Claims:We Claim,
1. A Novel acid addition salts of Tofacitinib, their solid states or solvates or hydrates, mixtures and their uses as medicaments thereof; wherein the acid addition salts being selected from the group comprising Gentisic acid, Erythorbic acid, p-coumaric acid, ferulic acid, sinapic acid, caffeic acid, chlorogenic acid, caftaric acid, coutaric acid, pantothenic acid, Erythorbic acid Cyclamic acid, Saccharin, Sorbic acid, Cholic acid, Poly glutamic acid, Pimelic acid, L-Pyroglutamic acid, Glucoheptonoic acid, Glycolic acid, acetylsalicylic acid, meso-tartaric acid, Glyoxylic acid, Pyruvic acid, asparatic acid, lipoic acid, quinic acid, meso-tartaric acid and Pantothenic acid.
2. A Novel acid addition salts of Tofacitinib, wherein Tofacitinib Gentisic acid salt is characterized by an X-ray diffraction (XRD) pattern substantially in accordance with Figure. 1.
3. A Novel acid addition salts of Tofacitinib, comprising Tofacitinib Gentisic acid salt or its solvates or hydrates thereof.
4. A Novel acid addition salts of Tofacitinib, wherein Tofacitinib Glyoxylic acid salt is characterized by an X-ray diffraction (XRD) pattern substantially in accordance with Figure. 2.
5. A Novel acid addition salts of Tofacitinib, comprising Tofacitinib Glyoxylic acid salt or its solvates or hydrates thereof.
6. A Novel acid addition salts of Tofacitinib, wherein Tofacitinib Cyclamic acid salt is characterized by an X-ray diffraction (XRD) pattern substantially in accordance with Figure. 4.
7. A Novel acid addition salts of Tofacitinib, comprising Tofacitinib Cyclamic acid salt or its solvates or hydrates thereof.
8. A Novel acid addition salts of Tofacitinib, wherein Tofacitinib Pyruvic acid salt is characterized by an X-ray diffraction (XRD) pattern substantially in accordance with Figure. 5.
9. A Novel acid addition salts of Tofacitinib, comprising Tofacitinib Pyruvic acid salt or its solvates or hydrates thereof.
10. A Novel acid addition salts of Tofacitinib, wherein Tofacitinib Saccharine salt is characterized by an X-ray diffraction (XRD) pattern substantially in accordance with Figure. 6.
11. A Novel acid addition salts of Tofacitinib, comprising Tofacitinib Saccharine salt or its solvates or hydrates thereof.
12. A Novel acid addition salts of Tofacitinib, wherein Tofacitinib Cholic acid salt is characterized by an X-ray diffraction (XRD) pattern substantially in accordance with Figure. 7.
13. A Novel acid addition salts of Tofacitinib, comprising Tofacitinib Cholic acid salt or its solvates or hydrates thereof.
14. A Novel acid addition salts of Tofacitinib, wherein Tofacitinib Aspartic acid salt is characterized by an X-ray diffraction (XRD) pattern substantially in accordance with Figure. 9.
15. A process for preparing acid addition salt of Tofacitinib, or its solvates or hydrates thereof, comprising the steps of:
a) providing a solution comprising Tofacitinib and acid in one or more solvents, and;
b) isolating the Tofacitinib acid addition salt; wherein the acid addition salt is being selected from the group comprising Gentisic acid, p-coumaric acid, ferulic acid, sinapic acid, caffeic acid, chlorogenic acid, caftaric acid, coutaric acid, pantothenic acid, Erythorbic acid Cyclamic acid, Saccharin, sorbic acid, Cholic acid, Poly glutamic acid, pimelic acid, L-Pyroglutamic acid, Glucoheptonoic acid, Glycolic acid, acetylsalicylic acid, meso-tartaric acid, Glyoxylic acid, Pyruvic acid, asparatic acid, lipoic acid, quinic acid, meso-tartaric acid and Pantothenic acid.
16. The process according to claim 15, wherein the step a) further comprises:
a) dissolving any form of Tofacitinib in suitable organic solvent at a suitable temperature to form a solution, and;
b) mixing the acid as natural form or in solution form to the solution ; wherein the acid is being selected from the group comprising Gentisic acid, p-coumaric acid, ferulic acid, sinapic acid, caffeic acid, chlorogenic acid, caftaric acid, coutaric acid, pantothenic acid, Erythorbic acid Cyclamic acid, Saccharin, sorbic acid, Cholic acid, Poly glutamic acid, pimelic acid, L-Pyroglutamic acid, Glucoheptonoic acid, Glycolic acid, acetylsalicylic acid, meso-tartaric acid, Glyoxylic acid, Pyruvic acid, asparatic acid, lipoic acid, quinic acid, meso-tartaric acid and Pantothenic acid.
