Abstract: ABSTRACT The present invention relates to the crystalline forms of (3a,5p\6a,7a)-6-ethyl-3,7-dihydroxycholan-24-oic acid, commonly known as Obeticholic acid (1) and process for the preparation of the same.
We claim:
1. A crystalline form B1 of Obeticholic acid (1),
wherein the by X-ray powder diffraction (XRPD) pattern of crystalline form Bl is having 2 theta values at 3.06, 5.61, 6.23, 7.64, 7.95, 8.21, 9.39, 11.09, 12.46, 13.47, 13.90, 15.4, 15.7,16.48, 18.52, 18.87, 20.03, 20.40, 21.06,22.05, 22.53, 23.02, 23.28, 23.90, 24.58, 25.30, 25.64, 26.04, 27.54, 38.74 and 39.63 ± (0.2) degrees.
2. A process for preparing crystalline form Bl of Obeticholic acid (1) as claimed
in claim 1 comprising:
i. adding a suitable solvent to Obeticholic acid (1);
ii. heating the reaction mixture to 40 °C - 70 °C; iii. cooling the reaction mixture to a suitable temperature; iv. isolating the crystalline forms of Obeticholic acid (1); and
v. optionally, drying crystalline Obeticholic acid (1) using a suitable technique at a suitable temperature.
3. The process of claim 2, wherein the solvents is selected from a group
comprising of acetone, acetonitrile, nitromethane, 1,4-dioxane, diethyl ether,
dichloromethane, ethyl acetate, N, N-dimethylformamide, methyl tertiary butyl
ether, hexane, butyl acetate cyclohexane, toluene, tetrahydrofuran or mixtures
thereof.
4. Crystalline form Bl of Obeticholic acid (1) as claimed in claim 1, characterized
by:
a) differential scanning calorimetry (DSC) having endothermic peak at 295.68 °C as shown in figure 2, and
b) thermal gravimetric analysis (TGA) thermogram as shown in figure 3.
5. Crystalline form B2 of Obeticholic acid (1) characterized by X-ray powder diffraction (XRPD) pattern having 2 theta values at 4.30, 5.94, 6.50, 8.14, 8.39, 9.25, 9.51, 10.09, 11.12, 12.64, 14.31, 15.81, 16.05, 16.80, 17.28, 18.08, 18.86, 20.32, 20.53, 21.98 and 22.22 + 0.2 degrees.
6. A process for preparing crystalline forms B2 of Obeticholic acid (1) as claimed in claim 4 comprising:
1) adding a suitable solvent to Obeticholic acid (1) and stirring;
2) adding another suitable solvent to the step 1) reaction mass;
3) cooling the reaction mixture to a suitable temperature;
4) isolating the crystalline form B2 of Obeticholic acid (1); and
5) optionally, drying the isolated crystalline form of Obeticholic acid (1) using a suitable technique at a suitable temperature.
7. The process of claim 5, wherein the solvents is selected from a group comprising of acetone, acctonitrile, nitromethane, 1,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, N, N-dimethylformamide, methyl tertiary butyl ether, hexane, butyl acetate cyclohexane, toluene, tetrahydrofuran or mixtures thereof.
8. A process for preparing crystalline forms B3 of Obeticholic acid (1) comprising:
a. adding a suitable solvent to Obeticholic acid (1) and stirring;
b. heating the reaction mixture to a suitable temperature;
c. adding another suitable solvent to the step b) reaction mixture;
d. filtering the reaction mixture and cooling the filtrate to a suitable
temperature;
e. isolating the crystalline form B3 of Obeticholic acid (1); and
f. optionally, drying the isolated crystalline form B3 of Obeticholic acid
(1) using a suitable technique at a suitable temperature.
9. A process for preparing crystalline forms B4 of Obeticholic acid (1)
comprising:
A. adding a suitable first solvent to Obeticholic acid (1) and stirring;
B. heating the reaction mixture to a suitable temperature;
C. adding a second solvent to the step B) reaction mixture;
D. filtering the reaction mixture and optionally, cooling the filtrate to a
suitable temperature;
E. isolating crystalline form B4 of Obeticholic acid (1); and
F. optionally, drying the isolated crystalline form B4 of Obeticholic acid
(1) using a suitable technique at a suitable temperature.
