DESC:The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The present application relates to novel polymorphs of Canagliflozin and process for their preparation. The application further relate to a sealed pack comprising an amorphous Canagliflozin and at least one stabilizer such as, for example, a moisture absorber, an oxygen absorber or a combination thereof.
BACKGROUND
Inhibitors of sodium glucose co-transporter 2 (SGLT2) have recently been developed as a novel potential therapeutic option for the treatment of type 2 diabetes. SGLT2 inhibitors (gliflozins) lower the plasma glucose concentration by inhibition of glucose re-uptake in the kidney, without weight gain. As the mechanism of action of SGLT2 inhibitors is in dependent of insulin secretion and insulin action, they lower the plasma glucose concentration with lower risk of hypoglycemia.
Canagliflozin is chemically described as (1S)-1,5-anhydro-1-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol. It has the chemical structure of formula (I).

Formula 1
Canagliflozin, an inhibitor of sodium-glucose co-transporter 2 (SGLT2), is useful for the treatment of type 2 diabetes.
The US patent document 7,943,788 discloses Canagliflozin in example 84, which is prepared in accordance with examples 1 through 4. The examples disclose the isolation of the crude desired compound in the form of a residue, which is then purified by column chromatography.
The US patent document 7,943,582 discloses crystalline hemihydrate form of Canagliflozin and process for its preparation.
Various polymorphs of Canagliflozin and process for their preparation have been reported in the patent publications US9024009B2, US9056850B2, US8999941B2, US8772512, WO2012154812, WO2015071761?2, CN103936725A, CN103896930A and WO2014195966A2.
The US patent application document US8999941B2 discloses that amorphous form of Canagliflozin is hygroscopic as per Dynamic vapor sorption (DVS) analysis. Amorphous form undergoes physical changes. Further discloses, the preparation of amorphous Canagliflozin by adding a solution of Canagliflozin in toluene to n-heptane.
Canagliflozin is known to occur in various crystalline forms as well as amorphous form. However, amorphous form can be susceptible to oxidation, heat, light, moisture, as compared to crystalline forms. Impurities generated upon degradation of active substances can reduce the therapeutic effects of an active substance and unnecessarily burden the body with degradation products.
There remains a need to provide alternate forms of Canagliflozin and processes for their preparation and a need to provide a packaging system for amorphous Canagliflozin so as to enhance its stability in turn makes it storage stable amorphous form.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an illustration of a powder X-ray diffraction (PXRD) pattern of crystalline form R1 of Canagliflozin propylene glycol solvate.
Figure 2 is an illustration of a powder X-ray diffraction (PXRD) pattern of crystalline form R2 of Canagliflozin propylene glycol solvate.
Figure 3 is an illustration of a powder X-ray diffraction (PXRD) pattern of crystalline form R3 of Canagliflozin propylene glycol solvate.
Figure 4 is an illustration of a powder X-ray diffraction (PXRD) pattern of crystalline form R4 of Canagliflozin propylene glycol solvate.
Figure 5 is an illustration of a powder X-ray diffraction (PXRD) pattern of crystalline form R5 of Canagliflozin propylene glycol solvate.
Figure 6 is an illustration of a powder X-ray diffraction (PXRD) pattern of initial amorphous form of Canagliflozin.
Figure 7 is an illustration of a powder X-ray diffraction (PXRD) pattern of example 9 of amorphous form of Canagliflozin for 1 month accelerated study.
Figure 8 is an illustration of a powder X-ray diffraction (PXRD) pattern of example 9 of amorphous form of Canagliflozin for 1 month long term study.
Figure 9 is an illustration of a powder X-ray diffraction (PXRD) pattern of example 9 of amorphous form of Canagliflozin for 1 month intermediate study.
Figure 10 is an illustration of a powder X-ray diffraction (PXRD) pattern of example 10 of amorphous form of Canagliflozin for 1 month accelerated study.
Figure 11 is an illustration of a powder X-ray diffraction (PXRD) pattern of example 10 of amorphous form of Canagliflozin for 1 month long term study.
Figure 12 is an illustration of a powder X-ray diffraction (PXRD) pattern of example 10 of amorphous form of Canagliflozin for 1 month intermediate study.
SUMMARY OF THE INVENTION
Aspects of the present application provide Canagliflozin propylene glycol solvate.
In one aspect, the present application provides Canagliflozin propylene glycol solvate, wherein it is crystalline.
In the first embodiment, the present application provides crystalline form R1 of Canagliflozin propylene glycol solvate.
