SAXAGLIPTIN HYDROCHLORIDE POLYMORPHIC FORMS

INTRODUCTION

Aspects of the present application relate to amorphous form of saxagliptin hydrochloride and solid dispersion of amorphous saxagliptin hydrochloride together with one or more pharmaceuticallyly acceptable carriers which is useful in making pharmaceuticallyly acceptable dosage forms, and processes for its preparation.

The drug compound having the adopted name saxagliptin hydrochloride, has a chemical name (1 S,3S,5S)-2-[(2S)-2-Amino-2-(3hydroxytricyclo[3.3.1.137]dec-1 -yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride, and is represented by structure of formula I.

Formula I

Saxagliptin is a dipeptidyl peptidase-4 inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. U.S. Patent No. 6,395,767 discloses saxagliptin and its pharmaceuticallyly acceptable salts including hydrochloride salt.

U.S. Patent No. 7,943,656 specifically discloses several crystalline forms of saxagliptin hydrochloride and process for the preparation thereof. International Application Publication No. WO2010/115974A1 discloses anhydrous crystalline forms of saxagliptin hydrochloride (denoted as l-S, HT-S, HT-IVS and IVS) and process for the preparation of thereof.

The occurrence of different polymorphs is possible for some compounds. A single compound may give rise to a variety of solids having distinct physical properties. This variation in solid forms may be significant and may result in differences-with respect to bioavailability, stability, and other differences for formulated pharmaceutically products. Because polymorphic forms can vary in their physical properties, regulatory authorities require that efforts shall be made to identify all polymorphic forms, e.g., crystalline, amorphous, solvated, etc., of new drug substances.

The existence and possible numbers of polymorphic forms for a given compound cannot be predicted, and there are no "standard" procedures that can be used to prepare polymorphic forms of a substance. However, new forms of a pharmaceuticallyly useful compound may provide an opportunity to improve the performance characteristics of pharmaceutically products. Further, discovery of additional polymorphic forms, including solvate polymorphs, may help in the identification of the polymorphic content of a batch of an active pharmaceutically ingredient. For example, in some cases, different forms of the same drug can exhibit very different solubility and different dissolution rates. The discovery of new polymorphic forms enlarges selection of materials with which formulation scientists can design a pharmaceuticallyly acceptable dosage form of a drug with a targeted release profile or other desired characteristics. Therefore, there remains a need for preparing new and stable polymorphic forms of saxagliptin hydrochloride.

SUMMARY OF THE INVENTION

In an aspect, the present application provides an amorphous form of saxagliptin hydrochloride.

In an aspect, the present application provides a process for the preparation of amorphous form of saxagliptin hydrochloride, comprising:

a) providing a solution of saxagliptin hydrochloride in a solvent;
b) removing the solvent; and
b) isolating amorphous form of saxagliptin hydrochloride.

In an aspect, the present application provides solid dispersion comprising saxagliptin hydrochloride, together with one or more pharmaceuticallyly acceptable excipients.

In an aspect, the present application provides a process for preparing a solid dispersion of amorphous saxagliptin hydrochloride together with one or more pharmaceuticallyly acceptable carriers, comprising

a) providing a solution of saxagliptin hydrochloride in combination with one or more pharmaceuticallyly acceptable carriers, in a suitable solvent or mixture of solvents; and

b) isolating a solid dispersion of amorphous saxagliptin hydrochloride together wtttrone or more pharmaceuticallyly acceptable carriers.

BRIEF DESCRIPTION OF THE DRAWING

Fig 1 depicts a PXRD pattern of amorphous saxagliptin hydrochloride, obtained by the procedure of Example 1.

Fig 2 depicts a PXRD pattern of amorphous saxagliptin hydrochloride, obtained by the procedure of Example 2.

Fig 3 depicts a PXRD pattern of amorphous saxagliptin hydrochloride, obtained by the procedure of Example 3.

DETAILED DESCRIPTION

In an aspect, the present application provides amorphous form of saxagliptin hydrochloride characterized by its powder X-ray diffraction (PXRD) pattern.

In an aspect, the present application provides a process for the preparation of amorphous form of saxagliptin hydrochloride, comprising:

a) providing a solution of saxagliptin hydrochloride in a solvent;
b) removing the solvent; and
b) isolating amorphous form of saxagliptin hydrochloride. Providing a solution of saxagliptin hydrochloride in step a) includes:
i) direct use of a reaction mixture containing saxagliptin hydrochloride that is obtained in the course of its synthesis; or
ii) dissolving saxagliptin hydrochloride in a solvent.

Any physical form of saxagliptin hydrochloride may be utilized for providing the solution of saxagliptin hydrochloride in step a). The dissolution temperatures may range from about 0°C to about the reflux temperature of the solvent, or less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, or any other suitable temperatures, as long as a clear solution of saxagliptin hydrochloride is obtained without affecting its quality. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.

