DESC:SOLID DISPERSION OF EMPAGLIFLOZIN AND PHARMACEUTICAL COMPOSITIONS THEREOF
FIELD OF INVENTION
The present invention relates to a solid state of form of empagliflozin. In particular, the present invention relates to solid dispersion of empagliflozin and processes for the preparation of the same. Furthermore, the present invention relates to the pharmaceutical composition comprising a solid dispersion of amorphous empagliflozin and one or more of pharmaceutically acceptable excipients used for use in the treatment of diseases related to hypoglycemia.
BACKGROUND
Type 2 diabetes is an increasingly prevalent disease that due to a high frequency of complications leads to a significant reduction of life expectancy. Because of diabetes-associated microvascular complications, type 2 diabetes is currently the most frequent cause of adult-onset loss of vision, renal failure, and amputations in the industrialized world. In addition, the presence of type 2 diabetes is associated with a two to five fold increase in cardiovascular disease risk.
The high incidence of therapeutic failure is a major contributor to the high rate of long-term hyperglycemia-associated complications or chronic damages (including micro- and macrovascular complications such as e.g. diabetic nephrophathy, retinopathy or neuropathy, or cardiovascular complications) in patients with type 2 diabetes.
Therefore, there is an unmet medical need for methods, medicaments and pharmaceutical compositions with a good efficacy with regard to glycemic control, with regard to disease-modifying properties and with regard to reduction of cardiovascular morbidity and mortality while at the same time showing an improved safety profile.
Empaghflozin is a novel SGLT2 (sodium/glucose cotransporter-2) inhibitor that is described for the treatment or improvement in glycemic control in patients with type 2 diabetes mellitus.
JARDIANCE® tablets contains empagliflozin and chemically known as ( 1 S)- 1 ,5-anhydro-l-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl] phenyl] -D-glucitol.
US Patent No. 7,579,449 discloses glucopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture.
US Patent No. 7,713,938 discloses stable a crystalline form of empagliflozin and a pharmaceutical composition or medicament comprising the crystalline form. Additional crystalline forms of empagliflozin are disclosed in U.S. Patent No. 7,723,309 and U.S. Patent No. 8,802,842.
US Patent publication No. 2011/0014284 Covers a pharmaceutical composition comprising empagliflozin & disintegrant to binder ratio of 1.5:3.5 to 1:1 along with pharmacokinetic parameters.
It was now surprisingly found that the amorphous form of empagliflozin can be stabilized by various formulation principles. Hence, in a first aspect the present invention relates to formulation principles that stabilize the amorphous form of empagliflozin. More specifically, the present invention describes various formulation principles capable of stabilizing the amorphous form of empagliflozin including solid dispersions, cyclodextrin complexes, and co-milling with excipients.
Solid dispersions comprising amorphous forms of drugs are generally known to improve the stability and solubility of drug products. The present invention provides stable solid dispersions comprising amorphous forms of empagliflozin.

