NEW CRYSTAL FORM OF SODIUM-GLUCOSE CO-TRANSPORTER INHIBITOR PROCESSES FOR PREPARATION AND USE THEREOF
20190169219 ยท 2019-06-06
Assignee
Inventors
- Minhua Chen (Suzhou, Jiangsu, CN)
- Yanfeng Zhang (Suzhou, Jiangsu, CN)
- Po ZOU (Suzhou, Jiangsu, CN)
- Kai Liu (Suzhou, Jiangsu, CN)
- Xiaoyu ZHANG (Suzhou, Jiangsu, CN)
Cpc classification
C07H15/14
CHEMISTRY; METALLURGY
A61K31/7028
HUMAN NECESSITIES
International classification
Abstract
The present disclosure relates to novel crystalline forms of a sodium-glucose co-transporter inhibitor drug (Sotagliflozin), processes for preparation and use thereof. The present disclosure also relates to pharmaceutical composition comprises novel crystalline forms of Sotagliflozin and use of novel crystalline forms and pharmaceutical composition of Sotagliflozin for preparing drugs for treating diseases. The crystalline forms provided by the present disclosure have advantages of good stability, relatively low hygroscopicity, suitability for process development and post-treatment, simple processes for preparation, low cost, and has significant value for future drug optimization and development.
Claims
1. A crystalline Form I of Sotagliflozin, wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 3.60.2, 12.70.2 and 14.10.2 using CuK radiation.
2. The crystalline Form I according to claim 1, wherein the X-ray powder diffraction pattern shows one or two or three characteristic peaks at 2theta values of 15.60.2, 17.10.2 and 18.70.2 using CuK radiation.
3. The crystalline Form I according to claim 1, wherein the X-ray powder diffraction pattern shows one or two or three characteristic peaks at 2theta values of 9.00.2, 21.00.2 and 25.70.2 using CuK radiation.
4. A crystalline Form II of Sotagliflozin, wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 3.70.2, 4.50.2 and 14.60.2 using CuK radiation.
5. The crystalline Form II according to claim 4, wherein the X-ray powder diffraction pattern shows one or two or three characteristic peaks at 2theta values of 13.40.2, 18.10.2 and 6.20.2 using CuK radiation.
6. The crystalline Form II according to claim 4, wherein the X-ray powder diffraction pattern shows one or two or three characteristic peaks at 2theta values of 22.00.2, 10.60.2 and 15.90.2 using CuK radiation.
7. A crystalline Form III of Sotagliflozin, wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 4.30.2, 14.60.2 and 19.60.2 using CuK radiation.
8. The crystalline Form III according to claim 7, wherein the X-ray powder diffraction pattern shows one or two or three characteristic peaks at 2theta values of 4.90.2, 15.30.2 and 17.50.2 using CuK radiation.
9. The crystalline Form III according to claim 7, wherein the X-ray powder diffraction pattern shows one or two or three characteristic peaks at 2theta values of 12.80.2, 25.00.2 and 26.40.2 using CuK radiation.
10. A crystalline Form V of Sotagliflozin, wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 5.40.2, 9.90.2 and 19.70.2 using CuK radiation.
11. The crystalline Form V according to claim 10, wherein the X-ray powder diffraction pattern shows one or two or three characteristic peaks at 2theta values of 12.80.2, 13.60.2 and 15.10.2 using CuK radiation.
12. The crystalline Form V according to claim 10, wherein the X-ray powder diffraction pattern shows one or two or three characteristic peaks at 2theta values of 6.50.2, 18.20.2 and 20.40.2 using CuK radiation.
13. A crystalline Form VI of Sotagliflozin, wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 4.80.2, 9.50.2 and 14.50.2 using CuK radiation.
14. The crystalline Form VI according to claim 13, wherein the X-ray powder diffraction pattern shows one or two or three characteristic peaks at 2theta values of 11.10.2, 19.10.2 and 21.50.2 using CuK radiation.
15. The crystalline Form VI according to claim 13, wherein the X-ray powder diffraction pattern shows one or two or three characteristic peaks at 2theta values of 7.70.2, 20.00.2 and 25.40.2 using CuK radiation.
16. A crystalline Form VII of Sotagliflozin, wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 10.50.2, 13.80.2 and 15.80.2 using CuK radiation.
17. The crystalline Form VII according to claim 16, wherein the X-ray powder diffraction pattern shows one or two or three characteristic peaks at 2theta values of 16.70.2, 20.30.2 and 22.60.2 using CuK radiation.
18. The crystalline Form VII according to claim 16, wherein the X-ray powder diffraction pattern shows one or two or three characteristic peaks at 2theta values of 6.70.2, 18.50.2 and 19.10.2 using CuK radiation.
19. A crystalline Form VIII of Sotagliflozin, wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 6.20.2, 10.90.2 and 17.70.2 using CuK radiation.
20. The crystalline Form VIII according to claim 19, wherein the X-ray powder diffraction pattern shows one or two or three characteristic peaks at 2theta values of 14.90.2, 15.70.2 and 20.90.2 using CuK radiation.
21. The crystalline Form VIII according to claim 19, wherein the X-ray powder diffraction pattern shows one or two or three characteristic peaks at 2theta values of 10.40.2, 18.80.2 and 24.10.2 using CuK radiation.
22. A process for preparing crystalline Form I of Sotagliflozin according to claim 1, wherein the process comprises: 1) Dissolving a solid of Sotagliflozin into an alcohol, ketone or cyclic ether to obtain a solution, adding water slowly and dropwise into the solution or adding the solution dropwise into water to obtain a solid precipitation, then stirring the mixture at room temperature for 1-72 hours, filtering and drying to obtain a white solid; or 2) Adding a solid of Sotagliflozin into water to prepare a suspension, stirring at room temperature for 5-15 days, filtering and drying to obtain a white solid.
23. A process for preparing crystalline Form II of Sotagliflozin according to claim 4, wherein the process comprises: 1) Dissolving a solid of Sotagliflozin into an alkyl nitrile to obtain a Sotagliflozin solution, adding water slowly and dropwise into the solution or adding the solution dropwise into water to obtain a solid precipitation, then stirring the mixture at room temperature for 1-72 hours, filtering and drying to obtain a white solid; or 2) Dissolving a solid of Sotagliflozin into a cyclic ether or ester to obtain a Sotagliflozin solution, adding n-heptane dropwise into the solution or adding the solution dropwise into n-heptane to obtain a solid precipitation, then stirring the mixture at room temperature for 1-72 hours, filtering and drying to obtain a white solid; or 3) Dissolving a solid of Sotagliflozin into a ketone to obtain a Sotagliflozin solution, adding toluene dropwise into the solution or adding the solution dropwise into toluene to obtain a solid precipitation, then stirring the mixture at room temperature for 1-72 hours, filtering and drying to obtain a white solid; or 4) Suspending a solid of Sotagliflozin into a mixed solvent of a ketone or an alkyl nitrile with water, stirring at 50-75 C. for 5-20 days, filtering and drying.
