WO2015114657A2

WO2015114657A2 - Amorphous form of sitagliptin free base

Info

Publication number: WO2015114657A2
Application number: PCT/IN2015/000035
Authority: WO
Inventors: Shri Prakash Dhar Dwivedi; Brij Khera; Kumar Kamlesh SINGH; Kirtipalsinh Sajjansinh Solanki
Original assignee: Cadila Healthcare Limited
Priority date: 2014-01-21
Filing date: 2015-01-21
Publication date: 2015-08-06
Also published as: WO2015114657A3; IN2014MU00212A

Abstract

The present invention provides an amorphous form of sitagliptin free base of Formula (I). The invention further provides a process for preparation of an amorphous form of sitagliptin free base. The process comprises a) providing a solution or suspension of sitagliptin free base in one or more solvents; and b) obtaining the amorphous form of sitagliptin free base by the removal of the solvent.(I)

Description

AMORPHOUS FORM OF SITAGLIPTIN FREE BASE

FIELD OF THE INVENTION

The field of present invention relates to an amorphous form of sitagliptin free base. In particular, the invention relates to process for preparation of an amorphous form of sitagliptin free base.

BACKGROUND OF THE INVENTION

The following discussion of the prior art is intended to present the current invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field. Sitagliptin free base (CAS 486460-32-6) is an oral antihyperglycemic (antidiabetic drug) of the dipeptidyl peptidase-4 (DPP-4) inhibitor class. It was developed, and is marketed, by Merck & Co under the trade name of JANUVIA. The tablets contain sitagliptin phosphate, an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme.

Sitagliptin free base is chemically named as 7-[(3R)-3-amino-l-oxo-4-(2,4,5- trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-l ,2,4-triazolo[4,3- ajpyrazine and has the following structural Formula (I).

(I) U.S. Patent No. 6,699,871 B2 (the US'871 Patent) and J Med. Chem. 2005, Vol. 48(1), 141-151 discloses process for the preparation of sitagliptin.

U.S. PG-Pub No. 2006/0287528 Al discloses sitagliptin phosphate anhydrous Form I, II and III and an ethanol solvate; and International (PCT) Publication No WO 2005/030127 Al discloses sitagliptin phosphate anhydrous form IV. U.S. PG- Pub. No US 2010/0041885 Al discloses a crystalline sitagliptin phosphate; and U.S. Patent No. 7,326,708 B2 discloses crystalline sitagliptin phosphate monohydrate.

U.S. Patent No. 7,326,708 B2 and U.S. PG-Pub. No. 2009/0221595 Al discloses the isolation of sitagliptin free base in a crystalline form. U.S. Patent No. 8,334,385 B2 discloses crystalline sitagliptin free base characterized by X-ray powder diffraction pattern and Differential Scanning Calorimetry data.

U.S. PG-Pub. No. 2009/0221592 Al and International (PCT) Publication Nos. WO 2010/000469, WO 2010/122578, WO 2011/018494, WO 2012/007455 and WO 2012/076973 disclose various polymorphic forms of sitagliptin salts. International (PCT) Publication No. WO 2013/001514 Al discloses amorphous solid dispersion of sitagliptin dihydrogen phosphate.

The prior-art provides one or the other crystalline form of sitagliptin free base or salts thereof. The different physical properties exhibited by polymorphs affect important pharmaceutical parameters such as storage, stability, compressibility, density and dissolution rates (important in determining bioavailability). Therefore, one of the objectives of the present invention is to provide an amorphous form of sitagliptin free base and process for preparation thereof which provides at least an useful alternative approach over those disclosed in the art. SUMMARY OF THE INVENTION

In one general aspect, there is provided an amorphous form of sitagliptin free base of Formula (I).

In another general aspect, there is provided an amorphous form of sitagliptin free base substantially free from residual solvents. In another general aspect, there is provided an amorphous solid dispersion of sitagliptin free base with at least one pharmaceutically acceptable career.

In another general aspect, there is provided process for preparation of amorphous form of sitagliptin free base.

In another general aspect, there is provided a process for preparation of amorphous form of sitagliptin free base by adding an anti-solvent to a solution of sitagliptin free base or by removal of solvent therefrom. In another general aspect, there is provided a process for preparation of amorphous form of sitagliptin free base by temperature alterations of sitagliptin free base in presence or absence of a solvent.

