Crystalline forms of buralcamesin hydrochloride, their preparation process and their use

Abstract

The present disclosure relates to a novel crystalline form of bularcamesine hydrochloride (hereinafter referred to as "Compound I"), methods for its preparation, pharmaceutical compositions containing the crystalline form, and uses of the crystalline form in the preparation of medicaments for treating sigma-1 receptor agonists and Rett syndrome, Alzheimer's disease, and Parkinson's disease dementia. [Formula 1] JPEG2025514292000048.jpg51170 Compound I hydrochloride

Description

[Technical field]

[0001] The present disclosure relates to the field of chemical crystallography, and in particular to novel crystalline forms of bularcamesin hydrochloride, methods for their preparation and uses. [Background technology]

[0002] Alzheimer's disease is a degenerative brain disorder and the most common form of dementia. It is an irreversible, progressive brain disease that gradually destroys memory and thinking skills, eventually rendering people unable to carry out even the simplest tasks. Experts predict that by 2050, the number of people suffering from dementia worldwide will exceed 130 million, creating a huge demand for medicines.

[0003] Parkinson's disease is a neurodegenerative disorder that involves the clearance of damaged proteins, mitochondrial dysfunction, and brain inflammation. More than half of people with Parkinson's disease may develop Parkinson's disease dementia. Parkinson's disease is progressive and causes many cognitive and behavioral disorders, including anxiety, difficulty thinking and speaking, sleep disorders, and dementia. More than 10 million people worldwide have been diagnosed with Parkinson's disease, making it the 14th leading cause of death.

[0004] Rett syndrome is a rare genetic neurological disorder that first appears during infancy. It causes severe disabilities and affects nearly every aspect of a person's life. Associated symptoms include breathing and sleep abnormalities, seizures, spinal curvature, abnormal muscle tone, and gastrointestinal problems. There are approximately 350,000 people with Rett syndrome worldwide, and it is the second most common cause of severe intellectual disability in women. However, there are currently no drugs on the market specifically targeted to treat Rett syndrome.

[0005] Of note, blarcamesine, an oral sigma-1 receptor agonist developed by Anavex Life Sciences, is in clinical trials for Rett syndrome, early Alzheimer's disease, and Parkinson's disease dementia and has shown promising clinical results. The chemical name of blarcamesine is tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine (Compound I), and the structure of Compound I hydrochloride is: [ka] Compound I Hydrochloride

[0006] In the development of small molecule drugs, drug polymorphism is a common phenomenon and an important factor affecting the quality of drugs. A crystalline form is a solid in which compound molecules are arranged in a three-dimensional order in the microstructure, forming a lattice. Polymorphism refers to the phenomenon that a compound exists in multiple crystalline forms. A compound may exist in one or more crystalline forms, but their existence and properties cannot be specifically predicted. Different crystalline forms of drugs have different physicochemical properties, which may affect the dissolution and absorption of drugs in vivo and affect the clinical efficacy and safety of drugs to some extent. Especially for poorly soluble oral solid or semi-solid preparations, the crystalline form is crucial for the performance of the product. In addition, drugs with different polymorphs have different manufacturability, such as compressibility and flowability. These properties may affect the drug mixing and tableting process. Therefore, polymorphism is an important part of pharmaceutical research and drug quality control.

[0007] Therefore, a comprehensive study on the crystallization behavior of Compound I hydrochloride is necessary to achieve a crystalline form that satisfies the pharmaceutical requirements of Compound I, such as acceptable physicochemical properties such as chemical stability, thermal stability, solubility, hygroscopicity, and / or particle size, manufacturability such as yield, impurity rejection during crystallization, filtration properties, drying properties, and grinding properties, and formulation feasibility such as crystal stability against pressure or compression forces during tableting.

[0008] Prior art WO2021158586A1 discloses n-butanol solvate form B3 of the hydrochloride salt of Compound I. Currently, no drug products using n-butanol sorbate are marketed in the United States because the FDA's Inactive Ingredients Database (IID) does not contain information on maximum daily intake and maximum daily exposure of n-butanol across all routes of administration.

[0009] Prior art WO2017013498A1 discloses three forms of Compound I hydrochloride, namely Form I, Form II, and Form III. Forms I, II, and III all require preparation under high pressure conditions using supercritical fluids, and the manufacturing process is complicated and difficult to scale up. Furthermore, the XRPD patterns of this prior art reveal that Forms I and II contain significant amounts of amorphous matter, which may affect the stability, processability, storage stability, hygroscopicity, and dissolution rate of the active pharmaceutical ingredient. Furthermore, SEM images show that Form III forms fine needle-like crystals, which may exhibit strong electrostatic adsorption, making them difficult to filter and difficult to scale up production.

[0010] Prior art WO2019200345A1 discloses eight forms of Compound I hydrochloride, namely, Forms I, II, III, IV, V, VI, VII and VIII. Paragraph 0085 of the disclosure mentions that Form II is hygroscopic and prone to variable water content. Paragraph 0093 mentions that Form IV is a mixture containing amorphous material. As shown in the XRPD pattern in Figure 9, it contains a large amount of amorphous material. Paragraph 0099 states that Form VIII is a trihydrate that is prone to rapid dehydration to Form I. Furthermore, paragraph 0081 specifies that Form I is the thermodynamically favored polymorph and is currently used in the clinical phase. Thus, Form I disclosed in WO2019200345A1 (hereinafter referred to as "Prior Art Form I") represents the polymorph with the most optimal properties among those disclosed in the prior art.

[0011] Further research by the inventors revealed that the powder properties of Form I are not ideal (e.g., poor flowability, poor compressibility), highly hygroscopic, and poor solubility in common organic solvents. These problems may lead to uneven dispersion during product formulation, difficulties in tablet compression such as poor tablet formation, cracking, and crumbling, and variations in the active pharmaceutical ingredient content between particles within the same batch. Poor content uniformity or large weight differences may lead to variations in the intake of active pharmaceutical ingredients from patient to patient or even from the same patient over time, which may affect drug absorption and blood concentration, thereby affecting therapeutic efficacy.

[0012] To overcome the shortcomings of the prior art, the development of pharmaceutical products containing Compound I hydrochloride salts remains necessary for novel crystalline forms that meet pharmaceutical standards.

[0013] After careful research and extensive experiments, the inventors of the present disclosure have surprisingly discovered crystalline forms of Compound I hydrochloride. Based on a good balance of stability, they have advantages in at least one aspect, such as solubility, hygroscopicity, purification ability, stability, adhesion, compressibility, flowability, in vitro and in vivo solubility, bioavailability, etc. In particular, they have the advantages of no solvent residue, high solubility in organic solvents, high in vitro solubility, low hygroscopicity, high purification ability, high flowability, high compressibility, etc., which solves the problems existing in the prior art and is of great significance for the development of pharmaceuticals containing Compound I. Summary of the Invention

[0014] The present disclosure provides novel crystalline forms of Compound I hydrochloride, methods of preparation, and pharmaceutical compositions containing the crystalline forms.

[0015] In accordance with the purposes of the present disclosure, a tartaric acid co-crystal of Compound I hydrochloride is provided.

[0016] For purposes of this disclosure, there is provided a tartaric acid co-crystal Form CSII of Compound I hydrochloride (hereinafter referred to as Form CSII).

[0017] In one embodiment provided herein, the X-ray powder diffraction pattern of Form CSII uses CuKα radiation consisting of one or two or three characteristic peaks at 2θ values ​​of 8.6°±0.2°, 12.8°±0.2°, and 20.5°±0.2°. Preferably, the X-ray powder diffraction pattern of Form CSII includes characteristic peaks at 2θ values ​​of 8.6°±0.2°, 12.8°±0.2°, and 20.5°±0.2° using CuKα radiation.

[0018] Additionally, the X-ray powder diffraction pattern of Form CSII contains one or two or three peaks characteristic of 2θ values ​​of 14.7°±0.2°, 21.1°±0.2° and 21.8°±0.2° using CuKα radiation. Preferably, the X-ray powder diffraction pattern of Form CSII contains peaks characteristic of 2θ values ​​of 14.7°±0.2°, 21.1°±0.2° and 21.8°±0.2° using CuKα radiation.

[0019] Additionally, the X-ray powder diffraction pattern of Form CSII contains one or two or three peaks characteristic of 2θ values ​​of 13.5°±0.2°, 15.6°±0.2° and 17.5°±0.2° using CuKα radiation. Preferably, the X-ray powder diffraction pattern of Form CSII contains peaks characteristic of 2θ values ​​of 13.5°±0.2°, 15.6°±0.2° and 17.5°±0.2° using CuKα radiation.