17. The process according to claim 16, wherein the suitable organic solvent is selected form the group consisting of water, lower alcohols, ketones, esters, ethers, C5-C7 linear, branched or cyclic, saturated or unsaturated hydrocarbons, nitriles, halogenated hydrocarbons, or mixtures thereof.
18. The process according to claim 17, wherein the suitable organic solvent is selected from the group consisting of methanol, ethanol, isopropanol, butanol, acetone, methylethylketone, methyl iso butyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran (THF), isopropyl ether (IPE), diethyl ether, ter-butyl methyl ether, acetonitrile, propionitrile, methylene chloride, chloroform, toluene, cyclohexane, hexane, heptanes, and mixtures thereof.
19. The process according to claim 16, wherein the suitable temperature is at about 20°C to about 100°C.
20. The process according to claim 16, wherein the acid addition salt is mixed with the solution of Tofacitinib in the form of either in solid or solute.
21. The process according to claim 15, wherein the isolation is carried out by the known techniques comprising filtration, cooling the solution to precipitation, crystallization, solvent precipitation, total evaporation methods such as reduced pressure, spray drying, freeze drying, agitated thin film evaporator (ATFE) and the like.
22. The process according to claim 1-21, wherein solvates are as intermediates in preparation of Tofacitinib acid addition salts of acids which are having lower PKa value than the acids used to prepare the acid addition salts of Tofacitinib.
23. A pharmaceutical composition according to claim 1-21, comprising a therapeutically effective amount of one or more of the Tofacitinib salts.
24. A pharmaceutical composition according to claim 23, wherein the use of Tofacitinib salts, their solid states, hydrates, solvates as medicament.
25. According to claim 1, wherein Tofacitinib acid addition salts of Cyclamic acid and Saccharine are useful in preparation of sublingual, orally disintegrated and syrup preparations of medicaments.
, Description:Field of the invention:
The present invention relates to novel acid addition salts of Tofacitinib, processes for its preparation and a pharmaceutical composition containing the same.

Back ground of the invention:
Tofacitinib, (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo [2,3-d]pyrimidin-4-ylamino-ß-oxo-1-piperidine propanenitrile (Formula-I) generally named as Tofacitinib, (formerely Tasocitinib CP-690550), has the following chemical structure:

Tofacitinib (trade names Xeljanz and Jakvinus) is a drug of the junuskinase (JAK) inhibitor class, discovered and developed by Pfizer. It is currently approved for the treatment of rheumatoid arthritis (RA) in the United States and Russia, and is being studied for treatment of psoriasis, inflammatory bowel disease, and other immunological diseases, as well as for the prevention of organ transplant rejection, xeno transplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn’s disease, Alzheimer’s disease, leukemia and other indications, where immunosuppression would be desirable.
Tofacitinib, as well as certain pharmaceutically acceptable salts thereof, is described in WO2001/042246, WO2002/096909, WO2003/048162, WO2012/135338, WO2013/090490 and US2015/0225406 describes crystalline forms and describes process for preparing certain other Tofacitinib salts.
Tofacitinib Citrate is disclosed in WO 01/42246 and WO 02/096909.

WO 03/048162 relates to a novel amorphous and crystalline forms of (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo [2,3-d]pyrimidin-4-ylamino-ß-oxo-1-piperidine propanenitrile mono citrate salt, useful as inhibitors of protein kinases and to their methods of preparation.
WO 2012/135338 is directed to Tofacitinib acid addition salts and solid state forms thereof, particularly amorphous Tofacitinib acetate, as well as pharmaceutical compositions comprising one or more of them. The invention further provides a process for producing Tofacitinib acid addition salt, in particular, Tofacitinib mono-citrate salt.
WO 2012/137111 discloses novel crystalline and non-crystalline forms of (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo [2,3-d]pyrimidin-4-ylamino-ß-oxo-1-piperidine propanenitrile, pharmaceutical composition containing the same, preparations thereof and the uses thereof.
