所述的 C1 晶型阿法替尼二环己烷氨基碩酸盐的制备方 法， 包括以下步骤： 将按照权利要求 54所述制备方法得到的阿法替尼二环己烷氨基磺酸盐在 有机溶剂中形成浆液并搅拌， 浆液在 -10-50°C下保持 1〜72小时， 进而除去溶剂， 其中所述有 机溶剂选自甲醇、 丙酮、 乙腈、 乙酸乙酯、 正庚烷、 甲基叔丁基醚或其混合物； 优选所述制备 方法的操作温度为室温。 59. The preparation method of the C1 crystal form afatinib dicyclohexane aminosate according to any one of claims 55 to 57, comprising the following steps: converting the afatinib obtained according to the preparation method of claim 54 Tinidicyclohexane sulfamate is formed into a slurry in an organic solvent and stirred. The slurry is maintained at -10-50°C for 1 to 72 hours, and then the solvent is removed, wherein the organic solvent is selected from methanol, acetone, and acetonitrile. , ethyl acetate, n-heptane, methyl tert-butyl ether or a mixture thereof; preferably, the operating temperature of the preparation method is room temperature.
60、 阿法替 4-氨基苯磺酸盐， 其结构式如下： 60. Afatine 4-aminobenzene sulfonate, its structural formula is as follows:
Figure imgf000046_0001
Figure imgf000046_0001
61、 权利要求 60所述阿法替尼二 4-氨基苯磺酸盐的制备方法， 包括以下步骤： 分 别形成阿法替尼在可溶溶剂中的溶液体系和 4-氨基苯磺酸在有机溶剂中的悬浮液体系， 阿 法替尼和 4-氨基苯磺酸的摩尔比为 1 :2-1 :4， 混合两个体系形成浆液， 进而除去溶剂； 优选 所述可溶溶剂或有机溶剂为腈类、 醇类、 酮类、 烷烃类、 醚类或其混合物， 更优选为乙腈、 甲醇、 丙酮、 乙酸乙酯、 正庚烷或甲基叔丁基醚； 优选采用旋干法除去溶剂。 61. The preparation method of afatinib di-4-aminobenzene sulfonate according to claim 60, comprising the following steps: forming a solution system of afatinib in a soluble solvent and 4-aminobenzenesulfonic acid in an organic solvent, respectively. In the suspension system in the solvent, the molar ratio of afatinib and 4-aminobenzenesulfonic acid is 1:2-1:4. Mix the two systems to form a slurry, and then remove the solvent; the soluble solvent or organic solvent is preferred It is nitriles, alcohols, ketones, alkanes, ethers or mixtures thereof, more preferably acetonitrile, methanol, acetone, ethyl acetate, n-heptane or methyl tert-butyl ether; the solvent is preferably removed by spin drying. .
62、 根据权利要求 60所述的阿法替尼二 4-氨基苯磺酸盐， 其特征在于， 所述阿法 替尼二 4-氨基苯磺酸盐为 A1晶型阿法替尼二 4-氨基苯磺酸盐， 使用 Cu-Κα辐射， 其 X射 线粉末衍射图在衍射角 2Θ 为 12.9±0.2。、 17.1±0.2。、 18.2±0.2。、 23.8±0.2。、 24.5±0.2。和 62. The afatinib di-4-aminobenzene sulfonate according to claim 60, characterized in that the afatinib di-4-aminobenzene sulfonate is A1 crystal form afatinib di-4 - Aminobenzene sulfonate, using Cu-Kα radiation, its X-ray powder diffraction pattern at the diffraction angle 2Θ is 12.9±0.2. , 17.1±0.2. , 18.2±0.2. , 23.8±0.2. , 24.5±0.2. and
25.7±0.2°处具有特征峰。 There is a characteristic peak at 25.7±0.2°.
