WO2015104658A2

WO2015104658A2 - Amorphous solid dispersion of dapagliflozin and process for the preparation of amorphous dapagliflozin

Info

Publication number: WO2015104658A2
Application number: PCT/IB2015/050113
Authority: WO
Inventors: Deepika PATHIVADA; Arshad Alam MOHAMMED
Original assignee: Dr. Reddy’S Laboratories Limited
Priority date: 2014-01-08
Filing date: 2015-01-07
Publication date: 2015-07-16
Also published as: WO2015104658A3

Abstract

Aspects of the present invention relate to process for preparation of amorphous form of dapagliflozin, amorphous solid dispersion of dapagliflozin together with one or more pharmaceutically acceptable carriers, process for its preparation and pharmaceutical composition thereof.

Description

AMORPHOUS SOLID DISPERSION OF DAPAGLIFLOZIN AND PROCESS FOR THE PREPARATION OF AMORPHOUS DAPAGLIFLOZIN

INTRODUCTION

Aspects of the present application relate to process for the preparation of amorphous dapagliflozin, amorphous solid dispersion of dapagliflozin together with one or more pharmaceutically acceptable carriers, process for its preparation and pharmaceutical composition thereof.

Diabetes mellitus is a serious and chronic metabolic disease that is characterized by high blood glucose (hyperglycemia) and affects millions of people world-wide. SGLT2 is a Sodium-dependent GLucose co-Transporter protein which affects the reabsorption of glucose in the kidney. It is estimated that 90% of renal glucose reabsorption is facilitated by SGLT2. Since glucose reabsorption is mediated predominantly by SGLT2 and because high glucose levels have been identified as a cause of disease in diabetes, SGLT2 has become a drug target for type 2 diabetes therapy. Selective inhibition of SGLT2 has the potential to reduce hyperglycemia by inhibiting glucose reabsorption in the kidney with elimination of glucose by excretion in the urine (glucosuria).

Dapagliflozin (trade name: Forxiga) is an active pharmaceutical ingredient (API) and a selective inhibitor of SGLT2 that is being developed for the treatment of type 2 diabetes mellitus.

Dapagliflozin is chemically described as (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4- ethoxybenzyl)phenyl)-6-(hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol, and is also known as (1 S)-1 ,5-anhydro-1 -C-{4-chloro-3-[(4-ethoxyphenyl)methyl] phenyl}-D- glucitol. dapagliflozin is a white to off-white powder with a molecular formula of C21 H25CIO6 and a molecular weight of 408.87. The structure of dapagliflozin is shown as formula I.

I

U.S. Patent No. 6,515,1 17 specifically discloses dapagliflozin and its pharmaceutically acceptable salts, a method for treating diabetes and related diseases employing dapagliflozin alone or in combination with another antidiabetic agent or other therapeutic agent.

U.S. Patent No. 6,515,1 17 discloses process for the preparation of dapagliflozin. As stated at column 5, lines 1 -2 of U.S. Patent No. 7,919,598 "The compound of formula I (dapagliflozin) in the form of an non-crystalline solid is disclosed in U.S. Patent No. 6,515,1 17".

Journal of Medicinal Chemistry, 2008, Vol. 51 , No. 5 discloses process for the preparation of amorphous dapagliflozin. U.S. Patent No.7, 919,598 describes crystalline (S)-propylene glycol solvate hydrate of dapagliflozin and its process.

U.S. Patent application No.2013/0303467A1 describes different crystalline forms of dapagliflozin. International Publication No. WO201 3/079501 A1 describes crystalline dapagliflozin hydrate and its process. International Publication No. WO2013/064909A2 describes amorphous form of dapagliflozin.

The occurrences of different solid forms are possible for some compounds. A single compound may exist in different solid forms. Various solid forms of a drug substance can have different chemical and physical properties, including melting point, chemical reactivity, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can have a direct effect on the ability to process and/or manufacture the drug substance and the drug product, as well as on drug product stability, dissolution, and bioavailability. Thus, solid forms can affect the quality, safety, and efficacy of the drug product, regulatory authorities require that efforts shall be made to identify all solid forms, e.g., crystalline, amorphous, solvated, etc., of drug substances.

