WO2022048675A1 - Risdiplam晶型及其制备方法和用途 - Google Patents

Risdiplam晶型及其制备方法和用途 Download PDF

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WO2022048675A1
WO2022048675A1 PCT/CN2021/116817 CN2021116817W WO2022048675A1 WO 2022048675 A1 WO2022048675 A1 WO 2022048675A1 CN 2021116817 W CN2021116817 W CN 2021116817W WO 2022048675 A1 WO2022048675 A1 WO 2022048675A1
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crystal form
crystal
preparation
ray powder
powder diffraction
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PCT/CN2021/116817
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English (en)
French (fr)
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陈敏华
朱宏艳
邹思茗
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苏州科睿思制药有限公司
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    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention mainly relates to the field of crystal chemistry. Specifically, it relates to the crystalline form of Risdiplam and its preparation method and use.
  • SMA Spinal muscular atrophy
  • SMA is a disease caused by inactivating mutations or deletions of the survival motor neuron 1 (SMN1) gene on both chromosomes, resulting in loss of function of the SMN1 gene.
  • Symptoms of SMA include muscle weakness, hypotonia, weak crying, weak coughing, weakness or slipping easily, difficulty sucking or swallowing, difficulty breathing, accumulation of secretions in the lungs or throat, sweating with clenched fists, tongue fluttering/vibrating, head Frequent leaning of the waist to one side (even when lying down), legs tending to be weaker than arms, legs often in a "frog leg” position, difficulty feeding, increased susceptibility to respiratory infections, bowel/bladder weakness, lower than normal weight values, inability to sit unsupported, inability to walk, inability to crawl, and hypotonia, loss of reflexes, and multiple congenital contractures (joint contractures) associated with loss of anterior horn cells.
  • SMA patients rely
  • Risdiplam (trade name Evrysdi) is a motor neuron survival gene 2 (SMN2) splicing modifier developed for the treatment of all types of SMA (type 1, 2, 3).
  • SMA 2 motor neuron survival gene 2
  • Evrysdi received FDA approval for the treatment of children and adults with SMA 2 months of age and older.
  • PRV Priority Review Voucher
  • Evrysdi is the first oral therapy for SMA and the first SMA therapy that can be administered at home.
  • Risdiplam 7-(4,7-diazaspiro[2.5]oct-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazine-6 -yl)pyrido[1,2-a]pyrimidin-4-one (hereinafter referred to as "Compound I”), its structural formula is as follows:
  • a drug co-crystal consists of two or more different molecules (one of which is an active pharmaceutical ingredient (API)) in the same crystal lattice in a stoichiometric ratio through non-ionic bonds and non-ionic bonds.
  • One of the advantages of drug co-crystals is that they can be used to increase 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 more solid-state forms for some APIs that are difficult to salt due to the lack of ionizable functional groups.
  • a crystal is a solid in which the molecules of a compound are arranged in a three-dimensional order in a microstructure to form a crystal lattice.
  • Polymorphism refers to the phenomenon in which a compound exists in multiple crystal forms (or crystal forms). Compounds may exist in one or more crystalline 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. Especially for some poorly soluble oral solid or semi-solid preparations, the crystal form is very important to the product performance. In addition to this, the physicochemical properties of the crystal form are crucial to the production process. Therefore, polymorphism is an important part of drug research and drug quality control.
  • WO2020079203A1 discloses 7 crystal forms of compound I, the specification only discloses the preparation method and characterization data of crystal form A and crystal form D, and does not disclose other crystal forms (crystal form B, crystal form C, crystal form E, crystal form F , the preparation method of crystal form G). According to the text of the patent application, those skilled in the art cannot obtain the crystal form B, crystal form C, crystal form E, crystal form F and crystal form G of compound I. From the information disclosed in the specification, Form A has improved chemical stability and improved processability in filtration compared to Form D. However, the inventors of the present application have found through extensive research that crystal form A has disadvantages such as low solubility, residual solvent, poor powder properties, and poor light stability.
  • the present invention provides a new crystal form of compound I, a preparation method thereof, and a pharmaceutical composition comprising the new crystal form.
  • a co-crystal of compound I is provided. Further, the co-crystal is a co-crystal of compound I and vanillin.
  • co-crystal is the vanillin co-crystal CSVIII of compound I (hereinafter referred to as "crystal form CSVIII").
  • the X-ray powder diffraction pattern of the crystalline form CSVIII has characteristic peaks at diffraction angle 2 ⁇ values of 5.1° ⁇ 0.2°, 12.6° ⁇ 0.2°, 25.3° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSVIII has a diffraction angle 2 ⁇ value of 9.3° ⁇ 0.2°, 21.9° ⁇ 0.2°, 26.8° ⁇ 0.2°, or 2 There are characteristic peaks at or at 3 places; preferably, the X-ray powder diffraction pattern of the crystalline form CSVIII has characteristic peaks at diffraction angle 2 ⁇ values of 9.3° ⁇ 0.2°, 21.9° ⁇ 0.2°, 26.8° ⁇ 0.2° .
  • the X-ray powder diffraction pattern of the crystalline form CSVIII has a diffraction angle 2 ⁇ value of 7.5° ⁇ 0.2°, 13.6° ⁇ 0.2°, 29.8° ⁇ 0.2°, or 2 There are characteristic peaks at or at 3 places; preferably, the X-ray powder diffraction pattern of the crystalline form CSVIII has characteristic peaks at diffraction angle 2 ⁇ values of 7.5° ⁇ 0.2°, 13.6° ⁇ 0.2°, 29.8° ⁇ 0.2° .
  • the X-ray powder diffraction pattern of the crystalline form CSVIII has diffraction angle 2 ⁇ values of 5.1° ⁇ 0.2°, 12.6° ⁇ 0.2°, 25.3° ⁇ 0.2°, 7.5° ⁇ 0.2°, 9.3° ⁇ 0.2°, 13.6° ⁇ 0.2°, 21.9° ⁇ 0.2°, 26.8° ⁇ 0.2°, 29.8° ⁇ 0.2° any one, or two, or three, or four, or five , or 6, or 7, or 8, or 9 with characteristic peaks.
  • the X-ray powder diffraction pattern of Form CSVIII is substantially as shown in FIG. 1 or FIG. 3 .
  • thermogravimetric analysis diagram of the crystalline form CSVIII is basically shown in Figure 2.
  • it When it is heated to 80 °C, it has a mass loss of about 5.2%, corresponding to the weight loss of water; when heated from 80 °C to 200 °C, There is a mass loss of about 26.2%, corresponding to the weight loss of vanillin.
  • Form CSVIII is a hydrate.
  • the present invention provides single crystal data of Form CSVIII, as shown in Table 1.
  • the present invention also provides the preparation method of described crystal form CSVIII, described preparation method comprises:
  • compound I solid and vanillin solid are placed in water, the mixed solvent of water and aromatic hydrocarbons, the mixed solvent of water, halogenated hydrocarbons and alkanes, or the mixed solvent of water, nitriles and alkanes, Stir at room temperature, separate the solid, and dry to obtain the crystalline form CSVIII; or
  • the molar feeding ratio of compound I solid described in method (1) and vanillin solid is preferably 1:1-1:4; the molar feeding ratio of compound I solid described in method (2) and vanillin solid is preferably 1 :1-1:2.
  • the stirring time is preferably not less than 1 hour; the placing time of the method (2) is preferably not less than 2 days, and the placing conditions are preferably a temperature of 50-70° C. and a humidity of 70-90% RH.
  • stirring temperature in the method (2) is preferably lower than 10°C.
  • the aromatic hydrocarbon solvent is preferably toluene
  • the halogenated hydrocarbon solvent is preferably methylene chloride
  • the alkane solvent is preferably n-heptane
  • the nitrile solvent is preferably acetonitrile
  • the water in the mixed solvent The volume fraction is preferably 1%-10%.
  • the vanillin co-crystal CSVII of compound I (hereinafter referred to as "crystal form CSVII") is provided.
  • the X-ray powder diffraction pattern of the crystalline form CSVII has characteristic peaks at diffraction angle 2 ⁇ values of 7.5° ⁇ 0.2°, 9.1° ⁇ 0.2°, 15.6° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSVII has a diffraction angle 2 ⁇ value of 22.9° ⁇ 0.2°, 18.2° ⁇ 0.2°, 11.9° ⁇ 0.2° at 1 or 2
  • a diffraction angle 2 ⁇ value of 22.9° ⁇ 0.2°, 18.2° ⁇ 0.2°, 11.9° ⁇ 0.2° at 1 or 2
  • the X-ray powder diffraction pattern of the crystalline form CSVII has characteristic peaks at the diffraction angle 2 ⁇ values of 22.9° ⁇ 0.2°, 18.2° ⁇ 0.2°, 11.9° ⁇ 0.2° .
  • the X-ray powder diffraction pattern of the crystal form CSVII has a diffraction angle 2 ⁇ value of 6.0° ⁇ 0.2°, 24.5° ⁇ 0.2°, 27.5° ⁇ 0.2° at 1 place, or 2 There are characteristic peaks at or at 3 places; preferably, the X-ray powder diffraction pattern of the crystalline form CSVII has characteristic peaks at diffraction angle 2 ⁇ values of 6.0° ⁇ 0.2°, 24.5° ⁇ 0.2°, 27.5° ⁇ 0.2° .
  • the X-ray powder diffraction pattern of the crystalline form CSVII has diffraction angle 2 ⁇ values of 7.5° ⁇ 0.2°, 9.1° ⁇ 0.2°, 15.6° ⁇ 0.2°, 22.9° ⁇ 0.2°, 6.0° ⁇ 0.2°, 11.9° ⁇ 0.2°, 18.2° ⁇ 0.2°, 24.5° ⁇ 0.2°, 27.5° ⁇ 0.2° any one, or two, or three, or four, or five , or 6, or 7, or 8, or 9 with characteristic peaks.
  • the X-ray powder diffraction pattern of the crystalline form CSVII is substantially as shown in FIG. 5 .
  • thermogravimetric analysis diagram of the crystalline form CSVII is basically shown in FIG. 6 , when it is heated to 70° C., it has a mass loss of about 9.0%, corresponding to the weight loss of water.
  • mass loss of water When heated from 70°C to 130°C, there is a mass loss of about 8.6%, and when heated from 130°C to 250°C, there is a mass loss of about 16.0%, corresponding to the weight loss of vanillin.
  • Form CSVII is a hydrate.
  • the present invention also provides the preparation method of described crystal form CSVII, described preparation method comprises:
  • the solid compound I and the solid vanillin are placed in water, stirred, the solids are separated, and dried to obtain the crystal form CSVII, wherein the temperature of the stirring is lower than 10°C.
  • the molar feeding ratio of the solid compound I and the solid vanillin is preferably 1:1-1:2, and the stirring time is preferably not less than 1 hour.
  • the crystalline form CSX of compound I (hereinafter referred to as "crystalline form CSX") is provided.
  • the X-ray powder diffraction pattern of the crystalline form CSX has diffraction angle 2 ⁇ values of 7.3° ⁇ 0.2°, 10.4° ⁇ 0.2°, 13.2° ⁇ 0.2°, 22.0° ⁇ 0.2° There are characteristic peaks.
  • the X-ray powder diffraction pattern of the crystal form CSX has a diffraction angle 2 ⁇ value of 14.9° ⁇ 0.2°, 15.3° ⁇ 0.2°, 25.2° ⁇ 0.2°, or 2 There are characteristic peaks at or at 3 places; preferably, the X-ray powder diffraction pattern of the crystalline form CSX has characteristic peaks at diffraction angle 2 ⁇ values of 14.9° ⁇ 0.2°, 15.3° ⁇ 0.2°, 25.2° ⁇ 0.2° .
  • the X-ray powder diffraction pattern of the crystalline form CSX has characteristic peaks at the diffraction angle 2 ⁇ value of 19.8° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSX is substantially as shown in FIG. 7 or FIG. 8 or FIG. 9 .
  • thermogravimetric analysis diagram of the crystalline form CSX is substantially as shown in FIG. 10 , which has a mass loss of about 2.1% when heated to 120°C.
  • the present invention also provides the preparation method of described crystal form CSX, and described preparation method comprises:
  • Compound I solid is dissolved in halogenated hydrocarbons or a water-containing halogenated hydrocarbon solvent, filtered, and the filtrate is added to the hydrocarbon solvent and stirred, or the hydrocarbon solvent is added to the filtrate and stirred, and the solid is precipitated and separated to obtain compound I Form CSX.
  • halogenated hydrocarbons are halogenated hydrocarbons with a carbon number of C1-C3
  • hydrocarbons are hydrocarbons with a carbon number of C5-C8.
  • hydrocarbon solvent is preferably alkane, and further, preferably cyclohexane, n-hexane or n-heptane.
  • halogenated hydrocarbon is preferably chloroform or dichloromethane.
  • the present invention provides a crystalline form CSIV of Compound I (hereinafter referred to as "crystalline form CSIV").
  • the X-ray powder diffraction pattern of the crystalline form CSIV has characteristic peaks at diffraction angle 2 ⁇ values of 4.9° ⁇ 0.2°, 11.7° ⁇ 0.2°, 14.2° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSIV has diffraction angle 2 ⁇ values of 4.9° ⁇ 0.2°, 11.7° ⁇ 0.2°, 14.2° ⁇ 0.2°, 6.9° ⁇ 0.2° , 27.0° ⁇ 0.2°, 13.1° ⁇ 0.2°, 14.8° ⁇ 0.2°, 15.5° ⁇ 0.2°, 24.8° ⁇ 0.2° any 3, or 4, or 5, or 6, or 7 There are characteristic peaks at, or 8, or 9.
  • the X-ray powder diffraction pattern of crystalline form CSIV is substantially as shown in FIG. 11 .
  • the present invention also provides the preparation method of described crystal form CSIV, and described preparation method comprises:
  • the solid compound I was dissolved in a mixed solvent of alcohols and halogenated hydrocarbons, filtered and obtained by rotary evaporation.
  • the alcohol solvent is preferably a C1-C3 alcohol, more preferably methanol or ethanol;
  • the halogenated hydrocarbon solvent is preferably dichloromethane or chloroform; the volume of alcohols and halogenated hydrocarbons in the mixed solvent The ratio is 1:50-5:1, preferably 1:1.
  • the present invention provides the crystal form CSV of compound I (hereinafter referred to as "crystal form CSV").
  • the X-ray powder diffraction pattern of the crystalline form CSV has characteristic peaks at diffraction angle 2 ⁇ values of 7.7° ⁇ 0.2° and 22.8° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSV has a diffraction angle 2 ⁇ value of 13.4° ⁇ 0.2°, 10.5° ⁇ 0.2°, 24.6° ⁇ 0.2° at one, or two, or three places. Characteristic peaks; preferably, the X-ray powder diffraction pattern of the crystalline form CSV has characteristic peaks at 3 of the diffraction angle 2 ⁇ values of 13.4° ⁇ 0.2°, 10.5° ⁇ 0.2°, and 24.6° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form CSV has characteristic peaks at one or two positions in the diffraction angle 2 ⁇ value of 37.7° ⁇ 0.2°, 22.4° ⁇ 0.2°; preferably, the crystal form
  • the X-ray powder diffraction pattern of CSV has characteristic peaks at two of the diffraction angle 2 ⁇ values of 37.7° ⁇ 0.2° and 22.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSV has diffraction angle 2 ⁇ values of 7.7° ⁇ 0.2°, 13.4° ⁇ 0.2°, 10.5° ⁇ 0.2°, 24.6° ⁇ 0.2° , 22.8° ⁇ 0.2°, 37.7° ⁇ 0.2°, 22.4° ⁇ 0.2° any 1 place, or 2 places, or 3 places, or 4 places, or 5 places, or 6 places, or 7 places have characteristic peaks .