In another general aspect, there is provided a process for preparation of amorphous form of sitagliptin free base using spray drying. In another general aspect, there is provided a process for preparation of amorphous form of sitagliptin free base by milling or grinding.

In another general aspect, there is provided a process for preparation of an amorphous solid dispersion of sitagliptin free base having at least one pharmaceutically acceptable career using a solvent-based approach or in absence of solvent.

BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS

FIG 1 : X-ray diffractogram (XRD) of amorphous sitagliptin.

DETAILED DESCRIPTION OF THE INVENTION

The above mentioned objectives of present invention are fulfilled by one or more of the processes described herein. All ranges recited herein include the endpoints, including those that recite a range "between" two values. Terms such as "about", "generally", and "substantially," are to be construed as modifying a term or value such that it is not an absolute. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.

As used herein, the terms "suspending" may be interchanged with "slurrying" or "triturating", and refer to a process carried out in a heterogeneous mixture where complete dissolution does not occur. Also, heating the suspension or slurry can result in a homogenous mixture where complete or partial dissolution occurs at an elevated temperature or ambient temperature.

As used herein, the term "solution" does not limit to a clear solution only and includes a hazy solution or a slurry which is a heterogeneous mixture.

As used herein, the term "solid dispersion" means any solid composition having at least two components. In certain embodiments, a solid dispersion as disclosed herein includes an active ingredient sitagliptin free base dispersed among at least one other component, for example a polymer.

As used herein, the term "immobilize" as used with reference to the immobilization of the active compound in the polymer matrix, means that molecules of the active compound interact with molecules of the polymer in such a way that the molecules of the active ingredients are held in the aforementioned matrix and prevented from crystal nucleation due to lack of mobility. As used herein, the term "anti-solvent" does not limit to a solvent in which sitagliptin free base is completely insoluble and includes a solvent in which solubility of sitagliptin free base is less than that of a solvent in which the solution is prepared. As used herein, the term "temperature alterations" means change of temperature which includes increasing or decreasing the temperature.

As used herein, the term "grinding" or "milling" includes mixers, mills (ball mill, jet mill etc.), blenders, and micronizers or a combination thereof. The terms "grinding", "milling", "mixing", and "blending" are interchangeable.

The term "pharmaceutical compositions" herein includes pharmaceutical formulations selected from tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and/or injection preparations.

As used herein, the terms "obtaining" means isolating the amorphous form of sitagliptin free base by way of filtration, filtration under vacuum, centrifugation, decantation. The product obtained may be further or additionally dried to achieve the desired moisture values. For example, the product may be dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier. In one general aspect, there is provided an amorphous form of sitagliptin free base of Formula (I).

In another general aspect, there is provided an amorphous form of sitagliptin free base having purity by HPLC of greater than about 99% and a residual solvent less than about 0.5%. In general, the amorphous form of sitagliptin free base is substantially free from residual solvents. The term "substantially free" means residual solvents within the permissible ICH limits suitable for pharmaceutical preparations. For example but not limited to less than 0.5%, particularly less than 0.3% or more particularly less than 0.2%.

In another general aspect, there is provided a process for preparation of an amorphous form of sitagliptin free base, the process comprising:

(a) providing a solution of sitagliptin free base in one or more of solvents; and

(b) obtaining the amorphous form of sitagliptin free base by removal of the solvent. The step (a) above involves providing a solution of sitagliptin free base in one or more of solvent or mixture thereof.

The solution for step (a) can he obtained by known methods that include: (i) direct use of a reaction mixture containing sitagliptin free base that is obtained in the course of its synthesis; or

(ii) dissolving sitagliptin free base in one or more of solvents or mixture thereof.

In general, in step (a), any physical form of sitagliptin free base may be utilized for providing the solution of sitagliptin free base in one or more of solvents or mixture thereof. The dissolution temperatures may be from about below 0°C to about the reflux temperature of the solvent.

In general, the solvent comprises one or more of alcohol, ketone, ester, halogenated hydrocarbon, polar aprotic solvent, acetonitrile, tetrahydrofuran, 2- methyltetrahydrofuran, dioxane or mixtures thereof.

