This application claims priority to Indian patent applications numbered 902/CHE/2012 filed on March 12, 2012; 1677/CHE/2012 filed on April 30, 2012 & 5131/CHE/2012 filed on Dec 10, 2012 the contents of which are incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to a process for preparation of amorphous Saxagliptin hydrochloride.

BACK GROUND OF THE INVENTION

Saxagliptin is orally active reversible dipeptidyl peptidase-4 (DPP4) inhibitor, which is therapeutic agent for treatment of type-2 diabetes mellitus, obesity or related disease. Saxagliptin is chemically known as (1S, 3S, 5S)-2-[(2S)-2-amino-2-(3-hydroxy-1-adamantyl) acetyl]-2-azabicyclo [3.1.0] hexane-3-carbonitrile and having the below structure of formula.

US7943656B2 patent disclosed certain crystal forms of Saxagliptin base and acid addition salts including hydrochloride, hydrobromide, and hydrogen iodide, nitrate, trifluoroacetic acid, benzoate, fumarate, tartarate, ammonium sulfate salt. More preferred are saxagliptin hydrchloride polymorphic forms H2-1, H2-1, 0.75-3, H1.67-1 and P-5.

WO2010115974A1 application disclosed four anhydrous crystalline forms of Saxaglipitn hydrochloride, form l-S, form HT-S, form HT-IV-S and form IV-S. This application also disclosed that a solution of Saxagliptin Hydrochloride in n-butanol is evaporated to dryness to produce an amorphous or weakly crystalline saxagliptin hydrochloride.

US20120083517A1 application disclosed crystalline Saxagliptin hydrochloride form K, form Z, form D, form S, form Z and amorphous Saxagliptin hydrochloride.

Though amorphous saxagliptin hydrochloride process is disclosed in the prior art, there is a need to develop an improved process. The present invention is simple, cost effective and commercially feasible in large scale production.

SUMMARY OF THE INVENTION

The main aspect of the present invention is to provide a process for the preparation of amorphous saxagliptin hydrochloride.

One aspect of the present invention is to provide a process for the preparation of amorphous Saxagliptin hydrochloride comprising the steps of;

a) dissolving saxagliptin hydrochloride in a solvent or mixture thereof,
b) removing the solvent from step a) solution under spray drying technique to get an amorphous saxagliptin hydrochloride.

Another aspect of the present invention is to provide a process for the preparation of amorphous Saxagliptin hydrochloride comprising the steps of;

a) dissolving saxagliptin hydrochloride and a polymer in a solvent or mixture thereof,
b) removing the solvent to get amorphous saxagliptin hydrochloride.

Another aspect of the present invention is to provide a process for the preparation of amorphous Saxagliptin hydrochloride comprising the steps of;

a) dissolving saxagliptin hydrochloride and a polymer in a solvent or mixture thereof,
b) removing the solvent to get a residue,
c) adding hydrocarbon or ether solvent to the residue, and
d) isolating amorphous saxagliptin hydrochloride.

Yet another aspect of the present invention is to provide a process for the preparation of amorphous Saxagliptin hydrochloride comprising the steps of;

a) dissolving saxagliptin hydrochloride, a polymer and an organic acid in a solvent or mixture thereof,
b) removing the solvent to get an amorphous saxagliptin hydrochloride.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a representative X-ray diffraction pattern of amorphous saxagliptin hydrochloride.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of amorphous saxagliptin hydrochloride, wherein the saxagliptin hydrochloride is dissolved in a solvent and evaporating to get amorphous saxagliptin hydrochloride. The present invention also relates to a preparation of a stable amorphous saxagliptin hydrochloride by dissolving saxagliptin hydrochloride in a solvent treating with a polymer in the presence of an organic acid, removing the solvent to get amorphous saxagliptin hydrochloride.

One embodiment of the present invention is to provide a process for the preparation of amorphous Saxagliptin hydrochloride comprising the steps of,

a) dissolving saxagliptin hydrochloride in a solvent or mixture thereof,

b) removing the solvent from step a) solution under spray drying technique to get an amorphous saxagliptin hydrochloride

According to the present invention, saxagliptin hydrochloride is dissolved in a solvent at ambient temperature, undissolved particles are filtered through hy-flow bed and solvent is removed by known techniques to get an amorphous saxagliptin hydrochloride.

According to the present invention, the solvent used for dissolution of saxagliptin hydrochloride is selected from alcohol solvent, chlorinated solvent, ketone solvent, ester solvent, water or mixture thereof.