It is well known that molecules can arrange to form different crystal polymorphs. Polymorphs have the same composition, but exhibit different solid-state properties as e.g. stability or solubility.
SUMMARY OF INVENTION
The present invention relates to solid state forms of empagliflozin and processes for preparation thereof.
The invention relates to formulation principles that stabilize the amorphous form of empagliflozin.
The present invention relates to a solid dispersion comprising amorphous form of empagliflozin and one or more pharmaceutically acceptable excipients.
Furthermore the present invention relates to a process of preparing solid dispersion comprising amorphous form of empagliflozin and one or more pharmaceutically acceptable excipients.
The present invention relates to a pharmaceutical composition comprising solid dispersion of empagliflozin and one or more pharmaceutically acceptable excipients.
Furthermore the present invention relates to a process of preparing pharmaceutical composition comprising solid dispersion of empagliflozin and one or more pharmaceutically acceptable excipients.
Furthermore the present invention relates to a pharmaceutical formulation comprising solid dispersion of empagliflozin and metformin and one or more other pharmaceutically acceptable excipients.
Furthermore the present invention relates to a pharmaceutical formulation comprising solid dispersion of empagliflozin and linagliptin and one or more other pharmaceutically acceptable excipients.
DETAILED DESCRIPTION
In an aspect, the present invention relates to solid state forms of empagliflozin and processes for preparation thereof.
In an aspect, the invention relates to formulation principles that stabilize the amorphous form of empagliflozin.
In an aspect, the present invention relates to a solid dispersion comprising amorphous form of empagliflozin and one or more pharmaceutically acceptable excipients.
In an aspect, the present invention further relates to a process of preparing solid dispersion comprising amorphous form of empagliflozin and one or more pharmaceutically acceptable excipients.
The term “empagliflozin” as used in the context of the present invention relates to the free base form, acid form, salt form, polymorphic crystalline or amorphous form, solvates, ethers, esters, etc.
Solid dispersion as used herein refers to the dispersion of one or more active ingredients in an inert excipient or polymer or carrier, where the active ingredients exist in solubilized or amorphous state. Solid dispersion consists of two or more components, generally inert excipient, polymer or carrier and drug optionally along with stabilizing agent (and/or surfactant or other additives). The most important role of the added polymer or carrier or excipient in solid dispersion is to reduce the molecular mobility of the drug to avoid the phase separation and re-crystallization of drug during storage. The resulting solid dispersions may have increased solubility. The increase in solubility of the drug in solid dispersion is mainly because drug remains in amorphous form which is associated with a higher energy state as compared to crystalline counterpart and due to that it requires very less external energy to dissolve.
A solid dispersion is a molecular dispersion of a compound, particularly a drug substance within excipient, polymer or carrier. Formation of a molecular dispersion provides a means of reducing the particle size to nearly molecular levels (i.e. there are no particles). As the excipient, polymer or carrier dissolves, the drug is exposed to the dissolution media as fine particles that are amorphous, which can dissolve and be absorbed more rapidly than larger particles.
In general, the term "solid dispersion" refers to a system in a solid state comprising at least two components, wherein one component is dispersed throughout the other component or components. The term "solid dispersion" as used herein, refers to stable solid dispersions comprising amorphous drug substance and one or more excipients, polymers or carriers. Further the term "solid dispersion" as used herein also refers to stable solid dispersions comprising amorphous drug substance and one or more excipients, polymers or carriers with or without adsorbent/absorbent. By "amorphous drug substance," it is meant that the amorphous solid contains drug substance in a substantially amorphous solid state form i.e. at least about 80% of the drug substance in the dispersion is in an amorphous form. More preferably at least about 90% and most preferably at least about 95% of the drug substance in the dispersion is in amorphous form.
The solid dispersion of empagliflozin of the present invention can be made by any of the numerous methods that result in a solid dispersion comprising amorphous form of empagliflozin. Several approaches can be used for the preparation of solid dispersion which includes, but not limited to spray drying, fusion method, solvent evaporation, hot-melt extrusion, ball milling, particle size reduction, supercritical fluid (SCF) processes, kneading, inclusion complexes, electrostatic spinning method.
Suitable solvents which can be used for dissolving the empagliflozin include but are not limited to: alcohol solvents such as methanol, ethanol, isopropyl alcohol, n-propanol, isoamyl alcohol n-butanol, 2-butanol and the like; halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, chloroform, carbon tetrachloride and the like; ketones such as acetone, ethyl methyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; nitriles such as acetonitrile, propionitrile and the like; dimethylformamide, dimethylacetamide and dimethylsulfoxide, and any mixtures of two or more thereof.
In an aspect, the present invention relates to a pharmaceutical formulation comprising solid dispersion of empagliflozin and one or more other pharmaceutically acceptable excipients.
The term "excipient" or "pharmaceutically acceptable excipient" means a component of pharmaceutical compositions that is not an active ingredient, that are useful in preparing pharmaceutical compositions are generally safe, non-toxic, and neither biologically nor otherwise undesirable, and are acceptable for veterinary use as well as human pharmaceutical use. An "excipient" or a “pharmaceutically acceptable excipient" are such as, but not limited to diluent, binder, stabilizer, lubricant, glidant, disintegrating agent, surfactant, film coating material, plasticizer, pigment, coloring agents, flavouring agent and sweetening agent and any other materials that are commonly used in solid pharmaceutical dosage form preparations.
Suitable pharmaceutically acceptable excipients which can be used in present in pharmaceutical compositions include, but not limited to diluents such as calcium sulfate, cellulose acetate, dextrates, dextrin, dextrose, fructose, kaolin, lactitol, maltitol, maltodextrin, maltose, polymethacrylates, sodium chloride, sucrose, lactose, mannitol, copovidone, cellulose derivatives, and the like. Different grades of lactose include, but are not limited to, lactose monohydrate, lactose DT (direct tableting), lactose anhydrous, Flowlac™, Pharmatose™ and others. Various cellulose compounds that can be used include crystalline cellulose, powdered cellulose, and cellulose acetate. Examples of crystalline cellulose products include, but are not limited to, Ceolus™ KG801, Avicel™ PH101, PH102, PH301, PH302, and PH-F20, microcrystalline cellulose 114, silicified microcrystalline cellulose, and microcrystalline cellulose 112, Microcelac™100. Other useful diluents include, but are not limited to, carmellose, sugar alcohols such as mannitol, sorbitol, and xylitol, calcium carbonate, magnesium carbonate, sodium carbonate, sodium bicarbonate, light magnesium oxide, heavy magnesium oxide, sodium hydrogen phosphate, calcium sulfate, disodium hydrogen phosphate, basic calcium phosphate, and tribasic calcium phosphate and the like, binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, copovidone, hydroxypropyl celluloses, hydroxypropyl methylcelluloses such as HPMC-Phthalate, HPMC-AS, HPMC-15 CPS; 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 pharmaceutically 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.
