Field of the Invention:
The present invention relates to an amorphous solid dispersion of (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1, represented by the following structural formula.
The invention also relates to process for the preparation of amorphous solid dispersion of (lS)-ls5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl] -D-glucitol and further its pharmaceutical compositions comprising therapeutically effective amount of the amorphous form and use of said composition for treatment of diabetes, obesity and diabetic complications, especially in type-2 diabetes.
Background of the Invention:
-(15)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol, also known as Canagliflozin, belongs to a novel therapeutic class of sodium-glucose co-transporter 2 inhibitors. US drug regulatory approval was received in march 2013 for canagliflozin (INVOKANA™) as an adjunct to diet and exercise to improve glycemic control in adults with type-2 diabetes mellitus.
US Patent No, 7,943,788 B2 first discloses canagliflozin or salts thereof and the process for its preparation.
US Patent Nos. 7,943,582 B2 (herein after referred as "582") and 8,513,202 B2 (herein after referred as "202") discloses crystalline form of canagliflozin hemihydrate and process for preparation thereof.
US Publication No. 2013/0237487 Al (herein after referred as US "487" Al) discloses

amorphous dapagliflozin and amorphous canagliflozin. The US "487" Al also discloses 1:1 crystalline complex of canagliflozin with L-proline (Form CS1), ethanol solvate of a 1:1 crystalline complex of canagliflozin with D-proline (Form CS2), 1:1 crystalline complex of canagliflozin with L-phenylalanine (Form CS3), 1:1 crystalline complex of canagliflozin with D-proline (Form CS4).
The US "487" Al further discloses that amorphous canagliflozin obtained by the above process is hygroscopic in nature which was confirmed by Dynamic vapor sorption (DVS) analysis. Further, it was observed that the amorphous form underwent a physical change between the sorption/desorption cycle, making the sorption/desorption behavior different between the two cycles. The physical change that occurred was determined to be a conversion or partial conversion from the amorphous state to a crystalline state. This change was supported by a change in the overall appearance of the sample as the humidity increased from 70% to 90% RH.
The canagliflozin assessment report EMA/718531/2013 published by EMEA discloses that canagliflozin hemihydrate is a white to off-white powder practically insoluble in water and freely soluble in ethanol and non-hygroscopic. Polymorphism has been observed for canagliflozin and the manufactured Form I is a hemihydrate, and an unstable amorphous Form II. Form I is consistently produced by the proposed commercial synthesis process.
Therefore, it is evident from the prior art that the reported amorphous form of canagliflozin is unstable and hygroscopic as well as not suitable for pharmaceutical preparations due to higher amount of residual solvents above the ICH acceptable limits.
Hence, there is a need to provide a stable amorphous form of canagliflozin which is suitable for pharmaceutical preparations.
In general, for commercial use it is important that a product should have good handling qualities. Additionally, there is a need to produce the product which enable formulations to meet exacting pharmaceutical requirements and specifications.
And it is desirable that the product should be in a form that is readily filterable and easily dried. Additionally, it is economically desirable that the product be stable for extended periods of time without the need for specialized storage conditions.

In view of the above, it is therefore, desirable to provide stable canagliflozin amorphous form as well as an efficient, economical and eco-friendly process for the preparation of highly pure canagliflozin amorphous form.
Brief description of the Invention:
The first aspect of the present invention is to provide amorphous solid dispersion of (15)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1 with one or more pharmaceutical acceptable carrier.
The second aspect of the present invention is to provide a process for the preparation of amorphous solid dispersion of (15)-l,5-aimydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl] methyl]-4-methylphenyl]-D-glucitol compound of formula-1 in combination with one or more pharmaceutical acceptable carrier.
Brief description of Drawings:
Figure 1: Illustrates the PXRD pattern of amorphous solid dispersion of (lS)-l,5-anhydro-l-
[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-
1.
Detailed description of the Invention:
The present invention provides amorphous solid dispersion of (15)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1 and process for its preparation thereof.
. As used herein the term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, pentane, cycloheptane, methylcyclohexane, ethylbenzene, m-, o-, or p-xylene, octane, indane, nonane, or naphthalene and the like; "ether solvents" such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; "polar-aprotic solvents such as

