Crystalline forms of GSK1278863, preparation method and pharmaceutical use thereof
11649217 · 2023-05-16
Assignee
Inventors
Cpc classification
International classification
Abstract
The present disclosure relates to crystalline form CS1 and CS9 of a hypoxia-inducible factor prolyl hydroxylase inhibitor compound (I) GSK1278863, processes for preparation, and uses for preparing drugs treating and/or preventing anemia thereof. ##STR00001##
Claims
1. A composition of crystalline Form CS1 of N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxo-5-pyrimidinyl)carbonyl]-glycine, wherein the X-ray powder diffraction pattern of Form CS1 shows characteristic peaks at 2theta values of 6.4°±0.2°, 7.5°±0.2°, and 7.9°±0.2° using CuKα radiation, and wherein the content of other crystalline forms is less than 10% (w/w).
2. The composition according to claim 1, wherein the X-ray powder diffraction pattern of Form CS1 shows one or more characteristic peaks at 2theta values of 17.2°±0.2°, 21.0°±0.2°, 24.0°±0.2°, and 19.3°±0.2° using CuKα radiation.
3. The composition according to claim 1, wherein the X-ray powder diffraction pattern of Form CS1 is substantially as depicted in
4. The composition according to claim 1, wherein the Form CS1 has an endothermic peak at around 242° C. as measured by differential scanning calorimetry using a heating rate of 10° C./min and a purge gas of nitrogen.
5. The composition according to claim 1, wherein the chemical purity of Form CS1 is higher than 99%.
6. The composition according to claim 5, wherein the chemical purity remains substantially unchanged when the composition is stored under conditions of 60° C. 75% RH for 3 months.
7. A composition of crystalline Form CS9 of N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxo-5-pyrimidinyl)carbonyl]-glycine, wherein the X-ray powder diffraction pattern of Form CS9 shows characteristic peaks at 2theta values of 4.6°±0.2°, 6.6°±0.2°, and 21.1°±0.2° using CuKα radiation, and wherein the content of other crystalline forms is less than 10% (w/w).
8. The composition according to claim 7, wherein the X-ray powder diffraction pattern of Form CS9 shows one or more characteristic peaks at 2theta values of 9.4°±0.2°, 20.2°±0.2°, and 24.2°±0.2° using CuKα radiation.
9. The composition according to claim 7, wherein the X-ray powder diffraction pattern of Form CS9 is substantially as depicted in
10. The composition according to claim 7, wherein Form CS9 has a first endothermic peak at around 145° C. and a second endothermic peak at around 237° C. as measured by differential scanning calorimetry using a heating rate of 10° C./min and a purge gas of nitrogen.
11. The composition according to claim 7, wherein the chemical purity of Form CS9 is higher than 99%.
12. The composition according to claim 11, wherein the chemical purity remains substantially unchanged when the composition is stored under conditions of 60° C./75% RH for 1 month.
13. A pharmaceutical composition, wherein said pharmaceutical composition comprises a therapeutically effective amount of the composition of crystalline Form CS1 according to claim 1, and pharmaceutically acceptable carriers, diluents or excipients.
14. A pharmaceutical composition according to claim 13, wherein the crystalline form does not change following one-month storage at 40° C./75% RH.
15. A method of treating anemia, comprising administering to a subject in need thereof a therapeutically effective amount of the composition of crystalline Form CS1 according to claim 1.
16. A pharmaceutical composition, wherein said pharmaceutical composition comprises a therapeutically effective amount of the composition of crystalline Form CS9 according to claim 7, and pharmaceutically acceptable carriers, diluents or excipients.
17. A pharmaceutical composition according to claim 16, wherein the crystalline form does not change following one-month storage at 40° C./75% RH.
18. A method of treating anemia, comprising administering to a subject in need thereof a therapeutically effective amount of the composition of crystalline Form CS9 according to claim 7.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
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DETAILED DESCRIPTION
(20) The present disclosure is further illustrated by the following examples which describe the preparation and use of the crystalline forms of the present 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 present disclosure.