10. The process of claim 8 and 9, wherein the solvents is selected from a group
comprising of acetone, acctonitrile, nitromethane, 1,4-dioxane, diethyl ether,
dichloromethane, ethyl acetate, N, N-dimethylformamide, methyl tertiary butyl
ether, hexane, butyl acetate cyclohexanc, toluene, tetrahydrofuran or mixtures
thereof.
| # | Name | Date |
|---|---|---|
| 1 | Form 5_As Filed_09-04-2018.pdf | 2018-04-09 |
| 2 | Form 3_As Filed_09-04-2018.pdf | 2018-04-09 |
| 3 | Form 2 Title Page_Provisional_09-04-2018.pdf | 2018-04-09 |
| 4 | Form 1_As Filed_09-04-2018.pdf | 2018-04-09 |
| 5 | Drawings_As Filed_09-04-2018.pdf | 2018-04-09 |
| 6 | Description Provisional_As Filed_09-04-2018.pdf | 2018-04-09 |
| 7 | Correspondence by Applicant_As Filed_09-04-2018.pdf | 2018-04-09 |
| 8 | Abstract_As Filed_09-04-2018.pdf | 2018-04-09 |
| 9 | 201841013461-FORM 3 [03-04-2019(online)].pdf | 2019-04-03 |
| 10 | 201841013461-ENDORSEMENT BY INVENTORS [03-04-2019(online)].pdf | 2019-04-03 |
| 11 | 201841013461-COMPLETE SPECIFICATION [03-04-2019(online)].pdf | 2019-04-03 |
| 12 | Correspondence by Applicant_Form2,Form3,Form5,_08-04-2019.pdf | 2019-04-08 |
| 13 | 201841013461-Request Letter-Correspondence [27-04-2019(online)].pdf | 2019-04-27 |
| 14 | 201841013461-Form 1 (Submitted on date of filing) [27-04-2019(online)].pdf | 2019-04-27 |
| 15 | 201841013461-FORM 3 [30-04-2019(online)].pdf | 2019-04-30 |
| 16 | Correspondence by Agent _Form-3 _06-05-2019.pdf | 2019-05-06 |
| 17 | 201841013461-FORM 3 [20-01-2020(online)].pdf | 2020-01-20 |
| 18 | 201841013461-Form3_(As Filed)_24-01-2020.pdf | 2020-01-24 |
| 19 | 201841013461-Correspondence_24-01-2020.pdf | 2020-01-24 |
| 20 | 201841013461-POA [09-04-2022(online)].pdf | 2022-04-09 |
| 21 | 201841013461-FORM-26 [09-04-2022(online)].pdf | 2022-04-09 |
| 22 | 201841013461-FORM 18 [09-04-2022(online)].pdf | 2022-04-09 |
| 23 | 201841013461-FORM 13 [09-04-2022(online)].pdf | 2022-04-09 |
| 24 | 201841013461-AMENDED DOCUMENTS [09-04-2022(online)].pdf | 2022-04-09 |
| 25 | 201841013461-FER.pdf | 2022-04-19 |
| 26 | 201841013461-Information under section 8(2) [13-09-2022(online)].pdf | 2022-09-13 |
| 27 | 201841013461-FORM 3 [13-09-2022(online)].pdf | 2022-09-13 |
| 28 | 201841013461-FER_SER_REPLY [13-09-2022(online)].pdf | 2022-09-13 |
| 29 | 201841013461-DRAWING [13-09-2022(online)].pdf | 2022-09-13 |
| 30 | 201841013461-CORRESPONDENCE [13-09-2022(online)].pdf | 2022-09-13 |
| 31 | 201841013461-CLAIMS [13-09-2022(online)].pdf | 2022-09-13 |
| 32 | 201841013461-ABSTRACT [13-09-2022(online)].pdf | 2022-09-13 |
| 33 | 201841013461-US(14)-HearingNotice-(HearingDate-29-11-2023).pdf | 2023-10-30 |
| 34 | 201841013461-FORM-26 [27-11-2023(online)].pdf | 2023-11-27 |
| 35 | 201841013461-Correspondence to notify the Controller [27-11-2023(online)].pdf | 2023-11-27 |
| 36 | 201841013461-Written submissions and relevant documents [09-12-2023(online)].pdf | 2023-12-09 |
| 37 | 201841013461-PatentCertificate14-12-2023.pdf | 2023-12-14 |
| 38 | 201841013461-IntimationOfGrant14-12-2023.pdf | 2023-12-14 |
| 1 | SearchE_18-04-2022.pdf |