Crystal form of upadacitinib, preparation method therefor, and use thereof
11572365 · 2023-02-07
Assignee
Inventors
Cpc classification
A61P29/00
HUMAN NECESSITIES
A61K31/4985
HUMAN NECESSITIES
International classification
Abstract
Crystalline forms of upadacitinib and processes for preparation thereof are disclosed. The present disclosure also relates to pharmaceutical compositions containing the upadacitinib crystalline forms, use of the upadacitinib crystalline forms for preparing JAK1 inhibitor drugs, and use of the upadacitinib crystalline forms for preparing drugs treating rheumatoid arthritis, Crohn's disease, ulcerative colitis, atopic dermatitis and psoriatic arthritis. The crystalline forms of upadacitinib provided by the present disclosure have one or more improved properties compared with prior arts and have significant values for future drug optimization and development. ##STR00001##
Claims
1. A crystalline form CSVI of upadacitinib, wherein crystalline form CSVI is a co-crystal of upadacitinib and succinic acid ##STR00003##
2. The crystalline form CSVI according to claim 1, wherein the crystalline form CSVI exhibits an X-ray powder diffraction pattern comprising one or two or three characteristic peaks at 2theta values of 4.7°±0.2°, 6.2°±0.2° and 22.7°±0.2° using CuKα radiation.
3. The crystalline form CSVI according to claim 1, wherein the crystalline form CSVI exhibits an X-ray powder diffraction pattern comprising one or two or three characteristic peaks at 2theta values of 15.8°±0.2°, 17.3°±0.2° and 23.5°±0.2° using CuKα radiation.
4. The crystalline form CSVI according to claim 1, wherein the crystalline form CSVI exhibits an X-ray powder diffraction pattern comprising one or two or three characteristic peaks at 2theta values of 11.1°±0.2°, 14.1°±0.2° and 13.1° 0.2° using CuKα radiation.
5. The crystalline form CSVI according to claim 1, wherein the crystallilne form CSVI exhibits an X-ray powder diffraction pattern is comprising as depicted in
6. A process for preparing crystalline form CSVI according to claim 1, wherein the process comprises: 1) adding upadacitinib and succinic acid into a mixture of an ester and an ether, stirring to obtain crystalline form CSVI, or 2) adding upadacitinib and succinic acid into a mixture of an ether, an alcohol, water and an alkane, or a mixture of an alcohol and an alkane, stirring to obtain crystalline form CSVI.
7. The process according to claim 6, wherein said ester is isopropyl acetate, said ether is methyl tert-butyl ether, said alcohol is n-propanol, isopropanol, isobutyl alcohol or n-butanol, said alkane is n-heptane.
8. A crystalline form CSVII of upadacitinib, wherein crystalline form CSVII is a co-crystal of upadacitinib and adipic acid ##STR00004##
9. The crystalline form CSVII according to claim 8, wherein the crystalline form CSVII exhibis an X-ray powder diffraction pattern comprising one or two or three characteristic peaks at 2theta values of 4.8°±0.2°, 6.0°±0.2° and 22.4°±0.2° using CuKα radiation.
10. The crystalline form CSVII according to claim 8, wherein crystalline form CSVII exhibits an X-ray powder diffraction pattern comprising one or two or three characteristic peaks at 2theta values of 21.1°±0.2°, 15.4°±0.2° and 16.2°±0.2° using CuKα radiation.
11. The crystalline form CSVII according to claim 8, wherein the crystalline form CSVII exhibits an X-ray powder diffraction pattern comprising one or two or three characteristic peaks at 2theta values of 25.4°±0.2°, 12.8°±0.2° and 20.2°±0.2° using CuKα radiation.