24. A process for preparing crystalline Form III of Sotagliflozin according to claim 7, wherein the process comprises: dissolving a solid of Sotagliflozin into a halogenated alkane or a mixed solvent of a halogenated alkane and an alkane, slowly evaporating at room temperature to obtain a white solid.
25. A process for preparing crystalline Form V of Sotagliflozin according to claim 10, wherein the process comprises: dissolving a solid of Sotagliflozin into a mixed solvent of an alcohol and water at 40-70 C. to obtain a clear solution, transferring the obtained clear solution to a cool environment at 0-10 C., stirring for 12-96 hours, filtering and drying to obtain a white solid.
26. A process for preparing crystalline Form VI of Sotagliflozin according to claim 13, wherein the process comprises: suspending a solid of Sotagliflozin into water, stirring the suspension at 35-65 C. for 24-96 hours, filtering and drying to obtain the crystalline Form VI.
27. A process for preparing crystalline Form VII of Sotagliflozin according to claim 16, wherein the process comprises: heating a crystalline Form II of Sotagliflozin, of which the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 3.70.2, 4.50.2 and 14.60.2 using CuK radiation, to 90-100 C. with a heating rate of 5-10 C./min, and keeping at 90-100 C. for 0.5-5 minutes to obtain a white solid.
28. A process for preparing crystalline Form VIII of Sotagliflozin according to claim 19, wherein the process comprises: heating a crystalline Form V of Sotagliflozin, of which the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 5.40.2, 9.90.2 and 19.70.2 using CuK radiation, to 60-80 C., and keeping at 60-80 C. for more than 2 minutes to obtain said crystalline Form III.
29. A pharmaceutical composition, comprising a therapeutically effective amount of crystalline Form I according to claim 1 and pharmaceutically acceptable carriers, diluents or excipients.
30. A pharmaceutical composition, comprising a therapeutically effective amount of crystalline Form II according to claim 4 and pharmaceutically acceptable carriers, diluents or excipients.
31. A pharmaceutical composition, comprising a therapeutically effective amount of crystalline Form III according to claim 7 and pharmaceutically acceptable carriers, diluents or excipients.
32. A pharmaceutical composition, comprising a therapeutically effective amount of crystalline Form V according to claim 10 and pharmaceutically acceptable carriers, diluents or excipients.
Description
BRIEF DESCRIPTION OF DRAWINGS
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DETAILED DESCRIPTION OF THE DISCLOSURE
[0174] The present disclosure is further illustrated by the following examples which describe the preparation and use of the crystalline forms of the disclosure in detail. It is obvious to those skilled in the art that many changes in the materials and methods can be accomplished without departing from the scope of the disclosure.
[0175] The abbreviations used in the present disclosure are explained as follows:
[0176] XRPD: X-ray Powder Diffraction
[0177] DSC: Differential Scanning calorimetry
[0178] TGA: Thermal Gravimetric Analysis
[0179] DVS: Dynamic Vapor Sorption
[0180] PSD: Particle Size Distribution
[0181] PLM: Polarized Light microscopy
[0182] .sup.1H NMR: proton Nuclear Magnetic Resonance
[0183] MV: Average particle size based on volume
[0184] D10: The D10 describes the diameter where 10% of the distribution has a smaller particle size.
[0185] D50: The D50 describes the diameter where 50% of the distribution has a smaller particle size. The median is also called D50.
[0186] D90: The D90 describes the diameter where 90% of the distribution has a smaller particle size.
[0187] The instruments and methods used to collect data:
[0188] X-ray powder diffraction (XRPD) pattern in the present disclosure is acquired by a Panalytical Empyrean X-ray powder diffractometer. The parameters of the X-ray powder diffraction method of the present disclosure are as follows:
[0189] X-ray Reflection: Cu, K
[0190] K1 (): 1.540598; K2 (): 1.544426
[0191] K2/K1 intensity ratio: 0.50
[0192] Voltage: 45 (kV)
[0193] Current: 40 (mA)
[0194] Scan range: from 3.0 degree to 40.0 degree
[0195] The data of a differential scanning calorimetry (DSC) are acquired by a TA Instruments Q2000 MDSC, with Thermal Advantage as instrument control software and Universal Analysis as analysis software. Generally, 110 mg of sample is put into an aluminum crucible (unless otherwise specified, the aluminum crucible is covered). The temperature of sample was raised from room temperature to 300 C. with a heating rate of 10 C./min under the protection of dry nitrogen with a flow rate of 50 mL/min, while the TA software records the heat change of the sample during the heating process. In the present disclosure, melting point is reported based on DSC onset temperature.
[0196] The data of thermogravimetric analysis (TGA) are acquired by a TA Instruments Q5000 TGA, with Thermal Advantage as instrument control software and Universal Analysis as analysis software. Generally, 515 mg of sample is put into a platinum crucible. The temperature of sample was raised from room temperature to 300 C. with a heating rate of 10 C./min under the protection of dry nitrogen with a flow rate of 50 mL/min, while the TA software records the weight change of the sample during the heating process. The water content of the crystalline forms in the present disclosure is estimated and calculated according to the weight loss in TGA. As is known by those skilled in the art, weight loss in TGA is the reference of water content in crystalline forms, but does not necessarily represent the number of water molecules contained in crystalline forms.
[0197] Dynamic Vapor Sorption (DVS) is measured via a SMS (Surface Measurement Systems Ltd.) intrinsic DVS. Typical Parameters for DVS test are as follows:
[0198] Temperature: 25 C.
[0199] Gas and flow rate: N.sub.2, 200 mL/min
[0200] dm/dt: 0.002%/min
[0201] Relative Humidity (RH) range: 20% RH-95% RH-0% RH-95% RH
[0202] Proton Nuclear Magnetic Resonance (.sup.1HNMR) spectrum data are collected from a Bruker Avance II DMX 400M HZ NMR spectrometer. 1-5 mg of sample was weighed, dissolved in 0.5 mL of deuterated dimethyl sulfoxide or deuterochloroform to obtain a solution with the concentration of 2-10 mg/mL.
