DESC:FIELD OF THE INVENTION

The present invention relates to process for the preparation of amorphous Canagliflozin substantially free of hydroperoxide impurity.

BACKGROUND OF THE INVENTION

Canagliflozin is chemically described as 1-([p-D-glucopyranosyl)-4-methyl-3-[5-(4- fluoro phenyl)-2-thienylmethyl]benzene, which is a sodium glucose co-transporter 2 (SGLT2) inhibitor used for the treatment of type-2 diabetes mellitus. It has the chemical structure:

U.S. Patent No. 7,943,788 discloses Canagliflozin, its pharmaceutically acceptable salts and process for its preparation. U.S. Patent No. 7,943,582 discloses crystalline form of Canagliflozin hemihydrate and process for its preparation.

Various processes for the preparation of Canagliflozin, its polymorphs and intermediates, have been reported in the patent publications US20090233874, US20100099883, US8772512, US20110087017, US20130052266, WO2012140120, WO2012154812, WO2013068850, WO2013064909, CN103896930A and WO2014195966A2.

PCT Publication No. 2017093949 (“The WO ‘949 publication”) disclosed substantially pure canagliflozin, which is substantially free of hydroperoxide impurity of formula I (“hydroperoxide impurity”).

Further, provided process for the preparation of crystalline canagliflozin, which is substantially free of hydroperoxide impurity by treating canagliflozin in dichloromethane solution, which is obtained from the previous step, with either butylated hydroxytoluene (hereinafter “BHT”) or butylated hydroxyanisole (hereinafter “BHA”). This process further involves treatment with solvents such as dichloromethane, methyl tert-butyl ether and water multiple times, maintaining for 5-7 hrs at each treatment and seeding with canagliflozin to give crude canagliflozin. The resulting crude compound is finally treated with BHT or BHA in a mixture of isopropyl acetate, dichloromethane and water in the presence of canagliflozin seed to get crystalline canagliflozin.

However, this publication suffers from several drawbacks such as use of about 0.2 to about 0.3 molar equivalents of BHT or BHA, treatment with multiple solvents and maintaining for 5-7 hrs at each treatment. This publication moreover failed to provide the content of the hydroperoxide impurity in the final crystalline canagliflozin using the process of the invention.

IN Publication No. 201741045226 (“The IN ‘5226 publication”)disclosed canagliflozin, which is substantially free of hydroperoxide impurity and its preparation. The process involves breaking the canagliflozin DL-proline co-crystal with aq. sodium carbonate in DM water and recovering canagliflozin as a residue. The product is crystallized from the residue in methyl tert-butyl ether and cyclohexane in presence of an antioxidant to provide canagliflozin having hydroperoxide content of about 0.27 ppm. However, even the disclosed process yields canagliflozin with lesser content of hydroperoxide impurity but consistency in getting the same result may not be expected as the process involves one step treatment with antioxidant and this has possibility to increase the peroxide impurity content from the additional solvents utilized in the process.

In general, amorphous compounds are more difficult to purify compared to crystalline compounds. Amorphous solids tend to recrystallize during manufacturing or storageand have a higher degradation rate than the crystalline state. They have greater molecular mobility and lack crystal lattice stabilization energy, and as a result, oxygen permeability will be higher. The decrease in the physical and chemical stability, relative to their crystalline form, poses major challenges in their use. It has been found that amorphous canagliflozin generates more impurities, especially oxidative impurities, when compared with the crystalline canagliflozin, making the preparation of amorphous canagliflozin in a commercial scale is very difficult.

In view of this, it would be desirable to produce stable amorphous canagliflozin with substantially free of hydroperoxide impurity consistently. The inventors of the present invention have found and implemented certain of the process parameters that enables the effective control or removal of the hydroperoxide impurity from the amorphous canagliflozin with reproducible manner.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides effective control or removal of hydroperoxide impurity during the preparation of amorphous canagliflozin.

In accordance with one embodiment, the present invention provides amorphous canagliflozin substantially free of hydroperoxide impurity and process for its preparation and pharmaceutical compositions containing the same.

In accordance with another embodiment, the present invention provides amorphous canagliflozin having less than 50 ppm of hydroperoxide impurity by LC-MS.

In accordance with another embodiment, the present invention provides amorphous canagliflozin having less than 0.1% of antioxidants by HPLC.
In accordance with another embodiment, the present invention provides amorphous canagliflozin having less than 50 ppm of hydroperoxide impurity by LC-MS and less than 0.1% of antioxidants by HPLC.