In the second embodiment, the present application provides crystalline form R1 of Canagliflozin propylene glycol solvate characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2? at about 11.62°, 16.81° and 17.70° ± 0.2°.
In the third embodiment, the present application provides crystalline form R1 of Canagliflozin propylene glycol solvate further characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2? at about 15.16°, 20.43° and 22.69 ± 0.2°.
In the fourth embodiment, the present application provides crystalline form R1 of Canagliflozin propylene glycol solvate characterized by an X-ray powder diffraction pattern substantially as illustrated by Figure 1.
In the fifth embodiment, the present application provides crystalline form R2 of Canagliflozin propylene glycol solvate.
In the sixth embodiment, the present application provides crystalline form R2 of Canagliflozin propylene glycol solvate characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2? at about 6.48°, 14.77°, 20.04° and 22.31° ± 0.2°.
In the seventh embodiment, the present application provides crystalline form R2 of Canagliflozin propylene glycol solvate further characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2? at about 11.27°, 13.45°, 16.37°, 17.34° and 22.88° ± 0.2°.
In the eighth embodiment, the present application provides crystalline form R2 of Canagliflozin propylene glycol solvate characterized by an X-ray powder diffraction pattern substantially as illustrated by Figure 2.
In the ninth embodiment, the present application provides crystalline form R3 of Canagliflozin propylene glycol solvate.
In the tenth embodiment, the present application provides crystalline form R3 of Canagliflozin propylene glycol solvate characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2? at about 4.18°, 6.88°, 11.99°, 14.85°, 19.89°, 22.06° ± 0.2°.
In the eleventh embodiment, the present application provides crystalline form R3 of Canagliflozin propylene glycol solvate further characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2? at about 13.61°, 15.53°, 16.15°, 20.36° and 23.51° ± 0.2°.
In the twelfth embodiment, the present application provides crystalline form R3 of Canagliflozin propylene glycol solvate furthermore characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2? at about 17.56°, 18.09°, 25.71°, and 28.33° ± 0.2°.
In the thirteenth embodiment, the present application provides crystalline form R3 of Canagliflozin propylene glycol solvate characterized by an X-ray powder diffraction pattern substantially as illustrated by Figure 3.
In the fourteenth embodiment, the present application provides crystalline form R4 of Canagliflozin (S)-propylene glycol solvate.
In the fifteenth embodiment, the present application provides crystalline form R4 of Canagliflozin (S)-propylene glycol solvate characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2? at about 11.05°, 16.19°, 17.09°, 19.77° and 22.10° ± 0.2°.
In the sixteenth embodiment, the present application provides crystalline form R4 of Canagliflozin (S)-propylene glycol solvate further characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2? at about 13.20°, 14.55° and 22.62 ± 0.2°.
In the seventeenth embodiment, the present application provides crystalline form R4 of Canagliflozin (S)-propylene glycol solvate characterized by an X-ray powder diffraction pattern substantially as illustrated by Figure 4.
In the eighteenth embodiment, the present application provides crystalline form R5 of Canagliflozin (R)-propylene glycol solvate.
In the nineteenth embodiment, the present application provides crystalline form R5 of Canagliflozin (R)-propylene glycol solvate characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2? at about 12.05°, 14.85°, 19.87°, 25.02°and 25.78° ± 0.2°.
In the twentieth embodiment, the present application provides crystalline form R5 of Canagliflozin (R)-propylene glycol solvate further characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2? at about 13.58° and 28.23° ± 0.2°.
In the twenty first embodiment, the present application provides crystalline form R5 of Canagliflozin (R)-propylene glycol solvate characterized by an X-ray powder diffraction pattern substantially as illustrated by Figure 5.
In the twenty second embodiment, the present application provides a storage stable amorphous form of Canagliflozin.
In the twenty third embodiment, the present application provides a sealed packaging comprising an amorphous form of Canagliflozin and at least one stabilizer.
In the twenty fourth embodiment, the present application provides a method of stabilizing an amorphous form of Canagliflozin using a sealed packing comprising an amorphous form of Canagliflozin and at least one stabilizer.
In the twenty fifth embodiment, the present application provides a sealed packaging comprising an amorphous form of Canagliflozin and at least one stabilizer wherein the said packaging comprises:
i) placing amorphous form of Canagliflozin in a first bag,
ii) placing the said first bag comprising amorphous form of Canagliflozin and at least one stabilizer in a second bag,
iii) sealing the said second bag,
iv) optionally, placing the said second bag in a third bag or a rigid container with or without stabilizer.