12. The crystalline form CSVII according to claim 8, wherein the crystalline form CSVII exhibits an X-ray powder diffraction pattern as depicted in
13. A process for preparing crystalline form CSVII according to claim 8, wherein the process comprises: 1) adding upadacitinib and adipic acid into a mixture of an ester and an ether, stirring to obtain crystalline form CSVII, or 2) adding upadacitinib and adipic acid into a mixture of an alcohol and an alkane, stirring, isolation, and then drying to obtain crystalline form CSVII.
14. The process according to claim 13, wherein said ester is isopropyl acetate, said ether is methyl tert-butyl ether, said alcohol is n-propanol, isopropanol, n-butanol or isobutyl alcohol, said alkane is n-heptane.
15. A pharmaceutical composition, wherein said pharmaceutical composition comprises a therapeutically effective amount of crystalline form CSVI according to claim 1 and pharmaceutically acceptable excipients.
16. A pharmaceutical composition, wherein said pharmaceutical composition comprises a therapeutically effective amount of crystalline form CSVII according to claim 8, and pharmaceutically acceptable excipients.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
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DESCRIPTION OF PREFERRED EMBODIMENTS
(19) 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.
(20) The abbreviations used in the present disclosure are explained as follows: XRPD: X-ray Powder Diffraction DSC: Differential Scanning Calorimetry TGA: Thermo Gravimetric Analysis DVS: Dynamic Vapor Sorption .sup.1H NMR: Proton Nuclear Magnetic Resonance HPLC: High Performance Liquid Chromatography FaSSIF: Fasted-state simulated intestinal fluid FeSSIF: Fed-state simulated intestinal fluid PBS: Phosphate Buffered Saline RPM: Revolutions Per Minute
(21) Instruments and methods used for data collection:
(22) X-ray powder diffraction patterns in the present disclosure were acquired by a Bruker D2 PHASER X-ray powder diffractometer. The parameters of the X-ray powder diffraction method of the present disclosure are as follows: X-Ray: Cu, Kα Kα1 (Å): 1.54060. Kα2 (Å): 1.54439 Kα2/Kα1 intensity ratio: 0.50 Voltage: 30 (kV) Current: 10 (mA) Scan range (2θ): from 3.0 degree to 40.0 degree
(23) Thermo gravimetric analysis (TGA) data in the present disclosure were acquired by a TA Q500. The parameters of the TGA method of the present disclosure are as follows: Heating rate: 10° C./min Purge gas: nitrogen
(24) 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 are as follows: Heating rate: 10° C./min, unless otherwise specified. Purge gas: nitrogen
(25) Dynamic Vapor Sorption (DVS) is measured via an SMS (Surface Measurement Systems Ltd.) intrinsic DVS instrument. Its control software is DVS-Intrinsic control software. Typical parameters for DVS test are as follows: Temperature: 25° C. Gas and flow rate: N.sub.2, 200 mL/min RH range: 0% RH to 95% RH
(26) Proton nuclear magnetic resonance spectrum data (H 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 or deuterated methanol to obtain a solution with a concentration of 2-10 mg/mL.