63、 根据权利要求 62所述 A1晶型阿法替尼二 4-氨基苯磺酸盐， 其特征在于， 其 X 射线粉末衍射图在衍射角 2Θ为 5.6±0.2°、12.9±0.2°、17.1±0.2°、18.2±0.2°、21.3±0.2°、23.8±0.2°、 24.5±0.2。、 25.7±0.2。、 27.6±0.2。和 34.3±0.2。处具有特征峰。 63. The A1 crystal form afatinib di-4-aminobenzene sulfonate according to claim 62, characterized in that its X-ray powder diffraction pattern at the diffraction angle 2Θ is 5.6±0.2°, 12.9±0.2°, 17.1 ±0.2°, 18.2±0.2°, 21.3±0.2°, 23.8±0.2°, 24.5±0.2. , 25.7±0.2. , 27.6±0.2. and 34.3±0.2. There are characteristic peaks.
64、 根据权利要求 63所述的 A1晶型阿法替尼二 4-氨基苯磺酸盐， 其特征在于， 其 X射线粉末衍射图的衍射角 2Θ特征峰及其相对强度如下： 64. The A1 crystal form afatinib di-4-aminobenzene sulfonate according to claim 63, characterized in that the diffraction angle 2Θ characteristic peak of its X-ray powder diffraction pattern and its relative intensity are as follows:
衍射角 2Θ 相对强度％ Diffraction angle 2Θ Relative intensity %
5.6±0.2° 10.5 5.6±0.2° 10.5
12.9±0.2° 23.9 12.9±0.2° 23.9
17.1±0.2° 1 1.9 17.1±0.2° 1 1.9
18.2±0.2° 100.0 18.2±0.2° 100.0
21.3±0.2° 12.9 21.3±0.2° 12.9
23.8±0.2° 19.1 23.8±0.2° 19.1
24.5±0.2° 29.6 24.5±0.2° 29.6
25.7±0.2° 23.1 25.7±0.2° 23.1
27.6±0.2° 18.3 27.6±0.2° 18.3
34.3±0.2。 16.1 34.3±0.2. 16.1
65、 权利要求 62-64中任一项所述 A1晶型阿法替尼二 4-氨基苯磺酸盐的制备方法， 包括以下步骤：分别形成阿法替尼在可溶溶剂中的溶液体系和 4-氨基苯磺酸在有机溶剂中的 悬浮液体系， 阿法替尼和 4-氨基苯磺酸的摩尔比为 1 :2-1 :4， 混合两个体系形成浆液并搅拌， 在 -10-50°C下保持 1-48小时， 进而除去溶剂， 其中所述可溶溶剂或有机溶剂选自 C2-C4腈、 d-C4醇、 C3-C5酮、 C6-C9烷烃、 C4-C6醚或其混合物；优选所述可溶溶剂或有机溶剂为乙腈、 甲醇、 丙酮、 正庚烷、 甲基叔丁基醚或其混合物； 优选所述制备方法的操作温度为室温。 65. The preparation method of the A1 crystal form afatinib di-4-aminobenzene sulfonate according to any one of claims 62 to 64, comprising the following steps: forming a solution system of afatinib in a soluble solvent respectively and 4-aminobenzenesulfonic acid in an organic solvent. The molar ratio of afatinib and 4-aminobenzenesulfonic acid is 1:2-1:4. Mix the two systems to form a slurry and stir, in - Keep it at 10-50°C for 1-48 hours, and then remove the solvent, wherein the soluble solvent or organic solvent is selected from C 2 -C 4 nitrile, dC 4 alcohol, C 3 -C 5 ketone, C 6 -C 9 Alkanes, C 4 -C 6 ethers or mixtures thereof; preferably the soluble solvent or organic solvent is acetonitrile, methanol, acetone, n-heptane, methyl tert-butyl ether or mixtures thereof; the preferred operating temperature of the preparation method is room temperature.