[0020] In another embodiment provided herein, the X-ray powder diffraction pattern of Form CSII contains characteristic peaks at 2θ values ​​of 8.6°±0.2°, 12.8°±0.2°, 20.5°±0.2°, 14.7°±0.2°, 21.1°±0.2°, 21.8°±0.2°, 13.5°±0.2°, 15.6°±0.2°, 17.5°±0.2°, 5.1°±0.2°, and 6.8°±0.2° using CuKα radiation.

[0021] Without meaning to be limiting, the XRPD pattern of Form CSII is substantially as depicted in FIG. 1 or FIG. 4 using CuKα radiation.

[0022] Without being meant to be limiting in any way, the TGA curve for Form CSII is substantially as depicted in FIG. 2, and exhibits a weight loss of about 0.2% when heated to 130° C.

[0023] Without implying any limitation, the DSC curve for Form CSII is substantially as depicted in Figure 3, which shows an endothermic peak at about 163°C (onset temperature) which corresponds to the melting endothermic peak.

[0024] Without being limited thereto, Form CSII is a co-crystal of Compound I hydrochloride with L-tartaric acid.

[0025] Without implying any limitation, the molar ratio of Compound I hydrochloride to L-tartaric acid in Form CSII is 1:0.5.

[0026] Although not particularly limited, CSII is anhydrous.

[0027] According to the object of the present disclosure, there is also provided a process for preparing Form CSII, which includes: (1) mixing compound I hydrochloride, tartaric acid, and ketone solvent, grinding, then suspending and stirring the mixture in ketone solvent for a period of time, and isolating to obtain Form CSII; or (2) placing compound I hydrochloride, Form CSII seeds, and tartaric acid in ether solvent, suspending and stirring for a period of time, and isolating the solid to obtain Form CSII;

[0028] Furthermore, the feed ratio of Compound I hydrochloride to tartaric acid is preferably 1:0.4 to 1:2.5. The ketone solvent is preferably a C3-C8 ketone, more preferably methyl isobutyl ketone. The ether solvent is preferably a C3-C8 ether, more preferably 2-methyltetrahydrofuran. The stirring time is preferably 0.5 hours or more. The tartaric acid is preferably L-tartaric acid.

[0029] In accordance with the present disclosure, there is provided a citric acid co-crystal of Compound I hydrochloride.

[0030] For purposes of this disclosure, there is provided citric acid co-crystal Form CSIII of the hydrochloride salt of Compound I (hereinafter referred to as Form CSIII).

[0031] In one embodiment provided herein, the X-ray powder diffraction pattern of Form CSIII contains characteristic one or two or three peaks at 2θ values ​​of 16.6°±0.2°, 20.2°±0.2°, and 21.1°±0.2° using CuKα radiation. Preferably, the X-ray powder diffraction pattern of Form CSIII contains characteristic peaks at 2θ values ​​of 16.6°±0.2°, 20.2°±0.2°, and 21.1°±0.2° using CuKα radiation.

[0032] Additionally, the X-ray powder diffraction pattern of Form CSIII contains one or two or three peaks characteristic of 2θ values ​​of 4.3°±0.2°, 11.1°±0.2° and 12.9°±0.2° using CuKα radiation. Preferably, the X-ray powder diffraction pattern of Form CSIII contains peaks characteristic of 2θ values ​​of 4.3°±0.2°, 11.1°±0.2° and 12.9°±0.2° using CuKα radiation.

[0033] In another embodiment provided herein, the X-ray powder diffraction pattern of Form CSIII contains characteristic peaks at 2θ values ​​of 16.6°±0.2°, 20.2°±0.2°, 21.1°±0.2°, 4.3°±0.2°, 11.1°±0.2°, 12.9°±0.2°, 15.2°±0.2°, 17.7°±0.2°, 21.8°±0.2°, 23.0°±0.2°, and 27.1°±0.2° using CuKα radiation.

[0034] Without implying any limitation, the XRPD pattern of Form CSIII is substantially as depicted in FIG. 7 using CuKα radiation.

[0035] Without implying any limitation, the TGA curve for Form CSIII is substantially as depicted in FIG. 5, and exhibits a weight loss of about 0.1% when heated to 100° C.

[0036] Without intending to be limiting in any way, the DSC curve for Form CSIII is substantially as depicted in Figure 6, which shows two endothermic peaks. The first endothermic peak is at about 104°C (onset temperature) and the second endothermic peak is at about 186°C.

[0037] Without implying any limitation, the molar ratio of Compound I hydrochloride to citric acid in Form CSIII is 1:1.

[0038] Without implying any limitation, Form CSIII is anhydrous.

[0039] According to the object of the present disclosure, there is also provided a process for preparing Form CSIII, which includes the steps of: (1) mixing and grinding Compound I hydrochloride, citric acid, and ketone solvent, then suspending and stirring the mixture in ketone solvent for a period of time, and isolating the solid to obtain Form CSIII; or (2) placing Compound I hydrochloride, Form CSIII seeds, and citric acid in ketone solvent, suspending and stirring for a period of time, and isolating the solid to obtain Form CSIII.

[0040] Furthermore, the supply ratio of Compound I hydrochloride to citric acid is preferably 1:0.8 to 1:2. The ketone solvent is preferably a C3-C8 ketone, more preferably methyl isobutyl ketone. The stirring time is preferably 0.5 hours or more.

[0041] In accordance with the present disclosure, there is provided a malic acid co-crystal of Compound I hydrochloride.

[0042] For purposes of this disclosure, there is provided malic acid co-crystal Form CSIV of Compound I hydrochloride (hereinafter referred to as Form CSIV).

[0043] In one embodiment provided herein, the X-ray powder diffraction pattern of Form CSIV contains characteristic one or two or three peaks at 2θ values ​​of 8.6°±0.2°, 20.5°±0.2°, and 21.8°±0.2° using CuKα radiation. Preferably, the X-ray powder diffraction pattern of Form CSIV contains characteristic peaks at 2θ values ​​of 8.6°±0.2°, 20.5°±0.2°, and 21.8°±0.2° using CuKα radiation.

[0044] Additionally, the X-ray powder diffraction pattern of Form CSIV contains one or two or three peaks characteristic of 2θ values ​​of 12.7°±0.2°, 11.1°±0.2° and 17.5°±0.2° using CuKα radiation. Preferably, the X-ray powder diffraction pattern of Form CSIV contains peaks characteristic of 2θ values ​​of 12.7°±0.2°, 11.1°±0.2° and 17.5°±0.2° using CuKα radiation.

[0045] Additionally, the X-ray powder diffraction pattern of Form CSIV contains one or two or three peaks characteristic of 2θ values ​​of 6.8°±0.2°, 10.2°±0.2° and 21.0°±0.2° using CuKα radiation. Preferably, the X-ray powder diffraction pattern of Form CSIV contains peaks characteristic of 2θ values ​​of 6.8°±0.2°, 10.2°±0.2° and 21.0°±0.2° using CuKα radiation.

[0046] In another form provided herein, Form CSIV has an X-ray powder diffraction pattern with 2θ values ​​of 8.6°±0.2°, 20.5°±0.2°, 21.8°±0.2°, 12.7°±0.2°, 11.1°±0.2°, 17.5°±0.2°, 6.8°±0.2°, 10.2°±0.2°, 21.0°±0.2°, 15.6±0.2°, and 15. 3±0.2°, 13.4±0.2°, 14.6±0.2°, 22.2±0.2°, 25.7±0.2°, 27.4±0.2°, including one or two or three or four or five or six or seven or eight or nine or ten or eleven or twelve or thirteen or fourteen or fifteen or sixteen characteristic peaks.

[0047] Without being limiting, the XRPD pattern of form CSIV using CuKα radiation is substantially as shown in FIG. 8 or FIG.

[0048] Without implying any limitation, the TGA curve for Form CSIV is substantially as depicted in FIG. 9 and exhibits a weight loss of about 0.3% upon heating to 100° C.

[0049] Without meaning to be limiting in any way, the DSC curve for Form CSIV is substantially as depicted in Figure 11 and shows three endothermic peaks: the first endothermic peak at about 148°C (onset temperature), the second endothermic peak at about 177°C, and the third endothermic peak at about 220°C.

[0050] Without limitation, Form CSIV is a DL-malic acid co-crystal of Compound I hydrochloride.

[0051] Without implying any limitation, the molar ratio of Compound I hydrochloride to DL-malic acid in Form CSIV is 1:0.5.

[0052] CSIV is anhydrous.

[0053] According to the purpose of the present disclosure, there is also provided a process for preparing Form CSIV, which includes mixing Compound I hydrochloride, malic acid, and a ketone solvent, suspending and stirring, and then isolating to obtain Form CSIV.

[0054] Furthermore, the feed ratio of Compound I hydrochloride to malic acid is preferably 1:0.5 to 1:2. The ketone solvent is preferably a C3-C8 ketone, more preferably methyl isobutyl ketone. The stirring time is preferably 0.5 hours or more.

