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

INTRODUCTION
Aspects of the present application relate to process for the preparation of crystalline propane-1,2,3-triol solvate of dapagliflozin, process for the preparation of L-proline complex of dapagliflozin and pharmaceutical formulations of crystalline propane-1,2,3-triol solvate of dapagliflozin.
Diabetes mellitus is a serious and chronic metabolic disease that is characterized by high blood glucose (hyperglycemia) and affects millions of people world-wide. SGLT2 is a Sodium-dependent GLucose co-Transporter protein which affects the reabsorption of glucose in the kidney. It is estimated that 90% of renal glucose reabsorption is facilitated by SGLT2. Since glucose reabsorption is mediated predominantly by SGLT2 and because high glucose levels have been identified as a cause of disease in diabetes, SGLT2 has become a drug target for type 2 diabetes therapy. Selective inhibition of SGLT2 has the potential to reduce hyperglycemia by inhibiting glucose reabsorption in the kidney with elimination of glucose by excretion in the urine (glucosuria).
Dapagliflozin (trade name: Forxiga) is an active pharmaceutical ingredient (API) and a selective inhibitor of SGLT2 that is being developed for the treatment of type 2 diabetes mellitus.
Dapagliflozin is chemically described as (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol, and is also known as (1S)-1,5-anhydro-1-C-{4-chloro-3-[(4-ethoxyphenyl)methyl] phenyl}-D-glucitol. The structure of dapagliflozin is shown as formula I.

I
U.S. Patent No. 6,515,117 specifically discloses dapagliflozin and its pharmaceutically acceptable salts, a method for treating diabetes and related diseases employing dapagliflozin alone or in combination with another antidiabetic agent or other therapeutic agent.
U.S. Patent No. 6,515,117 discloses process for the preparation of dapagliflozin. As stated at column 5, lines 1-2 of U.S. Patent No. 7,919,598 “The compound of formula I (dapagliflozin) in the form of an non-crystalline solid is disclosed in U.S. Patent No. 6,515,117”.
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 5 discloses process for the preparation of amorphous dapagliflozin.U.S. Patent No.7,919,598 describes crystalline (S)-propylene glycol solvate hydrate of dapagliflozin and its process.
U.S. Patent application No.2013/0303467A1 describes different crystalline forms of dapagliflozin. International Publication No. WO2013/079501A1 describes crystalline dapagliflozin hydrate and its process. International Publication No. WO2013/064909A2 describes amorphous form of dapagliflozin. International Publication No. WO2015/011113A1 describes Amorphous solid dispersion of dapagliflozin.
The occurrences of different solid forms are possible for some compounds. A single compound may exist in different solid forms. Various solid forms of a drug substance can have different chemical and physical properties, including melting point, chemical reactivity, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can have a direct effect on the ability to process and/or manufacture the drug substance and the drug product, as well as on drug product stability, dissolution, and bioavailability. Thus, solid forms can affect the quality, safety, and efficacy of the drug product, regulatory authorities require that efforts shall be made to identify all solid forms, e.g., crystalline, amorphous, solvated, etc., of drug substances.
There still remains an unmet need for solid state forms of dapagliflozin having good physicochemical properties, desirable bioavailability, and advantageous pharmaceutical parameters.
SUMMARY OF THE INVENTION
A first aspect of the present application provides a crystalline propane-1,2,3-triol solvate of dapagliflozin.
A second aspect of the present application provides a process for the preparation of crystalline propane-1,2,3-triol solvate of dapagliflozin, comprising the steps of;
a) providing a solution of dapagliflozin in a solvent;
b) adding propane-1,2,3-triol to the solution obtained in step a);
c) optionally seeding with crystalline propane-1,2,3-triol solvate of dapagliflozin;
d) optionally combining the solution of step b) or c) with suitable anti solvent;
e) optionally adding water to the solution obtained in step b) or c) or d);
f) isolating the crystalline propane-1,2,3-triol solvate of dapagliflozin.
A third aspect of the present application provides a process for the preparation of L-proline complex of dapagliflozin comprising:
a) preparing a solution of dapagliflozin in a solvent;
b) adding L-proline;
c) isolating the L-proline complex of dapagliflozin.