66、 权利要求 62-64中任一项所述 A1晶型阿法替尼二 4-氨基苯磺酸盐的制备方法， 包括以下步骤： 将按照权利要求 61所述制备方法得到的阿法替尼二 4-氨基苯磺酸盐在有机 溶剂中形成浆液并搅拌， 浆液在 -10-50°C下保持 1〜72小时， 进而除去溶剂， 其中所述有机 溶剂选自甲醇、 丙酮、 乙腈、 乙酸乙酯、 正庚烷、 甲基叔丁基醚或其混合物； 优选所述制备 方法的操作温度为室温。 66. The preparation method of the A1 crystal form afatinib di-4-aminobenzene sulfonate according to any one of claims 62 to 64, comprising the following steps: converting the afatinib obtained according to the preparation method according to claim 61 Nibis 4-aminobenzene sulfonate forms a slurry in an organic solvent and stirs. The slurry is maintained at -10-50°C for 1 to 72 hours, and then the solvent is removed, wherein the organic solvent is selected from methanol, acetone, acetonitrile, Ethyl acetate, n-heptane, methyl tert-butyl ether or a mixture thereof; preferably, the operating temperature of the preparation method is room temperature.
67、 阿法 67. Alpha
HOCH COOH
Figure imgf000047_0001
HOCH COOH
Figure imgf000047_0001
68、 权利要求 67所述阿法替尼甘醇酸盐的制备方法， 包括以下步骤： 分别形成阿 法替尼和甘醇酸在可溶溶剂中的溶液体系， 阿法替尼和甘醇酸的摩尔比为 1 : 1-1 :2， 混合两 个体系形成浆液， 然后除去溶剂； 优选所述可溶溶剂为醇类、 酮类、 酯类、 烷烃类、 醚类 或其混合物， 更优选所述可溶溶剂为甲醇、 丙酮、 乙酸乙酯、 正庚烷或甲基叔丁基醚； 优 选采用旋干法除去溶剂。 68. The preparation method of afatinib glycolate according to claim 67, comprising the following steps: forming a solution system of afatinib and glycolic acid in a soluble solvent, respectively. The molar ratio is 1:1-1:2, mix the two systems to form a slurry, and then remove the solvent; preferably the soluble solvent is alcohols, ketones, esters, alkanes, ethers or mixtures thereof, more preferably The soluble solvent is methanol, acetone, ethyl acetate, n-heptane or methyl tert-butyl ether; the solvent is preferably removed by spin drying.
69、 根据权利要求 67所述的阿法替尼甘醇酸盐， 其特征在于， 所述阿法替尼甘醇酸 盐为 G1-1晶型阿法替尼甘醇酸盐， 使用 Cu-Κα辐射， 其 X射线粉末衍射图在衍射角 2Θ为 5.1±0.2。、 6.4±0.2。、 13.0±0.2。、 13.3±0.2。、 20.8±0.2。和 25.0±0.2。处具有特征峰。 69. The afatinib glycolate according to claim 67, characterized in that the afatinib glycolate is G1-1 crystalline afatinib glycolate, using Cu- Kα radiation, its X-ray powder diffraction pattern at the diffraction angle 2Θ is 5.1±0.2. , 6.4±0.2. , 13.0±0.2. , 13.3±0.2. , 20.8±0.2. and 25.0±0.2. There are characteristic peaks.
70、 根据权利要求 69所述的 G1-1晶型阿法替尼甘醇酸盐， 其特征在于， 其 X射线 粉末衍射图在衍射角 2Θ为 5.1±0.2°、 6.4±0.2。、 7.0±0.2。、 13.0±0.2。、 13.3±0.2。、 17.2±0.2。、 70. The G1-1 crystal form afatinib glycolate according to claim 69, characterized in that its X-ray powder diffraction pattern at the diffraction angle 2Θ is 5.1±0.2° and 6.4±0.2. , 7.0±0.2. , 13.0±0.2. , 13.3±0.2. , 17.2±0.2. ,
17.9±0.2。、 19.7±0.2。、 20.8±0.2。、 22.4±0.2。、 25.0±0.2°和 25.9±0.2°处具有特征峰。 17.9±0.2. , 19.7±0.2. , 20.8±0.2. , 22.4±0.2. There are characteristic peaks at , 25.0±0.2° and 25.9±0.2°.
