Claims:We Claim:
1. A process for the preparation of stable Dapagliflozin or its pharmaceutical salts thereof, comprising:
i. treating Dapagliflozin complex with acid;
ii. adding an anti-solvent to step (i) or vice versa; and
iii. isolating the stable form of Dapagliflozin or its pharmaceutical salts thereof.

2. The process as claimed in claim 1, wherein the said Dapagliflozin complex used in the step 1(i) includes complex of Dapagliflozin with L-proline or L-phenylalanine or lysine or leucine or isoleucine or cysteine or aspartic acid or serine or valine or L-pyroglutamic acid or piperazine or fumaric acid or oxalic acid or malonic acid or succinic acid or citric acid or L-glutaric acid or L-glycine or L-tyrosine or arginine or phenethylamine or butyl amines or ethyl amine or methylamine or mannitol or ammonia or nicotinic acid or pyridine or isonicotinic acid or pyrazole or imidazole or morpholine or pyrazine-2-carboxylic acid or pyrazole or isonipecotic acid or pipecolic acid.

3. The process as claimed in claim 1, wherein the said acid includes hydrochloric acid, sulphuric acid, nitric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, sulphamic acid, formic acid, acetic acid, trifluoroacetic acid or combination thereof.

4. The process as claimed in claim 1, wherein the said anti-solvent includes n-pentane, n-hexane, n-heptane, n-octane, 3-methyl pentane, 2,3-dimethylbutane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethyl pentane, 3-ethylpentane, 2,2,3-trimethylbutane, 3-methylheptane, cyclohexane, cycloheptane or combination thereof.

5. The process as claimed in claim 1, wherein the said stable form of Dapagliflozin or its pharmaceutical salts thereof of the said pharmaceutical composition is selected from but not limiting to Dapagliflozin (S)-propylene glycol ((S)-PG) hydrate (SC-3) or Dapagliflozin (R)-propylene glycol ((R)-PG) hydrate (SD-3) or Crystalline Dapagliflozin hydrate or amorphous form of Dapagliflozin 1,2-propanediol/hydrates or amorphous Dapagliflozin.

6. The process as claimed in claim 1, further providing the pharmaceutical composition comprising of:
i. said stable form of Dapagliflozin or its pharmaceutical salts thereof,
ii. a solubilizer, and
iii. one or more pharmaceutically acceptable excipients.

7. The process as claimed in claim 6, wherein the said solubilizer of the said pharmaceutical composition is selected from water-soluble organic solvents, water-insoluble organic solvents, polysaccharide polymers or surfactants or a combination thereof.

8. The process as claimed in claim 6, wherein the said one or more pharmaceutically acceptable excipients of the said pharmaceutical composition are selected from fillers, binders, disintegrants, lubricants and/or glidants or a combination thereof.

9. The process as claimed in claim 6, wherein the said pharmaceutical composition can further comprise of second active ingredient selected from a group consisting of Sulfonylureas, Biguanides, Thiazolidinediones, Dipeptidyl- peptidase-4 (DPP-4) inhibitors.

10. The process as claimed in claim 6, wherein the said pharmaceutical composition is used for the treatment of Type-II Diabetes Mellitus.

11. A process for preparing the pharmaceutical composition as claimed in claim 7 using wet granulation process, comprising of steps:
i. preparing a solubilizer solution by dissolving a solubilizer in a suitable solvent;
ii. granulating one or more said pharmaceutically acceptable excipients by using the said solubilizer solution of step (i);
iii. adding Dapagliflozin or its pharmaceutically acceptable salts in step (i) or step (ii);
iv. drying the granulates of step (ii) followed by pre-lubrication and lubrication of the said dried granules with said pharmaceutically acceptable excipient/s;
v. compressing the lubricated blend of step (iv) for forming a solid unit dosage form; and
vi. optionally coating the said dosage form.

12. The process for preparing the wet granulated pharmaceutical composition as claimed in claim 12, wherein the said solvent is selected from water, esters; ketones; alcohols; dichloromethane or a combination thereof.

13. The process for preparing the wet granulated pharmaceutical composition as claimed in claim 12, wherein the said solid dosage form includes tablets (mono layer / bi layer), mini-tablets, pellets, capsules, powders, granules or sachets.
, Description:FIELD OF THE INVENTION
The present invention relates to a process for preparation of stable Dapagliflozin or its pharmaceutical salts thereof. The present invention also relates to method of treating diabetes using a pharmaceutical composition comprising stable form of Dapagliflozin or its pharmaceutical salts thereof and/or in combination with other anti-diabetic agents and one or more pharmaceutically acceptable excipients, and processes for their preparation.

BACKGROUND OF THE INVENTION
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 is an active pharmaceutical ingredient (API) and a selective inhibitor of SGLT2 which is approved with Trade Name FARXIGA® and marketed by AstraZeneca that is being developed for the treatment of type 2 diabetes mellitus.

Dapagliflozin is described chemically as (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol. The commercially available formulations of Dapagliflozin i.e. FARXIGA® contain the propanediol (propylene glycol) monohydrate solvate of Dapagliflozin as the active ingredient. The drug substance is crystalline in nature. The structure of Dapagliflozin is shown as Formula I

Formula-I

WO 2003/099836 A1 specifically discloses Dapagliflozin and its salts, its preparation, method for treating diabetes employing Dapagliflozin alone or in combination with another anti-diabetic agent or other therapeutic agent.