The abbreviations used in the present disclosure are explained as follows:
(21) XRPD: X-ray Powder Diffraction
(22) DSC: Differential Scanning calorimetry
(23) TGA: Thermal Gravimetric Analysis
(24) .sup.1H NMR: Proton Nuclear Magnetic Resonance
(25) DMSO: Dimethyl sulfoxide
(26) Instruments and Methods Used for Data Collection
(27) X-ray powder diffraction patterns in the present disclosure were acquired by a Panalytical Empyrean X-ray powder diffractometer. The parameters of the X-ray powder diffraction method of the present disclosure were as follows:
(28) X-ray Reflection: Cu, Kα
(29) Kα1 (Å): 1.540598; Kα2 (Å): 1.544426
(30) Kα2/Kα1 intensity ratio: 0.50
(31) Voltage: 45 (kV)
(32) Current: 40 (mA)
(33) Scan range: from 3.0 degree to 40.0 degree
(34) Differential scanning calorimetry (DSC) data in the present disclosure were acquired by a TA Q2000. The parameters of the DSC method of the present disclosure were as follows:
(35) Heating rate: 10° C./min
(36) Purge gas: nitrogen
(37) Thermal gravimetric analysis (TGA) data in the present disclosure were acquired by a TA Q500. The parameters of the TGA method of the present disclosure were as follows:
(38) Heating rate: 10° C./min
(39) Purge gas: nitrogen
(40) Proton nuclear magnetic resonance spectrum data CH NMR) were collected from a Bruker Avance II DMX 400M HZ NMR spectrometer. 1-5 mg of sample was weighed, and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to obtain a solution with a concentration of 2-10 mg/mL.
High Performance Liquid Chromatography (HPLC) data of purity test in the present disclosure were collected from an Agilent 1260 with UV Variable Wavelength Detector (VWD). The HPLC method parameters for purity test in the present disclosure are as follows:
(41) Column: Waters XBridge C8, 150×4.6 mm, 3.5 μm
(42) Mobile Phase: A: 0.1% TFA in H.sub.2O B: 0.1% TFA in Acetonitrile
(43) Gradient:
(44) TABLE-US-00001 Time (min) % B 0.0 20 5.0 50 30.0 80 35.0 80 35.1 20 40.0 20
(45) Flow rate: 1.0 mL/min
(46) Injection Volume: 34
(47) Column Temperature: 40° C.
(48) Diluent: MeOH
(49) High Performance Liquid Chromatography (HPLC) data of solubility test in the present disclosure were collected from an Agilent 1260 with UV Variable Wavelength Detector (VWD). The HPLC method parameters are as follows:
(50) The HPLC method parameters for solubility test in the present disclosure are as follows:
(51) Column: Waters XBridge C8 150×4.6 mm, 5 μm
(52) Mobile Phase: A: 0.1% TFA in H.sub.2O B: 0.1% TFA in Acetonitrile
(53) Gradient:
(54) TABLE-US-00002 Time (min) % B 0.0 65 10.0 80 12.0 80 12.1 65 16.0 65
(55) Flow rate: 1.1 mL/min
(56) Injection Volume: 5 μL
(57) Column Temperature: 40° C.
(58) Diluent: MeOH
(59) Unless otherwise specified, the following examples were conducted at room temperature.
(60) Raw materials of GSK1278863 used in the following examples were prepared by known methods in the prior art, for example, the method disclosed in CN101505752B. The prior art solid in the following examples refer to the solid of GSK1278863 obtained by repeating the preparation method disclosed in CN101505752B.