A fourth aspect of the present invention also provides pharmaceutical formulations comprising crystalline propane-1,2,3-triol solvate of dapagliflozin together with one or more pharmaceutically acceptable excipients.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 illustrates an X-ray powder diffraction pattern of crystalline propane-1,2,3-triol solvate of dapagliflozin.
DETAILED DESCRIPTION
A first aspect of the present application provides a crystalline propane-1,2,3-triol solvate of dapagliflozin.
In specific aspect of the application provides a crystalline propane-1,2,3-triol solvate of dapagliflozin has an XRPD pattern with characteristic peak at about 21.57, 24.35, 24.69, 25.24, 28.13 and 31.39±0.2°2?. Crystalline propane-1,2,3-triol solvate of dapagliflozin further characterized by PXRD pattern comprising peaks at about 3.85, 12.35, 15.56, 16.03, 16.60 and 18.60±0.2°2?.
A second aspect of the present application provides a process for the preparation of crystalline propane-1,2,3-triol solvate of dapagliflozin, comprising the steps of;
a) providing a solution of dapagliflozin in a solvent;
b) adding propane-1,2,3-triol to the solution obtained in step a);
c) optionally seeding with crystalline propane-1,2,3-triol solvate of dapagliflozin;
d) optionally combining the solution of step b) or c) with suitable anti solvent;
e) optionally adding water to the solution obtained in step b) or c) or d);
f) isolating the crystalline propane-1,2,3-triol solvate of dapagliflozin.
Providing a solution of dapagliflozin in step a) includes:
i) direct use of a reaction mixture containing dapagliflozin that is obtained in the course of its synthesis; or
ii) dissolving dapagliflozin in a solvent.
Any physical form of dapagliflozin may be utilized for providing the solution of dapagliflozin in step a). Dapagliflozin that may be used as the input for the process of the present invention may be obtained by any process including the processes described in the art. For example dapagliflozin may be prepared by the processes described in IN3942/CHE/2010, US6515117B2 or US7375213B2. Suitable solvents that may be used in step a) include, but are not limited to, ester solvents; alcohol solvents; halogenated hydrocarbon solvents; nitrile solvents; polar aprotic solvents; ketone solvents; ether or mixtures thereof.
The dissolution temperatures may range from about 10°C to about the reflux temperature of the solvent, depending on the solvent used for dissolution, as long as a clear solution of dapagliflozin is obtained without affecting its quality. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and/or to clarify the solution.
Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing through paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
In embodiments of step b) involves adding propane-1,2,3-triol to the solution obtained in step a), propane-1,2,3-triol may be added directly to the solution of step a) or it can be combined with any of the solvent described in step a) before the addition.
In embodiments of step b) involves the molar ratio of dapagliflozin and propane-1,2,3-triol is in the range of 1:0.5 to 1:10. In an even more preferred embodiment the molar ratio of dapagliflozin and propane-1,2,3-triol is in the range of 1:1 to 1:3.
In embodiments of step c) involves optionally seeding with crystalline propane-1,2,3-triol solvate of dapagliflozin;
In embodiments of step d), optionally adding suitable anti solvent to the reaction mass of step b) or c), wherein the anti-solvent include, but are not limited to hydrocarbon solvents.
In specific embodiments of step d), suitable antisolvents that may be used include, but are not limited to cyclohexane.
In embodiments of step d), the isolation may be effected by combining the solution of step b) or c) with a suitable anti-solvent. Adding the solution obtained in step b) or c) to the anti-solvent, or adding an anti-solvent to the solution obtained in step b) or c), to effect the crystallization process are both within the scope of the present invention. Optionally, the addition may be carried out after concentrating the solution obtained in step b) or c). After adding anti-solvent, the reaction mass may be maintained from 15 minutes to 10 hours.
In embodiments of step e) involves optionally adding water to the solution obtained in step b) or c) or d);
In embodiments of step f), the compound obtained from step d) may be collected using techniques such as direct filtration or by scraping, or by shaking the container, or other techniques specific to the equipment used. Small quantity of solvent or anti solvent may be added to the reaction flask or the reactor to make the slurry or suspension when the solvent is completely removed, which will be useful for easy filtration.
The product thus isolated may be optionally further dried to afford a crystalline propane-1,2,3-triol solvate of dapagliflozin.
