WO2019197962A1

WO2019197962A1 - Crystalline forms of (3α, 5β, 6α, 7α)-6-ethyl-3, 7-dihydroxycholan-24-oic acid (obeticholic acid) and processes thereof

Info

Publication number: WO2019197962A1
Application number: PCT/IB2019/052863
Authority: WO
Inventors: Manik Reddy Pullagurla; Jagadeesh Babu Rangisetty
Original assignee: Biophore India Pharmaceuticals Pvt Ltd
Current assignee: Biophore India Pharmaceuticals Pvt Ltd
Priority date: 2018-04-09
Filing date: 2019-04-08
Publication date: 2019-10-17
Anticipated expiration: 2020-10-09

Abstract

The present invention relates to the crystalline forms of (3α, 5β, 6α, 7α)-6-ethyl-3,7-dihydroxycholan-24-oic acid, commonly known as Obeticholic acid (1). Further, the present invention also provides process for the preparation of Obeticholic acid crystalline forms thereof. More specifically, the present invention provides crystalline forms B1, B2, B3 and B4 of Obeticholic acid and the process for the preparation thereof.

Description

“CRYSTALLINE FORMS OF (3a, 5b, 6a, 7a)-6-ETHYL-3, 7- DIHYDROXY CHOLAN-24-OIC ACID (OBETICHOLIC ACID) AND

PROCESSES THEREOF” CROSS REFERENCE

This application claims the priority from Indian Patent Application No.

201841013461 filed Indian Patent Office on April 09, 2018.

FIELD OF THE INVENTION

The invention relates to crystalline forms of Obeticholic acid (1) and process for preparation thereof. Specifically, the present invention relates to crystalline forms B 1 , B2, B3 and B4 of Obeticholic acid (1).

BACKGROUND OF INVENTION

Obeticholic acid (1) is a synthetically modified derivative of bile acid and a potent farnesoid X nuclear receptor (FXR) agonist, used to treat liver diseases including primary biliary cholangitis (PBC) as monotherapy in adults who are unable to tolerate ursodeoxycholic acid (UDCA) or as combination therapy with in adults with inadequate response to UDCA. Chemically, it is (3a, 5b, 6a, 7a)-6-ethyl-3, 7- dihydroxycholan-24-oic acid (1).

Obeticholic acid (1) is being marketed as Ocaliva and supplied as tablets for oral administration. It was approved by the United States Food and Drug Administration for the treatment of primary biliary cholangitis on May 27, 2016 and by the European Medicines Agency since 12 December 2016. The following patents and applications describe the synthesis of Obeticholic acid (1) and its different salts and polymorphs. US9238673 discloses crystalline form C and non-crystalline form 1 of Obeticholic acid (1). It discloses preparation of crystalline form C. It further discloses other different crystalline polymorphic forms A, D, F and G of Obeticholic acid (1) which are unsuitable for use in pharmaceutical industries due to various unwanted physiochemical parameters.

WO2017008773 discloses crystalline forms 1-2 and 1-3 and the method of preparation of amorphous form of Obeticholic acid (1).

WO2017115324 relates to the crystalline forms a, b, g and d of Obeticholic acid (1) and their preparation.

Still there is a need to develop crystalline forms with high purity and stability which would be helpful in developing effective pharmaceutical formulations. Hence, the present inventors hereby report crystalline forms B 1, B2, B3 and B4 of Obeticholic acid ( 1).

OBJECTIVE OF THE INVENTION

Accordingly, the primary objective of the present invention is to provide novel crystalline forms of Obeticholic acid (1).

Another objective of the invention is to provide process for the preparation of a novel crystalline forms of Obeticholic acid (1).

Yet another objective of the invention is to provide process for the preparation of crystalline forms B l, B2, B3 and B4 of Obeticholic acid (1).

SUMMARY OF THE INVENTION

Accordingly, one objective of the present invention is to provide crystalline forms Bl, B2, B3 and B4 of Obeticholic acid (1). In another objective, the present invention provides crystalline form Bl of Obeticholic acid (1) characterized by its X-ray powder diffraction pattern having peaks at about 2(0) values of 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.

In yet another objective, the present invention provides crystalline form B l of Obeticholic acid (1) which is characterized by X-ray powder diffraction pattern substantially as shown in figure 1.

In yet another objective, the present invention provides process for the preparation of crystalline form Bl of Obeticholic acid (1) comprising:

i. adding a suitable solvent to Obeticholic acid (1)

ii. heating the reaction mixture to 35 °C - 70 °C

iii. cooling the reaction mixture to a suitable temperature

iv. isolating the crystalline forms of Obeticholic acid (1)

v. optionally, drying the isolated crystalline form Bl of Obeticholic acid (1) using a suitable technique at a suitable temperature.

