WO2022007629A1 - 乌帕替尼的晶型及其制备方法和用途 - Google Patents

乌帕替尼的晶型及其制备方法和用途 Download PDF

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WO2022007629A1
WO2022007629A1 PCT/CN2021/101784 CN2021101784W WO2022007629A1 WO 2022007629 A1 WO2022007629 A1 WO 2022007629A1 CN 2021101784 W CN2021101784 W CN 2021101784W WO 2022007629 A1 WO2022007629 A1 WO 2022007629A1
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crystal form
csvii
csvi
preparation
crystal
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PCT/CN2021/101784
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English (en)
French (fr)
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陈敏华
张婧
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苏州科睿思制药有限公司
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Priority to KR1020237004415A priority Critical patent/KR20230038229A/ko
Priority to JP2023501177A priority patent/JP2023532787A/ja
Priority to CN202180004707.8A priority patent/CN114206878B/zh
Priority to AU2021303629A priority patent/AU2021303629A1/en
Priority to CA3189037A priority patent/CA3189037A1/en
Priority to EP21837088.0A priority patent/EP4180435A1/en
Publication of WO2022007629A1 publication Critical patent/WO2022007629A1/zh
Priority to US17/700,273 priority patent/US11572365B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/10—Succinic acid
    • 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
    • C07C55/14—Adipic acid
    • 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 present invention relates to the field of crystal chemistry. Specifically, it relates to the crystalline form of Upatinib and its preparation method and use.
  • Rheumatoid arthritis is an autoimmune disease that causes chronic inflammation of the joints and other parts of the body, leading to permanent joint destruction and deformity. Untreated, the disease can lead to substantial disability and pain due to loss of joint function, ultimately leading to reduced life expectancy. Crohn's disease is an inflammatory bowel disease. Symptoms usually include: abdominal pain, diarrhea, fever, and weight loss. People with this condition have a greater risk of bowel cancer. Ulcerative colitis is a chronic disease that causes inflammation and ulcers in the colon and rectum. The main symptoms of the onset include abdominal pain and diarrhea with bloody stools. The symptoms usually develop slowly and vary in severity.
  • Psoriatic arthritis is an inflammatory joint disease associated with psoriasis, with a psoriatic rash associated with joint and surrounding soft tissue pain, swelling, tenderness, stiffness, and dyskinesia.
  • JAK1 is a target of immune-inflammatory diseases, and its inhibitors are beneficial for the treatment of immune-inflammatory disorders such as rheumatoid arthritis, Crohn's disease, ulcerative colitis, atopic dermatitis and psoriatic arthritis.
  • Upatinib is a second-generation oral JAK1 inhibitor developed by AbbVie, which exhibits high selectivity for inhibiting JAK1.
  • the chemical name of the drug is: (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N -(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, its structural formula is as follows:
  • a crystal form is a solid in which the molecules of a compound are arranged in a three-dimensional order in the microstructure to form a crystal lattice.
  • the compounds may exist in one or more salt, crystalline or co-crystal forms, but their existence and identity cannot be specifically expected.
  • APIs with different crystal forms have different physicochemical properties, which may lead to different dissolution and absorption of the drug in the body, thereby affecting the clinical efficacy of the drug to a certain extent.
  • the crystal form is very important to the product performance.
  • the physical properties of the crystalline form are critical to the production process, for example, a certain crystalline form may be more prone to solvate formation, or difficult to remove impurities. Therefore, polymorphism is an important part of drug research and drug quality control.
  • Amorphous is an amorphous material without long-range order, and its XRPD pattern usually shows a broad "steamed bread peak".
  • Amorphous solids have disordered arrangement of molecules and poor stability, so amorphous drugs are prone to crystallization transition during production and storage. The poor stability of amorphous form may lead to changes in drug bioavailability, dissolution rate, etc., resulting in changes in clinical efficacy of drugs.
  • drug co-crystals are formed by two or more different molecules, one of which is an active pharmaceutical ingredient (API), bound by non-ionic and non-covalent bonds in the same crystal lattice crystalline material.
  • API active pharmaceutical ingredient
  • One advantage of drug co-crystals is that they can be used to improve the bioavailability and stability of the drug and improve the processability of the drug substance during drug production.
  • Another advantage of drug co-crystals is that drug co-crystals can provide better solid-state forms for some APIs that are difficult to salt due to the lack of ionizable functional groups.
  • succinic acid and adipic acid are included in the US FDA evaluation of food additive safety indicators (GRAS, Generally Recognized as Safe), and are included in the FDA inactive substance database, indicating that succinic acid and adipic acid are safe for medicinal use co-crystal ligands.
  • GRAS food additive safety indicators
  • WO2017066775A1 discloses upatinib free form crystal form A, crystal form B, crystal form C, crystal form D and amorphous and its salts. It is disclosed in the patent text that crystal form A and crystal form B have poor and unstable crystallinity, and are easily dehydrated and transformed into amorphous; crystal form D can only be obtained at low water activity, and the crystallization is slow and the repeatability is poor. It will transform into crystal form C under water activity; compared with other free form crystal forms of Upatinib disclosed in WO2017066775A1, crystal form C has better properties, but crystal form C has the disadvantages of poor repeatability and not easy to crystallize from solution .
  • WO2020063939A1 discloses the acetic acid solvate crystal form CSI
  • WO2020115213A1 discloses two acetic acid solvate crystal forms A HOAC and B HOAC , wherein the crystal form A HOAC is the same crystal form CSI.
  • the inventors of the present application have found that the acetic acid solvate has poor stability and does not meet the needs of medicinal development.
  • the crystal form CSVI and crystal form CSVII of Upatinib provided by the present invention have the advantages of solubility, hygroscopicity, purification effect, stability, adhesion, compressibility, fluidity, in vitro and in vivo dissolution , at least one of the aspects of bioavailability has advantages, especially good solubility and stability, high dissolution rate, and high safety of co-crystal ligands, which solves the problems existing in the crystal form of the prior art.
  • the drug development of Nis is of great significance.
  • the present invention provides a new crystal form of upatinib and a preparation method thereof, as well as a pharmaceutical composition comprising the new crystal form and use thereof.
  • the present invention provides the succinic acid co-crystal CSVI of Upatinib (hereinafter referred to as "crystal form CSVI").
  • the X-ray powder diffraction of the crystalline form CSVI is at 1 or 2 of the diffraction angle 2 ⁇ values of 4.7° ⁇ 0.2°, 6.2° ⁇ 0.2°, 22.7° ⁇ 0.2° , or 3 characteristic peaks; preferably, the X-ray powder diffraction of the crystalline form CSVI has characteristic peaks at diffraction angle 2 ⁇ values of 4.7° ⁇ 0.2°, 6.2° ⁇ 0.2°, and 22.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CSVI has a diffraction angle 2 ⁇ value of 15.8° ⁇ 0.2°, 17.3° ⁇ 0.2°, 23.5° ⁇ 0.2° at 1 place, or at 2 places , or three characteristic peaks; preferably, the X-ray powder diffraction of the crystalline form CSVI has characteristic peaks at diffraction angle 2 ⁇ values of 15.8° ⁇ 0.2°, 17.3° ⁇ 0.2°, and 23.5° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CSVI has a diffraction angle 2 ⁇ value of 11.1° ⁇ 0.2°, 14.1° ⁇ 0.2°, 13.1° ⁇ 0.2° at 1 place, or at 2 places , or 3 characteristic peaks; preferably, the X-ray powder diffraction of the crystalline form CSVI has characteristic peaks at diffraction angle 2 ⁇ values of 11.1° ⁇ 0.2°, 14.1° ⁇ 0.2°, and 13.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CSVI has diffraction angle 2 ⁇ values of 4.7° ⁇ 0.2°, 6.2° ⁇ 0.2°, 22.7° ⁇ 0.2°, 15.8° ⁇ 0.2°, Any of 17.3° ⁇ 0.2°, 23.5° ⁇ 0.2°, 11.1° ⁇ 0.2°, 14.1° ⁇ 0.2°, 13.1° ⁇ 0.2°, 20.2° ⁇ 0.2°, 16.2° ⁇ 0.2°, 21.3° ⁇ 0.2° 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12 characteristic peaks; preferably, the crystal form CSVI
  • the X-ray powder diffraction has characteristic peaks at the diffraction angle 2 ⁇ values of 4.7° ⁇ 0.2°, 6.2° ⁇ 0.2°, 22.7° ⁇ 0.2°, 15.8° ⁇ 0.2°, 14.1° ⁇ 0.2°.
  • the XRPD pattern of the crystalline form CSVI is shown in FIG. 1 .
  • TGA diagram of the crystalline form CSVI is shown in Figure 2, with a weight loss of about 1.2% upon heating to 100°C.
  • the molar ratio of succinic acid to Upatinib in the crystal form CSVI is 0.4:1-1.1:1, and further, the molar ratio of succinic acid to Upatinib in the crystal form CSVI is preferably 0.5: 1-1:1.
  • the present invention also provides a preparation method of the crystal form CSVI, the preparation method comprising: (1) placing upatinib and succinic acid in a mixed solvent of esters and ethers and stirring to obtain Form CSVI; or
  • esters are preferably isopropyl acetate
  • the ethers are preferably methyl tert-butyl ether
  • the alcohols are preferably n-propanol, isopropanol, isobutanol or n-butanol
  • the alkanes are N-heptane is preferred.