Drying may be suitably carried out in a tray dryer, vacuum oven, buchi rotavapor, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to several hours.
The dried product may be optionally milled to get desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller and hammer mills, and jet mills. etc., to produce a desired particle size distribution. Dapagliflozin obtained according to certain processes of the present application has a particle size distribution wherein: d(0.5) is less than about 100 µm, or less than about 25 µm, or less than about 10 µm; and d(0.9) is less than about 200 µm, or less than about 50 µm, or less than about 30 µm. Particle size distributions can be determined using any means, including laser light diffraction equipment sold by Malvern Instruments limited, Malvern, Worcestershire, United Kingdom, Coulter counters, microscopic procedures, etc. The term d(x) means that a particular fraction has particles with a maximum size being the value given; 0.5 represents 50% of the particles and 0.9 represents 90% of the particles.
Preferably, in the crystalline propane-1,2,3-triol solvate of dapagliflozin the molar ratio of dapagliflozin and propane-1,2,3-triol is in the range of 1:0.5 to 1:6. In an even more preferred embodiment the molar ratio of dapagliflozin and propane-1,2,3-triol is in the range of 1:1 to 1:3.
In an aspect, the application provides a crystalline propane-1,2,3-triol solvate of dapagliflozin has an XRPD pattern with characteristic peak at about 21.57, 24.35, 24.69, 25.24, 28.13 and 31.39±0.2°2?. Crystalline propane-1,2,3-triol solvate of dapagliflozin further characterized by PXRD pattern comprising peaks at about 3.85, 12.35, 15.56, 16.03, 16.60 and 18.60±0.2°2?.
Example of crystalline propane-1,2,3-triol solvate of dapagliflozin obtained using the above process is characterized by powder X-ray diffraction (“PXRD”) pattern substantially as illustrated.
In another embodiment, the crystalline propane-1,2,3-triol solvate of dapagliflozin may contain water and the molar ratio of water may vary between 0.5 moles to 8 moles with respect to 1 mole of dapagliflozin.
In the embodiment, the crystalline propane-1,2,3-triol solvate of dapagliflozin obtained according to the present invention can be used as an intermediate for making any crystalline form of dapagliflozin including solvates, complexes or amorphous form of dapagliflozin or solid dispersion of dapagliflozin along with the other pharmaceutically acceptable excipients.
A third aspect of the present application provides a process for the preparation of L-proline complex of dapagliflozin comprising:
a) preparing a solution of dapagliflozin in a solvent;
b) adding L-proline;
c) isolating the L-proline complex of dapagliflozin.
In embodiments of step a), suitable solvents that may be used include, but are not limited to, ester solvents, halogenated hydrocarbon solvents, ether solvent; nitrile solvents; alcohol solvents; polar aprotic solvents; ketone solvents; or mixtures thereof.
In specific embodiments suitable solvents that may be used in step a) is selected from ethyl acetate, dichloromethane or mixtures thereof.
In embodiments of step a), preparing a solution of dapagliflozin includes:
i) direct use of a reaction mixture containing dapagliflozin that is obtained in the course of its synthesis; or
ii) dissolving dapagliflozin in a solvent.
The dissolution temperatures may range from about 20°C to about the reflux temperature of the solvent, depending on the solvent used for dissolution, as long as a clear solution of dapagliflozin is obtained without affecting its quality.
In embodiments of step b), the L-proline used as solid or making the solution using solvents which are mentioned under step a. In embodiments of step b), the L-proline or L-proline solution may be added to the dapagliflozin solution obtained in step a) or vice-versa.
In embodiments of step b), the reaction mass is maintained at the temperature 10°C to about 70°C for about 15 minutes to about 10 hours, or longer.
In embodiments of step c), the isolation may be done using techniques such as direct filtration or by scraping, or by shaking the container, removal of the solvent include using a rotational distillation device such as a buchi rotavapor, spray drying, agitated thin film drying, freeze drying (lyophilization), and the like, or other techniques specific to the equipment used. Small quantity of solvent or anti solvent may be added to the reaction flask or the reactor to make the slurry or suspension when the solvent is completely removed, which will be useful for easy filtration.
The product thus isolated may be optionally further dried to afford L-proline complex of dapagliflozin.
Drying may be suitably carried out in a tray dryer, vacuum oven, buchi rotavapor, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to several hours.
