DESC:The following specification particularly describes the invention and the manner in which it is to be performed:
PROCESS FOR PREPARATION OF SOLID STATE FORMS OF EMPAGLIFLOZIN

FIELD OF THE INVENTION
The present application relates to processes for preparation of amorphous and crystalline forms of empagliflozin.

BACKGROUND OF THE INVENTION
The drug compound having the adopted name Empagliflozin, has a chemical name 1-chloro-4(beta-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl)-benzene, and is represented by the structure of formula I.

Empagliflozin is a sodium-dependent glucose cotransporter 2 (SGLT 2) inhibitor and is used for the treatment of patients with type 2 diabetes mellitus.
Empagliflozin and its synthetic methods are described in US Patent No. 7,579,449 (US ‘449). Example 3 of US ‘449 describes isolation of empagliflozin as “the organic phase (ethylacetate phase) is dried over sodium sulphate, the solvent is removed and the residue is purified using silica gel column chromatography (dichloromethane/ methanol 1:0?5:1).
US Patent No. 7,713,938 (US ‘938) discloses a crystalline form of empagliflozin and a pharmaceutical composition comprising the crystalline form. The US ‘938 also discloses that “the method of manufacturing empagliflozin as described in product patent process does not yield a crystalline form”.
Indian patent application (IN1985MUM2013A), PCT applications (WO2016051368A1, WO2016131431A1, WO2016169534A1 and WO2017046730A1), and Chinese patent applications (CN104788438A, CN105384730A1, CN105481843A, CN105496966A, CN106188021A and CN106317035A) describe various solid state forms and co-crystals of empagliflozin and processes for preparation thereof.
There remains a need to provide commercially viable and advantageous processes for preparation of pure and stable amorphous form and crystalline forms of empagliflozin.
SUMMARY OF THE INVENTION
The present application relates to amorphous empagliflozin, amorphous solid dispersion of empagliflozin, and process for preparation of crystalline form of empagliflozin, and pharmaceutical compositions thereof.
In the first aspect, the present application provides stable amorphous empagliflozin.
In the second aspect, the present application provides amorphous empagliflozin having a glass transition onset temperature of at least 60 °C or above.
In the third aspect, the present application provides a process for preparing amorphous empagliflozin having a glass transition onset temperature of at least 60 °C or above, comprising;
a) providing a solution of empagliflozin in a solvent or a mixture solvents;
b) removing solvent from the solution obtained in step (a); and
c) recovering amorphous form of empagliflozin.
In the fourth aspect, the present application provides amorphous solid dispersion of empagliflozin, , having a glass transition onset temperature of at least 55 °C or above, comprising empagliflozin and one or more pharmaceutically acceptable carriers.
In the fifth aspect, the present application provides a process for preparing amorphous solid dispersion of empagliflozin, having a glass transition onset temperature of at least 55 °C or above, comprising empagliflozin and one or more pharmaceutically acceptable carriers, comprising;
a) providing a solution comprising empagliflozin and one or more pharmaceutically acceptable carriers,
b) removing solvent from the solution obtained in step (a), and
c) recovering an amorphous solid dispersion comprising empagliflozin and one or more pharmaceutically acceptable carriers.
In the sixth aspect, the present application provides a process for preparing crystalline form of empagliflozin characterized by PXRD peaks at 18.84°, 20.36°, and 25.21° 2 theta, which comprises;
a) providing a solution of empagliflozin in a solvent or a mixture of solvents;
b) heating the solution to a temperature higher than the temperature at which the solution is prepared;
c) adding an anti-solvent to the hot solution; and
d) isolating crystalline form of empagliflozin characterized by PXRD peaks at 18.84°, 20.36°, and 25.21° 2 theta.
In the seventh aspect, the present application provides a process for purification of empagliflozin, comprising:
a) providing a solution of empagliflozin L-proline complex, characterized by an X-Ray Powder Diffraction (XRPD) pattern having peaks at about 4.36 ± 0.2, 12.97 ± 0.2, 15.67 ± 0.2 and 18.80 ± 0.2 °2?, in a mixture of an organic solvent and water;
b) optionally, heating the solution obtained in step (a);
c) separating the organic layer from the mixture obtained in step (b); and
d) isolating pure empagliflozin from the organic layer of step (c).