  • the molar ratio of Upatinib and succinic acid described in the method (1) is preferably 1:1-1:3; the volume ratio of the esters and ethers is preferably 1:1-1:3;
  • the stirring temperature is preferably 0°C-50°C; the stirring time is preferably more than 12 hours.
  • the molar ratio of Upatinib and succinic acid described in the method (2) is preferably 1:0.6-1:2.
  • Higher solubility is conducive to improving the absorption of drugs in the human body, improving bioavailability, and enabling drugs to play a better therapeutic role; in addition, higher solubility can reduce the dosage of drugs while ensuring the efficacy of drugs, thereby reducing the amount of drugs. side effects and improve the safety of medicines.
  • the crystal form CSVI bulk drug provided by the present invention has good stability.
  • the crystal form of the crystalline form CSVI API has not changed for at least 6 months under the condition of 40°C/75%RH, and the crystal form of the crystalline form CSVI API has not changed for at least 1 month under the closed condition of 60°C/75%RH.
  • the chemical purity is above 99.8%, and the purity remains basically unchanged during storage.
  • the crystal form CSVI is mixed with excipients to make a pharmaceutical preparation, and placed under the conditions of 25°C/60%RH and 40°C/75%RH, the crystal form has not changed for at least 3 months, and the chemical purity is above 99.8%.
  • the storage process Medium purity remains largely unchanged.
  • Crystal form CSVI has good physical and chemical stability, ensuring consistent and controllable quality of raw materials and preparations, reducing drug quality changes, bioavailability changes, and toxic and side effects caused by crystal form changes or impurities.
  • the crystal form CSVI preparation provided by the present invention has better in vitro dissolution rate.
  • the dissolution rate of the crystal form CSVI preparation in 0.1N HCl medium is higher than 85% at 30 minutes, which meets the requirements of rapid dissolution, and the dissolution rate of the crystal form CSVI in 0.1N HCl is faster than that of the crystal form C. It is speculated that the crystal form CSVI phase Compared with Form C, it has the advantage of in vivo bioavailability.
  • Dissolution is an important prerequisite for drug absorption. Different crystal forms of drugs may lead to different dissolution kinetics in vivo, and ultimately lead to differences in clinical efficacy. According to BCS (Biopharmaceutics Classification System) guidelines, in vitro dissolution testing can predict the performance of a drug in vivo.
  • the crystalline form CSVI medicine provided by the present invention has better dissolution rate in vitro, which indicates that its in vivo absorption degree is higher, its exposure characteristics are better, and thus its bioavailability is higher and its curative effect is better.
  • the crystalline form CSVI bulk drug provided by the invention has a higher dissolution rate, so that the drug can quickly reach the highest concentration value in the plasma after administration, thereby ensuring the rapid onset of the drug.
  • the present invention provides upatinib adipate co-crystal CSVII (hereinafter referred to as "crystal form CSVII").
  • the X-ray powder diffraction of the crystalline form CSVII is at 1 or 2 of the diffraction angle 2 ⁇ values of 4.8° ⁇ 0.2°, 6.0° ⁇ 0.2°, 22.4° ⁇ 0.2° , or 3 characteristic peaks; preferably, the X-ray powder diffraction of the crystal form CSVII has characteristic peaks at diffraction angle 2 ⁇ values of 4.8° ⁇ 0.2°, 6.0° ⁇ 0.2°, and 22.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CSVII has a diffraction angle 2 ⁇ value of 21.1° ⁇ 0.2°, 15.4° ⁇ 0.2°, 16.2° ⁇ 0.2° at 1 place, or at 2 places , or three characteristic peaks; preferably, the X-ray powder diffraction of the crystalline form CSVII has characteristic peaks at diffraction angle 2 ⁇ values of 21.1° ⁇ 0.2°, 15.4° ⁇ 0.2°, and 16.2° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CSVII has a diffraction angle 2 ⁇ value of 25.4° ⁇ 0.2°, 12.8° ⁇ 0.2°, 20.2° ⁇ 0.2° at 1 place, or at 2 places , or 3 characteristic peaks; preferably, the X-ray powder diffraction of the crystalline form CSVII has characteristic peaks at diffraction angle 2 ⁇ values of 25.4° ⁇ 0.2°, 12.8° ⁇ 0.2°, and 20.2° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CSVII has diffraction angle 2 ⁇ values of 4.8° ⁇ 0.2°, 6.0° ⁇ 0.2°, 22.4° ⁇ 0.2°, 21.1° ⁇ 0.2°, Any 3 or 4 of 15.4° ⁇ 0.2°, 16.2° ⁇ 0.2°, 25.4° ⁇ 0.2°, 12.8° ⁇ 0.2°, 20.2° ⁇ 0.2°, 17.4° ⁇ 0.2°, 21.7° ⁇ 0.2° , or 5, or 6, or 7, or 8, or 9, or 10, or 11 characteristic peaks.
  • Form CSVII is shown in FIG. 6 .
  • TGA profile of the crystalline form CSVII is shown in Figure 8, with a weight loss of about 0.1% upon heating to 100°C.
  • the molar ratio of adipic acid to Upatinib in crystal form CSVII is preferably 0.4:1-1.1:1, and further, the molar ratio of adipic acid to Upatinib in crystal form CSVII is preferably 0.5: 1-1:1.
  • the present invention also provides a preparation method of the crystal form CSVII, the preparation method comprising: (1) placing upatinib and adipic acid in a mixed solvent of esters and ethers and stirring to obtain a crystal Type CSVII; or
  • ester solvent is preferably isopropyl acetate
  • the ether is preferably methyl tert-butyl ether
  • the alcohol is preferably n-propanol, isopropanol, n-butanol or isobutanol
  • the alkane is preferably The class is preferably n-heptane.
  • the molar ratio of Upatinib and adipic acid described in the method (1) is preferably 1:1-1:3; the volume ratio of the esters and ethers is preferably 1:1-1:10;
  • the stirring temperature is preferably 0°C-50°C, and the stirring time is preferably more than 12 hours.
  • the molar ratio of upatinib and adipic acid in the method (2) is preferably 1:0.6-1:2; the drying is preferably vacuum drying at 40°C-80°C.
  • Higher solubility is conducive to improving the absorption of drugs in the human body, improving bioavailability, and enabling drugs to play a better therapeutic role; in addition, higher solubility can reduce the dosage of drugs while ensuring the efficacy of drugs, thereby reducing the amount of drugs. side effects and improve the safety of medicines.
  • the crystal form CSVII bulk drug provided by the present invention has good stability.
  • the crystalline form CSVII API was placed under the condition of 25°C/60%RH, and the crystal form did not change for at least 6 months; the crystal form did not change when placed under the closed condition of 40°C/75%RH for at least 6 months; at 60°C The crystal form did not change for at least 1 month under the closed condition of /75%RH, and the chemical purity was above 99.9%, and the purity remained basically unchanged during storage.
  • the crystal form CSVII is mixed with excipients to make a pharmaceutical preparation, and placed under the conditions of 25°C/60%RH and 40°C/75%RH, the crystal form does not change for at least 3 months, and the purity remains basically unchanged during storage.
  • the stability of drug substances and drug products under accelerated and more severe conditions is critical for pharmaceuticals.
  • High temperature and high humidity conditions caused by seasonal differences, climate differences in different regions and weather factors will affect the storage, transportation and production of APIs.
  • the crystalline form CSVII API and preparation have good stability under harsh conditions, which is beneficial to avoid the influence on the quality of the drug due to crystal transformation or decrease in purity during the drug storage process.
  • the good physical and chemical stability of the crystalline form of the bulk drug can ensure that the drug will not be crystallized during the production and storage process, and basically no impurities will be generated.
  • the crystal form CSVII has good physical and chemical stability, ensuring consistent and controllable quality of the API and preparation, and reducing drug quality changes, bioavailability changes, and toxic and side effects caused by crystal form changes or impurities.
  • the crystal form CSVII preparation provided by the present invention has better dissolution rate in vitro.
  • the dissolution rate of crystal form CSVII preparation in 0.1N HCl medium was higher than 85% at 30 minutes, which met the requirement of rapid dissolution, and the dissolution rate of crystal form CSVII in 0.1N HCl and pH6.8PBS was faster than that of crystal form C.
  • Form CSVII has an in vivo bioavailability advantage over Form C.
  • Dissolution is an important prerequisite for drug absorption. Different crystal forms of drugs may lead to different dissolution kinetics in vivo, and ultimately lead to differences in clinical efficacy. According to BCS (Biopharmaceutics Classification System) guidelines, in vitro dissolution testing can predict the performance of a drug in vivo.
  • the crystal form CSVII medicine provided by the present invention has better dissolution rate in vitro, which indicates that its absorption degree in vivo is higher and its exposure characteristics are better, so that the bioavailability is higher and the curative effect is better.
  • the crystalline form CSVII bulk drug provided by the invention has a higher dissolution rate, so that the drug can quickly reach the highest concentration value in the plasma after administration, thereby ensuring the rapid onset of the drug.
  • the present invention also provides a pharmaceutical composition comprising an effective therapeutic amount of crystal form CSVI, crystal form CSVII and pharmaceutically acceptable excipients.
  • the present invention provides the use of crystal form CSVI and crystal form CSVII in the preparation of JAK1 inhibitor pharmaceutical preparations.
  • the present invention provides the use of crystal form CSVI and crystal form CSVII in the preparation of pharmaceutical preparations for the treatment of rheumatoid arthritis, Crohn's disease, ulcerative colitis, atopic dermatitis and psoriatic arthritis.