[0055] In accordance with the objectives of the present disclosure, there is provided a pharmaceutical composition comprising a therapeutically effective amount of Form CSII, Form CSIII, Form CSIV, or any combination of these three forms, together with a pharma- ceutically acceptable excipient.

[0056] For purposes of this disclosure, there is provided the use of form CSII, form CSIII, form CSIV, or any combination of these three forms, in the preparation of a sigma-1 receptor agonist.

[0057] For purposes of this disclosure, there is provided the use of form CSII, form CSIII, form CSIV, or any combination of these three forms, in the preparation of a medicament for treating Rett Syndrome, Alzheimer's disease, and / or Parkinson's disease dementia.

[0058] Beneficial Effects and Technical Problems Solved by the Present Disclosure The technical problem that the present disclosure addresses is to provide a new crystalline form that is different from the prior art.This crystalline form does not have solvent residue.Compared with the prior art form I, the crystalline form has higher solubility, lower hygroscopicity, better flowability and excellent compressibility, while maintaining excellent stability and good dissolution base, thus solving the problems existing in the prior art.

[0059] Form CSII of the present disclosure has the following beneficial effects:

[0060] (1) Compared with Form I of the prior art, Form CSII of the present disclosure 1732689560723_0 The weight gain of the prior art Form I at 70% RH is 2.3 times that of Form CSII of the present disclosure. In one aspect, high hygroscopicity tends to cause chemical decomposition and polymorphic conversion, which affects the physicochemical stability of the drug. In addition, high hygroscopicity reduces the flowability of the drug substance, thereby affecting the processing of the drug substance. In another aspect, a drug substance with high hygroscopicity requires a low humidity environment during production and storage, which imposes strict requirements on production and increases costs. More importantly, high hygroscopicity is prone to cause variations in the content of active pharmaceutical ingredients in the formulation, which affects the quality of the formulation. Form CSII provided by the present disclosure, which has low hygroscopicity, has no requirements on production and storage conditions, reduces the costs of production, storage and quality control, and has strong economic value.

[0061] (2) Compared with Form I of the prior art, Form CSII of the present disclosure has better compressibility. Better compressibility can avoid the failure in hardness / friction test and tablet cracking problems, make the preparation process more reliable, improve the appearance of the product, and promote the product quality and production efficiency.

[0062] (3) Compared with the prior art Form I, Form CSII of the present disclosure has higher solubility in common alcohols, ketones and ethers. In particular, in n-propanol, the solubility of Form CSII is at least 2-4 times that of Form I of the prior art. Form CSII of the present disclosure exhibits higher solubility in common organic solvents, which is beneficial for production and preparation. It also reduces the amount of solvent required in the manufacturing process, making it more energy efficient and environmentally friendly.

[0063] (4) Form CSII of the present disclosure has no residual solvent. Residual solvent may affect the safety, quality and stability of the drug, and may lead to crystal alteration or the formation of impurities during drug manufacturing and storage, which may affect the bioavailability and toxicity of the drug. The absence of residual solvent in Form CSII effectively addresses the problems associated with low drug stability, poor efficacy and high toxicity caused by low purity or high residual solvent.

[0064] (5) Form CSII of the present disclosure has good purification effect. After the starting material is converted to form CSII, the purity is significantly increased. In a specific embodiment of the present disclosure, the purity of the starting material used is 99.14%. The purity of form CSII produced from the starting material is 99.79%. The purity is improved by more than 0.65%. Chemical purity is very important to ensure the efficacy and safety of drugs and prevent the occurrence of side effects. Drug regulations have strict requirements for the content of impurities. Form CSII of the present disclosure has good purification ability and is excellent in removing impurities in the crystallization process. Therefore, a high purity drug can be obtained by crystallization, and the disadvantages of low stability, low efficacy, and high toxicity caused by low purity drugs can be effectively overcome.

[0065] (6) Form CSII of the present disclosure has good physical stability under mechanical forces. The crystalline state of Form CSII does not change after tableting, grinding and formulation processes. In the manufacturing process of drugs, grinding and crushing are often required. High physical stability of the drug substance can reduce the risk of crystallinity deterioration and crystal deterioration in the pharmaceutical manufacturing process. In addition, the CSII formulation shows good physical stability under various pressures, which is beneficial for not changing the crystalline form during the tableting process.

[0066] (7) Form CSII of the present disclosure has good photostability. When Form CSII is exposed to light for at least 2 weeks under certain conditions, it does not change and its purity is relatively stable. Light can promote the oxidation of drugs, cause photodecomposition, and result in color change and precipitation, which not only reduces the efficacy of drugs but also seriously affects their quality and even increases their toxicity. Therefore, the stability of drugs against light is extremely important for drugs. Form CSII has good photostability and can prevent the impact on the quality of pharmaceutical products caused by crystal deterioration and purity loss during storage.

[0067] (8) The CSII formulation and the formulation of the present disclosure have good stability. The crystalline state of the CSII drug form does not change for at least 9 months when stored under conditions of 25°C / 60%RH. The chemical purity does not change much during storage. When the CSII formulation is mixed with excipients to prepare a formulation and then stored under conditions of 25°C / 60%RH, the crystalline state of the CSII formulation does not change for at least 1 month. These results indicate that the CSII formulation and the formulation of the present disclosure have good stability under long-term conditions, which is beneficial for the storage of the drug.

[0068] Meanwhile, the crystalline state of the drug substance in form CSII does not change for at least 6 months when stored under the conditions of 40°C / 75%RH. The crystalline state of the drug substance in form CSII does not change for at least 1 month when stored under the conditions of 60°C / 75%RH. The chemical purity is 99.9% or more and hardly changes during storage. These results indicate that the drug substance in form CSII has good stability under accelerated and stressed conditions. During storage, transportation, and manufacturing processes, the drug substance and the formulation pass through high temperature and high humidity conditions caused by different seasons, regional climates, and environments. Therefore, high stability under accelerated and stressed conditions is very important for drug development. The drug substance and the formulation in form CSII have good stability under stressed conditions, which is beneficial to avoid the impact on the quality of the drug due to crystal deterioration and purity reduction during drug storage.

[0069] The good physical and chemical stability of the drug substance means that no crystal alteration or impurities occur during manufacturing and storage. Form CSII has good physical and chemical stability, ensuring consistent and controllable quality of the drug substance and drug product, and minimizing quality changes, bioavailability changes and toxicity due to crystal alteration and impurity formation.

[0070] (9) The CSII formulation of the present disclosure has good in vitro solubility. In PBS with pH 6.8, the solubility of the CSII formulation after 10 minutes is up to 97.0%. Drug dissolution is a prerequisite for drug absorption. Drugs with different crystal forms may have different in vivo solubility, which ultimately leads to different clinical efficacy. According to the BCS guidelines, in vitro dissolution may be relevant to predict the in vivo performance of a drug. The good in vitro solubility of the CSII drug provided by the present disclosure leads to higher in vivo absorption, better in vivo exposure, thereby improving the bioavailability and efficacy of the drug. The high intrinsic dissolution rate of the CSII formulation is beneficial for the drug to achieve peak concentration in plasma quickly after administration, thus ensuring rapid drug action.

[0071] Form CSIII of the present disclosure has the following beneficial effects:

[0072] (1) Compared with Form I in the prior art, Form CSIII of the present disclosure has better compressibility. Better compressibility can avoid the problems of failure in hardness / friability test and tablet cracking, make the preparation process more reliable, improve the appearance of the product, and promote the product quality and production efficiency.

[0073] (2) Compared with Form I of the prior art, Form CSIII of the present disclosure has better flowability. The flowability evaluation results show that the flowability of Form CSIII is significantly better than that of the prior art form. The better flowability can prevent clogging of the manufacturing equipment and increase the manufacturing efficiency. The excellent flowability of Form CSIII ensures the content uniformity of the formulation, reduces the weight variation of the formulation, and improves the quality of the product.

[0074] (3) Compared with Form I of the prior art, Form CSIII of the present disclosure has higher solubility in common alcohols, esters and ethers. In particular, in tetrahydrofuran, the solubility of Form CSIII is at least 13 times that of Form I of the prior art. Form CSIII of the present disclosure exhibits higher solubility in common organic solvents, which is beneficial for production and preparation. It also reduces the amount of solvent required in the manufacturing process, making it more energy efficient and environmentally friendly.

[0075] (4) Form CSIII of the present disclosure has no residual solvent. Residual solvent may affect the safety, quality and stability of the drug, and may lead to crystal alteration or the formation of impurities during drug manufacturing and storage, which may affect the bioavailability and toxicity of the drug. The absence of residual solvent in Form CSIII effectively addresses the problems related to low drug stability, poor efficacy and high toxicity caused by low drug purity or high residual solvent.

