WO2014083554A1

WO2014083554A1 - Stable amorphous form of linagliptin

Info

Publication number: WO2014083554A1
Application number: PCT/IB2013/060576
Authority: WO
Inventors: Suresh Babu Jayachandra; Raghuram Morampudi; Udaibhan Singh GAHLOT
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2012-11-30
Filing date: 2013-12-02
Publication date: 2014-06-05

Abstract

The present invention relates to a stable amorphous form of linagliptin, a process for its preparation, a pharmaceutical composition comprising it, and its use for the treatment of type 2 diabetes mellitus.

Description

STABLE AMORPHOUS FORM OF LINAGLIPTIN

Field of the Invention

The present invention provides a stable amorphous form of linagliptin, a process for its preparation, a pharmaceutical composition comprising it, and its use for the treatment of type 2 diabetes mellitus.

Background of the Invention

Linagliptin is an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme. It is chemically designated as lH-purine-2,6-dione, 8-[(3R)-3-amino-l- piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2- quinazolinyl)methyl]. Its chemical structure is depicted below in Formula I.

FORMULA I

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Linagliptin is marketed in the United States under the trade name Tradjenta for the treatment of type 2 diabetes mellitus. It is also marketed in the United States in combination with metformin hydrochloride, under the trade name Jentadueto^®, for the treatment of type 2 diabetes mellitus.

IP.com disclosure nos. TPCOM000210079D and IPCOM000219543D disclose processes for the preparation of amorphous linagliptin using organic solvent(s).

The inventors of the present invention have observed that amorphous linagliptin prepared by using organic solvent(s) is unstable as it gets converted into crystalline linagliptin at elevated temperature.

Additionally, as per the International Conference on Harmonization (ICH) guidelines for residual solvents, in order to protect patients from potential adverse effects due to the inherent toxicity associated with organic solvents, the amount of residual solvents in pharmaceutical products needs to be controlled. Thus, there exists a need in the art for an alternate simple, cost effective, and commercially advantageous process for the preparation of a stable amorphous form of linagliptin that avoids the use of organic solvents and that does not convert into crystalline linagliptin on heating to an elevated temperature.

Summary of the Invention

The present invention provides a simple, eco-friendly, cost effective, and commercially advantageous process for the preparation of a stable amorphous form of linagliptin. The process of the present invention involves the use of water for the preparation of amorphous linagliptin and avoids the use of organic solvents and costly equipment, such as a spray dryer, for the preparation of amorphous linagliptin. The amorphous form of linagliptin obtained by the process of the present invention is stable towards conversion to crystalline linagliptin on heating to an elevated temperature. The stable amorphous form of linagliptin of the present invention is substantially free of residual organic solvent(s).

A first aspect of the present invention provides a stable amorphous form of linagliptin.

A second aspect of the present invention provides a process for the preparation of a stable amorphous form of linagliptin using water.

A third aspect of the present invention provides a process for the preparation of a stable amorphous form of linagliptin comprising contacting a reaction mixture containing an acid addition salt of linagliptin in water with a base.

A fourth aspect of the present invention provides a pharmaceutical composition comprising a stable amorphous form of linagliptin and one or more pharmaceutically acceptable carriers, diluents, or excipients, and optionally other therapeutic ingredients.

A fifth aspect of the present invention provides the use of a stable amorphous form of linagliptin for the treatment of type 2 diabetes mellitus.

Brief Description of Figures

Figure 1 : X-ray diffraction pattern of the stable amorphous form of linagliptin of the present invention. Figure 2: X-ray diffraction pattern of amorphous linagliptin prepared using an organic solvent.

Figure 3 : X-ray diffraction pattern of amorphous linagliptin prepared using an organic solvent after heating.

Detailed Description of the Invention

Various embodiments and variants of the present invention are described hereinafter.

The term "ambient temperature", as used herein, refers to a temperature in the range of about 20°C to about 35°C.

The term "about", as used herein, refers to any value which lies within the range defined by a variation of ±10% of the value.

The term "contacting", as used herein, includes dissolving, slurrying, stirring, or a combination thereof.

The term "stable amorphous", as used herein, refers to amorphous linagliptin stable towards conversion to crystalline linagliptin on heating to elevated temperatures.

The term "substantially free of residual organic solvent(s)", as used herein, refers to the stable amorphous form of linagliptin of the present invention having less than 5000 ppm of residual organic solvent(s).

The preparation of the stable amorphous form of linagliptin is carried out by contacting a reaction mixture containing an acid addition salt of linagliptin in water with a base at about - 10°C to about +10°C, heating the reaction mixture, stirring for about 1 hour to about 5 hours, optionally cooling to about 0°C to about 10°C, stirring for about 30 minutes to 5 hours, filtering, and washing with water.

The acid addition salts of linagliptin include salts of linagliptin formed with pharmaceutically acceptable inorganic and organic acids. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, ortho-phosphoric acid, and nitric acid.

