Crystal form of sodium-glucose cotransporter 2 inhibitor
10793588 ยท 2020-10-06
Assignee
- JI LIN HUI SHENG BIO-PHARMACEUTICAL CO., LTD. (Jilin, CN)
- BEIJING HUIZHIHENG BIOTECHNOLOGY CO., LTD. (Beijing, CN)
Inventors
Cpc classification
C07D207/16
CHEMISTRY; METALLURGY
A61P5/50
HUMAN NECESSITIES
International classification
Abstract
The present invention relates to a crystalline form of a co-crystal of an inhibitor against sodium-glucose cotransporter 2 with L-proline, a method for preparing the same, a pharmaceutical composition comprising the same, and use thereof. Specifically, the present invention relates to a crystalline form of a co-crystal of an inhibitor against sodium-glucose cotransporter 2 represented by formula (1), i.e., (2S,3R,4R,5S,6R)-2-(3-(4-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)benzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, with L-proline, a method for preparing the same, a pharmaceutical composition comprising the same, and use thereof. ##STR00001##
Claims
1. Crystalline Form I of a co-crystal of the compound of Formula (1) with L-proline, wherein the compound of Formula (1) is (2S,3R,4R,5S,6R)-2-(3-(4-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)benzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, the compound of Formula (1) with L-proline are present in a molar ratio of 1:2, the crystalline Form I exhibits an X-ray powder diffraction pattern having characteristic peaks at the 2 positions of 4.00.2, 17.90.2, 18.50.2 and 19.70.2, as determined by using Cu-K radiation, ##STR00005##
2. The crystalline Form I according to claim 1, wherein the X-ray powder diffraction pattern further has characteristic peaks at the 2 positions of 12.50.2, 13.70.2 and 15.00.2, as determined by using Cu-K radiation.
3. The crystalline Form I according to claim 2, wherein the X-ray powder diffraction pattern further has characteristic peaks at the 2 positions of 11.30.2, 16.50.2 and 24.20.2, as determined by using Cu-K radiation.
4. The crystalline Form I according to claim 3, wherein the X-ray powder diffraction pattern further has characteristic peaks at the 2 positions of 15.50.2, 19.00.2 and 22.70.2, as determined by using Cu-K radiation.
5. The crystalline Form I according to claim 1, which exhibits a differential scanning calorimetry thermogram having an endothermic conversion peak at the range from 130 C. to 170 C.
6. The crystalline Form I according to claim 5, wherein the differential scanning calorimetry thermogram has the endothermic conversion peak at the range from 140 C. to 160 C.
7. A method for preparing the crystalline Form I according to claim 1, including the steps of: dissolving the compound of the Formula (1) and L-proline in a single solvent or a mixed solvent under a heating condition to produce a solution; then heating the solution to a certain temperature; maintaining the temperature for a certain period of time; cooling the solution to form a crystal; and isolating and drying the crystal to obtain the crystalline Form I.
8. A method for preparing the crystalline Form I according to claim 1, including the steps of: dissolving the compound of the Formula (1) and L-proline in a single solvent or a mixed solvent under a heating condition; adding an organic solvent thereto to produce a solution; cooling the solution to form a crystal; and then isolating and drying the crystal to obtain the crystalline Form I.
9. The method according to claim 7, wherein the single solvent is selected from the group consisting of: alcohols, esters, ketones, nitriles, and oxygen-containing heterocycles, and the mixed solvent is selected from the group consisting of: a mixture of alcohol and water, a mixture of ketone and water, a mixture of nitrile and water, and a mixture of oxygen-containing heterocycle and water.
10. The method according to claim 8, wherein the organic solvent is selected from the group consisting of alcohols, ketones, esters, ethers, nitriles, alkanes, and any mixtures thereof.
11. The method according to claim 9, wherein the single solvent is selected from the group consisting of lower alcohols and ketones.
12. A pharmaceutical composition comprising the crystalline Form I according to claim 1 and one or more pharmaceutically acceptable carrier, wherein the pharmaceutical composition is suitable for being formulated into any of pharmaceutically acceptable dosage forms.