  • the X-ray powder diffraction pattern of Form CSV is substantially as shown in Figure 12 or 13 or 14.
  • the present invention also provides a preparation method of the crystal form CSV, the preparation method comprises: dissolving the solid compound I in a mixed solvent of esters and halogenated alkanes, filtering and volatilizing to obtain.
  • volatilization temperature is 5°C-30°C, preferably room temperature.
  • the mixed solvent ratio of the halogenated hydrocarbons and esters is 2:1-5:1, preferably 3:1.
  • halogenated hydrocarbon solvent is a halogenated hydrocarbon with C1-C3 carbon atoms, more preferably dichloromethane.
  • ester solvent is an ester with C3-C6 carbon atoms, more preferably isopropyl acetate.
  • the crystal form CSVIII, crystal form CSVII, crystal form CSX, crystal form CSIV, crystal form CSV or any mixture of the above crystal forms provided by the present invention are used for the preparation of other crystal forms or salts of compound I.
  • the present invention also provides a pharmaceutical composition, the pharmaceutical composition comprising an effective therapeutic amount of compound I of crystal form CSVIII, crystal form CSVII, crystal form CSX, crystal form CSIV, crystal form CSV or the above crystal form Any mixture of types and pharmaceutically acceptable excipients.
  • the present invention provides the use of the crystal form CSVIII, crystal form CSVII, crystal form CSX, crystal form CSIV, crystal form CSV or any mixture of the above crystal forms of compound I in the preparation of a motor neuron survival gene 2 splicing modifier medicine .
  • the present invention provides the use of the crystal form CSVIII, crystal form CSVII, crystal form CSX, crystal form CSIV, crystal form CSV or any mixture of the above crystal forms of Compound I in the preparation of a medicament for the treatment of spinal muscular atrophy.
  • the crystal form CSVIII provided by the present invention has higher solubility. Equilibrated in the biological medium FaSSIF (simulated fasting state intestinal fluid) for 1 hour and 4 hours, the solubility of crystal form CSVIII is 13 times and 18 times that of the prior art crystal form A, respectively.
  • the crystal form CSVIII provided by the present invention has higher solubility, which is beneficial to improve the absorption of the drug in the human body and improve the bioavailability; in addition, the higher solubility can reduce the dosage of the drug while ensuring the curative effect of the drug, thereby reducing the amount of the drug side effects and improve the safety of medicines.
  • the crystal form CSVIII provided by the present invention has better adhesion.
  • the adhesion evaluation results show that the adhesion amount of the prior art crystal form A is about 10 times that of the crystal form CSVIII of the present invention.
  • the crystal form CSVIII provided by the present invention has no organic solvent residue.
  • the crystal form CSVIII of the present invention can be prepared by using water as a single solvent, without introducing other organic solvents, on the one hand, zero organic solvent residues can be achieved, and the drug toxicity effect of the crude drug due to solvent residues can be reduced. On the other hand, the production cost is reduced.
  • Residue dissolution control is one of the difficult problems in the pharmaceutical preparation process.
  • an accurate and efficient detection method for residue dissolution needs to be developed during the preparation of the API. It is often necessary to add steps such as recrystallization and vacuum drying, which increases production costs.
  • the crystalline form CSVIII bulk drug and preparation provided by the present invention have good stability.
  • the crystalline form CSVIII API has not changed when placed under the condition of 25°C/60%RH for at least 6 months. After the crystal form CSVIII is mixed with excipients to make a pharmaceutical preparation, and placed under the conditions of 25°C/60% RH, the crystal form has not changed for at least 3 months. It shows that the crystalline form CSVIII API and preparation have good stability under long-term conditions, which is beneficial to the storage of the drug.
  • the crystal form of the bulk drug of crystal form CSVIII has not changed when placed at 40°C/75%RH for at least 6 months, and the crystal form has not changed when placed at 60°C/75%RH for at least one month.
  • the crystalline form CSVIII API has good stability under accelerated conditions and more severe conditions. High temperature and high humidity conditions caused by seasonal differences, climate differences in different regions and environmental factors will affect the storage, transportation and production of APIs. Therefore, the stability of the drug substance under accelerated and more severe conditions is critical for the drug.
  • the crystalline form CSVIII API has better stability under harsh conditions, which is beneficial to avoid the influence on the quality of the drug due to transcrystallization or decrease in purity during the drug storage process.
  • Crystal form CSVIII has good physical stability, ensuring consistent and controllable quality of raw materials and preparations, and reducing drug quality changes, bioavailability changes, and side effects caused by crystal form changes.
  • the crystalline form CSVIII has good mechanical stability.
  • the crystal form of the crystal form CSVIII remains unchanged under a pressure of at least 20 kN, and the crystal form remains unchanged before and after grinding.
  • it is often necessary to grind and pulverize the API and good physical stability can reduce the risk of lowering the crystallinity of the API or crystallizing during the preparation process.
  • the crystalline form CSVIII API has good physical stability, which is conducive to maintaining the crystal form stability in the preparation tableting process.
  • the crystal form CSVIII provided by the present invention has low hygroscopicity.
  • the test results show that the hygroscopic weight gain of the crystal form CSVIII of the present invention is only 0.14% under the condition of 80% RH, which belongs to no or almost no hygroscopicity.
  • high hygroscopicity can easily lead to chemical degradation and crystal transformation of the API, which directly affects the physicochemical stability of the API.
  • high hygroscopicity will reduce the fluidity of the API and affect the processing performance of the API.
  • APIs with high hygroscopicity need to maintain low humidity during production and storage, which puts forward higher requirements for production and requires high costs. More importantly, the high hygroscopicity can easily cause changes in the content of active ingredients in the drug, affecting the quality of the drug.
  • the crystal form CSVIII provided by the invention has low hygroscopicity, is favorable for maintaining the physical and chemical stability of the raw material medicine, does not require harsh environment for production and storage, reduces the production cost, and has strong economic value.
  • the crystal form CSVII provided by the present invention has higher solubility. Equilibrated in the medium FaSSIF (simulated fasting state intestinal fluid) for 1 hour and 4 hours, the solubility of crystal form CSVII is 7 times and 10 times higher than that of the prior art crystal form A, respectively.
  • the crystal form CSVII provided by the present invention has higher solubility, which is beneficial to improve the absorption of the drug in the human body and improve the bioavailability; in addition, the higher solubility can reduce the dosage of the drug while ensuring the curative effect of the drug, thereby reducing the amount of the drug side effects and improve the safety of medicines.
  • the crystal form CSVII provided by the present invention has better adhesion.
  • the adhesion evaluation results show that the adhesion amount of the prior art crystal form A is about 3 times that of the crystal form CSVII of the present invention.
  • the crystal form CSVII provided by the present invention has no organic solvent residue.
  • the crystal form CSVII of the present invention can be prepared by a single solvent of water, without introducing other organic solvents in the process, on the one hand, zero organic solvent residues can be achieved, and the drug toxicity effect of the crude drug due to solvent residues can be reduced. On the other hand, the production cost is reduced.
  • Residue dissolution control is one of the difficult problems in the pharmaceutical preparation process. In order to ensure that the solvent residue meets the pharmaceutical requirements, an accurate and efficient detection method for residue dissolution needs to be developed during the preparation of the API. It is often necessary to add steps such as recrystallization and vacuum drying, which increases production costs.
  • the crystal form CSVII bulk drug and preparation provided by the present invention have good stability.
  • the crystal form of CSVII bulk drug has not changed after being placed at 25°C/60%RH for at least 6 months.
  • the crystal form CSVII is mixed with excipients to prepare a pharmaceutical preparation, and placed under the conditions of 25° C./60% RH, the crystal form does not change for at least 3 months. It shows that the crystalline form CSVII API and preparation have good stability under long-term conditions, which is beneficial to the storage of the drug.
  • the crystal form of the bulk drug of crystalline form CSVII was kept closed for at least 6 months under the condition of 40°C/75%RH, and the crystal form did not change under the condition of 40°C/75%RH for at least 2 months. It shows that the crystalline form CSVII API has good stability under accelerated conditions and more severe conditions. High temperature and high humidity conditions caused by seasonal differences, climate differences in different regions and environmental factors will affect the storage, transportation and production of APIs. Therefore, the stability of the drug substance under accelerated and more severe conditions is critical for the drug.
  • the crystalline form CSVII API has better stability under harsh conditions, which is beneficial to avoid the influence on the quality of the drug due to transcrystallization or decrease in purity during drug storage.
  • the good physical stability of the bulk drug crystal form can ensure that the drug will not undergo crystal transformation during the production and storage process.
  • the crystal form CSVII has good physical stability, which ensures the consistent and controllable quality of the API and the preparation, and reduces drug quality changes, bioavailability changes, and toxic and side effects caused by changes in the crystal form.
  • the crystalline form CSVII has good mechanical stability.
  • the crystal form of CSVII remains unchanged under the pressure of at least 20 kN, and the crystal form remains unchanged before and after the grinding experiment.
  • it is often necessary to grind and pulverize the API and good physical stability can reduce the risk of lowering the crystallinity of the API and the risk of crystal transformation during the preparation process.
  • the crystalline form CSVII API has good physical stability, which is beneficial to keep the crystal form stable in the preparation and tableting process.
  • the crystal form CSVII provided by the present invention has low hygroscopicity.
  • the test results show that the hygroscopic weight gain of the crystal form CSVII of the present invention is only 0.53% under the condition of 80% RH, which is slightly hygroscopic.
  • high hygroscopicity can easily lead to chemical degradation and crystal transformation of the API, which directly affects the physicochemical stability of the API.
  • high hygroscopicity will reduce the fluidity of the API and affect the processing performance of the API.
  • APIs with high hygroscopicity need to maintain low humidity during production and storage, which puts forward higher requirements for production and requires high costs. More importantly, the high hygroscopicity can easily cause changes in the content of active ingredients in the drug, affecting the quality of the drug.
  • the crystal form CSVII provided by the invention has low hygroscopicity, is conducive to maintaining the physical and chemical stability of the raw material medicine, does not have harsh environmental requirements for production and storage, reduces the production cost, and has strong economic value.
  • the crystal form CSX provided by the present invention has higher solubility. Equilibrated in the medium FaSSIF (simulated fasting state intestinal fluid) for 1 hour and 4 hours, the solubility of crystal form CSX is 11 times and 15 times that of the prior art crystal form A, respectively.
  • the crystal form CSX provided by the present invention has higher solubility, which is beneficial to improve the absorption of the drug in the human body and improve the bioavailability; in addition, the higher solubility can reduce the dosage of the drug while ensuring the curative effect of the drug, thereby reducing the amount of the drug side effects and improve the safety of medicines.
  • Both the crystalline form CSX bulk drug and the preparation provided by the present invention have good stability.
  • the crystal form of CSX API was sealed and placed open for at least 6 months under the condition of 25°C/60%RH, and the crystal form did not change.
  • the crystal form CSX is mixed with excipients to make a pharmaceutical preparation, and placed under the conditions of 25°C/60% RH, the crystal form has not changed for at least 3 months. It shows that the crystalline form CSX API and preparation have good stability under long-term conditions, which is beneficial to the storage of the drug.
  • the crystalline form CSX API has been sealed and placed open for at least 6 months under the condition of 40°C/75%RH, and the crystal form has not changed. type has not changed. It shows that the crystalline form CSX API has good stability under accelerated conditions and more severe conditions. High temperature and high humidity conditions caused by seasonal differences, climate differences in different regions and environmental factors will affect the storage, transportation and production of APIs. Therefore, the stability of the drug substance under accelerated and more severe conditions is critical for the drug.
  • the crystalline form CSX API has better stability under harsh conditions, which is beneficial to avoid the influence on the quality of the drug due to transcrystallization or decrease in purity during drug storage.
  • Crystal form CSX has good physical stability, ensuring consistent and controllable quality of raw materials and preparations, reducing drug quality changes, bioavailability changes, and side effects caused by crystal form changes.
  • the crystalline form CSX has good mechanical stability.
  • the crystal form of CSX remained unchanged before and after the grinding experiment.
  • it is often necessary to grind and pulverize the API, and good physical stability can reduce the risk of lowering the crystallinity of the API and the risk of crystal transformation during the preparation process.
  • the crystal form CSX provided by the present invention has low hygroscopicity.
  • the test results show that the hygroscopic weight gain of the crystal form CSX of the present invention is only 0.12% under the condition of 80% RH, which belongs to no or almost no hygroscopicity.
  • high hygroscopicity can easily lead to chemical degradation and crystal transformation of the API, which directly affects the physicochemical stability of the API.
  • high hygroscopicity will reduce the fluidity of the API and affect the processing performance of the API.
  • APIs with high hygroscopicity need to maintain low humidity during production and storage, which puts forward higher requirements for production and requires high costs. More importantly, high hygroscopicity can easily lead to changes in the content of active ingredients in medicines, affecting the quality of medicines.
  • the crystal form CSX provided by the invention has low hygroscopicity, is favorable for maintaining the physical and chemical stability of the raw material medicine, does not have harsh environmental requirements for production and storage, reduces the production cost, and has strong economic value.
  • the crystalline form CSIV provided by the present invention has better adhesion.
  • the adhesion evaluation results show that the adhesion amount of the existing crystal form is 28 times that of the crystal form CSIV.
  • the crystalline form CSIV provided by the present invention has better compressibility.
  • the good compressibility of the crystal form CSIV can effectively improve the hardness/friability unqualified, splinter and other problems in the tableting process, make the formulation process more reliable, improve product appearance, and improve product quality and production efficiency.
  • Both the crystalline form CSIV bulk drug and the preparation provided by the present invention have good stability.
  • the crystal form of the CSIV API has not changed when placed at 25°C/60% RH for at least 12 months. After the crystalline form CSIV is mixed with excipients to prepare a pharmaceutical preparation, and placed under the condition of 25°C/60% RH, the crystalline form has not changed for at least 3 months. It shows that the crystalline form CSIV API and preparation have good stability under long-term conditions, which is beneficial to the storage of the drug.
  • Crystal form CSIV has good physical stability, ensuring consistent and controllable quality of APIs and preparations, and reducing drug quality changes, bioavailability changes, and side effects caused by changes in crystal form.
  • the crystalline form CSIV has good mechanical stability.
  • the crystal form of CSIV remains unchanged under the pressure of at least 14kN, and the crystal form remains unchanged before and after the grinding experiment.
  • it is often necessary to grind and pulverize the API and good physical stability can reduce the risk of lowering the crystallinity of the API and the risk of crystal transformation during the preparation process.
  • the crystalline form CSIV API has good physical stability, which is conducive to maintaining the crystal form stability in the preparation and tableting process.
  • the crystal form CSV provided by the present invention has better light stability.
  • the crystal form CSV was placed for 7 days under the conditions of 25°C/60%RH, 8k lux, and 1.5w/m2 of UV illumination, the chemical purity remained above 99%, the purity basically did not change, and the number of impurities was only grow two.
  • the crystal form A of the prior art was placed for 7 days under the conditions of 25°C/60%RH, 8k ⁇ lux, and 1.5w/m2 of ultraviolet illumination, the chemical purity was reduced from 99.30% to 98.82%, and the number of impurities was reduced by 9 increased to 20.
  • Illumination experiment is an important part of drug stability research. It has important guiding significance for the development of API preparation methods and drug application. It is one of the basis for drug storage conditions and packaging selection.
  • the good light stability of the bulk drug crystal form can ensure that the drug is not easily degraded to generate impurities in the process of conventional production and storage.
