WO2015166466A1

WO2015166466A1 - Crystalline form of saxagliptin acetate

Info

Publication number: WO2015166466A1
Application number: PCT/IB2015/053198
Authority: WO
Inventors: Ramendra Singh Rathore; Amit Sharma; Ashwani Kumar Singh; Ram Chander Aryan
Original assignee: Sun Pharmaceutical Industries Ltd
Current assignee: Sun Pharmaceutical Industries Ltd
Priority date: 2014-05-01
Filing date: 2015-05-01
Publication date: 2015-11-05
Anticipated expiration: 2016-11-01

Abstract

The present invention provides a crystalline form of saxagliptin acetate designated as Form II, a process for its preparation, and pharmaceutical compositions thereof.

Description

CRYSTALLINE FORM OF SAXAGLIPTIN ACETATE

Cross-Reference to Related Application

This application is a patent-of-addition of 2061/DEL/2012 filed on 2 July 2012, the contents of which are hereby incorporated by reference in their entirety.

Field of the Invention

The present invention provides a crystalline form of saxagliptin acetate, designated as Form II, a process for its preparation, and pharmaceutical compositions thereof.

Background of the Invention

Saxagliptin of Formula A, an orally-active inhibitor of the dipeptidyl peptidase IV enzyme, chemically designated as (\S,3S,5S)-2-[(2S)-2-A ino-2-(3- hydroxytricyclo[3.3.1. l³'⁷]dec-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile, is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Formula A

U.S. Patent No. 6,395,767 provides a process for the preparation of the saxagliptin trifluoroacetate. This patent also provides the hydrochloride salt of saxagliptin.

Several processes are known in the literature for making saxagliptin or salts thereof, for example, U.S. Patent No. 7,943,656; Chinese Publication No. CN 102086172; and PCT Publication Nos. WO 2004/052850, WO 2005/115982, WO 2005/106011, WO 2005/108594, WO 2005/094323, WO 2010/115974, WO 2012/017028, WO 2012/017029, WO 2012/047871, WO 2012/162507, and WO 2013/111158.

In the pharmaceutical industry, there is a constant need to identify the critical physicochemical parameters such as novel salts and novel polymorphic forms that affect a drug's performance, stability, etc., which may play a key role in determining a drug's market acceptance and success.

The discovery of new polymorphic forms of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, storage stability, and ease of purification, or desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New polymorphic forms of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. Accordingly, the present inventors have found a novel crystalline form of saxagliptin acetate, which is

thermodynamically stable.

Summary of the Invention

A first aspect of the present invention provides a crystalline form of saxagliptin acetate, designated as Form II.

A second aspect of the present invention provides a process for the preparation of crystalline saxagliptin acetate Form II, which comprises treating saxagliptin or salts thereof with acetic acid in the presence of a solvent.

A third aspect of the present invention provides a pharmaceutical composition comprising crystalline saxagliptin acetate Form II and a pharmaceutically acceptable carrier.

A fourth aspect of the present invention provides a method of treating type 2 diabetes mellitus which comprises administering to a patient in need thereof a therapeutically effective amount of crystalline saxagliptin acetate Form II and a pharmaceutically acceptable carrier.

Detailed Description of the Invention

The term "about," as used herein, refers to the range defined by a variation of up to ±10% of the actual value.

Embodiments of this aspect may include one or more of the following features: The crystalline saxagliptin acetate Form II of the present invention is characterized by an X-Ray Powder Diffractogram (XRPD) pattern substantially the same as depicted in Figure 1, exhibiting interplanar spacing (d) values at about 11.32, 10.48, 5.53, and 4.81 (A), and further exhibiting interplanar spacing (d) values substantially at about 8.75, 5.88, 5.66, 4.45, 3.75, and 3.70 (A). The crystalline form of saxagliptin acetate has an XRPD pattern with characteristic peak values (2Θ) at 7.80, 8.43, 16.01, and 18.43 ±0.2°, and additional characteristic peak values (2Θ) at 10.10, 15.05, 15.64, 19.94, 23.68, and 23.97 ±0.2°. The crystalline saxagliptin acetate Form II of the present invention is characterized by a Differential Scanning Calorimetry (DSC) thermogram as depicted in Figure 2, with a characteristic endothermic peak value at about 127.11°C and a characteristic exothermic peak value at about 130.98°C. The crystalline saxagliptin acetate Form II of the present invention is characterized by a Thermogravimetric Analysis (TGA) thermogram as depicted in Figure 3.