13. The method according to claim 8, wherein the single solvent is selected from the group consisting of: alcohols, esters, ketones, nitriles, and oxygen-containing heterocycles, and the mixed solvent is selected from the group consisting of: a mixture of alcohol and water, a mixture of ketone and water, a mixture of nitrile and water, and a mixture of oxygen-containing heterocycle and water.
14. The method according to claim 9, wherein the single solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, acetone, and butanone.
15. The method according to claim 10, wherein the single solvent is selected from the group consisting of lower alcohols and ketones; and the organic solvent is selected from the group consisting of saturated hydrocarbons and alcohol/saturated hydrocarbon.
16. The method according to claim 15, wherein the single solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, acetone, and butanone.
17. The method according to claim 15, wherein the organic solvent is selected from the group consisting of n-pentane, isopentane, n-hexane, isohexane, cyclohexane, and ethanol/n-hexane.
18. A method for treating non-insulin dependent diabetes mellitus or a complication thereof, an insulin resistance disease or obesity, comprising administering to a patient the crystalline Form I according to claim 1.
Description
DESCRIPTION OF FIGURES
(1)
(2)
(3)
SPECIFIC MODE FOR CARRYING OUT THE INVENTION
(4) The above contents of the present invention will be further described in detail below by way of specific embodiments in the form of examples. However, it should not be understood that the scopes of the above-described subject matters of the present invention are limited to the following examples. All techniques implemented in accordance with the above-described contents of the present invention are within the scope of the present invention.
Example 1 Preparation of the Crystalline Form I of the Co-Crystal of the Compound of Formula (1) with L-proline (1)
(5) ##STR00004##
(6) The compound of Formula (1) (1478 g, 3.21 mol) and L-proline (739 g, 6.42 mol) were placed in a 10 L round bottom flask, then 7094 mL of ethanol and 784 mL of water were added thereto under mechanically stirring, and the raw materials were heated and quickly dissolved. When the temperature was raised to 30 C., a white solid precipitated. The temperature was further raised to 80 C., and the solvent began to reflux and the solution became clear. After refluxed for half an hour, the solution was slowly cooled to 29 C. to precipitate a solid, and continued to cool down and stood overnight. After suction filtration, the filter cake was washed with a mixed solvent of cold ethanol:water=9:1 (750 mL2), and dried under vacuum at 40 C. to give 1806 g of solid, with a yield of 81.5%. The resulting solid was determined by XRPD as crystalline Form I.
Example 2 Preparation of the Crystalline Form I of the Co-Crystal of the Compound of Formula (1) with L-proline (2)
(7) The compound of Formula (1) (200 mg, 0.43 mmol) was placed in a 100 mL round bottom flask, then 1.5 mL of isopropyl alcohol was added thereto, and the mixture was heated to 58 C. to be dissolved. To L-proline (50 mg, 0.43 mmol) in a container, 2 mL of a mixed solvent of isopropanol:water=24:1 was added to dissolve L-proline, and the L-proline solution was added dropwise to the round bottom flask. The container was washed with 0.5 mL of a mixed solvent of isopropanol:water=24:1 and the washing solution was poured in the round bottom flask. After 2 minutes, a white solid precipitated. The temperature was maintained at 55 C. for 30 minutes, and then lowered to 14 C. After filtration, the filter cake was dried under vacuum at 35 C. to give 125 mg of solid, with a yield of 50%. The resulting solid was determined by XRPD as crystalline Form I.
Example 3 Preparation of the Crystalline Form I of the Co-Crystal of the Compound of Formula (1) with L-proline (3)
(8) To the compound of Formula (1) (230 mg, 0.5 mmol) and L-proline (115 mg, 1.0 mmol), 1.46 mL of ethanol and 0.16 mL of water were added, and a white solid precipitated immediately after dissolution. The temperature was raised and the solution gradually became clear and began to reflux. To the solution, 0.20 mL of n-hexane was added dropwise, and there was no significant change. After 7 minutes of reflux, the solution was cooled, and a solid was formed at 44 C. After the solution was cooled to room temperature, the solution was filtered. The filter cake was dried under vacuum at 35 C. to give 181 mg of solid, with a yield of 52.5%. The resulting solid was determined by XRPD as crystalline Form I.