The said solid dispersion of empagliflozin may be 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 the like; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze dried compositions and the like.
The term “composition” as used in the context of the present invention includes pharmaceutical dosage forms such as but not limited to tablets, capsules, pills, sachets, granules and the like.
In an aspect, the present invention relates to processes for the preparation of pharmaceutical compositions comprising empagliflozin and one or more pharmaceutically acceptable excipients, wherein methods of preparing said compositions includes but not limited to one or more from direct compression, wet granulation, dry granulation, solvent evaporation, hot melt granulation, hot melt extrusion, fluid bed granulation, spray drying, extrusion-spheronization and the like.
In an aspect, the present invention relates to a pharmaceutical composition comprising solid dispersion of empagliflozin and one or more pharmaceutically acceptable excipients.
In an aspect, the present invention relates to a process of preparing pharmaceutical composition comprising solid dispersion of empagliflozin and one or more pharmaceutically acceptable excipients.
In an aspect, the present invention relates to a pharmaceutical formulation comprising solid dispersion of empagliflozin and metformin and one or more other pharmaceutically acceptable excipients.
In an aspect, the present invention relates to a pharmaceutical formulation comprising solid dispersion of empagliflozin and linagliptin and one or more other pharmaceutically acceptable excipients.
The diluents may be selected from the group consisting of different grades of starches, such as maize starch, potato starch, rice starch, wheat starch, pregelatinized starch, fully pregelatinized starch; cellulose derivatives, such as microcrystalline cellulose or silicified microcrystalline cellulose; sugar alcohols such as mannitol, erythritol, sorbitol, xylitol; monosaccharides like glucose; oligosaccharides like sucrose and lactose such as lactose monohydrate, lactose anhydrous, spray dried lactose or anhydrous lactose; calcium salts, such as calcium hydrogenphosphate; particularly preferably the diluents are selected from the group consisting of, microcrystalline cellulose, silicified microcrystalline cellulose, lactose monohydrate, spray dried lactose, and anhydrous lactose.
The binders may be selected from the group consisting of polyvinyl pyrrolidone (Povidone), polyvinyl alcohol, copolymers of vinylpyrrolidone with other vinylderivatives (Copovidone), hydroxypropyl methylcellulose, methylcellulose, hydroxypropylcellulose, powdered acacia, gelatin, guar gum, carbomer such as carbopol, polymethacrylates and pregelatinized starch.
The disintegrants may be selected from the group consisting of carmellose calcium, carboxymethylstarch sodium, croscarmellose sodium (cellulose carboxymethylether sodium salt, crosslinked), starch, modified starch such as pregelatinized starch, starch derivatives such as sodium starch glycolate, crosslinked polyvinylpyrrolidone (crospovidone), and low-substituted hydroxypropylcellulose, and disintegrating aids such as magnesium slumino-metasilicate and ion exchange resins like polacrilin potassium; particularly preferably the disintegrants are selected from the group consisting of sodium starch glycolate, croscarmellose sodium and crospovidone.
The lubricants may be selected from the group consisting of stearic acid, talc, glyceryl behenate, sodium stearyl fumarate and magnesium stearate; particularly preferably the lubricant are magnesium stearate and sodium stearyl fumarate.
Glidants may be selected from the group consisting of colloidal silica, hydrophobic colloidal silica and magnesium trisilicate, such as talc; particularly preferably the glidants are selected from the group consisting of colloidal silica and hydrophobic colloidal silica.
Suitable sweeteners may be selected from the group consisting of aspartame, saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia, thaumatin, and the like.
Suitable film-forming agents and coating materials according to the present invention include, but are not limited to hydroxypropyl methylcellulose (hypromellose, HPMC), hydroxypropyl cellulose, polyvinylalcohol, , methylcellulose, ethylcellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, shellac, liquid glucose, hydroxyethyl cellulose, polyvinylpyrrolidone, copolymers of vinylpyrrolidone and vinylacetate such as Kollidon® VA64 BASF, copolymers of acrylic and/or methacrylic acid esters with trimethylammoniummethylacrylate, copolymers of dimethylaminomethacrylic acid and neutral methacrylic acid esters, polymers of methacrylic acid or methacrylic acid esters, copolymers of acrylic acid ethylester and methacrylic acid methyl ester, and copolymers of acrylic acid and acrylic acid methylester.
Suitable plasticizers according to the present invention include, but are not limited to, polyethylene glycol, diethyl phthalate and glycerol. Preference is given to polyethylene glycol. Suitable coloring agents according to the present invention include, but are not limited to, pigments, inorganic pigments, FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel, ferric oxide red, ferric oxide yellow and titanium dioxide.
In an aspect, the present invention relates to processes for the preparation of pharmaceutical compositions comprising empagliflozin and one or more pharmaceutically acceptable excipients, wherein methods of preparing said compositions includes but not limited to, one or more from direct compression, wet granulation, dry granulation, solvent evaporation, hot melt granulation, hot melt extrusion, fluid bed granulation, spray drying, extrusion-spheronization and the like.
In an aspect, the present invention relates to method for preparing a solid dispersion comprising amorphous empagliflozin and one or more pharmaceutically acceptable excipients comprising the steps of:
a) providing a mixture of empagliflozin and one or more pharmaceutically acceptable excipient in a solvent; and
b) isolating solid dispersion comprising amorphous form of empagliflozin and one or more pharmaceutically acceptable excipients.
Any physical form of empagliflozin may be utilized for providing the mixture of empagliflozin in step (a).
Isolation of solid dispersion may be carried out by removing solvent from a solution or suspension or mixture.
Solid dispersions may be formed utilizing other conventional techniques known to those skilled in the art, such as but not limited to vacuum drying, fluid-bed drying, freeze-drying, rotary evaporation, rotary vacuum paddle dryer, drum drying, hot-melt extrusion and the like.
In an aspect, the present invention relates to method for preparing a solid dispersion comprising empagliflozin and one or more pharmaceutically acceptable excipients comprising the steps of:
(a) blending empagliflozin and at least one pharmaceutically acceptable excipients
(b) loading the blend of step (a) in a hot-melt extruder to obtain extrudates
In an aspect, the present invention relates to method for preparing a solid dispersion comprising amorphous empagliflozin and one or more pharmaceutically acceptable excipients comprising the steps of:
(a) blending amorphous empagliflozin and at least one pharmaceutically acceptable excipients
(b) loading the blend of step (a) in a hot-melt extruder to obtain extrudates