WO 2008/002824 A1 discloses crystalline forms and solvates of (1S)-1,5-anhydro-1-C-[3((phenyl)methyl)phenyl)-D-glucitol derivatives and their complexes with amino acids such as propylene glycol hydrate.

WO 2013/079501 A1 discloses crystalline Dapagliflozin hydrate, process for the preparation and its composition.

US 2015/307540 A1 discloses an amorphous form of Dapagliflozin 1,2-propanediol or hydrates and its composition. Amorphous Dapagliflozin form preparation has further been described in the art, for example in WO 2013/064909 A2; WO 2015/104658 A2; WO 2015/132803 A2; WO2015/040571 A1 and WO 2017/046730 A1.

Further, WO 2008/116179 A1 discloses an immediate release pharmaceutical formulation comprising Dapagliflozin propylene glycol hydrate and a pharmaceutically acceptable carrier, wherein formulation is in a form of a tablet, a stock granulation, and a capsule.

WO 2010/138535 A1 discloses a method for treating type 2 diabetes in a mammalian patient who has previously been treated with one or more oral anti-diabetic agents and/or one or more injectable anti-diabetic agents, which previous treatment has failed, which comprises administering to said patient in need of treatment a therapeutically effective amount of an SGLT2 inhibitor.

It is now widely accepted that glycemic control makes a difference in type II diabetes patients. The goal of diabetes therapy today is to achieve and maintain as near normal glycemia as possible to prevent the long-term microvascular and macrovascular complications associated with elevated glucose in the blood. Oral therapeutic options for the treatment of type II diabetes mellitus include compounds known as: sulfonylureas, biguanides (metformin), thiazolidinediones, and alpha-glucosidase inhibitors. The active agents from each class are generally administered to patients alone. It is further known that whenever such monotherapy becomes inadequate, combination therapy sets the rational course of action.

Further, WO 2015/128853 A1 discloses a pharmaceutical composition comprising a solid dispersion of Dapagliflozin and one or more pharmaceutically acceptable excipients and further discloses process for the preparation,

WO 2015/011113 A1 discloses an amorphous solid dispersion of at least one suitable polymer and Dapagliflozin; it further discloses composition comprising amorphous Dapagliflozin and adsorbate comprising amorphous Dapagliflozin.

WO 2011/060256 A1 discloses a bilayer tablet comprising: a first layer wherein the first layer is a metformin extended release formulation; a second layer wherein the second layer is an SGLT2 inhibitor formulation; and optionally a film coating that covers the first layer and the second layer.

Although several solid forms of Dapagliflozin are known in the art, finding an optimal form with regards to bioavailability, inter-patient variability, and safety remains a considerable challenge, in particular when the compound exhibits polymorphism, not all solid forms of Dapagliflozin are equally suitable with regard to stability, flow properties, compressibility and dissolution rate. For instance, amorphous forms can be thought as liquids that have been solidified by the removal of thermal energy or a solvent, in a manner that circumvents crystallization. The amorphous form can have different solubility, stability, and mechanical behavior that can be exploited by pharmaceutical scientists. However, amorphous forms are sometimes better soluble than crystalline forms.

Despite the above described methods and preparations of Dapagliflozin and its formulations, there is a need to develop industrially viable and stable Dapagliflozin with high purity and enhanced yield. Further, there is a need to have an improved composition containing said active pharmaceutical ingredient (API), relating to a dissolution profile, content uniformity, and/or improved process. Further, there is a need for a pharmaceutical composition comprising said API exhibiting satisfying stability on storage.

SUMMARY OF THE INVENTION
The present invention provides a process for preparation of stable Dapagliflozin or its pharmaceutically acceptable salts, comprising:
i. treating Dapagliflozin complex with acid;
ii. adding an anti-solvent to step-i) or vice versa;
iii. isolating the stable Dapagliflozin or its pharmaceutically acceptable salts.

In one of the embodiment of the present invention discloses a method of treating diabetes using a novel pharmaceutical composition comprising stable Dapagliflozin or its pharmaceutically acceptable salts and/or in combination with other anti-diabetic agents and one or more pharmaceutically acceptable excipients, and process for their preparation.

In yet another embodiment the present invention describes a pharmaceutical composition comprising of:
i. stable form of Dapagliflozin or its pharmaceutically acceptable salts,
ii. a solubilizer, and
iii. one or more pharmaceutically acceptable excipients.

In yet another embodiment the present invention describes a process for preparing the wet granulated pharmaceutical composition comprising of:
i. preparing a solubilizer solution by dissolving a solubilizer in a suitable solvent;
ii. granulating one or more said pharmaceutically acceptable excipients by using the said solubilizer solution of step (i);
iii. adding Dapagliflozin or its pharmaceutically acceptable salts optionally either in step (i) or step (ii);
iv. drying the granulates of step (ii) followed by pre-lubrication and lubrication of the said dried granules with said pharmaceutically acceptable excipient/s;
v. compressing the lubricated blend of step (iv) for forming a solid unit dosage form; and
vi. optionally coating the said dosage form.