In another objective, the present invention provides crystalline form B2 of Obeticholic acid (1) characterized by its X-ray powder diffraction pattern having peaks at about 2(0) values of 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.

In yet another objective, the present invention provides crystalline form B2 of Obeticholic acid (1) which is characterized by X-ray powder diffraction pattern substantially as shown in figure 4. In some objective, the present invention provides process for the preparation of crystalline form B2 of Obeticholic acid (1) comprising:

1) adding a suitable solvent to Obeticholic acid (1) and stirring

2) adding second 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)

5) optionally, drying the isolated crystalline form B2 of Obeticholic acid (1) using a suitable technique at a suitable temperature. In another objective, the present invention provides crystalline form B3 of Obeticholic acid (1) characterized by its X-ray powder diffraction pattern having peaks at about 2(0) values of 3.32, 4.34 ,5.28 ,6.44 ,7.77, 9.62, 11.13, 12.64, 16.01, 16.52, 19.16 and 19.38 ± 0.2 degrees. In yet another objective, the present invention provides crystalline form B3 of Obeticholic acid (1) which is characterized by X-ray powder diffraction pattern substantially as shown in figure 5.

In some objective, the present invention provides process for the preparation of crystalline form 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 second 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)

f) optionally, drying thee isolated crystalline form B3 of Obeticholic acid (1) using a suitable technique at a suitable temperature. In another objective, the present invention provides crystalline form B4 of Obeticholic acid (1) characterized by its X-ray powder diffraction pattern having peaks at about 2(0) values of 4.50, 5.29, 6.47, 7.68, 9.11, 9.59, 10.16, 10.48, 11.34, 11.61,12.08, 12.42, 12.84, 14.55, 15.08, 15.91, 16.13, 16.62, 183.67, 19.25, and 21.0 ± 0.2 degrees. In yet another objective, the present invention provides crystalline form B4 of Obeticholic acid (1) which is characterized by X-ray powder diffraction pattern substantially as shown in figure 6.

In some embodiment, the present invention provides process for the preparation of crystalline form B4 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 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 )

F. optionally, drying the isolated crystalline form B4 of Obeticholic acid (1) using a suitable technique at a suitable temperature.

In yet another objective, the crystalline forms of Obeticholic acid (1) obtained by the present invention were having purity more than 99.5% by HPLC.

BRIEF DESCRIPTION OF DRAWINGS

Figure 1: illustrates X-Ray powder diffraction (XPRD) pattern of crystalline form B l of Obeticholic acid ( 1 ) as prepared in example- 1

Figure 2: illustrates Differential scanning calorimetry thermogram (DSC) of crystalline form Bl of Obeticholic acid (1) as prepared in example- 1

Figure 3: illustrates Thermogravimetric analysis (TGA) curve of crystalline form B 1 of Obeticholic acid ( 1 ) as prepared in example- 1 Figure 4: illustrates X-Ray powder diffraction (XPRD) pattern of crystalline form B2 of Obeticholic acid ( 1 ) as prepared in example-2

Figure 5: illustrates X-Ray powder diffraction (XPRD) pattern of crystalline form B3 of Obeticholic acid ( 1 ) as prepared in example-3

Figure 6: illustrates X-Ray powder diffraction (XPRD) pattern of crystalline form B4 of Obeticholic acid ( 1 ) as prepared in example-4

DETAILED DESCRIPTION OF THE INVENTION

Accordingly, the first embodiment of the present invention is to provide novel crystalline forms B l, B2, B3 and B4 of Obeticholic acid (1).

In another objective, the present invention provides crystalline form Bl of Obeticholic acid characterized by its X-ray powder diffraction (XPRD) pattern having peaks at about 2(q) values of 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.

In some objective, the present invention provides a process for the preparation of crystalline form Bl of Obeticholic acid (1) comprising:

i. adding a suitable solvent to Obeticholic acid (1)

ii. heating the reaction mixture to 35 °C - 70 °C

iii. cooling the reaction mixture to a suitable temperature

iv. isolating the crystalline forms of Obeticholic acid (1)

In some embodiment, the crystalline form B l of Obeticholic acid (1) may be prepared by adding Obeticholic acid (1) to a suitable solvent. The suitable solvent may be selected from an aprotic solvent. The reaction mixture may be heated to a temperature at about 35 °C to about 70 °C, preferably 35 °C to 40 °C. The reaction mass may be filtered and cooled to a temperature at about -10 to about 10 °C, preferably at temperature about 0 °C to about 5 °C. In another embodiment dichloromethane can be used as solvent for the preparation of crystalline form Bl of Obeticholic acid (1).