[0203] The result of particle size distribution (PSD) in the present disclosure was acquired by laser particle size analyzer with S3500 model from Microtrac Company. The Microtrac S3500 is equipped with a SDC (Sample Delivery Controller) sampling system. This experiment uses a wet method and the dispersion medium is Isopar G. The method and parameters of the laser particle size analyzer are as follows:
TABLE-US-00001 Size distribution: Volume distribution Run time: 10 s Dispersion medium: Isopar G Particle coordinates: Standard Run number: 3 Disperse medium refractive index: 1.42 Transparency: Transparent Residual: Enabled Particle refractive index: 1.5 Flow rate: 60%* Particle shape: Irregular Filtration: Enabled Ultrasonic power: 30 W Ultrasonic time: 30 s *Flow rate 60% is 60% of 65 mL/s.
[0204] The HPLC method parameters for purity test in the present disclosure are as follows:
TABLE-US-00002 HPLC Agilent 1100 with DAD detector Column Waters Xbridge C.sub.18, 150 4.6 mm, 5 m Mobile Phase A: 0.1% TFA (trifluoroacetic acid) in H.sub.2O B: 0.1% TFA (trifluoroacetic acid) in acetonitrile Time (min) % B Gradient 0.0 30 20.0 80 25.0 80 26.0 30 32.0 30 Time 32.0 min Flow rate 1.0 mL/min Injection Volume 5 L Detection wavelength 225 nm Column Temperature 40 C. Diluent ACN:H.sub.2O = 1:1
[0205] The HPLC method parameters for solubility test in the present disclosure are as follows:
TABLE-US-00003 HPLC Agilent 1100 with DAD detector Column Waters XBridge C18 150 * 4.6 mm, 5 m Mobile Phase H.sub.2O:ACN:TFA = 45:55:0.1 Time 6.0 min Flow rate 1.0 mL/min Injection Volume 5 L Detection wavelength UV at 230 nm, reference 500 nm Column Temperature 40 C. Diluent ACN:H.sub.2O = 1:1
[0206] Unless otherwise specified, the following examples were conducted at room temperature.
[0207] Raw materials of Sotagliflozin used in the following examples are prepared by the method disclosed in CN101343296B or purchased from market, or prepared according to the method in the present invention.
Example 1 Preparation of Form I of Sotagliflozin
[0208] 456.4 mg of Sotagliflozin was added into a 20-mL glass vial followed by adding 2.0 mL of acetone to form a clear solution. The clear solution was slowly added into 18 mL of water under magnetic stirring, and white solid precipitated immediately. The sample was stirred at room temperature for 3 days, then filtered and dried to obtain a white solid.
[0209] The solid obtained in example 1 conformed to Form I. The XRPD data were listed in Table 1, and the XRPD pattern was substantially as depicted in
TABLE-US-00004 TABLE 1 2theta () d spacing Intensity % 3.64 24.25 84.09 9.04 9.78 28.39 9.58 9.23 25.55 10.41 8.49 7.12 10.95 8.08 12.55 12.73 6.95 70.82 14.11 6.28 100.00 14.62 6.06 83.36 15.58 5.69 3.73 17.13 5.18 72.62 18.16 4.88 5.03 18.74 4.74 40.78 19.25 4.61 3.29 20.02 4.44 3.16 20.95 4.24 31.08 21.64 4.11 4.12 22.03 4.03 14.09 23.66 3.76 0.56 24.33 3.66 1.27 25.65 3.47 18.25 26.89 3.32 6.76 28.48 3.13 3.18 29.10 3.07 2.16 29.51 3.03 10.36 29.84 2.99 9.77 30.88 2.90 6.85 31.65 2.83 3.84 32.70 2.74 7.68 34.55 2.60 5.43 36.45 2.47 6.05 37.13 2.42 6.77 38.02 2.37 5.82 38.26 2.35 8.16 38.97 2.31 1.82
Example 2 Preparation of Form I of Sotagliflozin
[0210] 41.4 mg of Sotagliflozin was added into a 5-mL glass vial followed by adding 0.2 mL of acetone to form a clear solution. White precipitation appeared after 2.0 mL of H.sub.2O being slowly added under magnetic stirring. The sample was stirred for 24 hours, then filtered and dried to obtain a white solid.
[0211] The solid obtained in example 2 conformed to Form I. The XRPD data were listed in Table 2, and the XRPD pattern was substantially as depicted in
TABLE-US-00005 TABLE 2 2theta () d spacing Intensity % 3.63 24.36 100.00 9.11 9.71 13.21 9.61 9.21 11.92 12.79 6.92 27.92 14.18 6.24 38.88 14.65 6.05 25.53 15.65 5.66 14.91 17.15 5.17 26.56 18.81 4.72 15.44 19.78 4.49 8.52 21.05 4.22 26.59 21.74 4.09 20.20 22.05 4.03 7.39 23.52 3.78 4.64 25.70 3.47 10.65 26.92 3.31 19.09 27.69 3.22 3.52 28.44 3.14 5.24 29.59 3.02 5.66 29.89 2.99 6.85 30.97 2.89 2.83 32.76 2.73 5.37 33.86 2.65 3.17 34.69 2.59 1.96 36.55 2.46 6.01 37.27 2.41 3.91 38.41 2.34 5.52 39.03 2.31 2.15
Example 3 Preparation of Form I of Sotagliflozin
[0212] 8.1 mg of Sotagliflozin was added into a 1.5-mL glass vial followed by adding 0.2 mL of MeOH to form a clear solution. White precipitation appeared after 1.5 mL of H.sub.2O being slowly added under magnetic stirring. The sample was stirred at room temperature for 24 hours, then filtered and dried to obtain a white solid.
[0213] The solid obtained in example 3 conformed to Form I. The XRPD data were listed in Table 3, and the XRPD pattern was substantially as depicted in
TABLE-US-00006 TABLE 3 2theta () d spacing Intensity % 3.67 24.10 100.00 9.02 9.80 26.87 9.57 9.24 23.03 10.92 8.10 6.98 12.72 6.96 43.51 14.09 6.28 57.44 14.61 6.06 58.67 15.58 5.69 21.55 17.12 5.18 38.86 18.73 4.74 23.59 20.95 4.24 24.07 21.70 4.10 12.42 22.04 4.03 9.06 25.70 3.47 14.94 26.92 3.31 10.69 28.38 3.14 3.43 29.52 3.03 5.47 29.87 2.99 6.66 36.43 2.47 5.71 37.27 2.41 4.55 38.34 2.35 5.39
Example 4 Preparation of Form I of Sotagliflozin
[0214] 8.5 mg of Sotagliflozin was added into a 1.5-mL glass vial followed by adding 0.075 mL of acetone to form a clear solution. White precipitation appeared after 1.5 mL of H.sub.2O being slowly added under magnetic stirring. The sample was stirred at room temperature for 24 hours, then filtered and dried to obtain a white solid.
