A hydrate crystal form c of a taxane compound and a preparation method and use thereof

Abstract

The present application relates to the field of compound crystal form, and particularly relates to a hydrate crystal form C of a taxane compound and a preparation method and use thereof.The hydrate crystal form C of the taxane compound of the technical scheme has the advantages of high solubility in water, good solid-state physical and chemical stability and good bioavailability.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemical crystal preparation technology, specifically relating to a hydrate crystal form C of a taxane compound, as well as a method for preparing the hydrate crystal form C and its uses. Background Technology

[0002] Drug molecules typically exist in different solid forms, including salts, polymorphs, eutectics, amorphous forms, hydrates, or solvates. Different crystal forms of the same drug molecule can exhibit significant differences in properties such as crystal structure, stability, manufacturability, and bioavailability, thereby affecting the drug's efficacy and development potential. Stability is also crucial for maintaining the drug's efficacy in clinical applications. Therefore, selecting a safe, effective, and stable crystal form has become an important aspect of new drug and generic drug development.

[0003] {2aR-[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]}-β-{[(1,1-dimethylethoxy)carbonyl]amino}-α-hydroxyphenylpropionic acid{6-[(4-acetylphenyl)carbamoyloxy]-12b-acetoxy-12-benzoyloxy-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecylhydro-4,1 1-Dihydroxy-4a,8,13,13-tetramethyl-5-oxo-7,11-methylene-1H-cyclodecopenteno[3,4]benzo[1,2-b]oxazolidinyl-9-yl ester is a novel taxane drug molecule developed by Jiangsu Jibeier Pharmaceutical Co., Ltd., project code: JJH201601. This compound has been disclosed and granted in patent application number CN201810185012.4. The molecular structure is shown in the figure below:

[0004]

[0005] Preliminary efficacy studies show that the drug significantly improves efficacy in nude mouse models and reduces toxic side effects. It can eliminate tumors (tumor inhibition rate of over 99%), and no tumor recurrence was observed during the observation period after drug withdrawal. These results were validated in lung cancer A549, liver cancer HepG2, and pancreatic cancer Panc-1 models. The compound is currently in the administrative approval stage and is expected to be widely used in the clinical treatment of related diseases.

[0006] Currently, there are no reports regarding the JJH201601 crystal form. Summary of the Invention

[0007] The purpose of this invention is to provide a crystal form of taxane compound JJH201601 with high water solubility, good solid-state physicochemical stability, and good bioavailability, as well as its preparation method and uses, which are suitable for large-scale application in production and clinical practice.

[0008] To achieve the above-mentioned technical objectives, the present invention provides the following technical solution: a hydrate crystal form C of a taxane compound, the X-ray powder diffraction pattern of which exhibits diffraction peaks at at least three of the following 2θ angles: 6.356°±0.2, 6.653°±0.2, 7.970°±0.2, 9.204°±0.2, 11.284°±0.2, 13.285°±0.2; the taxane compound has the structure shown in Formula I:

[0009]

[0010] Furthermore, its X-ray powder diffraction pattern has diffraction peaks at at least four of the following 2θ angles: 6.356°±0.2, 6.653°±0.2, 7.970°±0.2, 9.204°±0.2, 11.284°±0.2, and 13.285°±0.2.

[0011] Furthermore, its X-ray powder diffraction pattern exhibits diffraction peaks at at least five of the following 2θ angles: 6.356°±0.2, 6.653°±0.2, 7.970°±0.2, 9.204°±0.2, 9.966°±0.2, 11.284°±0.2, 12.318°±0.2, 13.052°±0.2, and 13.285°±0.2.

[0012] Furthermore, its X-ray powder diffraction pattern exhibits diffraction peaks at at least seven locations at the following 2θ angles: 6.356°±0.2, 6.653°±0.2, 7.970°±0.2, 9.204°±0.2, 9.966°±0.2, 11.284°±0.2, 12.318°±0.2, 13.052°±0.2, and 13.285°±0.2.

[0013] Furthermore, the hydrate crystal form C of the taxane compound exhibits weight loss at 150°C.

[0014] Furthermore, the molar ratio of taxane compound to water of crystallization in the hydrate crystal form C is 1:0.5-2.

[0015] Furthermore, the molar ratio of taxane compound to water of crystallization in the hydrate crystal form C is 1:0.5, 1:1, 1:1.5, or 1:2.