In an aspect, the present invention relates to a pharmaceutical composition comprising solid dispersion of empagliflozin and one or more pharmaceutically acceptable excipients.
In an aspect, the present invention relates to pharmaceutical compositions comprising
a) about 1- about 40% of empagliflozin,
b) about 10- about 90% diluent,
c) about 1- about 20% binder,
d) about 1- about 15% disintegrant,
e) about 0.05- about 10% lubricant and/or glidant;
In an aspect, the present invention relates to pharmaceutical compositions comprising
a) about 1%- about 40% of empagliflozin,
b) about 10%- about 80% of microcrystalline cellulose
c) about 1%- about 20% copovidone,
d) about 1- about 15% croscarmellose,
e). about 0.05%- about 10% of colloidal silicon
f). about 0.05%- about 10% magnesium stearate;
In an aspect, the present invention relates to a pharmaceutical composition comprising solid dispersion of empagliflozin and one or more pharmaceutically acceptable excipients and optionally contains coating.

In an aspect, the present invention relates to a process of preparing pharmaceutical composition comprising solid dispersion of empagliflozin and one or more pharmaceutically acceptable excipients.
In an aspect, the present invention relates to process of preparation of pharmaceutical composition comprising solid dispersion of empagliflozin and one or more pharmaceutically acceptable excipients comprising steps of
a) blending amorphous empagliflozin and at least one pharmaceutically acceptable excipients
(b) loading the blend of step (a) in a hot-melt extruder to obtain extrudates
(c) milling the extrudates of step (b) and blending the milled extrudates with diluent, binder, disintegrant, glidant, and/or lubricant
In an aspect, the present invention relates to process of preparation of pharmaceutical composition comprising solid dispersion of empagliflozin and one or more pharmaceutically acceptable excipients comprising steps of
a) Blending amorphous empagliflozin and at least one pharmaceutically acceptable excipients
(b) Loading the blend of step (a) in a hot-melt extruder to obtain extrudates
(c) Milling the extrudates of step (b) and blending the milled extrudates with diluent, binder, disintegrant, glidant, and/or lubricant
(d) Compressing the blend of step (c) into tablets