BRIEF DESCRIPTION OF THE DRAWINGS:
These and other features, aspects and advantages of the present invention are better understood when the following detailed description of the invention is read with reference to the accompanying drawings, in which:
Figure 1 is the characteristic powder XRD pattern of stable amorphous Dapagliflozin prepared as per present invention.

DETAILED DESCRIPTION
Before the present invention is described, it is to be understood that this invention is not limited to particular methodologies and materials described, as these may vary as per the person skilled in the art. It is also to be understood that the terminology used in the description is for the purpose of describing the particular embodiments only, and is not intended to limit the scope of the present invention.

Before the present invention is described, it is to be understood that unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention-'belongs. Further, it is to be understood that the present invention is not limited to the methodologies and materials similar, equivalent to those described herein are used in the practice, or testing of the present invention, the preferred methods and materials are described, as these may vary within the specification indicated. Unless stated to the contrary, any use of the words such as "including," "containing," "comprising," "having" and the like, means "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims. Further, the terms disclosed embodiments are merely exemplary methods of the invention, which may be embodied in various forms.

The present invention provides a process for the preparation of stable Dapagliflozin or its pharmaceutically acceptable salts, comprising:
i. treating Dapagliflozin complex with acid;
ii. adding an anti-solvent to step-i) or vice versa;
iii. isolating the stable Dapagliflozin or its pharmaceutically acceptable salts.
As used herein, the term "stable" means and includes, that the said stabilized form of Dapagliflozin does not undergo any conversion to either in polymorphic form or chemical purity. Further stable Dapagliflozin or its pharmaceuticals form thereof includes herein is selected from the group consisting of Dapagliflozin (S)-propylene glycol ((S)-PG) hydrate (SC-3), Dapagliflozin (R)-propylene glycol ((R)-PG) hydrate (SD-3) or crystalline Dapagliflozin hydrate or amorphous form of Dapagliflozin 1,2 propanediol or its hydrates and amorphous Dapagliflozin free base, preferably amorphous Dapagliflozin free base.

The starting compounds Dapagliflozin complex of step (i) can be obtained by processes known in the art.

In another embodiment of the present invention, the said Dapagliflozin complex used in the step (i) is selected from the group comprising of complex of Dapagliflozin with L-proline or L-phenylalanine or lysine or leucine or isoleucine or cysteine or aspartic acid or serine or valine or L-pyroglutamic acid or piperazine or fumaric acid or oxalic acid or malonic acid or succinic acid or citric acid or L-glutaric acid or L-glycine or L-tyrosine or arginine or phenethylamine or butyl amines or ethyl amine or methylamine or mannitol or ammonia or nicotinic acid or pyridine or isonicotinic acid or pyrazole or imidazole or morpholine or pyrazine-2-carboxylic acid or pyrazole or isonipecotic acid or pipecolic acid and most preferably with Piperazine.

The acid used in step (i) is selected from the group comprising of inorganic and organic acids such as hydrochloric acid, sulphuric acid, nitric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, sulphamic acid, formic acid, acetic acid, trifluoroacetic acid, or combination thereof and most preferably hydrochloric acid.

Further, in step (i) the reaction of Dapagliflozin complex with acid optionally carried out in presence of solvent which is selected from the group consisting of but not limited to ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate; ethers such as methyl tertiary butyl ether, tetrahydrofuran, dimethyl ether, diisopropyl ether, 1,4-dioxane; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; nitriles such as acetonitrile, propionitrile; aromatic hydrocarbons such as toluene, xylene; chlorinated solvents such as methylene chloride, dichloroethane, chloroform, carbon tetrachloride or N,N-dimethyl formamide, N,N-dimethylacetamide, dimethyl sulfoxide, water or combination thereof and most preferably ethyl acetate.

The anti-solvent used in Step (ii) is selected from the group comprising of n-pentane, n-hexane, n-heptane, n-octane, 3-methyl pentane, 2,3-dimethylbutane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethyl pentane, 3-ethylpentane, 2,2,3-trimethylbutane, 3-methylheptane, cyclohexane, cycloheptane or mixtures thereof and most preferably n-Pentane.

The reaction of Step (iii) involves isolating stable Dapagliflozin or optionally further converting to its pharmaceutical salts thereof by any conventional methods known in the prior art.

The present invention further describes a method of treating diabetes using a pharmaceutical composition comprising stable Dapagliflozin or its pharmaceutical salts thereof alone or in combination with other anti-diabetic agents. The pharmaceutical composition of the present invention comprises of:
i. stable form of Dapagliflozin or its pharmaceutical salts thereof,
ii. a solubilizer, and
iii. one or more pharmaceutically acceptable excipients.

According to the present invention, the said pharmaceutical composition comprises a therapeutically effective amount of stable Dapagliflozin or its pharmaceutical salts thereof which is selected from Dapagliflozin (S)-propylene glycol ((S)-PG) hydrate (SC-3) or (R)-propylene glycol ((R)-PG) hydrate (SD-3) or crystalline Dapagliflozin hydrate or amorphous form of Dapagliflozin 1,2 propanediol or its hydrates and amorphous Dapagliflozin free base. Preferably amorphous Dapagliflozin free base.