  • the "room temperature” is not a specific temperature value, but refers to a temperature range of 10-30°C.
  • the "stirring" is accomplished by conventional methods in the field, such as magnetic stirring or mechanical stirring, and the stirring speed is 50-1800 rev/min, wherein, the magnetic stirring is preferably 300-900 rev/min, and the mechanical stirring It is preferably 100-300 revolutions per minute.
  • the "drying” can be carried out at room temperature or higher.
  • the drying temperature is from room temperature to about 80°C, or to 60°C, or to 50°C, or to 40°C. Drying time can be 2-48 hours, or overnight. Drying takes place in a fume hood, blast oven or vacuum oven.
  • the “characteristic peak” refers to a representative diffraction peak used to identify crystals.
  • the peak position can usually have an error of ⁇ 0.2°.
  • the "water-saturated solvent” is formulated by conventional methods in the art. For example, the excess water is mixed with the corresponding solvent ultrasonically, and the organic solvent phase is taken after standing for layers.
  • crystal or “crystal form” can be characterized by X-ray powder diffraction.
  • X-ray powder diffraction pattern will vary depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample.
  • the relative intensities of the diffraction peaks in the X-ray powder diffraction pattern may also vary with the experimental conditions, so the intensity of the diffraction peaks cannot be used as the only or decisive factor for determining the crystal form.
  • the relative intensities of the diffraction peaks in the X-ray powder diffraction pattern are related to the preferred orientation of the crystals, and the diffraction peak intensities shown in the present invention are illustrative and not for absolute comparison. Therefore, those skilled in the art can understand that the X-ray powder diffraction pattern of the crystal form protected by the present invention does not have to be completely consistent with the X-ray powder diffraction pattern in the embodiments referred to here, and any X-ray powder diffraction pattern with the characteristic peaks in these patterns Crystal forms with the same or similar X-ray powder diffraction patterns all fall within the scope of the present invention. Those skilled in the art can compare the X-ray powder diffraction pattern listed in the present invention with an X-ray powder diffraction pattern of an unknown crystal form to confirm whether the two sets of images reflect the same or different crystal forms.
  • the crystalline form CSVI, crystalline form CSVII of the present invention is pure and substantially not mixed with any other crystalline form.
  • substantially free when used to refer to a new crystal form means that the crystal form contains less than 20% by weight of other crystal forms, especially less than 10% by weight of other crystal forms, more particularly Less than 5% (by weight) of other crystal forms, more refers to less than 1% (by weight) of other crystal forms.
  • Figure 4 XRPD comparison chart of crystal form CSVI before and after placing (from top to bottom: before placing, after placing at 40°C/75%RH closed for 6 months, and after placing at 40°C/75%RH open for 6 months, After 1 month at 60°C/75%RH closed mouth)
  • Figure 10 XRPD comparison diagram of crystal form CSVII before and after placing (from top to bottom: before placing, after placing at 25°C/60%RH closed for 6 months, after placing at 25°C/60%RH open for 6 months, After 6 months at 40°C/75%RH closed, after 1 month at 60°C/75%RH)
  • Figure 12 XRPD comparison diagram before and after the preparation of crystal form CSVI (from top to bottom: blank excipients, after crystal form CSVI preparation process, crystal form CSVI)
  • Figure 13 XRPD comparison diagram before and after the preparation of crystal form CSVII (from top to bottom: blank excipients, crystal form CSVII after preparation process, crystal form CSVII)
  • Figure 14 XRPD comparison chart of crystal form CSVI preparation stability (from top to bottom: before placing, add 1g desiccant at 25°C/60%RH closed for 3 months, add 1g at 40°C/75%RH closed After the desiccant is placed for 3 months)
  • Figure 15 XRPD comparison chart of crystal form CSVII preparation stability (from top to bottom: before placing, add 1g of desiccant at 25°C/60%RH closed for 3 months, add 1g at 40°C/75%RH closed After the desiccant is placed for 3 months)
  • Figure 16 Dissolution curves of Form CSVI formulation and Form C formulation in 0.1N HCl
  • Figure 17 Dissolution curves of Form CSVII formulation and Form C formulation in 0.1N HCl
  • FaSSIF artificial intestinal fluid in fasting state
  • FeSSIF artificial intestinal fluid in the fed state
  • PBS Phosphate Buffered Saline
  • the X-ray powder diffraction pattern of the present invention was collected on a Bruker D2 PHASER X-ray powder diffractometer.
  • the method parameters of X-ray powder diffraction of the present invention are as follows:
  • thermogravimetric analysis (TGA) plots described in the present invention were collected on a TA Q500.
  • the method parameters of thermogravimetric analysis (TGA) of the present invention are as follows:
  • DSC Differential Scanning Calorimetry
  • the dynamic moisture adsorption (DVS) map of the present invention is collected on the Intrinsic dynamic moisture adsorption instrument produced by SMS company (Surface Measurement Systems Ltd.).
  • the instrument control software is DVS-Intrinsic control software.
  • the method parameters of the described dynamic moisture adsorption instrument are as follows:
  • Relative humidity range 0%RH-95%RH
  • Hydrogen nuclear magnetic resonance data ( 1 H NMR) were obtained from a Bruker Avance II DMX 400M HZ nuclear magnetic resonance spectrometer. Weigh 1-5 mg of the sample, dissolve it with 0.5 mL of deuterated dimethyl sulfoxide or deuterated methanol, and prepare a solution of 2-10 mg/mL.
  • the stoichiometric ratio test parameters in the present invention are as follows:
  • test parameters of dynamic solubility in the present invention are as follows:
  • test parameters of the related substance detection in the present invention are as follows:
  • test parameters of preparation dissolution detection in the present invention are as follows:
  • the Upatinib and/or its salts as raw materials include, but are not limited to, solid forms (crystalline or amorphous), oily forms, liquid forms and solutions.
  • upatinib and/or a salt thereof as a starting material is in solid form.
  • Upadatinib and/or its salts (corresponding to the starting materials in the examples) used in the following examples can be prepared according to the prior art, for example, according to the method described in the document WO2017066775A1. Unless otherwise specified, the following examples are operated at room temperature.
  • Form C The solubility of Form C is disclosed in WO2017066775A1.
  • Take about 15-30 mg of the crystalline form CSVI of the present invention, disperse in 1.8 mL of FeSSIF, 1.8 mL of FaSSIF and 1.8 mL of pH 7.4 phosphate buffer, respectively, and test saturation by HPLC after equilibrating for 24 hours and 48 hours.
  • the results of the content of Upatinib in the solution are shown in Table 2.
  • the crystalline form CSVI is stable for at least 1 month under the condition of 60°C/75%RH (closed), and it can be seen that the crystalline form CSVI is also very stable under more severe conditions.
  • Embodiment 7 The preparation method of crystal form CSVII
  • the isolated solid was transferred to 40° C./75% RH for about 1 day to obtain crystal form CSVII.
  • the X-ray powder diffraction pattern of the crystal form CSVII is shown in FIG. 6
  • the X-ray powder diffraction data is shown in Table 4.
  • the TGA diagram of the crystalline form CSVII is shown in Fig. 7, and it has a mass loss of about 1.2% when it is heated to 100 °C.
  • the suspension was filtered and the filter cake was washed with n-heptane, then transferred to 75° C. for vacuum drying for about 16 hours to obtain crystalline form CSVII.
  • the molar ratio of adipic acid to upatinib in crystalline form CSVII was detected by 1 H NMR to be 0.65:1.
  • Embodiment 10 The preparation method of crystal form CSVII
  • the suspension was filtered and the filter cake was washed with n-heptane, then transferred to 75° C. for vacuum drying for about 16 hours to obtain crystalline form CSVII.
  • the molar ratio of adipic acid to upatinib in crystal form CSVII was detected by 1 H NMR to be 0.77:1.
  • the suspension was filtered and the wet cake was washed with the filtrate.
  • the wet filter cake was placed in a 50°C oven for vacuum drying for about 24 hours, taken out and dried at room temperature for about 8.5 hours, and then placed in a 75°C oven for vacuum drying for about 15 hours to obtain crystal form CSVII.
  • TGA is shown in Figure 8, and it has a mass loss of about 0.1% when it is heated to 100 °C.
  • DSC in Fig. 9 an endothermic peak began to appear around 105°C.
  • the molar ratio of adipic acid to upatinib in crystal form CSVII was detected by 1 H NMR to be 0.99:1.
  • Form C The solubility of Form C is disclosed in WO2017066775A1.
  • Take about 15-30 mg of the crystal form CSVII of the present invention, disperse in 1.8 mL of FeSSIF, 1.8 mL of FaSSIF and 1.8 mL of pH 7.4 phosphate buffer, equilibrate for 24 hours and 48 hours, respectively, test saturation by HPLC
  • Table 5 The results of the content of Upatinib in the solution are shown in Table 5.
  • the crystalline form CSVII can be stable for at least 6 months under the conditions of 25°C/60%RH and 40°C/75%RH (closed), it can be seen that the crystalline form CSVII can maintain good stability under long-term and accelerated stability conditions sex. It can be stable for at least 1 month under the condition of 60°C/75%RH (closed mouth), and it can be seen that the crystal form CSVII can also maintain good stability under more severe conditions.
  • crystal forms CSVI, CSVII and crystal form C were prepared into tablets according to the formulation formula in Table 7 and the formulation process in Table 8.