Though, there are processes available in the literature for the preparation of amorphous dapagliflozin, still there remains a need for the environmentally-friendly, stable, cost effective and industrially applicable process for the preparation of amorphous dapagliflozin.

SUMMARY OF THE INVENTION

In an aspect, the present application provides a process for the preparation of amorphous form of dapagliflozin, comprising the steps of;

a) providing a solution of dapagliflozin in a solvent;

b) removing solvent from the solution obtained in step a), and

c) isolating the amorphous form of dapagliflozin. In an aspect, the present invention provides a process for the preparation of amorphous dapagliflozin comprising:

a) providing a solution of dapagliflozin in a solvent selected from methanol, ethyl acetate, dichloromethane, acetonitrile, acetone, methyl isobutyl ketone, methyl ethyl ketone, 2-methyl tetrahydrofuran or mixtures thereof;

b) removing solvent from the solution obtained in step a), and

c) isolating amorphous dapagliflozin.

In an aspect, the present invention also provides pharmaceutical formulations comprising amorphous dapagliflozin together with one or more pharmaceutically acceptable excipients.

In an aspect, the present application provides an amorphous solid dispersion of dapagliflozin together with one or more pharmaceutically acceptable carriers.

In an aspect, the present invention provides a process for preparing an amorphous solid dispersion of dapagliflozin together with one or more pharmaceutically acceptable carriers, comprising:

a) providing a solution or suspension of dapagliflozin in combination with one or more pharmaceutically acceptable carriers in a solvent or mixture of solvents;

b) removing solvent from the solution obtained in step a), and

c) isolating amorphous solid dispersion of dapagliflozin together with one or more pharmaceutically acceptable carrier.

In an aspect, the present invention provides a process for the preparation of amorphous solid dispersion of dapagliflozin together with one or more pharmaceutically acceptable carriers, comprising:

a) providing a solution of dapagliflozin in combination with one or more pharmaceutically acceptable carriers selected from polyvinylpyrrolidones, hydroxypropyl methylcelluloses, hydroxypropyl celluloses or hydroxypropyl methylcellulose acetate succinate in a solvent;

b) removing solvent from the solution obtained in step a), and

c) isolating amorphous solid dispersion of dapagliflozin together with one or more pharmaceutically acceptable carrier selected from polyvinylpyrrolidones, hydroxypropyl methylcelluloses, hydroxypropyl celluloses or hydroxypropyl methylcellulose acetate succinate. In an aspect, the present invention also provides pharmaceutical formulations comprising amorphous solid dispersions of dapagliflozin together with one or more pharmaceutically acceptable excipients.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 illustrates an X-ray powder diffraction pattern of amorphous dapagliflozin, obtained according to the procedure of example 1 .

Figure 2 illustrates an X-ray powder diffraction pattern of amorphous solid dispersion of dapagliflozin, obtained according to the procedure of example 2.

Figure 3 illustrates an X-ray powder diffraction pattern of amorphous dapagliflozin, obtained according to the procedure of example 5.

Figure 4 illustrates an X-ray powder diffraction pattern of amorphous dapagliflozin, obtained according to the procedure of example 6.

Figure 5 illustrates an X-ray powder diffraction pattern of amorphous solid dispersion of dapagliflozin, obtained according to the procedure of example 1 1 .

DETAILED DESCRIPTION

a) providing a solution of dapagliflozin in a solvent;

b) removing solvent from the solution obtained in step a), and

c) isolating the amorphous form of dapagliflozin.

Providing a solution of dapagliflozin in step a) includes:

i) direct use of a reaction mixture containing dapagliflozin that is obtained in the course of its synthesis; or

ii) dissolving dapagliflozin in a solvent.

Any physical form of dapagliflozin may be utilized for providing the solution of dapagliflozin in step a). Dapagliflozin that may be used as the input for the process of the present invention may be obtained by any process including the processes described in the art. For example dapagliflozin may be prepared by the processes described in IN3942/CHE/2010, US65151 1 7B2 or US7375213B2.

Suitable solvents that may be used in step a) include, but are not limited to, alcohol solvents; halogenated hydrocarbon solvents; ester solvents; nitrile solvents; polar aprotic solvents; ketone solvents; ether; or mixtures thereof.