In twenty sixth embodiment, the present application provides a sealed packaging of a solid pharmaceutical composition comprising an amorphous form of Canagliflozin and one or more pharmaceutically acceptable carriers wherein the packaging comprises at least one stabilizer.
In twenty seventh embodiment, the present application provides a method of stabilizing a solid pharmaceutical composition comprising an amorphous form of Canagliflozin and one or more pharmaceutically acceptable carriers wherein the packing comprises at least one stabilizer.
In twenty eighth embodiment, the present application provides a method of preparing Canagliflozin propylene glycol solvate comprising:
a) forming a solution of Canagliflozin in propylene glycol,
b) optionally seeding the resulting solution with Canagliflozin,
c) stirring the resulting solution for a sufficient time,
d) isolating the resulting Canagliflozin propylene glycol solvate.
DETAILED DESCRIPTION
The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1% of its value. For example "about 10" should be construed as meaning within the range of 9 to 11, preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.
Room temperature as used herein refers to ‘the temperatures of the thing close to or same as that of the space, e.g., the room or fume hood, in which the thing is located’. Typically, room temperature can be from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about normal pressure, unless the context requires otherwise. All temperatures are in degrees Celsius unless specified otherwise. As used herein, "comprising" (open-ended) means the element or elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open-ended. As used herein, "consisting essentially of" means that the application may include elements in addition to those recited in the claim, but only if the additional elements do not materially alter the basic and novel characteristics. All ranges recited herein include the endpoints, including those that recite a range "between" two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
Unless specified otherwise, the word "pure" as used herein means that the material is at least about 99% pure. In general, this refers to purity with regard to unwanted degradation products and/or with regard to undesirable crystalline forms of Canagliflozin. "Substantially pure" as used herein means at least about 98% pure and, likewise, "essentially pure" as used herein means at least about 95% pure.
"Substantially free of one or more of its corresponding impurities" as used herein, unless otherwise defined refers to the compound that contains less than about 2%, or less than about 1 %, or less than about 0.5%, or less than about 0.3%, or less than about 0.2%, or less than about 0.1 %, or less than about 0.05%, or less than about 0.03%, or less than about 0.01 %, by weight, of each individual impurity.
"Storage stable" as used herein, mean the amorphous form of Canagliflozin which is stable in packaging and storage conditions given in the present application and shows no change in polymorphic form by x-ray powder diffraction.
The “stabilizer” as user herein, means oxygen absorber and/or moisture absorber.
The term “oxygen absorber” as used herein, means agents used to trap oxygen that is present in the overhead space of closed container. Concerning the chemical and physical mechanisms of active oxygen absorbers, they can be classified into the following categories:
- inorganic, metal based oxygen absorber
- ascorbic acid based absorber
- enzymatic absorber
- polymer based oxygen absorber
Inorganic, metal-based oxygen absorbers are inexpensive, available with different O2-scavenging capacities in sachets and common for food and beverages. The broadest ranges of iron-based products are offered by Mitsubishi Gas Chemicals Ageless™. Similar products are also offered by Multisorb under the trade name Fresh Pax™.
Ascorbic acid is a well-known preserving agent. The enzymatic oxygen absorber is based on glucose/glucose oxidase. Polymer based scavengers are suitable for moisture protected applications. Polymer-based compounds consist of high molecular weight, ethylenically-unsaturated hydrocarbons. An activation step often enables the user to start the oxygen scavenging when desired.
Commercially available sachets include D Series FreshPax™ (available from Multisorb Technologies Inc), Ageless™ Z (Ageless-Z is designated as Z-100, Z-1000, etc., to indicate the milliliters of oxygen with which a single packet will react), StabilOx D (available from Multisorb Technologies Inc) and ZPTJ™ sachets (both available from Mitsubishi Gas Corporation), O-Buster™ (available from Hsiao Sung Non-Oxygen Chemical Co., Ltd), Bioka™ Oxygen Absorber (available from Bioka Ltd) and the like.
The moisture absorber includes activated carbon, silicas, zeolites, molecular sieves, hydrogels, calcium oxide and diatomaceous earth. The particular moisture-retaining materials used will depend upon the humidity level of the environment. The moisture absorber can be supplied in the form of a sachet, cartridge or canister. A preferred form is a canister of silica gel, such as SorBit™ (commercially supplied by Sud-Chemie Corporation). Multisorb provides variety of moisture absorbers under trade name of Natrasorb M, Natrasorb S, Natrasorb C, and Hi-dry, which comprise diatomaceous earth, silica gel, calcium oxide and molecular sieve, respectively.