In another embodiment, the solid obtained may be isolated in step iv) by any suitable technique. Specifically, the solid may be isolated from the mixture by filtration. The filtration can be carried out under vacuum pressure at 25 °C to 30 °C.

In another embodiment of the present application, drying of crystalline form Bl of Obeticholic acid (1) may be carried out using suitable drying technique. Drying may be carried out using air tray dryer, vacuum tray dryer, fluidized bed dryer or the like. Preferably, air tray dryer is used for the drying of the crystalline form B 1 of Obeticholic acid (1).

In another objective, the present invention provides crystalline form Bl of Obeticholic acid which is characterized by X-ray powder diffraction (XPRD) pattern substantially as shown in figure 1. In another objective, the present invention provides differential scanning calorimetry (DSC) of Obeticholic acid (1) with an endothermic peak at 295.68 °C as shown in figure 2.

In another objective, the present invention provides the thermal gravimetric analysis (TGA) of crystalline form Bl of Obeticholic acid (1) shows as shown in figure 3. In yet another objective, the crystalline form Bl of Obeticholic acid (1) is more stable, reproducible and commercially feasible at larger scale.

In some embodiment, the present invention provides crystalline form B2 of Obeticholic acid (1) characterized by its powder X-ray powder diffraction (XPRD) pattern having peaks at 2Q values of 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. In some objective, the present invention provides process for the preparation of crystalline form B2 of Obeticholic acid (1) comprising:

1) adding a suitable first solvent to Obeticholic acid (1) and stirring

2) adding second 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) from a third solvent

5) optionally, drying the isolated crystalline form B2 of Obeticholic acid (1) using a suitable technique at a suitable temperature.

In some embodiment, the crystalline form B2 of Obeticholic acid (1) may be prepared by adding Obeticholic acid (1) to a suitable first solvent at a temperature of about 25 °C to 35 °C. The reaction mass may be filtered under vacuum at temperature of about 25 °C to 35 °C. The suitable first solvent used in step 1) is selected from an aprotic solvent.

In another embodiment the second solvent is added to the reaction mixture from step 2) and the third solvent used in step 4) for isolation of crystalline form B2 of

Obeticholic acid (1) is an aprotic solvent. The reaction mass may be cooled to a temperature of about -10 °C to about 20 °C preferably 10 °C to 15 °C.

In another embodiment, acetone is used as first solvent in step 1), dichloromethane is used as second solvent in the step 2) and cyclohexane is used in the step 4) as third solvent for the preparation of crystalline form B2 of Obeticholic acid (1).

In another embodiment, the solid obtained may be isolated in step 4) by any suitable technique. Specifically, the solid may be isolated from the mixture by filtration. The filtration can be carried out under vacuum pressure at 25 °C to 30 °C.

In another embodiment of the present application, drying crystalline form B2 of Obeticholic acid (1) may be carried out using suitable drying technique. Drying may be carried out using air tray dryer, vacuum tray dryer, fluidized bed dryer or the like. Preferably air tray dryer (ATD) is used for the drying of the crystalline form B2 of Obeticholic acid. The drying can be carried out at a suitable temperature ranging from 30 °C to about 80 °C, preferably from 40 °C to 45 °C.

In some embodiment, the present application provides crystalline form B2 of Obeticholic acid (1) characterized by an X-ray powder diffraction pattern (XPRD) as illustrated in figure 4.

In another embodiment, the present invention provides crystalline form B3 of Obeticholic acid (1) characterized by its X-ray powder diffraction (XPRD) pattern having peaks at 2Q values of about 3.32, 4.34 ,5.28 ,6.44 ,7.77, 9.62, 11.13, 12.64, 16.01, 16.52, 19.16 and 19.38 ± 0.2 degrees.

a) adding a suitable first solvent to Obeticholic acid (1) and stirring;

b) heating the reaction mixture to a suitable temperature

c) adding second solvent to the step b) reaction mixture

f) optionally, drying thee isolated crystalline form B3 of Obeticholic acid (1) using a suitable technique at a suitable temperature.