(27) The method parameters of stoichiometric ratio test in the resent disclosure are as follows:
(28) TABLE-US-00001 HPLC Agilent 1260 with VWD Column Welch Ultimate OAA, 4.6 * 300 m Mobile phase A: 10 mM KH.sub.2PO.sub.4 aqueous solution (pH = 2.0, H.sub.3PO.sub.4) B: Acetonitrile Gradient Time (min) % B 0.0 5 15.0 40 20.0 80 25.0 80 25.1 5 35.0 5 Running time 35.0 min Equilibration time 0.0 min Flow rate 0.8 mL/min Injection volume 5 μL Detection wavelength UV 205 nm, 270 nm Column Temperature 32° C. Temperature of sample Room Temperature tray Diluent 30% acetonitrile aqueous solution (volume ratio)
(29) The method parameters of kinetic solubility test in the present disclosure are as follows:
(30) TABLE-US-00002 HPLC Waters ACQUITY UPLC H-Class PLUS with PDA Column ACE Excel 3 C18, 3.0 * 100 mm, 3.0 μm Mobile phase A: 10 mM KH.sub.2PO.sub.4 aqueous solution (pH = 4.5, H.sub.3PO.sub.4) B: Acetonitrile Gradient Time (min) % B 0.0 20 1.0 20 8.5 50 13.0 80 15.0 80 16.0 20 18.0 20 Running time 18.0 min Equilibration time 0.0 min Flow rate 0.5 mL/min Injection volume 1 μL Detection wavelength UV 210 nm Column Temperature 40° C. Temperature of sample Room Temperature tray Diluent 50% acetonitrile aqueous solution (volume ratio)
(31) The method parameters for related substances test in the present disclosure are as follows:
(32) TABLE-US-00003 HPLC Agilent 1260 with VWD/DAD Column Waters Xbridge C18, 4.6 * 250 mm, 5.0 μm Mobile phase A: 10 mM ammonium acetate aqueous solution (pH 7.5, TEA):acetonitrile = 95:5 (v/v) B: Acetonitrile:Methanol = 70:30 (v/v) Gradient Time (min) % B 0.0 20 20.0 50 35.0 90 38.0 90 38.1 20 45.0 20 Running time 45.0 min Equilibrium time 0.0 min Flow rate 0.8 mL/min Injection volume 5 μL Detection wavelength UV 230 nm Column temperature 35° C. Temperature of sample Room Temperature tray Diluent 50% acetonitrile aqueous solution (volume ratio)
(33) The method parameters for drug products dissolution measurement in the present disclosure are as follows:
(34) TABLE-US-00004 HPLC Waters ACQUITY UPLC H-Class PLUS with PDA Column ACE Excel 3 C18, 3.0 * 100 mm, 3.0 μm Mobile phase A: 10 mM KH.sub.2PO.sub.4 aqueous solution (pH 4.5, H.sub.3PO.sub.4) B: Acetonitrile Gradient Time (min) % B 0.0 20 1.0 20 8.5 50 13.0 80 15.0 80 16.0 20 18.0 20 Running time 18.0 min Equilibration time 0.0 min Flow rate 0.5 mL/min Injection volume 5 μL Detection wavelength UV 210 nm Column Temperature 40° C. Temperature of sample Room Temperature tray Diluent 50% acetonitrile aqueous solution (volume ratio)
(35) According to the present disclosure, upadacitinib and/or its salt used as a raw material is solid (crystalline or amorphous), oil, liquid form or solution. Preferably, upadacitinib and/or its salt used as a raw material is a solid.
(36) Upadacitinib and/or a salt thereof used in the following examples (corresponding to the starting materials in the examples) were prepared by known methods, for example, the method disclosed in WO2017066775A1. Unless otherwise specified, the following examples were conducted at room temperature.
EXAMPLES
Example 1 Preparation of Form CSVI
(37) 16.9 mg of upadacitinib and 9.8 mg of succinic acid were weighed into a glass vial, and 0.3 mL of isopropyl acetate/tert-butyl methyl ether (1:2, v/v) saturated with water was added. Then the sample was transferred to an oven at 35° C. and stirred for about 4 days, and another 0.2 mL of isopropyl acetate/tert-butyl methyl ether (1:2, v/v) saturated with water was added. The sample was stirred in the oven at 35° C. for about another 3 days, and a solid was obtained after isolation. The solid was stored under 40° C./75% RI open condition for about 2 days, then Form CSVI was obtained. The XRPD pattern of Form CSVI is substantially as depicted in
(38) TABLE-US-00005 TABLE 1 2θ d spacing Intensity % 4.72 18.73 52.19 6.21 14.24 77.65 9.52 9.29 26.73 9.80 9.03 11.71 10.23 8.64 6.46 11.08 7.98 18.00 12.10 7.32 7.39 12.42 7.13 19.62 13.12 6.75 28.53 14.14 6.26 25.18 14.88 5.96 15.80 15.78 5.62 37.64 16.17 5.48 44.29 16.89 5.25 15.79 17.30 5.13 41.84 17.96 4.94 37.99 18.82 4.72 36.14 19.17 4.63 31.44 20.23 4.39 54.54 20.48 4.34 36.16 20.80 4.27 34.07 21.32 4.17 38.36 22.25 3.99 33.58 22.65 3.93 100.00 23.48 3.79 35.96 24.81 3.59 25.39 25.57 3.48 27.12 27.40 3.26 16.48 27.96 3.19 10.11 30.04 2.97 6.19
Example 2 Preparation of Form CSVI
(39) 1.1086 g of upadacitinib and 0.5140 g of succinic acid were weighed into a glass vial, and 19.5 mL of tert-butyl methyl ether/isopropyl alcohol/water (10:1:0.1, v/v/v) was added. The sample was stirred at 55° C. for 50 minutes, then 55.4 mg of Form CSVI seed was added. After stirring at 55° C. for another 17.5 hours, the sample was cooled to 45° C. and stirred for 1 hour.