[0215] The solid obtained in example 4 conformed to Form I. The XRPD data were listed in Table 4, and the XRPD pattern was substantially as depicted in
TABLE-US-00007 TABLE 4 2theta () d spacing Intensity % 3.65 24.23 75.50 9.04 9.78 12.93 9.57 9.24 12.57 10.95 8.08 13.52 12.73 6.95 30.67 14.11 6.28 42.82 14.62 6.06 100.00 15.58 5.69 16.35 17.14 5.17 38.31 18.26 4.86 2.40 18.74 4.74 23.10 20.96 4.24 14.57 21.66 4.10 6.82 22.02 4.04 7.60 25.70 3.46 18.95 26.91 3.31 6.91 29.53 3.03 14.41 30.92 2.89 3.19 32.72 2.74 6.04 34.57 2.59 4.03 36.46 2.46 4.48 37.18 2.42 6.04 38.31 2.35 5.73
Example 5 Preparation of Form I of Sotagliflozin
[0216] 8.0 mg of Sotagliflozin was added into a 1.5-mL glass vial followed by adding 0.075 mL of THF to form a clear solution. The clear solution was slowly added into 1.5 mL of water under magnetic stirring, and white solid precipitated immediately. The sample was stirred at room temperature for 24 hours, then filtered and dried to obtain a white solid.
[0217] The solid obtained in example 5 conformed to Form I. The XRPD data were listed in Table 5, and the XRPD pattern was substantially as depicted in
TABLE-US-00008 TABLE 5 2theta () d spacing Intensity % 3.66 24.16 100.00 9.04 9.78 24.71 9.58 9.24 24.22 10.41 8.50 5.08 10.95 8.08 6.91 12.73 6.96 59.25 14.11 6.28 81.65 14.62 6.06 63.19 15.58 5.69 25.79 17.13 5.18 50.02 18.75 4.73 31.86 19.74 4.50 13.54 20.95 4.24 44.43 21.70 4.10 3.39 22.04 4.03 17.63 23.50 3.79 6.17 25.65 3.47 16.01 26.92 3.31 27.49 27.71 3.22 5.51 28.36 3.15 6.31 29.50 3.03 10.12 29.85 2.99 10.54 32.69 2.74 6.26 33.84 2.65 5.00 36.52 2.46 4.75 37.25 2.41 5.16 38.24 2.35 5.55
Example 6 Preparation of Form I of Sotagliflozin
[0218] 10.4 mg of Sotagliflozin (the existing crystalline Form 2) was added into a 1.5-mL glass vial followed by adding 0.5 mL of H.sub.2O to form a suspension. The suspension was stirred at room temperature for eight days, then filtered and dried to obtain a white solid.
[0219] The solid obtained in example 6 conformed to Form I. The XRPD data were listed in Table 6, and the XRPD pattern was substantially as depicted in
TABLE-US-00009 TABLE 6 2theta () d spacing Intensity % 3.66 24.16 100.00 9.04 9.78 17.51 9.58 9.23 17.83 10.39 8.51 4.94 10.93 8.10 14.52 12.73 6.95 50.78 14.10 6.28 74.17 14.61 6.06 81.09 15.59 5.69 26.51 17.13 5.18 54.75 18.73 4.74 28.86 19.74 4.50 7.45 20.97 4.24 29.78 21.69 4.10 20.67 22.03 4.04 10.90 23.50 3.79 4.90 25.70 3.47 21.77 26.87 3.32 16.11 28.46 3.14 7.14 29.50 3.03 10.43 30.76 2.91 4.27 32.73 2.74 6.95 34.52 2.60 3.69 36.46 2.46 6.10 37.16 2.42 7.14 38.21 2.36 6.20
Example 7 Preparation of Form II of Sotagliflozin
[0220] 39.5 mg of Sotagliflozin was added into a 20-mL glass vial followed by adding 0.8 mL of EtOAc to form a clear solution, and then 5.0 mL of n-heptane was slowly added under magnetic stirring. The sample was stirred for 24 hours, then filtered and dried to obtain a white solid.
[0221] The solid obtained in example 7 conformed to Form II. The XRPD data were listed in Table 7, and the XRPD pattern was substantially as depicted in
TABLE-US-00010 TABLE 7 2theta () d spacing Intensity % 3.63 24.32 53.76 4.44 19.90 37.45 5.26 16.81 16.15 6.22 14.21 13.53 7.26 12.18 14.75 7.90 11.19 20.16 9.14 9.68 20.00 10.57 8.37 31.29 12.42 7.12 15.47 13.40 6.61 46.21 14.16 6.25 30.33 14.61 6.06 100.00 15.89 5.58 38.14 18.15 4.89 52.34 18.69 4.75 15.15 19.04 4.66 15.39 19.42 4.57 21.35 20.92 4.25 17.99 22.02 4.04 40.68 22.41 3.97 16.00 23.30 3.82 11.21 23.88 3.73 11.99 25.01 3.56 17.21 25.42 3.50 12.17 25.84 3.45 18.31 26.62 3.35 10.16 29.12 3.07 7.60 29.44 3.03 8.05 30.16 2.96 6.94 31.39 2.85 5.29 32.08 2.79 5.09 34.42 2.61 3.17 37.03 2.43 1.76
Example 8 Preparation of Form II of Sotagliflozin
[0222] 8.5 mg of Sotagliflozin was added into a 1.5-mL glass vial followed by adding 0.3 mL of ACN to form a clear solution. White precipitation appeared after 1.5 mL of H.sub.2O being slowly added under magnetic stirring. The sample was stirred at room temperature for 24 hours, then filtered and dried to obtain a white solid.
[0223] The solid obtained in example 8 conformed to Form II. The XRPD data were listed in Table 8, and the XRPD pattern was substantially as depicted in
TABLE-US-00011 TABLE 8 2theta () d spacing Intensity % 3.67 24.05 79.75 4.47 19.78 51.83 5.29 16.71 27.66 6.19 14.29 18.29 7.30 12.11 23.28 7.92 11.17 13.55 9.13 9.69 10.12 10.58 8.36 13.10 13.37 6.62 13.13 14.17 6.25 10.22 14.61 6.06 100.00 15.89 5.58 9.98 18.13 4.89 39.54 19.05 4.66 7.84 20.91 4.25 6.52 22.03 4.03 34.58 23.91 3.72 4.26 24.99 3.56 3.97 25.40 3.51 7.21 25.88 3.44 10.78 29.48 3.03 5.47
Example 9 Preparation of Form II of Sotagliflozin
[0224] 8.4 mg of Sotagliflozin was added into a 1.5-mL glass vial followed by adding 0.075 mL of THF to form a clear solution. White precipitation appeared after 1.5 mL of n-heptane being slowly added under magnetic stirring. The sample was stirred at room temperature for 24 hours, then filtered and dried to obtain a white solid.