In accordance with another embodiment, the present invention provides a process for the preparation of amorphous canagliflozin having less than 50 ppm of hydroperoxide impurity by LC-MS and less than 0.1% of antioxidants by HPLC, comprising:
a) treating an organic solvent S2 under nitrogen atmosphere with an antioxidant to obtain a solution,
b) dissolving canagliflozin in to the solution of step a) under nitrogen atmosphere,
c) adding the step b) reaction mass into an anti-solvent or vice versa, which is pre-treated with an antioxidant under nitrogen atmosphere; and
d) isolating the amorphous canagliflozin.

In accordance with another embodiment, the present invention provides a process for the preparation of amorphous canagliflozin having less than 50 ppm of hydroperoxide impurity by LC-MS and less than 0.1% of antioxidants by HPLC, comprising:
a) treating canagliflozin co-crystals in water with a base to obtain canagliflozin,
b) treating an organic solvent S1 under nitrogen atmosphere with an antioxidant to obtain a solution,
c) dissolving the canagliflozin of step a) in to the solution of step b),
d) removing the organic solvent S1 from step c) to get a residue,
e) treating an organic solvent S2 under nitrogen atmosphere with an antioxidant to obtain a solution,
f) dissolving the residue of step d) in to the solution of step e) under nitrogen atmosphere,
g) adding the step f) reaction mass into an anti-solvent or vice versa, which is pre-treated with an antioxidant under nitrogen atmosphere; and
h) isolating the amorphous canagliflozin.

In accordance with another embodiment, the present invention provides a pharmaceutical composition comprising amorphous canagliflozin having less than 50 ppm of hydroperoxide impurity by LC-MS.

In accordance with another embodiment, the present invention provides a pharmaceutical composition comprising amorphous canagliflozin having about0.1% of antioxidant by HPLC.

In accordance with another embodiment, the present invention provides a pharmaceutical composition comprising amorphous canagliflozin having less than 50 ppm of hydroperoxide impurity by LC-MS and having about 0.1% of antioxidant by HPLC.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “substantially free of hydroperoxide impurity” refers to amorphous canagliflozin prepared in accordance with the present invention containing less than 500 ppm, more preferably less than 50 ppm, and even more preferably less than 10 ppm of the corresponding hydroperoxide impurity as characterized by LCMS.

The present invention provides amorphous canagliflozin substantially free of hydroperoxide impurity, process for its preparation and pharmaceutical compositions containing the same.

To date the reported processes involves preparation of canagliflozin particularly its crystalline form having lower levels of its hydroperoxide impurity using antioxidants. However, the present inventors have came to know that using antioxidant alone will not suffice to control the hydroperoxide impurity to pharmaceutically acceptable levels as defined by the regulatory authorities. This may be due to cross contamination of the peroxides during the process from the solvents utilized in each step of the process as hydroperoxides may be present in many commercially available organic solvents and water and these can promote further oxidative degradation of canagliflozin. In order to overcome this drawback inventors of the present invention have found and suggested that solvent utilized in each stage of the synthesis may be pretreated with an antioxidant in presence of nitrogen atmosphere preferably nitrogen purging as well as treatment with antioxidant prior to reaction with canagliflozin is necessary.

Further, inventors of the present invention have observed that product obtained from the reported literatures having contamination with antioxidants, which may be due to the use of excess antioxidant to reduce the content of hydroperoxide impurity but this step creates additional burden to the process. The use of both nitrogen purging step and antioxidant not only reduces the overall quantity of antioxidant as required and also significantly avoids cross contamination of the antioxidant to the final product.

Further, the process reported in the art was restricted to the preparation of crystalline canagliflozin and was inefficient in the removal of hydroperoxide impurity and the same process may not be applicable to amorphous canagliflozin. Generally amorphous compounds are more difficult to purify compared to crystalline counterparts. They have greater molecular mobility and lack crystal lattice stabilization energy, and as a result, oxygen permeability will be higher. The decrease in the physical and chemical stability, relative to their crystalline form, poses major challenges in their use. It has been found that amorphous canagliflozin generates more impurities, especially oxidative impurities, when compared with the crystalline canagliflozin, making the preparation of amorphous canagliflozin in a commercial scale very difficult.

To date many known processes involves preparation of amorphous form of canagliflozin by at least one of the step is concentrated by evaporation or distillation. The risk associated with peroxide formation increases if the peroxide crystallizes or becomes concentrated by evaporation or distillation.