(40) Then the sample was cooled to 40° C. and stirred for 190 minutes, then cooled to 35° C. and stirred for 280 minutes, and cooled to 25° C. and stirred for 1 day. Another 1.0 mL of tert-butyl methyl ether/isopropyl alcohol/water (10:1:0.1, v/v/v) and 3.0 mL of n-heptane were added, and the sample was stirred at 25° C. for about 4 days. Another 5.0 mL of n-heptane was added, and the solid was isolated after stirring at 25° C. for another 5 hours (The temperature of all the above procedures was controlled by a hotplate stirrer). The isolated solid was vacuum dried at 75° C. for about 17.5 hours and placed under 40° C./75% RH in open condition for about 5 days, then Form CSVI was obtained. The TGA curve of Form CSVI shows about 1.2% weight loss when heated to 100° C., which is substantially as depicted in
Example 3 Preparation of Form CSVI
(41) 1.0236 g of upadacitinib and 0.2796 g of succinic acid were dissolved in 6 mL of n-propanol, and the solution was filtered into a jacketed reactor whose temperature was 60° C. After mechanical stirring for about 5-10 minutes, 10 mL of n-heptane was added slowly. 0.0500 g of Form CSVI was weighed and dispersed evenly in 2 mL of n-heptane. Next the suspension was added into the reactor. The system was aged at 60° C. for about 1 hour and cooled to 35° C. (in 5 hours). After aging at 35° C. for about 13 hours, 18 mL of n-heptane was added drop by drop (taking 3 hours) and the system was aged for another hour. The system was cooled to 5° C. (taking 3 hours) and aged for about 15 hours. The wet cake obtained by filtration was dried at room temperature for about 9 hours, followed by vacuum drying in oven at 75° C. for about 38 hours. The dried solid was jet milled (the feeding pressure is 0.3 MPa, the milling pressure is 0.1 MPa) and vacuum dried in oven at 75° C. for about 23 hours, then Form CSVI was obtained. The DSC curve of Form CSVI is substantially as depicted in
Example 4 Preparation of Form CSVI
(42) 1.0237 g of upadacitinib and 0.3413 g of succinic acid were dissolved in 6 mL of n-propanol, and the solution was filtered into a jacketed reactor whose temperature was 60° C. After mechanical stirring for about 5-10 minutes, 10 mL of n-heptane was added slowly. 0.0500 g of Form CSVI was weighed then dispersed evenly in 2 mL of n-heptane, next the suspension was added into the reactor. The system was aged at 60° C. for about 1 hour and cooled to 35° C. (taking 5 hours). After aging at 35° C. for about 13 hours, 18 mL of n-heptane was added drop by drop (taking 3 hours) and the system was aged for another hour. The reaction mass was cooled to 5° C. (taking 3 hours) and aged for about 15 hours. The wet cake obtained by filtration was dried at room temperature for about 9 hours, followed by vacuum drying in oven at 75° C. for about 38 hours. The dried solid was jet milled (the feeding pressure was 0.3 MPa, the milling pressure was 0.1 MPa) and vacuum dried in oven at 75° C. for about 23 hours, then Form CSVI was obtained. The molar ratio of succinic acid to upadacitinib in Form CSVI is 0.85:1 determined by HPLC.
