FINGOLIMOD POLYMORPHS AND THEIR PROCESSES

• US 20130281739A1
• Filed: 08/29/2011
• Published: 10/24/2013
• Est. Priority Date: 11/25/2010
• Status: Active Grant

• Current Assignee: Shilpa Pharma Incorporated
• Original Assignee: Shilpa Medicare Limited
• Inventors: Shrawat, Vimal Kumar, Singh, Vinod Kumar, Purohit, Prashant, N/A, Veereshappa
• Granted Patent: US 9,266,816 B2
• Time in Patent Office: Days
• US Class Current: 564/360
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07C 213/10 Separation; Purification; Stabilisation; Use of additives
• CPC Class Codes: C07C 215/28 and containing six-membered aromatic rings

Abstract

The present invention provides crystalline polymorphic forms of Fingolimod HCl (I) and processes for preparation thereof.

The application provides processes for preparation of crystalline polymorphic forms-α, β and μ substantially free from process related impurities. The crystalline polymorphic forms of Fingolimod HCl (I) obtained by the processes according to the present invention having an XRDP pattern as per FIGS. 1, 3 and 5, which are useful as active pharmaceutical ingredient in pharmaceutical compositions for the treatment or prevention of autoimmune related disorder including multiple sclerosis.

Claims

1. Fingolimod hydrochloride crystalline Form-α

characterized by X-ray powder diffraction pattern comprising at least 5 characteristic 2θ

°

peaks selected from the XRPD peak set of 10.51, 15.20, 19.27, 21.77, 23.12, 24.91, 26.14, 26.46, 29.03, 33.47 and 35.46±

0.1 2θ

°

.

2. Fingolimod hydrochloride crystalline Form-α

according to claim-1, which is further characterized by DSC isotherm comprising at least three endothermic peaks ranging between—

a. Peak-1—

Between 40 to 43°

C.

b. Peak-2—

Between 65 to 68°

C.

c. Peak-3—

Between 105 to 110°

C.

d. Peak-4—

Between 270 to 280°

C.

8. Fingolimod hydrochloride crystalline Form-β

according to claim-1, which is further characterized by DSC isotherm comprising at least three endothermic peaks ranging between—

a. Peak-1—

Between 40 to 45°

C.

b. Peak-2—

Between 65 to 70°

C.

c. Peak-3—

Between 107 to 115°

C.

d. Peak-4—

Between 265 to 270°

C.

3. Fingolimod hydrochloride crystalline Form-α

characterized by X-ray powder diffraction pattern comprising at least 5 characteristic 2θ

°

peaks selected from the XRPD peak set of 10.51, 15.20, 19.27, 21.77, 23.12, 24.91, 26.14, 26.46, 29.03, 33.47 and 35.46±

0.1 2θ

° and

DSC isotherm comprising the endothermic peaks ranging between 40 to 43°

C. (Peak-1), 65 to 68°

C. (Peak-2), 105 to 110°

C. (Peak-3) and/or 270 to 280°

C. (Peak-4).

4. Fingolimod hydrochloride crystalline Form-α

according to claim-3, characterized by X-ray powder diffraction pattern substantially according to FIG. 1 and DSC isothermal pattern substantially according to FIG. 2.

5. A process for preparing Fingolimod hydrochloride crystalline Form-α

comprising the steps of—

a. Combining the Fingolimod hydrochloride with an organic acid

b. Optionally heating up to about 40-50°

C.

c. cooling the solution up to about 0-5°

C.

d. isolating the crystalline Form-α

.

6. A process for preparing Fingolimod hydrochloride crystalline Form-α

according to claim 5, wherein organic acid may be selected from C1 to C4 carboxylic acids.

7. Fingolimod hydrochloride crystalline Form-β

characterized by X-ray powder diffraction pattern comprising at least 4 characteristic 2θ

°

peaks selected from the XRPD peak set of 3.54, 7.07, 10.66, 15.35, 20.52, 21.43 and 25.10±

0.1 2θ

°

.

9. Fingolimod hydrochloride crystalline Form-β

characterized by X-ray powder diffraction pattern comprising at least 4 characteristic 2θ

°

peaks selected from the XRPD peak set of 3.54, 7.07, 10.66, 15.35, 20.52, 21.43 and 25.10±

0.1 2θ

° and

DSC isotherm comprising the endothermic peaks ranging between 40 to 45°

C. (Peak-1), 65 to 70°

C. (Peak-2), 107 to 115°

C. (Peak-3) and/or 265 to 270°

C. (Peak-4)

10. Fingolimod hydrochloride crystalline Form-α

according to claim-9, characterized by X-ray powder diffraction pattern substantially according to FIG. 3 and DSC isothermal pattern substantially according to FIG. 4.

11. A process for preparing Fingolimod hydrochloride crystalline Form-α

comprising the steps of—

a. Combining the Fingolimod hydrochloride with organic solvent

b. Optionally heating up to about 40-50°

C. followed by cooling

c. isolating the crystalline Form-β

using another co-solvent by recrystallization.

12. A process for preparing Fingolimod hydrochloride crystalline Form-β

according to claim 11, wherein organic solvent may be selected from dimethylformamide, dimethylacetamide, tetrahydrofuran, 2-methoxyethanol and co-solvent selected from ketone or nitrile or alcohol.

13. Fingolimod hydrochloride crystalline Form-μ

characterized by X-ray powder diffraction pattern comprising at least 4 characteristic 2θ

°

peaks selected from the XRPD peak set of 3.54, 8.65, 10.64, 12.49, 19.45, 21.38 and 24.05±

0.1 2θ

°

.

14. Fingolimod hydrochloride crystalline Form-μ

according to claim-13, characterized by X-ray powder diffraction pattern substantially according to FIG. 5.

15. A process for preparing Fingolimod hydrochloride crystalline Form-μ

comprising the steps of—

a. Raising the Fingolimod hydrochloride temperature up to at least melting point but less than 130°

C.

b. Cooling the melt liquid

c. isolating the crystalline Form-μ

.