The saxagliptin or salts thereof used as the starting material may be prepared by the process exemplified herein or any of the methods known in the art including those described in, for example, U.S. Patent Nos. 6,395,767, and 7,943,656 or PCT Publication Nos. WO 2004/052850, WO 2005/115982, WO 2005/10601 1, WO 2005/108594, WO 2005/094323, WO 2010/115974, WO 2012/017028, WO 2012/017029, WO 2012/047871, WO 2012/162507, and WO 2013/111158.

The saxagliptin or salts thereof prepared by any of the methods known in the art may be isolated or directly treated with acetic acid in the presence of a solvent. The saxagliptin salt may optionally be converted to saxagliptin before treatment with acetic acid.

The treatment of saxagliptin or salts thereof with acetic acid may include adding, dissolving, slurrying, stirring, or combinations thereof.

The term "solvent," as used herein, includes any solvent or solvent mixture, such as water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, and mixtures thereof. Examples of esters include ethyl acetate, ^-propyl acetate, isopropyl acetate, and n- butyl acetate, preferably ethyl acetate. Examples of alkanols include those primary, secondary, and tertiary alcohols having from one to six carbon atoms. Examples of suitable alkanols include methanol, ethanol, «-propanol, isopropanol, and butanol.

Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2- dichloroethane. Examples of ketones include acetone and methyl ethyl ketone. Examples of ethers include diethyl ether and tetrahydrofuran. Examples of polar aprotic solvents include N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile, and N-methylpyrrolidone.

In a specific embodiment of this aspect, saxagliptin in a mixture of ethanol and ethyl acetate is treated with acetic acid at a temperature of from about 5°C to about 15°C, preferably, from about 10°C to about 13°C. The formation of the saxagliptin acetate may be accelerated by stirring the reaction mixture for about 20 minutes to about 2 hours at a temperature of from about 0°C to about 30°C, preferably from about 0°C to about 25°C.

The crystalline saxagliptin acetate Form II can be isolated from the reaction mixture by filtration, decantation, solvent precipitation, trituration, evaporation, distillation, or combinations thereof.

A fourth aspect of the present invention provides a method of treating type 2 diabetes mellitus which comprises administering to a patient in need thereof a

therapeutically effective amount of crystalline saxagliptin acetate Form II and a pharmaceutically acceptable carrier.

Brief Description of the Drawings

Figure 1 depicts the XRPD pattern of crystalline saxagliptin acetate Form II prepared as per Example 1.

Figure la depicts the associated values of the XRPD pattern depicted in Figure 1.

Figure 2 depicts the DSC thermogram of saxagliptin acetate Form II prepared as per Example 1. Figure 3 depicts the TGA thermogram of saxagliptin acetate Form II prepared as per Example 1.

The XRPD of the sample was determined by using a PANalytical^® instrument; Mode: X'pert PRO; Detector: X'Celerator^®; Step size: 0.02; Range: 3-40 degree 2 theta; CuKa radiation at 45kV.

The DSC of the sample was determined by using a Mettler Toledo^®, DSC 82 le. Data collection parameters: Scanning rate: 10°C/min; Temperature: 30°C to 300°C.

The TGA of the sample was determined by using a TA, TGA Q500. Data collection parameters: Scanning rate: 10°C/min; Temperature: 30°C to 300°C.

While the present invention has been described in terms of its specific

embodiments, certain modifications and equivalents will be apparent to those skilled in the art, and are intended to be included within the scope of the present invention.