  • the XRPD comparison diagrams before and after the formulation are shown in Figure 12 (crystal form CSVI) and Figure 13 (crystal form CSVII), the crystal forms of CSVI and crystal form CSVII are stable before and after the formulation process.
  • the tablets containing crystal forms CSVI and CSVII obtained in Example 14 were packaged in HDPE bottles, 1 g of desiccant was added to them, placed under the conditions of 25°C/60%RH and 40°C/75%RH, and samples were taken to detect the crystal forms and impurities, the results are shown in Table 9. The results showed that the crystalline forms CSVI and CSVII preparations were stable for at least 3 months at 25°C/60%RH and 40°C/75%RH, and the purity remained basically unchanged.
  • the in vitro dissolution was tested on the preparation containing CSVI and crystal form C obtained in Example 14, and the test method is shown in Table 10.
  • the in vitro dissolution of crystalline form CSVI preparations is shown in Table 11 and Figure 16, indicating that the cumulative dissolution rate of crystalline form CSVI in 0.1N HCl for 30 minutes is greater than 85%, which meets the requirements of rapid dissolution, and the dissolution of crystalline form CSVI in 0.1N HCl The rate is faster than that of the crystal form C, and it is speculated that the crystal form CSVI has the advantage of in vivo bioavailability compared with the crystal form C.
  • the in vitro dissolution was tested on the preparation containing CSVII and crystal form C obtained in Example 14, and the test method is shown in Table 12.
  • the in vitro dissolution of the crystalline form CSVII preparation is shown in Table 13-14 and Figure 17-18, indicating that the cumulative dissolution rate of the crystalline form CSVII in 0.1N HCl for 30min is greater than 85%, which meets the rapid dissolution requirements; and the crystalline form CSVII is in 0.1N HCl.
  • the dissolution rate of HCl and pH6.8PBS was faster than that of crystal form C, and it was speculated that crystal form CSVII had an advantage in in vivo bioavailability compared with crystal form C.
  • Form C Form CSVII 0 0.0 0.0 5 85.0 88.3 10 88.6 91.0 15 89.8 91.7 20 90.7 92.4 30 91.1 92.7 45 91.6 93.0 60 91.7 93.1 90 91.7 93.1 120 91.6 93.2

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Abstract

一种乌帕替尼的新晶型及其制备方法，含有该晶型的药物组合物，以及该晶型在制备JAK1抑制剂药物和治疗类风湿性关节炎、克罗恩病、溃疡性结肠炎、异位性皮炎和银屑病关节炎药物中的用途。所述乌帕替尼晶型比现有技术具有一种或多种改进的特性，对未来该药物的优化和开发具有重要价值。

Description

乌帕替尼的晶型及其制备方法和用途 技术领域
本发明涉及晶体化学领域。具体而言，涉及乌帕替尼的晶型及其制备方法和用途。
背景技术
类风湿性关节炎是一种自身免疫性疾病，会引起关节和身体其他部位的慢性炎症，并导致永久性的关节破坏和畸形。若该疾病不经治疗，可由于关节功能的损失而导致实质性残疾和疼痛，最终导致预期寿命缩短。克罗恩病(Crohn's disease)是一种发炎性肠道疾病。症状通常包含：腹痛、腹泻、发烧和体重减轻。患有此疾病的人罹患肠癌的风险更大。溃疡性结肠炎是一种会导致结肠与直肠发炎与溃疡的慢性疾病，其发作时的主要症状包括腹痛与伴有血便的腹泻，通常其症状发生的进程缓慢，且轻重不一。异位性皮肤炎常见症状包含发痒、红肿以及皮肤龟裂，许多患者常伴有干草热及哮喘的症状。银屑病关节炎是一种与银屑病相关的炎性关节病，有银屑病皮疹并伴有关节和周围软组织疼痛、肿胀、压痛、僵硬和运动障碍。
JAK1作为免疫-炎症疾病的靶标，其抑制剂对治疗类风湿性关节炎、克罗恩病、溃疡性结肠炎、异位性皮炎和银屑病关节炎等免疫炎症障碍疾病是有益的。
乌帕替尼是由艾伯维公司研发的第二代口服JAK1抑制剂，对抑制JAK1表现出较高的选择性。该药物的化学名称为：(3S,4R)-3-乙基-4-(3H-咪唑并[1,2-a]吡咯并[2,3-e]吡嗪-8-基)-N-(2,2,2-三氟乙基)吡咯烷-1-甲酰胺，其结构式如下：
Figure PCTCN2021101784-appb-000001
晶型是化合物分子在微观结构中三维有序排列而形成晶格的固体。化合物可能以一种或多种盐、晶体形式或共晶形式存在，但是无法具体预期其存在与特性。不同晶型的原料药有不同的理化性质，可能导致药物在体内有不同的溶出、吸收，进而在一定程度上影响药物的临床疗效。特别是一些难溶性口服固体或半固体制剂，晶型对产品性能至关重要。除此之外，晶型的物理性质对生产过程至关重要，例如某一种晶型可能更容易形成溶剂合物，或难以去除杂质。因此，多晶型是药物研究和药物质量控制的重要内容。
无定形是不具有长程有序的非晶型材料，其XRPD图通常表现为较宽的“馒头峰”。无定形固体中分子无序排列，稳定性差，因此无定形药物在生产和贮存过程中容易发生结晶转变。无定形较差的稳定性，可能导致药物生物利用度、溶出度等发生变化，导致药物临床疗效改变。
根据美国FDA药物共晶指南，药物共晶由两种或两种以上不同的分子(其中一个是活性药物成分(API))在同一个晶格中通过非离子键和非共价键结合而成的晶体材料。药物共晶 的一个优点是可以用来提高药物的生物利用度和稳定性，并在药物生产过程中提高原料药的加工性能。药物共晶的另一个优点是，对于一些因缺少可电离官能团而难以成盐的原料药，药物共晶可为其提供更好的固态形式。丁二酸和己二酸都列入了美国FDA评价食品添加剂安全性指标(GRAS，Generally Recognized as Safe)，且都收录在FDA非活性物质数据库中，说明丁二酸和己二酸是安全的药用共晶配体。
WO2017066775A1中公开了乌帕替尼游离形式晶型A、晶型B、晶型C、晶型D和无定形及其盐。该专利文本中披露，晶型A与晶型B结晶度较差且不稳定，易脱水转变为无定形；晶型D只在低水活度时才能得到，且结晶慢，重复性差，在高水活度下会转变为晶型C；相较于WO2017066775A1公开的乌帕替尼其他游离形式晶型，晶型C具有较优性质，但晶型C具有重复性差、不易从溶液中结晶的缺点。
WO2020063939A1中公开了醋酸溶剂合物晶型CSI，WO2020115213A1公开了两个醋酸溶剂合物晶型A HOAC和晶型B HOAC，其中，晶型A HOAC同晶型CSI。经本申请发明人研究发现，醋酸溶剂合物稳定性差，不符合药用开发需求。
为克服现有技术的缺点，本领域仍然需要一种符合药用需求的新晶型，以用于含乌帕替尼药物的开发。本申请的发明人意外发现了本发明提供的乌帕替尼晶型CSVI、晶型CSVII，其在溶解度，引湿性，提纯效果，稳定性，黏附性，可压性，流动性，体内外溶出，生物有效性等方面中的至少一方面存在优势，特别是溶解度和稳定性好，溶出度高，共晶配体安全性高，解决了现有技术晶型存在的问题，对含乌帕替尼的药物开发具有非常重要的意义。