The inventors have tried to reproduce the ‘5226 process but failed to get consistent results and was sometimes contaminated with the hydroperoxide impurity and the antioxidant used. The reason attributable for this may be that the process involves treatment with antioxidant only once and the peroxide contamination is possible from other solvents used in the later processes.

Moreover, the prior art processes presented substantial difficulties in producing amorphous canagliflozin substantially free of hydroperoxide impurity. The reported process involved use of higher amounts of antioxidants which leads to contamination of the product by antioxidants which usually remains, unless a thorough repeated crystallization from organic solvents is done, which is not only unacceptable for stability of the compound but also for economy of the process.

The present inventors had recognized that changes in manufacturing parameters might lead to decrease in the hydroperoxide impurity from amorphous canagliflozin. Hence, the present invention relates to a process for the preparation of amorphous canagliflozin which overcomes all the drawbacks associated with the prior art processes. The current process is not only advantageous in producing amorphous canagliflozin substantially free of the hydroperoxide impurity but also minimises the antioxidant contamination in a consistent manner which is very practical at large scale production.

Therefore, the present invention provides amorphous canagliflozin substantially free of hydroperoxide impurity and having acceptable limits of antioxidant, process for its preparation and pharmaceutical compositions containing the same.

In accordance with one embodiment, the present invention provides a process for the preparation of amorphous canagliflozin having less than 50 ppm of hydroperoxide impurity by LC-MS and less than 0.1% of antioxidants by HPLC, comprising:
a) treating an organic solvent S2 under nitrogen atmosphere with an antioxidant to obtain a solution,
b) dissolving canagliflozin in to the solution of step a) under nitrogen atmosphere,
c) adding the step b) reaction mass into an anti-solvent or vice versa, which is pre-treated with an antioxidant under nitrogen atmosphere; and
d) isolating the amorphous canagliflozin.

Step a) of the foregoing process involves first purging the organic solvent S2 with nitrogen gas to prevent any oxygen enrichment and subsequently treating with an antioxidant at a temperature of about 10°C to about 60°C, preferably at 20°C to about 50°C,for about 5 minutes to about 30 minutes. However, it is utmost important that the organic solvent S2 has to be purged with nitrogen gas first and then treated with antioxidant prior to the addition of canagliflozin.

Examples of organic solvent S2 used herein for step (a) include but are not limited to alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol and the like; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; esters such as ethyl acetate, isopropyl acetate, isobutyl acetate and the like; ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 1,4-dioxane and the like; aliphatic hydrocarbons such as hexane, heptane, pentane and the like; aromatic hydrocarbons such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, chloroform and the like; nitriles such as acetonitrile, propionitrile, benzonitrile and the like and mixtures thereof; preferably methyl tert-butyl ether.

Examples of antioxidants include but are not limited to ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxyalanine (BHA), sodium metabisulfite, propyl gallate, cysteine, tert-butyl hydroquinone, triphenyl phosphine, tocopherol, ascorbic acid, sodium ascorbate, calcium ascorbate, ascorbylpalmitate, thioglycerol, thioglycolic acid, lipoic acid, uric acid, carotenes, glutathione, melatonin, erythorbic acid, sodium erythorbate, 4-hexylresorcinol, polyphenols,Resveratrol, pterostilbene, curcumin, cinnamic acid, p-coumaric acid, ferulic acid, Sinapic acid, caffeic acid, chlorogenic acid, p-hydroxybenzoic acid, vanillic acid, syringic acid, protocatechuic acid, quinic acid, 4-(4-phenoxybenzoyl)benzoic acid or any other suitable antioxidant and mixtures thereof; preferably butylated hydroxytoluene or butylated hydroxyalanine.

The molar ratio of the antioxidant used in the total process of the present invention preferably ranges from about 0.001 to about 0.1 moles to starting canagliflozin, more preferably ranges from about 0.01 to about 0.05 moles.

Step b) of the foregoing process includes dissolving any form of canagliflozin in the solution of step a). Typically canagliflozin can be stirred in the solution of step a) at a suitable temperature such as 25°C to reflux temperature of the solvent. Preferably, the reaction temperature is about 30°C to about 60°C and stirred for a period of time from about 5 minutes to until completion dissolution, preferably 10 to 50 minutes. After complete dissolution of canagliflozin, the resultant solution may be cooled to 20°C to 50°C.

The starting canagliflozin used in the present invention is known in the art and can be prepared by any known method, for example starting canagliflozinmay be synthesized as disclosed in U.S. Patent Nos.7,943,788 and U.S. Patent No. 7,943,582 which are incorporated herein by reference.