The dissolution temperatures may range from about 10°C to about the reflux temperature of the solvent, depending on the solvent used for dissolution, as long as a clear solution of dapagliflozin 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 and/or to clarify the solution.

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. The solution may be filtered by passing through paper, glass fiber, 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.

Step b) involves the removal of solvents from the solution obtained from step a). Suitable techniques which may be used for the removal of the solvent include using a rotational distillation device such as a rotavapor, spray drying, agitated thin film drying, freeze drying (lyophilization), Hot-Melt Extrusion (HME) and the like, or any other suitable technique.

The solvent may be removed, optionally under reduced pressures, at temperatures less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C or any other suitable temperatures.

Step c) involves isolation of an amorphous form of dapagliflozin from the solution of step b). The compound obtained from step b) may be collected using techniques such as by scraping, or by shaking the container, or adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used.

In embodiments of step c), the amorphous obtained from step b) may be optionally dried. Drying may be suitably carried out in a tray dryer, vacuum oven, rotavapor, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.

In an aspect, the present invention provides a process for the preparation of amorphous form of dapagliflozin comprising:

a) providing a solution of dapagliflozin in a solvent selected from methanol, ethyl acetate, dichloromethane, acetonitrile or mixtures thereof; b) removing solvent from the solution obtained in step a), and c) isolating the amorphous form of dapagliflozin.

Providing a solution of dapagliflozin in step a) includes:

ii) dissolving dapagliflozin in a solvent selected from methanol, ethyl acetate, dichloromethane, acetonitrile or mixtures thereof;

Any physical form of dapagliflozin may be utilized for providing the solution of dapagliflozin in step a). Dapagliflozin that may be used as the input for the process of the present invention may be obtained by any process including the processes described in the art. For example dapagliflozin may be prepared by the processes described in IN3942/CHE/2010, US651 51 17B2 or US7375213B2.

The dried product may be optionally milled to get 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 and hammer mills, and jet mills.

Examples of amorphous dapagliflozin obtained using the above process is characterized by powder X-ray diffraction ("PXRD") pattern substantially as illustrated by Figs. 1 , 3 and 4.

In the embodiment, the amorphous form of dapagliflozin obtained according to the present invention can be used as an intermediate for making any crystalline form of dapagliflozin or solid dispersion of dapagliflozin along with the other pharmaceutically acceptable excipients.

In an aspect, the present application provides pharmaceutical formulations comprising amorphous form of dapagliflozin, together with one or more pharmaceutically acceptable excipients. Amorphous form of dapagliflozin together with one or more pharmaceutically acceptable excipients of the present application may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, or capsules; liquid oral dosage forms such as, but not limited to, syrups, suspensions, dispersions, or emulsions; or injectable preparations such as, but not limited to, solutions, dispersions, or 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, or 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, or extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, or 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, 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 pharmaceutically acceptable excipients that are of use include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, or the like.

In an aspect, the present invention provides amorphous solid dispersion of dapagliflozin together with one or more pharmaceutically acceptable carriers.

b) removing solvent from the solution obtained in step a), and

Providing the solution in step a) includes: (i) direct use of a reaction mixture containing dapagliflozin that is obtained in the course of its manufacture, if desired, after addition of one or more pharmaceutically acceptable carriers; or

(ii) dissolution of dapagliflozin in a suitable solvent, either alone or in combination with one or more pharmaceutically acceptable carriers.

Any physical form of dapagliflozin may be utilized for providing a solution in step a).

Pharmaceutically acceptable carriers that may be used for the preparation of amorphous solid dispersions of dapagliflozin of the present invention include, but are not limited to: pharmaceutical hydrophilic carriers such as polyvinylpyrrolidones (homopolymers or copolymers of N-vinyl pyrrolidone), gums, cellulose derivatives (including hydroxypropyl methylcelluloses, hydroxypropyl celluloses, hydroxypropyl methylcellulose acetate succinate, microcrystalline celluloses and others), polymers of carboxymethyl celluloses, cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, polyethylene glycols, polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives, or the like; water soluble sugar derivatives including any pharmaceutically acceptable water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol, or the like; or organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and guanidine or its derivatives. The use of mixtures of more than one of the pharmaceutical excipients to provide desired release profiles or for the enhancement of stability is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, and mixtures are all within the scope of this invention without limitation.