发明内容
本发明提供乌帕替尼的新晶型及其制备方法以及包含该新晶型的药物组合物及其用途。
根据本发明的目的，本发明提供乌帕替尼的丁二酸共晶CSVI(以下称作“晶型CSVI”)。
一方面，使用Cu-Kα辐射，所述晶型CSVI的X射线粉末衍射在衍射角2θ值为4.7°±0.2°、6.2°±0.2°、22.7°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSVI的X射线粉末衍射在衍射角2θ值为4.7°±0.2°、6.2°±0.2°、22.7°±0.2°处有特征峰。
进一步地，使用Cu-Kα辐射，所述晶型CSVI的X射线粉末衍射在衍射角2θ值为15.8°±0.2°、17.3°±0.2°、23.5°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSVI的X射线粉末衍射在衍射角2θ值为15.8°±0.2°、17.3°±0.2°、23.5°±0.2°处有特征峰。
进一步地，使用Cu-Kα辐射，所述晶型CSVI的X射线粉末衍射在衍射角2θ值为11.1°±0.2°、14.1°±0.2°、13.1°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSVI的X射线粉末衍射在衍射角2θ值为11.1°±0.2°、14.1°±0.2°、13.1°±0.2°处有特征峰。
另一方面，使用Cu-Kα辐射，所述晶型CSVI的X射线粉末衍射在衍射角2θ值为4.7°±0.2°、6.2°±0.2°、22.7°±0.2°、15.8°±0.2°、17.3°±0.2°、23.5°±0.2°、11.1°±0.2°、14.1°±0.2°、13.1°±0.2°、20.2°±0.2°、16.2°±0.2°、21.3°±0.2°中的任意3处、或4处、或5处、或6处、或7处、或8处、或9处、或10处、或11处、或12处有特征峰；优选地，所述晶型CSVI的X射线粉末衍射在衍射角2θ值为4.7°±0.2°、6.2°±0.2°、22.7°±0.2°、15.8°±0.2°、14.1°±0.2°处有特征峰。
非限制性地，晶型CSVI的XRPD图如图1所示。
非限制性地，晶型CSVI的TGA图如图2所示，在加热至100℃具有约1.2％的失重。
非限制性地，晶型CSVI的DSC图如图3所示，在124℃附近开始出现吸热峰。
非限制性地，晶型CSVI中丁二酸与乌帕替尼的摩尔比为0.4:1-1.1:1，进一步的，晶型CSVI中丁二酸与乌帕替尼的摩尔比优选0.5:1-1:1。
根据本发明的目的，本发明还提供所述晶型CSVI的制备方法，所述制备方法包括：(1)将乌帕替尼和丁二酸置于酯类和醚类的混合溶剂中搅拌得到晶型CSVI；或
(2)将乌帕替尼和丁二酸置于醚类/醇类/水/烷烃类的混合溶剂或醇类/烷烃类的混合溶剂中搅拌获得晶型CSVI。
进一步地，所述酯类优选乙酸异丙酯，所述醚类优选甲基叔丁基醚，所述醇类优选正丙醇、异丙醇、异丁醇或正丁醇，所述烷烃类优选正庚烷。
进一步地，方法(1)中所述乌帕替尼和丁二酸的投料摩尔比优选1:1-1:3；所述酯类与醚类的体积比优选1:1-1:3；所述搅拌温度优选0℃-50℃；所述搅拌的时间优选12小时以上。
进一步地，方法(2)中所述乌帕替尼和丁二酸的投料摩尔比优选1:0.6-1:2。
本发明提供的晶型CSVI具有以下有益效果：
(1)与现有技术相比，本发明提供的晶型CSVI具有更高的溶解度。特别是在FaSSIF、FeSSIF和pH＝7.4的磷酸盐缓冲液中均具有更高的溶解度，溶解度是现有技术晶型C的4-8倍。
更高的溶解度有利于提高药物在人体内的吸收，提高生物利用度，使药物发挥更好的治疗作用；另外，更高的溶解度能够在保证药物疗效的同时，降低药品的剂量，从而降低药品的副作用并提高药品的安全性。
(2)本发明提供的晶型CSVI原料药具有良好的稳定性。晶型CSVI原料药在40℃/75％RH条件下，至少6个月晶型未发生变化，晶型CSVI原料药在60℃/75％RH闭口条件下至少1个月晶型未发生变化，且化学纯度均在99.8％以上，储存过程中纯度基本保持不变。晶型CSVI与辅料混合做成药物制剂后，在25℃/60％RH和40℃/75％RH条件下放置，至少3个月晶型未发生变化，且化学纯度在99.8％以上，储存过程中纯度基本保持不变。
原料药和制剂在加速条件及更严苛的条件下的稳定性对于药物至关重要。季节差异、不同地区气候差异和天气因素等带来的高温和高湿条件会影响原料药的储存、运输、生产。晶型CSVI原料药和制剂在苛刻的条件下具有较好的稳定性，有利于避免药物储存过程中因转晶或纯度下降对药物质量产生影响。
原料药晶型良好的物理和化学稳定性可以确保药物在生产和存储的过程中不会发生转晶且基本没有杂质产生。晶型CSVI具有良好的物理化学稳定性，保证原料药和制剂质量一致可控，减少由于晶型改变或杂质产生引起的药物质量变化，生物利用度变化，和毒副作用。
(3)与现有技术相比，本发明提供的晶型CSVI制剂具有更优的体外溶出度。晶型CSVI制剂在0.1N HCl介质中，30分钟时的溶出度高于85％，符合快速溶出要求，且晶型CSVI在0.1N HCl中的溶出速率快于晶型C，推测晶型CSVI相较于晶型C具有体内生物利用度优势。
溶出是药物被吸收的重要前提。药物晶型不同可能导致其在体内有不同的溶出动力学过程，最终导致临床药效的差异。根据BCS(Biopharmaceutics Classification System)指南，体外溶出试验可以预测药物在体内的性能。本发明提供的晶型CSVI药物有更优的体外溶出度， 预示其在体内吸收程度更高，暴露特性更好，从而生物利用度更高，疗效更好。本发明提供的晶型CSVI原料药有更高的溶出速率，使得给药后药物在血浆中能够很快达到最高浓度值，进而确保药物快速起效。
根据本发明的目的，本发明提供乌帕替尼己二酸共晶CSVII(以下称作“晶型CSVII”)。
一方面，使用Cu-Kα辐射，所述晶型CSVII的X射线粉末衍射在衍射角2θ值为4.8°±0.2°、6.0°±0.2°、22.4°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSVII的X射线粉末衍射在衍射角2θ值为4.8°±0.2°、6.0°±0.2°、22.4°±0.2°处有特征峰。
进一步地，使用Cu-Kα辐射，所述晶型CSVII的X射线粉末衍射在衍射角2θ值为21.1°±0.2°、15.4°±0.2°、16.2°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSVII的X射线粉末衍射在衍射角2θ值为21.1°±0.2°、15.4°±0.2°、16.2°±0.2°处有特征峰。
进一步地，使用Cu-Kα辐射，所述晶型CSVII的X射线粉末衍射在衍射角2θ值为25.4°±0.2°、12.8°±0.2°、20.2°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSVII的X射线粉末衍射在衍射角2θ值为25.4°±0.2°、12.8°±0.2°、20.2°±0.2°处有特征峰。
另一方面，使用Cu-Kα辐射，所述晶型CSVII的X射线粉末衍射在衍射角2θ值为4.8°±0.2°、6.0°±0.2°、22.4°±0.2°、21.1°±0.2°、15.4°±0.2°、16.2°±0.2°、25.4°±0.2°、12.8°±0.2°、20.2°±0.2°、17.4°±0.2°、21.7°±0.2°中的任意3处、或4处、或5处、或6处、或7处、或8处、或9处、或10处、或11处特征峰。
非限制性地，晶型CSVII的XRPD图如图6所示。
非限制性地，晶型CSVII的TGA图如图8所示，在加热至100℃具有约0.1％的失重。
非限制性地，晶型CSVII的DSC图如图9所示，在加热至105℃开始出现吸热峰。
非限制性地，晶型CSVII中己二酸与乌帕替尼的摩尔比优选0.4:1-1.1:1，进一步的，晶型CSVII中己二酸与乌帕替尼的摩尔比优选0.5:1-1:1。
根据本发明的目的，本发明还提供所述晶型CSVII的制备方法，所述制备方法包括：(1)将乌帕替尼和己二酸置于酯类和醚类的混合溶剂中搅拌得到晶型CSVII；或
(2)将乌帕替尼和己二酸置于醇类和烷烃类的混合溶剂中搅拌，分离后干燥，得到晶型CSVII。
进一步地，所述酯类溶剂优选乙酸异丙酯，所述醚类优选甲基叔丁基醚，所述醇类优选正丙醇、异丙醇、正丁醇或异丁醇，所述烷烃类优选正庚烷。
进一步地，方法(1)中所述乌帕替尼和己二酸的投料摩尔比优选1:1-1:3；所述酯类与醚类的体积比优选1:1-1:10；所述搅拌温度优选0℃-50℃，所述搅拌的时间优选12小时以上。
进一步地，方法(2)中所述乌帕替尼和己二酸的投料摩尔比优选1:0.6-1:2；所述干燥优选40℃-80℃真空干燥。
本发明提供的晶型CSVII具有以下有益效果：
(1)与现有技术相比，本发明提供的晶型CSVII具有更高的溶解度。特别是在晶FaSSIF、FeSSIF和pH＝7.4的磷酸盐缓冲液中均具有更高的溶解度，溶解度是现有技术晶型C的4-8倍。
更高的溶解度有利于提高药物在人体内的吸收，提高生物利用度，使药物发挥更好的治疗作用；另外，更高的溶解度能够在保证药物疗效的同时，降低药品的剂量，从而降低药品 的副作用并提高药品的安全性。
(2)本发明提供的晶型CSVII原料药具有良好的稳定性。晶型CSVII原料药在25℃/60％RH条件下放置，至少6个月晶型未发生变化；在40℃/75％RH闭口条件下放置至少6个月晶型未发生变化；在60℃/75％RH闭口条件下至少1个月晶型未发生变化，且化学纯度均在99.9％以上，储存过程中纯度基本保持不变。晶型CSVII与辅料混合做成药物制剂后，在25℃/60％RH和40℃/75％RH条件下放置，至少3个月晶型未发生变化，储存过程中纯度基本保持不变。
