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WO2016055945A1 - Polymorphes de la canagliflozine - Google Patents

Polymorphes de la canagliflozine Download PDF

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Publication number
WO2016055945A1
WO2016055945A1 PCT/IB2015/057657 IB2015057657W WO2016055945A1 WO 2016055945 A1 WO2016055945 A1 WO 2016055945A1 IB 2015057657 W IB2015057657 W IB 2015057657W WO 2016055945 A1 WO2016055945 A1 WO 2016055945A1
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WO
WIPO (PCT)
Prior art keywords
canagliflozin
propylene glycol
glycol solvate
crystalline form
present application
Prior art date
Application number
PCT/IB2015/057657
Other languages
English (en)
Inventor
Dharma Jagannadharao VELAGA
Vishweshwar Peddy
Srividya Ramakrishnan
Seetha DASYAM
Galeebu SHEIK
Original Assignee
Dr. Reddy’S Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dr. Reddy’S Laboratories Limited filed Critical Dr. Reddy’S Laboratories Limited
Publication of WO2016055945A1 publication Critical patent/WO2016055945A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C31/00—Saturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C31/18—Polyhydroxylic acyclic alcohols
    • C07C31/20—Dihydroxylic alcohols
    • C07C31/205—1,3-Propanediol; 1,2-Propanediol