Further, there are certain commercially available packets or sachets which comprise a combination of oxygen absorber and moisture absorber such as PharmaKeep oxygen- and moisture-absorbing packets (PharmaKeep KD or KC) (distributed jointly by Süd-Chemie and Mitsubishi Gas Chemical Company).
In addition, combination of oxygen absorber and moisture absorber can be used together in a vacuum-packaged system. Oxygen absorbers usually lead to an increase in moisture levels, hence a combination of moisture absorber and oxygen absorber will regulate moisture levels as well as oxygen levels, and these levels may have impact on stability of the drug substance as well as composition.
The size and number of moisture/oxygen absorbers can depend on the amount of residual moisture or oxygen hence would mainly depend on package system such as HDPE bottle or permeable/impermeable bags. The moisture/oxygen absorber may be in the form of packet, sachet, strips or canisters. The packet, sachet, strips or canisters may additionally comprise a moisture-indicating card.
The packaging material for packaging system could comprise oxygen as well as moisture-impermeable material so that vacuum created during packaging is maintained throughout the shelf life of the drug. It can be chosen from Polyethylene (PE), bi-axially oriented polypropylene (BOPP), PET (polyethylene terpthalate), oriented polyamide (OPA), aluminum foil, or a blend of these polymers or a laminated structure of these polymers. Possible structures of the laminate are PET/aluminum foil/PE, or OPA/PET/PE, and various other permutations and combinations are possible. The laminate structure would primarily depend on moisture/light or gas barrier required by the drug or the composition.
The rigid container as used herein include non-airtight/air-tight plastic/metal drums, corrugated shipper or fiberboard drum for drug packaging and HDPE (high density polyethylene), PP (polypropylene), LDPE (low density polyethylene), PET, PVC (polyvinyl chloride) bottle for composition packaging.
The “inert gas” as used herein includes nitrogen gas and argon gas.
According to one aspect, the present application provides Canagliflozin propylene glycol solvate.
In one aspect, the present application provides Canagliflozin propylene glycol solvate, wherein it is crystalline.
According to one aspect of the present application, there is provided a crystalline form of Canagliflozin propylene glycol solvate, designated as Form R1, characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2? at about 11.62°, 16.81°, and 17.70° ± 0.2°. It may be further characterized by XRD peaks at about 15.16°, 20.43°, and 22.69 ± 0.2° 2?. Figure 1 is an illustration of X-ray powder diffraction pattern of “Form R1”.
According to another aspect of the present application, there is provided a crystalline form of Canagliflozin propylene glycol solvate, designated as Form R2, characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2? at about 6.48°, 14.77°, 20.04° and 22.31° ± 0.2°. It may be further characterized by XRD peaks at about 11.27°, 13.45°, 16.37°, 17.34°, and 22.88° ± 0.2° 2?. Figure 2 is an illustration of X-ray powder diffraction pattern of “Form R2”.
According to another aspect of the present application, there is provided a crystalline form of Canagliflozin, designated as Form R3 propylene glycol solvate, characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2? at about 4.18°, 6.88°, 11.99°, 14.85°, 19.89°, 22.06° ± 0.2°. It may be further characterized by XRD peaks at about 13.61°, 15.53°, 16.15°, 20.36° and 23.51° ± 0.2° 2?. It may be furthermore characterized by XRD peaks at about 17.56°, 18.09°, 25.71°, and 28.33° ± 0.2° 2?. Figure 3 is an illustration of X-ray powder diffraction pattern of “Form R3”.
According to another aspect of the present application, there is provided a crystalline form of Canagliflozin (S)-propylene glycol solvate, designated as Form R4, characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2? at about 11.05°, 16.19°, 17.09°, 19.77° and 22.10° ± 0.2° 2?. It may be further characterized by XRD peaks at about 13.20°, 14.55° and 22.62 ± 0.2°2?. Figure 4 is an illustration of X-ray powder diffraction pattern of “Form R4”.
According to another aspect of the present application, there is provided a crystalline form of Canagliflozin (R)-propylene glycol solvate, designated as Form R5, characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2? at about 12.05°, 14.85°, 19.87°, 25.02°and 25.78° ± 0.2°. It may be further characterized by XRD peaks at about 13.58° and 28.23° ± 0.2° 2?. Figure 5 is an illustration of X-ray powder diffraction pattern of “Form R5”.
The crystalline forms of the present application can be optionally milled to get desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the compound. Techniques that may be used for particle size reduction include, without limitation, ball, roller, hammer mills and jet mills.