Example 1˜4: Preparation of Form CS1
Example 1
(61) 6.4 mg of GSK1278863 was weighed and dissolved in 0.5 mL of tetrahydrofuran. The obtained solution was evaporated at room temperature for about 2 days to precipitate solid. The obtained solid was confirmed to be Form CS1. The XRPD pattern is substantially as depicted in
(62) The .sup.1H NMR spectrum of Form CS1 is substantially as depicted in
(63) The DSC curve of Form CS1 is substantially as depicted in
(64) The TGA curve of Form CS1 shows about 0.6% weight loss when heated to 150° C., which is substantially as depicted in
(65) TABLE-US-00003 TABLE 1 Diffraction d Intensity angle 2θ spacing % 3.94 22.44 7.43 5.53 15.98 3.05 6.41 13.80 41.18 7.51 11.77 100.00 7.94 11.14 52.84 10.16 8.71 1.90 12.80 6.91 2.00 13.47 6.57 2.08 15.20 5.83 5.68 15.89 5.58 2.92 17.15 5.17 15.13 18.52 4.79 3.88 19.25 4.61 13.52 19.92 4.46 7.60 20.41 4.35 11.08 20.99 4.23 24.54 22.60 3.93 2.29 24.04 3.70 10.32 26.08 3.42 2.46 27.19 3.28 2.23 32.89 2.72 0.61
Example 2˜3
(66) As shown in Table 2, certain amount of GSK1278863 was weighed and dissolved in corresponding solvents. The obtained solution was evaporated at 50° C. to obtain solid. The solid obtained in example 2 and example 3 was collected and labeled as sample 2 and sample 3. Sample 2 and sample 3 were confirmed to be Form CS1. Sample 2 was selected for tests. The XRPD pattern is substantially as depicted in
(67) TABLE-US-00004 TABLE 2 Amount Volume Example (mg) Solvent (mL) Label 2 6.7 Methyl 0.7 2 isobutyl ketone 3 6.6 Acetone 0.7 3
(68) TABLE-US-00005 TABLE 3 Diffraction angle 2θ d spacing Intensity % 3.93 22.47 5.30 6.35 13.93 37.90 7.53 11.75 100.00 7.92 11.17 41.23 10.12 8.74 1.65 12.80 6.92 2.37 13.44 6.59 2.83 15.19 5.83 6.22 15.92 5.57 0.81 17.13 5.18 8.90 18.60 4.77 1.07 19.27 4.61 14.44 19.75 4.50 7.17 20.00 4.44 5.18 20.41 4.35 5.27 21.00 4.23 28.87 22.64 3.93 1.35 24.02 3.71 7.91 25.04 3.56 1.66 26.11 3.41 2.34 27.24 3.27 1.55 28.18 3.17 0.69 28.83 3.10 0.58 32.76 2.73 0.86 36.60 2.46 0.50
Example 4
(69) 10.1 mg of GSK1278863 was weighed and dissolved in 0.5 mL of 1, 4-dioxane. Then, 2.0 mL of water was added dropwise as an anti-solvent. The obtained solution was stirred at room temperature for 2 h, centrifuged, and dried under vacuum to obtain crystalline solid. The obtained solid was confirmed to be Form CS1.
Example 5˜6: Preparation of Form CS9
Example 5
(70) 4.6 mg of GSK1278863 was weighed and dissolved in 0.7 mL methyl tert-butyl ether solvent, followed by adding polymer. The polymer was composed of polycaprolactone, polyoxyethylene, polymethyl methacrylate, hydroxyethyl cellulose, and sodium alginate of equal masses. The solution was evaporated at 50° C. for about 1 day to precipitate solid. The obtained solid was confirmed to be Form CS9. The XRPD pattern is substantially as depicted in
(71) The .sup.1H NMR spectrum of Form CS9 is substantially as depicted in
(72) TABLE-US-00006 TABLE 4 Diffraction angle 2θ d spacing Intensity % 4.58 19.29 19.65 6.56 13.47 100.00 9.37 9.44 13.93 10.50 8.43 4.37 13.34 6.64 2.86 15.10 5.87 1.57 17.13 5.18 4.23 18.51 4.79 1.99 19.54 4.54 4.14 20.18 4.40 17.65 21.14 4.20 15.46 24.23 3.67 7.74 30.20 2.96 0.63
Example 6
(73) 6.9 mg of GSK1278863 raw materials was weighed and dissolved in 0.7 mL of ethyl acetate:ethanol (V/V, 1:1). The obtained solution was evaporated at 50° C. for about 4 days to precipitate solid. The obtained solid was confirmed to be Form CS9.
(74) The DSC curve of Form CS9 is substantially as depicted in
(75) The TGA curve of Form CS9 shows about 0.2% weight loss when heated to 150° C., which is substantially as depicted in
Example 7: Hygroscopicity Comparison of Form CS1, Form CS9 and the Prior Art Solid
(76) Dynamic vapor sorption (DVS) was applied to test hygroscopicity of Form CS1, Form CS9 and the prior art solid with about 10 mg of samples under 25° C. The results are listed in Table 5. The DVS plots of Form CS1, Form CS9 and the prior art solid are substantially as depicted in
(77) TABLE-US-00007 TABLE 5 Comparison of hygroscopicity Weight gain under Form 80% Relative Humidity Form CS1 0.53% Form CS9 0.22% The prior art solid 1.14%
(78) The result indicates that under 25° C./80% RH, Form CS1 and Form CS9 can hardly absorb water and gain weight. Form CS1 and Form CS9 are very stable at high humidity conditions and not hygroscopic. In comparison, the prior art solid shows higher weight gain and higher hygroscopicity under the same conditions.