Additionally, other anti diabetic drugs in a therapeutically effective amount can be combined with the present pharmaceutical composition including, but not limiting to Sulfonylureas such as Gliclazide, Glimepiride or Glyburide; Biguanides such as Metformin; Thiazolidinediones such as Rosiglitazone, Pioglitazone; Dipeptidyl-peptidase-4 (DPP-4) inhibitors such as Linagliptin, Saxagliptin, Sitagliptin or Alogliptin.

The said pharmaceutical composition as discussed above comprises one or more pharmaceutically acceptable excipient(s) including but not limiting to fillers/diluents, binder, disintegrants, surfactants (solubilizers/wetting), lubricants, and/ or glidants or a combination thereof.

The said pharmaceutical composition comprises an inert substrate or filler selected from, but are not limiting to isomalt, dicalcium phosphate dihydrate, calcium sulfate, anhydrous lactose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pre-gelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate, or a combination thereof.

The said pharmaceutical composition comprises binder which is selected from but not limited to one or more of cellulose derivatives like hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methylcellulose; gums like xanthan gum, gum acacia, tragacanth; water-soluble vinylpyrrolidone polymers like polyvinylpyrrolidone, copolymer of vinylpyrrolidone and vinyl acetate; sugars like sorbitol, mannitol and a combination thereof.

The said pharmaceutical composition comprises disintegrants selected from, but is not limited to carboxy methyl cellulose calcium, carboxy methyl cellulose sodium, microcrystalline cellulose, silicon dioxide, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, methyl cellulose, povidone, magnesium aluminum silicate, starch or a combination thereof.

The said pharmaceutical composition comprises solubilizer which includes but not limited to water-soluble organic solvents, water-insoluble organic solvents, polysaccharide polymers or/and surfactants or a combination thereof.

The said pharmaceutical composition comprises water-soluble organic solvents selected from, but are not limiting to Dimethylacetamide, Dimethyl sulfoxide, Glycerin, polyethylene glycol, propylene glycol or a combination thereof.

The pharmaceutical composition further comprises water-insoluble organic solvent selected from, but are not limited to Beeswax, Soy fatty acids, medium chain (C8/C10) mono and diglycerides medium-chain triglycerides or/and long-chain triglycerides or a combination thereof.

The pharmaceutical composition also comprises polysaccharide polymers selected from but are not limited to xanthan gum, dextran, welan gum, gellan gum, diutan gum or/and pullulan or a combination thereof.

The pharmaceutical composition comprises suitable surfactant which is selected from anionic, cationic and non-ionic surfactants. Anionic surfactants includes, but are not limited to docusate, ammonium lauryl sulfate, sodium lauryl sulfate, sodium lauryl ether sulfate and perfluoro octane sulfonate or a combination thereof. Cationic surfactants include, but are not limited to cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, benzethonium chloride and dimethyl dioctadecyl ammonium chloride or a combination thereof. Non ionic surfactants includes, but are not limited to polyethylene glycol alkyl ethers (Brij), polypropylene glycol alkyl ethers, polyoxyethylene glycol sorbitan alkyl esters, polysorbate, sorbitan alkyl esters, spans and block copolymers of polyethylene glycol and polypropylene glycol, poloxamers or a combination thereof.

The pharmaceutical composition comprises lubricant which is added to a pharmaceutical composition for ease in processing, and it also help in preventing adhesion to the equipment during processing. Lubricants used in the composition includes, but are not limited to, calcium stearate, magnesium stearate, mineral oil, glyceryl behenate, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, vegetable oil, sodium lauryl sulfate, silicon dioxide, carnauba wax, sucrose stearate and zinc stearate or a combination thereof.

The pharmaceutical composition comprises glidant which improves flowability and accuracy of dosing. Glidants used in the composition includes, but are not limited to, colloidal silicon dioxide, magnesium trisilicate, starch, talc, or tribasic calcium phosphate or a combination thereof.

The said pharmaceutical composition can be prepared by any suitable process, for example dry granulation process i.e. roller compaction, the roller compact or functions by uniformly applying pressure on a mixed powder blend by passing the blend between two counter-rotating rollers. The pressure imparted on the blend by the rollers compresses the powder into a compact, such as a sheet or ribbon, which is typically milled to produce granules.

The conventionally known aspect of the process, wherein the stable Dapagliflozin or its pharmaceutical salts thereof is mixed with one or more of pharmaceutical excipients such as filler, solubilizer, disintegrant and lubricant in a suitable blender. The mixing time can vary from about 10 to 60 minutes. The resultant blend can either be directly compressed into solid dosage form or compacted by roller compaction. The resultant blend for compaction is subsequently transferred to a roller compactor in a known manner. The roller speed, roller gap width and force of compaction are then adjusted and the blend is fed through the roller compactor. The typical force and other conditions can be easily selected and adjusted by those skilled in the art. This compact sheet is fed to a mill, such as an oscillating mill, fitted with a screen. The screen can be selected with variable whole diameters depending upon the size of the granules required. After passing through the mill and the screen, the compact is converted into granules of the desired particle size distribution. The granules can also be mixed with one or more of pharmaceutically acceptable excipients and compressed into solid dosage form.