  • Crystal form CSV has good light stability, ensuring consistent and controllable quality of API and preparations, and reducing drug quality changes, bioavailability changes, and side effects caused by the degradation of APIs. At the same time, better light stability can reduce the extra cost caused by avoiding light and taking dark operation and storage during the production process.
  • the crystalline form of the CSV API provided by the present invention remains unchanged for at least 3 months under the airtight condition of 40°C/75%RH, and the crystal form remains unchanged under the airtight condition of 60°C/75%RH for at least 3 months.
  • the change indicates that the crystalline form CSV API has good stability under accelerated and more severe conditions. High temperature and high humidity conditions caused by seasonal differences, climate differences in different regions and environmental factors will affect the storage, transportation and production of APIs. Therefore, the stability of the drug substance under accelerated and more severe conditions is critical to the drug.
  • the crystalline form CSV API has better stability under harsh conditions, which is beneficial to avoid the influence on the quality of the drug due to transcrystallization or decrease in purity during the drug storage process.
  • Crystal form CSV has good physical stability, ensuring consistent and controllable quality of APIs and preparations, and reducing drug quality changes, bioavailability changes, and side effects caused by crystal form changes.
  • the crystal form CSV provided by the present invention has low hygroscopicity.
  • the test results show that the hygroscopic weight gain of the crystal form CSV of the present invention is only 0.10% under the condition of 80% RH, which belongs to no or almost no hygroscopicity.
  • high hygroscopicity can easily lead to chemical degradation and crystal transformation of the API, which directly affects the physicochemical stability of the API.
  • high hygroscopicity will reduce the fluidity of the API and affect the processing performance of the API.
  • APIs with high hygroscopicity need to maintain low humidity during production and storage, which puts forward higher requirements for production and requires high costs. More importantly, the high hygroscopicity can easily cause changes in the content of active ingredients in the drug, affecting the quality of the drug.
  • the crystal form CSV provided by the invention has low hygroscopicity, is favorable for maintaining the physical and chemical stability of the raw material medicine, does not have harsh environmental requirements for production and storage, reduces the production cost, and has strong economic value.
  • Fig. 1 is the XRPD pattern of the crystal form CSVIII prepared in Example 1
  • Fig. 2 is the TGA diagram of the crystal form CSVIII prepared in Example 1
  • Figure 3 is the XRPD pattern of the crystal form CSVIII prepared in Example 2.
  • Figure 4 is a structural diagram of an asymmetric unit in the single crystal structure of crystal form CSVIII
  • Figure 5 is the XRPD pattern of the crystal form CSVII prepared in Example 4.
  • Figure 6 is the TGA diagram of the crystal form CSVII prepared in Example 4.
  • Figure 10 is the TGA diagram of the crystal form CSX prepared in Example 7
  • Figure 11 is the XRPD pattern of the crystalline form CSIV prepared in Example 8.
  • Figure 12 is the XRPD pattern of the crystal form CSV prepared in Example 10.
  • Figure 13 is the XRPD pattern of the crystal form CSV prepared in Example 11
  • Figure 14 is the XRPD pattern of the crystal form CSV prepared in Example 12
  • Figure 15 is the XRPD comparison chart of crystal form CSVIII placed under different storage conditions (from top to bottom: before placing, 25°C/60%RH closed for 6 months, 25°C/60%RH open for 6 months month, 40°C/75%RH airtight storage for 6 months, 60°C/75%RH airtight storage for 1 month)
  • Figure 16 is the XRPD comparison chart of the crystal form CSVIII before and after tableting (from top to bottom: before tableting, 5kN, 10kN, 20kN)
  • Figure 17 is the XRPD comparison diagram of the crystal form CSVIII before and after grinding (top: before grinding; bottom: after grinding)
  • Figure 18 is the DVS diagram of crystal form CSVIII
  • Figure 19 is the XRPD comparison chart of the crystalline form CSVIII before and after the wettability test (top: before DVS; bottom: after DVS)
  • Figure 20 is the XRPD comparison diagram before and after the crystal form preparation (from top to bottom: blank mixed powder, after crystal form CSVIII preparation, crystal form CSVIII)
  • Figure 21 is the XRPD comparison diagram before and after the crystal form preparation (from top to bottom: blank mixed powder, after crystal form CSVII preparation, crystal form CSVII)
  • Figure 22 is the XRPD comparison diagram before and after the crystal preparation (from top to bottom: blank mixed powder, after crystal form CSX preparation, crystal form CSX)
  • Figure 23 is the XRPD comparison diagram before and after the crystal form preparation (from top to bottom: blank mixed powder, after crystal form CSIV preparation, crystal form CSIV)
  • Figure 24 is the XRPD comparison chart of crystal form CSVII placed under different storage conditions (from top to bottom: before placing, 25°C/60%RH closed for 6 months, 25°C/60%RH open for 6 months month, 6 months at 40°C/75%RH closed, 2 months at 40°C/75%RH open)
  • Figure 25 is the XRPD comparison diagram of the crystal form CSVII before and after tableting (from top to bottom: before tableting, 5kN, 10kN, 20kN)
  • Figure 26 is the XRPD comparison diagram of crystal form CSVII before and after grinding (top: before grinding; bottom: after grinding)
  • Figure 27 is the DVS diagram of crystal form CSVII
  • Figure 28 is the XRPD comparison chart of the crystalline form CSVII before and after the hygroscopicity test (top: before DVS; bottom: after DVS)
  • Figure 29 is the XRPD comparison chart of crystal form CSX placed under different storage conditions (from top to bottom: before placing, 25°C/60%RH closed for 6 months, 25°C/60%RH open for 6 months 6 months at 40°C/75%RH closed, 6 months at 40°C/75%RH open, 3 months at 60°C/75%RH closed, 3 open at 60°C/75%RH moon)
  • Figure 30 is the XRPD comparison diagram of crystal form CSX before and after grinding (top: before grinding; bottom: after grinding)
  • Figure 31 is the DVS diagram of crystal form CSX
  • Figure 32 is the XRPD comparison chart before and after the wettability test of crystal form CSX (top: before DVS; bottom: after DVS)
  • Figure 33 is the XRPD comparison chart of crystalline form CSIV placed under different storage conditions (from top to bottom: before placing, 25°C/60%RH sealed for 12 months, 25°C/60%RH open for 12 months moon)
  • Figure 34 is the XRPD comparison chart of the crystal form CSIV before and after tableting (upper: before tableting; lower: 14kN)
  • Figure 35 is the XRPD comparison chart of the crystal form CSV placed under storage conditions (top: 40°C/75%RH sealed for 3 months, bottom: before storage)
  • Figure 36 is the XRPD comparison chart of crystalline form CSV placed under storage conditions (top: 60°C/75%RH sealed for 3 months, bottom: before storage)
  • Figure 37 is the DVS diagram of the crystal form CSV
  • Figure 38 is the XRPD comparison chart before and after the wettability test of the crystal form CSV (top: before DVS; bottom: after DVS)
  • FaSSIF Simulates fasting state intestinal fluid
  • PE polyethylene
  • the X-ray powder diffraction patterns of the present invention were collected on a Bruker 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:
  • 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:
  • 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 and prepare a solution of 2-10 mg/mL with 0.5 mL of deuterated chloroform.
  • the single crystal X-ray diffraction (SC-XRD) described in the present invention is equipped with a CMOS area detector and Mo K ⁇ radiation
  • the Bruker D8QUEST diffractometer of the Microfocal Enclosed X-ray Generator collected single crystal X-ray diffraction data.
  • the single crystal was at 193K at the time of data collection.
  • Example 33 crystal form CSV of the present invention The purity test parameters of Example 33 crystal form CSV of the present invention are shown in Table 4:
  • the "stirring" is accomplished by conventional methods in the art, 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 “separation” is accomplished by conventional methods in the art, such as centrifugation or filtration.
  • the operation of "centrifugation” is: put the sample to be separated into a centrifuge tube, and centrifuge at a speed of 10,000 rpm until all the solids sink to the bottom of the centrifuge tube.
  • the "drying” can be carried out at room temperature or higher.
  • the drying temperature is room temperature to about 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.
  • rotary evaporation is accomplished by conventional methods in the art.
  • the operation of rotary evaporation is as follows: the flask containing the solution is rotated at a constant speed under the condition of a certain temperature and a certain negative pressure to evaporate the solvent.
  • the "volatilization” is accomplished by conventional methods in the art, such as slow volatilization or rapid volatilization. Slow volatilization is to seal the container with sealing film, poke holes, and stand to volatilize; rapid volatilization is to leave the container open to volatilize.
  • room temperature is not a specific temperature value, but refers to a temperature range of 10-30°C.
  • 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 "LC” includes HPLC and UPLC.
  • the temperature has an error range of ⁇ 2°C
  • the humidity has an error range of ⁇ 5%RH.
  • crystal or “polymorph” refers to a solid as evidenced by X-ray powder diffraction pattern characterization.
  • X-ray powder diffraction patterns generally vary with instrument conditions.
  • the relative intensities of diffraction peaks in X-ray powder diffraction patterns may also vary with experimental conditions, so the order of diffraction peak intensities cannot be used as the only or decisive factor.
  • 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.
  • the experimental error of the diffraction peak positions is usually 5% or less, and the error of these positions should also be taken into account, and an error of ⁇ 0.2° is usually allowed.
  • the overall shift of the diffraction peak angle will be caused, and a certain shift is usually allowed.
  • 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.
  • Form CSVIII, Form CSVII, Form CSX, Form CSIV, Form CSV of the present invention are pure and substantially not admixed with any other forms.
  • 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, and even less More than 5% (weight) of other crystal forms, more than 1% (weight) of other crystal forms.
  • the compound I as a starting material includes, but is not limited to, solid form (crystalline or amorphous), oily, liquid form and solution.
  • the compound I as starting material is in solid form.
  • the solid compound I and the solid vanillin of the mass shown in Table 5 were weighed into a glass vial, and the solvent shown in Table 5 was added thereto, stirred at room temperature, centrifuged, and dried to obtain a crystalline solid.
  • the obtained crystalline solids are all crystal form CSVIII, wherein the XRPD data of sample 1 is shown in Table 6, and the XRPD pattern is shown in Figure 1.
  • TGA of sample 1 is shown in Figure 2, when it is heated to 80 °C, it has a mass loss of about 5.2%; when heated from 80 °C to 200 °C, it has a mass loss of about 26.2%.
  • Form CSVIII is a hydrate.
  • pandan The active hydrogen on the hydroxyl group of plain phenol and the active hydrogen on the piperazinyl group of compound I do not appear peaks.
  • the obtained solid was crystal form CSVIII.
  • the X-ray single crystal diffraction data of the crystal form CSVIII were collected, and after analysis, the unit cell parameters were shown in Table 8, and the structure of the asymmetric unit was shown in Figure 4.
  • the results show that an asymmetric unit of crystal form CSVIII includes one compound I molecule, one vanillin molecule and one water molecule, and crystal form CSVIII is a monohydrate of compound I vanillin co-crystal.
  • TGA has a mass loss of about 9.0% when it is heated to 70°C, corresponding to the loss of water.
  • mass loss of about 8.6% When heated from 70 °C to 130 °C, there is a mass loss of about 8.6%, and when heated from 130 °C to 250 °C, there is a mass loss of about 16.0%, corresponding to the loss of vanillin, and the crystal form CSVII is a eutectic hydrate.
  • the active hydrogen on the phenolic hydroxyl group of vanillin and the active hydrogen on the piperazinyl group of compound I do not appear peaks.
  • the obtained crystalline solid is the crystal form CSX described in the present invention. Its XRPD diagram is shown in Figure 9, and the XRPD data is shown in Table 14.
  • TGA has a mass loss of about 2.1% when the crystal form CSX is heated to 120°C.
  • the obtained solid was crystalline form CSIV.
  • the XRPD data of the crystalline form CSIV is shown in Table 15, and the XRPD pattern is shown in FIG. 11 .
  • the obtained solid was crystalline form CSIV.
  • the X-ray powder diffraction pattern of crystalline form CSIV has characteristic peaks at 2 ⁇ values of 4.9° ⁇ 0.2°, 11.7° ⁇ 0.2° and 14.2° ⁇ 0.2°.
  • the obtained crystalline solid is crystal form CSV, its XRPD data is shown in Table 16, and the XRPD diagram is shown in Figure 12.
  • the obtained crystalline solid is crystal form CSV, its XRPD data is shown in Table 17, and the XRPD diagram is shown in Figure 13 .
  • the obtained crystalline solid is crystal form CSV, its XRPD pattern is shown in Figure 14, and the XRPD data is shown in Table 18.
  • Example 14 Adhesion of Form CS VIII to Prior Art Form A
  • a certain amount of the crystal form CSVIII prepared by the present invention is weighed and placed under the conditions of 25°C/60%RH, 40°C/75%RH and 60°C/75%RH respectively, and the crystal form is determined by XRPD.
  • the results are shown in Table 21, and the XRPD comparison graph is shown in Figure 15.
  • Placement conditions packing condition put time Crystal form 25°C/60%RH Glass bottle + aluminum foil bag seal 6 months
  • Form CSVIII 25°C/60%RH exposure 6 months
  • Form CSVIII 40°C/75%RH Glass bottle + aluminum foil bag seal 6 months
  • Form CSVIII 60°C/75%RH Glass bottle + aluminum foil bag seal 1 month
  • Form CSVIII 60°C/75%RH Glass bottle + aluminum foil bag seal 1 month
  • the crystalline form CSVIII is stable for at least 6 months at 25°C/60% RH and for at least 6 months at 40°C/75% RH. It can be seen that the crystalline form CSVIII is stable under both long-term and accelerated conditions. Can maintain good stability. It can be stable for at least one month under the condition of 60°C/75%RH, and it can be seen that the stability is also very good under more severe conditions.
  • the crystalline form CSVIII was placed in a mortar and manually ground for 5 minutes. XRPD tests were performed before and after grinding. The test results are shown in Figure 17 . The results show that the crystalline form CSVIII has good grinding stability.
  • the DVS diagram of the crystalline form CSVIII is shown in FIG. 18 , which has a weight gain of 0.14% after equilibration under the condition of 60%RH-80%RH, and has no or almost no hygroscopicity.
  • the XRPD comparison charts of the crystal form CSVIII before and after the hygroscopicity are shown in Figure 19. Before and after the DVS test, the crystal form CSVIII did not transform into crystals and had good stability.
  • Moisture gain is less than 15.0% but not less than 2.0%
  • wet weight gain is less than 2.0% but not less than 0.2%
  • wet weight gain is less than 0.2%
  • Example 18 Formulation preparation of crystal forms CSVII, CSVIII, CSX, CSIV
  • Example 19 Stability in Formulations of Forms CSVII, CSVIII, CSX, CSIV
  • Example 20 Dynamic solubility of crystal form CSVII and prior art crystal form A
  • Example 21 Adhesion of crystal form CSVII to prior art crystal form A
  • a certain amount of the crystal form CSVII prepared by the present invention is weighed and placed under the conditions of 25°C/60%RH and 40°C/75%RH respectively, and the crystal form is determined by XRPD. The results are shown in Table 27, and the XRPD comparison chart is shown in Figure 24.
  • Placement conditions packing condition put time Crystal form 25°C/60%RH Glass bottle + aluminum foil bag seal 6 months
  • Form CSVII 25°C/60%RH exposure 6 months
  • the crystal form CSVII was placed in a mortar and manually ground for 5 minutes. XRPD tests were performed before and after grinding. The test results are shown in Figure 26. The results show that the crystal form CSVII has good grinding stability.
  • the crystal form CSVII of the present invention use a dynamic moisture absorption (DVS) instrument to test its hygroscopicity, cycle once under 70%-95%-0-95% relative humidity, and record the mass change under each humidity.