EXAMPLES

Example 1 : Preparation of crystalline saxagliptin acetate Form II

Dichloromethane (3 L), tert-Butyl[(\S)-2-[(\S,3S,5S)-3-cyano-2- azabicyclo[3.1.0]hex-2-yl]-l-(3-hydroxytricyclo[3.3.1. l³'⁷]dec-l-yl)-2-oxoethyl]carbamate (380 g) and methanol (380 mL) were charged into a round bottomed flask at 20°C and the mixture was cooled to -6°C. Concentrated hydrochloric acid (1140 mL) was added to the mixture at -5°C to -2°C, and then the mixture was stirred for 30 minutes to 120 minutes at 2°C to 6°C. The pH of the reaction mixture was adjusted to 9.62 by the addition of 40% w/v aqueous sodium hydroxide solution at -5°C to 5°C. Sodium chloride (380 g) was added to the mixture at 5°C, and then the mixture was stirred for 10 minutes. The reaction mixture was allowed to settle, and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane (760 mL) at 5°C to 10°C and the organic layer was separated. The organic layers were combined, and then washed with a mixture of 20% w/v aqueous ammonium chloride and 20% w/v aqueous sodium chloride solution (380 mL in 1: 1 ratio). The organic layer was separated and concentrated under vacuum at 15°C to 20°C to obtain a residue. Dichloromethane (1900 mL) was added to the residue and the mixture was stirred for 5 minutes. Activated carbon (38 g) was added at 15°C and the mixture was stirred for 10 minutes to 15 minutes. The reaction mixture was filtered through a Hyflo^®. The Hyflo^® was washed with dichloromethane (760 mL). The filtrate was concentrated under vacuum at 15°C to 20°C to obtain a residue. Ethanol (760 mL) was added to the residue and the mixture was stirred for 10 minutes to obtain a homogenous solution. The solution was concentrated under vacuum at 15°C to 20°C to obtain a residue. To the residue, ethanol (270 mL) was added and the mixture was stirred for 10 minutes to obtain a homogenous solution. Ethyl acetate (2660 mL) was added to the solution at 15°C to 20°C. The mixture was stirred, and then cooled to 10°C. Acetic acid solution (105 mL acetic acid in 380 mL ethyl acetate) was added to the reaction mixture at 10°C to 13°C. The temperature of the reaction mixture was raised to 20°C while stirring over 20 minutes. The mixture was stirred for 15 minutes to 20 minutes at 18°C to 20°C, and then cooled to 0°C while stirring over 15 minutes. The mixture was stirred for 30 minutes to 40 minutes at 0°C to 5°C. The solid obtained was filtered under vacuum in a nitrogen environment, washed with chilled ethyl acetate (760 mL), and then dried under vacuum at 20°C to 25°C for 90 minutes to 120 minutes.

Yield: 202 g

Claims

We claim:

1. Crystalline saxagliptin acetate Form II characterized by an XRPD pattern substantially the same as depicted in Figure 1.

2. The crystalline saxagliptin acetate Form II of claim 1, characterized by an XRPD pattern having interplanar spacing (d) values at 11.32, 10.48, 5.53, and 4.81 (A).

3. The crystalline saxagliptin acetate Form II of claim 2, further characterized by interplanar spacing (d) values at 8.75, 5.88, 5.66, 4.45, 3.75, and 3.70 (A).

4. The crystalline saxagliptin acetate Form II of claim 1, characterized by an XRPD pattern having characteristic peak values (2Θ) at 7.80, 8.43, 16.01, and 18.43 ±--0.2°.

5. The crystalline saxagliptin acetate Form II of claim 4, further characterized by characteristic peak values (2Θ) at 10.10, 15.05, 15.64, 19.94, 23.68, and 23.97 ±-0.2°.

6. Crystalline saxagliptin acetate Form II characterized by a DSC thermogram as depicted in Figure 2.

7. The crystalline saxagliptin acetate Form II of claim 6, characterized by an endothermic peak value at about 127.11°C and an exothermic peak value at about 130.98°C in the DSC thermogram.

8. Crystalline saxagliptin acetate Form II characterized by a TGA thermogram as depicted in Figure 3.

9. A process for the preparation of crystalline saxagliptin acetate Form II, which comprises treating saxagliptin or salts thereof with acetic acid in the presence of a solvent.

10. The process according to claim 9, wherein the solvent is selected from water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.

11. The process according to claim 10, wherein the ester is selected from ethyl acetate, ^-propyl acetate, isopropyl acetate, and «-butyl acetate.

12. The process according to claim 10, wherein the alkanol is selected from methanol, ethanol, «-propanol, isopropanol, and butanol.

13. The process according to claim 10, wherein the halogenated hydrocarbon is selected from dichloromethane, chloroform, and 1,2-dichloroethane.

14. The process according to claim 10, wherein the ketone is selected from acetone and methyl ethyl ketone.

15. The process according to claim 10, wherein the ether is selected from diethyl ether and tetrahydrofuran.

16. The process according to claim 10, wherein the polar aprotic solvent is selected from NN-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile, and N-methylpyrrolidone.

17. The process according to claim 9, wherein the treatment of saxagliptin or salts thereof with acetic acid is carried out at a temperature of 5°C to 15°C.

18. The process according to claim 17, wherein the treatment of saxagliptin or salts thereof with acetic acid is carried out at a temperature of 10°C to 13°C.

19. A pharmaceutical composition comprising crystalline saxagliptin acetate Form II and a pharmaceutically acceptable carrier.

20. A method of treating type 2 diabetes mellitus which comprises administering to a patient in need thereof a therapeutically effective amount of crystalline saxagliptin acetate Form II and a pharmaceutically acceptable carrier.