Example 5 Kinetic Solubility of Form CSVI
(43) The solubility of Form C is disclosed in WO2017066775A1. Approximately 15-30 mg of Form CSVI in the present disclosure was suspended into 1.8 mL of FeSSIF, 1.8 mL of FaSSIF and 1.8 mL of pH=7.4 PBS. After equilibration for 24 hours and 48 hours, the concentration of upadacitinib in saturated solutions were tested by HPLC and the results are listed in Table 2.
(44) TABLE-US-00006 TABLE 2 Solubility Form C (mg/mL) Form CSVI (mg/mL) Media 24-48 hours 24 hours 48 hours FeSSIF (pH 5.0, 37° C.) 0.47 2.20 2.22 FaSSIF (pH 6.5, 37° C.) 0.22 1.87 1.71 pH 7.4, 25° C. 0.19 0.88 0.85
The results show that Form CSVI has higher solubility in FeSSIF, FaSSIF and pH=7.4 PBS.
Example 6 Stability of Form CSVI
(45) Approximately 5 mg of Form CSVI in the present disclosure was stored under 40° C./75% RH and 60° C./75% RH conditions. The purity and crystalline form were tested before and after storage by HPLC and XRPD. The results are listed in Table 3 and the XRPD overlay is substantially as depicted in
(46) TABLE-US-00007 TABLE 3 Condition Time Solid form Purity Initial — Form CSVI 99.89% 40° C./75% RH Sealed 6 months Form CSVI 99.92% Open 6 months Form CSVI 99.89% 60° C./75% RH Sealed 1 month Form CSVI 99.91%
(47) The results show that Form CSVI is stable for at least 6 months under 40° C./75% RH (sealed) and 40° C./75% RH (open) conditions. It can be seen that Form CSVI has good stability under accelerated conditions. Form CSVI is stable for at least 1 month under 60° C./75% RH (sealed) condition. It can be seen that Form CSVI has good stability under more stressed condition as well. Approximately 10 mg of Form CSVI in the present disclosure underwent a humidity cycle of 0% RH-95% RH-0% RH with a dynamic vapor sorption (DVS) analyzer. The crystalline form before and after humidity cycle was tested by XRPD and the results are shown in
Example 7 Preparation of Form CSVII
(48) 16.3 mg of upadacitinib and 11.5 mg of adipic acid were weighed into a glass vial, and 0.3 mL of isopropyl acetate/tert-butyl methyl ether (1:3, v/v) was added. The sample was transferred to an oven at 35° C. and stirred for about 4 days. Another 0.2 mL of isopropyl acetate/tert-butyl methyl ether (1:3, v/v) was added. The sample was stirred in an oven at 35° C. for about another 3 days, and then stirred at room temperature for 6 days. A solid was obtained after isolation. After vacuum drying at 30° C. overnight, Form CSVII was obtained.