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is powder X-ray power diffraction pattern of an amorphous form of empagliflozin prepared according to Example 1.
Figure 2 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and HPMC Phthalate prepared according to Example 6.
Figure 3 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and methyl cellulose prepared according to Example 7.
Figure 4 is powder X-ray power diffraction pattern of crystalline form of empagliflozin prepared according to Example 8.
Figure 5 is powder X-ray power diffraction pattern of empagliflozin L-proline complex prepared according to Example 13.
Figure 6 is DSC thermogram of amorphous Empagliflozin prepared according to Example 15.
DETAILED DESCRIPTION
Empagliflozin used as the input in the process for preparation of stable amorphous empagliflozin and amorphous solid dispersion of the present invention can be prepared by any process known in the art.
In the first aspect, the present application provides stable amorphous empagliflozin.
In the second aspect, the present application provides amorphous empagliflozin having a glass transition onset temperature of at least 60 °C or above.
In the third aspect, the present application provides a process for preparing amorphous empagliflozin having a glass transition onset temperature of at least 60 °C or above, comprising;
a) providing a solution of empagliflozin in a solvent or a mixture solvents;
b) removing solvent from the solution obtained in step (a); and
c) recovering amorphous empagliflozin having a glass transition onset temperature of at least 60 °C or above.
Providing a solution in step (a) includes direct use of a reaction mixture containing empagliflozin that is obtained in the course of its synthesis or dissolving empagliflozin in a solvent or a mixture of solvents.
Any physical form of empagliflozin may be utilized for providing the solution of empagliflozin in step (a). Suitable solvents which can be used for dissolving empagliflozin include but are not limited to: alcohol solvents such as methanol, ethanol, isopropyl alcohol, n-propanol, isoamyl alcohol n-butanol, 2-butanol and the like; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; dimethylformamide, dimethylacetamide and dimethylsulfoxide; and any mixtures of two or more thereof.
After dissolution in step (a), the obtained solution may be optionally filtered to remove any insoluble particles. Suitable techniques to remove insoluble particles are filtration, centrifugation, decantation, and any other known techniques in the art. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as Celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature precipitation of solid.
Step (b) involves removing solvent from the solution of empagliflozin. Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, agitated thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying or any other suitable technique known in the art.
Step (c) involves recovering an amorphous form of empagliflozin. The said recovery can be achieved by using the processes known in the art.
The resulting compound in step (c) may optionally be further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the empagliflozin is not degraded in its quality. The drying can be carried out for any desired times until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.
In another aspect, the present application provides amorphous Empagliflozin having a chemical purity of at least 99% by HPLC or at least 99.5% by HPLC or at least 99.9% by HPLC.
The amorphous empagliflozin is stable for 3 months in ICH storage conditions i.e. (i) 25°C ± 2°C and 60%RH ± 5RH, (ii) 40°C±2°C and 75%RH ± 5RH, (iii) 30 °C ± 2 °C and 75%RH ± 5RH and (iv) 2°C - 8°C. Packing conditions used for amorphous empagliflozin are incorporated below.
Packing method-1: Take the sample in a clear anti-static polyethylene bag and tie it with plastic strip by twisting after removing air. Keep the above in a black polythene bag along with Molecular sieve pouch, fill it with nitrogen gas and tie it with plastic strip. Keep the bag in triple laminated bag and seal it with VNS Sealer, keep the above triple laminated bag in another triple laminated bag and seal it with VNS Sealer. Finally keep the packet in HDPE container and store in the stability chamber.
Packing method-2: Take the sample in a clear anti-static polyethylene bag and tie it with plastic strip by twisting after removing air. Keep the above in a black polythene bag fill it with nitrogen gas and tie it with plastic strip. Keep the bag in triple laminated bag and seal it with VNS Sealer, keep the above triple laminated bag in another triple laminated bag and seal it with VNS Sealer. Finally keep the packet in HDPE container and store in the stability chamber.
Amorphous empagliflozin of the present application was found to be stable under mechanical stress such as grinding and milling and stable under hygroscopic conditions such as higher relative humidity conditions of more than 60% RH.