Examples of organic acids include acetic acid, 2,2-dichloroacetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamido-benzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1,2- disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene- 1,5-disulfonic acid, naphthalene-2-sulfonic acid, l-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, salicyclic acid, 4-aminosalicyclic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, toluenesulfonic acid, and undecylenic acid. In a preferred embodiment of the present invention, the acid addition salt is linagliptin phosphate.

The preparation of the acid addition salt of linagliptin is carried out by methods known in the literature, such as by the process described in PCT Publication No. WO 2010/072776, the contents of which are incorporated herein in their entirety be reference for the teaching of methods for preparing acid addition salts. The acid addition salt of linagliptin is further purified by treatment with an organic solvent and water. Examples of organic solvents to be used for the purification of the acid addition salt of linagliptin include alcohols, chlorinated hydrocarbons, ketones, alkyl acetates, ethers, amides, nitriles, sulphoxides, or mixtures thereof. Examples of alcohols include methanol, ethanol, n-propanol, iso-propanol, n-butanol, sec-butanol, and iso-butanol. Examples of chlorinated hydrocarbons include dichloromethane, chloroform, dichloroethane, and carbon tetrachloride. Examples of ketones include acetone, methyl ethyl ketone, and methyl isobutyl ketone. Examples of alkyl acetates include methyl acetate, ethyl acetate, propyl acetate, and butyl acetate. Examples of ethers include diethyl ether, ethyl methyl ether, tetrahydrofuran, and 1 ,4-dioxane. Examples of amides include N,N- dimethylformamide and Ν,Ν-dimethylacetamide. Examples of nitriles include acetonitrile and propionitrile. Examples of sulphoxides include dimethyl sulfoxide and diethyl sulphoxide. In a preferred embodiment of the present invention, the purification of the acid addition salt of linagliptin is carried out using iso-propanol and water.

The base to be used for the preparation of the stable amorphous form of linagliptin is selected from inorganic and organic bases. Examples of inorganic bases include carbonates, bicarbonates, and hydroxides of alkali metals. Examples of alkali metal carbonates include sodium carbonate and potassium carbonate. Examples of alkali metal bicarbonates include sodium bicarbonate and potassium bicarbonate. Examples of alkali metal hydroxides include lithium hydroxide, sodium hydroxide, and potassium hydroxide. Examples of organic bases include triethyl amine, tributyl amine, diisopropyl amine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 4-ethylmorpholine, and 1 ,4- diazabicyclo[2.2.2]octane. In a preferred embodiment of the present invention, sodium bicarbonate is used as the base.

Isolation of the stable amorphous form of linagliptin may be carried out by concentration, precipitation, cooling, filtration, centrifugation, or a combination thereof, followed by drying. Drying may be carried out using any suitable method such as drying under reduced pressure, air drying, or vacuum tray drying at ambient temperature to about 100°C for about 2 hours to 20 hours. In a preferred embodiment of the present invention, isolation of the stable amorphous form of linagliptin is carried out by drying at about 80°C to about 90°C for about 8 hours to about 14 hours under reduced pressure.

In a preferred embodiment of the present invention, the stable amorphous form of linagliptin is prepared by contacting the reaction mixture containing linagliptin phosphate in water with sodium bicarbonate at about 3°C to about 5°C. The reaction mixture is heated to about 40°C to about 45°C, and stirred for about 3 hours. The reaction mixture is cooled to about 3°C to about 5°C, stirred for about 1 hour, filtered, washed with water, and dried at about 85°C to about 90°C under reduced pressure for about 12 hours to obtain the stable amorphous form of linagliptin.

The amorphous linagliptin obtained by the process of the present invention is stable towards conversion to crystalline linagliptin on heating to an elevated temperature.

The stable amorphous form of linagliptin of the present invention is substantially free of residual organic solvent(s).

The stable amorphous form of linagliptin obtained by the process of the present invention may be administered as part of a pharmaceutical composition for the treatment of type 2 diabetes mellitus. Accordingly, in a further aspect, there is provided a pharmaceutical composition comprising the stable amorphous form of linagliptin and one or more pharmaceutically acceptable carriers, diluents, or excipients, and optionally other therapeutic ingredients. The stable amorphous form of linagliptin of the present invention may conventionally be formulated into tablets, capsules, suspensions, dispersions, injectable, and other pharmaceutical forms. Any suitable route of administration may be employed, for example peroral or parental. In the foregoing section, embodiments are described by way of an example to illustrate the process of the invention. However, this is not intended in any way to limit the scope of the present invention. Several variants of the example would be evident to persons ordinarily skilled in the art which are within the scope of the present invention. Methods

X-ray diffraction pattern was recorded using a PANalytical^® X'Pert PRO instrument.

HPLC purity was determined using a Kromasil^® C18 (250 x 4.6) mm, 5 μιη column with a flow rate: 1.0 mL/minute; column oven temperature: 30°C; detector: UV at 225nm; injection volume: ΙΟμί; run time: 50 minutes; using a phosphate buffer having a pH of 6.50 ± 0.05; and using a 1 : 1 mixture of water and acetonitrile as diluent.