71、 根据权利要求 70所述的 G1-1晶型阿法替尼甘醇酸盐， 其特征在于， 其 X射线 粉末衍射图的衍射角 2Θ特征峰及其相对强度如下： 71. The G1-1 crystal form afatinib glycolate according to claim 70, characterized in that the diffraction angle 2Θ characteristic peak of its X-ray powder diffraction pattern and its relative intensity are as follows:
衍射角 2Θ 相对强度％ Diffraction angle 2Θ Relative intensity %
5.1±0.2° 28.9 5.1±0.2° 28.9
6.4±0.2° 100.0 6.4±0.2° 100.0
7.0±0.2° 11.5 7.0±0.2° 11.5
13.0±0.2° 21.7 13.0±0.2° 21.7
13.3±0.2° 19.0 13.3±0.2° 19.0
17.2±0.2° 14.7 17.2±0.2° 14.7
17.9±0.2° 13.9 17.9±0.2° 13.9
19.0±0.2° 11.2 19.0±0.2° 11.2
19.7±0.2° 11.5 19.7±0.2° 11.5
20.8±0.2° 24.7 20.8±0.2° 24.7
21.2±0.2° 12.0 21.2±0.2° 12.0
22.4±0.2° 14.8 22.4±0.2° 14.8
23.5±0.2° 12.6 23.5±0.2° 12.6
25.0±0.2° 67.5 25.0±0.2° 67.5
25.9±0.2° 20.1 25.9±0.2° 20.1
72、 权利要求 69-71中任一项所述 G1-1晶型阿法替尼甘醇酸盐的制备方法， 包括以 下步骤： 分别形成阿法替尼和甘醇酸在可溶中的溶液体系， 阿法替尼和甘醇酸的摩尔比为 1 : 1-1 :2， 混合两个体系形成浆液并搅拌， 在 -10-50°C下保持 1-48小时， 进而除去溶剂， 其中 所述可溶溶剂选自 d-C4醇、 C3-C5酮、 C4-C5酯、 C6-C9烷烃、硝基取代的 d-C3烷烃、 C4-C6 醚或其混合物；优选所述可溶溶剂为乙酸乙酯或硝基甲烷； 优选所述制备方法的操作温度为 室温。 72. The preparation method of the G1-1 crystal form afatinib glycolate according to any one of claims 69-71, comprising the following steps: forming a solution of afatinib and glycolic acid in soluble materials respectively system, the molar ratio of afatinib and glycolic acid is 1:1-1:2, mix the two systems to form a slurry and stir, keep it at -10-50°C for 1-48 hours, and then remove the solvent, where The soluble solvent is selected from dC 4 alcohol, C 3 -C 5 ketone, C 4 -C 5 ester, C 6 -C 9 alkane, nitro-substituted dC 3 alkane, C 4 -C 6 ether or a mixture thereof; Preferably, the soluble solvent is ethyl acetate or nitromethane; preferably, the operating temperature of the preparation method is room temperature.
73、 权利要求 69-71中任一项所述 G1-1晶型阿法替尼甘醇酸盐的制备方法，包括以 下步骤： 将按照权利要求 68 所述制备方法得到的阿法替尼甘醇酸盐在有机溶剂中形成浆 液并搅拌， 浆液在 -10-50°C下保持 1〜72 小时， 进而除去溶剂， 其中所述有机溶剂选自甲 醇、 丙酮、 乙腈、 乙酸乙酯、 硝基甲烷、 正庚烷、 甲基叔丁基醚或其混合物； 优选所述制 备方法的操作温度为室温。 73. The preparation method of the G1-1 crystal form afatinib glycolate according to any one of claims 69-71, comprising the following steps: converting the afatinib glycolate obtained according to the preparation method of claim 68 The alkyd salt is formed into a slurry in an organic solvent and stirred. The slurry is maintained at -10-50°C for 1 to 72 hours, and then the solvent is removed. The organic solvent is selected from methanol, acetone, acetonitrile, ethyl acetate, and nitrocellulose. Methane, n-heptane, methyl tert-butyl ether or mixtures thereof; Preferably, the operating temperature of the preparation method is room temperature.