(79) Crystalline form with low hygroscopicity doesn't require special drying conditions during the preparation process, which simplifies the preparation and post-treatment process of the drug and is easy for industrial production. Form CS1 and Form CS9 of the present disclosure have lower hygroscopicity than the prior art solid, which reduces the requirements of the storage environment. For example, it doesn't require special storage humidity, which reduces the cost and is beneficial for long-term storage of drug substance and drug products.
Example 8: Purity Comparison of Form CS1, Form CS9 and the Prior Art Solid
(80) HPLC was applied to test the chemical purity of Form CS1, Form CS9 and prior art solid. The results are listed in Table 6.
(81) TABLE-US-00008 TABLE 6 Form Form The prior Form CS1 CS9 art solid Purity 99.88% 99.86% 81.06% Impurities 0.12% 0.14% 18.94% content
(82) The purity of the drug substance is important for ensuring the efficacy and safety of the drug products and preventing the adverse drug reactions. The impurity content of the prior art solid is extremely high, up to 18.94%, which will lead to significantly lowered active ingredient content or reduced drug activity. High impurity content will also lead to significantly increased toxicity and side effects of the drug products. Therefore, the prior art solid cannot be used directly in the preparation of drug products.
(83) The crystalline forms of the present disclosure have high purity, which meets the strict requirements for the purity of the drug substance in the formulations, and is suitable for the subsequent formulation preparation and drug production.
Example 9: Stability Assessment of Form CS1
(84) Form CS1 was stored under different conditions of 25° C./60% RH, 40° C./75% RH and 60° C./75% RH. The XRPD pattern overlay before and after being stored is substantially as depicted in
(85) TABLE-US-00009 TABLE 7 Initial Solid form solid form Condition Time after storage Form CS1 25° C./60% RH 3 months Form CS1 (Top of FIG. 13) (Bottom of FIG. 13) Form CS1 40° C./75% RH 3 months Form CS1 (Top of FIG. 14) (Bottom of FIG. 14) Form CS1 60° C./75% RH 3 months Form CS1 (Top of FIG. 15) (Bottom of FIG. 15)
(86) Furthermore, the inventors also studied the purity change of Form CS1 before and after being stored under the conditions of 25° C./60% RH, 40° C./75% RH and 60° C./75% RH for 3 months, and the results are shown in Table 8.
(87) TABLE-US-00010 TABLE 8 Initial Purity after Purity Condition purity 3 months change 25° C./60% RH 99.88% 99.78% 0.10% 40° C./75% RH 99.81% 0.07% 60° C./75% RH 99.81% 0.07%
(88) Form CS1 of the present disclosure doesn't change for at least 3 months when stored under the condition of 25° C./60% RH, 40° C./75% RH and 60° C./75% RH, indicating that Form CS1 has good physical stability. The chemical purity remains substantially unchanged during storage, which indicates that Form CS1 does not degrade easily and has good chemical stability.
(89) As active pharmaceutical ingredient plays an important part in drug products, it is vital that the crystalline active pharmaceutical ingredient has good physical and chemical stability. Good physical stability of Form CS1 avoids crystal transformation during the storage and formulation processes, thereby ensuring consistent and controllable quality of the drug substance and drug products.
(90) During the storage of drug products, the purity decrease will result in significantly lower drug substance content and reduced drug activity. The decrease in purity also significantly increase the toxicity and side effects, affecting the efficacy and safety of drug products. Good chemical stability of Form CS1 makes the purity keep basically unchanged during storage, which is of great significance to ensure the efficacy and safety of drugs and prevent the occurrence of adverse drug effects. In addition, stable crystalline form is more controllable in the crystallization process, and less prone to impurities and mixed crystals, which is conducive to industrial production.
(91) The stability of drug products containing Form CS1 can be forecasted from the stability results of Form CS1 drug substance, providing a guarantee for the preparation of stable drug products.