Example 8 Preparation of Form CSVII
(49) 195.8 mg of upadacitinib and 158.8 mg of adipic acid were weighed into a glass vial, and 5 mL of isopropyl acetate/tert-butyl methyl ether (1:2, v/v) was added. The sample was stirred at room temperature overnight, and 10.1 mg of Form CSVII seed was added. The sample was stirred at room temperature for about another 5 days. A solid was obtained after isolation and vacuum dried at 35° C. for 2.5 hours. 150.9 mg of the obtained solid was weighed into a glass vial, and 3.0 mL of tert-butyl methyl ether saturated with water was added. The sample was stirred at room temperature for about 2 days, and a solid was obtained by isolation. 25.4 mg of the solid obtained was placed under 40° C./75% RH condition for about 1 day, and Form CSVII was obtained. The XRPD pattern of Form CSVII is substantially as depicted in
(50) TABLE-US-00008 TABLE 4 2θ d spacing Intensity % 4.79 18.45 34.78 5.98 14.78 72.97 9.38 9.43 27.03 9.66 9.15 16.57 11.14 7.94 8.58 12.01 7.37 10.03 12.54 7.06 19.36 12.79 6.92 26.60 14.34 6.17 32.86 15.40 5.75 24.28 16.18 5.48 36.97 16.59 5.34 22.65 16.87 5.26 25.41 17.40 5.10 36.40 18.04 4.92 20.46 18.63 4.76 29.55 18.98 4.68 25.75 19.36 4.59 22.32 19.89 4.46 38.85 20.18 4.40 41.39 21.05 4.22 60.95 21.74 4.09 39.11 22.40 3.97 100.00 23.38 3.81 24.23 24.82 3.59 23.56 25.37 3.51 38.77 26.31 3.39 12.78 27.12 3.29 14.86 29.22 3.06 15.27 31.31 2.86 4.28 34.23 2.62 3.34
Example 9 Preparation of Form CSVII
(51) 1.0001 g of upadacitinib and 0.4228 g of adipic acid were dissolved with 6 mL of n-propanol/n-butanol (3:1, v/v), then the solution was filtered into a reactor for mechanical stirring. After the temperature of the reactor was raised to 60° C., 10 mL of n-heptane was added slowly. 0.1018 g of Form CSVII was dispersed evenly in 2 mL of n-heptane, and the suspension was added into the reactor slowly. After aging at 60° C. for 2 hours, the reaction mass was cooled to 35° C. (taking 8 hours) and aged for another 5.5 hours. The suspension was filtered, and the wet cake was washed with n-heptane. The wet cake was transferred to vacuum drying at 75° C. for about 16 hours, then Form CSVII was obtained. The molar ratio of adipic acid to upadacitinib in Form CSVII is 0.65:1 determined by .sup.1H NMR.
Example 10 Preparation of Form CSVII
(52) 0.9997 g of upadacitinib and 0.4611 g of adipic acid were dissolved with 6 mL n-propanol/n-butanol (3:1, v/v), then the solution was filtered into a 50 mL reactor for mechanical stirring. After the temperature of reactor was raised to 60° C., 10 mL of n-heptane was added slowly. 0.1018 g of Form CSVII was suspended in 2 mL of n-heptane at room temperature, and the suspension was added into the reactor slowly. After aging at 60° C. for 2 hours, the reaction mass was cooled to 35° C. (taking 8 hours) and aged for another 5.5 hours. The suspension was filtered, and the wet cake was washed with n-heptane. The wet cake was transferred to vacuum drying at 75° C. for about 16 hours, then Form CSVII was obtained. The molar ratio of adipic acid to upadacitinib in Form CSVII is 0.77:1 determined by .sup.1H NMR.
Example 11 Preparation of Form CSVII
(53) 501.2 mg of upadacitinib and 230.2 mg of adipic acid were weighed into a 50 ml reactor, and 20 mL of iso-butanol/n-heptane (1:3, v/v) was added. The system was mechanically stirred, and a clear solution was obtained when the temperature was raised up to 75° C. The system was cooled to 55° C. and aged for 0.5 hour, then cooled to 45° C. and aged for 0.5 hour. Approximately 5 mg of Form CSVII was dispersed evenly in about 0.2 mL of iso-butanol/n-heptane (1:3, v/v), and the suspension was added into the reactor slowly. After aging for about 2 hours, the system was cooled to 25° C. (taking 4 hours) and aged for about 85 hours. The suspension was filtered, and the wet cake was washed with the filtrate. The wet cake was vacuum dried at 50° C. for about 24 hours and followed by drying at room temperature for about 8.5 hours. Then the solid was vacuum dried at 75° C. in an oven for about 15 hours, and Form CSVII was obtained. The TGA curve of Form CSVII shows about 0.1% weight loss when heated to 100° C., which is substantially as depicted in
Example 12 Kinetic Solubility of Form CSVII
(54) The solubility of Form C is disclosed in WO2017066775A1. Approximately 15-30 mg of Form CSVII in the present disclosure was suspended into 1.8 mL of FeSSIF, 1.8 mL of FaSSIF and 1.8 mL of pH=7.4 PBS. After equilibration for 24 hours and 48 hours, the concentration of upadacitinib in saturated solutions was tested by HPLC and the results are listed in Table 5.