[0016] This application also discloses a method for preparing the hydrate crystal form C of the taxane compound as described above, wherein the taxane compound shown in Formula I is dissolved in a mixture of a polar aprotic solvent and a polar protic solvent, heated and stirred, then cooled to room temperature to obtain a solid, and the obtained solid is dried to obtain the hydrate crystal form C.

[0017] Furthermore, the polar aprotic solvent is acetonitrile or acetone, and the polar protic solvent is water;

[0018] Furthermore, the mixture is a mixture of acetonitrile and water in a volume ratio of 1:4 or a mixture of acetone and water in a volume ratio of 1:4.

[0019] Furthermore, the heating temperature is 40-55℃;

[0020] Furthermore, the heating temperature is 50°C.

[0021] This application also discloses a pharmaceutical composition comprising an effective amount of the taxane compound hydrate crystal form C as described above;

[0022] Furthermore, this also includes pharmaceutically acceptable excipients.

[0023] This application also discloses the use of the taxane compound hydrate crystal form C as described above or the pharmaceutical composition as described above in the preparation of a medicament for the prevention and treatment of tumor diseases;

[0024] Furthermore, the tumor diseases include lung cancer, liver cancer, and pancreatic cancer;

[0025] Furthermore, the tumor diseases specifically include lung cancer A549, liver cancer HepG2, and pancreatic cancer Panc-1.

[0026] Due to the adoption of the above technologies, the significant advantages of this invention compared with the prior art are as follows:

[0027] 1) The technical solution of the present invention uses a mixture of polar aprotic solvent and polar protic solvent as solvent to prepare taxane compound hydrate crystal form C under heating conditions. It has the advantages of high water solubility and good solid physicochemical stability. In particular, the water solubility is increased to more than 1.7 μg / mL, which is suitable for application in the pharmaceutical preparation process. It solves the inconvenience caused by the low water solubility of taxane compound in the preparation and storage process in the prior art.

[0028] 2) The taxane compound hydrate crystal form C of the present invention has superior biological activity compared with conventional amorphous taxane compounds and other crystal forms, and is more suitable for clinical use. Attached Figure Description

[0029] Figure 1 The XRPD spectrum of the taxane compound hydrate crystal form C of the present invention is shown below.

[0030] Figure 2 The TGA / DCS characterization results of the taxane compound hydrate crystal form C of the present invention are shown below;

[0031] Figure 3 The XRPD characterization results before and after the solubility test of taxane compound hydrate crystal form C of the present invention are shown.

[0032] Figure 4 The XRPD characterization results of the solid-state stability test of the taxane compound hydrate crystal form C of the present invention are shown below.

[0033] Figure 5 The results of the hygroscopicity evaluation test for the taxane compound hydrate crystal form C of the present invention;

[0034] Figure 6 The XRPD characterization results before and after the hygroscopicity evaluation test of the taxane compound hydrate crystal form C of the present invention are shown. Detailed Implementation

[0035] The following examples further illustrate the above-described content of the present invention, but it should not be construed as limiting the scope of the subject matter of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention.

[0036] XRPD determination method:

[0037] XRPD data of the samples in the project were acquired using a PANalytical X'Pert3 and an Empyrean X-ray powder diffractometer.

[0038] Spread an appropriate amount of sample evenly on a single-crystal silicon sample disk, and perform XRPD testing using the following parameters:

[0039] Table 1 Experimental parameters for XRPD

[0040]

[0041] TGA and DSC determination methods:

[0042] TGA and DSC spectra were acquired using a TAQ5000 / Discovery 5500 thermogravimetric analyzer and a TAQ2000 / Discovery2500 differential scanning calorimeter, respectively. The experimental parameters are as follows:

[0043] Table 2 Test parameters for TGA and DSC

[0044]

[0045] Example 1

[0046] The method for preparing taxane compound hydrate crystal form C in this embodiment is carried out according to the following steps:

[0047] Amorphous samples of compound JJH201601 were subjected to cyclic heating and cooling in a mixed solvent of acetonitrile / water (1:4, v / v). After stirring in suspension at 0.05℃ / min for 8 days, the solid sample was collected and air-dried at room temperature to obtain crystalline form C. Its XRPD pattern is shown below. Figure 1 As shown, the specific diffraction peak data are shown in Table 3. The test results are as follows: Figure 2 As shown, the sample exhibits endothermic peaks at 77.1℃, 173.7℃, and 215.9℃ (peak temperatures).