In general, the alcohol is selected from methanol, ethanol, n-propanol, isopropanol (IPA), and n-butanol; the ketone is selected from acetone, methyl ethyl ketone, and methyl isobutyl ketone; the ester is selected from ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; the halogenated hydrocarbon is selected from methylene dichloride, ethylene dichloride, carbon tetrachloride and chlorobenzene; the polar aprotic solvent is selected from dimethylformamide, dimethylsulfoxide, and N-methylpyrrolidone or mixture thereof. In particular, IPA may be used.

The step (b) above involves obtaining of an amorphous form of sitagliptin free base from the solution of step (a). The isolation of an amorphous form of sitagliptin free base may be affected by removing the solvent. The techniques which may be used for the removal of solvent comprises one or more of distillation, distillation under vacuum, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization), filtration, decantation, and centrifugation. The solvent may also be removed, optionally, at reduced pressure and/or elevated temperature.

In general, freeze drying (lyophilization) may be performed by freezing a solution of sitagliptin free base at low temperatures and reducing the pressure to remove the solvent from the frozen solution of sitagliptin free base. Temperatures that may be required to freeze the solution, depending on the solvent chosen to make the solution of sitagliptin free base may range from about -70°C to about 10°C. In another general aspect, there is provided a process for preparation of amorphous form of sitagliptin free base by adding an anti-solvent to a solution of sitagliptin free base or by removal of solvent therefrom.

The anti-solvent comprises one which reduces the solubility of sitagliptin free base in the solution, causing the crystallization or precipitation spontaneously or upon stirring. In particular, the anti-solvent may be added to the solution of sitagliptin free base or sitagliptin free base solution may be added to the anti- solvent. In general, the anti-solvent comprises one or more of water, hexane, n-heptane, cyclohexane, cyclohexene, cyclohexanone, toluene, xylene, diethyl ether, diisopropyl ether, and methyl tert-butyl ether.

In another general aspect, there is provided a process for preparation of amorphous form of sitagliptin free base using spray drying the solution of sitagliptin free base in a solvent.

In another general aspect, there is provided a process for preparation of amorphous form of sitagliptin free base by temperature alterations of sitagliptin, optionally in presence or absence of solvent. In another general aspect, there is provided a process for preparation of amorphous form of sitagliptin free base, the process comprising:

(a) providing sitagliptin free base, optionally in presence of one or more of a solvents at first temperature; and

(b) converting sitagliptin free base of step (a) to a second temperature; or

(c) optionally converting sitagliptin free base of step (b) to a third temperature.

The first temperature may be higher than the second temperature or the second temperature may be higher than the first temperature. The difference in the amplitude between the first and the second temperatures may be atleast about 0- 15°C, or about 0-50°C, or more about 0-100°C. The third temperature may be same or different from first temperature.

In general, sitagliptin free base may be heated with a solvent at first temperature and then cooled to a second temperature to obtain amorphous sitagliptin free base.

In general, freeze-dried sitagliptin, as described herein above, at a first temperature may be heated to a second temperature to obtain amorphous sitagliptin free base.

In general, sitagliptin free base may be heated to a first temperature which may be less than or equal to its melting point, or optionally higher than the melting point and cooled to a second temperature which is lower than the first temperature to obtain amorphous sitagliptin free base.

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In another general aspect, there is provided a process for preparation of amorphous form of sitagliptin free base by milling or grinding.

In general, the milling or grinding comprise of sieving, ball milling, multi-milling, and grinding. The process may include further forming the product so obtained into a finished dosage form. In another general aspect, there is provided a process for the preparation of amorphous form of sitagliptin free base by grinding sitagliptin free base. In general, sitagliptin free base may be sieved through 30 to 60 mesh for obtaining homogeneous solid mixture of sitagliptin free base and further may be subjected to a grinding.

In another general aspect, there may be provided a composition of an amorphous sitagliptin free base having at least one polymer, as well as methods for production of such compositions from a solvent-based medium.

In general, the composition is an amorphous solid dispersion comprising sitagliptin free base and one or more pharmaceutically acceptable excipients.

In general, the polymer may be a non-ionic polymer or an ionic polymer. The polymer comprises of hydroxyprppylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulose, methacrylic acid copolymers, and polyvinylpyrrolidone (PVP). In particular, PVP of different grades is selected from K-15, K-30, K-60, K-90 and K-120, which may be used for the preparation of amorphous composition. More particular, hydroxypropylmethyl cellulose acetate succinate and PVP K-30 may be used.