According to the present invention alcohol solvent is selected from methanol, ethanol, propanol, isopropanol, butanol, pentanol or mixture thereof; chlorinated solvent is selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixture thereof; ketone solvent is selected from acetone, methylethylketone, methylisobutylketone or mixture thereof; ester solvent is etheylacetate, ethyl acetoacetate, methyl acetate isopropyl acetate or mixture thereof.

Another embodiment of the present invention is to provide a process for the preparation of amorphous saxagliptin hydrochloride comprising the steps of;

a) dissolving saxagliptin hydrochloride and a polymer in a solvent or mixture thereof,
b) removing the solvent to get amorphous saxagliptin hydrochloride.

According to the present invention, saxagliptin hydrochloride is dissolved in a solvent with a polymer capable of forming the solid dispersion at ambient temperature. Solvent is removed by known techniques to get an amorphous saxagliptin hydrochloride.

According to the present invention, the solvent used for dissolution of saxagliptin hydrochloride and polymer is selected from alcohol solvent, chlorinated solvent, ketone solvent, ester solvent, water or mixture thereof.

According to the present invention alcohol solvent is selected from methanol, ethanol, propanol, isopropanol, butanol, pentanol or mixture thereof; chlorinated solvent is selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixture thereof; ketone solvent is selected from acetone, methylethylketone, methylisobutylketone or mixture thereof; ester solvent is etheylacetate, ethyl acetoacetate, methyl acetate isopropyl acetate or mixture thereof.

According to present invention, solvent is removed by the know techniques such as spray dry, evaporation, distillation, liophilization, agitated thin film drier (ATFD) or filteration. Preferably solvent is removed by spray dry at a temperature 40 to 100 °C, preferably 40 to 80 °C.
According to present invention, the preferred polymer/agent employed is selected from plasdone S-630 or PVP K-30.

Another embodiment of the present invention is to provide a process for the preparation of amorphous saxagliptin hydrochloride comprising the steps of;

a) dissolving saxagliptin hydrochloride and a polymer in a solvent or mixture thereof,
b) removing the solvent to get a residue,
c) adding hydrocarbon or ether solvent to the residue, and
d) isolating amorphous saxagliptin hydrochloride.

According to the present invention, saxagliptin hydrochloride is dissolved in a solvent with a polymer capable of forming the solid dispersion at ambient temperature. The clear solution is distilled out completely to get a residue. Hydrocarbon or ether solvent is added to the residue, stirred the mixture and obtained solid is filtered to get amorphous saxagliptin hydrochloride.

According to the present invention, the solvent used for dissolution of saxagliptin hydrochloride and polymer is selected from alcohol solvent, chlorinated solvent, ketone solvent, ester solvent, water or mixture thereof.

According to the present invention alcohol solvent is selected from methanol, ethanol, propanol, isopropanol, butanol, pentanol or mixture thereof; chlorinated solvent is selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixture thereof; ketone solvent is selected from acetone, methylethylketone, methylisobutylketone or mixture thereof; ester solvent is etheylacetate, ethyl acetoacetate, methyl acetate isopropyl acetate or mixture thereof.

According to the present invention the hydrocarbon solvent is selected from hexane, cyclohexane, heptane, pentane and the ether solvent is selected from dietheyether or diisopropyl ether.

According to present invention, solvent is removed by the know techniques such as spray dry, evaporation, distillation, liophilization, agitated thin film drier (ATFD) or filteration. Preferably solvent is removed by spray dry at a temperature 40 to 100 °C, preferably 40 to 80 °C.

According to present invention, the preferred polymer/agent employed is selected from plasdone S-630 or PVP K-30.

Yet another embodiment of the present invention is to provide a process for the preparation of amorphous Saxagliptin hydrochloride premix comprising the steps of;

a) dissolving saxagliptin hydrochloride, a polymer and an organic acid in a solvent or mixture thereof,

b) removing the solvent to get an amorphous saxagliptin hydrochloride.

According to the present invention saxagliptin hydrochloride, polymer and organic acid is dissolved in a solvent capable of forming the solid dispersion and an organic acid at ambient temperature. Undissolved particles are filtered through hi-flow bed. The clear solution is distilled out completely to get amorphous saxagliptin hydrochloride.

According to the present invention, the solvent used for dissolution of saxagliptin hydrochloride, polymer or organic acid is selected from alcohol solvent, chlorinated solvent, ketone solvent, ester solvent, water or mixture thereof.