In embodiments, saxagliptin hydrochloride can be dissolved in any suitable solvent. Suitable solvents include any solvents that have no adverse effect on the compound and can dissolve the starting material to a useful extent. Examples of such solvents include, but are not limited to: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, or dimethoxyethane; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, or diethyl ketone; esters, such as ethyl acetate, propyl acetate, isopropyl acetate, or butyl acetate; alcohols, such as methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, or CrC6 alcohols; nitriles, such as acetonitrile or propionitrile; amides, such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or hexamethyl phosphoric triamide; sulfoxides, such as dimethylsulfoxide; halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride, or chlorobenzene; aromatic hydrocarbons, such as toluene; or any mixtures of two or more thereof.

Step b) involves isolating amorphous form of saxagliptin hydrochloride from the solution obtained in step a). Isolation of amorphous form of saxagliptin hydrochloride in step b) may involve methods including removal of solvent, cooling, crash cooling, concentrating the mass, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying, adding anti-solvent, extraction with a solvent, adding seed to induce isolation, or the-like. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation. The amorphous form of saxagliptin hydrochloride as isolated may carry some amount of occluded mother liquor and may have higher than desired levels of impurities. If desired, this amorphous form may be washed with a solvent or a mixture of solvents to wash out the impurities:

Suitable temperatures for isolation may be less than about 120°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, less than about 0°C, less than about -10°C, less than about -40°C or any other suitable temperatures.

Optionally, isolation may be effected by combining a suitable anti-solvent with the solution obtained in step a). Anti-solvent as used herein refers to a liquid in which saxagliptin hydrochloride is less soluble or poorly soluble. An inert anti-solvent has no adverse effect on the reaction and it can assist in the solidification or precipitation of the dissolved starting material. Suitable anti-solvents that may be used include, but are not limited to: saturated or unsaturated, linear or branched, cyclic or acyclic, Ci to C10 hydrocarbons, such as heptanes, cyclohexane, or methylcyclohexane; water; or any mixtures thereof.

The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the saxagliptin hydrochloride is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller or hammer milling; or jet milling.

In an aspect, the present application provides solid dispersion comprising saxagliptin hydrochloride, together with one or more pharmaceuticallyly acceptable excipients.

In an aspect, the present application provides a process for preparing-a-solid — dispersion of amorphous saxagliptin hydrochloride together with one or more pharmaceuticallyly acceptable carriers, comprising

a) providing a solution of saxagliptin hydrochloride in combination with one or more pharmaceuticallyly acceptabler carrier, in a suitable solvent or mixture of solvents;

b) isolating a solid dispersion of amorphous saxagliptin hydrochloride Together with one or more pharmaceuticallyly acceptable carriers.

Step a) involves providing a solution of saxagliptin hydrochloride in combination with at least one pharmaceuticallyly acceptable carrier, in a suitable solvent or mixture of solvents;

Step a) may involve forming a solution of saxagliptin hydrochloride together with one or more pharmaceuticallyly acceptable carriers. In embodiments, a carrier enhances stability of the amorphous solid upon removal of solvent.

Providing the solution in step a) includes:

i) direct use of a reaction mixture containing saxagliptin hydrochloride that is obtained in the course of its manufacture, if desired, after addition of one or more pharmaceuticallyly acceptable carriers; or

ii) dissolution of saxagliptin hydrochloride in a suitable solvent, either alone or in combination with one or more pharmaceuticallyly acceptable carriers.

Any physical form of saxagliptin hydrochloride, such as crystalline, amorphous or their mixtures may be utilized for providing a solution in step a).

Pharmaceuticallyly acceptable carriers that may be used in step a) include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methyl celluloses, pregelatinized starches, or the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, or the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, or the like; glidants such as colloidal silicon dioxide or the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins or resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes, or the like. Other pharmaceuticallyly acceptable excipients that are of use include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, or thelike.

The dissolution temperatures may range from about 0°C to about the reflux temperature of the solvent, or less than about 60°C, less than about 50°C, less than about 40°C, less than about 3(TC, less than about 20°C, less than about 10*C, or any other suitable temperatures, as long as a clear solution of saxagliptin hydrochloride is obtained without affecting its quality. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.

Suitable solvents that may be used in step a) include but are not limited to: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, or dimethoxyethane; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, or diethyl ketone; esters, such as ethyl acetate, propyl acetate, isopropyl acetate, or butyl acetate; alcohols, such as methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, iso¬butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, or Ci-C6 alcohols; nitriles, such as acetonitrile or propionitrile; amides, such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or hexamethyl ^hosphoric^ triamide; sulfoxides, such as ^limethylsulfoxide; halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride, or chlorobenzene; aromatic hydrocarbons, such as toluene; or any mixtures of two or more thereof.