In another aspect, the amorphous empagliflozin of the present invention is showing glass transition onset temperature of 66.29 °C, and glass transition temperature of 70.13 °C. The DSC thermogram is shown in Figure 35.
In the fourth aspect, the present application provides amorphous solid dispersion of empagliflozin, having a glass transition onset temperature of at least 55 °C or above, comprising empagliflozin and one or more pharmaceutically acceptable carriers.
In the fifth aspect, the present application provides a process for preparing amorphous solid dispersion of empagliflozin, having a glass transition onset temperature of at least 55 °C or above, comprising empagliflozin and one or more pharmaceutically acceptable carriers, comprising;
a) providing a solution comprising empagliflozin and one or more pharmaceutically acceptable carriers,
b) removing solvent from the solution obtained in step (a), and
c) recovering an amorphous solid dispersion having a glass transition onset temperature of at least 60 °C or above, comprising empagliflozin and one or more pharmaceutically acceptable carriers.
Providing a solution in step (a) includes direct use of a reaction mixture containing empagliflozin that is obtained in the course of its synthesis or dissolving empagliflozin and pharmaceutically acceptable carrier in a solvent.
Any physical form of empagliflozin may be utilized for providing the solution of empagliflozin in step (a).
Suitable pharmaceutically acceptable carriers which can be used in step (a) include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, Polyethylene glycol, Copovidone, Soluplus, Silicified microcrystalline cellulose mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses such as HPMC-Phthalate, HPMC-AS, HPMC-15 CPS; pregelatinized starches and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, 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 and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes and 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, and the like.
In a preferred aspect, the pharmaceutically acceptable carriers are hydroxypropyl methylcellulose phthalate (HPMC-Phthalate) and methyl cellulose.
Suitable solvents which can be used for dissolving the empagliflozin include but are not limited to: alcohol solvents such as methanol, ethanol, isopropyl alcohol, n-propanol, isoamyl alcohol n-butanol, 2-butanol and the like; halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, chloroform, carbon tetrachloride and the like; ketones such as acetone, ethyl methyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; nitriles such as acetonitrile, propionitrile and the like; dimethylformamide, dimethylacetamide and dimethylsulfoxide, and any mixtures of two or more thereof.
After dissolution in step (a), optionally undissolved particles, if any, may be removed suitably by filtration, centrifugation, decantation, and any other known techniques. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as celite. 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.
Step (b) involves removing solvent from the solution obtained in step (a);
Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, agitated thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying, filtration or any other technique known in the art.
Step (c) involves recovering an amorphous solid dispersion comprising empagliflozin and one or more pharmaceutically acceptable carriers. The said recovery can be achieved by using the processes known in the art.
The resulting compound obtained in step (c) may optionally be further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the empagliflozin is not degraded in its quality. The drying can be carried out for any desired time until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.
When the active ingredient is hygroscopic or the formulation contains a hygroscopic ingredient, and to increase the stability of the amorphous form or a solid dispersion comprising amorphous empagliflozin, addition of other carriers such as syloid, methyl cellulose, colloidal silicon dioxide, Eudragit, amorphous silica, micro crystalline cellulose, and the like, in the formulation has been found to be of particular value. Therefore these ingredients may be combined during the preparation of solid dispersion or after the preparation of amorphous empagliflozin or solid dispersion to control hygroscopicity and to improve stability.
In the sixth aspect, the present application provides a process for preparing crystalline form of empagliflozin characterized by PXRD peaks at 18.84°, 20.36°, and 25.21° 2 theta, which comprises;
a) providing a solution of empagliflozin in a solvent or a mixture of solvents;
b) heating the solution to a temperature higher than the temperature at which the solution is prepared;
c) adding an anti-solvent to the hot solution; and
d) isolating crystalline form of empagliflozin characterized by PXRD peaks at 18.84°, 20.36°, and 25.21° 2 theta.
Providing a solution in step (a) includes direct use of a reaction mixture containing empagliflozin that is obtained in the course of its synthesis or dissolving empagliflozin in a solvent or a mixture of solvents.