[0048] Table 3 XRPD diffraction peak data

[0049]

[0050]

[0051] Example 2

[0052] The method for preparing taxane compound hydrate crystal form C in this embodiment is carried out according to the following steps:

[0053] The amorphous sample of compound JJH201601 was magnetically stirred at room temperature for 7 days in a dimethyl sulfoxide / water (1:9, v / v) solvent system. The solid sample was then collected and placed under ambient humidity at room temperature to obtain crystalline form C. Its XRPD pattern is similar to... Figure 1 Similarly, endothermic peaks exist at 77.1℃, 173.7℃, and 215.9℃ (peak temperatures).

[0054] Example 3

[0055] The method for preparing taxane compound hydrate crystal form C in this embodiment is carried out according to the following steps:

[0056] The amorphous sample of compound JJH201601 was prepared into crystalline form C by cyclic heating and cooling in an acetone / water (1:4, v / v) solvent system in the presence of crystalline form C seed crystals. Its XRPD pattern is similar to... Figure 1 Similarly, endothermic peaks exist at 77.1℃, 173.7℃, and 215.9℃ (peak temperatures).

[0057] Example 4

[0058] Taxane hydrate crystal form C loses approximately 3.0% weight when heated from room temperature to 150℃. The sample exhibits endothermic peaks at 77.1℃, 173.7℃, and 215.9℃ (peak temperature). Specific TGA / DCS characterization results are as follows... Figure 2 As shown. Based on the TGA / DCS characterization results, the molar ratio of compound molecules to water molecules in this hydrate is calculated to be 1:1.5.

[0059] Example 5

[0060] 24-hour equilibrium solubility test of taxane compound hydrate crystal form C:

[0061] Approximately 2 mg of the corresponding solid sample was weighed and placed in a 2 mL centrifuge tube. 1 mL of pure water was added, and the tube was sealed. The tube was shaken on a shaker (800 rpm) at room temperature (25 ± 3 °C) for 24 hours, followed by centrifugation to separate the solid and liquid phases. The remaining solid sample was characterized using XRPD to observe crystal form changes, and the concentration of compound JJH201601 in the solution was analyzed by HPLC to characterize the sample's solubility in water. The evaluation results are summarized in Table 4-1. The solubility of the amorphous initial sample in water was significantly lower than that of crystal form C. Meanwhile, the XRPD characterization results are as follows: Figure 3 As shown, crystal form C did not change after the solubility test.

[0062] Table 4-1 Summary of Equilibrium Solubility Assessment Results in Water over 24 Hours

[0063] Evaluation of crystal form solubility pH Remaining solid crystal form amorphous 0.82 μg / mL 7.7 amorphous Crystal form C 1.7 μg / mL 6.61 Crystal form C

[0064] Example 6

[0065] Solid-state stability assessment of taxane compound hydrate crystal form C:

[0066] Appropriate amounts of the corresponding crystalline form C solid samples were weighed and placed in the open at 25℃ / 60%RH and 40℃ / 75%RH for one week, respectively. Simultaneously, another group of crystalline form C solid samples was placed in the closed container at 80℃ for 24 hours. The samples after placement were characterized by XRPD and HPLC to detect changes in crystal form and chemical purity.

[0067] XRPD of samples before and after the experiment Figure 4 As shown. The evaluation results show:

[0068] No crystal form change or significant decrease in purity was observed in crystal form C under three stability test conditions (80℃ / closed / 24h, 25℃ / 60%RH / 1week, 40℃ / 75%RH / 1week), while significant decrease in purity was found in amorphous samples under the above test conditions.

[0069] Table 4-2 Summary of Solid State Stability Assessment Results

[0070]

[0071] Example 7

[0072] Hygroscopicity assessment test of taxane compound hydrate crystal form C:

[0073] Hygroscopicity was further assessed using a dynamic moisture adsorption (DVS) meter. The experimental results are as follows: Figure 5 As shown. The evaluation results show that the water adsorption of crystalline form C sample at 25℃ / 80%RH is 5.87%. After DVS characterization, crystalline form C did not undergo a crystal form transformation (e.g., Figure 6 (As shown).