  • the DVS diagram of the crystal form CSVII is shown in Fig. 27, the weight gain is 0.53% after equilibration under the conditions of 60%RH ⁇ 80%RH, which is slightly hygroscopic.
  • the XRPD comparison charts of the crystal form CSVII before and after the hygroscopicity are shown in Figure 28. Before and after the DVS test, the crystal form CSVII did not change crystals and had good stability.
  • Example 25 Dynamic Solubility of Form CSX and Prior Art Form A
  • a certain amount of crystal form CSX prepared by the present invention is weighed and placed under the conditions of 25°C/60%RH, 40°C/75%RH and 60°C/75%RH respectively, and the crystal form is determined by XRPD.
  • the results are shown in Table 30, and the XRPD comparison graph is shown in Figure 29.
  • the crystal form CSX can be stable for at least 6 months under the conditions of 25°C/60%RH and 40°C/75%RH. It can be seen that the crystal form CSX can maintain good stability under both long-term and accelerated conditions. It can be stable for at least 3 months under the condition of 60°C/75%RH, and it can be seen that the stability is also very good under more severe conditions.
  • the crystalline form CSX was placed in a mortar and manually ground for 5 minutes. XRPD tests were performed before and after grinding. The test results are shown in Figure 30. The results show that the crystalline form CSX has good grinding stability.
  • the crystal form CSX of the present invention use a dynamic moisture adsorption (DVS) instrument to test its hygroscopicity, cycle once under a relative humidity of 40%-95%-0-95%, and record the mass change under each humidity.
  • the DVS diagram of the crystalline form CSX is shown in Fig. 31 , which has a weight gain of 0.12% after equilibration under the conditions of 60%RH-80%RH, and has no or almost no hygroscopicity.
  • the XRPD comparison chart of the crystal form CSX before and after the wettability is shown in Figure 32. Before and after the DVS test, the crystal form CSX did not turn crystal, and the stability was better.
  • Example 29 Adhesion of Form CSIV to Prior Art Form A
  • Example 30 Compressibility of Form CSIV and Prior Art Form A
  • Form CSIV has better tensile strength than the prior art Form A. have better compressibility.
  • a certain amount of the crystal form CSIV prepared by the present invention is weighed, placed under the condition of 25° C./60% RH, and the crystal form is determined by XRPD. The results are shown in Table 33, and the XRPD comparison graph is shown in Figure 33.
  • the crystalline form CSIV was placed in a mortar and manually ground for 5 minutes. XRPD tests were performed before and after grinding. The results showed that the crystalline form of CSIV remained unchanged before and after grinding, and had good grinding stability.
  • Example 33 Light Stability of Form CSV and Prior Art Form A
  • a certain amount of the crystal form CSV prepared by the present invention is weighed and placed under the conditions of 40°C/75%RH and 60°C/75%RH respectively, and the crystal form is determined by XRPD.
  • the results are shown in Table 35, and the XRPD comparison charts are shown in Figures 35 and 36.
  • Placement conditions packing condition put time Crystal form 40°C/75%RH Single layer PE bag + aluminum foil bag sealing 3 months Form CSV 60°C/75%RH Single layer PE bag + aluminum foil bag sealing 3 months Form CSV
  • the DVS diagram of the crystalline form CSV is shown in 37. It has a weight gain of 0.10% after equilibration under the condition of 60%-80% RH, and has no or almost no hygroscopicity.
  • the XRPD comparison chart of the crystal form CSV before and after the hygroscopicity test is shown in 38. Before and after the DVS test, the crystal form CSV does not change crystals and has good stability.

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Abstract

提供Risdiplam（称为"化合物I"）的新晶型及其制备方法，含有该晶型的药物组合物，以及该晶型在制备治疗脊髓性肌萎缩症的药物中的用途。提供的化合物I新晶型比现有技术具有一种或多种改进的性质，解决了现有技术存在的问题，对未来该药物的优化和开发具有重要价值。

Description

Risdiplam晶型及其制备方法和用途 技术领域
本发明主要涉及晶体化学领域。具体而言，涉及Risdiplam的晶型及其制备方法和用途。
背景技术
脊髓性肌萎缩症(spinal muscular atrophy，SMA)是一种由两条染色体上的运动神经元生存基因1(SMN1)失活突变或缺失继而导致SMN1基因功能丧失引起的疾病。SMA的症状包括肌肉无力、肌张力低下、哭泣无力、咳嗽无力、柔弱或容易滑倒、吸吮或吞咽困难、呼吸困难、肺或咽喉分泌物积聚、握紧拳头出汗、舌头颤动/振动、头部经常向一侧倾斜(即使在躺下时)、腿部倾向于比手臂弱、腿部经常处于“蛙腿”姿势、摄食困难、呼吸道感染敏感度增加、肠/膀胱无力、体重低于正常值、不能无支撑坐立、无法行走、无法爬行、和肌张力减退、反射消失、以及与前角细胞丧失相关的多发性先天性挛缩(关节挛缩)。SMA患者依赖于SMN2基因产生SMN蛋白，有证据表明，提高SMN蛋白水平对各种类型的SMA患者有显著的临床益处。
Risdiplam(商品名Evrysdi)是一种运动神经元生存基因2(SMN2)剪接修饰剂，开发用于所有类型(1型、2型、3型)SMA的治疗。2020年8月，Evrysdi获得美国FDA批准，用于治疗2个月及以上儿童和成人SMA患者。在批准Evrysdi时，FDA颁发给了罗氏一张罕见儿科疾病优先审查凭证(PRV)。值得一提的是，Evrysdi是第一个治疗SMA的口服疗法，也是第一个可在家给药的SMA疗法。
Risdiplam的化学名称为：7-(4,7-二氮杂螺[2.5]辛-7-基)-2-(2,8-二甲基咪唑并[1,2-b]哒嗪-6-基)吡啶并[1,2-a]嘧啶-4-酮(以下称为“化合物I”)，其结构式如下：
Figure PCTCN2021116817-appb-000001
根据FDA药物共晶指南，药物共晶是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))在同一个晶格中按一定的化学计量比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，改善药物生产过程中原料药的加工性能。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多的固态形式。
晶体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。多晶型是指一种化合物存在多种晶体形式(或晶型)的现象。化合物可能以一种或多种晶型存在，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，晶型的理化性质对生产过程至关重要。因此，多晶型是药物研究和药物质量控制的重要内容。
WO2020079203A1公开了化合物I的7个晶型，说明书仅公开了晶型A和晶型D的制备方法及表征数据，未公开其他晶型(晶型B，晶型C，晶型E，晶型F，晶型G)的制备方法。根据该专利申请文本，本领域技术人员无法获得化合物I的晶型B，晶型C，晶型E，晶型F，晶型G。通过说明书中公开的信息可知，与晶型D相比，晶型A具有改善的化学稳定性，在过滤方面具有改进的加工性能。然而，本申请发明人通过大量研究发现，晶型A存在溶解度较低，有溶剂残留，粉体学性质差、光照稳定性差等缺点。
为克服现有技术的缺点，本领域仍然需要一种溶解度高、无溶剂残留、粉体学性质好的符合药用开发标准的新晶型，以用于含化合物I药物的开发。本申请的发明人通过研究意外发现了本发明提供的化合物I的晶型，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，特别是溶解度高，无溶剂残留，黏附性低，可压性好，解决了现有技术存在的问题，对含化合物I药物的开发具有非常重要的意义。
发明内容
本发明提供化合物I的新晶型及其制备方法以及包含该新晶型的药物组合物。
根据本发明的目的，提供化合物I的共晶。进一步地，所述共晶是化合物I和香兰素的共晶。
进一步地，所述共晶是化合物I的香兰素共晶CSⅧ(以下称作“晶型CSⅧ”)。
一方面，使用Cu-Kα辐射，所述晶型CSⅧ的X射线粉末衍射图在衍射角2θ值为5.1°±0.2°、12.6°±0.2°、25.3°±0.2°处有特征峰。
进一步地，使用Cu-Kα辐射，所述晶型CSⅧ的X射线粉末衍射图在衍射角2θ值为9.3°±0.2°、21.9°±0.2°、26.8°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSVIII的X射线粉末衍射图在衍射角2θ值为9.3°±0.2°、21.9°±0.2°、26.8°±0.2°处有特征峰。
进一步地，使用Cu-Kα辐射，所述晶型CSⅧ的X射线粉末衍射图在衍射角2θ值为7.5°±0.2°、13.6°±0.2°、29.8°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSVIII的X射线粉末衍射图在衍射角2θ值为7.5°±0.2°、13.6°±0.2°、29.8°±0.2°处有特征峰。
另一方面，使用Cu-Kα辐射，所述晶型CSⅧ的X射线粉末衍射图在衍射角2θ值5.1°±0.2°、12.6°±0.2°、25.3°±0.2°、7.5°±0.2°、9.3°±0.2°、13.6°±0.2°、21.9°±0.2°、26.8°±0.2°、29.8°±0.2°中的任意1处、或2处、或3处、或4处、或5处、或6处、或7处、或8处、或9处有特征峰。
非限制性地，晶型CSⅧ的X射线粉末衍射图基本如图1或图3所示。
非限制性地，晶型CSVIII的热重分析图基本如图2所示，将其加热至80℃时，具有约5.2％的质量损失，对应水的失重；从80℃加热至200℃时，具有约26.2％的质量损失，对应香兰素的失重。
非限制性地，晶型CSVIII为水合物。
非限制性地，本发明提供晶型CSVIII的单晶数据，如表1所示。
表1
Figure PCTCN2021116817-appb-000002
Figure PCTCN2021116817-appb-000003
根据本发明的目的，本发明还提供所述晶型CSⅧ的制备方法，所述制备方法包括:
(1)将化合物I固体和香兰素固体置于水，水和芳香烃类的混合溶剂，水、卤代烃类和烷烃类的混合溶剂，或水、腈类和烷烃类的混合溶剂中，室温条件下搅拌，分离固体，干燥得到晶型CSVIII；或
(2)将化合物I固体和香兰素固体置于水中，搅拌，分离固体，将所得固体密封，放置一段时间得到晶型CSVIII。
进一步地，方法(1)中所述化合物I固体和香兰素固体的摩尔投料比优选1:1-1:4；方法(2)中所述化合物I固体和香兰素固体的摩尔投料比优选1:1-1:2。
进一步地，所述搅拌的时间优选不小于1小时；方法(2)所述放置的时间优选不少于2天，所述放置的条件优选为温度50-70℃，湿度70-90％RH。
进一步地，方法(2)中所述搅拌的温度优选低于10℃。
进一步地，所述芳香烃类溶剂优选甲苯，所述卤代烃类溶剂优选二氯甲烷，所述烷烃类溶剂优选正庚烷，所述腈类溶剂优选乙腈，所述混合溶剂中的水的体积分数优选1％-10％。
根据本发明的目的，提供化合物I的香兰素共晶CSVII(以下称作“晶型CSVII”)。
一方面，使用Cu-Kα辐射，所述晶型CSVII的X射线粉末衍射图在衍射角2θ值为7.5°±0.2°、9.1°±0.2°、15.6°±0.2°处有特征峰。
进一步地，使用Cu-Kα辐射，所述晶型CSVII的X射线粉末衍射图在衍射角2θ值为22.9°±0.2°、18.2°±0.2°、11.9°±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射线粉末衍射图在衍射角2θ值为22.9°±0.2°、18.2°±0.2°、11.9°±0.2°处有特征峰。
进一步地，使用Cu-Kα辐射，所述晶型CSVII的X射线粉末衍射图在衍射角2θ值为6.0°±0.2°、24.5°±0.2°、27.5°±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射线粉末衍射图在衍射角2θ值为6.0°±0.2°、24.5°±0.2°、27.5°±0.2°处有特征峰。