In some embodiment, the crystalline form B3 of Obeticholic acid (1) may be prepared by adding Obeticholic acid (1) to a suitable first solvent at 25 °C to 35 °C. The reaction mixture may be heated from about 40 °C to 80 °C, preferably from about 55 °C to about 60 °C. The suitable first solvent used in step a) is selected from an aprotic solvent. A suitable second solvent was then added to the reaction mixture and filtered. The filtrate was cooled to a suitable temperature. The solid formed may be filtered and isolated from the second solvent and dried using a suitable technique at a suitable temperature ranging from 30-80 °C, preferably 40 to 45 °C to obtain crystalline form B3 of Obeticholic acid (1). In another embodiment the second solvent is added to the reaction mixture from step b) and in step e) for isolation of crystalline form B2 of Obeticholic acid (1) is an aprotic solvent. The reaction mass may be cooled to a temperature of about 10 °C to 40 °C, preferably to about 25 °C to 30 °C. In another embodiment, cyclohexane may be used as first solvent in step a) and methyl tert-butyl ether may be used as second solvent in step b) and in step e) for the isolation of crystalline form B3 of Obeticholic acid (1).

In another embodiment of step e) the solid obtained may be isolated by any suitable technique. Specifically, the solid may be isolated from the mixture by filtration. The filtration can be carried out under vacuum pressure at 25 °C to 30 °C.

In some embodiment, the present application provides crystalline form B3 of Obeticholic acid (1) characterized by an X-ray powder diffraction pattern (XPRD) as illustrated in figure 5.

In another embodiment, the present invention provides crystalline form B4 of Obeticholic acid (1) characterized by its powder X-ray powder diffraction (XPRD) pattern having peaks at about 2Q values of 4.50, 5.29, 6.47, 7.68, 9.11, 9.59, 10.16, 10.48, 11.34, 11.61,12.08, 12.42, 12.84, 14.55, 15.08, 15.91, 16.13, 16.62, 183.67, 19.25, and 21.0 ± 0.2 degrees.

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

E. isolating crystalline form B4 of Obeticholic acid ( 1 ) F. optionally, drying the isolated crystalline form B4 of Obeticholic acid (1) using a suitable technique at a suitable temperature.

In some embodiment, the crystalline form B4 of Obeticholic acid (1) may be prepared by adding Obeticholic acid (1) to a suitable first solvent at 25 °C to 35 °C. The reaction mixture may be heated from about 40 °C to about 80 °C, preferably from 55 °C to about 60 °C. A suitable second solvent may be then added to the reaction mixture and filtered. The filtrate may be cooled to a temperature and the solid formed may be isolated using a suitable technique and dried using a suitable technique at a suitable temperature ranging from 30 °C to about 80 °C, preferably from 40 °C to 45 °C to obtain crystalline form B4 of Obeticholic acid (1).

In another embodiment the suitable first solvent used in step A) and the suitable second solvent added in step B) and in step E) may be aprotic solvent. The reaction mass may be cooled to a temperature of about of about 35 °C to 60 °C, preferably to about 45 °C to 50 °C. In another embodiment, cyclohexane may be used as first solvent in step A) and methyl tert-butyl ether may be used as second solvent in step B) and in step E) for the isolation of crystalline form B4 of Obeticholic acid (1).

In another embodiment, the solid obtained in step E) may be isolated by any suitable technique. Specifically, the solid may be isolated from the mixture by filtration. The filtration can be carried out under vacuum pressure at 25 °C to 30 °C.

In some embodiment, the present invention provides crystalline form B4 of Obeticholic acid ( 1 ) characterized by an X-ray powder diffraction pattern (XPRD) as illustrated in figure 6.

In some embodiment, the suitable solvents used in the present invention may be selected from a group comprising, but not limited to organic or inorganic solvents, preferably organic solvents comprising of protic or aprotic solvents may be used. The aprotic solvents may be selected from of a group comprising of acetone, acetonitrile, nitromethane, l,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, N, N- dimethylformamide, methyl tertiary butyl ether, hexane, butyl acetate, cyclohexane, toluene, tetrahydrofuran or the like preferably dichloromethane, cyclohexane, acetone and methyl tertiary butyl ether, were used in the present invention.

In another embodiment of the present application, drying of crystalline forms of Obeticholic acid may be carried out using suitable drying technique comprising of but not limited to air tray dryer, vacuum tray dryer, fluidized bed dryer or the like. Preferably air tray dryer (ATD) is used for the drying in the present invention. The drying can be carried out at a suitable temperature ranging from 30 °C to about 80 °C, preferably from 40 °C to about 45 °C.

In another embodiment, the crystalline forms of Obeticholic acid (1) obtained by any of the above methods was having purity more than 99.5% by HPLC.