In an aspect, the present application provides a purifying the L-proline complex of dapagliflozin can be done by any of the procedures known in the art which include but not limited to recrystallization, slurry washing, purification through column chromatography etc. The solvents that can be used for the purification of L-proline complex of dapagliflozin may be selected from alcohol solvents; ether solvent; nitrile solvents; halogenated hydrocarbon solvents; ester solvents; polar aprotic solvents; ketone solvents; or mixtures thereof.
In specific embodiments suitable solvents that may be used for the purification of L-proline complex of dapagliflozin is selected from methanol, ethyl acetate or mixtures thereof.
In the embodiment, the L-proline complex of dapagliflozin obtained according to the present invention can be used as an intermediate for making any crystalline solvate form of Dapagliflozin including solvates, complexes or amorphous form of dapagliflozin or solid dispersion of dapagliflozin along with the other pharmaceutically acceptable excipients.
In an aspect, the present application provides pharmaceutical formulations comprising crystalline propane-1,2,3-triol solvate of dapagliflozin, together with one or more pharmaceutically acceptable excipients. crystalline propane-1,2,3-triol solvate of dapagliflozin together with one or more pharmaceutically acceptable excipients of the present application may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, or capsules; liquid oral dosage forms such as, but not limited to, syrups, suspensions, dispersions, or emulsions; or injectable preparations such as, but not limited to, solutions, dispersions, or freeze dried compositions. Formulations may be in the forms of immediate release, delayed release, or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, or modified release compositions that may 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 may be prepared using techniques such as direct blending, dry granulation, wet granulation, or extrusion and spheronization. Compositions may 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 are useful in the present application include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methyl celluloses, pregelatinized starches, or the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, or the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, or the like; glidants such as colloidal silicon dioxide or the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins or resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes, or the like. Other pharmaceutically acceptable excipients that are of use include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, or the like.
Different solid forms are characterized by scattering techniques, e.g., x-ray powder diffraction pattern, by spectroscopic methods, e.g., infra-red, 13C nuclear magnetic resonance spectroscopy, and by thermal techniques, e.g., differential scanning calorimetry or differential thermal analysis. The compound of this application is best characterized by the X-ray powder diffraction pattern determined in accordance with procedures that are known in the art. For a discussion of these techniques see J. Haleblian, J. Pharm. Sci. 1975 64:1269-1288, and J. Haleblian and W. McCrone, J. Pharm. Sci. 1969 58:911-929. Crystalline propane-1,2,3-triol solvate of dapagliflozin can be further processed to modulate particle size. For example, crystalline propane-1,2,3-triol solvate of dapagliflozin can be milled to reduce average crystal size and/or to prepare a sample suitable for manipulation or formulation.
In an aspect of the application, crystalline propane-1,2,3-triol solvate of dapagliflozin prepared according to the processes of the present application can be substantially pure having a chemical purity greater than about 99%, or greater than about 99.5%, or greater than about 99.9%, by weight, as determined using high performance liquid chromatography (HPLC).
Crystalline propane-1,2,3-triol solvate of dapagliflozin produced by the method of present invention can be chemically pure having purity greater than about 99.5% and containing no single impurity in amounts greater than about 0.15%, by HPLC.
DEFINITIONS
The term “solvate” as used herein designates a crystalline molecular compound in which molecules of the solvent(s) other than water are incorporated into the crystal lattice.
Hence, the term “crystalline propane-1,2,3-triol solvate of dapagliflozin” as used herein means a crystalline form of dapagliflozin containing propane-1,2,3-triol molecules combined in a definite ratio as an integral part of the crystal.
The term “anti-solvent” refers to a liquid that, when combined with a solution of dapagliflozin, reduces solubility of the dapagliflozin in the solution, causing crystallization or precipitation in some instances spontaneously.
The following definitions are used in connection with the present application unless the context indicates otherwise. In general, the number of carbon atoms present in a given group or compound is designated “Cx-Cy”, where x and y are the lower and upper limits, respectively. For example, a group designated as “C1-C6” contains from 1 to 6 carbon atoms. The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like.
An “ester solvent” is an organic solvent containing a carboxyl group -(C=O)-O- bonded to two other carbon atoms. “Ester solvents” include, but are not limited to, ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, C3-6 esters, or the like.