[0225] The solid obtained in example 9 conformed to be Form II. The XRPD data were listed in Table 9, and the XRPD pattern was substantially as depicted in
TABLE-US-00012 TABLE 9 2theta () d spacing Intensity % 3.65 24.21 100.00 4.44 19.88 91.39 5.28 16.73 36.18 6.20 14.26 24.64 7.27 12.16 13.40 7.91 11.18 15.39 9.11 9.71 13.78 10.56 8.38 17.31 12.42 7.12 6.32 13.38 6.62 25.51 14.60 6.07 78.78 15.87 5.58 16.26 18.15 4.89 32.76 19.39 4.58 6.67 20.89 4.25 5.87 22.03 4.04 20.43 25.84 3.45 5.58 29.16 3.06 1.83 34.17 2.62 1.61
Example 10 Preparation of Form II of Sotagliflozin
[0226] 8.4 mg of Sotagliflozin was added into a 1.5-mL glass vial followed by adding 0.075 mL of acetone to form a clear solution, and then 1.5 mL of Toluene was slowly added under magnetic stirring. The sample was stirred for 24 hours, then filtered and dried to obtain a white solid.
[0227] The solid obtained in example 10 conformed to be Form II. The XRPD data were listed in Table 10, and the XRPD pattern was substantially as depicted in
TABLE-US-00013 TABLE 10 2theta () d spacing Intensity % 3.65 24.20 47.15 4.43 19.93 71.37 5.28 16.74 26.67 6.18 14.30 20.56 7.28 12.14 12.33 7.91 11.17 14.46 9.13 9.68 17.08 10.58 8.36 20.02 10.93 8.09 8.25 12.40 7.14 8.83 13.39 6.62 40.04 14.19 6.24 15.74 14.60 6.07 100.00 15.90 5.57 22.02 18.15 4.89 38.85 18.64 4.76 7.78 19.46 4.56 9.65 20.95 4.24 8.48 21.38 4.16 6.51 22.03 4.03 29.40 22.45 3.96 8.03 23.31 3.82 4.95 23.95 3.72 4.57 24.48 3.64 4.12 24.99 3.56 8.52 25.44 3.50 7.14 25.90 3.44 10.55 26.67 3.34 3.35 29.51 3.03 4.74
Example 11 Preparation of Form II of Sotagliflozin
[0228] 8.3 mg of Sotagliflozin (the existing anhydrous crystalline Form 2) was added into a 1.5-mL glass vial followed by adding 0.35 mL of ACN/H.sub.2O (1:6, v/v). The sample was stirred at 70 C. for fourteen days, then filtered and dried to obtain a white solid.
[0229] The solid obtained in example 11 conformed to be Form II. The XRPD data were listed in Table 11, and the XRPD pattern was substantially as depicted in
TABLE-US-00014 TABLE 11 2theta () d spacing Intensity % 3.68 24.02 100.00 4.46 19.80 82.61 5.24 16.88 33.85 6.19 14.27 23.59 7.27 12.17 17.29 7.88 11.22 7.76 9.12 9.70 11.04 10.55 8.38 9.69 12.40 7.14 3.47 13.37 6.62 21.63 14.60 6.07 56.69 15.90 5.57 7.91 18.13 4.89 32.85 18.68 4.75 4.53 22.03 4.04 21.64 22.77 3.91 3.56 24.96 3.57 3.79 29.47 3.03 3.47 33.30 2.69 1.56 33.89 2.65 1.99
Example 12 Preparation of Form II of Sotagliflozin
[0230] 8.3 mg of Sotagliflozin (the existing crystalline Form 2) was added into a 1.5-mL glass vial followed by adding 0.35 mL of acetone/H.sub.2O (1:6, v/v), and then the glass vial was capped. The sample was stirred at 70 C. for fourteen days, then filtered and dried to obtain a white solid.
[0231] The solid obtained in example 12 conformed to Form II. The XRPD data were listed in Table 12, and the XRPD pattern was substantially as depicted in
TABLE-US-00015 TABLE 12 2theta () d spacing Intensity % 3.67 24.07 100.00 4.45 19.87 33.61 6.16 14.35 11.16 7.27 12.15 10.97 9.12 9.70 9.69 10.57 8.37 4.22 10.96 8.07 5.43 12.44 7.11 3.09 13.38 6.62 8.40 14.61 6.06 59.97 15.19 5.83 2.45 15.89 5.58 3.27 18.13 4.89 16.88 18.67 4.75 2.45 19.46 4.56 1.69 21.68 4.10 4.95 22.02 4.04 30.32 25.00 3.56 3.33 25.42 3.50 3.67 25.86 3.45 2.82 29.50 3.03 5.79 30.95 2.89 1.11 32.22 2.78 1.35 33.31 2.69 2.29 34.55 2.60 1.23
Example 13 Preparation of Form III of Sotagliflozin
[0232] 39.2 mg of Sotagliflozin was added into a 3-mL glass vial followed by adding 1.0 mL of CHCl.sub.3 to form a clear solution. The white solid was obtained after slow evaporation at room temperature.
[0233] The solid obtained in example 13 conformed to Form III. The XRPD data were listed in Table 13, and the XRPD pattern was substantially as depicted in
TABLE-US-00016 TABLE 13 2theta () d spacing Intensity % 3.62 24.42 23.29 4.33 20.39 100.00 4.95 17.87 32.99 7.29 12.12 11.62 8.15 10.85 6.78 8.96 9.87 13.75 11.17 7.92 6.23 12.53 7.06 8.09 12.84 6.89 14.94 13.31 6.65 7.65 14.65 6.05 75.97 14.93 5.93 44.75 15.32 5.78 30.60 15.64 5.67 17.28 16.35 5.42 4.06 17.47 5.08 22.73 17.96 4.94 7.73 18.61 4.77 15.04 19.60 4.53 42.47 20.97 4.24 6.70 21.53 4.13 15.24 22.01 4.04 5.30 22.48 3.95 8.56 22.93 3.88 7.08 23.97 3.71 5.64 24.57 3.62 10.61 25.01 3.56 9.38 25.89 3.44 4.87 26.35 3.38 11.83 26.65 3.34 5.17 28.38 3.15 2.37 28.74 3.11 3.28 29.86 2.99 3.45 33.67 2.66 2.12 35.41 2.53 1.46 36.53 2.46 1.94 37.25 2.41 2.75 38.46 2.34 2.17 40.01 2.25 2.38
Example 14 Preparation of Form III of Sotagliflozin
[0234] 5.4 mg of Sotagliflozin was added into a 1.5-mL glass vial followed by adding 0.5 mL of CHCl.sub.3/n-heptane (4:1, v/v) to form a clear solution. The white solid was obtained after slow evaporation at room temperature.