Step b) involves isolating a solid dispersion of amorphous saxagliptin hydrochloride together with one or more pftarmaceutically acceptable carriers. Isolation of solid dispersion of amorphous form of saxagliptin hydrochloride in step b) may involve methods including removal of solvent, cooling, crash cooling, concentrating the mass, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying, adding anti-solvent, extraction with a solvent, adding seed to induce isolation, or the like. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation. The amorphous form of saxagliptin hydrochloride as isolated may carry some amount of occluded mother liquor and may have higher than desired levels of impurities. If desired, this amorphous form may be washed with a solvent or a mixture of solvents to wash out the impurities.

Suitable temperatures for isolation may be less than about 120°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, less than about 0°C, less than about -10°C, less than about -40°C or any other suitable temperatures.

Optionally, isolation may be effected by combining a suitable anti-solvent with the solution obtained in step a). Anti-solvent as used herein refers to a liquid in which saxagliptin hydrochloride is less soluble or poorly soluble. An inert anti-solvent has no adverse effect on the reaction and it can assist in the solidification or precipitation of the dissolved starting material. Suitable anti-solvents that may be used include, but are not limited to: saturated or unsaturated, linear or branched, cyclic or acyclic, Ci to C10 hydrocarbons, such as heptanes, cyclohexane, or methylcyclohexane; water; or any mixtures thereof.

The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than ^bout 30°C, or any other suitable temperatures,^! atmospheric pressure or under a reduced pressure, as long as the saxagliptin hydrochloride is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes.

Milling or micronization may be performed before drying, or after the completion of drying ottfte product. Techniques that may be used for particle size reductiorrmclude, without limitation, ball, roller or hammer milling; or jet milling.

Amorphous form of saxagliptin hydrochloride or a solid dispersion of saxagliptin hydrochloride(together with one or more pharmaceutically^ acceptable excipients of the present application may be further formulated as: solid oral dosage forms such as, but not limited to: powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions. Formulations may be in the forms of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated. Compositions of the present application may further comprise one or more pharmaceutically^ acceptable excipients.

Pharmaceutically^ acceptable excipients that are useful in the present application include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes and the like. Other pharmaceuticallyly acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers; preservatives, antioxidants, and the like.

Different polymorphic forms are characterized by scattering techniques, e.g., x-ray powder diffraction pattern, by spectroscopic methodsre.a;., infra-red, 13C nuclear magnetic resonance spectroscopy, and by thermal techniques, e.g., differential scanning calorimetry or differential thermal analysis. The compound of this application is best characterized by the X-ray powder diffraction pattern determined in accordance with procedures that are known in the art. For a discussion of these techniques see J. Haleblian, J. Pharm. Sci. 1975 64:1269-1288, and J. Haleblian and W. McCrone, J. Pharm. Sci. 1969 58:911-929. Amorphous form of the application can be further processed to modulate particle size. For example, the amorphous form of the application can be milled to reduce average crystal size and/or to prepare a sample suitable for manipulation or formulation.

All PXRD data reported herein are obtained using a Bruker AXS D8 Advance Powder X-ray Diffractometer or a PANalytical X-ray Diffractometer, using copper Ka radiation.

DEFINITIONS

The following definitions are used in connection with the present application unless the context indicates otherwise. In general, the number of carbon atoms present in a given group or compound is designated "Cx-Cy", where x and y are the lower and upper limits, respectively. For example, a group designated as "CrC6" contains from 1 to 6 carbon atoms. The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like.

The term "anti-solvent" refers to a liquid that, when combined with a solution of saxagliptin hydrochloride, reduces solubility of the saxagliptin hydrochloride in the solution, causing crystallization or precipitation in some instances spontaneously, and in other instances with additional steps, such as seeding, cooling, scratching and/or concentrating. Celite® is flux-calcined diatomaceous earth. Celite® is a registered trademark of World Minerals Inc. Hyflow is flux-calcined diatomaceous earth treated with sodium carbonate. Hyflo Super Cel™ is a registered trademark of the Manville Corp. Polymorphs are different solids having the same molecular structure, yet having distinct physical properties when compared to other polymorptTS of the same structure.

An "alcohol" is an organic compound containing a carbon bound to a hydroxyl group. "CrC6 alcohols" include, but are not limited to, methanol, ethanol, 2-nitroethanoi, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethylether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, or the like.

An "aliphatic hydrocarbon" is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds. A liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called "aromatic." Examples of "C5-C8 aliphatic or aromatic hydrocarbons" include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, petroleum ethers, benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, or any mixtures thereof.