74、 一种阿法替尼二马来酸盐的晶型 N， 其特征在于， 使用 Cu-Κα辐射， 其 X射 线粉末衍射图在衍射角 2Θ为 4.8±0.2°、 9.7±0.2。、 14.5±0.2。、 17.0±0.2。、 19.5±0.2。、 20.1±0.2、 25.6±0.2°处具有特征峰。 74. A crystal form N of afatinib dimaleate, characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern at the diffraction angle 2Θ is 4.8±0.2° and 9.7±0.2. , 14.5±0.2. , 17.0±0.2. , 19.5±0.2. There are characteristic peaks at , 20.1±0.2 and 25.6±0.2°.
75、 根据权利要求 74所述阿法替尼二马来酸盐的晶型 N， 其特征在于， 其 X射线 粉末衍射图的衍射角 2Θ特征峰及其相对强度如下： 75. The crystal form N of afatinib dimaleate according to claim 74 is characterized in that the diffraction angle 2Θ characteristic peak of its X-ray powder diffraction pattern and its relative intensity are as follows:
衍射角 2Θ 相对强度％ Diffraction angle 2Θ Relative intensity %
4.8±0.2° 100.0 4.8±0.2° 100.0
9.7±0.2° 9.7±0.2°
14.5±0.2° 3.6 14.5±0.2° 3.6
17.0±0.2° 2.2 17.0±0.2° 2.2
19.5±0.2° 19.5±0.2°
20.1±0.2° 2.3 20.1±0.2° 2.3
25.5±0.2° 5.0 。 25.5±0.2° 5.0.
76、 权利要求 74〜75中任一项所述阿法替尼- -马来酸盐晶型 N的制备方法， 包括 以下步骤： 分别形成阿法替尼和马来酸在硝基甲烷中的溶液体系， 阿法替尼和马来酸的摩 尔比为 1 :2-1 :4， 混合两个体系形成浆液并搅拌， 在 -10-50°C下保持 1-48小时， 进而除去溶 剂。 76. The preparation method of afatinib-maleate crystal form N according to any one of claims 74 to 75, comprising the following steps: forming afatinib and maleic acid in nitromethane respectively. In the solution system, the molar ratio of afatinib and maleic acid is 1:2-1:4. Mix the two systems to form a slurry and stir, keep it at -10-50°C for 1-48 hours, and then remove the solvent.
77、 一种药物組合物， 包含治疗和 /或预防有效量的一种或者多种的选自根据权利 要求 1、 3、 4、 5、 8、 10、 11、 12、 15、 16、 17、 19、 21、 22、 23、 26、 28、 29、 30、 33、 35、 36、 39、 41、 42、 43、 46、 48、 49、 50、 53、 55、 56、 57、 60、 62、 63、 64、 67、 69、 70、 71、 74或 75所述的阿法替尼酸加成盐或其晶型以及至少一种药学上可接受的赋形剂。 77. A pharmaceutical composition comprising a therapeutically and/or preventively effective amount of one or more agents selected from the group consisting of Requirements 1, 3, 4, 5, 8, 10, 11, 12, 15, 16, 17, 19, 21, 22, 23, 26, 28, 29, 30, 33, 35, 36, 39, 41, 42 , 43, 46, 48, 49, 50, 53, 55, 56, 57, 60, 62, 63, 64, 67, 69, 70, 71, 74 or 75, the acid addition salt of afatinib or Its crystalline form and at least one pharmaceutically acceptable excipient.