When the solution or suspension of dapagliflozin is prepared together with a pharmaceutically acceptable carrier, the order of charging different materials to the solution is not critical for obtaining the desired solid dispersion. A specific order may be preferred with respect to the equipment being used and will be easily determined by a person skilled in the art. Dapagliflozin or pharmaceutically acceptable carrier may be completely soluble in the solvent or they may form a suspension. In embodiments, dapagliflozin and the pharmaceutically acceptable carrier dissolved either in the same solvent or in different solvents, and then combined to form a mixture.

Suitable solvents that may be used in step a) include, but are not limited to, alcohol solvents; ketone solvents; halogenated hydrocarbon solvents; ester solvents; polar aprotic solvents; nitrile solvents; or mixtures thereof.

Step b) involves the removal of solvents from the solution obtained from step a). Suitable techniques which may be used for the removal of the solvent include using a rotational distillation device such as a rotavapor, spray drying, agitated thin film drying, freeze drying (lyophilization), Hot-Melt Extrusion (HME)and the like, or any other suitable technique.

Step c) involves isolation of amorphous solid dispersion of dapagliflozin together with one or more pharmaceutically acceptable carriers from the solution of step b).

The compound obtained from step b), may be collected using techniques such as by scraping, or by shaking the container, or adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used. The product thus isolated may be optionally further dried to afford an amorphous form of Dapagliflozin together with a pharmaceutically acceptable excipients. Drying may be suitably carried out in a tray dryer, vacuum oven, rotavapor, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.

Examples of amorphous solid dispersions of dapagliflozin together with a pharmaceutically acceptable carrier obtained using the above process is characterized by powder X-ray diffraction ("PXRD") pattern substantially as illustrated by Figs. 2 and 5

b) removing solvent from the solution obtained in step a), and

c) isolating amorphous solid dispersion of dapagliflozin together with one or more pharmaceutically acceptable carrier selected from polyvinylpyrrolidones, hydroxypropyl methylcelluloses, hydroxypropyl celluloses or hydroxypropyl methylcellulose acetate succinate.

In embodiments of step a) the solution of dapagliflozin in combination with one or more pharmaceutically acceptable carriers selected from polyvinylpyrrolidones, hydroxypropyl methylcelluloses, hydroxypropyl celluloses or hydroxypropyl methylcellulose acetate succinate can be obtained by dissolving dapagliflozin in combination with one or more pharmaceutically acceptable carriers selected from polyvinylpyrrolidones, hydroxypropyl methylcelluloses, hydroxypropyl celluloses or hydroxypropyl methylcellulose acetate succinate in a solvent selected. Stirring and heating may be used to reduce the time required for the dissolution process.

In embodiments, a solution of dapagliflozin in combination with one or more pharmaceutically acceptable carriers selected from polyvinylpyrrolidones, hydroxypropyl methylcelluloses, hydroxypropyl celluloses or hydroxypropyl methylcellulose acetate succinate may be filtered to make it clear, free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.

Step c) involves isolation of amorphous solid dispersion of dapagliflozin in combination with one or more pharmaceutically acceptable carriers selected from polyvinylpyrrolidones, hydroxypropyl methylcelluloses, hydroxypropyl celluloses or hydroxypropyl methylcellulose acetate succinate from the solution of step b).

The compound obtained from step b) may be collected using techniques such as by scraping, or by shaking the container, or adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used. The product thus isolated may be optionally further dried to afford an amorphous form of Dapagliflozin in combination with one or more pharmaceutically acceptable carriers selected from polyvinylpyrrolidones, hydroxypropyl methylcelluloses, hydroxypropyl celluloses or hydroxypropyl methylcellulose acetate succinate. Drying may be suitably carried out in a tray dryer, vacuum oven, rotavapor, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer. The dried product may be optionally milled to get 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 and hammer mills, and jet mills.

In an aspect, the present invention also provides pharmaceutical formulations comprising amorphous solid dispersions of dapagliflozin together with one or more pharmaceutically acceptable excipients.

A solid dispersion of dapagliflozin together with one or more pharmaceutically acceptable excipients of the present invention 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 invention may further comprise one or more pharmaceutically acceptable excipients.

Pharmaceutically acceptable excipients that are useful in the present invention 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, 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 and 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 pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, or the like.