In an aspect, the present invention relates to process of preparation of pharmaceutical composition comprising solid dispersion of empagliflozin and one or more pharmaceutically acceptable excipients comprising the steps of:
(a) blending empagliflozin and copovidone
(b) loading the blend of step (a) in a hot-melt extruder to obtain extrudates;
(c) milling the extrudates of step (b) and blending the milled extrudates with at least one selected from diluent, binder, disintegrant, glidant, and lubricant; and
(d) compressing the blend of step (c) into tablets
In an aspect, the present invention relates to the use of amorphous empagliflozin for the preparation of a pharmaceutical composition, e.g. an oral solid dosage form, e.g. a tablet, having increased chemical stability after packaging in a polypropylene film and storage in the dark at 40 °C at a relative humidity of 75 % for a period of at least 14 days.
The term "amorphous empagliflozin" as used herein means especially that empagliflozin is maintained in the amorphous form after 1 month of storage at 40°C at 75% relative humidity.
The term "chemical stability" means that the sum of all degradation products derived from empagliflozin is below 2 percent, preferably below 0.5% of the total amount of empagliflozin after storage at defined conditions. Analysis and detection of degradation products is performed by HPLC. The term "chemical stability" may also mean "polymorphic stability". In the context of the present invention, the term "polymorphic stability" means that empagliflozin does not convert to a crystalline form, as determined by XRPD.
The following example illustrates certain specific aspects and embodiments of the invention and demonstrates the practice and advantages thereof. It is to be understood that the examples are provided solely for purposes of illustration and should not be regarded as limiting the scope of the invention in any manner.
Example 1:
Name of ingredient Amount
(in % ratio)
Empagliflozin 1 1 1 1 1
HPMC 2 3 5 6 7 8
Methanol qs qs qs qs qs qs
Dichloromethane qs qs qs qs qs qs

Procedure:
1). Empagliflozin is dissolved in a suitable amount of methanol.
2). HPMC is dissolved in a suitable amount of mixture of methanol and dichloromethane.
3). Mix both solutions and stir well.
4). isolating solid dispersion comprising amorphous form of empagliflozin hydroxypropylmethyl cellulose (HPMC).
Example 2
Name of ingredient Amount (in mg) per tab Amount (in mg) per tab Amount (in mg) per tab
Empagliflozin 25.66 25.66 25.66
HPMC 51.32 76.98 76.98
Croscarmellose sodium 4.00 4 37.50
Lactose monohydrate - - 16.50
Methanol qs qs qs
Dichloromethane qs qs qs
Lactose monohydrate 92.68 41.36 41.36
Microcrystalline cellulose 50.00 50.00 50.00
Colloidal silica 1 1 1
Magnesium stearate 1 1 1
Croscarmellose sodium 20 20 20
Supertab 11SD 40 40 40
MCC 102 40 40 40