[0076] (5) Form CSIII of the present disclosure has good purification effect. After the starting material is converted to form CSIII, the purity is significantly increased. In a specific embodiment of the present disclosure, the purity of the starting material used is 99.14%. The purity of form CSIII produced from the starting material is 99.86%. The purity is higher than 0.72%. Chemical purity is very important to ensure the efficacy, safety and prevent the occurrence of side effects of drugs. Pharmaceutical regulations have strict requirements for the content of impurities. Form CSIII of the present disclosure has good purification ability and is excellent in removing impurities in the crystallization process. Therefore, a high purity drug can be obtained by crystallization, and the shortcomings such as low stability, low efficacy and high toxicity caused by low purity drugs can be effectively overcome.

[0077] (6) Form CSIII of the present disclosure has good physical stability under mechanical force. The crystalline state of Form CSIII does not change after tableting, grinding and formulation processes. Grinding and crushing are often required in the manufacturing process of pharmaceutical products. If the physical stability of the drug substance is good, the risk of crystallinity deterioration and crystal change in the pharmaceutical manufacturing process can be reduced. In addition, the CSIII formulation has good physical stability under different pressures, which is beneficial for not changing the crystalline form in the tableting process.

[0078] (7) Form CSIII of the present disclosure has good photostability. When Form CSIII is exposed to light for at least 2 weeks under certain conditions, it does not change and its purity is relatively stable. Light can promote the oxidation of drugs, cause photodecomposition, and result in color change and precipitation, which not only reduces the efficacy of drugs but also seriously affects their quality and even increases their toxicity. Therefore, the stability of drugs against light is extremely important for drugs. Form CSIII has good photostability, which helps prevent the impact on the quality of pharmaceutical products caused by crystal alteration and purity loss during storage.

[0079] (8) The CSIII drug substance and formulation of the present disclosure have good stability. The crystalline state of the CSIII drug substance remains unchanged for at least 9 months when stored under conditions of 25°C / 60%RH. The chemical purity remains substantially unchanged during storage. After mixing CSIII form with excipients to form a formulation and storing under conditions of 25°C / 60%RH, the crystalline state of the CSIII formulation remains unchanged for at least 1 month. These results indicate that the CSIII formulation and formulation of the present disclosure have good stability under long-term conditions, which is beneficial for the storage of the drug.

[0080] Meanwhile, the crystalline state of the drug substance in form CSIII does not change for at least 3 months when stored under the conditions of 40°C / 75%RH. The crystalline state of the drug substance in form CSIII does not change for at least 2 months when stored under the conditions of 60°C / 75%RH. The chemical purity is more than 99% and hardly changes during storage. These results indicate that the drug substance in form CSIII has good stability under accelerated and stressed conditions. During storage, transportation and manufacturing, the drug substance and drug product go through high temperature and humidity conditions caused by different seasons, regional climates and environments. Therefore, showing good stability under accelerated and stressed conditions is very important for drug development. The drug substance and drug product in form CSIII show good stability under stressed conditions, which is beneficial to avoid the impact on the drug substance quality caused by crystal alteration and purity reduction during drug substance storage.

[0081] The physical and chemical stability of the drug substance is good, so no crystal changes or impurities are generated during manufacturing and storage. Form CSIII has good physical and chemical stability, ensuring consistent and controllable quality of drug substances and drug products, and minimizing quality changes, bioavailability changes and toxicity due to crystal changes or impurity generation.

[0082] (9) The CSIII formulation of the present disclosure has good in vitro solubility. In PBS at pH 6.8, the solubility of the CSIII formulation after 15 minutes is up to 97.5%. Drug dissolution is a prerequisite for drug absorption. Drugs with different crystal forms may have different in vivo solubility, which ultimately leads to different clinical efficacy. According to the BCS guidelines, in vitro dissolution may be relevant to predict the in vivo performance of a drug. The good in vitro solubility of the CSIII formulation of the present disclosure may result in higher in vivo absorption, and better in vivo exposure, thereby improving the bioavailability and efficacy of the drug. The high intrinsic dissolution rate of the CSIII formulation of the present disclosure is beneficial for the drug to achieve peak concentration in plasma quickly after administration, thus ensuring rapid drug action.

[0083] The CSIV form of the present disclosure has the following beneficial effects:

[0084] (1) Compared with Form I in the prior art, Form CSIV of the present disclosure has better compressibility. Better compressibility can avoid the problems of failure in hardness / friability test and tablet cracking, make the preparation process more reliable, improve the appearance of the product, and promote the product quality and production efficiency.

[0085] (2) Compared with Form I of the prior art, Form CSIV of the present disclosure has better flowability. The flowability evaluation results show that the flowability of Form CSIV is significantly better than that of the prior art form. The better flowability can prevent clogging of the manufacturing equipment and increase the manufacturing efficiency. The better flowability of Form CSIV ensures the uniformity of the drug content, reduces the variation of the drug weight, and improves the quality of the product.

[0086] (3) Form CSIV of the present disclosure has good physical stability under mechanical force. The crystalline state of Form CSIV does not change after crushing. In the manufacturing process of pharmaceuticals, crushing or grinding is often required. If the physical stability of the drug is good, the risk of crystallinity deterioration or crystal transformation in the manufacturing process of the drug can be reduced.

[0087] (4) Form CSIV of the present disclosure has good photostability. When Form CSIV is exposed to light for at least 2 weeks under certain conditions, it does not change and its purity is relatively stable. Light can promote the oxidation of drugs, cause photodecomposition, and cause color changes and precipitation, which not only reduces the efficacy of drugs but also seriously affects their quality and even increases their toxicity. Therefore, the stability of drugs against light is extremely important for drugs. Form CSIV has good photostability and can prevent the impact on the quality of drugs caused by crystal changes and purity reduction during storage.

[0088] (5) The CSIV drug substance and formulation of the present disclosure have good stability. When stored under conditions of 25°C / 60%RH, the crystalline state of the CSIV drug substance does not change for at least 6 months. The chemical purity does not change substantially during storage. These results indicate that the CSIV formulation has good stability during long-term storage.

[0089] Meanwhile, the crystalline state of the drug substance in form CSIV does not change for at least 6 months when stored under the conditions of 40°C / 75%RH. The crystalline state of the drug substance in form CSIV does not change for at least 2 weeks when stored under the conditions of 60°C / 75%RH. The chemical purity is 99.9% or more and changes little during storage. These results indicate that the drug substance in form CSIV has good stability under accelerated and stressed conditions. During storage, transportation and manufacturing, the drug substance and drug product pass through high temperature and humidity conditions due to different seasons, regional climates and environments. Therefore, showing good stability under accelerated and stressed conditions is very important for drug development. The drug substance in form CSIV shows good stability under stressed conditions, which is beneficial to avoid the impact on quality caused by crystal changes and purity reduction during drug substance storage.

[0090] The drug substance has good physical and chemical stability, so no crystal transformation or impurities are generated during manufacturing and storage. Form CSIV has good physical and chemical stability, ensuring consistent and controllable quality of drug substances and drug products, and minimizing quality changes, bioavailability changes and toxicity due to crystal transformation and impurity generation. [Brief description of the drawings]