Further in another embodiment of the present invention, the pharmaceutical composition can be prepared by wet granulation process by using rapid mixer granulator. Wet granulation process involves binding of the powder particles together with a solubilizing solution instead of compaction. This leads to development of bridges between the powder particles and the tensile strength of bond increases as amount of solution added is increased. Wet granulation process involves massing of a mix of dry primary powder particles in Rapid Mixer Granulator, by using a solubilizer solution. The said solubilizer solution contains a non toxic solvent which can be removed by drying. Typically such solvents includes but are not limiting to water, esters such as ethyl acetate; ketones such as acetone; alcohols such as methanol, ethanol, isopropanol, butanol; dichloromethane and a combination thereof. The said solubilizer solution may be used alone or as a solvent containing a dissolved solubilizer. The above obtained wet mass is dried till the required LOD (Limit of Detection) is achieved. Pre-lubrication and lubrication of dried granules with one or more pharmaceutically acceptable excipients is followed by compression of lubricated blend using suitable punches to obtain a solid dosage form.

Further in another embodiment of the present invention, the pharmaceutical compositions of the invention can be in the form of a solid dosage form, but are not limited to, tablets (mono layer / bi layer), mini-tablet, pellets, capsules, powders, granules and sachets. Preferably, the solid pharmaceutical dosage form is a tablet (mono layer / bi layer) or capsule.

Further in another embodiment of the present invention, the pharmaceutical composition may have a coating over the dosage form of composition and the coating material may be selected from but is not limited to Shellac, Zine, Cellulose acetate phthalate (CAP), polyvinyl acetate phthalate, hyroxylpropylcellulose, hydroxypropyl methyl cellulose and Opadry. Further coating portion may comprise of plasticizers and, inert excipients. The said inert excipients include not limiting to talc, titanium dioxide, colloidal silicon dioxide, hydroxypropyl methylcellulose and crospovidone or a combination thereof. The said plasticizers includes triacetin, citric acid esters, phthalic acid esters, dibutyl sebacate, cetyl alcohol, polyethylene glycols, polysorbates or other plasticizers or a combination thereof.

The following examples are illustrative of the present invention, and the examples should not be considered as limiting the scope of this invention in any way, as these examples and other equivalents thereof will become apparent to those versed in the art, in the light of the present disclosure.

Example 1: Preparation of Dapagliflozin piperazine complex
To the mixture of THF (60 mL), methanol (90 mL) and water (30 mL), (2S,3R,4S,5S,6R)-2-(acetoxymethyl)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl) tetrahydro-2H-pyran-3,4,5-triyl triacetate (10 g) was charged into a round bottom flask and cooled to 15-20°C. To the reaction mixture lithium hydroxide (1.0 g) was added and stirred. After completion reaction mass was evaporated and cooled. Water (20 mL) and ethyl acetate (50 mL) were added to the reaction mass and stirred. The layers were separated and aq layer was extracted with ethyl acetate (50 mL). The combined organic layer was washed with NaHCO3 solution followed by evaporation completely. Acetone (20 mL) was added to the reaction mass and evaporated to obtain residue. The obtained reaction mass was cooled to room temperature and Isopropyl alcohol (3 mL) was added to the reaction mass and stirred. Piperazine (3 g) was added to the reaction mass and stirred. The temperature of the reaction mass was raised to 40-45°C and stirred. Cyclohexane (80 mL) was added to the reaction mass and stirred. The reaction mass was cooled to room temperature and stirred. The obtained reaction mass was filtered, washed with cyclohexane (30 mL) and suck dried. The obtained wet solid, acetone (20 mL) and cyclohexane (30 mL) were charged into a round bottom flask and stirred. The obtained reaction mass was filtered, washed with cyclohexane (20 mL) and dried to give the title compound. Dry Weight: 8.8 g (88%).

Example 2: Preparation of amorphous Dapagliflozin
To the cool mixture of water (100 mL) and Conc. HCl (7 mL); Ethyl acetate (70 mL) and compound of example 1 (10 g) was added and stirred. The layers were separated and aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layer was washed with aq. HCl solution. The organic layer was evaporated under vacuum to get residue and Ethyl acetate (20 mL) was added to residue. Ethyl acetate was evaporated completely under vacuum again to give thick residue. Ethyl acetate (20 mL) was added to dissolve above residue under stirring followed by addition of n-Pentane (10 mL). The obtained reaction mass was added to round bottom flask containing n-pentane (250 mL) at below 0°C. The temperature of the reaction mass was raised and stirred. The obtained solid was filtered and washed with n-pentane (15mL) followed by drying to give the title compound. Dry Weight: 7.0 g (95%)

Example 3:
Sr. No Name of the Ingredient mg/tab (10 mg)
Dry Mix
1. Microcrystalline cellulose (Avicel PH 112) 120
2. Anhydrous lactose (supertab 21 N) 50
3. Crospovidone XL 6
Solubilizer Solution
4. Dapagliflozin 10
5. Polysorbate 80 5
6. Methylene dichloride
7. Isopropyl Alcohol
Pre Lubrication
8. Microcrystalline cellulose (Avicel PH 112) 30
9. Crospovidone XL 6
10. Colloidal silicon dioxide 5
Lubrication
11. Magnesium Stearate 4
Core Tablet
Seal Coating
12. HPMC E-3 3
13. PEG 6000PF 1
14. Talc 1
15. Methylene dichloride
16. Isopropyl Alcohol
17. Opadry 85F520253 7
18. Purified Water
Coated tablet