[0235] The solid obtained in example 14 conformed to Form III. The XRPD data were listed in Table 14, and the XRPD pattern was substantially as depicted in
TABLE-US-00017 TABLE 14 2theta () d spacing Intensity % 4.33 20.40 100.00 4.95 17.86 12.22 12.83 6.90 7.66 14.65 6.05 47.35 14.93 5.94 19.25 15.33 5.78 31.70 16.35 5.42 2.64 17.47 5.08 32.43 18.61 4.77 5.76 19.61 4.53 46.30 20.71 4.29 1.99 21.51 4.13 3.87 22.45 3.96 5.19 24.00 3.71 3.10 25.02 3.56 9.91 26.36 3.38 14.22 28.38 3.14 2.38 33.11 2.71 2.85 33.94 2.64 2.53 35.38 2.54 2.11 37.32 2.41 1.75
Example 15 Preparation of Form V of Sotagliflozin
[0236] 44.3 mg of Sotagliflozin was added into a 5-mL glass vial followed by adding 4 mL of MeOH/H.sub.2O (1:1, v/v) to form a clear solution at 50 C. The clear solution was stirred at 5 C. for three days to obtain a white solid.
[0237] The solid obtained in example 15 conformed to Form V. The XRPD data were listed in Table 15, and the XRPD pattern was substantially as depicted in
TABLE-US-00018 TABLE 15 2theta () d spacing Intensity % 5.42 16.30 100.00 6.54 13.52 28.05 6.83 12.95 11.09 7.60 11.63 4.48 8.12 10.89 3.11 9.19 9.62 7.06 9.90 8.93 76.05 10.48 8.44 17.21 12.24 7.23 7.96 12.80 6.92 35.18 13.11 6.75 6.18 13.63 6.50 17.96 15.12 5.86 27.13 15.47 5.73 7.98 15.64 5.67 6.59 15.93 5.56 14.04 17.60 5.04 8.76 18.18 4.88 13.48 19.74 4.50 38.20 20.42 4.35 11.13 21.88 4.06 9.62 22.30 3.99 3.88 23.65 3.76 9.75 24.19 3.68 7.87 25.07 3.55 4.58 27.47 3.25 6.05 29.45 3.03 5.02 30.78 2.91 0.93 31.69 2.82 1.11
Example 16 Preparation of Form V of Sotagliflozin
[0238] 101.8 mg of Sotagliflozin was added into a 20-mL glass vial followed by adding 10 mL of MeOH/H.sub.2O (2:3, v/v) to form a clear solution at 50 C. The clear solution was stirred at 5 C. for 24 hours to obtain a white solid.
[0239] The solid obtained in example 16 conformed to Form V. The XRPD data were listed in Table 16, and the XRPD pattern was substantially as depicted in
TABLE-US-00019 TABLE 16 2theta () d spacing Intensity % 5.42 16.30 93.32 6.53 13.54 41.77 6.83 12.95 23.87 7.61 11.62 10.71 9.18 9.63 12.99 9.90 8.93 100.00 10.48 8.44 35.35 12.25 7.23 16.13 12.80 6.92 57.47 13.12 6.75 9.19 13.62 6.50 39.72 15.13 5.86 31.65 15.45 5.73 12.61 15.64 5.67 12.42 15.94 5.56 17.52 17.59 5.04 13.03 18.18 4.88 27.23 19.74 4.50 51.29 20.43 4.35 19.73 21.90 4.06 12.93 22.29 3.99 6.02 23.67 3.76 14.82 24.21 3.68 13.74 25.08 3.55 5.95 27.48 3.25 8.99 29.52 3.03 5.95 30.88 2.90 3.78 35.25 2.55 1.96
Example 17 Preparation of Form VI of Sotagliflozin
[0240] 115.0 mg of Sotagliflozin (the existing crystalline Form 2) was added into a 5-mL glass vial followed by adding 3 mL of H.sub.2O. The sample was stirred at 50 C. for seven days, then filtered and dried to obtain a white solid.
[0241] The solid obtained in example 17 conformed to Form VI. The XRPD data were listed in Table 17, and the XRPD pattern was substantially as depicted in
TABLE-US-00020 TABLE 17 2theta () d spacing Intensity % 4.80 18.40 51.47 7.24 12.21 4.53 7.74 11.42 31.73 9.51 9.30 100.00 10.68 8.28 25.89 11.06 8.00 18.51 12.88 6.87 3.30 13.35 6.63 6.08 14.13 6.27 31.24 14.51 6.10 62.42 14.69 6.03 52.57 15.55 5.70 17.29 16.13 5.49 3.38 17.67 5.02 2.74 18.61 4.77 15.45 19.12 4.64 32.12 19.41 4.57 7.35 20.00 4.44 25.15 20.60 4.31 8.63 21.50 4.13 31.60 21.93 4.05 3.05 22.26 3.99 4.14 23.77 3.74 6.45 24.32 3.66 4.16 25.42 3.50 23.31 26.48 3.37 4.08 28.87 3.09 6.83 29.65 3.01 13.05 30.88 2.90 2.08 33.54 2.67 1.77 34.48 2.60 2.60 38.64 2.33 0.70
Example 18 Preparation of Form VI of Sotagliflozin
[0242] 18.8 mg of Sotagliflozin (the existing crystalline Form 2) was added into a 1.5-mL glass vial followed by adding 0.8 mL of H.sub.2O. The sample was stirred at 50 C. for three days, then filtered and dried to obtain a white solid.
[0243] The solid obtained in example 18 conformed to Form VI. The XRPD data were listed in Table 18, and the XRPD pattern was substantially as depicted in
TABLE-US-00021 TABLE 18 2theta () d spacing Intensity % 3.61 24.50 18.95 4.81 18.39 92.45 5.97 14.80 10.94 7.71 11.47 14.56 9.51 9.30 100.00 10.66 8.30 18.48 11.05 8.00 23.13 14.14 6.27 38.35 14.51 6.11 94.71 14.70 6.03 58.36 15.55 5.70 10.64 19.11 4.64 46.22 19.42 4.57 12.30 20.00 4.44 30.50 20.59 4.31 8.40 21.50 4.13 30.51 23.75 3.75 12.87 24.33 3.66 6.56 25.41 3.51 34.58 28.89 3.09 11.62 29.64 3.01 18.86 38.58 2.33 1.20
Example 19 Preparation of Form VII of Sotagliflozin
[0244] 5.6 mg of Sotagliflozin (crystalline Form II of the present disclosure) was heated to 90 C. at a heating rate of 10 C./min by programmed temperature controlling, and then kept at 90 C. for 0.5 min to obtain a white solid.