(55) TABLE-US-00009 TABLE 5 Solubility Form C (mg/mL) Form CSVII (mg/mL) Media 24-48 hours 24 hours 48 hours FeSSIF (pH 5.0, 37° C.) 0.47 2.28 2.47 FaSSIF (pH 6.5, 37° C.) 0.22 2.02 2.17 pH 7.4, 25° C. 0.19 0.92 0.85
(56) The results show that Form CSVII has higher solubility in FeSSIF, FaSSIF and pH=7.4 PBS.
Example 13 Stability of Form CSVII
(57) Approximately 5 mg of Form CSVII in the present disclosure was stored under 25° C./60% RH, 40° C./75% RH and 60° C./75% RH conditions. The purity and crystalline form were tested before and after storage by HPLC and XRPD. The results are listed in Table 6 and the XRPD overlay is substantially as depicted in
(58) TABLE-US-00010 TABLE 6 Condition Time Solid form Purity Initial — Form CSVII 99.92% 25° C./60% RH Sealed 6 months Form CSVII 99.92% Open 6 months Form CSVII 99.91% 40° C./75% RH Sealed 6 months Form CSVII 99.92% 60° C./75% RH Sealed 1 month Form CSVII 99.92%
(59) The results show that Form CSVII is stable for at least 6 months under 25° C./60% RH and 40° C./75% RH (sealed) conditions. It can be seen that Form CSVII has good stability under long-term and accelerated conditions. Form CSVII is stable for at least 1 month under 60° C./75% RH (sealed) condition. It can be seen that Form CSVII has good stability under more stressed condition as well.
(60) Approximately 10 mg of Form CSVII in the present disclosure underwent a humidity cycle of 0% RH-95% RH-0% RH with a dynamic vapor sorption (DVS) analyzer. The crystalline form before and after humidity cycle was tested by XRPD and the results are shown in
Example 14 Preparation of Drug Product
(61) The formulation and preparation process of Form CSVI, Form CSVII and Form C are shown in Table 7 and Table 8. The XRPD overlays before and after formulation process are shown in
(62) TABLE-US-00011 TABLE 7 mg/ % No. Component unit (w/w) Function 1 Crystalline upadacitinib* 20.0 20.0 API 2 Microcrystalline cellulose (Avicel PH 70.0 70.0 Filler 102) 3 Crospovidone (Polyplasdone XL) 9.0 9.0 Disintegrant 4 Magnesium stearate (SH-YM-M) 1.0 1.0 Lubricant Remark: *The formulations are the same except for different solid forms of upadacitinib (Form CSVI, Form CSVII and Form C). 20 mg corresponds to the mass of upadacitinib free base, and the weight of different solid forms needs to be re-calculated accordingly.