Step c) of the foregoing process involves adding the step b) reaction mass into an anti-solvent or vice versa, which is pre-treated with an antioxidant under nitrogen atmosphere. In detail treating an anti-solvent with an antioxidant, but prior to the addition of antioxidant it is necessary to purge nitrogen gas in to the anti-solvent. The anti-solvent used for step c) includes but are not limited to hydrocarbon solvents such as n-pentane, n-hexane, n-heptane, cyclohexane, methyl cyclohexane, cycloheptane or mixture thereof; preferably cyclohexane. Typically, the antioxidant is added to the anti-solvent and stirred at a temperature of about 10°C to about 60°C, preferably at 20°C to about 50°C, for about 5 minutes to about 30 minutes. After dissolution of antioxidant in anti-solvent, the resultant solution may be cooled to 10°C to 40°C; preferably to 15°C to 30°C.

Thereafter, the step b) solution containing canagliflozin is added to the anti-solvent solution of step c) or adding an anti-solvent solution of step c) to the solution obtained in step b) to effect the precipitation of the product. The resultant reaction mass may be stirred for a period of about 5 minutes to about 50 minutes at a temperature of about 10°C to about 50°C; preferably 15°C to about 30°C.

The step of isolation of the resultant amorphous canagliflozin can be carried out by conventional technique known in the art, for example by filtration. The resultant wet product may be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like.

The process reported in the art was inefficient in the removal of hydroperoxide impurity consistently and particularly the process was not guided for the preparation of amorphous form of canagliflozin. Further, the reported process has certain disadvantages such as carrying out multiple treatments with solvents for 5-7 hrs at each treatment. Moreover, they involved treatment of canagliflozin already dissolved in a solvent with antioxidant which led to ineffective removal of the hydroperoxide impurity and presence of the antioxidant in the final product which required additional purifications not economical on large scale.

The present inventors have observed that purging of nitrogen gas and treatment with antioxidant to the solvents used in the process of the present invention prior to the introduction of canagliflozin effectively minimized the hydroperoxide impurity to less than 50 ppm by LC-MS. Moreover, the antioxidant contamination was also limited to less than about 0.1% by HPLC.

In accordance with another embodiment, the present invention provides a process for the preparation of amorphous canagliflozin having less than 50 ppm of hydroperoxide impurity by LC-MS and less than 0.1% of antioxidants by HPLC, comprising:
a) treating canagliflozin co-crystals in water with a base to obtain canagliflozin,
b) treating an organic solvent S1 under nitrogen atmosphere with an antioxidant to obtain a solution,
c) dissolving the canagliflozin of step a) in to the solution of step b),
d) removing the organic solvent S1 from step c) to get a residue,
e) treating an organic solvent S2 under nitrogen atmosphere with an antioxidant to obtain a solution,
f) dissolving the residue of step d) in to the solution of step e) under nitrogen atmosphere,
g) adding the step f) reaction mass into an anti-solvent or vice versa, which is pre-treated with an antioxidant under nitrogen atmosphere; and
h) isolating the amorphous canagliflozin.

The starting co-crystals of canagliflozin is used in the present invention are known in the art and can be prepared by any known method, for example starting co-crystals of canagliflozin may be synthesized as disclosed in U.S. Patent Nos. 8,999,941 and9,035,044, which are incorporated herein by reference. Alternatively, the co-crystals of canagliflozin disclosed in PCT Publication No. WO2017046730 may be used. For example, a co-crystal formed between canagliflozin and aco-crystal former selected from the group comprising DL-pipecolic acid, D-pipecolic acid, L-pipecolic acid and the like; preferably the co-crystal former is DL-pipecolic acid.
Step a) of the foregoing process involves treating canagliflozin co-crystals in water with a base to obtain canagliflozin. Typically the process involves treating Canagliflozin co-crystals particularly DL-pipecolic acid co-crystal in one or more solvents with a suitable base at a temperature of about 20°C to about reflux temperature of the solvent; preferably at 25°C to about 30°C.
Examples of one or more solvents used herein includes but are not limited to alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol and the like; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; esters such as ethyl acetate, isopropyl acetate, isobutyl acetate and the like; ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; aliphatic hydrocarbons such as hexane, heptane, pentane and the like; aromatic hydrocarbons such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, chloroform and the like; nitriles such as acetonitrile, propionitrile, benzonitrile and the like, water and mixtures thereof; preferably water.
Suitable base is either inorganic or organic base. The inorganic base used herein is selected from the group comprising of alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; alkali metal hydride such as sodium hydride, potassium hydride and the like. The organic base used herein is selected from the group comprising of primary amine, secondary amines and tertiary amines such as ammonia, di-isopropyl ethylamine, triethyl amine and the like; heterocyclic amines such as pyridine and the like; preferably the base is ammonia.
Isolation of canagliflozin may be carried out by known methods, for example filtration and the resultant canagliflozin may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like.
Step b) of the foregoing process involves first purging nitrogen gas in to an organic solvent S1 for a sufficient period of time to prevent any oxygen enrichment and subsequently treated with an antioxidant at a temperature of about 10°C to about 60°C, preferably at 20°C to about 50°C, for about 5 minutes to about 30 minutes to remove any peroxides from the organic solvent S1. However, it is utmost important that the organic solvent S1 has to be purged with nitrogen gas first and then treated with antioxidant prior to the addition of canagliflozin.