原料药和制剂在加速条件及更严苛的条件下的稳定性对于药物至关重要。季节差异、不同地区气候差异和天气因素等带来的高温和高湿条件会影响原料药的储存、运输、生产。晶型CSVII原料药和制剂在苛刻的条件下具有较好的稳定性，有利于避免药物储存过程中因转晶或纯度下降对药物质量产生影响。
原料药晶型良好的物理和化学稳定性可以确保药物在生产和存储的过程中不会发生转晶且基本没有杂质产生。晶型CSVII具有良好的物理化学稳定性，保证原料药和制剂质量一致可控，减少由于晶型改变或杂质产生引起的药物质量变化，生物利用度变化，和毒副作用。
(3)与现有技术相比，本发明提供的晶型CSVII制剂具有更优的体外溶出度。晶型CSVII制剂在0.1N HCl介质中，30分钟时的溶出度高于85％，符合快速溶出要求，且晶型CSVII在0.1N HCl和pH6.8PBS中溶出速率快于晶型C，推测晶型CSVII相较于晶型C具有体内生物利用度优势。
溶出是药物被吸收的重要前提。药物晶型不同可能导致其在体内有不同的溶出动力学过程，最终导致临床药效的差异。根据BCS(Biopharmaceutics Classification System)指南，体外溶出试验可以预测药物在体内的性能。本发明提供的晶型CSVII药物有更优的体外溶出度，预示其在体内吸收程度更高，暴露特性更好，从而生物利用度更高，疗效更好。本发明提供的晶型CSVII原料药有更高的溶出速率，使得给药后药物在血浆中能够很快达到最高浓度值，进而确保药物快速起效。
根据本发明的目的，本发明还提供一种药物组合物，所述药物组合物包含有效治疗量的晶型CSVI、晶型CSVII及药学上可接受的辅料。
进一步地，本发明提供晶型CSVI、晶型CSVII在制备JAK1抑制剂药物制剂中的用途。
更进一步地，本发明提供晶型CSVI、晶型CSVII在制备治疗类风湿性关节炎、克罗恩病、溃疡性结肠炎、异位性皮炎和银屑病关节炎药物制剂中的用途。
本发明中，所述“室温”不是特定的温度值，是指10-30℃温度范围。
本发明中，所述“搅拌”，采用本领域的常规方法完成，例如磁力搅拌或机械搅拌，搅拌速度为50-1800转/分钟，其中，磁力搅拌优选为300-900转/分钟，机械搅拌优选为100-300转/分钟。
所述“干燥”可以在室温或更高的温度下进行。干燥温度为室温到约80℃，或者到60℃，或者到50℃，或者到40℃。干燥时间可以为2-48小时，或者过夜。干燥在通风橱、鼓风烘箱或真空烘箱里进行。
所述“特征峰”是指用于甄别晶体的有代表性的衍射峰，使用Cu-Kα辐射测试时，峰位置通常可以有±0.2°的误差。
所述“用水饱和的溶剂”采用本领域的常规方法配制。例如将过量的水与相应溶剂超声混合，静置分层后取有机溶剂相。
本发明中，“晶体”或“晶型”可以用X射线粉末衍射表征。本领域技术人员能够理解，X射线粉末衍射图受仪器的条件、样品的准备和样品纯度的影响而有所改变。X射线粉末衍射图中衍射峰的相对强度也可能随着实验条件的变化而变化，所以衍射峰强度不能作为判定晶型的唯一或决定性因素。事实上，X射线粉末衍射图中衍射峰的相对强度与晶体的择优取向有关，本发明所示的衍射峰强度为说明性而非用于绝对比较。因而，本领域技术人员可以理解的是，本发明所保护晶型的X射线粉末衍射图不必和这里所指的实施例中的X射线粉末衍射图完全一致，任何具有和这些图谱中的特征峰相同或相似的X射线粉末衍射图的晶型均属于本发明的范畴之内。本领域技术人员能够将本发明所列的X射线粉末衍射图和一个未知晶型的X射线粉末衍射图相比较，以证实这两组图反映的是相同还是不同的晶型。
在一些实施方案中，本发明的晶型CSVI、晶型CSVII是纯的，基本没有混合任何其他晶型。本发明中，“基本没有”当用来指新晶型时，指这个晶型含有少于20％(重量)的其他晶型，尤其指少于10％(重量)的其他晶型，更指少于5％(重量)的其他晶型，更指少于1％(重量)的其他晶型。
本发明中术语“约”，当用来指可测量的数值时，例如质量、时间、温度等，意味着可围绕具体数值有一定的浮动的范围，该范围可以为±10％、±5％、±1％、±0.5％、或±0.1％。
附图说明
图1晶型CSVI的XRPD图
图2晶型CSVI的TGA图
图3晶型CSVI的DSC图
图4晶型CSVI放置前后的XRPD对比图(由上至下分别为：放置前，在40℃/75％RH闭口放置6个月后，在40℃/75％RH开口放置6个月后，在60℃/75％RH闭口放置1个月后)
图5晶型CSVI在DVS前后的XRPD对比图(上图为DVS前，下图为DVS后)
图6根据实施例9所得晶型CSVII的XRPD图
图7根据实施例9所得晶型CSVII的TGA图
图8根据实施例11所得晶型CSVII的TGA图
图9根据实施例11所得晶型CSVII的DSC图
图10晶型CSVII放置前后的XRPD对比图(由上至下分别为：放置前，在25℃/60％RH闭口放置6个月后，在25℃/60％RH开口放置6个月后，在40℃/75％RH闭口放置6个月后，在60℃/75％RH闭口放置1个月后)
图11晶型CSVII在DVS前后的XRPD对比图(上图为DVS前，下图为DVS后)
图12晶型CSVI制剂前后XRPD对比图(由上至下分别为：空白辅料、晶型CSVI制剂工艺后、晶型CSVI)
图13晶型CSVII制剂前后XRPD对比图(由上至下分别为：空白辅料、晶型CSVII 制剂工艺后、晶型CSVII)
图14晶型CSVI制剂稳定性XRPD对比图(由上至下分别为：放置前，在25℃/60％RH闭口加1g干燥剂放置3个月后，在40℃/75％RH闭口加1g干燥剂放置3个月后)
图15晶型CSVII制剂稳定性XRPD对比图(由上至下分别为：放置前，在25℃/60％RH闭口加1g干燥剂放置3个月后，在40℃/75％RH闭口加1g干燥剂放置3个月后)
图16晶型CSVI制剂与晶型C制剂在0.1N HCl中的溶出度曲线
图17晶型CSVII制剂与晶型C制剂在0.1N HCl中的溶出度曲线
图18晶型CSVII制剂与晶型C制剂在pH 6.8PBS中的溶出度曲线
具体实施方式
本发明进一步参考以下实施例说明，所述实施例详细描述本发明的晶型的制备和使用方法。对本领域技术人员显而易见的是，对于材料和方法两者的许多改变可在不脱离本发明范围的情况下实施。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
DSC：差示扫描量热分析
TGA：热重分析
DVS：动态水分吸附
1H NMR：液态核磁氢谱
HPLC：高效液相色谱
FaSSIF：空腹状态下人工肠液
FeSSIF：进食状态下人工肠液
PBS：磷酸盐缓冲盐溶液
RPM：每分钟转数
采集数据所用的仪器及方法：
本发明所述的X射线粉末衍射图在Bruker D2 PHASER X射线粉末衍射仪上采集。本发明所述的X射线粉末衍射的方法参数如下：
X射线光源：Cu,Kα
Figure PCTCN2021101784-appb-000002
1.54060；
Figure PCTCN2021101784-appb-000003
1.54439
Kα2/Kα1强度比例：0.50
电压：30仟伏特(kV)
电流：10毫安培(mA)
扫描范围(2θ)：自3.0至40.0度
本发明所述的热重分析(TGA)图在TA Q500上采集。本发明所述的热重分析(TGA)的方法参数如下：
扫描速率：10℃/min
保护气体：N 2
本发明所述的差示扫描量热分析(DSC)图在TA Q2000上采集。本发明所述的差示扫 描量热分析(DSC)的方法参数如下：
扫描速率：如无特别说明为10℃/min
保护气体：N 2
本发明所述动态水分吸附(DVS)图在由SMS公司(Surface Measurement Systems Ltd.)生产的Intrinsic动态水分吸附仪上采集。仪器控制软件是DVS-Intrinsic control software。所述的动态水分吸附仪的方法参数如下：
温度：25℃
载气，流速：N 2,200毫升/分钟
相对湿度范围：0％RH-95％RH
核磁共振氢谱数据( 1H NMR)采自于Bruker Avance II DMX 400M HZ核磁共振波谱仪。称量1-5mg样品，用0.5mL氘代二甲亚砜或氘代甲醇溶解，配成2-10mg/mL的溶液。
本发明中的化学计量比测试参数如下：
Figure PCTCN2021101784-appb-000004
本发明中的动态溶解度的测试参数如下：
Figure PCTCN2021101784-appb-000005
Figure PCTCN2021101784-appb-000006
本发明中有关物质检测的测试参数如下：
Figure PCTCN2021101784-appb-000007
本发明中制剂溶出度检测的测试参数如下：
Figure PCTCN2021101784-appb-000008
Figure PCTCN2021101784-appb-000009
根据本发明，作为原料的所述乌帕替尼和/或其盐包括但不限于固体形式(结晶或无定形)、油状、液体形式和溶液。优选地，作为原料的乌帕替尼和/或其盐为固体形式。
以下实施例中所使用的乌帕替尼和/或其盐(与实施例中起始物料对应)可根据现有技术制备得到，例如可以根据WO2017066775A1文献所记载的方法制备获得。除非特殊说明，以下实施例均在室温条件下操作。
具体实施方式
实施例1晶型CSVI的制备
将16.9mg乌帕替尼和9.8mg丁二酸称量至玻璃瓶中，加入0.3mL用水饱和的乙酸异丙酯/甲基叔丁基醚(1:2，v/v)混合溶剂，然后转移至35℃的烘箱中搅拌约4天后，再加入0.2mL用水饱和的乙酸异丙酯/甲基叔丁基醚(1:2，v/v)混合溶剂，继续在35℃烘箱中搅拌约3天，分离固体，将固体在40℃/75％RH条件下开口放置约2天后得到晶型CSVI。CSVI的XRPD图如图1所示，XRPD数据如表1所示。