BRIEF MANUFACTURING PROCESS:
The tablet composition of example 3 was prepared according to the process given below,
A. Dapagliflozin Part:-
1. Sift Microcrystalline Cellulose PH 112, anhydrous lactose (Supertab 21 N), Crospovidone XL through 40# sieve. Load the material in rapid mixer granulator and mix for suitable time.
2. Polysorbate 80 and Dapagliflozin was slowly added to the solution of isopropyl alcohol and methylene chloride and stirred till clear solution was formed.
3. Granulate step 1 by using step 2 solution in rapid mixer granulator and dry wet mass in GPCG 1.1 till required LOD achieved followed by sizing dried granules through 30# sieve.
4. Sift Microcrystalline Cellulose 112, crospovidone XL and colloidal silicon dioxide through 40# sieve.
5. Load dried granules and prelubrication part in blender and mix for suitable time followed by lubrication with magnesium stearate.
6. Compress lubricated blend using suitable punches.
B. Seal Coating:-
1. Hydroxypropyl methyl cellulose E3 and other ingredients were dispersed in isopropyl alcohol and stirred for suitable time till clear solution obtained.
2. Use seal coating dispersion for coating, coat tablets till required weight gain achieved.
C. Coating:-
1. Take required amount of purified water in SS. vessel to disperse Opadry 85F520253 under continuous stirring and coat tablets till required weight gain achieved.

The dissolution test for Dapagliflozin tablet is performed in 1000 mL of dissolution medium at 37°C, using USP apparatus 2 (paddles) method at a rotation speed of 60 rpm. Samples are removed after 5, 10, 15, 20 and 30 minutes and acetate buffer, acidic (2-5) pH has been used as dissolution medium.

In-vitro Dissolution profile of Example 3 in comparison to product available in market
Time points (Mins) Dissolution medium: Acetate Buffer (1000mL), pH 4.5, 60 rpm
Dapagliflozin Tablets 10 mg (Marketed Product) Test Product
0 0.00 0
5 68.99 82.4
10 93.85 91.9
15 94.79 91.9
20 95.19 91.7
30 94.97 93.3
45 96.68 94.0
60 97.22 93.8

Example 4:
Sr. No. Name of the Ingredient mg/tab (10mg)
Dry Mix
1. Dapagliflozin 10
2. Microcrystalline cellulose (Avicel PH 112) 114
3. Anhydrous lactose (Supertab 21 N) 50
4. Crospovidone XL 6
Solubilizer Solution
5. Poloxamer 188 20
6. Methylene dichloride (90%)
7. Isopropyl Alcohol (10%)
Pre Lubrication
8. Microcrystalline cellulose (Avicel PH 112) 24
9. Crospovidone XL 6
10. Colloidal silicon dioxide 5
Lubrication
11. Magnesium Stearate 4
Seal Coating
12. HPMC E-3 3
13. PEG 6000PF 0.5
14. Talc 1
15. Methylene dichloride
16. Isopropyl Alcohol
17. Opadry 85F520253 7.5
18. Purified Water

BRIEF MANUFACTURING PROCESS:
Manufacturing process for Dapagliflozin Tablet is similar to the one disclosed in Example 3, except the change of solubilizer i.e. Polysorbate 80 (Tween 80) has replaced with Poloxamer 188.

The dissolution testing conditions were same as Example 3.

In-vitro Dissolution profile of Example 4 in comparison to product available in market
Time points (Mins) Dissolution medium: Acetate Buffer (1000mL), pH 4.5, 60 rpm
Dapagliflozin Tablets 10 mg (Marketed Product) Test Product
0 0.00 0
5 68.99 33.4
10 93.85 92.3
15 94.79 95.4
20 95.19 95.8
30 94.97 96.1
45 96.68 96.4
60 97.22 96.8

Example 5:
Sr. No Name of the Ingredient mg/tab (10/1000mg)
Metformin Part
1. Metformin Hydrochloride 1000
2. Iron Oxide Yellow 1
Binder
3. Povidone K 30 50
4. Purified Water
Prelubrication
5. HPMC K 100 M Premium 75
6. HPMC K 200 M Premium CR 75
7. Microcrystalline Cellulose PH 102 16
8. Glyceryl dibehenate 10
Lubrication
9. Magnesium stearate 12
Dapagliflozin Part
10. Microcrystalline cellulose (Avicel PH 112) 123
11. Anhydrous lactose (supertab 21 N) 51
12. Crospovidone XL 6
Solubilizer Solution
13. Dapagliflozin 10
14. Polysorbate 80 5
15. Methylene dichloride
16. Isopropyl Alcohol
Pre Lubrication
17. Microcrystalline cellulose (Avicel PH 112) 31
18. Crospovidone XL 7
19. Colloidal silicon dioxide 5
Lubrication
20. Magnesium Stearate 4
Core Tablet
Seal Coating
21. HPMC E-3 21
22. PEG 6000PF 3
23. Talc 6
24. Methylene dichloride
25. Isopropyl Alcohol
26. Opadry 85F520254 30
27. Purified Water
Coated tablet