Example 10: Stability Assessment of Form CS9
(92) Form CS9 was stored under different conditions of 25° C./60% RH, 40° C./75% RH and 60° C./75% RH. The XRPD pattern overlay before and after being stored is substantially as depicted in
(93) TABLE-US-00011 TABLE 9 Initial Solid form solid form Condition Time after storage Form CS9 25° C./60% RH 3 months Form CS9 (Top of FIG. 16) (Bottom of FIG. 16) Form CS9 40° C./75% RH 3 months Form CS9 (Top of FIG. 17) (Bottom of FIG. 17) Form CS9 60° C./75% RH 3 months Form CS9 (Top of FIG. 18) (Bottom of FIG. 18)
(94) Furthermore, the inventors also studied the purity change of Form CS9 before and after being stored under the conditions of 25° C./60% RH, 40° C./75% RH and 60° C./75% RH for 1 month, and the results are shown in Table 10.
(95) TABLE-US-00012 TABLE 10 Initial Purity after Purity Condition purity 3 months change 25° C./60% RH 99.88% 99.72% 0.16% 40° C./75% RH 99.78% 0.10% 60° C./75% RH 99.76% 0.12%
(96) The crystalline form of Form CS9 of the present disclosure doesn't change for at least 3 months and the chemical purity remains for at least 1 month when stored under the condition of 25° C./60% RH, 40° C./75% RH and 60° C./75% RH, indicating that Form CS9 has good physical stability. The crystalline of Form CS9 remains substantially unchanged during storage, which indicates that Form CS9 does not degrade easily, providing a guarantee for the preparation of stable drug products.
Example 11: Kinetic Solubility of Form CS1 and Form CS9
(97) Solubility test method according to the Chinese Pharmacopoeia was used and different pHs of different organs in human body were considered. According to the above two references, a solvent media set with four pH values range from 1.2 to 7.5 were designed in the present disclosure. Specifically: SGF (Simulated gastric fluids, pH=1.8), FeSSIF (Fed state simulated intestinal fluids, pH=5.0), FaSSIF (Fasted state simulated intestinal fluids, pH=6.5), and pure water were used.
(98) Form CS1 and Form CS9 of the present disclosure were suspended into SGF, FeSSIF, FaSSIF and H.sub.2O to obtain saturated solutions. The solutions were sampled at fixed time points. Concentrations of the saturated solutions were measured by HPLC to measure the kinetic solubility of Form CS1 and Form CS9. The results are listed in Table 11 and 12.
(99) TABLE-US-00013 TABLE 11 Kinetic solubility of Form CS1 Solvent Solubility (mg/mL) media 1 h 4 h 24 h SGF 0.0031 0.0031 0.0030 FeSSIF 0.19 0.19 0.16 FaSSIF 0.063 0.050 0.027 H.sub.2O 0.014 0.026 0.016
(100) TABLE-US-00014 TABLE 12 Kinetic solubility of Form CS9 Solvent Solubility (mg/mL) media 1 h 4 h 24 h SGF 0.0039 0.0042 0.0093 FeSSIF 0.15 0.17 0.14 FaSSIF 0.058 0.081 0.081 H.sub.2O 0.020 0.038 0.060
(101) Solubility is one of the key properties of drug substance, which directly affects the absorption of drugs in human body. The solubility of different crystalline forms may be remarkably different, and the in vivo absorption dynamics may also change, which results in different bioavailability and ultimately affects the clinical safety and efficacy of drugs.
(102) Compound (I) is a poorly water-soluble drug. For poorly water-soluble drug, increasing solubility is even more important. Increase in solubility is conducive to increasing the bioavailability of drugs, thereby increasing the possibility of a successful drug products. In addition, the drug dose reduction without affecting efficacy is possible due to higher solubility, thereby reducing the side effects and improving the safety of drugs.
(103) Form CS1 and Form CS9 of the present disclosure have good solubility in SGF, FeSSIF, FaSSIF and pure water, providing guarantee for the good dissolution of the crystalline drug substance in the drug products, which is beneficial to the in vivo absorption of active ingredients in drugs, achieving ideal bioavailability and efficacy.
Example 12: Flowability of Form CS1 and Form CS9
(104) According to the United States Pharmacopeia (USP) 1174, flowability of Form CS1 and Form CS9 of the present disclosure were evaluated by the compressibility index. The bulk density, tapped density of Form CS1 and Form CS9 were tested, and compressibility index was calculated. The results are listed in Table 13.