An “alcohol solvent” is an organic solvent containing a carbon bound to a hydroxyl group. “Alcoholic solvents” include, but are not limited to, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, C1-6 alcohols, or the like.
A “halogenated hydrocarbon solvent” is an organic solvent containing a carbon bound to a halogen. “Halogenated hydrocarbon solvents” include, but are not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the like.
A “nitrile solvent” is an organic solvent containing a cyano -(C=N) bonded to another carbon atom. “Nitrile solvents” include, but are not limited to, acetonitrile, propionitrile, C2-6nitriles, or the like.
A “polar aprotic solvent” has a dielectric constant greater than 15 and is at least one selected from the group consisting of amide-based organic solvents, such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), formamide, acetamide, propanamide, hexamethyl phosphoramide (HMPA), and hexamethyl phosphorus triamide (HMPT); nitro-based organic solvents, such as nitromethane, nitroethane, nitropropane, and nitrobenzene; pyridine-based organic solvents, such as pyridine and picoline; sulfone-based solvents, such as dimethylsulfone, diethylsulfone, diisopropylsulfone, 2-methylsulfolane, 3-methylsulfolane, 2,4-dimethylsulfolane, 3,4-dimethy sulfolane, 3-sulfolene, and sulfolane; and sulfoxide-based solvents such as dimethylsulfoxide (DMSO).
A “ketone solvent” is an organic solvent containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “Ketone solvents” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, C3-6ketones, 4-methyl-pentane-2-one or the like.
An “ether solvent” is an organic solvent containing an oxygen atom –O- bonded to two other carbon atoms. “Ether solvents” include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, C2-6 ethers, or the like.
A “hydrocarbon solvent” refers to aliphatic hydrocarbon solvent.
An “aliphatic or alicyclic hydrocarbon solvent” refers to a liquid, non-aromatic, hydrocarbon, which may be linear, branched, or cyclic. It is capable of dissolving a solute to form a uniformly dispersed solution. Examples of a hydrocarbon solvents include, but are not limited to, cyclohexane, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, methylcyclohexane, cycloheptane, C5-C8 aliphatic hydrocarbons, petroleum ethers, or mixtures thereof.
The term "about" when used in the present invention 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 .
Certain specific aspects and embodiments of the present invention 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 invention in any manner.

EXAMPLES
EXAMPLE 1: Preparation of crystalline propane-1,2,3-triol solvate of Dapagliflozin.
Dapagliflozin (1 g) and isopropyl acetate (10 mL) were charged into a round bottom flask under nitrogen atmosphere at 28°C. The reaction mass was stirred to dissolve dapagliflozin completely. Propane-1,2,3-triol (0.2 mL) was charged into a flask under stirring at 28°C. The reaction mass was cooled to 10oC. Cyclohexane (30 mL) was added to the above obtained clear solution under stirring at 12°C. Water (0.044ml) was added to the flask containing the gummy mass and stirred for 50 minutes at 15°C. The resulting slurry was filtered under nitrogen atmosphere. The solid product was obtained as crystalline propane-1,2,3-triol solvate of dapagliflozin. Yield: 16.4%; Purity by HPLC: 99.57%.
EXAMPLE 2: Preparation of L-proline cocrystals of Dapagliflozin.
Dapagliflozin (63 g) and ethyl acetate (825 mL) were charged into a round bottom flask at 28°C. The reaction mass was heated to 44oC to produce a clear solution. L-proline (37.3 g) was added to the reaction mass at 44oC. The reaction mass was stirred for 2 hour at 44oC. The reaction mass cooled to 28oC and stirred for 5 hours. The resulting slurry was filtered and washed with ethyl acetate (125 mL). The solid was dried with suction at 28°C. The obtained solid (120 g) and methanol (63 mL) were charged into a round bottom flask at 28°C. The reaction mass was heated to 63oC to produce a clear solution. Ethyl acetate (630 mL) was added to the reaction mass at 63oC for 5 minutes. The reaction mass was stirred for 1 hour at 60oC. The reaction mass cooled to 28oC and stirred for 4 hours. The resulting slurry was filtered and washed with ethyl acetate (125 mL). The solid was dried with suction at 28°C. The solid was dried under vacuum at 53°C for 5 hours. The solid was dried at 53°C for 16 hours. Product weight: 81.0 g; Purity: 99.8% by HPLC.