Different solid forms are characterized by scattering techniques, e.g., x-ray powder diffraction pattern, by spectroscopic methods, e.g., 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. 1 975 64:1269-1288, and J. Haleblian and W. McCrone, J. Pharm. Sci. 1969 58:91 1 -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.

In an aspect of the application, amorphous dapagliflozin or amorphous solid dispersions of dapagliflozin prepared according to the processes of the present application can be substantially pure having a chemical purity greater than about 99%, or greater than about 99.5%, or greater than about 99.9%, by weight, as determined using high performance liquid chromatography (HPLC).

Amorphous dapagliflozin or amorphous solid dispersions of dapagliflozin produced by the method of present invention can be chemically pure having purity greater than about 99.5% and containing no single impurity in amounts greater than about 0.15%, by HPLC.

DEFINITIONS

The following definitions are used in connection with the present invention unless the context indicates otherwise. The term "amorphous" refers to a solid lacking any long-range translational orientation symmetry that characterizes crystalline structures although, it may have short range molecular order similar to a crystalline solid.

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 "C_x-C_y", where x and y are the lower and upper limits, respectively. For example, a group designated as "C C₆" 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.

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.

An "alcohol solvent" is an organic solvent containing a carbon bound to a hydroxyl group. "Alcoholic solvents" include, but are not limited to, 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, i-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, Ci-₆alcohols, or the like.

An "aliphatic or alicyclic hydrocarbon solvent" refers to a liquid, non-aromatic, hydrocarbon, which may be linear, branched, or cyclic. It is capable of dissolving a solute to form a uniformly dispersed solution. Examples of a hydrocarbon solvents 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, C₅-C₈ aliphatic hydrocarbons, petroleum ethers, or mixtures thereof.

"Aromatic hydrocarbon solvent" refers to a liquid, unsaturated, cyclic, hydrocarbon containing one or more rings which has at least one 6-carbon ring containing three double bonds. It is capable of dissolving a solute to form a uniformly dispersed solution. Examples of aromatic hydrocarbon solvents include, but are not limited to, benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, indane, naphthalene, tetralin, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, C6-C10 aromatic hydrocarbons, or mixtures thereof. An "ester solvent" is an organic solvent containing a carboxyl group -(C=0)-0- bonded to two other carbon atoms. "Ester solvents" 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, C3-6 esters, or the like.

A "halogenated hydrocarbon solvent" is an organic solvent containing a carbon bound to a halogen. "Halogenated hydrocarbon solvents" 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 like.

A "ketone solvent" is an organic solvent containing a carbonyl group -(C=0)- bonded to two other carbon atoms. "Ketone solvents" include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, C₃-₆ketones, 4- methyl-pentane-2-one or the like.

A "nitrile solvent" is an organic solvent containing a cyano -(C≡N) bonded to another carbon atom. "Nitrile solvents" include, but are not limited to, acetonitrile, propionitrile, C₂-₆nitriles, or the like.

A "polar aprotic solvent" has a dielectric constant greater than 15 and is at least one selected from the group consisting of amide-based organic solvents, such as Ν,Ν-dimethylformamide (DMF), Ν,Ν-dimethylacetamide (DMA), N- methylpyrrolidone (NMP), formamide, acetamide, propanamide, hexamethyl phosphoramide (HMPA), and hexamethyl phosphorus triamide (HMPT); nitro-based organic solvents, such as nitromethane, nitroethane, nitropropane, and nitrobenzene; pyridine-based organic solvents, such as pyridine and picoline; sulfone-based solvents, such as dimethylsulfone, diethylsulfone, diisopropylsulfone,

2- methylsulfolane, 3-methylsulfolane, 2,4-dimethylsulfolane, 3,4-dimethy sulfolane,

3- sulfolene, and sulfolane; and sulfoxide-based solvents such as dimethylsulfoxide (DMSO).

An "ether solvent" is an organic solvent containing an oxygen atom -O- bonded to two other carbon atoms. "Ether solvents" include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1 ,4-dioxane, dibutyl ether, dimethylfuran, 2- methoxyethanol, 2-ethoxyethanol, anisole, C2-6 ethers, or the like. Certain specific aspects and embodiments of the present invention will be explained in more detail with reference to the following examples, which are provided for purposes of illustration only and should not be construed as limiting the scope of the present invention in any manner.