Definitions

  • the present application relates to novel crystalline 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 adsorber, an oxygen adsorber or a combination thereof.
  • SGLT2 inhibitors 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 (1 S)-1 ,5-anhydro-1 -[3-[[5-(4- fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol. It has the chemical structure of formula (I).
  • 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.
  • US patent application document US8999941 B2 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.
  • 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.
  • Figure 1 is an illustration of a powder X-ray diffraction (PXRD) pattern of crystalline form R1 of Canagliflozin propylene glycol solvate.
  • PXRD powder X-ray diffraction
  • Figure 2 is an illustration of a powder X-ray diffraction (PXRD) pattern of crystalline form R2 of Canagliflozin propylene glycol solvate.
  • PXRD powder X-ray diffraction
  • 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.
  • PXRD powder X-ray diffraction
  • Figure 6 is an illustration of a powder X-ray diffraction (PXRD) pattern of initial amorphous form of Canagliflozin.
  • PXRD powder X-ray diffraction
  • 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.
  • PXRD powder X-ray diffraction
  • 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.
  • PXRD powder X-ray diffraction
  • 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.
  • PXRD powder X-ray diffraction
  • 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.
  • PXRD powder X-ray diffraction
  • Figure 1 1 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.
  • PXRD powder X-ray diffraction
  • 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.
  • PXRD powder X-ray diffraction
  • the present application provides Canagliflozin propylene glycol solvate, wherein it is crystalline.
  • the present application provides crystalline form R1 of Canagliflozin propylene glycol solvate.
  • 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 1 1.62°, 16.81 ° and 17.70° ⁇ 0.2°.
  • 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°.
  • 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 .
  • the present application provides crystalline form R2 of Canagliflozin propylene glycol solvate.
  • 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°.
  • 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 1 1.27°, 13.45°, 16.37°, 17.34° and 22.88° ⁇ 0.2°.
  • 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.
  • the present application provides crystalline form R3 of Canagliflozin propylene glycol solvate.
  • 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°, 1 1.99°, 14.85°, 19.89°, 22.06° ⁇ 0.2°.
  • 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°.
  • 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°.
  • 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.
  • the present application provides crystalline form R4 of Canagliflozin (S)-propylene glycol solvate.
  • 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 1 1.05°, 16.19°, 17.09°, 19.77° and 22.10° ⁇ 0.2°.
  • 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°.
  • 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.
  • the present application provides crystalline form R5 of Canagliflozin (R)-propylene glycol solvate.
  • 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°.
  • 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°.
  • 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.
  • the present application provides a storage stable amorphous form of Canagliflozin.
  • the present application provides a sealed packaging comprising an amorphous form of Canagliflozin and at least one stabilizer.
  • 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.
  • 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.
  • 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.
  • 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 present application provides a method of preparing Canagliflozin propylene glycol solvate comprising: a) forming a solution of Canagliflozin in propylene glycol,
  • Room temperature 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'.
  • room temperature can be from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.
  • 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 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.
  • oxygen absorber 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 02-scavenging capacities in sachets and common for food and beverages.
  • the broadest ranges of iron-based products are offered by Mitsubishi Gas Chemicals AgelessTM. Similar products are also offered by Multisorb under the trade name Fresh PaxTM.
  • 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.
  • sachets include D Series FreshPaxTM (available from Multisorb Technologies Inc), AgelessTM 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 ZPTJTM sachets (both available from Mitsubishi Gas Corporation), O-BusterTM (available from Hsiao Sung Non-Oxygen Chemical Co., Ltd), BiokaTM 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 SorBitTM (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.
  • 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 Sud-Chemie and Mitsubishi Gas Chemical Company).
  • PharmaKeep KD or KC PharmaKeep oxygen- and moisture-absorbing packets
  • 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.
  • HDPE high density polyethylene
  • PP polypropylene
  • LDPE low density polyethylene
  • PET PET
  • PVC polyvinyl chloride
  • the "inert gas” as used herein includes nitrogen gas and argon gas.
  • the present application provides Canagliflozin propylene glycol solvate.
  • the present application provides Canagliflozin propylene glycol solvate, wherein it is crystalline.
  • 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 1 1 .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 ".
  • 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 1 1 .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".
  • 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°, 1 1.99°, 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".
  • 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 1 1 .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".
  • 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°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.
  • crystalline forms of Canagliflozin of the present application may have a D 90 particle size of less than about 200 ⁇ , or less than about 150 ⁇ , or less than about 100 ⁇ , or less than about 90 ⁇ , or less than about 80 ⁇ , or less than about 60 ⁇ , or less than about 50 ⁇ , or less than about 40 ⁇ , or less than about 30 ⁇ , or less than about 20 ⁇ , or less than about 10 ⁇ , or less than about 5 ⁇ , 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.
  • 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.
  • the present application provides, a method of preparing Canagliflozin propylene glycol solvate comprising: a) forming a solution of Canagliflozin in propylene glycol,
  • step a) Canagliflozin is dissolved in propylene glycol to form a solution.
  • the Canagliflozin used as a seed material may be any crystalline form of Canagliflozin.
  • 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, Buchi® 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.
  • 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.
  • 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.
  • the present application provides a storage stable amorphous form of Canagliflozin.
  • the present application provides a sealed packaging comprising an amorphous form of Canagliflozin and at least one stabilizer.
  • 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.
  • 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,
  • 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.
  • 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.
  • 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.
  • 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.
  • compositions 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 starch,
  • HPLC detection was done using following conditions:
  • Canagliflozin (200 mg) and propylene glycol (150 ⁇ ) 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 ⁇ ) 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 ⁇ ) 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 ⁇ ) 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 ⁇ ) 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
  • 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 1 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.
  • 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, 1 1 and 12.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne le solvate de propylène glycol canagliflozine, des formes cristallines du solvate de propylène glycol Canagliflozine, son procédé de préparation et des compositions pharmaceutiques de celle-ci.
PCT/IB2015/057657 2014-10-08 2015-10-07 Polymorphes de la canagliflozine WO2016055945A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN5054/CHE/2014 2014-10-08
IN5054CH2014 2014-10-08
IN5784/CHE/2014 2014-11-17
IN5784CH2014 2014-11-17

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WO2016055945A1 true WO2016055945A1 (fr) 2016-04-14

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070015841A1 (en) * 2002-02-15 2007-01-18 Transform Pharmaceuticals, Inc. Pharmaceutical propylene glycol solvate compositions
WO2008116179A1 (fr) * 2007-03-22 2008-09-25 Bristol-Myers Squibb Préparations pharmaceutiques contenant de l'hydrate de propylèneglycol de dapagliflozine
WO2013064909A2 (fr) * 2011-10-31 2013-05-10 Scinopharm Taiwan, Ltd. Formes cristallines et non cristallines d'inhibiteurs de sglt2

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070015841A1 (en) * 2002-02-15 2007-01-18 Transform Pharmaceuticals, Inc. Pharmaceutical propylene glycol solvate compositions
WO2008116179A1 (fr) * 2007-03-22 2008-09-25 Bristol-Myers Squibb Préparations pharmaceutiques contenant de l'hydrate de propylèneglycol de dapagliflozine
WO2013064909A2 (fr) * 2011-10-31 2013-05-10 Scinopharm Taiwan, Ltd. Formes cristallines et non cristallines d'inhibiteurs de sglt2

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