WO 2013/090490 is directed to several Tofacitinib salts including Tofactinib mono-tartarate salt, Tofacitinib mono-malate salt and Tofacitinib mono-oxalate salt. These Tofacitinib salts can be in amorphous form. The invention is also directed toward a pharmaceutical composition comprising one or more of the Tofacitinib salts, and a process for preparing the composition. The Tofacitinib salts can be used to prepare Tofacitinib mono citrate salt. Another aspect of the invention is a process for preparing Tofacitinib mono citrate.
US 2015/0225406 A1 discloses solid and crystalline forms of Tofacitinib hydrochloride and Tofacitinib hydrobromide, processes for the preparation thereof and processes for the use thereof in preparing Tofacitinib citrate are provided.
It is well known that different salts of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics improving the dissolution profile, or improving stability and shelf-life. These variations in the properties of different salts may also provide improvements to the final dosage form, for instance, if they serve to improve bioavailability or to prepare injectable formulations. Different salts of an active pharmaceutical ingredient may also give solution to the bitterness problem in preparing sublingual, orally disintegrating dissolvable and syrup preparations. Different salts of an active pharmaceutical ingredient itself can advantageously be useful for therapeutical use and rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.
Therefore, there is a strong need for developing various Tofacitinib acid addition salts. The preset invention satisfies this need by providing pharmaceutically acceptable acid addition salts of Tofacitinib with enhanced solubility of water or aqueous media as an essential property of an Active Pharmaceutical Ingredients determining the performance of pharmaceutical formulations.
It is well-known that various salts and polymorphs differ from each other in important properties such as solubility, chemical stability, polymorph stability, bioavailability, filtration, drying and tabletting properties etc without modifying of primary pharmacological activity.
Although Tofacitinib citrate provides good pharmaceutical activity, it would be beneficial to discover new salts of Tofacitinib and new polymorphic forms of Tofacitinib or its salts, as Tofacitinib citrate is poorly soluble in water. Such discoveries can also enlarge the repertoire of materials that a formulation scientist has available for designing for example a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.
The pharmaceutically acceptable acid addition salts of Tofacitinib showing the same pharmacological activity as Tofacitinib citrate may be used as active ingredients of therapeutic uses such as; currently approved for the treatment of rheumatoid arthritis (RA) in the United States and Russia, and is being studied for treatment of psoriasis, inflammatory bowel disease, and other immunological diseases, as well as for the prevention of organ transplant rejection, xeno transplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn’s disease, Alzheimer’s disease, leukemia and other indications, where immunosuppression would be desirable. They may also serve as intermediates in manufacturing process of high pharmaceutically pure Tofacitinib.
Therefore, there is a strong need for developing various polymorphic forms of salts of Tofacitinib, having improved physical and/or chemical properties. The present invention satisfies this need by providing pharmaceutically acceptable acid addition salts of Tofacitinib with enhanced solubility in water or aqueous media as an essential property of active pharmaceutical ingredients determining the performance of pharmaceutical formulation.

Object of the invention:
It is an object of the present invention to provide novel acid addition salts of Tofacitinib. Another object of the present invention is to provide a novel acid addition salts prepared from anti-oxidant acids those can advantageously useful for therapeutical use as anti-oxidants can stabilize the bodies metabolism by defending against damages caused by free radicals. The anti-oxidant acid salts of Tofacitinib are may more effective properties with respect to therapeutic activity of Tofacitinib as compared to the Tofacitinib salt form with non anti-oxidant acids.
Yet another object of present invention provides a novel acid addition salts, those can improve the taste of the Tofacitinib as Tofacitinib citrate is highly bitter in taste. Those salts useful in preparation of orally disintegrating, sublingual and syrup preparations.
Yet another object of the present invention is to provide process for preparing novel acid addition salts of Tofacitinib.
Yet another object of the present invention is to provide a pharmaceutical composition comprising acid addition salts of Tofacitinib.
Summary of the invention:
It has now been found that novel acid addition salts of Tofacitinib of Formula 1 or their solid state forms or their hydrates or their solvates thereof. The present invention can be obtained which have improved properties as compared to presently-known form of such compound.
In an aspect, the improved pharmaceutical property is selected from the group consisting of: increased solubility, increased dissolution, increased bioavailability, increased dose response, decreased form diversity, more desired morphology, more desired taste, or other property described herein.