EXAMPLE 3: Preparation of L-proline cocrystals of Dapagliflozin.
Dapagliflozin (10 g), dichloromethane (220 mL) and L-proline (5.91 g) were charged into a round bottom flask at 28°C. The reaction mass was stirred for 5 hours at 28oC. The resulting slurry was filtered and washed with dichloromethane (20 mL). The solid was dried with suction at 28°C. The obtained solid (15.5 g) and methanol (15 mL) were charged into a round bottom flask at 28°C. The reaction mass was heated to 60oC to produce a clear solution. Ethyl acetate (100 mL) was added to the reaction mass at 60oC. The reaction mass cooled to 30oC and stirred for 2 hours. The resulting slurry was filtered and washed with ethyl acetate (20 mL). The solid was dried with suction at 28°C. The solid was dried under vacuum at 55°C for 6 hours.
EXAMPLE 4: Preparation of L-proline complex of dapagliflozin.
2R,3S,4R,5R)-1-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3,4,5,6-pentahydroxy hexan-1-one (50 g) and methanol (500 mL) were charged into a round bottom flask at 28°C. The reaction mass was stirred for 30 minutes at 28°C. The reaction mass was cooled to 5°C. Methanesulfonic acid (11.31g) was added to the reaction mass at 2°C . The reaction mass temperature raised to 17°C. The reaction mass was stirred for 9 hours at 17°C. Dichloromethane (350 mL) was added to the reaction mass at 22°C. 5% NaHCO3 solution (500 mL) was added to the reaction mass at 22°C. The reaction mass was stirred for 15 minutes at 25°C. The organic and aqueous layers were separated. Extracted the the product from aqueous layer with dichloromethane (2X200 mL). The combined organic layer was washed with 10% sodium chloride solution (2X250 mL). The organic layer was evaporated under vacuum at 45°C. Dichloromethane (2X200 mL) was added to the above obtained residue and evaporated under vacuum at 45°C. The residue product was obtained as (3R,4S,5S,6R)-2-(4-chloro-3-(4- ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol.
(2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxy methyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol solution (51.5 g in 50 mL of dichloromethane) was charged into a round bottom flask. Charged dichloromethane(750mL) to the residue.The solution was cooled to -35°C. Triethylsilane (34.1 g) was added to the reaction mass at -35°C. Boron trifluoride etherate (88.3 g ; 48%) was added to the reaction mass at -35°C. The reaction mass was stirred for 3 hours at -35°C. The reaction mass temperature raised to -5°C. The reaction mass was stirred for 4 hours at -5°C. Add slowly water (500 mL) to the reaction mass. The reaction mass temperature raised to 28°C. The organic and aqueous layers were separated. The organic layer was washed with water (500 mL). 2% NaHCO3 solution (250 mL), methanol (100 mL) and 20% NaCl solution (250mL) were added to the reaction mass. The reaction mass was stirred for 20 minutes. The organic and aqueous layers were separated. Methanol (100 mL) and 2% NaCl solution (250mL) were added to the reaction mass. The reaction mass was stirred for 20 minutes. The organic and aqueous layers were separated. The reaction mass was evaporated under vacuum at 45 °C. The residue product was obtained as crude dapagliflozin. Ethyl acetate (250 mL) was added to the reaction mass. The reaction mass was evaporated under vacuum at 55°C. Dapagliflozin residue (48.11 g in 50 mL of ethyl acetate) and ethyl acetate (350 mL) were charged into a round bottom flask. The reaction mass temperature raised to 57 °C. L-proline (13.5 g) was added to the reaction mass at 57°C, Flushed the funnel with ethyl acetate (25 mL) and stir the reaction mass for 2 hours at 57°C. L-proline (6.75 g) was added to the reaction mass at 57°C, Flushed the funnel with ethyl acetate (25 mL). The reaction mass was stirred for 1 hour at 57°C. L-proline (6.75 g) was added to the reaction mass at 57°C, Flushed the funnel with ethyl acetate (25 mL). The reaction mass was stirred for 1 hour at 55 °C. The reaction mass temperature cooled to 28°C. The reaction mass was stirred for 5 hours at 28°C. The resulting slurry was filtered and washed with ethyl acetate (150 mL). The solid was suck dried with suction at 28°C. Compound was dried under vaccume at 55°C for 4 hours to get LOD below 10 %.