Any physical form of empagliflozin may be utilized for providing the solution of empagliflozin in step (a). Suitable solvents which can be used for dissolving empagliflozin include but are not limited to: alcohol solvents such as methanol, ethanol, isopropyl alcohol, n-propanol, isoamyl alcohol n-butanol, 2-butanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like and the like; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride and the like; dimethylformamide, dimethylacetamide and dimethylsulfoxide; and any mixtures of two or more thereof.
If the empagliflozin is not dissolved in the solvent the mixture may be heated to get the complete dissolution.
After dissolution in step (a), the obtained solution may optionally be filtered to remove any insoluble particles. Suitable techniques to remove insoluble particles are filtration, centrifugation, decantation, and any other known techniques in the art. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as Celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature precipitation of solid.
Step (b) involves heating the solution obtained in step (a) to a temperature higher than the temperature at which the solution is prepared.
If the solution of step (a) is prepared at 30°C, the solution is heated to above 30°C, or If the solution of step (a) is prepared at 45°C, the solution is heated to above 45°C.
Step (c) involves adding an anti-solvent to the hot solution obtained step (c). The suitable anti-solvents may include, but not limited to water, pentane, n-hexane, cyclohexane, cylcoheptane, n-heptane, diethyl ether, methyl ter. butyl ether, di isopropyl ether, cyclopentyl methyl ether, pet ether and the like. Preferably suitable anti- solvents are water, n-heptane and pet ether.
The anti-solvent may be added to precipitate the crystalline form of empagliflozin or a reverse mode of addition may also be employed.
In an aspect, the mixture may be stirred for sufficient time i.e. 15 minutes to 10 hours or more.
In an aspect, anti-solvent addition may be carried out at suitable temperatures, such as at about 30°C to 100°C. Preferably suitable temperature may be at about 40 to 80°C.
In an aspect, anti-solvent addition may be carried out for sufficient time to complete precipitation of crystalline form of empagliflozin. In an aspect, anti-solvent addition may be carried out in sufficient volume to complete precipitation of crystalline form of empagliflozin.
Step (d) involves isolation of crystalline form of empagliflozin. Isolation of crystalline form of empagliflozin may be carried out by any known methods such as filtration of precipitated solid.
In one aspect, the isolation of crystalline form of empagliflozin is carried out at a temperature at which the precipitation is formed.
The crystalline form of empagliflozin obtained in step (d) may optionally be washed with the anti-solvent with sufficient volume to remove traces solvent from wet solid. The crystalline form of empagliflozin obtained as above may be dried, if desired, at suitable temperatures at about 50°C, or above. The drying may be performed at atmospheric or reduced pressures, for about 1 – 20 hours, or longer by using the drying equipment known in the art.
In another aspect, the crystalline form of empagliflozin characterized by PXRD peaks at 18.84°, 20.36°, and 25.21° ± 0.2 degrees 2 theta can be prepared by slurrying amorphous empagliflozin in water or on a similar solvent and isolating the crystalline form of empagliflozin by the known methods.
In another aspect, the present application provides the crystalline form of empagliflozin characterized by PXRD peaks at 18.84°, 20.36°, and 25.21° ± 0.2 degrees 2 theta prepared by the process described above having a chemical purity of at least 99% by HPLC or at least 99.5% by HPLC or at least 99.9% by HPLC.
In the seventh aspect, the present application provides an empagliflozin L-proline complex characterized by PXRD peaks at about 4.36 ± 0.2, 12.97 ± 0.2, 15.67 ± 0.2 and 18.80 ± 0.2 degrees 2-theta.
In the eighth aspect, the present application provides a process for preparation of the empagliflozin L-proline complex characterized by PXRD peaks at about 4.36 ± 0.2, 12.97 ± 0.2, 15.67 ± 0.2 and 18.80 ± 0.2 degrees 2-theta, comprising:
(a) mixing empagliflozin and L-proline in a solvent or a mixture of solvents;
(b) optionally, heating the mixture obtained in step (a);
(c) isolating the empagliflozin L-proline complex.
Step (a) of the process involves mixing empagliflozin and L-proline in a solvent or a mixture of solvents.