表1
衍射角2θ d值 强度％
4.72 18.73 52.19
6.21 14.24 77.65
9.52 9.29 26.73
9.80 9.03 11.71
10.23 8.64 6.46
11.08 7.98 18.00
12.10 7.32 7.39
12.42 7.13 19.62
13.12 6.75 28.53
14.14 6.26 25.18
14.88 5.96 15.80
15.78 5.62 37.64
16.17 5.48 44.29
16.89 5.25 15.79
17.30 5.13 41.84
17.96 4.94 37.99
18.82 4.72 36.14
19.17 4.63 31.44
20.23 4.39 54.54
20.48 4.34 36.16
20.80 4.27 34.07
21.32 4.17 38.36
22.25 3.99 33.58
22.65 3.93 100.00
23.48 3.79 35.96
24.81 3.59 25.39
25.57 3.48 27.12
27.40 3.26 16.48
27.96 3.19 10.11
30.04 2.97 6.19
实施例2晶型CSVI的制备
将1.1086g乌帕替尼和0.5140g丁二酸称量至玻璃瓶中，加入19.5mL甲基叔丁基醚/异丙醇/水(10:1:0.1,v/v/v)混合溶液后在5℃搅拌50分钟，加入55.4mg晶型CSVI晶种，继续55℃搅拌17.5小时，降温至45℃继续搅拌1小时，降温至40℃继续搅拌190分钟，降温至35℃继续搅拌280分钟，降温至25℃继续搅拌1天。再次加入1.0mL甲基叔丁基醚/异丙醇/水(10:1:0.1,v/v/v)混合溶液和3.0mL正庚烷后继续在25℃搅拌约4天。再次加入5.0mL正庚烷然后继续在25℃搅拌5小时后分离固体(以上过程均使用热台磁力搅拌器控制温度)。转移至75℃下真空干燥约17.5个小时，然后转移至40℃/75％RH条件下开口放置约5天后得到晶型CSVI。TGA如图2所示，将其加热至100℃时，具有约1.2％的质量损失。 1H NMR检测到晶型CSVI中丁二酸与乌帕替尼的摩尔比为0.79：1。
实施例3晶型CSVI的制备
将1.0236g乌帕替尼和0.2796g丁二酸溶解于6mL正丙醇中，然后过滤至60℃的夹套反应釜内。机械搅拌约5-10分钟后，缓慢加入10mL正庚烷。称量0.0500g晶型CSVI，均匀地悬浮分散在2mL正庚烷中，随后将悬浊液加入到反应釜中。反应在60℃熟化约1小时后，降温至35℃(历时5小时)。在35℃熟化约13小时后，滴加18mL正庚烷(历 时3小时)，熟化1小时，随后降温至5℃(历时3小时)并熟化约15小时。悬浮液过滤后将湿滤饼在室温条件下干燥约9小时后转移至75℃烘箱真空干燥约38小时。干燥固体进行气流粉碎(进料压力为0.3MPa，粉碎压力为0.1MPa)后转移至75℃烘箱真空干燥约23小时后得到晶型CSVI。DSC如图3所示，在124℃附近开始出现吸热峰。经HPLC检测，晶型CSVI中丁二酸与乌帕替尼的摩尔比为0.63：1。
实施例4晶型CSVI的制备
将1.0237g乌帕替尼和0.3413g丁二酸溶解于6mL正丙醇中，然后过滤至60℃的夹套反应釜内。机械搅拌约5-10分钟后，缓慢加入10mL正庚烷。称量0.0500g晶型CSVI，均匀地悬浮分散在2mL正庚烷中，随后将悬浊液加入到反应釜中。反应在60℃熟化约1小时后，降温至35℃(历时5小时)。在35℃熟化约13小时后，滴加18mL正庚烷(历时3小时)，熟化1小时，随后降温至5℃(历时3小时)并熟化约15小时。悬浮液过滤后将湿滤饼在室温条件下干燥约9小时后转移至75℃烘箱真空干燥约38小时。干燥固体进行气流粉碎(进料压力为0.3MPa，粉碎压力为0.1MPa)后转移至75℃烘箱真空干燥约23小时后得到晶型CSVI。经HPLC检测，晶型CSVI中丁二酸与乌帕替尼的摩尔比为0.85：1。
实施例5晶型CSVI的动态溶解度
WO2017066775A1中公开了晶型C的溶解度。取本发明的晶型CSVI约15-30mg，分别分散在1.8mL的FeSSIF、1.8mL的FaSSIF以及1.8mL的pH＝7.4的磷酸盐缓冲液中，平衡24小时和48小时后分别用HPLC测试饱和溶液中乌帕替尼的含量结果如表2所示。
表2
Figure PCTCN2021101784-appb-000010
结果表明晶型CSVI在FeSSIF、FaSSIF和pH 7.4的磷酸盐缓冲液中具有更高的溶解度。
实施例6晶型CSVI的稳定性
取本发明晶型CSVI约5mg，分别置于40℃/75％RH和60℃/75％RH条件下。放置前后取样采用HPLC和XRPD测定纯度和晶型，结果如表3所示，XRPD对比图如图4所示。
表3
Figure PCTCN2021101784-appb-000011
结果表明，晶型CSVI在40℃/75％RH(闭口)和40℃/75％RH(开口)条件下至少可稳定6个月，可见，晶型CSVI在加速条件下可保持良好的稳定性。晶型CSVI在 60℃/75％RH(闭口)条件下至少可稳定1个月，可见晶型CSVI在更严苛的条件下稳定性也很好。
称取本发明CSVI约10mg采用动态水分吸附(DVS)仪测试，在0％-95％-0％RH下循环一次，湿度循环前后进行XRPD测试，测试结果如图5所示，说明晶型CSVI测试前后晶型未变，具有较好的湿度稳定性。
实施例7晶型CSVII的制备方法
将16.3mg乌帕替尼和11.5mg己二酸称量至玻璃瓶中，加入0.3mL乙酸异丙酯/甲基叔丁基醚(1:3,v/v)，转移至35℃烘箱中，搅拌约4天，再加入0.2mL乙酸异丙酯/甲基叔丁基醚(1:3,v/v)，继续在35℃烘箱中搅拌约3天，转移至室温继续搅拌6天，分离得到固体，在30℃真空干燥过夜，得到晶型CSVII。
实施例8晶型CSVII的制备方法
将195.8mg乌帕替尼和158.8mg己二酸称量至玻璃瓶中，加入5mL乙酸异丙酯/甲基叔丁基醚(1:2,v/v)，在室温搅拌过夜，加入10.1mg晶型CSVII晶种，继续在室温搅拌约5天，分离固体并在35℃真空干燥2.5小时。将150.9mg上述固体称量至玻璃瓶中，加入3.0mL用水饱和的甲基叔丁基醚，室温搅拌约2天后，分离固体。将25.4mg分离得到的固体转移至40℃/75％RH条件下放置约1天后得到晶型CSVII。晶型CSVII的X射线粉末衍射图如图6所示，X射线粉末衍射数据如表4所示。晶型CSVII的TGA图如图7所示，将其加热至100℃时，具有约1.2％的质量损失。
表4
衍射角2θ d值 强度％
4.79 18.45 34.78
5.98 14.78 72.97
9.38 9.43 27.03
9.66 9.15 16.57
11.14 7.94 8.58
12.01 7.37 10.03
12.54 7.06 19.36
12.79 6.92 26.60
14.34 6.17 32.86
15.40 5.75 24.28
16.18 5.48 36.97
16.59 5.34 22.65
16.87 5.26 25.41
17.40 5.10 36.40
18.04 4.92 20.46
18.63 4.76 29.55
18.98 4.68 25.75
19.36 4.59 22.32
19.89 4.46 38.85
20.18 4.40 41.39
21.05 4.22 60.95
21.74 4.09 39.11
22.40 3.97 100.00
23.38 3.81 24.23
24.82 3.59 23.56
25.37 3.51 38.77
26.31 3.39 12.78
27.12 3.29 14.86
29.22 3.06 15.27
31.31 2.86 4.28
34.23 2.62 3.34
实施例9晶型CSVII的制备方法
将1.0001g乌帕替尼和0.4228g己二酸溶解于6mL正丙醇/正丁醇(3:1，v/v)中，随后过滤到反应釜中进行机械搅拌。将反应釜温度升高至60℃后，缓慢加入10mL正庚烷。将0.1018g晶型CSVII均匀地悬浮在2mL正庚烷中，缓慢将悬浮液加入反应釜中。反应在60℃熟化2小时后，降温至35℃(历时8小时)，熟化5.5小时。过滤悬浊液并用正庚烷洗涤滤饼，然后转移至75℃下真空干燥约16个小时，得到晶型CSVII。 1H NMR检测到晶型CSVII中己二酸与乌帕替尼的摩尔比为0.65：1。
实施例10晶型CSVII的制备方法
将0.9997g乌帕替尼和0.4611g己二酸溶于6mL正丙醇/正丁醇(3:1，v/v)，过滤到50mL反应釜中进行机械搅拌，将反应釜温度升高至60℃后，缓慢加入10mL正庚烷。将0.1018g晶型CSVII于室温下悬浮于2mL正庚烷中，缓慢将悬浮液加入反应釜中。反应在60℃熟化2小时后，降温至35℃(历时8小时)，并熟化5.5小时。过滤悬浊液并用正庚烷洗涤滤饼，然后转移至75℃下真空干燥约16个小时，得到晶型CSVII。 1H NMR检测到晶型CSVII中己二酸与乌帕替尼的摩尔比为0.77：1。
实施例11晶型CSVII的制备方法
将501.2mg乌帕替尼和230.2mg己二酸称量至50mL反应釜中，加入20mL异丁醇/正庚烷(1:3，v/v)并进行机械搅拌。反应釜温度升高至75℃得到澄清溶液。降温至55℃并熟化0.5小时，随后降温至45℃并熟化0.5小时。将约5mg晶型CSVII均匀地悬浮在约0.2mL异丁醇/正庚烷(1:3，v/v)中，缓慢将悬浊液加入反应釜中，熟化约2小时。降温至25℃(历时4小时)并熟化约85小时。过滤悬浮液并用滤液洗涤湿滤饼。将湿滤饼放到50℃烘箱真空干燥约24小时后取出于室温下干燥约8.5小时，再放到75℃烘箱真空干燥约15小时后得到晶型CSVII。其TGA如图8所示，将其加热至100℃时，具有约0.1％的质量损失。DSC如图9所示，在105℃附近开始出现吸热峰。 1H NMR检测到晶型CSVII中己二酸与乌帕替尼的摩尔比为0.99：1。