另一方面，使用Cu-Kα辐射，所述晶型CSVII的X射线粉末衍射图在衍射角2θ值7.5°±0.2°、9.1°±0.2°、15.6°±0.2°、22.9°±0.2°、6.0°±0.2°、11.9°±0.2°、18.2°±0.2°、24.5°±0.2°、27.5°±0.2°中的任意1处、或2处、或3处、或4处、或5处、或6处、或7处、或8处、或9处有特征峰。
非限制性地，晶型CSVII的X射线粉末衍射谱图基本如图5所示。
非限制性地，晶型CSVII的热重分析图基本如图6所示，将其加热至70℃时，具有约9.0％的质量损失，对应水的失重。从70℃加热到130℃时，具有约8.6％的质量损失，从130℃加热到250℃时，具有约16.0％的质量损失，对应香兰素的失重。
非限制性的，晶型CSVII为水合物。
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:
将化合物I固体和香兰素固体置于水中，搅拌，分离固体，干燥得到晶型CSVII，其中，所述搅拌的温度为低于10℃。
进一步地，所述化合物I固体和香兰素固体的摩尔投料比优选为1:1-1:2，所述搅拌的时间优选不小于1小时。
根据本发明的目的，提供化合物I的晶型CSX(以下称作“晶型CSX”)。
一方面，使用Cu-Kα辐射，所述晶型CSX的X射线粉末衍射图在衍射角2θ值为7.3°±0.2°、10.4°±0.2°、13.2°±0.2°、22.0°±0.2°处有特征峰。
进一步地，使用Cu-Kα辐射，所述晶型CSX的X射线粉末衍射图在衍射角2θ值为14.9°±0.2°、15.3°±0.2°、25.2°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSX的X射线粉末衍射图在衍射角2θ值为14.9°±0.2°、15.3°±0.2°、25.2°±0.2°处有特征峰。
进一步地，使用Cu-Kα辐射，所述晶型CSX的X射线粉末衍射图在衍射角2θ值为19.8°±0.2°处有特征峰。
另一方面，使用Cu-Kα辐射，所述晶型CSX的X射线粉末衍射图在衍射角2θ值7.3°±0.2°、10.4°±0.2°、13.2°±0.2°、22.0°±0.2°、14.9°±0.2°、15.3°±0.2°、25.2°±0.2°、19.8°±0.2°、16.4°±0.2°、18.5°±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处有特征峰。
非限制性地，晶型CSX的X射线粉末衍射谱图基本如图7或图8或图9所示。
非限制性地，晶型CSX的热重分析图基本如图10所示，将其加热至120℃时，具有约2.1％的质量损失。
根据本发明的目的，本发明还提供所述晶型CSX的制备方法，所述制备方法包括:
将化合物I固体溶解于卤代烃类或含水的卤代烃类溶剂中，过滤，将滤液加入烃类溶剂中搅拌，或者将烃类溶剂加入该滤液中搅拌，析出固体，分离，得到化合物I晶型CSX。
进一步地，所述卤代烃为碳原子数C1-C3的卤代烃，所述烃类为碳原子数C5-C8的烃。
进一步地，所述烃类溶剂优选烷烃，进一步地，优选环己烷、正己烷或正庚烷。
进一步地，所述卤代烃优选氯仿或二氯甲烷。
根据本发明的目的，本发明提供化合物I的晶型CSIV(以下称作“晶型CSIV”)。
一方面，使用Cu-Kα辐射，所述晶型CSIV的X射线粉末衍射图在衍射角2θ值为4.9°±0.2°、11.7°±0.2°、14.2°±0.2°处有特征峰。
另一方面，使用Cu-Kα辐射，所述晶型CSIV的X射线粉末衍射图在衍射角2θ值为4.9°±0.2°、11.7°±0.2°、14.2°±0.2°、6.9°±0.2°、27.0°±0.2°、13.1°±0.2°、14.8°±0.2°、15.5°±0.2°、24.8°±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处有特征峰。
非限制性地，晶型CSIV的X射线粉末衍射图基本如图11所示。
根据本发明的目的，本发明还提供所述晶型CSIV的制备方法，所述制备方法包括:
将化合物I固体溶解于醇类和卤代烃类的混合溶剂中，过滤后通过旋转蒸发获得。
进一步地，所述醇类溶剂优选C1-C3的醇，更优选为甲醇或乙醇；所述卤代烃类溶剂优选二氯甲烷或氯仿；所述混合溶剂中醇类与卤代烃类的体积比为1:50-5:1，优选1:1。
根据本发明的目的，本发明提供化合物I的晶型CSV(以下称作“晶型CSV”)。
一方面，使用Cu-Kα辐射，所述晶型CSV的X射线粉末衍射图在衍射角2θ值为7.7°±0.2°、22.8°±0.2°处有特征峰。
进一步地，所述晶型CSV的X射线粉末衍射图在衍射角2θ值为13.4°±0.2°、10.5°±0.2°、24.6°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSV的X射线粉末衍射图在衍射角2θ值为13.4°±0.2°、10.5°±0.2°、24.6°±0.2°中的3处有特征峰。
进一步地，所述晶型CSV的X射线粉末衍射图在衍射角2θ值为37.7°±0.2°、22.4°±0.2°中的1处、或2处有特征峰；优选地，所述晶型CSV的X射线粉末衍射图在衍射角2θ值为37.7°±0.2°、22.4°±0.2°中的2处有特征峰。
另一方面，使用Cu-Kα辐射，所述晶型CSV的X射线粉末衍射图在衍射角2θ值为7.7°±0.2°、13.4°±0.2°、10.5°±0.2°、24.6°±0.2°、22.8°±0.2°、37.7°±0.2°、22.4°±0.2°中的任意1处、或2处、或3处、或4处、或5处、或6处、或7处有特征峰。
非限制性地，晶型CSV的X射线粉末衍射图基本如图12或13或14所示。
根据本发明的目的，本发明还提供所述晶型CSV的制备方法，所述制备方法包括：将化合物I固体溶解于酯类和卤代烷烃类的混合溶剂中，过滤后挥发获得。
进一步地，所述挥发温度为5℃-30℃，优选室温。
更进一步地，所述卤代烃类和酯类混合溶剂比例为2:1-5:1，优选3:1。
更进一步地，所述卤代烃类溶剂为碳原子数C1-C3的卤代烃，进一步优选二氯甲烷。
更进一步地，所述酯类溶剂为碳原子数C3-C6的酯，进一步的优选乙酸异丙酯。
根据本发明的目的，本发明提供的晶型CSVIII、晶型CSVII、晶型CSX、晶型CSIV、晶型CSV或上述晶型的任意混合用于制备化合物I其他晶型或盐的用途。
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化合物I的晶型CSVIII、晶型CSVII、晶型CSX、晶型CSIV、晶型CSV或上述晶型的任意混合及药学上可接受的辅料。
进一步地，本发明提供化合物I的晶型CSVIII、晶型CSVII、晶型CSX、晶型CSIV、晶型CSV或上述晶型的任意混合在制备运动神经元生存基因2剪接修饰剂药物中的用途。
更进一步地，本发明提供化合物I的晶型CSVIII、晶型CSVII、晶型CSX、晶型CSIV、晶型CSV或上述晶型的任意混合在制备治疗脊髓性肌萎缩症的药物中的用途。
本发明提供的晶型CSVIII具有以下优势：
(1)与现有技术相比，本发明提供的晶型CSVIII具有更高的溶解度。在生物介质FaSSIF(模拟禁食状态肠液)中平衡1小时和4小时，晶型CSVIII的溶解度分别是现有技术晶型A的13倍和18倍。
本发明提供的晶型CSVIII有更高的溶解度，有利于提高药物在人体内的吸收，提高生物利用度；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)与现有技术相比，本发明提供的晶型CSVIII具有更优的黏附性。黏附性评价结果表明，现有技术晶型A的黏附量约为本发明晶型CSVIII的10倍。
更优的黏附性能有效减少原料药的团聚，能有效改善或者避免干法制粒和片剂压片等环节引起的黏轮、黏冲等现象，有利于原料和辅料混合时原料的分散，提高物料混合时的混合均匀度，最终提高产品质量。
(3)与现有技术相比，本发明提供的晶型CSVIII无有机溶剂残留。结合实施例1和2可知，本发明晶型CSVIII可以通过水作为单一溶剂制备获得，无需引入其他有机溶剂，一方面可以实现零有机溶剂残留，降低原料药因溶剂残留带来的药物毒性作用。另一方面，降低生产成本。
溶残控制是药物制备工艺中的难题之一，为了保证溶剂残留符合药用要求，原料药制备过程中需要开发出一套准确高效的溶残检测方法，此外，为降低溶剂残留，工艺过程中往往需要增加重结晶，真空干燥等步骤，增加生产成本。
(4)本发明提供的晶型CSVIII原料药和制剂均具有良好的稳定性。晶型CSVIII原料药在25℃/60％RH条件下放置至少6个月晶型未发生变化。晶型CSVIII与辅料混合做成药物制剂后，在25℃/60％RH条件下放置，至少3个月晶型未发生变化。说明晶型CSVIII原料药和制剂在长期条件下具有较好的稳定性，有利于药物的储存。
同时，晶型CSVIII原料药在40℃/75％RH条件下放置至少6个月晶型未发生变化，在60℃/75％RH条件下放置至少一个月晶型未发生变化。说明晶型CSVIII原料药在加速条件及更严苛的条件下，具有好的稳定性。季节差异、不同地区气候差异和环境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。因此，原料药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。晶型CSVIII原料药在苛刻的条件下具有更好的稳定性，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。晶型CSVIII具有良好的物理稳定性，保证原料药和制剂质量一致可控，减少由于晶型改变引起的药物质量变化，生物利用度变化，和副作用。
同时，晶型CSVIII具有良好的机械稳定性。晶型CSVIII在至少20kN压力条件下，晶型保持不变，研磨前后晶型保持不变。制剂加工过程中常需要将原料药研磨粉碎，良好的物理稳定性能够降低制剂加工过程中原料药结晶度降低或转晶的风险。在不同压力下，晶型CSVIII原料药均具有良好的物理稳定性，有利于在制剂压片工艺中保持晶型稳定。
(5)本发明提供的晶型CSVIII具有低的引湿性。测试结果表明，本发明晶型CSVIII在80％RH条件下引湿性增重仅为0.14％，属于无或几乎无引湿性。
一方面，引湿性高易引发原料药化学降解和晶型转变，直接影响原料药的物理化学稳定 性。此外，引湿性高会降低原料药的流动性，影响原料药的加工性能。
另一方面，引湿性高的原料药在生产和储存过程中需要维持低的湿度，对生产提出了更高的要求，需要很高的成本。更重要的是，引湿性高容易造成药物中有效成分含量的变化，影响药物的质量。
本发明提供的晶型CSVIII引湿性低，有利于保持原料药的物理化学稳定，对生产和储存的环境要求不苛刻，降低了生产成本，具有很强的经济价值。
本发明提供的晶型CSVII具有以下优势：
(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。在介质FaSSIF(模拟禁食状态肠液)中平衡1小时和4小时，晶型CSVII的溶解度分别是现有技术晶型A的7倍和10倍。
本发明提供的晶型CSVII有更高的溶解度，有利于提高药物在人体内的吸收，提高生物利用度；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)与现有技术相比，本发明提供的晶型CSVII具有更优的黏附性。黏附性评价结果表明，现有技术晶型A的黏附量约为本发明晶型CSVII的黏附量的3倍。
更优的黏附性能有效减少原料药的团聚，能有效改善或者避免干法制粒和片剂压片等环节引起的黏轮、黏冲等现象，有利于原料和辅料混合时原料的分散，提高物料混合时的混合均匀度，最终提高产品质量。
(3)与现有技术相比，本发明提供的晶型CSVII无有机溶剂溶残。结合实施例4可知，本发明晶型CSVII可以通过水单一溶剂制备获得，工艺中无需引入其他有机溶剂，一方面可以实现零有机溶剂残留，降低原料药因溶剂残留带来的药物毒性作用。另一方面，降低生产成本。溶残控制是药物制备工艺中的难题之一，为了保证溶剂残留符合药用要求，原料药制备过程中需要开发出一套准确高效的溶残检测方法，此外，为降低溶剂残留，工艺过程中往往需要增加重结晶，真空干燥等步骤，增加生产成本。
(4)本发明提供的晶型CSVII原料药和制剂均具有良好的稳定性。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。晶型CSVII与辅料混合做成药物制剂后，在25℃/60％RH条件下放置，至少3个月晶型未发生变化。说明晶型CSVII原料药和制剂在长期条件下具有较好的稳定性，有利于药物的储存。
同时，晶型CSVII原料药在40℃/75％RH条件下密闭放置至少6个月晶型未发生变化，在40℃/75％RH条件下敞口放置至少2个月晶型未发生变化。说明晶型CSVII原料药在加速条件及更严苛的条件下，具有好的稳定性。季节差异、不同地区气候差异和环境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。因此，原料药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。晶型CSVII原料药在苛刻的条件下具有更好的稳定性，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。晶型CSVII具有良好的物理稳定性，保证原料药和制剂质量一致可控，减少由于晶型改变引起的药物质量变化，生物利用度变化，和毒副作用。
同时，晶型CSVII具有良好的机械稳定性。晶型CSVII在至少20kN压力条件下，晶型保持不变，研磨实验前后晶型保持不变。制剂加工过程中常需要将原料药研磨粉碎，良 好的物理稳定性能够降低制剂加工过程中原料药结晶度降低和转晶的风险。在不同压力下，晶型CSVII原料药均具有良好的物理稳定性，有利于在制剂压片工艺中保持晶型稳定。
(5)本发明提供的晶型CSVII具有低的引湿性。测试结果表明，本发明晶型CSVII在80％RH条件下引湿性增重仅为0.53％，属于略有引湿性。
一方面，引湿性高易引发原料药化学降解和晶型转变，直接影响原料药的物理化学稳定性。此外，引湿性高会降低原料药的流动性，影响原料药的加工性能。
另一方面，引湿性高的原料药在生产和储存过程中需要维持低的湿度，对生产提出了更高的要求，需要很高的成本。更重要的是，引湿性高容易造成药物中有效成分含量的变化，影响药物的质量。
本发明提供的晶型CSVII引湿性低，有利于保持原料药的物理化学稳定，对生产和储存的环境要求不苛刻，降低了生产成本，具有很强的经济价值。
本发明提供的晶型CSX具有以下优势：
(1)与现有技术相比，本发明提供的晶型CSX具有更高的溶解度。在介质FaSSIF(模拟禁食状态肠液)中平衡1小时和4小时，晶型CSX的溶解度分别是现有技术晶型A的11倍和15倍。
本发明提供的晶型CSX有更高的溶解度，有利于提高药物在人体内的吸收，提高生物利用度；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CSX原料药和制剂均具有良好的稳定性。晶型CSX原料药在25℃/60％RH条件下密封和敞口放置至少6个月晶型未发生变化。晶型CSX与辅料混合做成药物制剂后，在25℃/60％RH条件下放置，至少3个月晶型未发生变化。说明晶型CSX原料药和制剂在长期条件下具有较好的稳定性，有利于药物的储存。
同时，晶型CSX原料药在40℃/75％RH条件下密封和敞口放置至少6个月晶型未发生变化，在60℃/75％RH条件下密封和敞口放置至少3个月晶型未发生变化。说明晶型CSX原料药在加速条件及更严苛的条件下，具有好的稳定性。季节差异、不同地区气候差异和环境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。因此，原料药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。晶型CSX原料药在苛刻的条件下具有更好的稳定性，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。晶型CSX具有良好的物理稳定性，保证原料药和制剂质量一致可控，减少由于晶型改变引起的药物质量变化，生物利用度变化，和副作用。
同时，晶型CSX具有良好的机械稳定性。晶型CSX在研磨实验前后晶型保持不变。制剂加工过程中常需要将原料药研磨粉碎，良好的物理稳定性能够降低制剂加工过程中原料药结晶度降低和转晶的风险。
(3)本发明提供的晶型CSX具有低的引湿性。测试结果表明，本发明晶型CSX在80％RH条件下引湿性增重仅为0.12％，属于无或几乎无引湿性。
一方面，引湿性高易引发原料药化学降解和晶型转变，直接影响原料药的物理化学稳定性。此外，引湿性高会降低原料药的流动性，影响原料药的加工性能。
另一方面，引湿性高的原料药在生产和储存过程中需要维持低的湿度，对生产提出了更高的要求，需要很高的成本。更重要的是，引湿性高容易造成药物中有效成分含量的变化， 影响药物的质量。
本发明提供的晶型CSX引湿性低，有利于保持原料药的物理化学稳定，对生产和储存的环境要求不苛刻，降低了生产成本，具有很强的经济价值。
本发明提供的晶型CSIV具有以下优势：
(1)与现有技术相比，本发明提供的晶型CSIV具有更优的黏附性。黏附性评价结果表明，现有技术晶型黏附量是晶型CSIV的28倍。
更优的黏附性能有效减少原料药的团聚，能有效改善或者避免干法制粒和片剂压片等环节引起的黏轮、黏冲等现象，有利于原料和辅料混合时原料的分散，提高物料混合时的混合均匀度，最终提高产品质量。
(2)与现有技术相比，本发明提供的晶型CSIV具有更优的可压性。晶型CSIV好的可压性可以有效改善压片工艺中的硬度/脆碎度不合格、裂片等问题，使制剂工艺更为可靠，改善产品外观，提升产品质量和生产效率。