dimethylacetamide (DMA), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutylketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanoI, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, 1, 2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; "polar solvents" such as water or mixtures thereof.
As used herein the term suitable "pharmaceutical acceptable carrier" is preferably a polymeric carrier, and more preferably is at least one from the group consisting of starches, modified starches, cellulose, methyl cellulose (MC), ethyl cellulose (EC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), polycarbophil, polyethylene glycol (PEG), polyethylene oxides, polyoxyalkylene derivatives, polymethacrylates, polyvinyl pyrrolidone (PVP), polyvinyl acetate (PVAc), PVP-vinylacetate-copolymer (PVP-VA), Kollidon® VA 64 (a vinylpyrrolidone -vinyl acetate copolymer), lactose, sorbitol, mannitol, maltitol, saccharose, isomalt, cyclodextrins such as cc-cyclodextrins, p-cyclodextrins, y-cyclodextrins, hydroxyl-propyl-cyclodextrins, hydroxypropyl-cyclodextrin (HppOii), sodium carboxymethyl cellulose cross -linked poly-acrylic acid (carbipol), or a mixture thereof.
The first aspect of the present invention provides amorphous solid dispersion of (15)-l,5-arihydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1 in combination with one or more pharmaceutical acceptable carrier.
Further, the preferred embodiment of the present invention relates to amorphous solid dispersion of (liS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl] * -D-glucitol compound of formula-1 as depicted in figure-1.
The second aspect of the present invention provides a process for the preparation of amorphous solid dispersion of (15)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyI phenyl]-D-glucitol compound of formula-1 in combination with one or more

pharmaceutical acceptable carrier; comprising of the following steps:
a) Adding a suitable solvent to (lS)-l,5-armydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl] methyl]-4-methylphenylJ-D-glucitol,
b) heating the reaction mixture to a suitable temperature,
c) adding a suitable solvent and pharmaceutical acceptable carrier to the reaction mixture,
d) stirring the reaction mixture,
e) isolating amorphous solid dispersion of (15)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1.
Wherein,
in step-a) and (c) the suitable solvent is selected from alcohol solvents, chloro solvents,
ester solvents, polar aprotic solvents, ketone solvents, hydrocarbon solvents and polar
solvent like water or mixture thereof;
in step-b) the suitable temperature is ranging from ambient temperature to reflux
temperature of the solvent used in the reaction;
in step-c) the suitable pharmaceutical acceptable carrier is selected from as defined
above.
In the present invention, the composition of the solid dispersion containing of a mole ratio of the amount of the canagliflozin compound of formula-1 to the amount of the pharmaceutical acceptable carrier is ranging from about 1:0.5 to 1:10 by weight.
The preferred embodiment of the present invention provides a process for the preparation of amorphous solid dispersion of (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1 in combination with HPC; comprising of the following steps:
a) Adding methanol to (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl phenyl]-D-glucitol,
b) heating the reaction mixture to 40-45°C,
c) adding methanol and hydroxypropyl cellulose (HPC) to the reaction mixture,
d) stirring the reaction mixture,
e) isolating amorphous solid dispersion of (15)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyI]-4-methyIphenyI]-D-glucitol compound of formula-1 in combination with

HPC.
Another, preferred embodiment of the present invention provides a process for the preparation of amorphous solid dispersion of (15)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl] methyl]-4-methylphenyl]-D-glucitol compound of formula-1 in combination with HPC; comprising of the following steps:
a) Adding dichloromethane to (1 S)-l ,5-anhydro-1 -[3-[[5-(4-fluorophenyl)-2-thienyl] methyl]-4-methyl phenyl]-D-glucitol,
b) heating the reaction mixture to 40-45°C,
c) adding dichlormethane and hydroxypropyl cellulose (HPC) to the reaction mixture,
' d) stirring the reaction mixture,
e) isolating amorphous solid dispersion of (15)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl] methyl]-4-methylphenyl]-D-glucitol compound of formula-1 in combination with HPC.
The amorphous solid dispersion of (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl] methyl]-4-methylphenyl]-D-glucitol obtained according to the present invention can be isolated using a rotational distillation device such as a Buchi Rotavapor, vacuum drying, spray drying, spray granulating, freeze drying and spray-freeze drying, agitated thin film drying (ATFD) or melt extrusion or freeze drying (lyophilization) or by any other suitable techniques.
The amorphous solid dispersion of (l£)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl phenyl]-D-glucitol obtained according to the present invention can be prepared from the crystalline (or) amorphous forms of (l5)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol known in the art.
Preferred solid dispersions are "solid solutions", where the dispersion of the components is such that the system is chemically and physically uniform or homogeneous throughout or even consists of one phase as defined by measurement of thermodynamic properties of the system, e.g. the amorphous canagliflozin and the water soluble excipients form a system that is chemically and physically uniform or homogeneous throughout or even consists of one phase as defined by measurement of thermodynamic properties of the system.
The invention also encompasses pharmaceutical compositions comprising the