实施例12晶型CSVII的动态溶解度
WO2017066775A1中公开了晶型C的溶解度。取本发明的晶型CSVII约15-30mg，分别分散在1.8mL的FeSSIF、1.8mL的FaSSIF以及1.8mL的pH＝7.4的磷酸盐缓冲液中，平衡24小时和48小时后分别用HPLC测试饱和溶液中乌帕替尼的含量结果如表5所示。
表5
Figure PCTCN2021101784-appb-000012
结果表明晶型CSVII在FeSSIF、FaSSIF和pH 7.4的磷酸盐缓冲液中具有更高的溶解度。
实施例13晶型CSVII的稳定性
取本发明晶型CSVII约5mg，分别置于25℃/60％RH、40℃/75％RH和60℃/75％RH条件下放置。放置前后取样采用HPLC和XRPD测定纯度和晶型，结果如表6所示，XRPD对比图如图10所示。
表6
Figure PCTCN2021101784-appb-000013
结果表明，晶型CSVII在25℃/60％RH和40℃/75％RH(闭口)条件下至少可稳定6个月，可见，晶型CSVII在长期和加速稳定性条件下可保持良好的稳定性。在60℃/75％RH(闭口)条件下至少可稳定1个月，可见，在更严苛的条件下晶型CSVII也可保持良好的稳定性。
称取本发明CSVII约10mg采用动态水分吸附(DVS)仪测试，在0％-95％-0％RH下循环一次，湿度循环前后进行XRPD测试，测试结果如图11所示，说明晶型CSVII测试前后晶型未变，具有较好的湿度稳定性。
实施例14制剂的制备
将晶型CSVI、CSVII和晶型C按表7的制剂处方和表8的制剂工艺制成片剂。制剂前后XRPD对比图如图12(晶型CSVI)和图13(晶型CSVII)所示，晶型CSVI和晶型CSVII在制剂处方工艺前后晶型稳定。
表7
Figure PCTCN2021101784-appb-000014
Figure PCTCN2021101784-appb-000015
表8
Figure PCTCN2021101784-appb-000016
实施例15制剂的稳定性
将实施例14获得的含晶型CSVI和CSVII的片剂用HDPE瓶封装，其中加入1g干燥剂，于25℃/60％RH和40℃/75％RH的条件下放置并取样检测晶型及杂质，结果如表9所示。结果表明，晶型CSVI和CSVII制剂在25℃/60％RH和40℃/75％RH条件下可以稳定至少3个月，且纯度基本保持不变。
表9
Figure PCTCN2021101784-appb-000017
实施例16晶型CSVI的溶出度
对实施例14获得的含CSVI和晶型C的制剂测试体外溶出情况，测试方法如表10所示。晶型CSVI制剂的体外溶出情况如下表11，图16所示，表明晶型CSVI在0.1N HCl中30min累积溶出度大于85％，符合快速溶出要求，且晶型CSVI在0.1N HCl中的溶出速率快于晶型C，推测晶型CSVI相较于晶型C具有体内生物利用度优势。
表10
溶出仪 Sotax AT7
方法 桨法
规格 20mg
介质体积 900mL
转速 50rpm
介质温度 37℃
取样点 0.1N HCl：5,10,15,20,30,45,60,90,120min
补充介质 否(每个时间点取样1mL)
表11
Figure PCTCN2021101784-appb-000018
实施例17晶型CSVII的溶出度
对实施例14获得的含CSVII和晶型C的制剂测试体外溶出情况，测试方法如表12所示。晶型CSVII制剂的体外溶出情况如下表13-14，图17-18所示，表明晶型CSVII在0.1N HCl中30min累积溶出度大于85％，符合快速溶出要求；且晶型CSVII在0.1N HCl和pH6.8PBS中溶出速率快于晶型C，推测晶型CSVII相较于晶型C具有体内生物利用度优势。
表12
溶出仪 Sotax AT7
方法 桨法
规格 20mg
介质体积 900mL
转速 50rpm
介质温度 37℃
取样点 5,10,15,20,30,45,60,90,120min
补充介质 否(每个时间点取样1mL)
表13
介质 0.1N HCl
时间(min) 累积溶出度(％)
  晶型C 晶型CSVII
0 0.0 0.0
5 85.0 88.3
10 88.6 91.0
15 89.8 91.7
20 90.7 92.4
30 91.1 92.7
45 91.6 93.0
60 91.7 93.1
90 91.7 93.1
120 91.6 93.2
表14
Figure PCTCN2021101784-appb-000019
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (17)

  1. 一种乌帕替尼
    Figure PCTCN2021101784-appb-100001
    的晶型CSVI，其特征在于，晶型CSVI为乌帕替尼丁二酸共晶。
  2. 根据权利要求1所述的晶型CSVI，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为4.7°±0.2°、6.2°±0.2°、22.7°±0.2°中的1处或2处或3处具有特征峰。
  3. 根据权利要求1所述的晶型CSVI，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为15.8°±0.2°、17.3°±0.2°、23.5°±0.2°中的1处或2处或3处具有特征峰。
  4. 根据权利要求1所述的晶型CSVI，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为11.1°±0.2°、14.1°±0.2°、13.1°±0.2°中的1处或2处或3处具有特征峰。
  5. 根据权利要求1所述的晶型CSVI，其特征在于，晶型CSVI的XRPD如图1所示。
  6. 一种权利要求1所述的晶型CSVI的制备方法，其特征在于：(1)将乌帕替尼和丁二酸置于酯类和醚类的混合溶剂中搅拌得到晶型CSVI；或
    (2)将乌帕替尼和丁二酸置于醚类/醇类/水/烷烃类的混合溶剂或醇类/烷烃类的混合溶剂中搅拌获得晶型CSVI。
  7. 根据权利要求6所述的制备方法，其特征在于：所述酯类为乙酸异丙酯，所述醚类为甲基叔丁基醚，所述醇类为正丙醇、异丙醇、异丁醇或正丁醇，所述烷烃类为正庚烷。
  8. 一种乌帕替尼
    Figure PCTCN2021101784-appb-100002
    的晶型CSVII，其特征在于，晶型CSVII为乌帕替尼己二酸共晶。
  9. 根据权利要求8所述的晶型CSVII，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为4.8°±0.2°、6.0°±0.2°、22.4°±0.2°中的1处或2处或3处具有特征峰。
  10. 根据权利要求8所述的晶型CSVII，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为21.1°±0.2°、15.4°±0.2°、16.2°±0.2°中的1处或2处或3处具有特征峰。
  11. 根据权利要求8所述的晶型CSVII，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为25.4°±0.2°、12.8°±0.2°、20.2°±0.2°中的1处或2处或3处具有特征峰。
  12. 根据权利要求8所述的晶型CSVII，其特征在于，晶型CSVII的XRPD如图6所示。
  13. 一种权利要求8所述的晶型CSVII的制备方法，其特征在于：(1)将乌帕替尼和己二酸置于酯类和醚类的混合溶剂中搅拌得到晶型CSVII；或
    (2)将乌帕替尼和己二酸置于醇类和烷烃类的混合溶剂中搅拌，分离后干燥，得到晶型CSVII。
  14. 根据权利要求13所述的制备方法，其特征在于：所述酯类溶剂为乙酸异丙酯，所述醚类为甲基叔丁基醚，所述醇类为正丙醇、异丙醇、正丁醇或异丁醇，所述烷烃类为正庚烷。
  15. 一种药物组合物，所述药物组合物包含有效治疗量的权利要求1中所述的晶型CSVI或权利要求8所述的晶型CSVII及药学上可接受的辅料。
  16. 权利要求1中所述的晶型CSVI、权利要求8所述的晶型CSVII在制备JAK1抑制剂药物中的用途。
  17. 权利要求1中所述的晶型CSVI、权利要求8所述的晶型CSVII在制备治疗类风湿性关节炎、克罗恩病、溃疡性结肠炎、异位性皮炎和银屑病关节炎药物中的用途。
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WO2020115213A1 (en) 2018-12-07 2020-06-11 Lek Pharmaceuticals D.D. Solvate of a selective jak1 inhibitor

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JP7436057B2 (ja) 2019-05-09 2024-02-21 スーチョウ ポンシュイ ファーマテック カンパニー、リミテッド ウパダシチニブのジ－ｐ－トルオイル－Ｌ－タートレートの結晶形

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