Examples

Example 1 : Preparation of Linagliptin Phosphate

Ethanol (400 mL) was added to a reaction vessel containing linagliptin (40 g) at ambient temperature. The reaction mixture was heated to about 45°C, stirred for about 15 minutes, and then cooled to ambient temperature. Ortho-phosphoric acid (9.8 g; about 85% solution) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for about 6 hours, filtered, washed with ethanol (2 x 50 mL), and dried at about 45°C under reduced pressure for about 12 hours to obtain crude linagliptin phosphate (HPLC purity: 98.88%).

Iso-propanol (500 mL) was added to crude linagliptin phosphate (47.5 g) at ambient temperature. The reaction mixture was heated to about 78°C. Water (220 mL) was added slowly into the reaction mixture. Activated carbon (2.5 g) was added. The reaction mixture was stirred for about 15 minutes, and then filtered through a celite bed. The celite bed was washed with 30% solution of water and iso-propanol (1 x 50 mL). The contents were slowly cooled to ambient temperature, stirred for about 4 hours and 30 minutes, filtered, washed with iso-propanol (2 x 50 mL), and dried at about 44°C for about 10 hours under reduced pressure to obtain the pure linagliptin phosphate.

Yield: 75.25%

HPLC Purity: 99.72% Example 2: Preparation of the Stable Amorphous Form of Linagliptin

Sodium bicarbonate (4.8 g) was added to a reaction vessel containing linagliptin phosphate (6.5 g) in water (87 mL) at about 3°C to about 5°C. The reaction mixture was heated to about 40°C to about 45°C, and stirred for about 3 hours. The reaction mixture was cooled to about 3°C to about 5°C, stirred for about 1 hour, filtered, washed with water (19.5 mL), and dried at about 85°C to about 90°C for about 12 hours to obtain the stable amorphous form of linagliptin.

Yield: 91.9%

Figure 1 provides the X-ray diffraction pattern of the stable amorphous form of linagliptin of the present invention.

Comparative Example for the Preparation of Amorphous Form of Linagliptin

Dichloromethane (50 mL) was added to a reaction vessel containing linagliptin (5 g) at ambient temperature. The solution was filtered through a hyflo bed, washed with dichloromethane (25 mL), and subjected to agitated thin-film drying at about 45°C. The solid material was dried at about 40°C to about 45°C under reduced pressure to obtain amorphous linagliptin as a wet solid.

The wet solid (0.6 g) was dried at about 80°C to about 85°C for about 12 hours under reduced pressure.

Figure 2 provides the X-ray diffraction pattern of amorphous linagliptin obtained as a wet solid.

Figure 3 provides the X-ray diffraction pattern of linagliptin obtained after drying at about 80°C to about 85°C for about 12 hours under reduced pressure.

As should be evident in comparing Figures 1 and 2, both figures show an amorphous from of linagliptin. However, as seen from Figures 2 and 3, upon heating the linagliptin according to the comparative example, the amorphous linagliptin (Figure 2) shows significant conversion to crystalline linagliptin (Figure 3). In contrast, when the stable, amorphous linagliptin according to the invention was heated to similar or even warmer temperatures, conversion from the amorphous form to the crystalline form was not seen. Therefore, upon heating the stable, amorphous form of linagliptin according to the invention to an elevated temperature, the linagliptin stays completely or substantially in amorphous form.

Claims

We claim:

1. A stable amorphous form of linagliptin.

2. The stable amorphous form of linagliptin according to claim 1, characterized by an X-ray diffraction pattern substantially as depicted in Figure 1.

3. A process for the preparation of a stable amorphous form of linagliptin using water.

4. A process for the preparation of a stable amorphous form of linagliptin comprising contacting a reaction mixture containing an acid addition salt of linagliptin in water with a base.

5. The process according to claim 4, wherein the acid addition salt is selected from the salts of linagliptin formed with pharmaceutically acceptable inorganic and organic acids.

6. The process according to claim 4, wherein linagliptin phosphate is used as the acid addition salt.

7. The process according to claim 4, wherein the base is selected from inorganic and organic bases.

8. The process according to claim 4, wherein sodium bicarbonate is used as the base.

9. The process according to claim 4, wherein the isolation of the stable amorphous form of linagliptin is carried out by drying at about 85°C to about 90°C under reduced pressure.

10. The stable amorphous form of linagliptin prepared according to the process of claim 3 or claim 4, stable towards conversion to crystalline linagliptin on heating to elevated temperature.

1 1. The stable amorphous form of linagliptin prepared according to the process of claim 3 or claim 4, substantially free of residual organic solvent(s).

12. A pharmaceutical composition comprising the stable amorphous form of linagliptin and one or more pharmaceutically acceptable carriers, diluents, or excipients, and optionally other therapeutic ingredients.

13. Use of a stable amorphous form of linagliptin for the treatment of type 2 diabetes mellitus.