amorphous solid dispersion of (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol of the invention. As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
Pharmaceutical compositions containing the amorphous solid dispersion of (15)-1,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol of the invention may be prepared by using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, coloring agents, flavoring agents, stabilizers, lubricants/glidants, plasticizers and surface active agents. Various modes of administration of the pharmaceutical compositions of the invention can be selected depending on the therapeutic purpose, for example tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
The amorphous solid dispersion of canagliflozin compound of formula-1 of the present invention may optionally be micronized to obtain the micronized amorphous solid dispersion of canagliflozin by the conventional methods known in the art.
P-XRD Method of Analysis:
PXRD analysis of compounds produced by the present invention were carried out using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention. Examples:
Example-1: Preparation of (15)-l,5-anhydro-l-(3-([5-(4-fluorophenyl)-2-thienyl) methyl]-4-methyl phenyl]-D-gIucitol in combination with HPC (Formula-1) Methanol (2.5 ml) was added to (15}-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl] methyl]-4-methylphenyl]-D-glucitol (5 gms) at 25-30°C and stirred for 15 minutes at the same temperature. Heated the reaction mixture to 40-45°C. Slowly added HPC {hydroxypropyl cellulose (5 gms) in methanol (2.5 ml)} solution to the reaction mixture at 40-45°C and stirred for 10 minutes at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure to provide the title compound. Yield: 2.5 gms.
The P-XRD pattern of the obtained compound was depicted in figure-1. Examplc-2: Preparation of (15)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl] methyl|-4-methyl phenyl]-D-glucitol in combination with HPC (Formula-1) Dichloromethane (30 ml) was added to (15)-l)5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol (250 gms) at 25-30°C and stirred for 15 minutes at the same temperature. Heated the reaction mixture to 40-45°C. Slowly added HPC (250 gms) was added to dichloromethane (30 ml)} solution to the reaction mixture at 40-45°C and stirred for 10 minutes at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure to provide the title compound. Yield: 100 gms. The P-XRD pattern of the obtained compound was depicted in figure-1.

We Claim:
1. Amorphous solid dispersion of (lS)-l55-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl] methyl]-4-methylphenyl]-D-glucitol with hydroxypropyl cellulose (HPC).
2. The solid dispersion of claim 1, having a powder X-ray diffractogram as shown in figure-1.
3. The composition of solid dispersion of claim 1, containing of a mole ratio of the amount ofthe(lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1 to the amount of the pharmaceutical acceptable carrier is ranging from 1:0.5 to 1:10 by weight.
4. The process for the preparation of amorphous solid dispersion of (15)-ls5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol compound of formula-1, the process comprising mixing of compound of formula-1 with pharmaceutical acceptable carrier in one or more organic solvent and obtaining the amorphous solid dispresion of (15)-l,5-anhydro-l-[3-[[5-(4-iluorophenyl)-2-thienyl] methyl]-4-methyl phenyl]-D-glucitol by the removal of the solvent.
5. The process according to claim-4, wherein, the suitable pharmaceutical acceptable carrier is selected from starches, modified starches, cellulose, methyl cellulose (MC), ethyl cellulose (EC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), polycarbophil, polyethylene glycol (PEG), polyethylene oxides, polyoxyalkylene
■ derivatives, polymethacrylates, polyvinyl acetate (PVAc), PVP-vinylacetate-copolymer (PVP-VA), Kollidon® VA 64 (a vinylpyrrolidone -vinyl acetate co-polymer), lactose, sorbitol, mannitol, maltitol, saccharose, isomalt, cyclodextrins such as cc-cyclodextrins, p-cyclodextrins, y-cyclodextrins, hydroxyl-propyl-cyclodextrins, hydroxypropyl-cyclodextrin (HppOu), sodium carboxymethyl cellulose cross -linked polyacrylic acid (carbipol), or a mixture thereof.
6. A process for the preparation of amorphous solid dispersion of (lS)-l,5-anhydro-l-[3-[[5-
(4-fluorophenyl)-2-thienyi]methyl]-4-methylphenyl]-D-glucitol compound of formula-1,

the process comprising mixing of compound of formula-1 with HPC in one or more organic solvent and obtaining the amorphous solid dispresion of (liS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl phenyl]-D-glucitol by the removal of the solvent.
7. The process according to claim-4 and 6, wherein, the suitable organic solvent is selected from alcohol solvents, chloro solvents, ester solvents, polar aprotic solvents, ketone solvents, hydrocarbon solvents and polar solvent like water or mixture thereof.
8. The process as claimed in claim-4 and 6, wherein removing the solvent comprises of rotational distillation, distillation under vacuum, spray drying, spray granulating, freeze drying and spray-freeze drying, agitated thin film drying or melt extrusion or freeze drying (iyophilization).
9. Amorpous solid dispersion of (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl] methyl]-4-methylphenyl]-D-glucitol compound of formula-1, according to any one of the preceding claims is free from crystalline forms and residual solvents.
10. Amorphous solid dispersion of (lS)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl] methyl]-4-methylphenyl]-D-glucitol compound of formula-1, according to any one of the preceding claims is useful in the preparation of pharmaceutical formulations thereof.