Accordingly, the present invention provides novel acid addition salts of Tofacitinib of Formula 1 its solid state forms or its solvates or hydrates thereof;

wherein the acid addition salts are selected from the group comprising an anti-oxidative acids such as Gentisic acid, p-coumaric acid, ferulic acid, sinapic acid, caffeic acid, chlorogenic acid, caftaric acid, coutaric acid, pantothenic acid, Erythorbic acid and the like; and other acids for better taste are such as Cyclamic acid, Saccharin and the like, and the other salts like sorbic acid, Cholic acid, Poly glutamic acid, pimelic acid, L-Pyroglutamic acid, Glucoheptonoic acid, Glycolic acid, acetylsalicylic acid, meso-tartaric acid, Glyoxylic acid, Pyruvic acid, asparatic acid, lipoic acid, quinic acid, meso-tartaric acid and Pantothenic acid.
In another embodiment, the present invention provides novel acid addition salts of Tofacitinib, which exist in the form of polymorphs of salts, co-crystals or polymorphs of co-crystals or amorphous powders.
In another embodiment, the present invention provides a process for preparation of acid addition salts of Tofacitinib of Formula 1 or its solvates or hydrates thereof, comprising:
a) providing a solution comprising Tofacitinib and acid in one or more solvents, and
b) isolating the Tofacitinib acid addition salt;
wherein the acid addition salts are selected from the group comprising anti-oxidative acids such as Gentisic acid, p-coumaric acid, ferulic acid, sinapic acid, caffeic acid, chlorogenic acid, caftaric acid, coutaric acid, pantothenic acid, Erythorbic acid and the like; and other acids for better taste are selected from the group comprising Cyclamic acid, Saccharin and the like, and the other acids like sorbic acid, Cholic acid, Poly glutamic acid, pimelic acid, L-Pyroglutamic acid, Glucoheptonoic acid, Glycolic acid, acetylsalicylic acid, meso-tartaric acid, Glyoxylic acid, Pyruvic acid, asparatic acid, lipoic acid, quinic acid, meso-tartaric acid and Pantothenic acid.
In another embodiment the present invention provides a pharmaceutical composition comprising acid addition salts of Tofacitinib prepared by the processes of the present invention.

Brief description of the drawings:
In the following, the present invention will be described in more detail by preferred embodiments and examples while referring to the attached drawings, noting, however, that these embodiments, examples and drawings are presented for illustrative purposes only and shall not limit the invention in any way.
Fig. 1 is the characteristic powder X-ray diffraction (XRD) pattern of crystalline Tofacitinib Gentisic acid salt.
Fig. 2 is the characteristic powder X-ray diffraction (XRD) pattern of crystalline Tofacitinib Glyoxylic acid salt.
Fig. 3 is the characteristic differential scanning calorimetric (DSC) thermogram of crystalline Tofacitinib Glyoxylic acid salt.
Fig. 4 is the characteristic powder X-ray diffraction (XRD) pattern of crystalline Tofacitinib Cyclamic acid salt.
Fig. 5 is the characteristic powder X-ray diffraction (XRD) pattern of crystalline Tofacitinib Pyruvic acid salt.
Fig. 6 is the characteristic powder X-ray diffraction (XRD) pattern of crystalline Tofacitinib Saccharine salt.
Fig. 7 is the characteristic powder X-ray diffraction (XRD) pattern of crystalline Tofacitinib Cholic acid salt.
Fig. 8 is the characteristic differential scanning calorimetric (DSC) thermogram of crystalline Tofacitinib Cholic acid salt.
Fig. 9 is the characteristic powder X-ray diffraction (XRD) pattern of crystalline Tofacitinib Aspartic acid salt.

Detailed description of the invention:
The present invention addresses a need in the art by providing new acid addition salts of Tofacitinib, or its solvates or hydrates thereof.
The present inventors have identified new acid addition salts of Tofacitinib, or its solvates or hydrates thereof. These salt forms may be in the form of solvates, hydrates, polymorphs of salts, co-crystals, or polymorphs of co-crystals.