[0245] The solid obtained in example 19 conformed to Form VII. The XRPD data were listed in Table 19, and the XRPD pattern was substantially as depicted in
TABLE-US-00022 TABLE 19 2theta () d spacing Intensity % 3.43 25.76 28.08 6.74 13.12 10.21 9.25 9.56 3.52 10.52 8.41 28.05 11.55 7.66 9.82 12.25 7.23 5.05 13.41 6.60 15.73 13.77 6.43 100.00 15.84 5.60 25.97 16.76 5.29 24.87 18.55 4.78 13.04 19.14 4.64 13.51 20.29 4.38 19.00 20.98 4.23 10.62 22.01 4.04 5.70 22.62 3.93 15.97 23.36 3.81 9.77 24.00 3.71 6.79 25.18 3.54 2.98 26.19 3.40 6.94 26.56 3.36 9.66 27.50 3.24 4.22 28.79 3.10 2.89 31.04 2.88 5.03 32.37 2.77 2.28 33.87 2.65 5.02 34.53 2.60 4.13 37.52 2.40 1.20
Example 20 Preparation of Form VIII of Sotagliflozin
[0246] 1.7 mg of Sotagliflozin (crystalline Form V of the present disclosure) was heated to 65 C. at a heating rate of 10 C./min by programmed temperature controlling, and then kept at 65 C. for 2 min to obtain a white solid.
[0247] The solid obtained in example 20 conformed to Form VIII. The XRPD data were listed in Table 20, and the XRPD pattern was substantially as depicted in
TABLE-US-00023 TABLE 20 2theta () d spacing Intensity % 6.23 14.19 100.00 6.44 13.72 52.98 8.91 9.93 2.27 10.37 8.53 27.84 10.89 8.12 70.03 12.50 7.08 9.74 13.68 6.47 6.05 14.88 5.95 54.69 15.74 5.63 41.14 17.71 5.01 72.38 18.32 4.84 18.25 18.82 4.72 33.91 19.43 4.57 10.41 19.92 4.46 12.53 20.86 4.26 66.09 21.12 4.21 42.29 21.85 4.07 15.63 24.13 3.69 34.81 26.26 3.39 12.55 27.52 3.24 10.01 28.23 3.16 7.13 29.87 2.99 3.93 31.60 2.83 7.07 33.16 2.70 7.22 37.17 2.42 3.12
Example 21 Stability Study
[0248] The mixture of existing crystalline Form 2 disclosed in CN102112483A, Form I and Form II was stirred in several solvent systems with different water activity (a.sub.w). After stirring for 70 hours, residual solids were analyzed by XRPD, and the results were listed in Table 21.
TABLE-US-00024 TABLE 21 Solvent system a.sub.w Initial form Final form H.sub.2O/IPA = 6:94 0.5 Form 2, Form I, Form II Form II H.sub.2O/IPA = 11:89 0.7 Form 2, Form I, Form II Form II H.sub.2O/IPA = 15:85 0.8 Form 2, Form I, Form II Form II H.sub.2O/IPA = 23:77 0.9 Form 2, Form I, Form II Form II H.sub.2O/IPA = 35:65 0.95 Form 2, Form I, Form II Form II H.sub.2O 1.0 Form 2, Form I, Form II Form I
[0249] The results indicate that Form I and Form II were more stable than Form 2 in high water activity (high humidity, 50% RH) environment.
[0250] It should be noted that the solvent systems for different water activity (a.sub.w) include but not limit to H.sub.2O and IPA. The same conclusion could be drawn with this experiment in other solvent systems suitable for the preparation of different water activity (a.sub.w).
Example 22 Hygroscopicity Assessment of Form I of the Present Invention
[0251] Dynamic vapor sorption (DVS) was applied to test hygroscopicity of crystalline Form I with 13.8 mg of sample Form I at 25 C. The weight gains at each relative humidity were recorded in a cycle of 20%-95%-0%-95% RH. Crystalline Form I had a low hygroscopicity with a 3.55% weight gain under 80% RH. The result was listed in Table 22 and the DVS plot was shown in
TABLE-US-00025 TABLE 22 Relative Humidity (RH) Weight gain under Form change before Weight gain (%) 80% RH and after DVS Form I 3.55% No form change
Example 23 Hygroscopicity Assessment of Form II of the Present Invention
[0252] Dynamic vapor sorption (DVS) was applied to test hygroscopicity of Form II with 10.4 mg of sample Form II at 25 C. The weight gains at each relative humidity were recorded in a cycle of 20%-95%-0%-95% RH. Form II had a low hygroscopicity with a 2.46% weight gain under 80% RH. The result was listed in Table 23 and the DVS plot was shown in
TABLE-US-00026 TABLE 23 Relative Humidity (RH) Weight gain under Form change before Weight gain (%) 80% RH and after DVS Form II 2.46% No form change
Example 24 Hygroscopicity Assessment of Form III of the Present Invention
[0253] Dynamic vapor sorption (DVS) was applied to test hygroscopicity of Form III with 9.1 mg of sample Form III at 25 C. The weight gains at each relative humidity were recorded in a cycle of 20%-95%-0%-95% RH. Form III had a low hygroscopicity with a 0.13% weight gain under 80% RH. The result was listed in Table 24 and the DVS plot was shown in
TABLE-US-00027 TABLE 24 Relative Humidity (RH) Weight gain under Form change before Weight gain (%) 80% RH and after DVS Form III 0.13% No form change
Example 25 Hygroscopicity Assessment of Form VI of the Present Invention
[0254] Dynamic vapor sorption (DVS) was applied to test hygroscopicity of Form VI with 4.5 mg of sample Form VI at 25 C. The weight gains at each relative humidity were recorded in a cycle of 20%-95%-0%-95% RH. Form VI had a low hygroscopicity with a 1.80% weight gain under 80% RH. The result was listed in Table 25 and the DVS plot was shown in
TABLE-US-00028 TABLE 25 Relative Humidity (RH) Weight gain under Form change before Weight gain (%) 80% RH and after DVS Form VI 1.80% No form change
Example 26 Dynamic Solubility
[0255] Saturated solutions of Form I, Form II, Form III, Form VII and the existing crystalline Form 2 in SGF (Simulated gastric fluids) were prepared. Saturated solutions of Form II, Form III, Form VII, Form VIII and the existing crystalline Form 2 in FaSSIF (Fasted state simulated intestinal fluids, pH=6.5) were prepared. After equilibrated for 1 hour, concentrations of the saturated solutions were measured by High Performance Liquid Chromatography (HPLC). The results were listed in Table 26 and Table 27. The results showed that the solubility of Form I, Form III and Form VII were 1.7 times, 2.2 times and 2.5 times as high as that of the existing crystalline Form 2 in SGF, respectively. The solubility of Form III, Form VII and Form VIII were 1.4 times, 1.5 times and 1.4 times as high as that of the existing crystalline Form 2 in FaSSIF, respectively.