78、 根据权利要求 77所述的药物組合物， 其特征在于， 所述药物組合物可为固态 或液态， 包括选自片剂、 颗粒剂、 散剂、 丸剂、 粉末或胶囊剂的固体口服剂型， 或者选自 溶液剂、 糖浆剂、 混悬剂、 分散剂或乳剂的液体口服剂型， 或者选自溶液剂、 分散剂或冻 干剂的可注射制剂， 或者选自适于活性成分的快速释放剂、 延迟释放剂或调节释放剂， 或 者选自常规的、 可分散的、 可咀嚼的、 口腔溶解的或快速熔化的剂型， 或者其给药途径选 自口服、 静脉皮下注射、 注射入組织给药、 透皮给药、 直肠给药或滴鼻给药。 78. The pharmaceutical composition according to claim 77, characterized in that the pharmaceutical composition can be in solid or liquid state, including solid oral dosage forms selected from tablets, granules, powders, pills, powders or capsules, Or a liquid oral dosage form selected from solutions, syrups, suspensions, dispersions or emulsions, or an injectable preparation selected from solutions, dispersions or lyophilized agents, or a rapid release formulation suitable for the active ingredient , delayed release agent or modified release agent, or selected from conventional, dispersible, chewable, orally dissolving or fast melting dosage forms, or its route of administration is selected from oral administration, intravenous subcutaneous injection, or injection into tissue. , transdermal administration, rectal administration or nasal administration.
79、 权利要求 1、 3、 4、 5、 8、 10、 11、 12、 15、 16、 17、 19、 21、 22、 23、 26、 28、 29、 30、 33、 35、 36、 39、 41、 42、 43、 46、 48、 49、 50、 53、 55、 56、 57、 60、 62、 63、 64、 67、 69、 70、 71、 74或 75中任一项所述的阿法替尼酸加成盐或其晶型在制备用 于治疗晚期非小细胞肺癌及 HER2阳性的晚期乳腺癌疾病的药物中的用途。 79. Claims 1, 3, 4, 5, 8, 10, 11, 12, 15, 16, 17, 19, 21, 22, 23, 26, 28, 29, 30, 33, 35, 36, 39, 41, 42, 43, 46, 48, 49, 50, 53, 55, 56, 57, 60, 62, 63, 64, 67, 69, 70, 71, 74 or 75. The use of tinic acid addition salt or its crystal form in preparing drugs for treating advanced non-small cell lung cancer and HER2-positive advanced breast cancer.
80、 一种治疗和 /或预防晚期非小细胞肺癌及 HER2 阳性的晚期乳腺癌的方法， 所 述方法包括给予需要的患者治疗和 /或预防有效量的权利要求 1、 3、 4、 5、 8、 10、 11、 12、 15、 16、 17、 19、 21、 22、 23、 26、 28、 29、 30、 33、 35、 36、 39、 41、 42、 43、 46、 48、 49、 50、 53、 55、 56、 57、 60、 62、 63、 64、 67、 69、 70、 71、 74或 75所述的阿法替尼 酸加成盐或其晶型或者权利要求 77、 78所述的药物組合物。 80. A method for treating and/or preventing advanced non-small cell lung cancer and HER2-positive advanced breast cancer, the method comprising administering a therapeutically and/or preventively effective amount of claims 1, 3, 4, 5, to a patient in need. 8, 10, 11, 12, 15, 16, 17, 19, 21, 22, 23, 26, 28, 29, 30, 33, 35, 36, 39, 41, 42, 43, 46, 48, 49, 50, 53, 55, 56, 57, 60, 62, 63, 64, 67, 69, 70, 71, 74 or 75, the afatinib acid addition salt or its crystal form or claims 77, 78 The pharmaceutical composition.
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