Examples of organic solvent S1 used herein for step (b) include but are not limited toalcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol and the like; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; esters such as ethyl acetate, isopropyl acetate, isobutyl acetate and the like; ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 1,4-dioxane and the like; aliphatichydrocarbons such as hexane, heptane, pentane and the like; aromatic hydrocarbons such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, chloroform and the like; nitriles such as acetonitrile, propionitrile, benzonitrile, water and the like and mixtures thereof; preferably dichloromethane.

Examples of antioxidants include ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxyalanine (BHA), sodium metabisulfite, propyl gallate, cysteine, tert-butyl hydroquinone, triphenyl phosphine, tocopherol, ascorbic acid, sodium ascorbate, calcium ascorbate, ascorbylpalmitate, thioglycerol, thioglycolic acid, lipoic acid, uric acid, carotenes, glutathione, melatonin, erythorbic acid, sodium erythorbate, 4-hexylresorcinol, polyphenols, Resveratrol, pterostilbene, curcumin, cinnamic acid, p-coumaric acid, ferulic acid, Sinapic acid, caffeic acid, chlorogenic acid, p-hydroxybenzoic acid, vanillic acid, syringic acid, protocatechuic acid, quinic acid, 4-(4-phenoxybenzoyl)benzoic acid or any other suitable antioxidant; preferably butylated hydroxytoluene or butylated hydroxyalanine.

The molar ratio of the antioxidant used in the total process of the present invention preferably ranges from about 0.001 to about 0.1 moles, more preferably ranges from about 0.01 to about 0.05 moles.

Step c) of the foregoing process involves dissolving canagliflozin obtained in step a) in the organic solvent S1 of step b) and stirring for a period of about 5 minutes to about 2 hrs at a temperature of about 10°C to about 60°C; preferably 20°C to about 50°Cto yield a solution containing canagliflozin.
The resultant solution is diluted with water, pH may be adjusted to about 4 to 7.5 with an acid such as hydrochloric acid and the like and the product containing organic layer may be separated and concentrated to form a residue containing canagliflozin.
Step e) of the foregoing process involves purging nitrogen gas in to an organic solvent S2 for a sufficient period of time to prevent any oxygen enrichment. The resulting oxygen free organic solvent S2 is treated with an antioxidant to remove any peroxides from the organic solvent S2 at a temperature from about 10°C to about 50°C, preferably at 20°C to about 45°C, and stirred for a period of about 5 minutes to about 30 minutes. Examples of one or more organic solvents S2 and the antioxidants used in step e) are defined just as above.
Step f) of the foregoing process includes dissolving the residue form of canagliflozin in the solution of step e). Typically the residue can be stirred in the solution of step e) at a suitable temperature such as 25°C to reflux temperature of the solvent to completely forming the clear solution. Preferably, the reaction temperature is about 30°C to about 60°C and stirred for a period of time from about 5 minutes to until completion dissolution, preferably 10 to 50 minutes. After complete dissolution of canagliflozin, the resultant solution may be cooled to 20°C to 50°C.

Step g) of the foregoing process involves adding the step f) reaction mass into an anti-solvent or vice versa, which is pre-treated with an antioxidant under nitrogen atmosphere. In detail treating an anti-solvent with an antioxidant, but prior to the addition of antioxidant it is necessary to purge nitrogen gas in to the anti-solvent. The anti-solvent used for step g) includes but are not limited to hydrocarbon solvents such as n-pentane, n-hexane, n-heptane, cyclohexane, methyl cyclohexane, cycloheptane or mixture thereof; preferably cyclohexane. Typically, the antioxidant is added to the anti-solvent and stirred at a temperature of about 10°C to about 60°C, preferably at 20°C to about 50°C, for about 5 minutes to about 30 minutes. After dissolution of antioxidant in anti-solvent, the resultant solution may be cooled to 10°C to 40°C; preferably to 15°C to 30°C.