[0091] [Figure 1] Figure 1 shows the XRPD pattern of form CSII. [Diagram 2] FIG. 2 shows the TGA curve of Form CSII. [Diagram 3] FIG. 3 shows the DSC curve of form CSII. [Figure 4] FIG. 4 shows the XRPD pattern of form CSII. [Diagram 5] FIG. 5 shows the TGA curve of Form CSIII. [Figure 6] FIG. 6 shows the DSC curve of form CSIII. [Figure 7] FIG. 7 shows the XRPD pattern of form CSIII. [Figure 8] FIG. 8 shows the XRPD pattern of form CSIV. [Figure 9] FIG. 9 shows the TGA curve of Form CSIV. [Figure 10] FIG. 10 shows the XRPD pattern of form CSIV. [Figure 11] FIG. 11 shows the DSC curve of Form CSIV. [Figure 12] FIG. 12 shows an overlay of XRPD patterns of form CSII before and after storage under different conditions (forms from top to bottom: initial, sealed with desiccant at 25° C. / 60% RH for 9 months, open at 25° C. / 60% RH for 9 months, sealed with desiccant at 40° C. / 75% RH for 6 months, and sealed with desiccant at 60° C. / 75% RH for 1 month). [Figure 13]FIG. 13 shows an overlay of the XRPD patterns of form CSII before and after tabletting (from top to bottom: 0 kN pressure, 5 kN pressure, 10 kN pressure, 20 kN pressure). [Figure 14] FIG. 14 shows an overlay of XRPD patterns of form CSII before and after ball milling (from top to bottom: before and after ball milling). [Figure 15] FIG. 15 shows an XRPD pattern overlay of Form CSII before and after the formulation process (from top to bottom: excipients, Form CSII formulation, Form CSII). [Figure 16] FIG. 16 shows the dissolution curve of form CSII. [Figure 17] FIG. 17 shows XRPD pattern overlays of Form CSII product before and after storage in a 25° C. / 60% RH environment sealed with 1 g of desiccant (from top to bottom: before storage, after 1 month storage). [Figure 18] FIG. 18 shows an overlay of XRPD patterns of form CSIII before and after storage under different conditions (forms top to bottom: initial, 9 months sealed with desiccant at 25° C. / 60% RH, 9 months open at 25° C. / 60% RH, 3 months sealed with desiccant at 40° C. / 75% RH, 2 months sealed with desiccant at 60° C. / 75% RH). [Figure 19] FIG. 19 shows an XRPD pattern overlay of Form CSIII before and after the formulation process (from top to bottom: excipients, Form CSIII formulation, Form CSIII). [Figure 20] FIG. 20 shows the dissolution curve of form CSIII. [Figure 21] FIG. 21 shows an overlay of XRPD patterns of Form CSIII product before and after encapsulation with 1 g of desiccant and storage at 25° C. / 60% RH (from top to bottom: before storage, after 1 month storage). [Figure 22] FIG. 22 shows an overlay of XRPD patterns of form CSIV before and after storage under different conditions (forms from top to bottom: initial, 25° C. / 60% RH sealed with desiccant for 6 months, 40° C. / 75% RH sealed with desiccant for 6 months, 60° C. / 75% RH sealed with desiccant for 2 weeks). [Figure 23] FIG. 23 shows an overlay of the X-ray diffraction patterns of the CSIV foam before and after ball milling (top to bottom: before ball milling, after ball milling). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0092] The present disclosure is further illustrated by the following examples detailing the preparation and use of the crystalline forms of the present disclosure. It will be apparent to those skilled in the art that variations in materials and methods may be accomplished without departing from the scope of the present disclosure.

[0093] The following abbreviations are used in this disclosure: RH: Relative humidity XRPD: X-ray powder diffraction TGA: Thermogravimetric analysis DSC: Differential scanning calorimetry DVS: Dynamic Vapor Sorption 1 H NMR: Proton nuclear magnetic resonance HPLC: High-performance liquid chromatography HDPE: High density polyethylene PBS: Phosphate buffer solution Instruments and methods used to collect data:

[0094] The XRPD patterns in this disclosure were obtained by a powder X-ray diffractometer. The parameters of the XRPD method in this disclosure are as follows: X-ray source:Cu,Kα Kα1(Å):1.54060;Kα2(Å):1.54439 Kα2 / Kα1 intensity ratio: 0.50

[0095] The DSC data in this disclosure was obtained on a TA Q2000. The DSC method parameters for this disclosure are as follows: Heating rate 10°C / min Purge gas N2

[0096] The TGA data in this disclosure was obtained on a TA Q500. The TGA method parameters for this disclosure are as follows: Heating rate 10℃ / min Purge gas N2

[0097] The DVS data in this disclosure was measured using an intrinsic DVS instrument from SMS (Surface Measurement Systems Ltd.). The instrument control software is the DVS-Intrinsic control software. Typical parameters for the DVS test are as follows: Temperature:25 Gas and flow rate: N2, 200mL / min RH range: 0%RH~95%RH

[0098] 1 H NMR data were collected on a Bruker Avance II DMX 400M Hz NMR spectrometer. Samples were weighed out in amounts of 1–5 mg and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to give solutions with concentrations ranging from 2–10 mg / mL.

[0099] The parameters for related substance detection of the present disclosure are shown in Table 1.

[0100] [Table 1]

[0101] The parameters for content detection in this disclosure are shown in Table 2.

[0102] [Table 2]

[0103] In this disclosure, a "co-crystal" is a crystalline material composed of two or more different molecules (one of which is an active pharmaceutical ingredient) in a defined stoichiometric ratio within the same crystal lattice, bound by non-ionic and non-covalent bonds.

[0104] "Anhydrous" refers to a solid material that does not contain water of crystallization or solvent.

[0105] The "stirring" is accomplished using conventional methods in the art, such as magnetic stirring or mechanical stirring, with a stirring speed of 50-1800 r / min. Preferably, the magnetic stirring speed is 300-900 r / min, and the mechanical stirring speed is 100-300 r / min.

[0106] The "separation" is achieved by using conventional methods in the art, such as centrifugation and filtration. The operation of "centrifugation" is as follows: the sample to be separated is placed in a centrifuge tube and centrifuged at a speed of 10000r / min until all solids sink to the bottom of the tube.

[0107] The "malic acid" may be DL-malic acid, L-malic acid, or D-malic acid.

[0108] The "tartaric acid" may be DL-tartaric acid, L-tartaric acid, or D-tartaric acid.

[0109] The "room temperature" is not a specific temperature, but is in the range of 10 to 30°C.

[0110] "Characteristic peaks" are typical diffraction peaks used to identify crystals, and when using CuKα radiation, there is usually a deviation of ±0.2°.

[0111] In this disclosure, "crystal" or "crystalline form" refers to a crystal or crystalline form identified by the X-ray diffraction pattern shown herein. Those skilled in the art will understand that X-ray powder diffraction patterns depend on the conditions of the instrument, the preparation of the sample, and the purity of the sample. In addition, the relative intensities of the diffraction peaks in an X-ray diffraction pattern may also vary depending on the experimental conditions, so the order of the diffraction peak intensities is not considered the sole or decisive factor. In fact, the relative intensities of the diffraction peaks in an X-ray powder diffraction pattern are related to the preferred orientation of the crystal, and the diffraction peak intensities shown herein are exemplary, and the same diffraction peak intensities are not required. Therefore, those skilled in the art will understand that the crystalline forms of this disclosure do not necessarily have to be completely identical to the X-ray diffraction patterns of the examples shown herein. All crystalline forms having the same or similar characteristic peaks in the X-ray diffraction pattern are within the scope of this disclosure. Those skilled in the art can compare the patterns shown in this disclosure with the patterns of unknown crystalline forms and identify whether these two groups of patterns reflect the same crystalline form or different crystalline forms.

[0112] In some embodiments, Form CSII, Form CSIII and Form CSIV of the present disclosure are pure and substantially free of other crystalline forms. In the present disclosure, when used to describe a novel crystalline form, the term "substantially free" means that the content of other crystalline forms in the novel crystalline form is less than 20% (w / w), specifically less than 10% (w / w), more specifically less than 5% (w / w), and even more specifically less than 1% (w / w).

[0113] In this disclosure, the term "about" when referring to a measurable value, such as weight, time, temperature, and the like, is meant to encompass variations of ±10%, ±5%, ±1%, ±0.5%, and even ±0.1% of the stated amount.

[0114] Unless otherwise noted, the following examples were carried out at room temperature.

[0115] According to the present disclosure, the compound I used as raw material includes but is not limited to solid (crystalline or amorphous), oil, liquid form or solution.Preferably, the compound I used as raw material is solid.

[0116] The starting compound I used in the following examples was prepared by methods known in the prior art, for example, the methods disclosed in WO2017013498A1.

[0117] Example 1 Preparation of Form CSII 22.8 mg of compound I hydrochloride and 10.8 mg of L-tartaric acid were weighed into a centrifuge tube, and 10 μL of methyl isobutyl ketone was added. After ball milling at 1000 rpm for 1 hour, an additional 0.4 mL of methyl isobutyl ketone was added. The mixture was suspended and stirred at room temperature for 9 days. The solid was then separated by centrifugation and dried in vacuum at 50 °C for 15 minutes. Approximately 0.6 mL of 2-methyltetrahydrofuran was then added, and the solid was separated and dried in vacuum at 30 °C for 25 minutes to obtain a crystalline solid.

[0118] The resulting crystalline solid was tested and confirmed to be Form CSII, with the XRPD pattern shown in Figure 1 and the XRPD data shown in Table 3.

[0119] The TGA curve of form CSII is shown in FIG. 2, which shows that form CSII exhibits a weight loss of about 0.2% when heated to 130° C.

[0120] The DSC curve of form CSII is shown in Figure 3. The endothermic peak around 163°C (onset temperature) corresponds to the melting process.

[0121] Morphology of CSII 1 H NMR data is as follows: 1H NMR(400MHz,DMSO-d6)δ7.64-7.58(m,2H),7.43-7.37(m,2H),7.37-7.27(m,4H),7.27-7.17(m,2H),4.31(s,1H),4.16(q ,J=7.8Hz,1H),3.76(td,J=8.8,4.8Hz,1H),3.60-3.51(m,1H),2.86-2.68(m,8H),2.23-2.12(m,1H),2.03-1.86(m,1H). 1 The H NMR results showed that there was almost no residual solvent in form CSII, and the molar ratio of compound I to L-tartaric acid in form CSII was 1:0.5. The NMR signal of the active hydrogen of HCl in the hydrochloride salt of compound I was not detected, and the NMR signal at the chemical shift of 4.31 ppm was the signal of L-tartaric acid.