Preferred solvents are alcoholic solvents such as methanol, ethanol, isopropyl alcohol, n-propanol, isoamyl alcohol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like. Any physical form of empagliflozin can be used as the starting material of the present invention.
The mixture of empagliflozin and L-proline is prepared in any method such as first the L-proline is added to the solvent and then empagliflozin is added or first empagliflozin is added to a solvent and then L-proline is added. In a specific aspect empagliflozin and L-proline are added at a time.
In certain aspects, about 1 equivalent of L-proline is used to prepare empagliflozin L-proline complex. In other aspects, about 2 equivalents of L-proline is used to prepare empagliflozin L-proline complex. In yet other aspects, greater than 2 equivalents of L-proline is used to prepare empagliflozin L-proline complex. In still other aspects, about 0.9 to about 1.1 equivalents of L-proline is used to prepare empagliflozin L-proline complex. In further aspects, about 1.8 to about 2.2 equivalents, such as about 1.98 to 2.02 equivalents, of L-proline is used to prepare empagliflozin L-proline complex.
Step (b) involves optionally heating the mixture obtained in step (a). The mixture obtained step (a) may be heated to a temperature of about 40°C to about 150°C. Preferably the mixture is heated to a temperature of about 60°C to about 80°C. The mixture may be stirred for about 10 minutes to about 10 hours or longer.
Step (c) involves isolation of empagliflozin L-proline complex from the mixture of step (b). The isolation of empagliflozin L-proline complex may be carried out by any known methods such as filtration of precipitated solid.
The empagliflozin L-proline complex obtained as above may be dried, if desired, at suitable temperatures at about 50°C, or above. The drying may be performed at atmospheric or reduced pressures, for about 1 – 20 hours, or longer by using the drying equipment known in the art.
Powder X-ray diffraction pattern (PXRD) the empagliflozin L-proline complex obtained by the process of the present application is depicted in Figure 5.
Similar process can be adopted to produce other amino acid complexes of empagliflozin. The amino acids which can be used to produce empagliflozin complexes include, but not limited to, glycine, alanine, serine, threonine, cysteine, valine, leucine, isoleucine, methionine, phenylalanine, tyrosine, tryptophan, aspartic acid, glutamic acid, asparagine, glutamine, histidine, lysine, arginine.
The amino acid complexes of empagliflozin may be useful as intermediate. During the formation of the complex, the empagliflozin crude may get purified as the impurities are removed during the complex formation. This intermediate can sufficiently be purified to produce the final empagliflozin in the desired form. The purification involves slurrying, recrystallization, crystallization etc.
In the ninth aspect, the present application provides a pharmaceutical composition comprising any of amorphous empagliflozin or empagliflozin solid dispersion or empagliflozin L-proline complex or the crystalline form of empagliflozin of the present invention and at least one pharmaceutically acceptable carrier.

DEFINITIONS
The following definitions are used in connection with the present invention unless the context indicates otherwise. The term “amorphous” refers to a solid lacking any long-range translational orientation symmetry that characterizes crystalline structures although; it may have short range molecular order similar to a crystalline solid.
As used herein, the term "complex" refers to a molecular entity formed by association involving two or more component molecular entities (ionic or uncharged), or by association involving two or more chemical species. The bonding between the components is non-covalent and is normally weaker than covalent bonding. Accordingly, the empagliflozin L-proline complex described herein is a molecular entity formed by the association between empagliflozin and L-proline. The empagliflozin- L-proline complex may in some embodiments exist as a solid state form that is referred to herein as a co crystal form of an empagliflozin-L-proline complex, or as an empalgiflozin L-proline co-crystal, or as a crystalline empagliflozin- L-proline complex.
The term “anti-solvent” refers to a liquid that, when combined with a solution of empagliflozin, reduces solubility of the empagliflozin in the solution, causing crystallization or precipitation in some instances spontaneously, and in other instances with additional steps, such as seeding, cooling, scratching and/or concentrating.
Celite is flux-calcined diatomaceous earth. Hyflo is flux-calcined diatomaceous earth treated with sodium carbonate.
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, glycerol, or the like.