Thereafter, the step f) solution containing canagliflozin is added to the anti-solvent solution of step g) or adding an anti-solvent solution of step g) to the solution obtained in step f) to effect the precipitation of the product. The resultant reaction mass may be stirred for a period of about 5 minutes to about 50 minutes at a temperature of about 10°C to about 50°C; preferably 15°C to about 30°C.

The step of isolation of the resultant amorphous canagliflozin can be carried out by conventional technique known in the art, for example by filtration. The resultant wet product may be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like.

The invention, therefore, aims to provide an improved process for making amorphous canagliflozin substantially free of hydroperoxide impurity. In accordance with the present invention, it is found that the addition of a relatively small quantity of an antioxidant during preparation of amorphous canagliflozin not only renders the amorphous canagliflozin stable against hydroperoxide impurity, but also limits the antioxidant contamination.

Further, in addition to the presence of the antioxidant throughout the preparation of amorphous canagliflozin, it is preferred to purge nitrogen gas to prevent oxygen enrichment before and during the entire process which leads to the final product, i.e., amorphous canagliflozin substantially free of hydroperoxide impurity. Hence, the process of the present invention provides amorphous canagliflozin having less than 50 ppm of hydroperoxide impurity by LC-MS and less than about 0.1% of antioxidants by HPLC.

In accordance with another embodiment, the present invention provides amorphous canagliflozin having less than 50 ppm of hydroperoxide impurity by LC-MS.

In accordance with another embodiment, the present invention provides amorphous canagliflozin having less than 0.1% of antioxidants by HPLC.

In accordance with another embodiment, the present invention provides amorphous canagliflozin having less than 50 ppm of hydroperoxide impurity by LC-MS and less than 0.1% of antioxidants by HPLC.

In accordance with another embodiment, the present invention provides a pharmaceutical composition comprising amorphous canagliflozin having less than 50 ppm of hydroperoxide impurity by LC-MS.

In accordance with another embodiment, the present invention provides a pharmaceutical composition comprising amorphous canagliflozin having about 0.1% of antioxidant by HPLC.

In accordance with another embodiment, the present invention provides a pharmaceutical composition comprising amorphous canagliflozin having less than 50 ppm of hydroperoxide impurity by LC-MS and having about 0.1% of antioxidant by HPLC.

The present invention provides amorphous canagliflozin, obtained by the process described herein, as analyzed using the high performance liquid chromatography (“HPLC”) with the conditions described below:
Column Symmetry shield RP18, (150 x 4.6 ) mm
Mobile phase Buffer and Acetonitrile
Buffer Sodium perchlorate in water (pH 3.0).
Diluent Diluent-1: Buffer and Acetonitrile (50:50),
Diluent-2: Water and Acetonitrile (20:80)
Flow rate 0.9mL/min
Wave length 225 nm
Injection volume 10 ?L
Elution Mode Gradient

Gradient program:
Time in min. Mobile phase-A Mobile phase-B
0 65 35
20 50 50
30 50 50
40 15 85
55 15 85
65 65 35

The present invention provides amorphous canagliflozin, obtained by the process described herein, as analyzed using the Liquid chromatography–mass spectrometry(“LC-MS”) with the conditions described below:
LC Conditions:

Column Eclipse XDB-C18 (150x4.6) mm
Mobile phase Buffer: Acetonitrile
Buffer Formic acid and water
Diluent Water and Acetonitrile (20:80)
Flow rate 0.5mL/min
Injection volume 10µL
Runtime 6 min

MS Conditions:

Ionization ES(-ve)
Capillary voltage 3.5 kV
Cone voltage 20 V
Desolvation temperature 500°C
Desolvation gas flow 650 L/Hr
Cone gas flow 50 L/Hr
Source temperature 150°C

EXAMPLES:

The present invention is further illustrated by the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.