An "ester" is an organic compound containing a carboxyl group -(C=0)-0-bonded to two other carbon atoms. "C3-C6 esters" include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like.

An "ether" is an organic compound containing an oxygen atom -O- bonded to two other carbon atoms. "C2-C6 ethers" include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether,—giyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane4 dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like.

A "halogenated hydrocarbon" is an organic compound containing a carbon bound to a halogen. Halogenated hydrocarbons include, but are not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the lite.

A "ketone" is an organic compound containing a carbonyl group -(C=0)-bonded to two other carbon atoms. "C3-C6 ketones" include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, or the like.

A "nitrile" is an organic compound containing a cyano -(CEN) bonded to another carbon atom. "C2-C6 Nitrites" include, but are not limited to, acetonitrile, propionitrile, butanenitrite, or the like.

All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, "comprising" means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range "between" two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present invention. While particular aspects of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

EXAMPLES

EXAMPLE 1: Preparation of amorphous form of saxagliptin hydrochloride.

Saxagliptin hydrochloride (1 g) and methanol (10 mL) were charged into a round bottom flask at 29°C and stirred for 5 minutes. Reaction mixture is filtered and filtrate solvent was evaporated at below 68°C under vacuum and-finally dried the material in buchi rotavapor at 60°C under vacuum to afford the title compound. The material was unloaded under nitrogen atmosphere.

Yield: 0.70g

The Powder X-ray diffraction (PXRD) pattern of saxagliptin hydrochloride obtained in above example is in accordance with Figure 1.

EXAMPLE 2: Preparation of solid dispersion of amorphous saxagliptin hydrochloride with polyvinylpyrrolidone.

Polyvinylpyrrolidone (1.0 g) and methanol (20 mL) were charged into a round bottom flask and heated to 65°C to dissolve polyvinylpyrrolidone completely. Saxagliptin hydrochloride (1.0 g) and methanol (10 mL) were charged into another round bottom flask at 25°C and stirred for 10 minutes. Reaction mixture is filtered and to the obtained filtrate polyvinylpyrrolidone solution was added. The resultant reaction mixture solvent was evaporated at below 60°C under vacuum and finally dried the material in buchi rotavapor at 60°C under vacuum to afford the title compound. The material was unloaded under nitrogen atmosphere.

Yield: 0.50g

The Powder X-ray diffraction (PXRD) pattern of saxagliptin hydrochloride obtained in above example is in accordance with Figure 2.

EXAMPLE 3: Preparation of solid dispersion of amorphous saxagliptin hydrochloride with Hydroxypropylcellulose.

Hydroxypropylcellulose (1.0 g) and methanol (100 mL) were charged into a round bottom flask and heated to 65°C to dissolve Hydroxypropylcellulose completely. Saxagliptin hydrochloride (1.0 g) and methanol (10 mL) were charged into another round bottom flask at 25°C and stirred for 10 minutes. Hydroxypropylcellulose solution was added to the reaction mixture. The resultant reaction mixture solvent was evaporated at below 60°C under vacuum and finally dried the material in buchi rotavapor at 60°C under-vacuum t© afford the title compound. The material was unloaded under nitrogen atmosphere. Yield: 0.50g

The Powder X-ray diffraction (PXRD) pattern of saxagliptin hydrochloride obtained in above example is in accordance with Figure 3.

CLAIMS:

1. A process for the preparation of amorphous form of saxagliptin hydrochloride, comprising:

a) providing a solution of saxagliptin hydrochloride in a solvent;
b) removing the solvent; and
c) isolating amorphous form of saxagliptin hydrochloride.

2. The process of claim 1, wherein the solvent is selected from alcohols, ketones or esters.

3. The process of claims 1-2, wherein the solvent is selected from methanol, isopropyl alcohol, acetone, methyl isobutyl ketone, methyl ethyl ketone or ethyl acetetae or mixture thereof.

4. The process of claim 1, wherein solvent is removed using buchi rotavapor, spray dryer or agitated thin-film dryer.

5. Amorphous solid dispersion comprising saxagliptin hydrochloride, together with one or more pharmaceuticallyly acceptable excipients.

6. The solid dispersion according to claim 5, wherein pharmaceuticallyly acceptable excipients are polyvinylpyrrolidone or hydroxypropylcellulose.

7. A process for preparing amorphous solid dispersion of saxagliptin hydrochloride together with one or more pharmaceuticallyly acceptable carriers, comprising

a) providing a solution of saxagliptin hydrochloride in combination with one or more pharmaceuticallyly acceptable carriers, in a suitable solvent or mixture of solvents; and

b) isolating a solid dispersion of amorphous saxagliptin hydrochloride together with one or more pharmaceuticallyly acceptable carriers.