According to the present invention alcohol solvent is selected from methanol, ethanol, propanol, isopropanol, butanol, pentanol or mixture thereof; chlorinated solvent is selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixture thereof; ketone solvent is selected from acetone, methylethylketone, methylisobutylketone or mixture thereof; ester solvent is etheylacetate, ethyl acetoacetate, methyl acetate isopropyl acetate or mixture thereof.

According to present invention, solvent is removed by the know techniques such as spray dry, evaporation, distillation, liophilization, agitated thin film drier (ATFD) or filteration. Preferably solvent is removed by spray dry at a temperature 40 to 100 °C, preferably 40 to 80 °C.

According to present invention, the preferred polymer/agent employed is selected from plasdone S-630 or PVP K-30 and the organic acid is selected from oxalic acid, succinic acid, fumaric acid, tartaric acid, malic acid or maleic acid

According to the present invention the input saxagliptin hydrochloride may be in crystalline or semi crystalline/weakly crystalline solid or a residue.

The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way.

EXPERIMENTAL SECTION

Powder X-ray Diffraction (PXRD)

The X-ray diffraction patterns of said polymorphs of the invention were measured on Bruker D8 Discover powder diffractometer equipped with goniometer of q/q configuration and LynxEye detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 28 range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.

Example 1: Preparation of amorphous Saxagliptin hydrochloride.

Saxagliptin hydrochloride (5g) was dissolved in methanol (50 ml) and filtered through hy-flow bed to remove any undissolved particulate. The clear solution was subjected to spray drying on Buchi Mini spray dryer (Model B-290) at 40°C. The solid obtained was identified as saxagliptin hydrochloride amorphous form (2g).

Example 2: Preparation of amorphous Saxagliptin hydrochloride.

Saxagliptin hydrochloride (2g) was dissolved in water (60 ml) and filtered through hy-flow bed to remove any undissolved particulate. The clear solution was subjected to spray drying on Buchi Mini spray dryer (Model B-290) at 80°C. The solid obtained was identified as saxagliptin hydrochloride amorphous form (0.5g).

Example 3: Preparation of amorphous Saxagliptin hydrochloride.

Saxagliptin hydrochloride (5g) was dissolved in acetone (50 ml) and filtered through hy-flow bed to remove any undissolved particulate. The clear solution was subjected to spray drying on Buchi Mini spray dryer (Model B-290) at 50°C. The solid obtained was identified as saxagliptin hydrochloride amorphous form (2g).

Example 4: Preparation of amorphous Saxagliptin hydrochloride.

Saxagliptin hydrochloride (5g) was dissolved in dichloromethane (50 ml) and filtered through hy-flow bed to remove any undissolved particulate. The clear solution was subjected to spray drying on Buchi Mini spray dryer (Model B-290) at 40°C. The solid obtained was identified as saxagliptin hydrochloride amorphous form (2 g).

Example 5: Preparation of amorphous Saxagliptin hydrochloride.

Saxagliptin hydrochloride (1g) and Plasdone S-630 (3g) was dissolved in methanol (40 ml) at 25-30°C. The resulting clear solution was then distilled out completely under vacuum at 30-40°C. The solid obtained was isolated and identified as amorphous Saxagliptin hydrochloride.

Example 6: Preparation of amorphous Saxagliptin hydrochloride.

Saxagliptin hydrochloride (1g) and Plasdone S-630 (3g) was dissolved in methanol (40 ml) at 25-30°C. The resulting clear solution was distilled out completely under vacuum at 30-40°C to get a residue, n-heptane (30 ml) was added to the residue and the mass was stirred for 15-30 minutes. Product was isolated and suck dried under reduced pressure at 25-30°C. The solid obtained and identified as amorphous Saxagliptin hydrochloride.

Example 7: Preparation of amorphous Saxagliptin hydrochloride.

Saxagliptin hydrochloride (1g) and Plasdone S-630 (3g) was dissolved in methanol (40 ml) at 25-30°C. The resulting clear solution was then distilled out completely under vacuum at 30-40°C to get a residue. Isopropyl ether (30 ml) was added to the residue and the mass is stirred for 15-30 minutes. The product was isolated and suck dried under reduced pressure at 25-30°C. The solid obtained was identified as amorphous Saxagliptin hydrochloride.

Example 8: Preparation of amorphous Saxagliptin hydrochloride.

Saxagliptin hydrochloride (1g) and PVP K-30 (3g) was dissolved in methanol (40 ml) at 25-30°C. The resulting clear solution was then distilled out completely under vacuum at 30-40°C. The solid obtained was isolated and identified as amorphous Saxagliptin hydrochloride.