[0122] [Table 3] JPEG2025514292000006.jpg119170

[0123] Example 2 Preparation of Form CSII 16.8 mg of compound I hydrochloride, 1.8 mg of form CSII (as a seed) obtained in Example 1, and 12.1 mg of L-tartaric acid were weighed into a vial, and 0.4 mL of 2-methyltetrahydrofuran was added. The mixture was suspended and stirred at room temperature for 2 days, after which 4.0 mg of L-tartaric acid was added and the suspension was stirred at room temperature for another day. An additional 0.6 mg of L-tartaric acid was added and the suspension was stirred at room temperature for another 3 days. The solid was separated and dried under vacuum at room temperature for 35 minutes to obtain a crystalline solid.

[0124] The resulting crystalline solid was tested and confirmed to be Form CSII, with the XRPD pattern shown in Figure 4 and the XRPD data shown in Table 4.

[0125] [Table 4] JPEG2025514292000008.jpg73170

[0126] Example 3 Preparation of Form CSIII Compound I hydrochloride (22.1 mg) and citric acid (20.1 mg) were weighed into a centrifuge tube, and methyl isobutyl ketone (10 μL) was added. After ball milling at 1000 rpm for 1 hour, methyl isobutyl ketone (400 μL) was added, suspended, and stirred at room temperature for 6 days. The solid was separated by centrifugation and vacuum dried at room temperature for about 2.5 hours to obtain a crystalline solid.

[0127] The resulting crystalline solid was tested and confirmed to be Form CSIII, and the XRPD data is shown in Table 5.

[0128] The TGA curve for form CSIII is shown in FIG. 5, which shows that form CSIII exhibits a weight loss of about 0.1% when heated to 100° C.

[0129] The DSC curve of Form CSIII is shown in Figure 6. The first endothermic peak is near 104°C (onset temperature) and the second peak is near 186°C (peak temperature).

[0130] 1 Form CSIII 1 The H NMR data is as follows: 1 H NMR(400MHz,DMSO-d6)δ7.66-7.56(m,2H),7.43-7.38(m,2H),7.37-7.27( m,4H),7.26-7.17(m,2H),4.16(q,J=7.8Hz,1H),3.76(td,J=8.8,4.8Hz,1 H),3.62-3.51(m,1H).16(q,J=7.8Hz,1H),3.76(td,J=8.8,4.8Hz,1H),3. 62-3.51(m,1H),2.83-2.60(m,12H),2.28-2.16(m,1H),1.98-1.87(m,1H). 1The H NMR results show that there is almost no residual solvent in form CSIII, and the molar ratio of compound I to citric acid in form CSIII is 1:1. The NMR signals of the four hydrogen atoms on the alkyl chain of citric acid are contained in the signals at 2.83-2.60 ppm, and the NMR signals of the active hydrogen atoms of citric acid and HCl in the hydrochloride salt of compound I are not detected.

[0131] [Table 5]

[0132] Example 4 Preparation of Form CSIII 19.9 mg of compound I hydrochloride and 24.3 mg of citric acid were weighed into a vial, and 200 μL of methyl isobutyl ketone was added. The mixture was suspended and stirred at room temperature for 5 days. A small amount of seeds of Form CSIII obtained in Example 3 were added, and the mixture was suspended and stirred at room temperature for another day. The suspension was allowed to stand at room temperature for 18 days, after which the solid was separated. Then, 1 mL of methyl isobutyl ketone was added, and the crystalline solid was separated.

[0133] The resulting crystalline solid was tested and confirmed to be Form CSIII, and the XRPD data is shown in Table 6.

[0134] [Table 6]

[0135] Example 5 Preparation of Form CSIII Compound I hydrochloride (19.6 mg) and citric acid (15.1 mg) were weighed into a vial, and methyl isobutyl ketone (0.4 mL) was added. The mixture was suspended and stirred at 50°C for 3 days, after which methyl isobutyl ketone (0.6 mL) saturated with citric acid was added. The suspension was stirred at room temperature for an additional 15 days. The solid was separated by centrifugation and dried in vacuum at 30°C for 6 hours to obtain a crystalline solid.

[0136] The resulting crystalline solid was tested and confirmed to be Form CSIII, with the XRPD pattern shown in Figure 7 and the XRPD data shown in Table 7.

[0137] [Table 7] JPEG2025514292000012.jpg36170

[0138] Example 6 Preparation of Form CSIV Compound I hydrochloride (13.9 mg) and DL-malic acid (6.1 mg) were weighed into a vial, and methyl isobutyl ketone (0.2 mL) was added. The mixture was suspended and stirred at 50° C. for 7 days. The solid was separated by centrifugation and dried in vacuum at room temperature for about 3 hours to obtain a crystalline solid.

[0139] The resulting crystalline solid was tested and confirmed to be Form CSIV, with the XRPD pattern shown in Figure 8 and the XRPD data shown in Table 8.

[0140] The TGA curve for form CSIV is shown in FIG. 9, which shows that form CSIV exhibits a weight loss of about 0.3% when heated to 100° C.

[0141] Morphology CSIV 1 H NMR data is as follows: 1 H NMR(400MHz,DMSO-d6)δ9.79(s,1H),7.67-7.56(m,2H),7.45-7.38(m,2H),7.3 7-7.28(m,4H),7.26-7.17(m,2H),4.26(dd,J=7.8,4.8Hz,0.5H),4.16(q,J=7. 8Hz,1H),3.76(td,J=8.8,4.7Hz,1H),3.62-3.52(m,1H),2.92-2.66(m,8H),2. 65-2.57(m,0.5H),2.47-2.39(m,0.5H),2.28-2.16(m,1H),2.03-1.86(m,1H). 1The H NMR results indicate that there is almost no residual solvent in form CSIV, and the molar ratio of compound I to DL-malic acid in form CSIV is 1:0.5. The NMR signals of DL-malic acid are 4.31 ppm, 2.65-2.57 ppm, and 2.47-2.39 ppm, and the NMR signals of the active hydrogen atoms of the hydroxyl and carboxyl groups of DL-malic acid are not detected.

[0142] [Table 8] JPEG2025514292000014.jpg120170

[0143] Example 7 Preparation of Form CSIV Compound I hydrochloride (10.1 mg) and L-malic acid (4.5 mg) were weighed into a vial, and methyl isobutyl ketone (0.2 mL) was added. The mixture was suspended and stirred at room temperature for 1 day, after which 4.8 mg of L-malic acid was added. The suspension was stirred at room temperature for an additional 7 days. The solid was separated and dried in vacuum at 30°C for about 2 hours to obtain a crystalline solid.

[0144] The resulting crystalline solid was tested and confirmed to be Form CSIV, with the XRPD pattern shown in Figure 10 and the XRPD data shown in Table 9.

[0145] [Table 9] JPEG2025514292000016.jpg128170

[0146] Example 8 DSC curve of CSIV form The DSC curve for Form CSIV is shown in Figure 11 and shows three endothermic peaks: the first endothermic peak at 148°C (onset temperature), the second endothermic peak at 177°C (peak temperature), and the third endothermic peak at 220°C (peak temperature).

[0147] Example 9 Hygroscopicity of CSII Form The dynamic vapor sorption (DVS) analyzer was applied using samples of approximately 10 mg each to evaluate the hygroscopicity of Form CSII and Form I in the prior art. The mass changes at each relative humidity were recorded in a 0%RH - 95%RH - 0%RH cycle. The results are shown in Table 10. From these results, it can be seen that the hygroscopic mass increase of the prior art Form I under 70%RH conditions is 2.3 times that of Form CSII, indicating that the hygroscopicity of Form CSII is superior to that of the prior art Form I.

[0148]

Table 10

[0149] Compressibility of Example 10 CSII The samples were pressed using an ENERPAC single - punch manual tablet press. The prior art Forms CSII and I were each added to an 80 mg, Φ6 mm round die and compressed into tablets under a pressure of 3 kN. After storing at room temperature for 24 hours to complete elastic recovery, the diameter (D) and thickness (L) of the tablets were measured with calipers, and the hardness (H) was tested with a tablet hardness tester. The tensile strength of the powder was calculated by the formula: T = 2H / πDL. Under a certain force, the greater the tensile strength, the better the compressibility. The results are shown in Table 11. These results indicate that Form CSII has better compressibility compared to the prior art Form I.

[0150]

Table 11

[0151] Solubility of Example 11 CSII Form Approximately 3 - 5 mg of the prior art Form CSII or Form I was weighed into each vial, and 0.05 mL of the corresponding solvent was added step - by - step until the solid was completely dissolved. The weight of the solid (m), the undissolved volume (v1), and the dissolved volume (v2) were recorded respectively. According to the formula: m / v2 < S < m / v1, m needs to be converted from the weighed mass to the corresponding mass of Compound I, and the solubility (S) results were calculated and shown in Table 12.