(9) The Crystalline Form I Prepared by the above Methods was Measured.
(10) Measurement with X-Ray Powder Diffraction
(11) The crystal structure of the present invention is not limited to a crystal structure having an X-ray powder diffraction pattern that is identical to the X-ray powder diffraction pattern shown in the drawings as disclosed in the present application, and any crystal structure having an X-ray powder diffraction pattern that is substantially the same as that disclosed in the drawings is encompassed in the scope of the present invention.
(12) Conditions under which X-ray powder diffraction measurement was carried out: Cu palladium, K1 (): 1.540598, step size 0.0262, 1 second per step.
(13) The crystalline Form I exhibits an X-ray powder diffraction pattern has characteristic peaks at the 2 positions of 4.00.2, 17.90.2, 18.50.2, 19.70.2, further has characteristic peaks at 12.50.2, 13.70.2, 15.00.2, further has characteristic peaks at 11.30.2, 16.50.2, 24.20.2 and further has characteristic peaks at 15.50.2, 19.00.2, 22.70.2.
(14) The co-crystal of the compound of Formula (1) with L-proline (crystalline Form) had an X-ray powder diffraction pattern substantially shown in
(15) Differential Scanning Calorimetry
(16) The solid state thermal properties of the crystalline Form I of the co-crystal of the compound of Formula (1) with L-proline were studied by differential scanning calorimetry (DSC). The DSC thermogram of the crystalline Form I was shown in
(17) Measurement conditions: nitrogen was purged at 100 mL/min, heating rate is 10 C./min, data was collected from room temperature to 300 C., and the thermogram was plotted with downward endothermic peaks.
(18) In the DSC measurement, the actually measured start temperature and maximum temperature varied to certain extend depending on the measurement parameters and the heating rate.
(19) Thermogravimetric Analysis
(20) Measurement conditions: nitrogen was purged at 100 mL/min, heating rate is 10 C./min, data was collected from room temperature to 300 C.
(21) The TGA curve of the crystalline Form I of the co-crystal of the compound of Formula (1) with L-proline was shown in
Example 4 Test on Stability of the Crystalline Form I of the Co-Crystal of the Compound of Formula (1) with L-proline
(22) Test Samples:
(23) The crystalline Form I of the co-crystal of the compound of Formula (1) with L-proline, which was prepared according to the methods in the examples; free compound of Formula (1).
(24) Test Conditions:
(25) The test samples were placed under conditions of 60 C., 40 C., RH 90%5%, RH 75%5%, 4500lx500lx or UV-Vis for 10 days, then sampled on the 5.sup.th and 10.sup.th days respectively, and the samples were tested for relevant substances and XRD pattern; and the results were compared with those of a sample on the 0.sup.th day.
(26) Determination of the relevant substances: the determination was carried out in accordance with High Performance Liquid Chromatography in Appendix V D in Pharmacopoeia of the People's Republic of China (2010) (Volume II).
(27) XRD measurement: the measurement was carried out in accordance with X-Ray Powder Diffraction in Appendix IX F in Pharmacopoeia of the People's Republic of China (2010) (Volume II).