Example 1: Preparation of amorphous canagliflozin

To a round bottom flask equipped with reflux condenser, nitrogen gas was purged to methyl tert-butyl ether (500 ml). BHT (0.064gms) was added and stirred at 25-35°C under nitrogen atmosphere. Canagliflozin (50gms) was added and was stirred the reaction mass for 20-30 min at 40-45°C under nitrogen atmosphere and cooled to 25-35 °C. In another round bottom flask, nitrogen gas was purged to cyclohexane (2000 ml) and BHT (0.013gms) was added at 25-35 °C under nitrogen atmosphere. The contents were stirred for 10-15 min at 25-35 °C and cooled to 18-22 °C. Under nitrogen atmosphere, the above methyl tert-butyl ether solution containing the product is added to cyclohexane over a period of 1.5-2.5 hrsat18-22°C and stirred at the same temperature for 15-20 min. The resulting solid was filtered under nitrogen atmosphere and washed with mixture of methyl tert-butyl ether & cyclohexane (40 ml methyl tert-butyl ether and 160 ml cyclohexane). The resulting solid was dried at 25-35°C for 3hrs and later at 55-60°C for 15-16hrs to obtain amorphous Canagliflozin (42gms).
Hydroperoxide content (by LC-MS): 11 ppm
BHT content (by HPLC): 0.042%.

Example 2: Preparation of amorphous canagliflozin

To a round bottom flask equipped with reflux condenser, water (150 ml) and Canagliflozin DL-pipecolic acid co-crystal (100gms) was added at 25-35°C. Aqueous ammonia solution (1000 ml) was added to the reaction mass at 25-35°C and stirred for 18-20 hrs at the same temperature. The resulting solid was filtered, washed with water and suck dried for 2-3 hrs. To another round bottom flask equipped with reflux condenser, nitrogen gas was purged to dichloromethane (1000 ml). BHT (0.5 gms) was added and stirred at 25-35°C for 10-15 mins under nitrogen atmosphere. The above filtered solid was added followed by methanol (100 ml) and stirred for 45-60 min at 25-35°C under nitrogen atmosphere. Water (500 ml) was added to the reaction mass and stirred at 25-35°C for 15-20 mins.pH of the reaction mass was adjusted to 4 to 7.5 with hydrochloric acid and the organic layer was separated out and washed with a mixture of methanol (100 ml) and water (500 ml). The resulting organic layer was charcolized, filtered and washed with dichloromethane (100 ml pre-treated with 0.05 gms BHT). The organic layer was concentrated and stripped off with methyl tert-butyl ether (100 ml methyl tert-butyl ether pre-treated with 0.02 gms BHT) to get a residue.

To a round bottom flask equipped with reflux condenser, nitrogen gas was purged to methyl tert-butyl ether (500 ml). BHT (0.1 gms) was added and stirred at 25-35°C under nitrogen atmosphere. The above residue was added and the reaction mass was stirred for 20-30 min at 40-45°C under nitrogen atmosphere and cooled to 25-35 °C. In another round bottom flask, nitrogen gas was purged to cyclohexane (2000 ml) and BHT (0.02 gms) was added at 25-35 °C under nitrogen atmosphere. The contents were stirred for 10-15 min at 25-35 °C and cooled to 18-22 °C. Under nitrogen atmosphere, the above methyl tert-butyl ether solution containing the product is added to cyclohexane over a period of 1.5-2.5 hrs at18-22°C and stirred at the same temperature for 15-20 min. The resulting solid was filtered under nitrogen atmosphere and washed with mixture of methyl tert-butyl ether & cyclohexane (40 ml methyl tert-butyl ether and 160 ml cyclohexane). The resulting solid was dried at 25-35°C for 3hrs and later at 55-60°C for 15-16hrs to obtain amorphous Canagliflozin (65 gms).
Hydroperoxide content (by LC-MS):8 ppm
BHT content (by HPLC): 0.08%.
,CLAIMS:We claim:

1. A process for the preparation of amorphous canagliflozin having less than 50 ppm of hydroperoxide impurity by LC-MS and less than 0.1% of antioxidants by HPLC, comprising:
a) treating an organic solvent S2 under nitrogen atmosphere with an antioxidant to obtain a solution,
b) dissolving canagliflozin in to the solution of step a) under nitrogen atmosphere,
c) adding the step b) reaction mass into an anti-solvent or vice versa, which is pre-treated with an antioxidant under nitrogen atmosphere; and
d) isolating the amorphous canagliflozin.

2. The process as claimed in claim 1, wherein the organic solvent S2 is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol; acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, isobutyl acetate, tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 1,4-dioxane, hexane, heptane, pentane, toluene, xylene, dichloromethane, chloroform, acetonitrile, propionitrile, benzonitrile, and mixtures thereof.