In one embodiment, the present invention provides novel acid addition salts of Tofacitinib of Formula 1 or its solid state forms or solvates or hydrates thereof;

FORMULA I wherein the acid addition salts are selected from the group comprising an anti-oxidative acids such as Gentisic acid, p-coumaric acid, ferulic acid, sinapic acid, caffeic acid, chlorogenic acid, caftaric acid, coutaric acid, pantothenic acid, Erythorbic acid and the like; and other acids for better taste are such as Cyclamic acid, Saccharin and the like, and the other salts like sorbic acid, Cholic acid, Poly glutamic acid, pimelic acid, L-Pyroglutamic acid, Glucoheptonoic acid, Glycolic acid, acetylsalicylic acid, meso-tartaric acid, Glyoxylic acid, Pyruvic acid, asparatic acid, lipoic acid, quinic acid, meso-tartaric acid and Pantothenic acid.
The anti-oxidant acids used in the present invention are not only intended for formation of pharmaceutically acceptable salt forms of, the obtained salts of Tofacitinib itself can advantageously be useful for therapeutical use, for example, anti-oxidant acids can stabilize the body's metabolism by defending against damage caused by free radicals. The anti-oxidant acid salts of Tofacitinib are more effective with respect to therapeutic activity of the Tofacitinib as compared to the Tofacitinib salt form with non anti-oxidant acids described in the afore mentioned literature.
In another embodiment, the present invention provides crystalline Tofacitinib salts characterized by an X-Ray diffraction (XRD) pattern substantially in accordance with Figures.
In another embodiment, the present invention provides a process for preparation of acid addition salts of Tofacitinib of Formula 1 or its solvates or hydrates thereof, comprising:
a) providing a solution comprising Tofacitinib and acid in one or more solvents, and
b) isolating the Tofacitinib acid addition salt;
wherein the acid addition salts are selected from the group comprising anti-oxidative acids such as Gentisic acid, p-coumaric acid, ferulic acid, sinapic acid, caffeic acid, chlorogenic acid, caftaric acid, coutaric acid, pantothenic acid, Erythorbic acid and the like; and other acids for better taste are such as Cyclamic acid, Saccharin and the like, and the other salts like sorbic acid, Cholic acid, Poly glutamic acid, pimelic acid, L-Pyroglutamic acid, Glucoheptonoic acid, Glycolic acid, acetylsalicylic acid, meso-tartaric acid, Glyoxylic acid, Pyruvic acid, asparatic acid, lipoic acid, quinic acid, meso-tartaric acid and Pantothenic acid.
The Tofacitinib in the step a) may be any crystalline or other form of Tofacitinib, including various solvates, hydrates or Tofacitinib obtaining as existing solution from a previous processing step. The one or more solvent include, but are not limited to water, lower alcohols, ketones, esters, ethers, C5-C7 linear, branched or cyclic, saturated or unsaturated hydrocarbons, nitriles, halogenated hydrocarbons, or mixtures thereof. Preferably the suitable organic solvent includes, but are not limited to methanol, ethanol, isopropanol, acetone, methylethylketone, methyl iso butyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran (THF), isopropyl ether (IPE), ter-butyl methyl ether, acetonitrile, propionitrile, methylene chloride, chloroform, toluene, cyclohexane, hexane, heptanes and the like and the mixtures thereof.
The solution comprising Tofacitinib free base and acid of step a) can be provided by mixing the solution of Tofacitinib free base with acid. Wherein, solution of Tofacitinib free base intern can be provided by dissolving Tofacitinib free base in suitable organic solvent.
Further acid may be added to the solution of Tofacitinib either in natural state or in solution. And solution of acid can be prepared by dissolving the acid in a suitable solvent.
The temperature suitable for providing a solution comprising Tofacitinib and acid in one or more solvents is from ambient temperature to about boiling point of the solvent; preferably at a temperature of about 30°C to about 100°C.
The isolation of the Tofacitinib acid addition salt can be induced by reducing the temperature of reaction mixture, especially if initial temperature of reaction mixture is elevated. The isolation can also be induced by reduction of solution volume, preferably under reduced pressure, spray drying, freeze drying, agitated thin film evaporator (ATFE), by complete evaporation of solvent or crystallization. Furthermore, the isolation may be caused by adding an anti-solvent to the reaction solution to precipitation.
In an alternative embodiment, the isolated acid addition salt of Tofacitinib can optionally be washed with one or more organic solvents, and finally resulted pure acid addition salt of Tofacitinib may be recovered by any conventional methods or known techniques. The suitable organic solvent used include any suitable solvent as described herein; preferably the suitable organic solvent is selected from the group consisting of water, methanol, ethanol, acetone, THF, Acetonitrile, ethyl acetate, IPE and mixtures thereof.