(28) Test Results:
(29) TABLE-US-00001 TABLE 1 Results of the stability test of the crystalline Form I Relevant Placement substances Test condition time Properties (%) XRD 60 C. 0.sup.th day Almost white 0.60 loose mass or powder 5.sup.th day Almost white 0.68 Identical to the XRD loose mass or pattern in 0.sup.th day powder 10.sup.th day Almost white 0.62 Identical to the XRD loose mass or pattern in 0.sup.th day powder 40 C. 5.sup.th day Almost white 0.67 Identical to the XRD loose mass or pattern in 0.sup.th day powder 10.sup.th day Almost white 0.65 Identical to the XRD loose mass or pattern in 0.sup.th day powder RH90% 5% 5.sup.th day Almost white 0.65 Identical to the XRD loose mass or pattern in 0.sup.th day powder 10.sup.th day Almost white 0.63 Identical to the XRD loose mass or pattern in 0.sup.th day powder RH75% 5% 5.sup.th day Almost white 0.66 Identical to the XRD loose mass or pattern in 0.sup.th day powder 10.sup.th day Almost white 0.64 Identical to the XRD loose mass or pattern in 0.sup.th day powder 4500 lx 500 lx* 5.sup.th day Almost white 0.66 Identical to the XRD loose mass or pattern in 0.sup.th day powder 10.sup.th day Almost white 0.71 Identical to the XRD loose mass or pattern in 0.sup.th day powder
(30) TABLE-US-00002 TABLE 2 Results of stability test of free compound of Formula (1) Relevant Test Placement substances condition time Properties (%) XRD 60 C. 0.sup.th day Almost white 1.35 Amorphism powder 10.sup.th day Almost white 1.43 Amorphism powder 40 C. 10.sup.th day Almost white 1.44 Amorphism powder RH90% 5% 6.sup.th day Hygroscopic Amorphism deliquescence RH75% 5% 6.sup.th day Hygroscopic Amorphism deliquescence UV-Vis* A period of Tawny powder 9.91 Amorphism time that meets the illumination requirement *total illumination of 1.2 10.sup.6 Lux .Math. h, near ultraviolet energy of 200 w .Math. h/m.sup.2
(31) Test Conclusions:
(32) After being placed in the conditions of the above temperature, humidity or light for 10 days, the property, the relevant substances and the XRD pattern of the crystalline Form I of the co-crystal of the compound of Formula (1) with L-proline did not change significantly.
(33) After being placed under the conditions of the above temperature for 10 days, the amount of relevant substances of the free base of the compound of Formula (1) was increased; after being placed under the conditions of the above humidity, the free base sample had a significant hygroscopic deliquescence on the 6.sup.th day; after being placed under the conditions that meet the illumination requirement, the relevant substances was increased by 8.56% relative to that on the 0.sup.th day, and the property of the sample changed from an almost white powder to a tawny powder.
(34) It can be seen from the above results that the crystalline Form I of the co-crystal of the compound of the Formula (1) with L-proline had better stability than the free base of the compound, which would help the preparation, transportation and storage of the drug, and ensure the effectiveness and safety of the drug when applied.
Example 5 Test on Residual Solvents of the Crystalline Form I of the Co-Crystal of the Compound of Formula (1) with L-Proline
(35) 1. Test Samples
(36) The compound of the Formula (1) was obtained according to the preparation method described in pages 10-14 of the description in the CN104761522A (while without treatment with preparative chromatography in the 12.sup.th step), and the residual amount of ethyl acetate in the compound was determined by gas chromatography. Meantime, the residual amount of ethyl acetate was determined in a co-crystal formed by adding L-proline to the compound of the Formula (1).
(37) 2. Test method: the determination was carried out in accordance with the method for determining residual solvents in Appendix VIII P of Pharmacopoeia of the People's Republic of China (2010) (Volume II).
(38) 3. Test Results
(39) TABLE-US-00003 TABLE 3 Determination results of residual solvent Co-crystal of the compound of Formula (1) with The compound of L-proline Determined item Formula (1) (crystalline Form I) Residual solvent 0.58% of ethyl Ethyl acetate was not acetate detected
(40) The ethyl acetate in the sample of the compound of Formula (1) was not removed after spin-drying treatment, and the amount of the ethyl acetate was over the limit provided in Pharmacopoeia of the People's Republic of China (Volume II). After the compound of Formula (1) formed a co-crystal with L-proline, the residual solvent was effectively removed, and a crystalline form with good properties was obtained, simplifying the post-treatment process, which was conducive to cost saving and quality control, and was conducive to industrialization in the industrial production.