Example 9: Preparation of amorphous Saxagliptin hydrochloride.

Saxagliptin hydrochloride (1g) and Plasdone S-630 (3g) was dissolved in methanol (50 ml) and filtered through hy-flow to remove any undissolved particulate. The clear solution was subjected to spray drying on Buchi Mini spray dryer (Model B-290) at 30-40°C. The solid obtained was identified as amorphous Saxagliptin hydrochloride.

Example 10: Preparation of amorphous Saxagliptin hydrochloride.

Saxagliptin hydrochloride (3g) and Plasdone S-630 (9g) was dissolved in methanol (150 ml) and filtered through hy-flow to remove any undissolved particulate. . The clear solution was subjected to agitated thin film drying (ATFD) under reduced pressure at 30-40°C. The obtained solid was identified as amorphous Saxagliptin hydrochloride.

Example 11: Preparation of amorphous Saxagliptin hydrochloride.

Saxagliptin hydrochloride (3g), Plasdone S-630 (9g) and oxalic acid (0.03g) were dissolved in methanol (60 ml) and filtered to remove any undissolved particulate. The clear solution was subjected to distillation under reduced pressure at 30-40°C. The solid obtained was identified as amorphous saxagliptin hydrochloride.

Example 12: Preparation of amorphous Saxagliptin hydrochloride.

Saxagliptin hydrochloride (3g), Plasdone S-630 (9g) and oxalic acid (0.01 g) were dissolved in methanol (60 ml) and filtered to remove any undissolved particulate. The clear solution was subjected to distillation under reduced pressure at 30-40°C to obtain viscous liquid. The liquid was transferred to petri dish and dried under vacuum at 40°C for 3-5h. The solid obtained was identified as amorphous saxagliptin hydrochloride.

Example 13: Preparation of amorphous Saxagliptin hydrochloride.

Saxagliptin hydrochloride (3g), Plasdone S-630 (93g) and oxalic acid (0.03g) were dissolved in methanol (60 ml) and filtered to remove any undissolved particulate. The clear solution was subjected to spray drying on Buchi Mini spray dryer (Model B-290) at 30-40°C. The solid obtained was identified as amorphous saxagliptin hydrochloride.

Example 14: Preparation of amorphous Saxagliptin hydrochloride.

Saxagliptin hydrochloride (3g), Plasdone S-630 (9g) and succinic acid (0.03g) were dissolved in methanol (60 ml) and filtered to remove any undissolved particulate. The clear solution was subjected to distillation under reduced pressure at 30-40°C. The solid obtained was identified as amorphous saxagliptin hydrochloride.

Example 15: Preparation of amorphous Saxagliptin hydrochloride.

Saxagliptin hydrochloride (3g), Plasdone S-630 (93g) and succinic acid (0.03g) were dissolved in methanol (60 ml) and filtered to remove any undissolved particulate. The clear solution was subjected to spray drying on Buchi Mini spray dryer (Model B-290) at 30-40°C. The solid obtained was identified as amorphous saxagliptin hydrochloride.

Example 16: Preparation of amorphous Saxagliptin hydrochloride.

Saxagliptin hydrochloride (1g) was dissolved in n-butanol (110 ml) and filtered through hy-flo to remove any undissolved particulate. The clear solution was subjected to spray drying on Buchi Mini spray dryer (Model B-290) at 50°C. The solid obtained was identified as saxagliptin hydrochloride amorphous form

Example 17: Preparation of amorphous Saxagliptin hydrochloride.

Saxagliptin hydrochloride (1g) was dissolved in n-butanol (250 ml) and filtered through hy-flo to remove any undissolved particulate. The clear solution was subjected to spray drying on Buchi Mini spray dryer (Model B-290) at 50°C. The solid obtained was identified as saxagliptin hydrochloride amorphous form

Example 18: Preparation of amorphous Saxagliptin hydrochloride.

Saxagliptin hydrochloride (1g) was dissolved in n-butanol (250 ml) and filtered through hy-flo to remove any undissolved particulate. The clear solution was subjected to distillation under vacuum at 60°C to obtain free powder.

Example 19: Preparation of amorphous Saxagliptin hydrochloride.

Saxagliptin hydrochloride (1g) was dissolved in n-butanol (100 ml) and filtered through hy-flo to remove any undissolved particulate. The clear solution was subjected to distillation under vacuum at 60°C to obtain free powder.