[0152] The results showed that in common alcohol, ketone and ether solvents, the solubility of Form CSII is higher than that of Form I in the prior art, and in particular in n-propanol, the solubility of Form CSII is at least 2-4 times that of Form I in the prior art.

[0153] [Table 12]

[0154] Example 12. Photostability of Form CSII The appropriate dosage of Form CSII of the present disclosure was adjusted to the following settings: Light: 8k lux, UV: 1.5w / m 2 The chemical purity and crystal form were tested by HPLC and XRPD, respectively, and the results are shown in Table 13. The results show that Form CSII has good light stability.

[0155] [Table 13] Example 13 Stability of Form CSII A suitable amount of form CSII of the present disclosure was stored under different conditions of 25°C / 60% RH, 40°C / 75% RH, and 60°C / 75% RH. Chemical purity and crystal morphology were tested by HPLC and XRPD, respectively. The results are shown in Table 14 and the XRPD overlay in FIG. 12. The results show that form CSII is stable after at least 9 months of storage under 25°C / 60% RH conditions, indicating that form CSII has good stability under long-term conditions. Form CSII is stable after at least 6 months of storage under 40°C / 75% RH conditions, indicating that form CSII has good stability under accelerated conditions. Form CSII is stable after at least 1 month of storage under 60°C / 75% RH conditions, indicating that form CSII has good stability under stress conditions.

[0156] [Table 14]

[0157] Release: The sample was placed in a glass vial and the vial was covered with aluminum foil with holes.

[0158] Sealed with desiccant: The sample was placed in a glass vial, the vial was covered with aluminum foil with holes, and the vial was sealed in an aluminum foil bag containing 1 g of silica gel desiccant.

[0159] Example 14 Stability of Form CSII against mechanical forces An appropriate amount of Form CSII was compressed into tablets at different pressures using a suitable tableting tool. The crystalline form before and after tableting was examined by XRPD. The results are shown in Table 15 and the XRPD overlay in Figure 13. The results show that Form CSII exhibits good stability under various pressures.

[0160] [Table 15]

[0161] Form CSII was milled in a ball mill at a vibration speed of 500 rpm for 5 minutes. The crystal forms before and after ball milling were examined by XRPD, and the XRPD overlay is shown in Figure 14. As a result, no shape change was observed in Form CSII after ball milling, indicating that Form CSII has good stability.

[0162] Example 15 Purification ability of Form CSII Form CSII of the present invention was prepared using starting materials with a purity of 99.14%. HPLC was applied to check the chemical purity of starting materials and form CSII, and the results are shown in Table 16. The results show that form CSII has good purification ability.

[0163] [Table 16]

[0164] Example 16 Preparation of Form CSII Formulation Formulation CSII was prepared as shown in Table 17, with the preparation steps shown in Table 18. The blank formulation is shown in Table 19. The blank mixed powder, samples before and after formulation were tested by XRPD, with the results shown in Figure 15. The results indicate that Form CSII is stable before and after the formulation steps.

[0165] [Table 17]

[0166] [Table 18]

[0167] [Table 19]

[0168] Example 17 Dissolution Profiles of CSII Formulations A dissolution test was carried out on the CSII formulation obtained in Example 16. <0931> The dissolution method according to the method described above was used. The test conditions are shown in Table 20. The dissolution results are shown in Table 21, and the dissolution curves are shown in Figure 16, which indicates that Form CSII formulation has good dissolution properties.

[0169] [Table 20]

[0170] [Table 21]

[0171] Example 18 Stability of CSII formulations Form CSII formulations were sealed with 1 g of desiccant and stored under 25° C. / 60% RH conditions. To confirm the stability of Form CSII formulations, the purity and crystalline form of the samples were tested by HPLC and XRPD, respectively. The results are shown in Table 22, with the XRPD overlay in FIG. 17. The results showed that Form CSII formulations were stable after storage at 25° C. / 60% RH conditions for at least one month.

[0172] [Table 22]

[0173] Example 19: Flowability of CSIII Form Approximately 500 mg of Form CSIII or Form I of the prior art was weighed gently into a 5 mL graduated cylinder to avoid vibration, and the volume before tapping was recorded. The bulk density ρ0 was calculated by the formula "bulk density ρ0 = powder mass / volume before beating". The sample was then tapped 1250 times on a ZS-2E tapped density tester, and the volume after tapping was recorded. Tapped density ρ f is the tap density ρ f The compressibility index (c), also known as the Carr index, was calculated based on the measured bulk density and tapped density of the sample using the formula c = (ρ - ρ f0 ) / ρ f *Calculated at 100%. Fluidity criteria according to ICH Q4B Annex 13 are shown in Table 23.

[0174] [Table 23]

[0175] The flowability evaluation results of Form CSIII and prior art Form I are shown in Table 24, and the flowability of Form CSIII is significantly superior to that of prior art Form I.

[0176] [Table 24]

[0177] Example 20 Compressibility of the CSIII Form The samples were pressed using an ENERPAC single-punch manual tablet press. The prior art forms CSIII and I were each added to an 80 mg, Φ6 mm round die and compressed at a pressure of 3 kN to form tablets. After storage at room temperature for 24 hours to complete elastic recovery, the diameter (D) and thickness (L) of the tablets were measured with calipers, and the hardness (H) was tested with a tablet hardness tester. The tensile strength of the powder was calculated by the following formula: T = 2H / πDL. Under a certain force, the greater the tensile strength, the better the compressibility. The results are shown in Table 25. This result shows that the CSIII form has better compressibility compared to the prior art form I.

[0178]

Table 25

[0179] Example 21 Solubility of the CSIII Form Approximately 3 - 5 mg of the prior art form CSIII or form I was weighed into each vial, and the corresponding solvent (0.05 mL) was added stepwise until the solid was completely dissolved. The weight (m) of the solid, the undissolved volume (v1), and the dissolved volume (v2) were recorded respectively. According to the formula: m / v2 < S < m / v1, m needs to be converted from the weighed mass to the corresponding mass of compound I, and the solubility (S) results were calculated and shown in Table 26.

[0180] As a result, in common alcohol, ketone, ester, and ether solvents, the solubility of the CSIII form is higher than that of the form I in the prior art. In particular, in tetrahydrofuran, the solubility of the CSIII form is shown to be at least 13 times that of the form I in the prior art.

[0181]

Table 26

[0182] Example 22 Photostability of Form CSIII The appropriate dosage of Form CSIII of the present disclosure was adjusted to the following settings: Light: 8k lux, UV: 1.5w / m 2 The chemical purity and crystal form were tested by HPLC and XRPD, respectively, and the results are shown in Table 27. The results indicate that Form CSIII has good light stability.

[0183] [Table 27]

[0184] Example 23 Stability of CSIII Form A suitable amount of form CSIII of the present disclosure was stored under different conditions of 25°C / 60%RH, 40°C / 75%RH and 60°C / 75%RH. Chemical purity and crystal morphology were tested by HPLC and XRPD, respectively. The results are shown in Table 28 and the XRPD overlay in Figure 18. The results show that form CSIII is stable after at least 9 months of storage under 25°C / 60%RH conditions, indicating that form CSIII has good stability under long-term conditions. Form CSIII is stable after at least 3 months of storage under 40°C / 75%RH conditions, indicating that form CSIII has good stability under accelerated conditions. Form CSIII is stable after at least 2 months of storage under 60°C / 75%RH conditions, indicating that form CSIII has good stability under stress conditions.

[0185] [Table 28]

[0186] Release: The sample was placed in a glass vial and the vial was covered with aluminum foil with holes.

[0187] Sealed with desiccant: The sample was placed in a glass vial, the vial was covered with aluminum foil with holes, and the vial was sealed in an aluminum foil bag containing 1 g of silica gel desiccant.

[0188] Example 24 Stability of Form CSIII against mechanical forces An appropriate amount of Form CSIII was compressed into tablets at different pressures using a suitable tableting tool. The crystal forms before and after tableting were tested by XRPD. The test results are shown in Table 29. The results show that Form CSIII has good stability under different pressures.

[0189] [Table 29]

[0190] Form CSIII was milled in a ball mill at a vibration speed of 500 rpm for 5 minutes. The crystal forms before and after ball milling were examined by XRPD. The results showed that no morphological changes of form CSIII were observed after ball milling, indicating that form CSIII has good stability.

[0191] Example 25 Purification Ability of Form CSIII Form CSIII of the present invention was prepared using starting material with a purity of 99.14%. HPLC was applied to test the chemical purity of starting material and form CSIII, and the results are shown in Table 30. The results show that form CSIII has good purification ability.