In another embodiment, the crystalline form B 1 of Obeticholic acid ( 1 ) as obtained in example 1 was having X-Ray powder diffraction (XPRD) pattern with characteristic peaks at (20) values as illustrated in figure 1 and the 2 theta values as provided in Table 1.

Table 1:

In another embodiment, the present invention provides the crystalline form B2 of Obeticholic acid (1) as obtained in example 2 was having X-Ray powder diffraction (XPRD) pattern with characteristic peaks at (2Q) values as illustrated in figure 4 and the 2 theta values provided in Table 2. Table 2:

In another embodiment, the present invention provides the crystalline form B3 of Obeticholic acid (1) as obtained in example 3 was having characterized by X-Ray powder diffraction (XPRD) pattern with characteristic peaks at (2Q) values as illustrated in figure 5 and the 2 theta values provided in Table 3.

Table 3:

In another objective the present invention provides the crystalline form B4 of Obeticholic acid (1), characterized by X-Ray powder diffraction (XPRD) pattern with characteristic peaks at (2Q) values as illustrated figure 6 and the 2 theta values provided in Table 4.

Table 4:

The following examples further illustrate the present invention, but should not be construed in anyway, as to limit its scope.

EXAMPLE-1: Preparation of crystalline form B1 of Obeticholic acid (1)

lg of Obeticholic acid (1) was added to 30mL of dichloromethane at 25 °C -35 °C and heated to 35 °C - 40 °C for 15-30 min. The reaction solution was then cooled to 0 °C - 5 °C and stirred for lhr. The solid formed was filtered and washed with lOmL of dichloromethane. The wet cake so formed was dried under vacuum, followed by drying in air tray dryer (ATD) at 40 °C - 45 °C to obtain crystalline form B 1 of Obeticholic acid (1). Yield: 92%; Purity: 99.85%; XPRD: Figure 1 ; DSC: Figure 2; TGA: Figure 3.

EXAMPLE-2: Preparation of crystalline form B2 of Obeticholic acid (1)

lg of Obeticholic acid (1) was added to lOmL of acetone at 25 °C -35 °C and filtered. 20 mL of dichloromethane was added to the filtrate and stirred for 15-30 min at 25 °C -35 °C. 40 mL of cyclohexane was then added to the reaction mixture, cooled to 10 °C -15 °C and stirred for 15-30 min. The solid so obtained was washed with 10 mL of cyclohexane and dried under vacuum, followed by drying in air tray dryer (ATD) at 40 °C - 45 °C to obtain crystalline form B2 of Obeticholic acid (1). Yield: 82%; Purity: 99.80%; XPRD: Figure 4.

EXAMPLE-3: Preparation of crystalline form B3 of Obeticholic acid (1)

lg of Obeticholic acid (1) was added to 40mL of cyclohexane at 25 °C -35 °C, heated to 55 °C - 65 °C and stirred for 15-30 min. 10 mL of methyl tertiary butyl ether was added to the reaction mass at 55 °C - 65 °C and filtered. The filtrate was cooled and stirred for 15-30 min at 25 °C - 35 °C. The solid so formed was filtered, washed with 10 mL of cyclohexane and dried under vacuum, followed by drying in air tray dryer (ATD) at 40 °C- 45 °C to obtain crystalline form B3 of Obeticholic acid (1) Yield: 85%; Purity: 99.88%; XPRD: Figure 5.

EXAMPLE-4: Preparation of crystalline form B4 of Obeticholic acid (1)

lg of Obeticholic acid (1) was added to 40m L of cyclohexane at 25 °C -35 °C and heated to 55 °C -65 °C. 10 mL of methyl tertiary butyl ether was added to the reaction mass and stirred for 15-30 min at 55 °C-65 °C. The reaction mixture was filtered, and the filtrate cooled to 45 °C-50 °C. The solid so obtained was washed with 10 mL of cyclohexane and dried under vacuum, followed by drying in air tray dryer (ATD) at 40 °C - 45 °C for to obtain crystalline form B4 of Obeticholic acid (1). Yield: 83%; Purity: 99.90%; XPRD: Figure 6.

Claims

We claim:

1. A crystalline form Bl of Obeticholic acid (1),

Obeticholic acid

(1)

wherein the by X-ray powder diffraction (XRPD) pattern of crystalline form B 1 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 B 1 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, l,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, acetonitrile, nitromethane, l,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

10. The process of claim 8 and 9, wherein the solvents is selected from a group comprising of acetone, acetonitrile, nitromethane, l,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, N, N-dimethylformamide, methyl tertiary butyl ether, hexane, butyl acetate cyclohexane, toluene, tetrahydrofuran or mixtures thereof.