In general, the sitagliptin free base of Formula (I) may be dispersed within a matrix formed by a polymer in its solid state such that it is immobilized in its amorphous form. The polymer may prevent intramolecular hydrogen bonding or weak dispersion forces between two or more drug molecules of sitagliptin.

In another general aspect, there is provided a process for preparation of an amorphous solid dispersion of sitagliptin free base having at least one pharmaceutically acceptable career using a solvent-based approach or in absence of solvent as described herein above.

In another general aspect, there is provided a process for the preparation of an amorphous solid dispersion comprising sitagliptin free base and one or more pharmaceutically acceptable excipients, the process comprising:

(a) providing a solution of sitagliptin free base and one or more pharmaceutically acceptable excipients in one or more solvents;

(b) optionally, filtering the solution to remove insoluble matter; and

(c) removing the solvent from the solution to obtain the amorphous solid dispersion of sitagliptin free base with the pharmaceutically acceptable excipients.

In general, the solvent comprises one or more of water, alcohol, ketone, ester, halogenated hydrocarbon, polar aprotic solvent, acetonitrile, tetrahydrofuran, 2- methyltetrahydrofuran, dioxane or mixtures thereof.

In another general aspect, there is provided an amorphous form of sitagliptin free base substantially free from residual solvents.

In another general aspect, there is provided an amorphous solid dispersion of sitagliptin free base with at least one pharmaceutically acceptable career. In another general aspect, an amorphous solid dispersion of sitagliptin free base having a purity by HPLC of more than about 99%.

In another general aspect, the present invention provides an amorphous form of sitagliptin free base having purity by HPLC of >99%. In particular, the purity by HPLC of > 99.5%, more particularly, the purity by HPLC of > 99.8%, most particularly, the purity by HPLC > 99.9%.

The invention also encompasses pharmaceutical compositions comprising sitagliptin free base of the invention. As used herein, the term "pharmaceutical compositions" includes pharmaceutical formulations comprises one or more of tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injection preparations.

In another general aspect, there is provided a pharmaceutical composition comprising an amorphous sitagliptin free base together with one or more pharmaceutically acceptable carriers, excipients or diluents.

In another general aspect, there is provided a pharmaceutical composition comprising an amorphous solid dispersion comprising sitagliptin free base together with one or more of pharmaceutically acceptable carriers, excipients or diluents.

In another general aspect, there is provided a pharmaceutical composition containing a stabilized amorphous form of sitagliptin free base, optionally with one or more pharmaceutically acceptable carriers and one or more pharmaceutically acceptable excipients.

Pharmaceutical compositions containing the sitagliptin free base of the invention may be prepared by using diluents or excipients selected from fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, and lubricants. Various modes of administration of the pharmaceutical compositions of the invention is selected depending on the therapeutic purpose, for example tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

Examples

Example-1: Preparation of Amorphous Sitagliptin Free Base by Temperature Alterations

Sitagliptin free base (5 g) and isopropanol (20 ml) were stirred at reflux temperature and cooled rapidly to 10-15°C in 1 min and further cooled to 0-5°C in 1 min. The mixture was stirred, filtered and dried to obtain amorphous sitagliptin free base. Example-2: Preparation of Amorphous Sitagliptin Free Base by Spray Drying

Sitagliptin free base (5 g) and ethanol (100 mL) were taken into a round bottom flask. The content was stirred for 1 hour at 60°C to 65 °C. The content was filtered through hyflosupercel and washed with 10.0 mL ethanol. The clear filtrate was subjected to spray drying in JISL Mini spray drier LSD-48 by maintaining the inlet temperature in the range of 50-55°C, under nitrogen pressure of 4.5 kg/cm² at a feed rate of 14%, to obtain amorphous sitagliptin free base.

Example-3: Preparation of Amorphous Sitagliptin Free Base by Solvent - Anti-Solvent Approach

Sitagliptin free base (5 g) and butanol (100 ml) were stirred at reflux temperature and cyclohexane (250 ml) was added dropwise over 15-30 min. The mixture was cooled to 25-30°C and stirred for 30 min. The obtained mass was filtered, washed with water and dried to obtain amorphous sitagliptin free base.

Example-4: Preparation of Amorphous Sitagliptin Free Base by Milling Sitagliptin free base (5 gm) was placed in 125 mL milling vessel of Ball Mill with 12 no's of tungsten carbide balls having diameter of 10 mm each, rotated for 18 hours at 150 rpm by using set time of 15 min every 10 min interval time to obtain amorphous sitagliptin free base.