[0074] Example 8

[0075] Weigh appropriate amounts of crystalline C and amorphous sample, add a small amount of water for injection and stir well. Then add an appropriate amount of fat emulsion to prepare a suspension of 1.2 mg / mL.

[0076] Twelve rats were randomly divided into two groups of six each, and administered the drug at a dose of 6 mg / kg. Blood samples were collected at different time points after intravenous injection of either crystalline C or amorphous suspension. Plasma samples were treated with protein precipitation and then analyzed by LC-MS / MS to conduct a comparative pharmacokinetic study in rats. The data are shown in Table 5. The results showed that the main pharmacokinetic parameter C, which was related to in vivo exposure, was... max and AUC 0-t The C group of crystal forms is much larger than that of the amorphous group, exhibiting better pharmacokinetic characteristics.

[0077] Table 5 Pharmacokinetic test data

[0078]

[0079] The above embodiments are merely preferred technical solutions of the present invention and should not be regarded as limitations on the present invention. The scope of protection of the present invention should be the technical solution described in the claims, including equivalent substitutions of the technical features described in the claims. That is, equivalent substitutions and improvements within this scope are also within the scope of protection of the present invention.

Claims

1. A hydrate crystal form C of a taxane compound, characterized in that, The hydrate crystal form C has a taxane compound to water of crystallization molar ratio of 1:0.5-2, and its X-ray powder diffraction pattern shows diffraction peaks at at least four of the following 2θ angles: 6.356°±0.2, 6.653°±0.2, 7.970°±0.2, 9.204°±0.2, 11.284°±0.2, and 13.285°±0.2; the taxane compound has the structure shown in Formula I. .

2. The hydrate crystal form C according to claim 1, characterized in that, Its X-ray powder diffraction pattern shows diffraction peaks at at least five of the following 2θ angles: 6.356°±0.2, 6.653°±0.2, 7.970°±0.2, 9.204°±0.2, 9.966°±0.2, 11.284°±0.2, 12.318°±0.2, 13.052°±0.2, and 13.285°±0.

2.

3. The hydrate crystal form C according to claim 2, characterized in that, Its X-ray powder diffraction pattern shows diffraction peaks at at least seven locations at the following 2θ angles: 6.356°±0.2, 6.653°±0.2, 7.970°±0.2, 9.204°±0.2, 9.966°±0.2, 11.284°±0.2, 12.318°±0.2, 13.052°±0.2, and 13.285°±0.

2.

4. The hydrate crystal form C according to claim 1, characterized in that, It loses weight at 150℃.

5. The hydrate crystal form C according to any one of claims 1-4, characterized in that, The molar ratio of taxane compound to water of crystallization in the hydrate crystal form C is 1:0.5, 1:1, 1:1.5, or 1:

2.

6. A method for preparing the hydrate crystal form C of the taxane compound as described in claim 1, characterized in that, The taxane compound shown in Formula I was dissolved in a mixture of a polar aprotic solvent and a polar protic solvent, heated and stirred, and then cooled to room temperature to obtain a solid. The obtained solid was dried to obtain the hydrate crystal form C.

7. The preparation method according to claim 6, characterized in that, The polar aprotic solvent is acetonitrile, dimethyl sulfoxide, or acetone, and the polar protic solvent is water.

8. The preparation method according to claim 7, characterized in that, The mixture is a mixture of acetonitrile and water in a volume ratio of 1:4 or a mixture of acetone and water in a volume ratio of 1:

4.

9. The preparation method according to claim 6, characterized in that, The heating temperature is 40-55℃.

10. The preparation method according to claim 9, characterized in that, The heating temperature is 50°C.

11. A pharmaceutical composition, characterized in that, Includes an effective amount of the taxane compound hydrate crystal form C as described in any one of claims 1-5.

12. The pharmaceutical composition according to claim 11, characterized in that, It also includes pharmaceutically acceptable excipients.

13. Use of the taxane compound hydrate crystal form C according to any one of claims 1-5 or the pharmaceutical composition according to any one of claims 11-12 in the preparation of a medicament for the prevention and treatment of tumor diseases.

14. The use according to claim 13, characterized in that, The tumor diseases mentioned include lung cancer, liver cancer, and pancreatic cancer.

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