In an aspect, crystalline forms of Canagliflozin of the present application may have a D90 particle size of less than about 200 µm, or less than about 150 µm, or less than about 100 µm, or less than about 90 µm, or less than about 80 µm, or less than about 60 µm, or less than about 50 µm, or less than about 40 µm, or less than about 30 µm, or less than about 20 µm, or less than about 10 µm, or less than about 5 µm, or any other suitable particle sizes.
Particle size distributions of crystalline forms of Canagliflozin of the present application may be measured using any techniques known in the art. For example, particle size distributions of Canagliflozin particles may be measured using microscopy or light scattering equipment, such as, for example, a Malvern Master Size 2000 from Malvern Instruments Limited, Malvern, Worcestershire, United Kingdom.
In another aspect the present application provides, a method of preparing Canagliflozin propylene glycol solvate comprising:
a) forming a solution of Canagliflozin in propylene glycol,
b) optionally seeding the resulting solution with Canagliflozin,
c) stirring the resulting solution for a sufficient time,
d) isolating the resulting Canagliflozin propylene glycol solvate.

In step a), Canagliflozin is dissolved in propylene glycol to form a solution. Optionally in step b) seeding the resulting solution of step a) with Canagliflozin. The Canagliflozin used as a seed material may be any crystalline form of Canagliflozin. For example crystalline form B as disclosed in CN 103554092A or Form R1 or any other suitable polymorphic form. The solution obtained from step a) or step b) started stirring in step c) for sufficient time. The stirring can be carried out for any time period required, such as from about 15 minutes to several hours. The desired polymorph is isolated in step d).
The isolation may be effected by methods such as, removal of solvent, crash cooling, using anti solvent, flash evaporation, drying, rotational drying, spray drying, thin-film drying, agitated nutsche filter drying, freeze drying, or any other suitable fast evaporation technique.
Drying can be suitably carried out in a tray dryer, vacuum oven, Büchi® Rotavapor®, air oven, fluidized bed dryer, spin flash dryer, flash dryer, cone dryer, agitated nutsche filter cum dryer, nauta dryer or the like or any other suitable dryer. The drying can be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 150°C, less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, or any other suitable temperatures. The drying can be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to several hours.
Suitable temperatures for isolation may be less than about 120°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, less than about 0°C, less than about -10°C, less than about -40°C or any other suitable temperatures.
The processes described herein can be carried out in air or under an inert atmosphere.
Any polymorphic form known in the art may be used as starting material to provide a solution of Canagliflozin in carrying the processes for the preparation of crystalline forms of Canagliflozin of the present application. In one variant, Form B of Canagliflozin used as seed in the process for the preparation of Form R1 of the present application may be obtained by the process described in the Chinese patent application document 103554092A or using the process disclosed in the current application.
According to another aspect of the present application there is provided a pharmaceutical composition comprising one or more of Form R1, Form R2, Form R3, Form R4 and Form R5 of Canagliflozin propylene glycol solvate and one or more pharmaceutically acceptable carriers.
According to another aspect, the present application provides a storage stable amorphous form of Canagliflozin.
According to another aspect, the present application provides a sealed packaging comprising an amorphous form of Canagliflozin and at least one stabilizer.
According to another aspect, the present application provides a method of stabilizing an amorphous form of Canagliflozin using a sealed packing comprising an amorphous form of Canagliflozin and at least one stabilizer.
According to another aspect, the present application provides a sealed packaging comprising an amorphous form of Canagliflozin and at least one stabilizer wherein the said packaging comprises:
i) placing amorphous form of Canagliflozin in a first bag,
ii) placing the said first bag comprising amorphous form of Canagliflozin and at least one stabilizer in a second bag,
iii) sealing the said second bag,
iv) optionally, placing the said second bag in a third bag or a rigid container with or without stabilizer.
According to another aspect, the present application provides a sealed packaging of a solid pharmaceutical composition comprising an amorphous form of Canagliflozin and one or more pharmaceutically acceptable carriers wherein the packaging comprises at least one stabilizer.
According to another aspect, the present application provides a method of stabilizing a solid pharmaceutical composition comprising an amorphous form of Canagliflozin and one or more pharmaceutically acceptable carriers wherein the packing comprises at least one stabilizer.
The amorphous form of Canagliflozin remains pure in the packaging conditions disclosed in the present application.