Example-5: Preparation of amorphous solid dispersion of sitagliptin free base

In 100 mL three necked round bottom flask equipped with mechanical stirrer, thermometer and an addition funnel, 1 g of sitagliptin free base and 15 mL methanol were taken in round bottom flask at 25-30°C. The reaction mixture was heated at 45-50°C to obtain clear solution. 1 g of PVP-K30 polymer was added and stirred at 45-50°C for 2 hours. The reaction mixture was distilled under vacuum at 60-65°C. The product was dried under vacuum at 55-60°C to obtain 0.7 g amorphous solid dispersion of sitagliptin free base. Example-6: Preparation of amorphous solid dispersion of sitagliptin free base

In 100 mL three necked round bottom flask equipped with mechanical stirrer, thermometer and an addition funnel, 1 g of sitagliptin free base and 15 mL isopropanol were taken at 25-30°C. The reaction mixture was heated at 60-70°C to obtain clear solution. 1 g of PVP-K30 polymer was added and stirred at 60- 70°C for 2 hours. The reaction mixture was distilled under vacuum at 60-65°C. The product was dried under vacuum at 55-60°C to obtain 0.7 g amorphous solid dispersion of sitagliptin free base.

Example-7: Preparation of amorphous solid dispersion of sitagliptin free base In 100 mL three necked round bottom flask equipped with mechanical stirrer, thermometer and an addition funnel, 1 g of sitagliptin free base and 20 mL isopropanol were taken at 25-30°C. The reaction mixture was heated at 50-55°C to obtain clear solution. 1 g of HPMC (3cps) polymer was added and stirred at 50- 55°C for 15 minutes. The reaction mixture was distilled under vacuum at 60- 65°C. The product was dried under vacuum at 55-60°C to obtain 1.2 g amorphous solid dispersion of sitagliptin free base. The obtained solid was amorphous as shown by the X-ray diffraction pattern given in FIG. 1.

Preparation of Sitagliptin Free Base as starting material:

Preparation-1: Preparation of (R)-tert-butyl 4-oxo-4-(3-(trifluoromethyl)-5,6- dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yI)-l-(2,4,5-trifluorophenyl) butan-2-ylcarbamate

In 2 L three necked round bottom flask equipped with mechanical stirrer, thermometer and an addition funnel, were added 400 mL DMF, 100 g (3i?)-N- (tert-butoxycarbonyl)-3-amino-4-(2,4,5-trifluorophenyl) butanoic acid and 72 g 3- (trifluoromethyl)-5,6,7,8-tetrahydro-l,2,4-triazolo-[4,3-a]pyrazine hydrochloride. The reaction mixture was cooled to 0 to 5°C and 106 g TBTU was added. 116.3 g DIPEA was added to the reaction mixture and stirred for 1 hour. After the completion of reaction, 1 L water and 600 mL 1% NaHC0₃ was added. The reaction mixture was stirred for 1 hour at 25°C to 35°C. The precipitates were filtered and washed with water. The product was dried under vacuum at 60°C for 4 hours to obtain 151.9 g of title compound. Preparation-2: Preparation of sitagliptin free base

In 2 L four necked round bottom flask equipped with mechanical stirrer, thermometer and an addition funnel, 150 g (J^l?)-tert-butyl 4-oxo-4-(3- (trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-l-(2,4,5- trifluorophenyl)butan-2-ylcarbamate obtained in preparation-1 and 450 mL of IPA were added. 285.8 mL IPA.HC1 16.6% solution was added to the reaction mixture and heated to 50°C for 4 hours. After the completion of reaction, IPA was distilled completely to get a semisolid mass under vacuum at about 60°C followed by addition of 600 mL MDC and 600 mL water. The reaction mixture was treated with 40% sodium hydroxide solution to adjust the pH of 12 to 13. The separated aqueous layer was extracted with 300 mL MDC. The MDC layer was washed with 300 mL water, charcoalized and filtered. The filtrate was distilled completely to remove MDC at about 50°C and treated with 150 mL of cyclohexane. The reaction mixture was distilled to remove cyclohexane and 150 mL of isopropaiiol and 750 mL of cyclohexane was added. The reaction mixture was heated to 70°C to 75°C for 1 hour and cooled to 0°C to 5°C. The product was filtered and washed with cyclohexane and dried at 50°C to obtain 102 g of sitagliptin free base.