1). Empagliflozin is dissolved in a suitable amount of methanol.
2). HPMC is dissolved in a suitable amount of mixture of methanol and dichloromethane.
3). Mix both solutions and stir well.
4). Empagliflozin and HPMC solution is sprayed onto powder mixture comprising lactose monohydrate, microcrystalline, croscarmellose sodium and a like to obtain granules.
5). Dry the granules, sieved blended with colloidal silica and microcrystalline cellulose
6). Blend with magnesium stearate and
7). Compressed into tablets.
Example 3
Name of ingredient Amount (in mg) per tab Amount (in mg) per tab
Empagliflozin 12.50 12.50
Metformin HCl 1000.00 1000.00
HPMC 60.00 75.00
Corn starch 62.50 57.50
Colloidal silica 5.00 5.00
Magnesium stearate 10.00 10.00
Weight of un-coated tablet 1150 1160
Coating 23.00 23.20
Weight of coated tablet 1173.00 1183.20

Procedure:
1). Empagliflozin is dissolved in a suitable amount of methanol.
2). HPMC is dissolved in a suitable amount of mixture of methanol and dichloromethane.
3). Mix both solutions (step 1 and step 2) and stir well
4). Spray step 3 solution powder mixture comprising metformin and corn starch.
5). Dry the granules.
6). Mix colloidal silica with dried granules in blender.
7). Add magnesium stearate and blend properly.
8). Compress the final blend of step 7
9) Coat the compressed tablets
Example 4:
Name of ingredient Amount
(in % ratio)
Empagliflozin 1 1 1 1 1 1 1 1 1
Copovidone 1 2 3 - - - - - -
HPMC - - - 1 2 3 - - -
HPC - - - - - - 1 2 3

Procedure:
1). Blending empagliflozin and copovidone, HPMC or HPC
2). Loading blend of step 1) in hot-melt extruder to obtain extrudates

Example 5-8
Name of ingredient Amount (in mg) per tab
Ex 5 Ex 6 Ex 7 Ex 8
Empagliflozin 25 25 25 25
HPMC 25 50 - -
Copovidone - - 25 50
Lactose 90 78 90 78
Microcrystalline cellulose 96 86 96 86
Croscarmellose sodium 12 9 12 9
Colloidal silicon dioxide 1 1 1 1
Magnesium stearate 1 1 1 1
Weight of un-coated tablet 250 250 250 250
Coating 10 10 10 10
Weight of coated tablet 260 260 260 260

The tablets of examples 5-8 were subjected for in-vitro dissolution in USP type II dissolution apparatus with 900 mL of 0.05 M Phosphate Buffer, (pH 6.8) at 37°C and 75 rpm. The results are provided below:
Time
(In minutes) Cumulative Percent of Empagliflozin Released
Example 5 Example 6 Example 7 Example 8
5 51 49 75 82
10 68 61 85 96
15 77 70 87 97
20 83 79 90 98
30 91 90 90 98

Chemical stability
The tablets of examples 5& 7 were stored in stability chamber and the results of the study indicates that the composition is stable under stress conditions.
,CLAIMS:1. A pharmaceutical composition comprising a solid dispersion of empagliflozin and one or more pharmaceutically acceptable excipients.
2. A pharmaceutical composition comprising a solid dispersion of empagliflozin and one or more pharmaceutically acceptable excipients selected from HPMC, Copovidone and HPC.
3. The pharmaceutical composition according to claim 1, wherein the solid dispersion is prepared by a hot-melt extrusion method.
4. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable excipients are selected from the group comprising diluents, binders, disintegrants, lubricants, glidants, and mixtures thereof.
5. A process for preparing pharmaceutical composition comprising empagliflozin, which process comprises the steps of:
(a) blending empagliflozin and at least one pharmaceutically acceptable excipient
(b) loading the blend of step (a) in a hot-melt extruder to obtain extrudates;
(c) milling the extrudates of step (b) and blending the milled extrudates with at least one pharmaceutically acceptable excipient; and
(d) compressing the blend of step (c) into tablets