TABLE-US-00029 TABLE 26 Solubility Media:SGF 1 hour (mg/mL) Form I 0.10 Form II 0.08 Form III 0.13 Form VII 0.15 Form 2 0.06
TABLE-US-00030 TABLE 27 Solubility Media:SGF 1 hour (mg/mL) Form II 0.15 Form III 0.18 Form VII 0.20 Form VIII 0.18 Form 2 0.13
Example 27 Stability Study
[0256] Form I, Form II, Form III and Form VI were stored under different conditions of 25 C./60% RH and 40 C./75% RH for 3 months. XRPD was applied to detect the crystalline forms. The XRPD overlay of Form I, Form II, Form III and Form VI before and after stored under above two conditions were shown in
TABLE-US-00031 TABLE 28 Storage Solid Form Initial Form Conditions time after storage Form I (the top 25 C./60% RH 3 Form I (the middle pattern in FIG. 44) months pattern in FIG. 44) 40 C./75% RH 3 Form I (the bottom months pattern in FIG. 44) Form II (the top 25 C./60% RH 3 Form II (the middle pattern in FIG. 45) months pattern in FIG. 45) 40 C./75% RH 3 Form II (the bottom months pattern in FIG. 45) Form III (the top 25 C./60% RH 3 Form III (the middle pattern in FIG. 46) months pattern in FIG. 46) 40 C./75% RH 3 Form III (the bottom months pattern in FIG. 46) Form VI (the top 25 C./60% RH 3 Form VI (the middle pattern in FIG. 47) months pattern in FIG. 47) 40 C./75% RH 3 Form VI (the bottom months pattern in FIG. 47)
Example 28 Morphology Assessment
[0257] The existing crystalline Form 2 and Form I in the present disclosure were tested by polarized light microscopy. The PLM results of the Form 2 and Form I were shown in
[0258] The results showed that existing crystalline Form 2 had a needle-like shape, while Form I in the present disclosure had a rod-like shape with uniform particle size distribution. The uniform particle size distribution was beneficial to the post-treatment of drug development and improved quality control. As depicted in
Example 29 Particle Size Distribution Assessment
[0259] Certain amount of Form I, Form V, Form VIII and existing crystalline Form 2 were taken for particle size distribution test, and the results were shown in Table 29.
TABLE-US-00032 TABLE 29 Solid form MV (m) SD D10 (m) D50 (m) D90 (m) Form 2 60.43 59.06 2.32 45.00 144.4 Form I 14.48 9.76 3.34 8.97 31.63 Form V 32.70 24.46 4.38 18.81 72.98 Form VIII 51.93 37.50 7.30 36.60 112.4
[0260] The particle size distribution diagram of the existing crystalline Form 2, Form I, Form V and Form VIII were shown in
[0261] The results showed that the particle size distribution of existing crystalline Form 2 was wide and bimodal, which supposed to be caused by agglomeration. The nonuniform particle size distribution and particle agglomeration had a very negative impact on the content uniformity of drug product, thereby having effects on dissolution, absorption of drug substance, and may causing variation of absorption or dissolution profile between batches. Inversely, the particle size distribution of Form I, Form V and Form VIII were narrow and normal. The uniform particle size distribution was beneficial to the content uniformity of drug product, which could also simplify the process and have a positive impact on drug development.
Example 30 Mechanical Stability Assessment
[0262] Solid sample of Form I, Form VI and the existing crystalline Form 2 were ground manually for 5 minutes in mortar. XRPD was applied to detect the crystalline form. The XRPD overlay of Form I, Form VI and the existing crystalline Form 2 before and after grinding were listed from
TABLE-US-00033 TABLE 30 Initial form Final form Crystallinity Form I Form I Decreased (Slightly amorphous) Form VI Form VI Decreased (Slightly amorphous) Form 2 Form 2 Decreased (Mainly amorphous)
[0263] The results showed that no crystalline form change of Form I and Form VI were observed under certain mechanical stress. Physical and chemical properties of Form I and Form VI could remain unchanged with only slightly decreased crystallinity and little amount of amorphous appeared. Inversely, the existing crystalline Form 2 had poor mechanical stability with significantly decreased crystallinity and large amount of amorphous appeared. Form I and Form VI are more suitable for drug preparation, storage and crystallization process because they had better mechanical stability than that of the existing crystalline Form 2.
Example 31 Hygroscopicity Assessment of Form VII of the Present Invention
[0264] Dynamic vapor sorption (DVS) was applied to test hygroscopicity of Form VII with 11.5 mg of sample Form VII at 25 C. The weight gains at each relative humidity were recorded in a cycle of 0%-95%-0% RH. Form VII had a low hygroscopicity with a 1.08% weight gain under 80% RH. The result was listed in Table 31 and the DVS plot was shown in
TABLE-US-00034 TABLE 31 Relative Humidity (RH) Weight gain under Form change before Weight gain (%) 80% RH and after DVS Form VII 1.08% No form change
Example 32 Hygroscopicity Assessment of Form VIII of the Present Invention
[0265] Dynamic vapor sorption (DVS) was applied to test hygroscopicity of Form VIII with 10.6 mg of sample Form VIII at 25 C. The weight gains at each relative humidity were recorded in a cycle of 0%-95%-0% RH. Form VIII had a low hygroscopicity with a 0.60% weight gain under 80% RH. The result was listed in Table 32 and the DVS plot was shown in
TABLE-US-00035 TABLE 32 Relative Humidity (RH) Weight gain under Form change before Weight gain (%) 80% RH and after DVS Form VIII 0.60% No form change
[0266] Those skilled in the art will understand that, under the teachings of this specification, it can make some modifications or variations of the present disclosure. Such modifications and variations are also in the scope of claims defined in the present disclosure.