[0192] [Table 30]

[0193] Example 26 Preparation of CSIII formulation CSIII formulations were prepared as shown in Table 31, with the preparation steps shown in Table 18. Blank formulations are shown in Table 19. Blank mixed powders, samples before and after formulation were tested by XRPD, with the results shown in Figure 19. The results indicate that Form CSIII is stable before and after the formulation steps.

[0194] [Table 31]

[0195] Example 27 Dissolution Profile of Form CSIII Formulation A dissolution test was conducted on the CSIII formulation obtained in Example 26. <0931> The test conditions are as shown in Table 20. The results of the dissolution test are shown in Table 32, and the dissolution curves are shown in Figure 20.

[0196] [Table 32]

[0197] Example 28. Stability of Form CSIII in the Formulation The Form CSIII formulation was sealed with 1 g of desiccant and stored under 25° C. / 60% RH conditions. The purity and crystal form of the sample were tested by HPLC and XRPD, respectively, to confirm the stability of the Form CSIII formulation. The results are shown in Table 33 and the XRPD overlay in FIG. 21. The results showed that the Form CSIII formulation was stable after at least one month of storage under 25° C. / 60% RH conditions.

[0198] [Table 33]

[0199] Example 29. Flowability of Form CSIV Approximately 500 mg of Form CSIV or prior art Form I was weighed gently into a 5 mL graduated cylinder to avoid vibration, and the volume before tapping was recorded. The bulk density ρ0 was calculated by the formula "bulk density ρ0 = powder mass / volume before tapping". The sample was then tapped 1250 times on a ZS-2E tap density tester, and the volume after tapping was recorded. Tap density ρ f is the tap density ρ f The compressibility index (c), also known as the Carr index, was calculated based on the measured bulk density and tapped density of the sample using the formula c = (ρ - ρ f0) / ρ f *Calculated at 100%. Fluidity criteria according to ICH Q4B Annex 13 are shown in Table 23.

[0200] The flowability evaluation results of Form CSIV and prior art Form I are shown in Table 34, and show that the flowability of Form CSIV is significantly superior to that of prior art Form I.

[0201] [Table 34]

[0202] Example 30 Compressibility of Form CSIV The samples were pressed on an ENERPAC single punch manual tablet press. 80 mg each of Form CSIV and Form I of the prior art were added to a Φ6mm round die and compressed into tablets with a pressure of 3kN. After storage at room temperature for 24 hours, the elastic recovery was completed, and the diameter (D) and thickness (L) of the tablets were measured with a vernier caliper and the hardness (H) was tested with a tablet hardness tester. The tensile strength of the powder was calculated by the following formula: T=2H / πDL. Under a certain force, the higher the tensile strength, the better the compressibility. The results are shown in Table 35. The results show that Form CSIV has better compressibility compared to Form I of the prior art.

[0203] [Table 35]

[0204] Example 31 Photostability of Form CSIV An appropriate amount of form CSIV of the present disclosure was placed in a photostability chamber with the following settings: Light: 8kLux, UV: 1.5w / m 2 The chemical purity and crystalline form were tested by HPLC and XRPD, respectively, and the results are shown in Table 36. The results indicate that CSIV has good photostability.

[0205] [Table 36]

[0206] Example 32 Stability of Form CSIV A suitable amount of form CSIV of the present disclosure was stored under different conditions of 25° C. / 60% RH, 40° C. / 75% RH, and 60° C. / 75% RH. The chemical purity and crystal form were tested by HPLC and XRPD, respectively. The results are shown in Table 37, and the XRPD overlay is shown in FIG. 22. The results show that CSIV is stable after at least 6 months of storage under 25° C. / 60% RH conditions, indicating that CSIV has good long-term stability. Form CSIV is stable after at least 6 months of storage under 40° C. / 75% RH conditions, indicating that form CSIV has good stability under accelerated conditions. Form CSIV is stable after at least 2 weeks of storage under 60° C. / 75% RH conditions, indicating that form CSIV has good stability under stress conditions.

[0207] [Table 37]

[0208] Sealed with desiccant: The sample was placed in a glass vial, the vial was covered with aluminum foil with holes, and the vial was sealed in an aluminum foil bag containing 1 g of silica gel desiccant.

[0209] Example 33 Stability of Form CSIV against mechanical forces Form CSIV was milled in a ball mill at a vibration speed of 500 rpm for 5 minutes. The crystal morphology before and after ball milling was examined by XRPD, and the XRPD overlay is shown in Figure 23. As a result, no shape change was observed for Form CSIV after ball milling, indicating that Form CSIV has good stability.

[0210] The above examples are intended to explain the technical concepts and features of the present disclosure, and are intended to enable those skilled in the art to understand and thus implement the present disclosure, and should not be concluded to limit the scope of protection of the present disclosure. Equivalent variations or modifications in accordance with the spirit of the present disclosure should be covered by the scope of protection of the present disclosure.

Claims

1. Tartaric acid co-crystal of Compound I hydrochloride. 【Chemistry 1】

2. 2. The tartaric acid co-crystal of claim 1, which is Form CSII and has an X-ray powder diffraction pattern including one or two or three characteristic peaks at 2θ values ​​of 8.6°±0.2°, 12.8°±0.2°, and 20.5°±0.2° using Cu-Kα radiation.

3. 3. Form CSII of claim 2, having an X-ray powder diffraction pattern containing one or two or three characteristic peaks at 2θ values ​​of 14.7°±0.2°, 21.1°±0.2°, and 21.8°±0.2° using Cu-Kα radiation.

4. 3. Form CSII of claim 2, wherein the powder X-ray diffraction pattern contains one or two or three characteristic peaks at 2θ values ​​of 13.5°±0.2°, 15.6°±0.2° and 17.5°±0.2° using Cu-Kα radiation.

5. 4. Form CSII of claim 3, wherein the X-ray powder diffraction pattern contains one or two or three characteristic peaks at 2θ values ​​of 13.5°±0.2°, 15.6°±0.2° and 17.5°±0.2° using Cu-Kα radiation.

6. 3. Form CSII of claim 2, having an X-ray powder diffraction pattern substantially as depicted in FIG. 1 or FIG. 4 using Cu-Kα radiation.

7. The tartaric acid cocrystal of claim 1, wherein the tartaric acid is L-tartaric acid.

8. 3. The form CSII of claim 2, wherein form CSII is anhydrous.

9. Citric acid co-crystal of Compound I hydrochloride. 【Chemistry 2】

10. It is Form CSIII and has an X-ray powder diffraction pattern containing one or two or three characteristic peaks at 2θ values ​​of 16.6°±0.2°, 20.2°±0.2° and 21.1°±0.2° using Cu-Kα radiation.

10. The citric acid cocrystal of claim 9.

11. 11. Form CSIII of claim 10, wherein the X-ray powder diffraction pattern contains one or two or three characteristic peaks at 2θ values ​​of 4.3°±0.2°, 11.1°±0.2° and 12.9°±0.2° using Cu-Kα radiation.

12. 11. Form CSIII of claim 10, having an X-ray powder diffraction pattern substantially as depicted in FIG. 7 using Cu-Kα radiation.

13. 11. The form CSIII of claim 10, wherein form CSIII is anhydrous.

14. Malic acid co-crystal of Compound I hydrochloride. 【Chemistry 3】

15. 15. The malic acid co-crystal of claim 14, wherein the malic acid co-crystal is Form CSIV and has an X-ray powder diffraction pattern including one or two or three characteristic peaks at 2θ values ​​of 8.6°±0.2°, 20.5°±0.2°, and 21.8°±0.2° using Cu-Kα radiation.

16. 16. Form CSIV of claim 15, wherein the powder X-ray diffraction pattern includes at least one characteristic peak at 2θ values ​​of 12.7°±0.2°, 11.1°±0.2°, and 17.5°±0.2° using Cu-Kα radiation.

17. 16. Form CSIV of claim 15, wherein the powder X-ray diffraction pattern includes at least one characteristic peak at 2θ values ​​of 6.8°±0.2°, 10.2°±0.2°, and 21.0°±0.2° using Cu-Kα radiation.

18. 17. Form CSIV of claim 16, wherein the powder X-ray diffraction pattern comprises at least one characteristic peak at 2θ values ​​of 6.8°±0.2°, 10.2°±0.2°, and 21.0°±0.2° using Cu-Kα radiation.

19. 16. Form CSIV of claim 15, having an X-ray powder diffraction pattern substantially as shown in FIG. 8 or FIG. 10 using Cu-Kα radiation.

20. The malic acid cocrystal according to claim 14, wherein the malic acid is DL-malic acid.

21. 16. The form CSIV of claim 15, wherein form CSIV is anhydrous.

22. 13. A pharmaceutical composition comprising a therapeutically effective amount of form CSII of claim 2, form CSIII of claim 10, form CSIV of claim 15, or a mixture thereof, and a pharma- ceutically acceptable excipient.

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