(3)本发明提供的晶型CSIV原料药和制剂均具有良好的稳定性。晶型CSIV原料药在25℃/60％RH条件下放置至少12个月晶型未发生变化。晶型CSIV与辅料混合做成药物制剂后，在25℃/60％RH条件下放置，至少3个月晶型未发生变化。说明晶型CSIV原料药和制剂在长期条件下具有较好的稳定性，有利于药物的储存。
原料药晶型良好的物理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。晶型CSIV具有良好的物理稳定性，保证原料药和制剂质量一致可控，减少由于晶型改变引起的药物质量变化，生物利用度变化，和副作用。
同时，晶型CSIV具有良好的机械稳定性。晶型CSIV在至少14kN压力条件下，晶型保持不变，研磨实验前后晶型保持不变。制剂加工过程中常需要将原料药研磨粉碎，良好的物理稳定性能够降低制剂加工过程中原料药结晶度降低和转晶的风险。在较大压力下，晶型CSIV原料药具有良好的物理稳定性，有利于在制剂压片工艺中保持晶型稳定。
本发明提供的晶型CSV具有以下优势：
(1)与现有技术相比，本发明提供的晶型CSV具有更好的光照稳定性。晶型CSV在25℃/60％RH，光照强度为8k·lux，紫外照度为1.5w/m 2的条件下放置7天，化学纯度保持在99％以上，纯度基本没有变化，杂质个数仅增长两个。现有技术晶型A在25℃/60％RH，光照强度为8k·lux，紫外照度为1.5w/m 2的条件下放置7天，化学纯度由99.30％降低至98.82％，杂质个数由9个增加至20个。
光照实验是药物稳定性研究中的重要部分，对于原料药制备方法的开发和药物的申报具有很重要的指导意义，是药物存储条件和包装选择的依据之一。原料药晶型良好的光照稳定性，可以确保药物在常规生产和存储的过程中不易降解产生杂质。晶型CSV具有良好的光照稳定性，保证原料药和制剂质量一致可控，减少由于原料药降解引起的药物质量变化，生物利用度变化，和副作用。同时，更优的光照稳定性，可以降低生产过程中因避免光照而采取避光操作和存储带来的额外成本。
(2)本发明提供晶型CSV原料药在40℃/75％RH密闭条件下至少放置3个月晶型未发生变化，在60℃/75％RH密闭条件下放置至少3个月晶型未发生变化，说明晶型CSV原料药在加速及更严苛的条件下，具有好的稳定性。季节差异、不同地区气候差异和环境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。因此，原料药 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。晶型CSV原料药在苛刻的条件下具有更好的稳定性，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。晶型CSV具有良好的物理稳定性，保证原料药和制剂质量一致可控，减少由于晶型改变引起的药物质量变化，生物利用度变化，和副作用。
(3)本发明提供的晶型CSV具有低的引湿性。测试结果表明，本发明晶型CSV在80％RH条件下引湿性增重仅为0.10％，属于无或几乎无引湿性。
一方面，引湿性高易引发原料药化学降解和晶型转变，直接影响原料药的物理化学稳定性。此外，引湿性高会降低原料药的流动性，影响原料药的加工性能。
另一方面，引湿性高的原料药在生产和储存过程中需要维持低的湿度，对生产提出了更高的要求，需要很高的成本。更重要的是，引湿性高容易造成药物中有效成分含量的变化，影响药物的质量。
本发明提供的晶型CSV引湿性低，有利于保持原料药的物理化学稳定，对生产和储存的环境要求不苛刻，降低了生产成本，具有很强的经济价值。
附图说明
图1为实施例1制备获得的晶型CSVIII的XRPD图
图2为实施例1制备获得的晶型CSVIII的TGA图
图3为实施例2制备获得的晶型CSVIII的XRPD图
图4为晶型CSVIII单晶结构中一个不对称单元结构图
图5为实施例4制备获得的晶型CSVII的XRPD图
图6为实施例4制备获得的晶型CSVII的TGA图
图7为实施例5制备获得的晶型CSX的XRPD图
图8为实施例6制备获得的晶型CSX的XRPD图
图9为实施例7制备获得的晶型CSX的XRPD图
图10为实施例7制备获得的晶型CSX的TGA图
图11为实施例8制备获得的晶型CSIV的XRPD图
图12为实施例10制备获得的晶型CSV的XRPD图
图13为实施例11制备获得的晶型CSV的XRPD图
图14为实施例12制备获得的晶型CSV的XRPD图
图15为晶型CSVIII在不同储存条件下放置的XRPD对比图(从上至下依次为：放置前，25℃/60％RH密闭放置6个月，25℃/60％RH敞口放置6个月，40℃/75％RH密闭放置6个月，60℃/75％RH密闭放置1个月)
图16为晶型CSVIII压片前后的XRPD对比图(从上到下依次为：压片前，5kN，10kN，20kN)
图17为晶型CSVIII研磨前后的XRPD对比图(上：研磨前；下：研磨后)
图18为晶型CSVIII的DVS图
图19为晶型CSVIII的引湿性测试前后的XRPD对比图(上：DVS前；下：DVS后)
图20为晶型制剂前后的XRPD对比图(从上到下依次为：空白混粉、晶型CSVIII制剂后，晶型CSVIII)
图21为晶型制剂前后的XRPD对比图(从上到下依次为：空白混粉、晶型CSVII制剂后，晶型CSVII)
图22为晶型制剂前后的XRPD对比图(从上到下依次为：空白混粉、晶型CSX制剂后，晶型CSX)
图23为晶型制剂前后的XRPD对比图(从上到下依次为：空白混粉、晶型CSIV制剂后，晶型CSIV)
图24为晶型CSVII在不同储存条件下放置的XRPD对比图(从上至下依次为：放置前，25℃/60％RH密闭放置6个月，25℃/60％RH敞口放置6个月，40℃/75％RH密闭放置6个月，40℃/75％RH敞口放置2个月)
图25为晶型CSVII压片前后的XRPD对比图(从上到下依次为：压片前，5kN，10kN，20kN)
图26为晶型CSVII研磨前后的XRPD对比图(上：研磨前；下：研磨后)
图27为晶型CSVII的DVS图
图28为晶型CSVII的引湿性测试前后的XRPD对比图(上：DVS前；下：DVS后)
图29为晶型CSX在不同储存条件下放置的XRPD对比图(从上至下依次为：放置前，25℃/60％RH密闭放置6个月，25℃/60％RH敞口放置6个月，40℃/75％RH密闭放置6个月，40℃/75％RH敞口放置6个月，60℃/75％RH密闭放置3个月，60℃/75％RH敞口放置3个月)
图30为晶型CSX研磨前后的XRPD对比图(上：研磨前；下：研磨后)
图31为晶型CSX的DVS图
图32为晶型CSX的引湿性测试前后的XRPD对比图(上：DVS前；下：DVS后)
图33为晶型CSIV在不同储存条件下放置的XRPD对比图(从上至下依次为：放置前，25℃/60％RH密闭放置12个月，25℃/60％RH敞口放置12个月)
图34为晶型CSIV压片前后的XRPD对比图(上：压片前；下：14kN)
图35为晶型CSV在储存条件下放置的XRPD对比图(上：40℃/75％RH密闭放置3个月，下：放置前)
图36为晶型CSV在储存条件下放置的XRPD对比图(上：60℃/75％RH密闭放置3个月，下：放置前)
图37为晶型CSV的DVS图
图38为晶型CSV的引湿性测试前后的XRPD对比图(上：DVS前；下：DVS后)
具体实施方式
结合以下实施例对本发明做详细说明，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
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
RH：相对湿度
FaSSIF：模拟禁食状态肠液
UPLC：超高效液相色谱法
LC：液相色谱
PE：聚乙烯
LDPE：低密度聚乙烯
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 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 PCTCN2021116817-appb-000004
1.54060；
Figure PCTCN2021116817-appb-000005
1.54439
Kα2/Kα1强度比例：0.50
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：0-95％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氘代氯仿，配成2-10mg/mL的溶液。
本发明所述单晶X射线衍射(SC-XRD)使用配有CMOS区域探测器和Mo Kα放射
Figure PCTCN2021116817-appb-000006
Figure PCTCN2021116817-appb-000007
的微焦斑封闭X射线发生器的Bruker D8QUEST衍射器收集单晶X射线衍射数据。在数据收集时，所述单晶处在193K。
本发明所述动态溶解度测试参数如表2所示：
表2
Figure PCTCN2021116817-appb-000008
Figure PCTCN2021116817-appb-000009
本发明所述实施例33现有技术晶型A的纯度测试参数如表3所示：
表3
Figure PCTCN2021116817-appb-000010
本发明所述实施例33晶型CSV的纯度测试参数如表4所示：
表4
Figure PCTCN2021116817-appb-000011
Figure PCTCN2021116817-appb-000012
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“分离”，采用本领域的常规方法完成，例如离心或过滤。“离心”的操作为：将欲分离的样品置于离心管中，以10000转/分的速率进行离心，至固体全部沉至离心管底部。
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“旋转蒸发”，采用本领域的常规方法完成，例如旋转蒸发的操作是：将装有溶液的烧瓶在一定温度，一定负压的条件下恒速旋转以蒸发溶剂。
所述“挥发”，采用本领域的常规方法完成，例如缓慢挥发或快速挥发。缓慢挥发是将容器封上封口膜，扎孔，静置挥发；快速挥发是将容器敞口放置挥发。
所述“室温”不是特定的温度值，是指10-30℃温度范围。
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“LC”包含HPLC和UPLC。
所述稳定性考察条件，温度约有±2℃的误差范围，湿度约有±5％RH的误差范围。
本发明中，“晶体”或“多晶型”指被X射线粉末衍射图表征证实的固体。本领域技术人员能够理解，这里所讨论的理化性质可以被表征，其中的实验误差取决于仪器的条件、样品的准备和样品的纯度。特别是，本领域技术人员公知，X射线粉末衍射图通常会随着仪器条件的不同而有所改变。特别需要指出的是，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，所以衍射峰强度的顺序不能作为唯一或决定性因素。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。另外，衍射峰位置的实验误差通常在5％或更少，这些位置的误差也应该被考虑进去，通常允许有±0.2°的误差。另外，由于样品厚度等实验因素的影响，会造成衍射峰角度的整体偏移，通常允许一定的偏移。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CSⅧ、晶型CSVII、晶型CSX、晶型CSIV、晶型CSV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％。
除非特殊说明，以下实施例均在室温条件下操作。
根据本发明，作为原料的所述化合物I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，作为原料的化合物I为固体形式。
以下实施例中所使用的化合物I可根据现有技术制备得到，例如根据WO2020079203A1专利所记载的方法制备获得。
实施例1-2：晶型CSⅧ的制备
实施例1
称量如表5所示质量的化合物I固体和香兰素固体于玻璃小瓶中，向其中加入表5中所示的溶剂，室温搅拌后离心分离，干燥得到结晶固体。
表5
Figure PCTCN2021116817-appb-000013
经检测，所得结晶固体均为晶型CSⅧ，其中样品1的XRPD数据如表6，XRPD图如图1所示。
样品1的TGA如图2所示，将其加热至80℃时，具有约5.2％的质量损失；从80℃加热至200℃时，具有约26.2％的质量损失。
晶型CSVIII为水合物。
晶型CSVIII的 1H NMR数据为： 1H NMR(400MHz,CDCl 3)δ9.82(s,1H),8.44(d,J ＝2.5Hz,1H),7.93(s,1H),7.80(s,1H),7.77–7.65(m,2H),7.42–7.40(m,2H),7.37(s,1H),7.04(d,J＝8.3Hz,1H),3.96(s,3H),3.30–3.23(m,2H),3.20–3.17(m,2H),3.08(s,2H),2.73(s,3H),2.54(s,3H),0.78–0.64(m,4H).其中：香兰素酚羟基上的活泼氢和化合物I哌嗪基上的活泼氢未出峰。
表6
衍射角2θ d值 强度％
5.15 17.17 29.30
7.53 11.75 3.49
8.98 9.85 8.63
9.26 9.55 19.99
12.59 7.03 100.00
13.62 6.50 6.16
14.04 6.31 4.74
15.53 5.71 5.60
16.09 5.51 11.83
16.35 5.42 15.77
17.04 5.20 12.35
18.01 4.92 5.90
18.93 4.69 7.45
19.96 4.45 1.32
20.36 4.36 1.58
21.38 4.16 5.00
21.87 4.06 17.16
22.18 4.01 8.06
23.53 3.78 4.60
24.47 3.64 3.62
25.29 3.52 44.65
25.77 3.46 15.41
26.84 3.32 11.63
27.37 3.26 3.07
28.49 3.13 2.59
29.79 3.00 6.80
30.48 2.93 1.23
31.85 2.81 1.18
32.34 2.77 1.56
33.07 2.71 0.79
34.00 2.64 1.70
35.01 2.56 1.08
实施例2
称量23.2mg化合物I固体和9.5mg香兰素固体于玻璃小瓶中，向其中加入0.3mL的水，5℃下悬浮搅拌过夜，离心分离出固体。将所得固体放入小瓶中，用铝箔袋密闭封装，并在60℃/75％RH条件下放置一周，得到固体。
经检测，所得固体为晶型CSⅧ，其XRPD图如图3所示，XRPD数据如表7所示。
表7
衍射角2θ d值 强度％
5.13 17.23 24.78
7.54 11.73 4.59
8.99 9.84 10.51
9.27 9.54 26.50
12.59 7.03 100.00
13.64 6.49 9.01
14.03 6.31 7.70
15.52 5.71 4.54
16.17 5.48 18.31
16.37 5.41 22.03
16.75 5.29 11.68
17.04 5.20 10.38
18.01 4.93 7.65
18.93 4.69 11.00
20.38 4.36 2.53
21.37 4.16 4.76
21.86 4.07 14.67
22.16 4.01 9.00
23.53 3.78 5.85
24.49 3.63 3.80
25.27 3.52 60.57
25.75 3.46 21.55
26.83 3.32 19.64
27.36 3.26 3.15
28.51 3.13 3.55
29.77 3.00 6.08
30.55 2.93 1.17
32.38 2.77 2.00
33.11 2.71 1.36
34.01 2.64 1.87
34.99 2.56 1.25
实施例3：晶型CSⅧ单晶的制备
称量40.3mg化合物I固体和30.4mg香兰素固体，向其中加入4.1mL氯仿/水(40:1,v/v)混合溶剂，得到澄清溶液。然后取0.68mL的澄清溶液置于小瓶中，盖上扎有小孔的盖子，将其置于装有3.5mL正己烷的玻璃瓶中，密闭，随后将样品在室温下静置，直至析出固体。
经XRPD检测，获得固体为晶型CSVIII。收集晶型CSVIII的X射线单晶衍射数据，经解析，其晶胞参数如表8所示，其不对称单元的结构如图4所示。结果表明：晶型CSVIII的一个不对称单元中包括1个化合物I分子，一个香兰素分子和一个水分子，晶型CSVIII为化合物I香兰素共晶的一水合物。
表8
Figure PCTCN2021116817-appb-000014
实施例4：晶型CSⅦ的制备
称量23.2mg化合物I固体和9.5mg香兰素固体于玻璃小瓶中，向其中加入0.3mL的水，5℃下悬浮搅拌过夜，离心分离出固体，将固体放置于30℃下真空干燥2小时，得到固体。
经检测，所得固体为晶型CSⅦ，其XRPD图如图5所示，XRPD数据如表9所示。
TGA如图6所示，将其加热至70℃时，具有约9.0％的质量损失，对应水的失去。从70℃加热到130℃时，具有约8.6％的质量损失，从130℃加热到250℃时，具有约16.0％的质量损失，对应香兰素的失去，晶型CSVII为共晶水合物。