(105) 1. Test method:
(106) Samples: Form CS1 and Form CS9
(107) Instrument: Tap density tester
(108) Utensil: 5 mL measuring cylinder
(109) Number of tapping: 500 times
Bulk density=m/v.sub.Q(Mass/volume before tapping)
Tapped density=m/v.sub.t(Mass/volume after tapping)
(110) 2. Calculation formula: compressibility index (%)=(tapped density−bulk density)/tapped density×100%
(111) 3. Test results:
(112) TABLE-US-00015 TABLE 13 Bulk Tapped density density Compressibility Form (g/mL) (g/mL) index (%) Flowability CS1 0.15 0.19 21 Passable CS9 0.11 0.14 21 Passable * Scale of flowability (according to US Pharmacopoeia 1174); compressibility index ≤10%, excellent flowability; 11%~15%, good flowability; 16%-20%, fair flowability; 21%-25%, passable flowability; 26%~31%, poor flowability; 32%~37%, very poor flowability; >38%, extremely poor flowability.
(113) The results show that the flowability of Form CS1 and Form CS9 of the present disclosure meets the requirements for formulation development, ensures the blend uniformity and content uniformity of the drug products, reduces the weight variation of the drug products and improves product quality, which is suitable for medicinal use.
Example 13: Study of Form CS1 and Form CS9 in Drug Products
(114) 1. Preparation of GSK1278863 Tablets:
(115) Form CS1 or Form CS9 of GSK1278863, microcrystalline cellulose, croscarmellose sodium and magnesium stearate were weighed according to formulation in Table 14 and blended for 2 minutes. The tablets were prepared using a manual tablet press at 5KN±1 KN pressure with a φ7 mm round tooling. The tablets tablet weight is 100 mg±1 mg. The obtained tablets were packed in 35 cc HDPE bottles (one tablet per bottle) with 1 g desiccant. The bottles were sealed with a sealer. The crystalline form of Form CS1 and Form CS9 drug substance doesn't change before and after formulation process.
(116) TABLE-US-00016 TABLE 14 Quantity Mass ratio Component (mg/unit) (%) Form CS1 or Form CS9 12.50 12.50 Microcrystalline Cellulose 81.50 81.50 Croscarmellose Sodium 5.00 5.00 Magnesium Stearate 1.00 1.00 Total 100 100
(117) 2. In Vitro Dissolution Profile:
(118) In vitro dissolution test was performed on obtained tablets and dissolution method according to Chinese Pharmacopoeia 2015<0931> was used. The conditions are as follows:
(119) Medium: pH=6.8 phosphate buffer solution+1% sodium dodecyl sulfate aqueous solution
(120) Method: Paddle
(121) Volume: 900 mL
(122) Speed: 75 rpm
(123) Temperature: 37° C.
(124) Dissolution results of Form CS1 are presented in Table 15 and
(125) Dissolution is a prerequisite for absorption. Good in vitro dissolution allows drugs to have a higher area under the curve (AUC) in the body, that is, higher in vivo absorption and better in vivo exposure, thereby improving drug's bioavailability and efficacy. High dissolution rate makes the drug have a shorter peak time (T.sub.max) and a higher peak concentration (C.sub.max) in the body, which is beneficial for the drug to achieve peak plasma concentration quickly after administration, thus ensuring rapid drug action.
(126) TABLE-US-00017 TABLE 15 Cumulative drug release (%) Time (min) Form CS1 5 0.0 10 67.7 20 75.8 30 84.8 45 90.1 60 95.2 90 98.3 120 102.5
(127) 3. Stability of Form CS1 and Form CS9 in Drug Products:
(128) The above obtained tablets were stored under 40° C./675% RH condition for 1 month. After testing, the crystalline form of Form CS1 and Form CS9 drug substance in the drug products does not change. The results are shown in Table 16, which indicate that Form CS1 and Form CS9 have good stability in the drug products.
(129) TABLE-US-00018 TABLE 16 Stability of Form CS1 and Form CS9 in drug products Crystalline forms of Sample Condition Time API after storage Tablets with Form CS1 40 °C./75% RH 1 month Form CS1 Tablets with Form CS9 40 °C./75% RH 1 month Form CS9
(130) Form CS1 and Form CS9 of the present disclosure have good stability in the drug products. Form CS1 and Form CS9 don't readily convert to other crystal forms during the formulation and storage process, ensuring the consistent and controllable quality of drug products.
(131) The examples described above are only for illustrating the technical concepts and features of the present disclosure, and intended to make those skilled in the art being able to understand the present disclosure and thereby implement it, and should not be concluded to limit the protective scope of this disclosure. Any equivalent variations or modifications according to the spirit of the present disclosure should be covered by the protective scope of the present disclosure.