EXAMPLES

EXAMPLE 1 : Preparation of amorphous form of dapagliflozin.

Dapagliflozin (3 g) and dichloromethane (60 mL) were charged into a round bottom flask at 27°C. The reaction mass was stirred and heated to 50°C to dissolve dapagliflozin completely. The obtained solution was filtered to obtain a clear solution. The resulting clear solution was subjected to spray drying in a Mini Spray Dryer at the inlet temperature of 60°C with purging of nitrogen gas. The solid product was obtained as amorphous dapagliflozin. Yield: 1 .3g

EXAMPLE 2: Preparation of amorphous solid dispersion of dapagliflozin with polyvinylpyrrolidone.

Dapagliflozin (2 g), dichloromethane (80 mL) and polyvinylpyrrolidone K-30 (2 gm) were charged into a round bottom flask at 27°C. The reaction mass was stirred and heated to 45°C to dissolve dapagliflozin completely. The obtained solution was filtered to obtain a clear solution. The resulting clear solution was subjected to spray drying in a Mini Spray Dryer at the inlet temperature of 60°C with purging of nitrogen gas to obtained title compound. Yield: 2.2g

EXAMPLE 3: Preparation of amorphous dapagliflozin.

Dapagliflozin (300 mg) and ethyl acetate (6 mL) were charged into a round bottom flask at 27°C. The reaction mass was stirred and heated to 50°C to dissolve dapagliflozin completely. The obtained solution was filtered to obtain a clear solution. The resulting solution was evaporated completely in rotavapor at 55°C under reduced pressure to obtained title compound. Yield: 160mg

EXAMPLE 4: Preparation of amorphous dapagliflozin.

Dapagliflozin (300 mg) and dichloromethane (3 mL) were charged into a round bottom flask at 27°C. The reaction mass was stirred to dissolve dapagliflozin completely. The obtained solution was filtered to obtain a clear solution. The resulting solution was evaporated completely in rotavapor at 50°C under reduced pressure to obtained title compound. Yield: 150mg

EXAMPLE 5: Preparation of amorphous dapagliflozin. Dapagliflozin (300 mg) and methanol (10 mL) were charged into a round bottom flask at 27°C. The reaction mass was stirred and heated to 60°C to dissolve dapagliflozin completely. The obtained solution was filtered to obtain a clear solution. The resulting solution was evaporated completely in rotavapor at 60°C under reduced pressure to obtained title compound. Yield: 21 Omg

EXAMPLE 6: Preparation of amorphous dapagliflozin.

Dapagliflozin (300 mg) and acetonitrile (5 mL) were charged into a round bottom flask at 27°C. The reaction mass was stirred to dissolve dapagliflozin completely. The obtained solution was filtered to obtain a clear solution. The resulting solution was evaporated completely in rotavapor at 65°C under reduced pressure to obtained title compound. Yield: 220mg

EXAMPLE 7: Preparation of amorphous dapagliflozin.

Dapagliflozin (0.5 g) and acetone (10 mL) were charged into a round bottom flask at 27°C. The reaction mass was stirred to dissolve dapagliflozin completely. The resulting solution was evaporated completely in rotavapor at 60°C under reduced pressure to obtained title compound.

EXAMPLE 8: Preparation of amorphous dapagliflozin.

Dapagliflozin (1 g) and methyl isobutyl ketone (20 mL) were charged into a round bottom flask at 27°C. The reaction mass was stirred to dissolve dapagliflozin completely. The resulting solution was evaporated completely in rotavapor at 1 10°C under reduced pressure to obtained title compound.

EXAMPLE 9: Preparation of amorphous dapagliflozin.

Dapagliflozin (1 g) and methyl ethyl ketone (20 mL) were charged into a round bottom flask at 27°C. The reaction mass was stirred to dissolve dapagliflozin completely. The resulting solution was evaporated completely in rotavapor at 60°C under reduced pressure to obtained title compound.

EXAMPLE 10: Preparation of amorphous dapagliflozin.

Dapagliflozin (1 g) and 2-methyl tetrahydrofuran (20 mL) were charged into a round bottom flask at 27°C. The reaction mass was stirred to dissolve dapagliflozin completely. The resulting solution was evaporated completely in rotavapor at 60°C under reduced pressure to obtained title compound.