晶型CSVII的 1H NMR数据为： 1H NMR(400MHz,CDCl 3)δ9.83(s,1H),8.45(d,J＝2.5Hz,1H),7.93(q,J＝1.1Hz,1H),7.80(d,J＝1.0Hz,1H),7.77–7.66(m,2H),7.44–7.41(m,2H),7.38(s,1H),7.04(d,J＝8.5Hz,1H),3.97(s,3H),3.27–3.24(m,2H),3.20–3.17(m,2H),3.08(s,2H),2.73(d,J＝1.1Hz,3H),2.55(s,3H),0.80–0.65(m,4H).其中：香兰素酚羟基上的活泼氢和化合物I哌嗪基上的活泼氢未出峰。
表9
衍射角2θ d值 强度％
5.95 14.85 2.51
7.51 11.78 15.73
9.08 9.74 71.62
10.08 8.77 2.43
11.94 7.41 14.85
12.55 7.05 2.24
13.43 6.59 3.71
14.26 6.21 2.38
15.12 5.86 6.14
15.62 5.67 100.00
16.81 5.27 2.23
17.97 4.94 16.09
18.24 4.86 9.34
20.25 4.38 4.39
20.64 4.30 6.62
21.38 4.16 5.79
22.27 3.99 1.83
22.85 3.89 14.54
23.58 3.77 4.69
24.07 3.70 5.80
24.54 3.63 12.90
25.14 3.54 6.69
26.04 3.42 3.85
26.76 3.33 9.28
27.14 3.29 10.99
27.53 3.24 13.11
28.82 3.10 2.83
30.37 2.94 3.40
31.55 2.84 3.20
32.43 2.76 2.54
33.85 2.65 1.26
36.03 2.49 1.79
36.45 2.47 1.82
36.99 2.43 1.54
38.62 2.33 1.83
实施例5-7：晶型CSX的制备
实施例5
称取一定质量的化合物I固体，溶解于表10中一定体积的正溶剂中，过滤，取一定体积的滤液，在一定温度下边搅拌边向滤液中逐滴加入反溶剂(环己烷)，停止搅拌，在一定温度下静置一定时间后，分离出固体，干燥，得到结晶固体。表10中实施例所得的固体分别标记为样品1-4，经检测，样品1-4均为化合物I的晶型CSX。
表10
Figure PCTCN2021116817-appb-000015
样品1的XRPD图如图7所示，XRPD数据如表11所示。
表11
衍射角2θ d值 强度％
7.27 12.16 65.73
8.25 10.72 2.11
10.41 8.50 100.00
13.24 6.69 87.92
14.60 6.07 5.24
14.89 5.95 8.42
15.33 5.78 5.87
16.39 5.41 9.51
16.59 5.34 3.08
18.27 4.86 6.52
18.50 4.79 3.60
19.78 4.49 5.60
20.92 4.25 1.88
21.99 4.04 8.72
22.29 3.99 2.27
22.73 3.91 1.35
23.66 3.76 0.92
24.46 3.64 0.73
25.22 3.53 13.13
26.68 3.34 1.23
27.30 3.27 1.75
32.07 2.79 0.30
33.15 2.70 0.84
33.53 2.67 0.63
37.08 2.42 5.02
实施例6
称取一定质量的化合物I固体，溶解于表12中一定体积的正溶剂(氯仿)中，过滤，取一定体积的滤液，室温条件下将该滤液边搅拌边滴加到反溶剂(环己烷)中，析出固体，停止搅拌，在一定温度下静置一定时间后，分离固体，干燥，得到化合物I结晶固体。表12中实施例所得的固体分别标记为样品1-5，经检测，样品1-5为化合物I晶型CSX。
表12
Figure PCTCN2021116817-appb-000016
Figure PCTCN2021116817-appb-000017
样品2的XRPD图如图8所示，XPRD数据如表13所示。
表13
衍射角2θ d值 强度％
7.28 12.15 41.48
8.26 10.71 2.29
10.41 8.50 100.00
13.24 6.69 67.14
14.61 6.06 2.31
14.89 5.95 13.24
15.33 5.78 8.34
16.41 5.40 5.60
16.59 5.34 3.54
18.11 4.90 2.63
18.51 4.79 4.26
19.77 4.49 3.58
20.93 4.25 1.95
21.99 4.04 4.84
22.73 3.91 2.22
23.67 3.76 1.20
25.21 3.53 5.42
25.30 3.53 5.00
26.64 3.34 1.27
27.18 3.28 0.91
29.05 3.07 0.60
30.05 2.97 0.87
32.04 2.79 0.40
33.51 2.67 0.50
37.06 2.42 2.06
实施例7
称取634.9mg的化合物I固体，溶解于50mL的氯仿/水饱和的氯仿(1:1,v/v)中，过滤，将所得滤液加入到200mL的环己烷中，析出固体后，停止搅拌，并将其置于-20℃下静置20min，分离固体，于50℃真空干燥过夜，得到结晶固体。
经XRPD检测，所得结晶固体为本发明所述的晶型CSX。其XRPD图如图9，XRPD数据如表14所示。
TGA如图10所示，将晶型CSX加热至120℃时，具有约2.1％的质量损失。
表14
衍射角2θ d值 强度％
7.28 12.15 21.87
8.27 10.69 2.31
10.41 8.50 100.00
13.23 6.69 71.30
14.89 5.95 13.19
15.34 5.78 8.30
16.42 5.40 7.76
18.11 4.90 4.09
18.50 4.80 5.89
19.78 4.49 4.58
20.92 4.25 2.16
21.98 4.04 2.90
22.72 3.91 2.46
23.67 3.76 1.16
25.26 3.53 10.21
26.66 3.34 1.80
27.20 3.28 1.84
28.38 3.14 0.81
29.98 2.98 0.66
32.05 2.79 0.46
33.46 2.68 0.59
37.07 2.43 0.79
实施例8：晶型CSIV的制备
称取391.5mg化合物I固体，溶解于16.0mL的甲醇/二氯甲烷(1:1,v/v)混合溶剂中，得到澄清溶液，过滤后将滤液在40℃下旋蒸，得到固体。
经检测，所得固体为晶型CSIV。晶型CSIV的XRPD数据如表15，XRPD图如图11所示。
表15
衍射角2θ d值 强度％
4.93 17.93 66.02
6.97 12.69 3.71
9.37 9.44 1.59
9.92 8.91 1.87
10.41 8.50 3.13
11.74 7.54 100.00
12.51 7.07 3.43
13.09 6.77 7.28
14.23 6.22 21.02
14.81 5.98 6.01
15.52 5.71 3.33
17.73 5.00 7.22
19.10 4.65 2.37
19.99 4.44 1.39
21.78 4.08 1.93
23.54 3.78 2.90
24.82 3.59 11.70
25.26 3.53 11.85
25.85 3.45 8.89
26.38 3.38 8.42
27.00 3.30 6.83
27.68 3.22 2.01
29.92 2.99 0.92
实施例9：晶型CSIV的制备
称取207.2mg化合物I固体，溶解于12.0mL的甲醇/二氯甲烷(1:1,v/v)混合溶剂中，得到澄清溶液，过滤后将滤液在40℃下旋蒸，得到固体。
经检测，所得固体为晶型CSIV。晶型CSIV的X射线粉末衍射图在2θ值为4.9°±0.2°、11.7°±0.2°、14.2°±0.2°处有特征峰。
实施例10-12：晶型CSV的制备
实施例10
称取10.1mg的化合物I固体，溶解于20.0mL的二氯甲烷/乙酸异丙酯(3:1,v/v)混合溶剂中，过滤后将滤液在室温下敞口挥发4天，得到结晶固体。
经检测，所得结晶固体为晶型CSV，其XRPD数据如表16，XRPD图如图12所示。
表16
衍射角2θ d值 强度％
7.66 11.54 43.29
10.47 8.45 79.94
13.39 6.61 100.00
16.58 5.35 6.42
18.53 4.79 6.21
19.22 4.62 9.62
22.39 3.97 16.82
22.81 3.90 21.38
24.53 3.63 41.60
27.53 3.24 5.25
30.44 2.94 7.67
37.65 2.39 25.60
实施例11
称取9.7mg的化合物I固体，溶解于20mL的二氯甲烷/乙酸异丙酯(3:1,v/v)混合溶剂中，过滤后将澄清溶液在5℃下敞口挥发10天，得到结晶固体。
经检测，所得结晶固体为晶型CSV，其XRPD数据如表17，XRPD图如图13所示。
表17
衍射角2θ d值 强度％
7.67 11.53 38.00
10.47 8.45 67.50
13.40 6.61 73.10
16.54 5.36 5.42
18.52 4.79 6.24
19.20 4.62 6.88
22.38 3.97 15.44
22.79 3.90 18.31
24.57 3.62 100.00
30.42 2.94 5.79
37.64 2.39 20.76
实施例12
称取0.13g化合物I于玻璃瓶中，加入200mL二氯甲烷/乙酸异丙酯(3:1,v/v)溶剂，室温下溶清，过滤后取20mL溶液在室温下挥发，得到的固体在30℃下真空干燥半小时，得结晶固体。
经检测，所得结晶固体为晶型CSV，其XRPD图如图14所示，XRPD数据如表18所示。
晶型CSV的 1H NMR数据为： 1H NMR(400MHz,CDCl 3)δ8.45(d,J＝2.4Hz,1H),7.93(d,J＝1.0Hz,1H),7.80(d,J＝0.7Hz,1H),7.75-7.68(m,2H),7.38(s,1H),3.33–3.23(m,2H),3.24–3.15(m,2H),3.09(s,2H),2.74(d,J＝0.9Hz,3H),2.55(s,3H),0.80-0.65(m,4H)。
表18
衍射角2θ d值 强度％
7.67 11.53 100.00
10.45 8.47 30.79
11.54 7.67 3.16
13.39 6.61 31.69
14.81 5.98 3.95
15.43 5.74 4.18
16.56 5.35 2.35
18.48 4.80 2.74
19.22 4.62 4.38
20.20 4.40 1.72
22.37 3.97 6.41
22.75 3.91 5.12
24.58 3.62 69.69
26.22 3.40 1.88
27.65 3.23 2.37
30.44 2.94 1.73
37.65 2.39 4.21
38.19 2.36 1.39
实施例13：晶型CSVIII与现有技术晶型A的动态溶解度
进行药物溶解度测试以预测药物体内性能的时候，很重要的一点是尽可能的模拟体内条件。对口服药，用FaSSIF(模拟禁食状态肠液)可以模拟体内条件。在此介质中测试的溶解度与人体环境中的溶解度更加接近。取本发明的晶型CSVIII及现有技术晶型A各25mg分别分散在2.5mL的FaSSIF中配制成饱和溶液，平衡1小时、4小时后分别用液相色谱法测试饱和溶液中样品的含量(mg/mL)，结果如表19所示。
表19
Figure PCTCN2021116817-appb-000018
结果表明，晶型CSVIII在生物介质中平衡1小时和4小时后具有更高的溶解度，溶解度分别是现有技术晶型A的13倍和18倍。
实施例14：晶型CSⅧ与现有技术晶型A的黏附性
分别将约30mg晶型CSVIII与现有技术晶型A加入到8mm圆形平冲中，采用10kN的压力进行压片，保持约半分钟，称量冲头吸附的粉末量。记录压制过程中冲头的最高黏附量和平均黏附量。实验结果见表20。
设备：ENERPAC手动压片机
参数：30mg，Φ8mm圆形平冲，10kN压力
表20
晶型 最高黏附量(mg) 平均黏附量(mg)
现有技术晶型A 4.4 2.8
晶型CSVIII 0.4 0.3
结果表明，现有技术晶型A的平均黏附量约为本发明晶型CSVIII的10倍，晶型CSVIII的黏附性远优于现有技术晶型A。
实施例15：晶型CSⅧ的稳定性
称取一定量本发明制备得到的晶型CSVIII，分别放置在25℃/60％RH、40℃/75％RH、60℃/75％RH条件下，采用XRPD测定晶型。结果如表21所示，XRPD对比图如图15所示。
表21
放置条件 包装条件 放置时间 晶型
25℃/60％RH 玻璃瓶+铝箔袋密封 6个月 晶型CSVIII
25℃/60％RH 敞口 6个月 晶型CSVIII
40℃/75％RH 玻璃瓶+铝箔袋密封 6个月 晶型CSVIII
60℃/75％RH 玻璃瓶+铝箔袋密封 1个月 晶型CSVIII
结果表明，晶型CSVIII在25℃/60％RH条件下至少可稳定6个月，在40℃/75％RH条件下可稳定至少6个月，可见，晶型CSVIII在长期和加速条件下均可保持良好的稳定性。在60℃/75％RH条件下放置至少可稳定一个月，可见在更严苛的条件下稳定性也很好。
实施例16：晶型CSⅧ的机械稳定性
压力稳定性：
取适量晶型CSVIII，选择直径为6毫米的圆形平冲，在不同压力下压制成形，压片前后进行XRPD测试，测试结果如表22所示，压片前后XRPD对比图如图16所示。结果表明，在不同的压力下，晶型CSVIII具有很好的稳定性。
表22
Figure PCTCN2021116817-appb-000019
研磨稳定性：
将晶型CSVIII置于研钵中，手动研磨5分钟，研磨前后进行XRPD测试，测试结果如图17所示。结果表明，晶型CSVIII具有很好的研磨稳定性。
实施例17：晶型CSⅧ的引湿性
取适量本发明晶型CSⅧ，采用动态水分吸附(DVS)仪测试其引湿性，在60％- 95％-0-95％相对湿度下循环一次，记录每个湿度下的质量变化。晶型CSVIII的DVS图如图18所示，其在60％RH-80％RH条件下平衡后增重0.14％，为无或几乎无引湿性。晶型CSVIII引湿性前后的XRPD对比图如图19所示，在DVS测试前后，晶型CSVIII不转晶，稳定性较好。
关于引湿性特征描述与引湿性增重的界定(中国药典2020年版通则9103药物引湿性试验指导原则，实验条件：25℃±1℃，80％±2％相对湿度)：
潮解：吸收足量水分形成液体
极具引湿性：引湿增重不小于15.0％
有引湿性：引湿增重小于15.0％但不小于2.0％
略有引湿性：引湿增重小于2.0％但不小于0.2％
无或几乎无引湿性：引湿增重小于0.2％
(欧洲药典第九版5.11中对引湿性的界定与中国药典类似)
实施例18：晶型CSVII、CSⅧ、CSX、CSIV的制剂制备
晶型CSVIII、CSⅧ、CSX、CSIV的制剂处方和制剂工艺分别如表23和表24所示。
1.制剂处方
表23
Figure PCTCN2021116817-appb-000020
2.制剂工艺
表24
Figure PCTCN2021116817-appb-000021
Figure PCTCN2021116817-appb-000022
测试空白混粉和制剂处方前后样品的XRPD，结果表明，晶型CSVIII(图20)、晶型CSVII(图21)、晶型CSX(图22)和晶型CSIV(图23)在制剂处方工艺前后晶型保持不变。
实施例19：晶型CSVII、CSⅧ、CSX、CSIV的制剂中的稳定性
将晶型CSVII、CSⅧ、CSX、CSIV制剂分别放置于25℃/60％的条件下并取样检测晶型，结果显示晶型CSVII、CSⅧ、CSX、CSIV制剂放置至少3个月晶型保持不变。
实施例20：晶型CSVII与现有技术晶型A的动态溶解度
进行药物溶解度测试以预测药物体内性能的时候，很重要的一点是尽可能的模拟体内条件。对口服药，用FaSSIF(模拟禁食状态肠液)可以模拟体内条件。在此介质中测试的溶解度与人体环境中的溶解度更加接近。取本发明的晶型CSVII及现有技术晶型A各25mg分别分散在2.5mL的FaSSIF中配制成饱和溶液，平衡1小时、4小时后分别液相色谱法测试饱和溶液中样品的含量(mg/mL)()，结果如表25所示。
表25
Figure PCTCN2021116817-appb-000023
结果表明，与现有技术晶型A相比，晶型CSVII在生物介质中平衡1小时和4小时后具有更高的溶解度，分别是现有技术晶型A的7倍和10倍。
实施例21：晶型CSVII与现有技术晶型A的黏附性
分别将约30mg晶型CSVII与现有技术晶型A加入到8mm圆形平冲中，采用10kN的压力进行压片，保持约半分钟，称量冲头吸附的粉末量。记录压制过程中冲头的最高黏附量和平均黏附量。具体的实验结果见表26。
设备：ENERPAC手动压片机
参数：30mg，Φ8mm圆形平冲，10kN压力
表26
晶型 最高黏附量(mg) 平均黏附量(mg)
现有技术晶型A 4.4 2.8
晶型CSVII 1.5 0.9
实验结果表明，现有技术晶型平均黏附量是本发明晶型CSVII的约3倍，晶型CSVII的黏附性远优于现有技术晶型。
实施例22：晶型CSVII的稳定性
称取一定量本发明制备得到的晶型CSVII，分别放置在25℃/60％RH、40℃/75％RH条件下，采用XRPD测定晶型。结果如表27所示，XRPD对比图如图24所示。
表27
放置条件 包装条件 放置时间 晶型
25℃/60％RH 玻璃瓶+铝箔袋密封 6个月 晶型CSVII