BRIEF MANUFACTURING PROCESS:
The tablet composition of example 5 was prepared according to the process given below,
A. Metformin Part:
1. Sift Metformin Hydrochloride through 20# sieve & Iron oxide yellow through 100#. Load in rapid mixer granulator.
2. Add Povidone K-30 to purified water under continuous stirring. Allow it to stir for 30 minutes.
3. Granulate the step 1 dry mix with step 2 binder solution followed by drying and sift the dried granules through 20# sieve.
4. Sift Hypromellose K 100 M Premium, Hypromellose K 200 M Premium CR, and Microcrystalline Cellulose PH 102 through 40# sieve, sift glyceryl dibehenate through 60# sieve and prelubricate with dried granules of step 5.
5. Sift Magnesium Stearate and lubricate with prelubricated blend of step 6.
B. Dapagliflozin Part:-
1. Process for the preparation of Dapagliflozin part is similar to the one disclosed in example 1.
C. Bilayer Compression:-
1. Compress above lubricated blend of Metformin part & Dapagliflozin part in bilayer compression machine using suitable punch set.
D. Seal Coating:-
1. Hydroxypropyl methyl cellulose E3 and other ingredients were dispersed in isopropyl alcohol and stirred for suitable time till clear solution obtained.
2. Use seal coating dispersion for coating, Coat tablets till required weight gain achieved.
E. Coating:-
1. Take required amount of purified water in SS. vessel to disperse Opadry 85F520253 under continuous stirring and coat tablets till required weight gain achieved.

The dissolution test for Dapagliflozin and Metformin HCl XR Tablet is performed in 1000 mL of dissolution medium at 37 °C., using USP Apparatus 1 (Basket- 20 mesh) method at a rotation speed of 100 rpm. For Dapagliflozin samples are removed after 5, 10, 15, 20, 30 and 45 minutes and for Metformin HCl samples are removed after 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours and Phosphate Buffer, pH 6.8 has been used as dissolution medium.

In-vitro Dissolution profile of Example 5 in comparison to product available in market
Dapagliflozin (Dissolution medium: Acetate Buffer (1000mL), pH 4.5, 60 rpm)
Time points (Hrs) Dapagliflozin & Metformin XR tablets 10mg/1000mg
(Marketed Product) Test Product
0 0 0
5 67 81
10 89
15 86 90
20 89 91
30 89 92
45 90 91
Metformin (Dissolution medium: Phosphate Buffer, pH 6.8 (1000mL), pH 4.5, 100 rpm)
Time points (Hrs) Dapagliflozin & Metformin XR tablets 10mg/1000mg
(Marketed Product) Test Product
0 0.0 0
0.5 17.5 23
1 29.0 37
2 44.6 57
3 56.2 77
4 65.7 80
6 78.9 93
8 87.18 99
10 91.42 101
12 92.09 102

Example 6:
Sr. No. Name of the Ingredient mg/tab (10/1000mg)
Metformin Part
1 Metformin Hydrochloride 1000
2 Iron Oxide Yellow 1
Granulating Solution
3 Povidone K 30 50
4 Purified Water
Prelubrication
5 HPMC K 100 M Premium 75
6 HPMC K 200 M Premium CR 75
7 Microcrystalline Cellulose PH 102 16
8 Glyceryl dibehenate 10
Lubrication
9 Magnesium stearate 12
Dapagliflozin Part
10 Dapagliflozin 10
11 Microcrystalline cellulose (Avicel PH 112) 157
12 Anhydrous lactose (supertab 21 N) 40
13 Crospovidone XL 10
Solubilizer Solution
14 Polysorbate 80 5
15 Methylene dichloride
16 Isopropyl Alcohol
Pre Lubrication
17 Crospovidone XL 10
18 Colloidal silicon dioxide 3
Lubrication
19 Magnesium Stearate 5
Core Tablet
Seal Coating
20 HPMC E-3 21
21 PEG 6000PF 3
22 Talc 6
23 Methylene dichloride
24 Isopropyl Alcohol
25 Opadry 85F520254 30
26 Purified Water
Coated tablet

BRIEF MANUFACTURING PROCESS:
Manufacturing process for Dapagliflozin and Metformin Extended Release Tablet is similar to the one disclosed in Example 5.
The dissolution conditions were same as mentioned in Example 5.

In-vitro Dissolution profile of Example 6 in comparison to product available in market
Dapagliflozin (Dissolution medium: Acetate Buffer (1000mL), pH 4.5, 60 rpm)
Time points (Mins) Dapagliflozin & Metformin XR tablets 10mg/1000mg
(Marketed Product) Test Product
0 0 0.0
5 67 82
10 0 83
15 86.6 82
20 89 82
30 89.8 84
45 90 84
Metformin (Dissolution medium: Phosphate Buffer, pH 6.8 (1000mL), pH 4.5, 100 rpm)
Time points (Hrs) Dapagliflozin & Metformin XR tablets 10mg/1000mg
(Marketed Product) Test Product
0 0.0 0.0
0.5 17 28
1 29 42
2 44 59
3 56 71
4 66 79
6 79 90
8 87 96
10 91 98
12 92 98