A “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 solvent include, but are not limited to, 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, cyclohexane, methylcyclohexane, cycloheptane, Examples of aromatic hydrocarbon solvents include, but are not limited to benzene, toluene, ethylbenzene, m-xylene, o xylene, p-xylene, indane, naphthalene, tetralin, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, C6-C10 aromatic hydrocarbons, or mixtures thereof.
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, n-propyl acetate, isopropyl 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.
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 “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 isopropyl ketone, methyl isobutyl ketone, C3-6ketones, 4- methyl-pentane-2-one 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), Nmethylpyrrolidone (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).
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 (THF), 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, C2-6 ethers, or the like.
As used herein, the term "co-crystal" refers to a crystal complex composed of at least two neutral molecules bound together in a crystal lattice by non-covalent interactions. The term “co-crystal” also can be referred as adduct.
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 amorphous form of empagliflozin.
Empagliflozin (2 gm) and n-Propanol (120 mL) were charged into a 250 mL round bottom flask at 27°C. The mixture was heated to 70°C and stirred for 15 min. The solution was filtered to remove the un-dissolved particles and the filtrate was evaporated by spray drying, using a Büchi® MINI Spray Dryer B-290 with Büchi® Inert Loop B-295 at 95°C to afford 880 mg of amorphous empagliflozin.
PXRD pattern: Fig. 1.
Parameters for the spray drier of the above experiment: Aspirator: 70 %; Feed rate: 20 mL/ min; Inlet temperature: 95°C; Outlet temperature: 60°C.
Example 2: Preparation of amorphous form of empagliflozin.
Empagliflozin (500 mg) and methanol (35 mL) were charged into a Buchi flask at 27°C. The mixture was heated to 55°C and stirred for 10 min. The solution was filtered to remove the un-dissolved particles and the filtrate was distilled under reduced pressure at 60°C. After distillation the solid was dried under vacuum at 25°C to get 260 mg of amorphous empagliflozin. PXRD pattern: amorphous
Example 3: Preparation of amorphous form of empagliflozin.
Empagliflozin (500 mg), dichloromethane (10 mL) and n-Propanol (10 mL) were added to a test tube at 27°C. The mixture was heated to 65°C and stirred for 15 min. The solution was filtered to remove the un-dissolved particles and the filtrate was distilled under reduced pressure at 60°C to get 180 mg of amorphous empagliflozin. PXRD pattern: amorphous.
Example 4: Preparation of amorphous form of empagliflozin.
Empagliflozin (500 mg) and acetone (40 mL) were charged into a round bottom flask at 27°C. The mixture was heated to 60°C and stirred for 15 min. The solution was filtered to remove the un-dissolved particles and the filtrate was distilled under reduced pressure at 60°C to get amorphous empagliflozin. PXRD pattern: amorphous.
Example 5: Preparation of amorphous form of empagliflozin.
Empagliflozin (2 gm) and 2-Butanol (170 mL) were charged into a 250 mL round bottom flask at 27°C. The mixture was heated to 75°C and stirred for 15 min. The solution was filtered to remove the un-dissolved particles and the filtrate was evaporated by spray drying, using a Büchi® MINI Spray Dryer B-290 with Büchi® Inert Loop B-295 at 95°C to afford 830 mg of amorphous empagliflozin. PXRD pattern: amorphous.
Parameters for the spray drier of the above experiment: Aspirator: 70%; Feed rate: 20 mL/min; Inlet temperature: 95°C; Outlet temperature: 60°C.
Example 6: Preparation of amorphous solid dispersion of empagliflozin and hydroxy propyl methyl cellulose phthalate (Hypromellose Phthalate; HPMC-Phthalate).
Empagliflozin (250 mg), Hypromellose Phthalate (250 mg) and methanol (30 mL) were charged into a round bottom flask at 27°C. The resulted mixture was heated to 60°C and stirred for 15 min. at 60°C. The clear solution was filtered to remove the un-dissolved particles and the filtrate was completely evaporated under reduced pressure at 60°C to get 180 mg of amorphous solid dispersion of empagliflozin and Hypromellose Phthalate. PXRD pattern: Fig. 2.
Example 7: Preparation of amorphous solid dispersion of empagliflozin and Methyl cellulose.