25℃/60％RH 敞口 6个月 晶型CSVII
40℃/75％RH 玻璃瓶+铝箔袋密封 6个月 晶型CSVII
40℃/75％RH 敞口 2个月 晶型CSVII
结果表明，晶型CSVII在25℃/60％RH条件下至少可稳定6个月，40℃/75％RH条件下密闭至少可稳定6个月，在40℃/75％RH条件下敞口至少可稳定2个月，可见，晶型CSVII在长期和加速条件下均可保持良好的稳定性。
实施例23：晶型CSVII的机械稳定性
压力稳定性：
取适量晶型CSVII，选择直径为6毫米的圆形平冲，在不同压力下压制成形，压片前后进行XRPD测试，测试结果如表28所示，压片前后对比图如图25所示。结果表明，在不同的压力下，晶型CSVII具有很好的稳定性。
表28
Figure PCTCN2021116817-appb-000024
研磨稳定性：
将晶型CSVII置于研钵中，手动研磨5分钟，研磨前后进行XRPD测试，测试结果如图26所示。结果表明，晶型CSVII具有很好的研磨稳定性。
实施例24：晶型CSVII的引湿性
取适量本发明晶型CSVII，采用动态水分吸附(DVS)仪测试其引湿性，在70％-95％-0-95％相对湿度下循环一次，记录每个湿度下的质量变化。晶型CSVII的DVS图如图27所示，其在60％RH～80％RH条件下平衡后增重0.53％，为略有引湿性。晶型CSVII引湿性前后的XRPD对比图如图28所示，在DVS测试前后，晶型CSVII不转晶，稳定性较好。
实施例25：晶型CSX与现有技术晶型A的动态溶解度
进行药物溶解度测试以预测药物体内性能的时候，很重要的一点是尽可能的模拟体内条件。对口服药，用FaSSIF(模拟禁食状态肠液)可以模拟体内条件。在此介质中测试的溶解 度与人体环境中的溶解度更加接近。取本发明的晶型CSX及现有技术晶型A各25mg分别分散在2.5mL的FaSSIF中配制成饱和溶液，平衡1小时、4小时后分别用液相色谱法测试饱和溶液中样品的含量(mg/mL)，结果如表29所示。
表29
Figure PCTCN2021116817-appb-000025
结果表明，与现有技术晶型A相比，晶型CSX在FaSSIF中平衡1小时和4小时后具有更高的溶解度，分别是现有技术晶型A的11倍和15倍。
实施例26：晶型CSX的稳定性
称取一定量本发明制备得到的晶型CSX，分别放置在25℃/60％RH、40℃/75％RH、60℃/75％RH条件下，采用XRPD测定晶型。结果如表30所示，XRPD对比图如图29所示。
表30
Figure PCTCN2021116817-appb-000026
结果表明，晶型CSX在25℃/60％RH和40℃/75％RH条件下至少可稳定6个月，可见，晶型CSX在长期和加速条件下均可保持良好的稳定性。60℃/75％RH条件下放置至少可稳定3个月，可见在更严苛的条件下稳定性也很好。
实施例27：晶型CSX的机械稳定性
将晶型CSX置于研钵中，手动研磨5分钟，研磨前后进行XRPD测试，测试结果如图30所示。结果表明，晶型CSX具有很好的研磨稳定性。
实施例28：晶型CSX的引湿性
取适量本发明晶型CSX，采用动态水分吸附(DVS)仪测试其引湿性，在40％-95％-0-95％相对湿度下循环一次，记录每个湿度下的质量变化。晶型CSX的DVS图如图31所示，其在60％RH-80％RH条件下平衡后增重0.12％，为无或几乎无引湿性。晶型CSX引湿性前后的XRPD对比图如图32所示，在DVS测试前后，晶型CSX不转晶，稳定性较好。
实施例29：晶型CSIV与现有技术晶型A的黏附性
分别将约30mg晶型CSIV和现有技术晶型A加入到8mm圆形平冲中，采用10kN的压力进行压片，保持约半分钟，称量冲头吸附的粉末量。记录压制过程中冲头的最高黏附量和平均黏附量。具体的实验结果见表31。
设备：ENERPAC手动压片机
参数：30mg，Φ8mm圆形平冲，10kN压力
表31
晶型 最高黏附量(mg) 平均黏附量(mg)
现有技术晶型A 4.4 2.8
晶型CSIV 0.20 0.10
结果表明，现有技术晶型A平均黏附量是本发明晶型CSIV的28倍，晶型CSIV黏附性远优于现有技术晶型。
实施例30：晶型CSIV与现有技术晶型A的可压性
采用手动压片机进行压片，压片时，选择Φ6mm圆形平冲，分别加入80mg晶型CSⅣ、现有技术晶型A，采用10kN的压力压制成圆形片剂，室温放置24h，待完全弹性复原后，采用游标卡尺测量片剂的直径(D)和厚度(L)，采用片剂硬度测定仪测试其径向破碎力(硬度，H)。利用公式T＝2H/πDL计算粉体的抗张强度。在一定的压力下，抗张强度越大的，表示其可压性越好。结果如下表32所示。
设备：ENERPAC手动压片机
数据和结论：晶型CSⅣ相比现有技术晶型A抗张强度更优。有更优的的可压性。
表32
晶型 厚度(mm) 直径(mm) 硬度(kgf) 抗张强度(MPa)
现有技术晶型A 2.26 6.06 2.83 1.29
晶型CSⅣ 2.25 6.07 3.15 1.44
实施例31：晶型CSIV的稳定性
称取一定量本发明制备得到的晶型CSIV，放置在25℃/60％RH条件下，采用XRPD测定晶型。结果如表33所示，XRPD对比图如图33所示。
表33
Figure PCTCN2021116817-appb-000027
结果表明，晶型CSIV在25℃/60％RH条件下至少可稳定12个月，可见，晶型CSIV在长期储存条件下可保持良好的稳定性。
实施例32：晶型CSIV的机械稳定性
压力稳定性：
取适量晶型CSIV，选择直径为6毫米的圆形平冲，在14kN压力下压制成形，压片前后 进行XRPD测试，压片前后对比图如图34所示。结果表明，在14kN压力下，晶型CSIV具有很好的稳定性。
研磨稳定性：
将晶型CSIV置于研钵中，手动研磨5分钟，研磨前后进行XRPD测试，结果表明，晶型CSIV研磨前后晶型不变，具有很好的研磨稳定性。
实施例33：晶型CSV和现有技术晶型A的光照稳定性
取适量本发明晶型CSV和现有技术晶型A，分别平铺分散在自封袋中，然后放于光照箱中，于7天后取样。箱体温湿度设置为25℃/60％RH，光照强度为8k·lux，紫外照度为1.5w/m 2。采用LC测定光照前后本发明的晶型CSV及现有技术晶型A的化学纯度，测试结果如表34所示。
表34
Figure PCTCN2021116817-appb-000028
结果表明：光照一周后，晶型CSV的纯度基本不变，杂质个数基本没有增长，现有技术晶型A纯度有明显下降，杂质个数由原来的9个增加至20个。晶型CSV有更好的光照稳定性。
实施例34：晶型CSV的稳定性
称取一定量本发明制备得到的晶型CSV，分别放置在40℃/75％RH、60℃/75％RH条件下，采用XRPD测定晶型。结果如表35所示，XRPD对比图如图35，36所示。
表35
放置条件 包装条件 放置时间 晶型
40℃/75％RH 单层PE袋+铝箔袋密封 3个月 晶型CSV
60℃/75％RH 单层PE袋+铝箔袋密封 3个月 晶型CSV
结果表明，晶型CSV在40℃/75％RH和60℃/75％RH条件下至少可稳定3个月，可见，晶型CSV在加速条件和更苛刻的条件下均可保持良好的稳定性。
实施例35：晶型CSV的引湿性
取适量本发明晶型CSV，采用动态水分吸附(DVS)仪测试其引湿性，在50％-95％-0-95％相对湿度下循环一次，记录每个湿度下的质量变化。晶型CSV的DVS图如37所示，其在60％-80％RH条件下平衡后增重0.10％，为无或几乎无引湿性。晶型CSV引湿性测试前后的XRPD对比图如38所示，在DVS测试前后，晶型CSV不转晶，稳定性较好。
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 (46)

  1. 化合物I的共晶，其特征在于，所述共晶是化合物I和香兰素的共晶
    Figure PCTCN2021116817-appb-100001
  2. 根据权利要求1所述的共晶，其特征在于，所述共晶为水合物。
  3. 根据权利要求1所述的共晶，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为5.1°±0.2°、12.6°±0.2°、25.3°±0.2°处具有特征峰。
  4. 根据权利要求3所述的共晶，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为9.3°±0.2°、21.9°±0.2°、26.8°±0.2°的至少一处有特征峰。
  5. 根据权利要求3所述的共晶，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为7.5°±0.2°、13.6°±0.2°、29.8°±0.2°的至少一处具有特征峰。
  6. 根据权利要求4所述的共晶，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为7.5°±0.2°、13.6°±0.2°、29.8°±0.2°的至少一处具有特征峰。
  7. 根据权利要求1所述的共晶，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图基本如图1所示。
  8. 权利要求3所述的共晶的制备方法，其特征在于：
    (1)将化合物I固体和香兰素固体置于水，水和芳香烃类的混合溶剂，水、卤代烃类和烷烃类的混合溶剂，或水、腈类和烷烃类的混合溶剂中，室温条件下搅拌，分离固体，干燥得到化合物I的共晶；或
    (2)将化合物I固体和香兰素固体置于水中搅拌，分离固体，将所得固体密封，放置一段时间得到化合物I的共晶。
  9. 根据权利要求8所述的制备方法，其特征在于，方法(1)中所述化合物I固体和香兰素固体的摩尔投料比为1:1-1:4；方法(2)中所述化合物I固体和香兰素固体的摩尔投料比为1:1-1:2。
  10. 根据权利要求8所述的制备方法，其特征在于，所述搅拌的时间不小于1小时；方法(2)所述放置的时间不少于2天，所述放置的条件为温度50-70℃，湿度70-90％RH。
  11. 根据权利要求8所述的制备方法，其特征在于，方法(2)中所述搅拌的温度为低于10℃。
  12. 根据权利要求8所述的制备方法，其特征在于，所述芳香烃类溶剂为甲苯，所述卤代烃类溶剂为二氯甲烷，所述烷烃类溶剂为正庚烷，所述腈类溶剂为乙腈，所述混合溶剂中水的体积分数为1％-10％。
  13. 根据权利要求1所述的共晶，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为7.5°±0.2°、9.1°±0.2°、15.6°±0.2°处具有特征峰。
  14. 根据权利要求13所述的共晶，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为22.9°±0.2°、18.2°±0.2°、11.9°±0.2°的至少一处具有特征峰。
  15. 根据权利要求13所述的共晶，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为6.0°±0.2°、24.5°±0.2°、27.5°±0.2°的至少一处具有特征峰。
  16. 根据权利要求14所述的共晶，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为6.0°±0.2°、24.5°±0.2°、27.5°±0.2°的至少一处具有特征峰。
  17. 根据权利要求1所述的共晶，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图基本如图5所示。
  18. 权利要求13所述的共晶的制备方法，其特征在于：将化合物I固体和香兰素固体置于水中搅拌，分离固体，干燥得到化合物I的共晶，其中，所述搅拌的温度为低于10℃。
  19. 根据权利要求18所述的制备方法，其特征在于，所述化合物I固体和香兰素固体的摩尔投料比为1:1-1:2，所述搅拌的时间不小于1小时。
  20. 一种化合物I的晶型CSX，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为7.3°±0.2°、10.4°±0.2°、13.2°±0.2°、22.0°±0.2°处有特征峰
    Figure PCTCN2021116817-appb-100002
  21. 根据权利要求20所述的晶型CSX，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为14.9°±0.2°、15.3°±0.2°、25.2°±0.2°的至少一处具有特征峰。
  22. 根据权利要求20所述的晶型CSX，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为19.8°±0.2°处具有特征峰。
  23. 根据权利要求21所述的晶型CSX，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为19.8°±0.2°处具有特征峰。
  24. 根据权利要求20所述的晶型CSX，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图基本如图7所示。
  25. 权利要求20所述的化合物I的晶型CSX的制备方法，其特征在于：将化合物I固体溶于卤代烃类或含水的卤代烃类溶剂中，过滤，将滤液加入烃类溶剂中搅拌，或者将烃类溶剂加入该滤液中搅拌，析出固体，分离，得到化合物I的晶型CSX。
  26. 根据权利要求25所述的制备方法，其特征在于，所述卤代烃为碳原子数C1-C3的卤代烃，所述烃类为碳原子数C5-C8的烃。
  27. 根据权利要求26所述的制备方法，其特征在于，所述烃类溶剂为烷烃。
  28. 根据权利要求27所述的制备方法，其特征在于，所述烷烃为环己烷、正己烷或正庚烷。
  29. 根据权利要求26所述的制备方法，其特征在于，所述卤代烃为氯仿或二氯甲烷。
  30. 一种化合物I的晶型CSIV，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为4.9°±0.2°、11.7°±0.2°、14.2°±0.2°处有特征峰
    Figure PCTCN2021116817-appb-100003
  31. 根据权利要求30所述的晶型CSIV，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图基本如图11所示。
  32. 权利要求30所述的晶型CSIV的制备方法，其特征在于：将化合物I固体溶解于醇类和卤代烃类的混合溶剂中，过滤后通过旋转蒸发获得。
  33. 根据权利要求32所述的制备方法，其特征在于，所述醇类溶剂为C1-C3的醇，所述卤代烃类溶剂为二氯甲烷或氯仿，所述混合溶剂中醇类与卤代烃类的体积比为1:50-5:1。
  34. 根据权利要求32所述的制备方法，其特征在于，所述醇类为甲醇或乙醇。
  35. 根据权利要求32所述的制备方法，其特征在于，所述醇类与卤代烃类的体积比为1:1。
  36. 一种化合物I的晶型CSV，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为7.7°±0.2°、22.8°±0.2°处有特征峰
    Figure PCTCN2021116817-appb-100004
  37. 根据权利要求36所述的晶型CSV，其特征在于，使用Cu-Kα辐射，X射线粉末衍射图在2θ值为13.4°±0.2°、10.5°±0.2°、24.6°±0.2°中的至少一处有特征峰。
  38. 根据权利要求36所述的晶型CSV，其特征在于，使用Cu-Kα辐射，X射线粉末衍射图在2θ值为37.7°±0.2°、22.4°±0.2°中的至少一处有特征峰。
  39. 根据权利要求37所述的晶型CSV，其特征在于，使用Cu-Kα辐射，X射线粉末衍射图在2θ值为37.7°±0.2°、22.4°±0.2°中的至少一处有特征峰。
  40. 根据权利要求36所述的晶型CSV，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图 基本如图12所示。
  41. 权利要求36所述的晶型CSV的制备方法，其特征在于：将化合物I固体溶解于酯类和卤代烃类的混合溶剂中，过滤后挥发获得。
  42. 根据权利要求41所述的制备方法，其特征在于，所述挥发的温度为5℃-30℃，所述卤代烃类和酯类混合溶剂比例为2:1-5:1，所述卤代烃类溶剂为碳原子数C1-C3的卤代烃，所述酯类溶剂为碳原子数C3-C6的酯。
  43. 根据权利要求41所述的制备方法，其特征在于，所述挥发的温度为室温，所述卤代烃类和酯类混合溶剂比例为3:1，所述卤代烃类为二氯甲烷，所述酯类为乙酸异丙酯。
  44. 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中所述的共晶，权利要求20所述的晶型CSX，权利要求30所述的晶型CSIV，权利要求36所述的晶型CSV或上述晶型的任意混合及药学上可接受的辅料。
  45. 权利要求1中所述的共晶，权利要求20所述的晶型CSX，权利要求30所述的晶型CSIV，权利要求36所述的晶型CSV或上述晶型的任意混合在制备运动神经元生存基因2剪接修饰剂药物中的用途。
  46. 权利要求1中所述的共晶，权利要求20所述的晶型，权利要求30所述的晶型，权利要求36所述的晶型或上述晶型的任意混合在制备治疗脊髓性肌萎缩症的药物中的用途。
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