Example 5: Purification of L-proline complex of Dapagliflozin.
Methanol (40 mL) was charged into a round bottom flask at 28°C. The reaction mass temperature was raised to 52 °C. L-proline complex of Dapagliflozin (20 g) was added to the reaction mass at 52°C. Flushed the funnel with methanol (10 mL). The reaction mass temperature was raised to 63°C.The reaction mass was stirred for 15 minutes at 63°C. Ethyl acetate (400 mL) was charged into separate round bottom flask at 28°C. Ethyl acetate temperature was raised to 60 °C. The reaction mass was slowly added to ethyl acetate at 60°C. Flushed the round bottom flask funnel with methanol (10 mL) and charged into reaction mass at 60°C. Stirred the reaction mass for 1 hour at 60°C. The reaction mass temperature cooled to 30°C. Stirred the reaction mass for 4 hours at 30°C. The resulting slurry was filtered and washed with ethyl acetate (60 mL). The solid was dried with suction at 28°C. The solid was further dried for 6 hours at 55°C. Product weight: 17.35 g; purity by HPLC: 99.97%.
Example 6: Purification of L-proline complex of Dapagliflozin.
Methanol (1.25 liters) was charged into a round bottom flask at 28°C. The reaction mass temperature was raised to 52 °C. L-proline complex of Dapagliflozin (1.0 Kg) was added to the reaction mass at 52°C. The reaction mass temperature was raised to 63°C.The reaction mass was stirred for 15 minutes at 63°C. Ethyl acetate (10 liters) was charged into separate round bottom flask at 28°C. Ethyl acetate temperature was raised to 60 °C. The reaction mass was slowly added to ethyl acetate at 60°C. Flushed the round bottom flask funnel with methanol (250 mL) and charged into reaction mass at 60°C. Stirred the reaction mass for 1 hour 20 minutes at 60°C. The reaction mass temperature cooled to 30°C. Stirred the reaction mass for 5 hours at 30°C. The resulting slurry was filtered and washed with ethyl acetate (500 mL). The solid was dried with suction at 28°C. The solid was further dried for 9 hours at 55°C. Product weight: 542 g; purity by HPLC: 99.86%.
,CLAIMS:We Claim:
1. A process for the preparation of crystalline propane-1,2,3-triol solvate of dapagliflozin comprising the steps of;
a) providing a solution of dapagliflozin in a solvent;
b) adding propane-1,2,3-triol to the solution obtained in step a);
c) optionally seeding with crystalline propane-1,2,3-triol solvate of dapagliflozin;
d) optionally combining the solution of step b) or c) with suitable anti solvent;
e) optionally adding water to the solution obtained in step b) or c) or d);
f) isolating the crystalline propane-1,2,3-triol solvate of dapagliflozin.
2. The process according to claim 1, wherein the solvent is selected from ester solvents, alcohol solvents, halogenated hydrocarbon solvents, nitrile solvents, polar aprotic solvents, ketone solvents, ether or mixtures thereof.
3. The process according to claim 1, wherein the ester solvent is selected from isopropyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate.
4. The process according to claim 2, wherein the ester solvent is selected from isopropyl acetate.
5. The process according to claim 1, wherein the anti solvent is hydrocarbon solvent.
6. The process according to claim 5, wherein the hydrocarbon solvent is cyclohexane.
7. A process for the preparation of L-proline complex of dapagliflozin comprising:
a) preparing a solution of dapagliflozin in a solvent selected from ester solvents, halogenated hydrocarbon solvents, nitrile solvents, polar aprotic solvents, ketone solvents, ether or mixtures thereof.
b) adding L-proline to the above obtained dapagliflozin solution;
c) isolating the L-proline complex of dapagliflozin;
d) optionally purifying the above obtained L-proline complex of dapagliflozin.
8. The process according to claim 7, wherein the ester solvent is selected from ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate.
9. The process according to claim 7, wherein the ester solvent is ethyl acetate.
10. The process according to claim 7, wherein the halogenated hydrocarbon solvent is selected from dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride.