DESC:The following specification particularly describes the invention and the manner in which it is to be performed:
FIELD OF THE INVENTION
The present application relates to processes for preparation of empagliflozin solid dispersion.

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.
Polymorphism, the occurrence of different crystal forms, is a phenomenon of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties. Polymorphs in general will have different melting points, thermal behaviors (e.g. measured by thermogravimetric analysis - "TGA", or differential scanning calorimetry - "DSC"), X-ray powder diffraction (XRPD or powder XRD) pattern, infrared absorption fingerprint, and solid state nuclear magnetic resonance (NMR) spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.
There remains a need to provide commercially viable and advantageous processes for preparation of pure and stable amorphous form and amorphous solid dispersion of empagliflozin.
SUMMARY OF THE INVENTION
The present application relates to amorphous solid dispersions of empagliflozin, their preparative processes and pharmaceutical compositions thereof.
In the first 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 second 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, having a glass transition onset temperature of at least 60 °C or above.
In the second aspect, the present application provides a pharmaceutical composition comprising any one of empagliflozin solid dispersion of the present invention and a pharmaceutically acceptable carrier.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is powder X-ray power diffraction pattern of an amorphous form of empagliflozin prepared according to Example 2.
Figure 2 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and L-HPC prepared according to Example 4.
Figure 3 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and ethyl cellulose prepared according to Example 5.
Figure 4 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and ethyl cellulose (at 40% RH) prepared according to Example 5.
Figure 5 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and Eudragit RLPO prepared according to Example 6.
Figure 6 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and Eudragit RLPO (at 40% RH) prepared according to Example 6.
Figure 7 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and hydroxypropyl methyl cellulose (HPMC) prepared according to Example 7.
Figure 8 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and hydroxypropyl methyl cellulose (at 40% RH) prepared according to Example 7.
Figure 9 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and hydroxypropyl methyl cellulose acetate succinate (HPMC-AS) prepared according to Example 8.
Figure 10 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and hydroxypropyl methyl cellulose acetate succinate (HPMC-AS) (at 40% RH) prepared according to Example 8.
Figure 11 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and Soluplus prepared according to Example 9.
Figure 12 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and Soluplus (at 40% RH) prepared according to Example 9.
Figure 13 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and Eudragit-E100 prepared according to Example 10.
Figure 14 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and Eudragit-E100 (at 40% RH) prepared according to Example 10.
Figure 15 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and hydroxypropyl methyl cellulose phthalate (HPMC-Phthalate) prepared according to Example 12.
Figure 16 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and hydroxypropyl methyl cellulose phthalate (HPMC-Phthalate) (at 40% RH) prepared according to Example 12.
Figure 17 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and methyl cellulose prepared according to Example 13.
Figure 18 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin and methyl cellulose (at 40% RH) prepared according to Example 13.
Figure 19 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin, hydroxypropyl methyl cellulose (HPMC) and Syloid (1:1:0.5) prepared according to Example 14.
Figure 20 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin, hydroxypropyl methyl cellulose (HPMC) and croscarmellose sodium (1:1:0.5) prepared according to Example 14.
Figure 21 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin, hydroxypropyl cellulose (HPC) and Syloid (1:1:0.5) prepared according to Example 15.
Figure 22 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising empagliflozin, hydroxypropyl cellulose (HPC) and croscarmellose sodium (1:1:0.5) prepared according to Example 15.
DETAILED DESCRIPTION
Empagliflozin used as the input in the process for preparation of empagliflozin solid dispersion of the present application can be prepared by any process known in the art.
In the first 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 second aspect, the present application provides a process for preparing an 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 of empagliflozin and pharmaceutically acceptable excipient;
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 excipient.
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 excipients 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, Polyethylene oxide, 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; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates (Eudragit®), 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 embodiment, the pharmaceutically acceptable carriers are hydroxypropyl cellulose, hydroxypropyl methylcellulose, copovidone 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; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; ethers such as diethyl ether, dimethyl ether, di-isopropyl ether, 1 ,4-dioxane and the like; and any mixtures of two or more thereof.
In a specific embodiment, the solvent used in step (a) is an alcohol solvent such as methanol, ethanol, IPA.
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.
Alternatively empagliflozin and the excipient is dissolved separately and the clear solutions are combined and filtered.
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, colloidal silicon dioxide, Eudragit, amorphous silica, micro crystalline cellulose, lactose monohydrate, croscarmellose sodium 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 another embodiment, the present application provides a process for preparing pure and stable 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.
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.
In a specific embodiment, the solvent used in step (a) is an alcohol such as methanol, ethanol, isopropyl alcohol, n-propanol, isoamyl alcohol n-butanol, 2-butanol and the like.
The mixture of the solvent and empagliflozin may be heated to a temperature of about 60 °C to dissolve empagliflozin in the solvent. After dissolution in step (a), the obtained solution may be 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 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.
The amorphous empagliflozin obtained by the processes of the present application contains a purity of greater than 99.5%.
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.
In another embodiment, the present application provides a pharmaceutical composition comprising the amorphous empagliflozin or its solid dispersion of the present invention as an active ingredient, and a pharmaceutically acceptable carrier.
In another embodiment, the present application provides a method of treating or preventing type 2 diabetes, comprising administering to a subject in need thereof an effective amount of amorphous empagliflozin or its solid dispersion of the present invention, or a pharmaceutical composition comprising the amorphous empagliflozin or its solid dispersion of the present invention.
“A therapeutically effective amount” as used herein refers to an amount of an agent which is effective, upon single or multiple dose administration to the subject in providing a therapeutic benefit to the subject. In one embodiment, the therapeutic benefit is maintaining glucose homeostasis, or regulating blood glucose levels. In additional embodiments, the empagliflozin amino acid complex of the present invention is used for the preparation of a medicament for treating conditions mediated by SLGT2, preferably type 2 diabetes.

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.
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.
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 “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.
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 (40 g) and methanol (800 mL) were charged into a 2000 mL round bottom flask at 30 °C. The mixture was heated to 50 °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 75°C to afford 26 g of amorphous empagliflozin. The solid was dried for 4 hours at 30 °C under reduced pressure to get 22 grams of amorphous empagliflozin. Purity by HPLC: 99.85%. Methanol content by GC: 1919 ppm
Parameters for the spray drier of the above experiment: Aspirator: 70 %; Feed rate: 9 mL/ min; Inlet temperature: 75°C; Outlet temperature: 60°C.
Example 2: Preparation of amorphous form of 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. PXRD pattern: Fig. 1.
Glass transition onset temperature is 66.29 °C
Glass transition temperature is 70.13 °C
Parameters for the spray drier of the above experiment: Aspirator: 75 %; Feed rate: 9 mL/ min; Inlet temperature: 75°C; Outlet temperature: 60°C.
Example 3: Preparation of amorphous form of empagliflozin.
Empagliflozin (60 g) and methanol (1200 mL) were charged into a 2000 mL round bottom flask at 25 °C. The mixture was heated to 50 °C and stirred for 10 min. The solution was cooled to 30 °C and 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 70 °C to afford 37 g of amorphous empagliflozin. The solid was dried for 4 hours at 30 °C under reduced pressure to get 31 grams of amorphous empagliflozin. Purity by HPLC: 99.81%. PXRD pattern: Fig. 1.
Parameters for the spray drier of the above experiment: Aspirator: 70 %; Feed rate: 9 mL/ min; Inlet temperature: 75°C; Outlet temperature: 60°C.
Example 4: Preparation of amorphous solid dispersion of empagliflozin and Low-Substituted Hydroxypropyl Cellulose (L-HPC).
Low-Substituted Hydroxypropyl Cellulose (L-HPC) (2 g) and methanol (50 mL) were charged into a Buchi rotavapor flask at 25 °C and the mixture was heated to 55 °C. In another flask Empagliflozin (2 g) and methanol (50 mL) were charged at 25 °C and stirred for 15 min. Both the clear solutions were combined and the solution was charged into a rotavapor and completely evaporated under reduced pressure at 55 °C to get 3 g of amorphous solid dispersion of empagliflozin and L-HPC. PXRD pattern: Fig. 2.
The solid amorphous material (1 g) was humidified at 30 °C and 40% RH for 10 hours. Flowable solid lumps obtained.
Example 5: Preparation of amorphous solid dispersion of empagliflozin and Ethyl Cellulose.
Empagliflozin (2 g) and methanol (50 mL) were charged into a Buchi rotavapor flask at 25 °C and stirred for 15 minutes. In another flask Ethyl Cellulose (2 g) and methanol (60 mL) were charged at 25 °C and heated to 58 °C to get clear solution. Both the clear solutions were combined and the solution was charged into a rotavapor and completely evaporated under reduced pressure at 60 °C to get 2.8 g of amorphous solid dispersion of empagliflozin and Ethyl Cellulose. PXRD pattern: Fig. 3.
Glass transition onset temperature is 66.79 °C
Glass transition temperature is 70.48 °C
The solid amorphous material (1 g) was humidified at 30 °C and 40% RH for 10 hours. Freely flowable amorphous solid obtained. PXRD pattern: 4
Example 6: Preparation of amorphous solid dispersion of empagliflozin and Eudragit RLPO.
Empagliflozin (2 g) and methanol (50 mL) were charged into a Buchi rotavapor flask at 25 °C and stirred for 15 minutes. In another flask Eudragit RLPO (2 g) and methanol (36 mL) were charged at 25 °C and heated to 55 °C to get clear solution. Both the clear solutions were combined and the solution was charged into a rotavapor and completely evaporated under reduced pressure at 60 °C to get 3.2 g of amorphous solid dispersion of empagliflozin and Eudragit RLPO. PXRD pattern: Fig. 5.
The solid amorphous material (1 g) was humidified at 30 °C and 40% RH for 10 hours. Amorphous solid (flowable upon disturbing) obtained. PXRD pattern: Fig. 6.
Glass transition onset temperature is 67.17 °C
Glass transition temperature is 70.87 °C
Example 7: Preparation of amorphous solid dispersion of empagliflozin and HPMC.
Empagliflozin (2 g) and methanol (50 mL) were charged into a Buchi rotavapor flask at 25 °C and stirred for 15 minutes and heated to 55 °C to get clear solution. In another flask hydroxy propyl methyl cellulose (HPMC) (2 g) and methanol (50 mL) were charged at 25 °C and stirred for 15 minutes. Both the clear solutions were combined and the solution was charged into a rotavapor and completely evaporated under reduced pressure at 60 °C to get 2.4 g of amorphous solid dispersion of empagliflozin and HPMC. PXRD pattern: Fig. 7.
The solid amorphous material (1 g) was humidified at 30 °C and 40% RH for 10 hours. Amorphous solid (flowable upon disturbing) obtained. PXRD pattern: Fig. 8.
Example 8: Preparation of amorphous solid dispersion of empagliflozin and HPMC-AS.
Empagliflozin (2 g) and methanol (50 mL) were charged into a Buchi rotavapor flask at 25 °C and stirred for 15 minutes and heated to 55 °C to get clear solution. In another flask hydroxy propyl methyl cellulose acetate succinate (HPMC-AS MG) (2 g) and methanol (50 mL) were charged at 25 °C and stirred for 15 minutes. Both the clear solutions were combined and the solution was charged into a rotavapor and completely evaporated under reduced pressure at 60 °C to get 2.8 g of amorphous solid dispersion of empagliflozin and HPMC-AS. PXRD pattern: Fig. 9.
The solid amorphous material (1 g) was humidified at 30 °C and 40% RH for 10 hours. Amorphous solid (flowable) obtained. PXRD pattern: Fig.10.
Example 9: Preparation of amorphous solid dispersion of empagliflozin and Soluplus.
Empagliflozin (2 g) and methanol (50 mL) were charged into a Buchi rotavapor flask at 25 °C and stirred for 15 minutes and heated to 55 °C to get clear solution. In another flask hydroxy propyl methyl cellulose acetate succinate (HPMC-AS MG) (2 g) and methanol (50 mL) were charged at 25 °C and stirred for 15 minutes. Both the clear solutions were combined and the solution was charged into a rotavapor and completely evaporated under reduced pressure at 60 °C to get 3.4 g of amorphous solid dispersion of empagliflozin and Soluplus. PXRD: Fig. 11.
Glass transition onset temperature is 74.42 °C; Glass transition temperature is 76.30 °C
The solid amorphous material (1 g) was humidified at 30 °C and 40% RH for 10 hours. Amorphous solid (sticky solid lumps) obtained. PXRD pattern: Fig.12.
Example 10: Preparation of amorphous solid dispersion of empagliflozin and Eudragit-E100.
Eudragit-E100 (2 g) and methanol (80 mL) were charged into a Buchi rotavapor flask at 25 °C and stirred for 15 minutes and heated to 65 °C to get clear solution. In another flask Empagliflozin (2 g) and methanol (50 mL) were charged at 25 °C and stirred for 15 minutes. Both the clear solutions were combined and the solution was charged into a rotavapor and completely evaporated under reduced pressure at 60 °C to get 3 g of amorphous solid dispersion of empagliflozin and Eudragit-E100. PXRD pattern: Fig. 13.
Glass transition onset temperature is 96.08 °C; Glass transition temperature is 99.22 °C
The solid amorphous material (1 g) was humidified at 30 °C and 40% RH for 10 hours. Amorphous solid (sticky solid lumps) obtained. PXRD pattern: Fig.14.
Example 11: Preparation of amorphous solid dispersion of empagliflozin and Microcrystalline Cellulose.
Empagliflozin (2 g) and methanol (80 mL) were charged into a Buchi rotavapor flask at 25 °C and stirred for 15 minutes and heated to 55 °C to get clear solution. Microcrystalline Cellulose (MCC; 2 g) was charged at 55 °C and stirred for 15 minutes. The solution was charged into a rotavapor and completely evaporated under reduced pressure at 65 °C. 2.7 g of crystalline sticky solid dispersion of empagliflozin and MCC was obtained.
Example 12: Preparation of amorphous solid dispersion of empagliflozin and hydroxy propyl methyl cellulose phthalate (Hypromellose Phthalate; HPMC-Phthalate).
Hypromellose Phthalate (2 g) and methanol (60 mL) were charged into a round bottom flask at 27°C. Empagliflozin (2 g) and methanol (50 mL) were charged into another flask and heated to 55 °C. The resulted mixture was heated to 55°C and stirred for 15 min. at 55°C. Both the clear solutions were combined and the solution was charged into a rotavapor and completely evaporated under reduced pressure at 60 °C to get 3 g of amorphous solid dispersion of empagliflozin HPMC-Phthalate. PXRD pattern: Fig. 15.
The solid amorphous material (1 g) was humidified at 30 °C and 40% RH for 10 hours. Amorphous solid obtained. PXRD pattern: Fig.16.
Example 13: Preparation of amorphous solid dispersion of empagliflozin and Methyl cellulose.
Methyl cellulose (2 g) and methanol (60 mL) were charged into a round bottom flask at 27°C. In another flask Empagliflozin (2 g) and methanol (50 mL) were charged at 27°C. Both the API and excipient solutions were combined and the solution was charged into a rotavapor and completely evaporated under reduced pressure at 62 °C to get 3.1 g of amorphous solid dispersion of empagliflozin Methyl Cellulose. PXRD pattern: Fig. 17.
The solid amorphous material (1 g) was humidified at 30 °C and 40% RH for 10 hours. Amorphous solid obtained. PXRD pattern: Fig.18.
Example 14: Preparation of amorphous solid dispersion of empagliflozin, HPMC and adsorbent.
Empagliflozin (5 g) and methanol (175 mL) were charged into a Buchi rotavapor flask at 25 °C and stirred for 15 minutes and heated to 55 °C to get clear solution. In another flask hydroxy propyl methyl cellulose (HPMC) (5 g) and methanol (125 mL) were charged at 25 °C and stirred for 15 minutes and heated to 55 °C to get clear solution. Both the clear solutions were combined and the solution was charged into a rotavapor and completely evaporated under reduced pressure at 60 °C to get 6.2 g of amorphous solid dispersion of empagliflozin and HPMC. PXRD: Fig. 7.
Glass transition onset temperature is 58.77 °C; Glass transition temperature is 73.92 °C
Taken 3 g of the above amorphous solid dispersion and divided into 3 parts (P1, P2 and P3) 1 g each part. Added 500 mg of Syloid to P1, 500 mg of Lactose to P2 and 500 mg of Croscarmellose sodium and kept all the three samples in humidification chamber at 40 % RH and 30 °C for 10 hours.