The pharmaceutical compositions comprising amorphous form or crystalline Form R1, Form R2, Form R3, Form R4 and/or Form R5 of Canagliflozin propylene glycol solvate and one or more pharmaceutically acceptable excipients of the present application can be further formulated as: solid oral dosage forms such as, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as, syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, solutions, dispersions, and freeze dried compositions. Formulations can be in the form of immediate release, delayed release or modified release. Further, immediate release compositions can be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that can comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions can be prepared by direct blending, dry granulation or wet granulation or by extrusion and spheronization. Compositions can be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. Compositions of the present application may further comprise one or more pharmaceutically acceptable excipients.
Pharmaceutically acceptable excipients that find use in the present application include, diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pregelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins, resins; release rate controlling agents such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl cellulose, various grades of methyl methacrylates, waxes and the like. Other pharmaceutically acceptable excipients that are of use include, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.
Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided for purposes of illustration only and should not be construed as limiting the scope of the present application in any manner.
All PXRD data reported herein are obtained using a Bruker AXS D8 Advance Powder X-ray Diffractometer or a PANalytical X-ray Diffractometer, using copper Ka radiation wavelength 1.5418Å.
HPLC detection was done using following conditions:
Column: X-Bridge C18 150x4.6 mm, 3.5µ
Detection: UV
Diluents: Acetonitrile : water, 8:2 (%v/v)
Elution: Gradient

Example 1: Preparation of crystalline Form R1 of Canagliflozin propylene glycol solvate.
Canagliflozin (200 mg) and propylene glycol (150 µl) were charged in round bottom flask and stirred for 1.5 hours at 26°C to get clear solution. The mixture was seeded with Form B of Canagliflozin (20 mg). The reaction mixture was further stirred for 19 hours at 26°C. The solid was isolated and dried under vacuum (650 mm Hg) for 56 hours at 26°C. The obtained solid (105 mg) is Form R1.
Example 2: Preparation of crystalline Form R2 of Canagliflozin propylene glycol solvate.
Canagliflozin (1 gm) and propylene glycol (750 µl) were charged in round bottom flask and stirred for 15 minutes at 26°C to get hazy solution. The mixture was further stirred for 3.5 hours at 26°C. The precipitated solid was filtered and suck dried for 2 hours. The compound was further dried in vacuum tray drier at 26°C for 65 hours to obtain Form R2.
Example 3: Preparation of crystalline Form R2 of Canagliflozin propylene glycol solvate.
Canagliflozin (1 gm) and propylene glycol (750 µl) were charged in round bottom flask and stirred for 30 minutes at 26°C to get clear solution. The mixture was further stirred for 3 hours at 26°C. After precipitation of solid started, n-heptane (10 ml) was added to the mixture and stirred at 26°C for 2 hours. The compound was filtered and suck dried under vacuum for 1 hour. The compound was further dried in vacuum tray drier at 26°C for 20 hours to obtain Form R2.
Example 4: Preparation of crystalline Form R2 of Canagliflozin propylene glycol solvate.
Canagliflozin (1 gm) and propylene glycol (750 µl) were charged in round bottom flask and stirred for 30 minutes at 26°C to get clear solution. The mixture was further stirred for 2.5 hours at 26°C. After precipitation of solid started, n-pentane (10 ml) was added to the mixture and stirred at 26°C for 2 hours. The compound was filtered and suck dried under vacuum for 50 minutes. The compound was further dried in vacuum tray drier at 26°C for 20 hours to obtain Form R2.
Example 5: Preparation of crystalline Form R3 of Canagliflozin propylene glycol solvate.
Canagliflozin (200 mg) and propylene glycol (150 µl) were charged in round bottom flask and stirred for 15 minutes at 26°C to get clear solution. The mixture was seeded with Form R1 of Canagliflozin (20 mg) and stirred at 26°C. After precipitation of solid started, the mixture was further stirred for 22 hours at 26°C. The compound was filtered and suck dried for 5 hours. The compound was dried under vacuum (650 mm Hg) for 44 hours in vacuum tray drier at 26°C to obtain Form R3 (102 mg).
Example 6: Preparation of crystalline Form R3 of Canagliflozin propylene glycol solvate.
Canagliflozin (5 gm) and propylene glycol (4.5 ml) were charged in round bottom flask and stirred for 30 minutes at 26°C to get clear solution. The mixture was further stirred for 4 hours at 27°C. The precipitated solid was filtered and suck dried for 1 hour. The compound was further dried in vacuum tray drier at room temperature for 5 days to obtain From R2. The dried material was slurried in n-heptane (50 ml) for about 5 hours at 26°C, the compound was filtered and suck dried for 1 hour at room temperature. The obtained compound was dried for 21 hours in vacuum tray drier at 25°C to obtain Form R3.
Example 7: Preparation of crystalline Form R3 of Canagliflozin propylene glycol solvate
Canagliflozin (2 gm) and n-Heptane (50 ml) were charged in round bottom flask and stirred for 30 minutes at 26°C. Propylene glycol (1.5 ml) was added to the mixture and stirred at 26°C. The mixture was stirred at 26°C for 22 hours. The precipitated compound was filtered and suck dried under vacuum for 3.5 hours. The compound was further dried in air tray drier at 40°C for 24 hours to obtain Form R3.
Example 8: Preparation of crystalline Form R4 of Canagliflozin (S)-propylene glycol solvate
Canagliflozin (1 gm) and n-Heptane (25 ml) were charged in round bottom flask and stirred for 45 minutes at 27°C. (S)-Propylene glycol (25 ml) was added to the mixture and stirred at 27°C. The mixture was stirred at 27°C for 9-10 hours. The precipitated compound was filtered and suck dried under vacuum for 4 hours. The compound was further dried in air tray drier at 40°C for 12 hours to obtain Form R4.
Example 9: Preparation of crystalline Form R5 of Canagliflozin (R)-propylene glycol solvate
Canagliflozin (200 mg) and n-Heptane (5 ml) were charged in round bottom flask and stirred for 45 minutes at 27°C. (R)-Propylene glycol (150 µl) was added to the mixture and stirred at 27°C. The mixture was stirred at 27°C for 8-9 hours. The precipitated compound was filtered and suck dried under vacuum for 2.5 hours. The compound was further dried in air tray drier at 40°C for 8 hours to obtain Form R5.
Example 10: Preparation of crystalline Form B of Canagliflozin.
Canagliflozin (200 mg) and water (5 ml) were charged in round bottom flask and stirred for 3 hours at 40°C. Additional water (10 ml) was added and mixture was stirred overnight at 40°C. The compound was filtered and suck dried under vacuum for 15 minutes. The obtained compound was dried for 2 hours in vacuum tray drier at 25°C to obtain Form B.
Example 11: Packaging condition for amorphous Canagliflozin
Amorphous Canagliflozin (1.5 g) was packaged in a polyethylene bag and flushed with nitrogen gas; the bag was tied; the bag was put into a black polyethylene bag along with molecular sieves (1 gm), filled with nitrogen and heat sealed; sealed bag was packaged into a triple laminated bag along with molecular sieves (1 gm) and sealed with VNS sealer (Vacuum Nitrogen Flushing and Sealing). The packed sample was kept in HDPE container and subjected to stability study. X-ray diffraction (PXRD) pattern after 1 month are shown in figure 7, 8 and 9.
Relative Retention Times
XRD 0.26 0.94 1.13 1.39 2.92 Total imp
INITIAL Amorphous 0.04 0.05 0.1 0.05 0.030 0.53
CONDITION INTERVAL
Accelerated
(40°C±2°C, 75%RH±5%RH) 15th day Complies 0.04 0.05 0.1 0.05 0.030 0.530
Accelerated 1 month Complies 0.03 0.052 0.096 0.048 0.036 0.576
Long term
(25°C±2°C, 60%RH±5%RH) 1 month Complies 0.054 0.054 0.095 0.05 0.039 0.557
Intermediate
(30°C±2°C, 65%RH±5%RH) 1 month Complies 0.022 0.05 0.099 0.049 0.040 0.560
Example 12: Packaging condition for amorphous Canagliflozin
Amorphous Canagliflozin (1.54 g) was packaged in a polyethylene bag and flushed with nitrogen gas; the bag was tied; the bag was put into a black polyethylene bag along with silica gel pouch (which is dried for 3 hours at 105°C under vacuum), filled with nitrogen and heat sealed; sealed bag was packaged into a triple laminated bag along with silica gel pouch (which is dried for 3 hours at 105°C under vacuum) and sealed with VNS sealer (Vacuum Nitrogen Flushing and Sealing). The packed sample was kept in HDPE container and subjected to stability study. X-ray diffraction (PXRD) pattern after 1 month are shown in figure 10, 11 and 12.
Relative Retention Times
XRD 0.26 0.94 1.13 1.39 2.92 Total imp
INITIAL Amorphous 0.04 0.05 0.1 0.05 0.030 0.53
CONDITION INTERVAL
Accelerated
(40°C±2°C, 75%RH±5%RH) 15th day Complies 0.03 0.05 0.1 0.04 0.030 0.530
Accelerated 1 month Complies 0.052 0.058 0.094 0.048 0.037 0.581
Long term
(25°C±2°C, 60%RH±5%RH) 1 month Complies 0.032 0.054 0.094 0.049 0.038 0.539
Intermediate
(30°C±2°C, 65%RH±5%RH) 1 month Complies 0.034 0.05 0.095 0.05 0.040 0.541
,CLAIMS:1. A Canagliflozin propylene glycol solvate.
2. A Canagliflozin propylene glycol solvate according to claim 1, wherein it is crystalline.
3. A crystalline form of Canagliflozin propylene glycol solvate according to claim 2, in the form of Form R1, having an X-ray powder diffraction pattern comprising peaks, expressed in 2?, at about 11.62°, 16.81° and 17.70° ± 0.2°.
4. A crystalline Form R1 of Canagliflozin propylene glycol solvate, according to claim 3, further comprising peaks, expressed in 2?, at about 15.16°, 20.43° and 22.69 ± 0.2°.
5. A crystalline Form R1 of Canagliflozin propylene glycol solvate according to claim 3, having an X-ray powder diffraction pattern substantially as shown in figure 1.
6. A crystalline form of Canagliflozin propylene glycol solvate according to claim 2, in the form of Form R2, having an X-ray powder diffraction pattern comprising peaks, expressed in 2?, at about 6.48°, 14.77°, 20.04° and 22.31° ± 0.2°.
7. A crystalline Form R2 of Canagliflozin propylene glycol solvate, according to claim 6, further comprising peaks, expressed in 2?, at about 11.27°, 13.45°, 16.37°, 17.34° and 22.88° ± 0.2°.
8. A crystalline Form R2 of Canagliflozin propylene glycol solvate according to claim 6, having an X-ray powder diffraction pattern substantially as shown in figure 2.
9. A crystalline form of Canagliflozin propylene glycol solvate according to claim 2, in the form of Form R3, having an X-ray powder diffraction pattern comprising peaks, expressed in 2?, at about 4.18°, 6.88°, 11.99°, 14.85°, 19.89°, 22.06° ± 0.2°.
10. A crystalline Form R3 of Canagliflozin propylene glycol solvate, according to claim 9, further comprising peaks, expressed in 2?, at about 13.61°, 15.53°, 16.15°, 20.36° and 23.51° ± 0.2°.
11. A crystalline Form R3 of Canagliflozin propylene glycol solvate, according to claim 9, further comprising peaks, expressed in 2?, at about 17.56°, 18.09°, 25.71°, and 28.33°± 0.2°.
12. A crystalline Form R3 of Canagliflozin propylene glycol solvate according to claim 9, having an X-ray powder diffraction pattern substantially as shown in figure 3.
13. A crystalline form of Canagliflozin (S)-propylene glycol solvate according to claim 2, in the form of Form R4, having an X-ray powder diffraction pattern comprising peaks, expressed in 2?, at about 11.05°, 16.19°, 17.09°, 19.77° and 22.10° ± 0.2°.
14. A crystalline form R4 of Canagliflozin (S)-propylene glycol solvate, according to claim 13, further comprising peaks, expressed in 2?, at about 13.20°, 14.55° and 22.62 ± 0.2°.
15. A crystalline Form R4 of Canagliflozin (S)-propylene glycol solvate according to claim 13, having an X-ray powder diffraction pattern substantially as shown in figure 4.
16. A crystalline form of Canagliflozin (R)-propylene glycol solvate, according to claim 2, in the form of Form R5, having an X-ray powder diffraction pattern comprising peaks, expressed in 2?, at about 12.05°, 14.85°, 19.87°, 25.02°and 25.78° ± 0.2°.
17. A crystalline Form R5 of Canagliflozin (R)-propylene glycol solvate, according to claim 16, further comprising peaks, expressed in 2?, at about 13.58° and 28.23° ± 0.2°.
18. A crystalline Form R5 of Canagliflozin (S)-propylene glycol solvate according to claim 16, having an X-ray powder diffraction pattern substantially as shown in figure 5.
19. A process for preparing a Canagliflozin propylene glycol solvate according to claim 1 comprising:
a) forming a solution of Canagliflozin in propylene glycol,
b) optionally seeding the resulting solution with Canagliflozin,
c) stirring the resulting solution for a sufficient time,
d) isolating the resulting Canagliflozin propylene glycol solvate.
20. A pharmaceutical composition comprising crystalline form R1, R2,R3, R4 and/ or R5 of Canagliflozin propylene glycol solvate and a pharmaceutically acceptable carrier.