Empagliflozin (250 mg), Methyl cellulose (250 mg), methanol (25 mL) and water (25 mL) were charged into a round bottom flask at 27°C. The resulted mixture was heated to 50°C and stirred for 15 min. at 50°C. The clear solution was filtered to remove the un-dissolved particles and the filtrate was completely evaporated under reduced pressure at 70°C to get 432 mg of amorphous solid dispersion of empagliflozin and Methyl cellulose. PXRD pattern: Fig. 3.
Example 8: Preparation of crystalline form of empagliflozin.
Empagliflozin (500 mg) and methanol (10 mL) were charged into a round bottom flask at 27°C. The mixture was heated to 40°C and stirred for 10 min. The solution was filtered to remove the un-dissolved particles and the hot filtrate was taken into another round bottom flask. Water (30 mL) was added to the flask at 50°C and the mixture was stirred at 50°C for 2 hours. The precipitate was filtered at 50°C and the solid was dried under vacuum at 50°C to get 254 mg of crystalline empagliflozin. PXRD pattern: Fig. 4.
Example 9: Preparation of crystalline form of empagliflozin.
Empagliflozin (500 mg) and methanol (10 mL) were charged into a round bottom flask at 27°C. The mixture was heated to 40°C and stirred for 10 min. The solution was filtered to remove the un-dissolved particles and the hot filtrate was added to water (25 mL) at 60°C. The mixture was stirred at 50°C for 2 hours. The precipitate was filtered at 60°C to get 320 mg of crystalline empagliflozin. PXRD pattern matches with Fig. 4.
Example 10: Preparation of crystalline form of empagliflozin.
Empagliflozin (500 mg) and DMSO (2 mL) were charged into a test tube at 27°C and stirred for 10 min. The solution was filtered to remove the un-dissolved particles. The clear solution was added to water (10 mL) at 50°C and the mixture was stirred at 50°C for 2 hours. The precipitate was filtered at 50°C to get 340 mg of crystalline empagliflozin. PXRD pattern matches with Fig. 4.
Example 11: Preparation of crystalline form of empagliflozin.
Empagliflozin (500 mg) and acetone (15 mL) were charged into an easymax reactor at 27°C. The mixture was heated to 55°C and stirred for 10 min. The solution was filtered to remove the un-dissolved particles and the hot filtrate was taken into another round bottom flask. The clear solution was added to Heptane (25 mL) at 70°C and stirred for 1 hour at 70°C. Pet ether (25 mL) was added the mixture at 70°C and the mixture was stirred at 70°C for 2 hours. The precipitate was filtered at 70°C to get 374 mg of crystalline empagliflozin. PXRD pattern matches with Fig. 4.
Example 12: Purification of empagliflozin
(a) Preparation of empagliflozin and L-proline complex
Isopropanol (4 mL) and L-proline (0.459 g) were charged into 50 mL 2 neck round bottom flask. Water (0.5 mL) was added to the mass at 26°C. The mixture was heated to 80°C and stirred for 30 minutes at 80°C. A solution of empagliflozin (purity: 91.6%) (1 g of empagliflozin in 4 mL of isopropanol) was added to the reaction mixture at 80°C and resulted mixture was stirred for 1 hour at 80°C. Reaction mixture was cooled to 27°C and MTBE (16 mL) was added to the mixture and the reaction mixture was stirred for 2 hours at 27°C. The precipitation was filtered and the wet cake was washed with MTBE (4 mL) and suck dried for 1 hour to get the title complex.
(b) Conversion of empagliflozin L-proline complex to empagliflozin
Empagliflozin and L-proline complex prepared in example 12 was dissolved in water (10 mL) and ethylacetate (10 mL) and the resulted solution was stirred for 20 minutes at 27°C. Separated the layers and the aqueous layer was extracted with ethylacetate (10 mL). The ethylacetate layers were combined and washed with saturated NaCl solution (5 mL). The organic layer was dried over sodium sulphate and was concentrated under vacuum at 40°C to yield 0.470 g of empagliflozin. Purity: 98.15 by HPLC.