Good improvement in flowability and stability is found by addition of adsorbents syloid, lactose, and croscarmellose sodium (API : HPMC : Adsorbent = 1:1:0.5) when exposed even for one day at 40% RH and 30 °C remained amorphous. P1 PXRD pattern: Fig 19; P3 PXRD pattern: Fig 20
P1: Glass transition onset temperature is 54.18 °C; Glass transition temperature is 63.71 °C
P2: Glass transition onset temperature is 71.36 °C; Glass transition temperature is 76.08 °C.
Example 15: Preparation of amorphous solid dispersion of empagliflozin, HPC and adsorbent.
Empagliflozin (5 g) and methanol (175 mL) were charged into a Buchi rotavapor flask at 25 °C and stirred for 15 minutes and heated to 55 °C to get clear solution. In another flask hydroxy propyl cellulose (HPC) (5 g) and methanol (125 mL) were charged at 25 °C and stirred for 15 minutes and heated to 55 °C to get clear solution. Both the clear solutions were combined and the solution was charged into a rotavapor and completely evaporated under reduced pressure at 60 °C to get 6.8 g of amorphous solid dispersion of empagliflozin and HPC. PXRD: Fig. 2.
Taken 3 g of the above amorphous solid dispersion and divided into 3 parts (P1, P2 and P3) 1 g each part. Added 5oo mg of Syloid to P1, 500 mg of Lactose monohydrate to P2 and 500 mg of Croscarmellose sodium and kept all the three samples in humidification chamber at 40 % RH and 30 °C for 10 hours. Good improvement in flowability and stability is found by addition of adsorbents syloid, lactose, and croscarmellose sodium (API : HPC : Adsorbent = 1:1:0.5) when exposed even for one day at 40% RH and 30 °C remained amorphous.
P1 PXRD pattern: Fig 21; P3 PXRD pattern: Fig 22.
Glass transition onset temperature is 73.32 °C. Glass transition temperature is 84.59 °C.
,CLAIMS:We claim
1. Amorphous empagliflozin having a glass transition onset temperature of at least 60 °C or above.
2. 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.
3. The process of claim 2, wherein the solvent is selected from the group comprising methanol, ethanol, isopropanol, n-propanol, tert-butanol, tetrahydrofuran, acetone, acetonitrile, dichloromethane, water and mixtures thereof.
4. Amorphous solid dispersion comprising empagliflozin and one or more pharmaceutically acceptable carriers, having a glass transition onset temperature of at least 55 °C or above.
5. The amorphous solid dispersion of empagliflozin of claim 4, wherein the pharmaceutically acceptable carrier is selected from the group comprising pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, Copovidone, Soluplus, Silicified microcrystalline cellulose, mannitol, sorbitol, acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidone, hydroxymethyl celluloses, ethylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, HPMC-Phthalate, HPMC-AS, HPMC-15 CPS, sodium starch glycolate, crospovidone, croscarmellose sodium, colloidal silicon dioxide stearic acid, magnesium stearate, zinc stearate, colloidal silicon dioxide and mixtures thereof.
6. The amorphous solid dispersion of empagliflozin of claim 4, wherein the pharmaceutically acceptable carrier is selected from the group comprising hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate (HPMC-Phthalate), methyl cellulose and Copovidone.
7. The amorphous solid dispersion of empagliflozin of claim 4, wherein the pharmaceutically acceptable carrier is Copovidone.
8. The amorphous solid dispersion of empagliflozin of claim 4, wherein the pharmaceutically acceptable carrier is hydroxypropyl methylcellulose phthalate (HPMC-Phthalate).
9. A process for preparing stable amorphous solid dispersion comprising empagliflozin and one or more pharmaceutically acceptable carriers, having a glass transition onset temperature of at least 60 °C or above, comprising;
d) providing a solution comprising empagliflozin and one or more pharmaceutically acceptable carriers,
e) removing solvent from the solution obtained in step (a), and
f) recovering an amorphous solid dispersion comprising empagliflozin and one or more pharmaceutically acceptable carriers.