Example 7:
Sr. No. Name of the Ingredient mg/tab (10 mg)
Dry Mix
1. Dapagliflozin 10
2. Microcrystalline cellulose 152
3. Anhydrous lactose (supertab 21 N) 40
4. Sepitrap 80 10
5. Crospovidone XL 20
Pre Lubrication
6. Magnesium Stearate 2
Lubrication
7. Colloidal silicon dioxide 3
8. Magnesium Stearate 2
Core tablet
Seal Coating
9. HPMC E-3 3
10. PEG 6000PF 0.5
11. Talc 1
12. Methylene dichloride
13. Isopropyl Alcohol
14. Opadry 85F520253 7.5
15. Purified Water
Coated tablet

BRIEF MANUFACTURING PROCESS:
The tablet composition of example 7 was prepared according to the process given below,
A. Dapagliflozin Part:-

1. Sift API & excipients from 1 to 5 through 40# sieve and load blend in blender & dry mix for 10 minutes.
2. Pre Lubrication: Sift Magnesium stearate through suitable mesh and add to the above mix for 2 minutes and granulate the lubricated blend with Dry granulation method (slugging/compaction).
3. Mill the obtained slugs/compacts through suitable mesh and collect the granules.
4. Lubrication: Sift Colloidal Silicon Dioxide & Magnesium stearate through suitable mesh. Add this to the above collected granules and mix for 2 minutes.
5. Compress Lubricated blend using suitable punches.
B. Seal Coating:-
1. Hydroxypropyl methyl cellulose E3 and other ingredients were dispersed in isopropyl alcohol and stirred for suitable time till clear solution obtained.
2. Use seal coating dispersion for coating, Coat tablets till required weight gain achieved.
C. Coating:-
1. Take required amount of purified water in s.s. vessel to disperse Opadry 85F520253 under continuous stirring and coat tablets till required weight gain achieved.

Example 8:
Sr. No Name of the Ingredient mg/tab (10/1000mg)
Metformin Part
1. Metformin Hydrochloride 1000
2. Iron Oxide Yellow 1
Binder
3. Povidone K 30 50
4. Purified Water
Prelubrication
5. HPMC K 100 M Premium CR 75
6. HPMC K 200 M Premium CR 75
7. Microcrystalline Cellulose PH 102 16
8. Glyceryl behenate 10
Lubrication
9. Magnesium stearate 12
Dapagliflozin Part
10. Dapagliflozin 10
11. Microcrystalline cellulose (Avicel PH 112) 152
12. Anhydrous lactose 40
13. Sepitrap 80 10
14. Crospovidone XL 20
Pre Lubrication
15. Magnesium Stearate 2
Lubrication
16. Colloidal silicon dioxide 3
17. Magnesium Stearate 2
Core Tablet
Seal Coating
18. HPMC E-3 24
19. PEG 6000PF 6
20. Talc 5
21. Purified Water
22. Opadry 85F520254 47.00
23. Purified Water
Coated tablet

BRIEF MANUFACTURING PROCESS:
The tablet composition of example 8 was prepared according to the process given below,
A. Metformin Part:
1. Process for the preparation of Metformin part is similar to the one disclosed in Example 4.
B. Dapagliflozin Part:-
1. Process for the preparation of Dapagliflozin part is similar to the one disclosed in Example 4.
C. Bilayer Compression:-
1. Compress above lubricated blend of Metformin part & Dapagliflozin part in bilayer compression machine using suitable punch set.
D. Seal Coating:-
1. Hydroxypropyl methyl cellulose E3 and other ingredients were dispersed in isopropyl alcohol and stirred for suitable time till clear solution obtained.
2. Use seal coating dispersion for coating, Coat tablets till required weight gain achieved.
E. Coating:-
1. Take required amount of purified water in s.s. vessel to disperse Opadry 85F520254 under continuous stirring,
2. Coat tablets till required weight gain achieved.

Example 9:
Sr. No Name of the Ingredient mg/tab (10/1000mg)
Metformin Part
1. Metformin Hydrochloride 1000
2. Iron Oxide Yellow 1
Binder
3. Povidone K 30 50
4. Purified Water
Prelubrication
5. HPMC K 100 M Premium 75
6. HPMC K 200 M Premium CR 75
7. Microcrystalline Cellulose PH 102 16
8. Glyceryl dibehenate 10
Lubrication
9. Magnesium stearate 12
Dapagliflozin Part
10. Microcrystalline cellulose 112 124
11. Anhydrous lactose 50
12. Crospovidone XL 6
Solubilizer Solution
13. Dapagliflozin 10
14. Pullulan 10
15. Purified water
Pre Lubrication
16. Microcrystalline cellulose 24
17. Crospovidone XL 6
18. Colloidal silicon dioxide 5
Lubrication
19. Magnesium Stearate 4
Core Tablet
Seal Coating
20. HPMC E-3 20
21. PEG 6000PF 3
22. Talc 6
23. Methylene dichloride
24. Isopropyl Alcohol
25. Opadry 85F520254 30
26. Purified Water
Coated tablet

BRIEF MANUFACTURING PROCESS:
Manufacturing process for Dapagliflozin and Metformin Extended Release Tablet is similar to the one disclosed in Example 5.