Example 13: Preparation of empagliflozin L-proline complex
Isopropanol (4 mL) and L-proline (0.459 g) were charged into 50 mL 2 neck round bottom flask. Water (0.5 mL) was added to the mass at 30°C. The mixture was heated to 82°C and stirred for 30 minutes at 82°C. A solution of empagliflozin (purity: 95%) (1 g of empagliflozin in 4 mL of isopropanol) was added to the reaction mixture at 82°C and resulted mixture was stirred for 1 hour at 82°C. Reaction mixture was cooled to 30°C and MTBE (16 mL) was added to the mixture and the reaction mixture was stirred for 2 hours at 33°C. The precipitation was filtered and the wet cake was washed with MTBE (4 mL) and suck dried under vacuum for 1 hour to get the 1.12 gm of title complex as white solid. Purity: 98.57% by HPLC. PXRD pattern: Fig. 5.
Example 14: Preparation of amorphous empagliflozin
Empagliflozin (45 g) and methanol (900 mL) were charged into a 2000 mL round bottom flask at 30 °C. The mixture was heated to 50 °C and stirred for 10 min. The solution was filtered to remove the un-dissolved particles and the filtrate was evaporated by spray drying, using a Büchi® MINI Spray Dryer B-290 with Büchi® Inert Loop B-295 at 75°C to afford 28 g of amorphous empagliflozin. The solid was dried for 4 hours at 30 °C under reduced pressure to get 28 grams of amorphous empagliflozin. Purity by HPLC: 99.9%. Methanol content by GC: 1189 ppm.
Glass transition onset temperature is 66.29 °C.
Glass transition temperature is 70.13 °C.
DSC thermogram: Fig. 35.
Parameters for the spray drier of the above experiment: Aspirator: 75 %; Feed rate: 9 mL/ min; Inlet temperature: 75°C; Outlet temperature: 60°C.

,CLAIMS:CLAIMS
We Claim:
1. A process for preparing crystalline form of empagliflozin characterized by PXRD peaks at about 18.84°, 20.36°, and 25.21° 2 theta, comprising;
a) providing a solution of empagliflozin in a solvent or a mixture of solvents;
b) heating the solution to a temperature higher than the temperature at which the solution is prepared;
c) adding an anti-solvent to the hot solution of step (b); and
d) isolating crystalline form of empagliflozin characterized by PXRD peaks at 18.84°, 20.36°, and 25.21° 2 theta.
2. The process of claim 1, wherein the solvent is methanol.
3. The process of claim 1, wherein the anti-solvent is water.
4. A process for purification of empagliflozin, comprising:
(a) providing a solution of empagliflozin L-proline complex, characterized by an X-Ray Powder Diffraction (XRPD) pattern having peaks at about 4.36 ± 0.2, 12.97 ± 0.2, 15.67 ± 0.2 and 18.80 ± 0.2 °2?, in a mixture of organic solvent and water;
(b) optionally heating the solution obtained in step (a);
(c) separating the organic layer from the mixture obtained in step (b); and
(d) isolating pure empagliflozin from the organic layer of step (c).
5. Amorphous empagliflozin having a glass transition onset temperature of at least 60 °C or above.
6. A process for preparation of amorphous empagliflozin having a glass transition onset temperature of at least 60 °C or above, comprising:
a) providing a solution of empagliflozin in a solvent or a mixture of solvents;
b) removing solvent from the solution obtained in step (a); and
c) recovering amorphous empagliflozin having a glass transition onset temperature of at least 60 °C or above.
7. The process of claim 9, wherein the solvent is selected from the group comprising methanol, ethanol, isopropanol, n-propanol, tert-butanol, tetrahydrofuran, acetone, acetonitrile, dichloromethane, water and mixtures thereof.
8. Amorphous solid dispersion of empagliflozin, having a glass transition onset temperature of at least 55 °C or above, comprising empagliflozin and one or more pharmaceutically acceptable carriers.
9. The amorphous solid dispersion of empagliflozin of claim 8, wherein the pharmaceutically acceptable carrier is selected from the group comprising hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate (HPMC-Phthalate), methyl cellulose and Copovidone.
10. The amorphous solid dispersion of empagliflozin of claim 8, wherein the pharmaceutically acceptable carrier is Copovidone.