EXAMPLE 11 : Preparation of amorphous solid dispersion of dapagliflozin with polyvinylpyrrolidone. Dapagliflozin (300 mg), methanol (15 mL) and polyvinylpyrrolidone K-30 (300 mg) were charged into a round bottom flask at 27°C. The reaction mass was stirred and heated to 60°C to dissolve dapagliflozin completely. The obtained solution was filtered to obtain a clear solution. The resulting solution was evaporated completely in rotavapor at 60°C under reduced pressure to obtained title compound. Yield: 550mg

EXAMPLE 12: Preparation of amorphous solid dispersion of dapagliflozin with hydro xypropyl methylcellulose.

Dapagliflozin (150 mg), methanol (10 mL) and hydroxypropyl methylcellulose

(150 mg) were charged into a round bottom flask at 27°C. The reaction mass was stirred and heated to 60°C to dissolve dapagliflozin completely. The obtained solution was filtered to obtain a clear solution. The resulting solution was evaporated completely in rotavapor at 60°C under reduced pressure to obtained title compound. Yield: 220mg

EXAMPLE 13: Preparation of amorphous solid dispersion of dapagliflozin with hydroxypropyl methylcellulose acetate succinate.

Dapagliflozin (200 mg), methanol (15 mL) and hydroxypropyl methylcellulose acetate succinate (200 mg) were charged into a round bottom flask at 27°C. The reaction mass was stirred and heated to 60°C to dissolve dapagliflozin completely. The obtained solution was filtered to obtain a clear solution. The resulting solution was evaporated completely in rotavapor at 60°C under reduced pressure to obtained title compound. Yield: 310mg

EXAMPLE 14: Preparation of amorphous solid dispersion of dapagliflozin with Hydroxypropyl cellulose.

Dapagliflozin (200 mg), methanol (15 mL) and Hydroxypropyl cellulose (200 mg) were charged into a round bottom flask at 27°C. The reaction mass was stirred and heated to 60°C to dissolve dapagliflozin completely. The obtained solution was filtered to obtain a clear solution. The resulting solution was evaporated completely in rotavapor at 60°C under reduced pressure to obtained title compound. Yield: 355mg

Claims

CLAIMS:

1 . A process for the preparation of amorphous form of dapagliflozin, comprising: a) dissolving dapagliflozin in a solvent selected from methanol, dichloromethane, acetonitrile, acetone, methyl isobutyl ketone, methyl ethyl ketone, 2-methyl tetrahydrofuran or mixtures thereof;

b) removing solvent from the solution obtained in step a), and

c) isolating the amorphous form of dapagliflozin.

2. An amorphous solid dispersion of dapagliflozin together with one or more pharmaceutically acceptable carriers.

3. The solid dispersion of dapagliflozin according to claim 2, wherein the pharmaceutically acceptable carriers selected from polyvinylpyrrolidones, hydroxypropyl methylcelluloses, hydroxypropyl celluloses or hydroxypropyl methylcellulose acetate succinate.

4. A process for the preparation of amorphous solid dispersion of dapagliflozin together with one or more pharmaceutically acceptable carriers, comprising:

a) dissolving dapagliflozin and pharmaceutically acceptable carriers in a solvent; b) removing solvent from the solution obtained in step a), and

c) isolating the amorphous solid dispersion of dapagliflozin together with one or more pharmaceutically acceptable carrier.

5. The process according to claim 4, wherein the solvent selected from methanol, dichloromethane or mixtures thereof.

6. The process according to claim 4, wherein the pharmaceutically acceptable carriers selected from polyvinylpyrrolidones, hydroxypropyl methylcelluloses, hydroxypropyl celluloses or hydroxypropyl methylcellulose acetate succinate.

7. The solid pharmaceutical formulation comprising the amorphous dapagliflozin or amorphous solid dispersion of dapagliflozin of any of claims 1 to 6 and one or more pharmaceutically acceptable carrier.

8. Use of amorphous dapagliflozin or amorphous solid dispersion of dapagliflozin according to any of claims 1 to 6 together with at least one pharmaceutically acceptable carrier, for the treatment of type 2 diabetes.