3. The process as claimed in claim 1, wherein the antioxidant is selected from ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxyalanine (BHA), sodium metabisulfite, propyl gallate, cysteine, tert-butyl hydroquinone, triphenyl phosphine, tocopherol, ascorbic acid, sodium ascorbate, calcium ascorbate, ascorbylpalmitate, thioglycerol, thioglycolic acid, lipoic acid, uric acid, carotenes, glutathione, melatonin, erythorbic acid, sodium erythorbate, 4-hexylresorcinol, polyphenols, Resveratrol, pterostilbene, curcumin, cinnamic acid, p-coumaric acid, ferulic acid, Sinapic acid, caffeic acid, chlorogenic acid, p-hydroxybenzoic acid, vanillic acid, syringic acid, protocatechuic acid, quinic acid, 4-(4-phenoxybenzoyl)benzoic acid and mixtures thereof.

4. The process as claimed in claim 1, wherein the molar ratio of antioxidant used is 0.001 to 0.1 moles.

5. The process as claimed in claim 1, wherein the anti-solvent is selected from the group consisting of n-pentane, n-hexane, n-heptane, cyclohexane, methyl cyclohexane, cycloheptane and mixture thereof.

6. The process as claimed in claim 1, wherein the organic solvent S2 is methyl tert-butyl ether; the anti-solvent is cyclohexane and the antioxidant is butylated hydroxytoluene.

7. A process for the preparation of amorphous canagliflozin having less than 50 ppm of hydroperoxide impurity by LC-MS and less than 0.1% of antioxidants by HPLC, comprising:
a) treating canagliflozin co-crystals in water with a base to obtain canagliflozin,
b) treating an organic solvent S1 under nitrogen atmosphere with an antioxidant to obtain a solution,
c) dissolving the canagliflozin of step a) in to the solution of step b),
d) removing the organic solvent S1 from step c) to get a residue,
e) treating an organic solvent S2 under nitrogen atmosphere with an antioxidant to obtain a solution,
f) dissolving the residue of step d) in to the solution of step e) under nitrogen atmosphere,
g) adding the step f) reaction mass into an anti-solvent or vice versa, which is pre-treated with an antioxidant under nitrogen atmosphere; and
h) isolating the amorphous canagliflozin.

8. The process as claimed in claim 7, wherein the canagliflozin co-crystals are selected from canagliflozin with co-crystal former selected from the group comprising DL-pipecolic acid, D-pipecolic acid, L-pipecolic acid.

9. The process as claimed in claim 7, wherein the base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, potassium hydride, ammonia, di-isopropyl ethylamine, triethyl amine and pyridine.

10. The process as claimed in claim 7, wherein the organic solvent S1 is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, isobutyl acetate, tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether, methyl tertiary butyl ether, 1,4-dioxane, hexane, heptane, pentane, toluene, xylene, dichloromethane, chloroform, acetonitrile, propionitrile, benzonitrile, water and mixtures thereof.

11. The process as claimed in claim 7, wherein the organic solvent S2 is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol; acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, isobutyl acetate, tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 1,4-dioxane, hexane, heptane, pentane, toluene, xylene, dichloromethane, chloroform, acetonitrile, propionitrile, benzonitrile, and mixtures thereof.

12. The process as claimed in claim 7, wherein the antioxidant is selected from ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxyalanine (BHA), sodium metabisulfite, propyl gallate, cysteine, tert-butyl hydroquinone, triphenyl phosphine, tocopherol, ascorbic acid, sodium ascorbate, calcium ascorbate, ascorbylpalmitate, thioglycerol, thioglycolic acid, lipoic acid, uric acid, carotenes, glutathione, melatonin, erythorbic acid, sodium erythorbate, 4-hexylresorcinol, polyphenols, Resveratrol, pterostilbene, curcumin, cinnamic acid, p-coumaric acid, ferulic acid, Sinapic acid, caffeic acid, chlorogenic acid, p-hydroxybenzoic acid, vanillic acid, syringic acid, protocatechuic acid, quinic acid, 4-(4-phenoxybenzoyl)benzoic acid and mixtures thereof.

13. The process as claimed in claim 7, wherein the anti-solvent is selected from the group consisting of n-pentane, n-hexane, n-heptane, cyclohexane, methyl cyclohexane, cycloheptane and mixture thereof.

14. The process as claimed in claim 7, wherein the organic solvent S1 is dichloromethane, S2 is methyl tert-butyl ether; anti-solvent is cyclohexane, base is ammonia and the antioxidant is butylated hydroxytoluene.