Example 20: Preparation of amorphous Saxagliptin hydrochloride.

Saxagliptin hydrochloride (2g) was dissolved in methanol (30ml) and acetone (70 ml) and filtered through hy-flo to remove any undissolved particulate.. The clear solution was subjected to spray drying on Buchi Mini spray dryer (Model B-290) at 40°C. The solid obtained was identified as saxagliptin hydrochloride amorphous form.

Example 21: Preparation of amorphous Saxagliptin hydrochloride.

Saxagliptin hydrochloride (2g) was dissolved in methanol (10ml) and acetone (90 ml) and filtered through hy-flo to remove any undissolved particulate.. The clear solution was subjected to spray drying on Buchi Mini spray dryer (Model B-290) at 40°C. The solid obtained was identified as saxagliptin hydrochloride amorphous form.

Example 22: Preparation of amorphous Saxagliptin hydrochloride.

Saxagliptin hydrochloride (10g), Plasdone S-630 (93g) and oxalic acid (0.03g) were dissolved in mixture of methanol (100 ml) and acetone (100 ml) was added. The clear solution was filtered toremove any undissolved particulate. The clear solution was subjected to spray drying on Buchi Mini spray dryer (Model B-290) at 40°C. The solid obtained was identified as amorphous saxagliptin hydrochloride.

Example 23: Preparation of amorphous Saxagliptin hydrochloride.

Saxagliptin hydrochloride (10g), Plasdone S-630 (9g) and oxalic acid (0.01g) were dissolved in methanol (100 ml) and acetone (100 ml) was added. The clear solution was filtered to remove any undissolved particulate. The clear solution was subjected to distillation under reduced pressure at 30-40°C to obtain viscous liquid. The liquid was transferred to petri dish and dried under vacuum at 40°C for 3-5h. The solid obtained was identified as amorphous saxagliptin hydrochloride.

Example 24: Physical stability of amorphous form

The physical stability of the amorphous form and premix amorphous form of saxaglitpin hydrochloride form was determined by storing samples at approximately 3.0 g of the sample a) at 5±3°C, b)25°C/60% relative humidity (RH) (LT) and c) at 40°C/75% relative humidity (RH) (ACC) over a period of 3 months. The samples were analyzed by PXRD and the results were shown in the following Table 1

Table 1

We claim:

1. A process for the preparation of amorphous Saxagliptin hydrochloride comprising the steps of;

a) dissolving saxagliptin hydrochloride in a solvent or mixture thereof,

b) removing the solvent from step a) solution under spray drying technique to get an amorphous saxagliptin hydrochloride.

2. A process for the preparation of amorphous saxagliptin hydrochloride comprising the steps of;

a) dissolving saxagliptin hydrochloride and a polymer in a solvent or mixture thereof,

b) removing the solvent to get amorphous saxagliptin hydrochloride.

3. A process for the preparation of amorphous Saxagliptin hydrochloride comprising the steps of;

a) dissolving saxagliptin hydrochloride and a polymer in a solvent or mixture thereof,

b) removing the solvent to get residue,

c) adding hydrocarbon or ether solvent to the residue, and

d) isolating amorphous Saxagliptin hydrochloride.

4. A process for preparation of amorphous Saxagliptin hydrochloride comprising the steps of;

a) dissolving saxagliptin hydrochloride, a polymer and an organic acid in a solvent or mixture thereof,

b) removing the solvent to get an amorphous saxagliptin hydrochloride.

5. The process as claimed in any of the preceding claims, wherein the solvent for the dissolution is selected from alcohol solvent, chlorinated solvent, ketone solvent, ester solvent, water or mixture thereof.

6. The process according to claims 5, wherein the alcohol solvent is selected from methanol, ethanol, propanol, isopropanol, butanol, pentanol; chlorinated solvent is selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride; ketone solvent is selected from acetone, methylethylketone, methylisobutylketone; ester solvent is etheylacetate, ethyl acetoacetate, and methyl acetate isopropyl acetate.

7. The process according to claims 2, 3 and 4 wherein the polymer is selected from plasdone S-630 or PVP K-30

8. The process according to claim 4, wherein the organic acid is selected from oxalic acid, succinic acid, fumaric acid, tartaric acid, malic acid or maleic acid

9. The process according to claim 3, wherein hydrocarbon solvent is selected from hexane, cyclohexane, pentane, heptane or methyl cyclohexane and the ether solvent is selected from diethylether or diisopropylether.