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.

Claims

We Claim:

1. An amorphous form of sitagliptin free base of Formula (I).

(I)

2. The amorphous form of sitagliptin free base according to claim 1 having a purity by HPLC of greater than about 99%.

3. The amorphous form of sitagliptin free base according to claim 1 having residual solvent less than about 0.5%.

4. A process for the preparation of an amorphous form of sitagliptin free base, the process comprising:

(a) providing a solution or suspension of sitagliptin free base in one or more solvents; and

(b) obtaining the amorphous form of sitagliptin free base by the removal of the solvent.

5. The process according to claim 5, wherein the solvent comprises one or more of alcohol, ketone, ester, halogenated hydrocarbon, polar aprotic solvent, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane or mixtures thereof.

6. The process according to claim 6, wherein the alcohol is selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1- pentanol, and 2-pentanol; the ketone is selected from acetone, butanone, 2- pentanone, 3-pentanone, methylbutyl ketone, and methyl isobutyl ketone; the ester is selected from ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; and the halogenated hydrocarbon is selected from methylene dichloride, ethylene dichloride, carbon tetrachloride and chlorobenzene; polar aprotic solvent selected from dimethylformamide, dimethylsulfoxide, and N-methyl- pyrrolidone.

7. The process according to claim 5, wherein the removal of the solvent comprises one or more of distillation, distillation under vacuum, spray drying, agitated thin film dyring ("ATFD"), freeze drying (lyophilization), filtration, decantation, and centrifugation.

8. A process for preparation of amorphous form of sitagliptin free base by milling or grinding.

9. The process according to claim 8, wherein the milling or grinding comprises of sieving, ball milling, multi -milling, and grinding.

10. A composition comprising an amorphous form of sitagliptin free base having at least one polymer.

11. The composition according to claim 10 is an amorphous solid dispersion comprising sitagliptin free base and one or more pharmaceutically acceptable excipients.

12. The amorphous solid dispersion according to claim 11, wherein the pharmaceutically acceptable excipient is a non-ionic polymer or an ionic polymer.

13. The amorphous solid dispersion according to claim 12, wherein the polymer is selected from methacrylic acid copolymers, polyvinylpyrrolidone (PVP), 4- vinylpyrrolidone-vinyl acetate copolymer (copovidone) or copolymers of methacrylic acid and ethylacrylate (EUDRAGIT® L100-55), hydroxypropyl cellulose, hydroxypropylmethyl cellulose (HPMC), hypromellose phthalate, hydroxypropylmethyl cellulose acetate succinate (HPMC-AS).

14. A process for the preparation of an amorphous solid dispersion comprising sitagliptin free base and one or more pharmaceutically acceptable excipients, the process comprising:

(d) providing a solution of sitagliptin free base and one or more pharmaceutically acceptable excipients in one or more solvents;

(e) optionally, filtering the solution to remove insoluble matter; and

(f) removing the solvent from the solution to obtain the amorphous solid dispersion of sitagliptin free base with the pharmaceutically acceptable excipients.

15. The process according to claim 12, wherein the solvent comprises one or more of water, alcohol, ketone, ester, halogenated hydrocarbon, polar aprotic solvent, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane or mixtures thereof.

16. The process according to claim 13, wherein the alcohol is selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1- pentanol, and 2-pentanol; the ketone is selected from acetone, butanone, 2- pentanone, 3-pentanone, methylbutyl ketone, and methyl isobutyl ketone; the ester is selected from ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; and the halogenated hydrocarbon is selected from methylene dichloride, ethylene dichloride, carbon tetrachloride and chlorobenzene; polar aprotic solvents selected from dimethylformamide, dimethylsulfoxide, and N-methyl- pyrrolidone.

17. An amorphous solid dispersion comprising sitagliptin free base and one or more pharmaceutically acceptable excipients which is substantially free from residual solvents.

18. An amorphous solid dispersion of sitagliptin free base having a purity by HPLC of more than about 99%.

19. A pharmaceutical composition comprising an amorphous sitagliptin free base together with one or more pharmaceutically acceptable carriers, excipients or diluents.

20. A pharmaceutical composition comprising an amorphous solid dispersion comprising sitagliptin free base together with one or more of pharmaceutically acceptable carriers, excipients or diluents.