(63) TABLE-US-00012 TABLE 8 Stage Procedure Pre-blending According to the formulation, No. 1-4 materials were weighed into an LDPE bag and manually blended for 2 minutes. Sifting The mixture was sieved through a 35-mesh sieve and then put in an LDPE bag and blended manually for 1 minute. Simulation The mixture was pressed by a single punch manual tablet of dry press (type: ENERPAC, die: φ 20 mm round, tablet weight: granulation 500 mg ± 20 mg, pressure: 5 ± 1 KN). The flakes were pulverized by mortar and sieved through a 20-mesh sieve. Tableting The mixture was tableted by a single punch manual tablet press (type: ENERPAC; die: φ7 mm round; tablet weight: 100 mg ± 2 mg; pressure: 5 ± 1 KN). Package The tablets were packed in 35 cc HDPE bottles, with one tablet and 1 g of desiccant per bottle.
Example 15 Stability of the Formulation
(64) The tablets of Form CSVI and Form CSVII obtained in example 14 were packed in HDPE bottles with 1 g of desiccant and stored under 25° C./60% RH and 40° C./75% RH conditions. Crystalline form and impurity of the samples were tested, and the results were listed in Table 9. The results indicate that drug products of Form CSVI and Form CSVII can keep stable under 25° C./60% RH and 40° C./75% RH conditions for at least 3 months, and the purity remains basically unchanged.
(65) TABLE-US-00013 TABLE 9 Solid form Condition Time Solid form Purity FIGS. Form Initial — Form CSVI 99.93% FIG. 14 CSVI 25° C./60% RH 3 months Form CSVI 99.90% 40° C./75% RH 3 months Form CSVI 99.87% Form Initial — Form CSVII 99.31% FIG. 15 CSVII 25° C./60% RH 3 months Form CSVII 99.32% 40° C./75% RH 3 months Form CSVII 99.33%
Example 16 Dissolution of Form CSVI
(66) Dissolution tests were performed on Form CSVI drug product and Form C drug product obtained from example 14, and the method and parameters are listed in Table 10. The dissolution data of Form CSVI drug product are presented in Table 11 and
(67) TABLE-US-00014 TABLE 10 Instrument Sotax AT7 Method Paddle Strength 20 mg Volume of medium 900 mL Speed 50 rpm Temperature of medium 37° C. Sampling Time 0.1N HCl: 5, 10, 15, 20, 30, 45, 60, 90, 120 min Supplement medium No (1 mL was sampled at each time point)
(68) TABLE-US-00015 TABLE 11 Medium 0.1N HCl Cumulative drug release (%) Time (min) Form C Form CSVI 0 0.0 0.0 5 85.0 93.8 10 88.6 97.2 15 89.8 97.8 20 90.7 98.3 30 91.1 98.5 45 91.6 98.3 60 91.7 98.5 90 91.7 98.4 120 91.6 98.4
Example 17 Dissolution of Form CSVII
(69) Dissolution tests were performed on Form CSVII drug product and Form C drug product obtained from example 14, and the test method is listed in Table 12. The dissolution data of Form CSVII drug product are presented in Table 13-14 and
(70) TABLE-US-00016 TABLE 12 Instrument Sotax AT7 Method Paddle Strength 20 mg Volume of medium 900 mL Speed 50 rpm Temperature of medium 37° C. Sampling Time 5, 10, 15, 20, 30, 45, 60, 90, 120 min Supplement medium No (1 mL was sampled at each time point)
(71) TABLE-US-00017 TABLE 13 Medium 0.1N HCl Cumulative drug release (%) Time (min) Form C Form CSVII 0 0.0 0.0 5 85.0 88.3 10 88.6 91.0 15 89.8 91.7 20 90.7 92.4 30 91.1 92.7 45 91.6 93.0 60 91.7 93.1 90 91.7 93.1 120 91.6 93.2
(72) TABLE-US-00018 TABLE 14 Medium pH 6.8 PBS Cumulative drug release (%) Time (min) Form C Form CSVII 0 0.0 0.0 5 38.2 39.1 10 56.7 61.0 15 65.1 71.4 20 70.6 77.1 30 77.3 83.4 45 82.6 87.6 60 85.3 89.7 90 87.7 91.3 120 89.8 92.2
(73) 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.