Finally the resulted pure acid addition salt of Tofacitinib may be recovered by any conventional methods such as filtration, solvent precipitation, spray drying, freeze drying, agitated thin film evaporator (ATFE) and the like.
In another embodiment, the present invention provides a process for preparing acid addition salts of Tofacitinib, wherein the acid addition salt, comprising
a) providing a solution of Tofacitinib and gentisic acid in one or more solvents and
b) isolating the Tofacitinib gentisic acid salt.
The suitable solvent used is selected from the group consisting of water, methanol, ethanol, acetone, THF, acetonitrile, ethyl acetate, IPE and mixtures thereof, preferably acetone.
The addition salt may be formed by heating the mixture at a temperature of about 20°C to about reflux temperature, preferably about 40°C to about 100°C. The acid addition salt can be isolated by any known techniques such as cooling the solution to precipitation, crystallization, solvent precipitation, spray drying, freeze drying, agitated thin film evaporator (ATFE) and the like.
Tofacitinib gentisic salt prepared according to such procedure exhibits a powder X-ray diffraction pattern substantially in accordance with Figure. 1.
In another embodiment, the present invention provides a process for preparing acid addition salts of Tofacitinib, wherein the acid addition salt, comprising
a) providing a solution of Tofacitinib and glyoxylic acid in one or more solvents and
b) isolating the Tofacitinib glyoxylic acid salt.
The suitable solvent used is selected from the group consisting of water, methanol, ethanol, acetone, THF, acetonitrile, ethyl acetate, IPE and mixtures thereof, preferably acetone.
The solution may be formed by heating the mixture at a temperature of about 30°C to about reflux temperature, preferably about 40°C to about 100°C. The acid addition salt can be isolated by any known techniques such as cooling the solution to precipitation, crystallization, solvent precipitation, spray drying, freeze drying, agitated thin film evaporator (ATFE) and the like.
Tofacitinib glyoxylic acid salt prepared according to such procedure exhibits a powder X-ray diffraction pattern substantially in accordance with Figure. 2.
Tofacitinib glyoxylic acid salt prepared according to such procedure exhibits a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure. 3.
In another embodiment, the present invention provides a process for preparing acid addition salts of Tofacitinib, wherein the acid addition salt, comprising
a) providing a solution of Tofacitinib and cyclamic acid in one or more solvents and
b) isolating the Tofacitinib cyclamic acid salt.
The suitable solvent used is selected from the group consisting of water, methanol, ethanol, acetone, THF, acetonitrile, ethyl acetate, IPE and mixtures thereof, preferably acetone.
The solution may be formed by heating the mixture at a temperature of about 30°C to about reflux temperature, preferably about 40°C to about 100°C. The acid addition salt can be isolated by any known techniques such as cooling the solution to precipitation, crystallization, solvent precipitation, spray drying, freeze drying, agitated thin film evaporator (ATFE) and the like.
Tofacitinib cyclamic acid salt prepared according to such procedure exhibits a powder X-ray diffraction pattern substantially in accordance with Figure. 4.
In another embodiment, the present invention provides a process for preparing acid addition salts of Tofacitinib, wherein the acid addition salt, comprising
a) providing a solution of Tofacitinib and pyruvic acid in one or more solvents and
b) isolating the Tofacitinib pyruvic acid salt.
The suitable solvent used is selected from the group consisting of water, methanol, ethanol, acetone, THF, acetonitrile, ethyl acetate, IPE and mixtures thereof, preferably acetone.
The solution may be formed by heating the mixture at a temperature of about 30°C to about reflux temperature, preferably about 40°C to about 100°C. The acid addition salt can be isolated by any known techniques such as cooling the solution to precipitation, crystallization, solvent precipitation, spray drying, freeze drying, agitated thin film evaporator (ATFE) and the like.
Tofacitinib pyruvic acid salt prepared according to such procedure exhibits a powder X-ray diffraction pattern substantially in accordance with Figure. 5.
In another embodiment, the present invention provides a process for preparing acid addition salts of Tofacitinib, wherein the acid addition salt, comprising
a) providing a solution of Tofacitinib and Saccharine in one or more solvents and
b) isolating the Tofacitinib Saccharine salt.
The suitable solvent used is selected from the group consisting of water, methanol, ethanol, acetone, THF, acetonitrile, ethyl acetate, IPE and mixtures thereof, preferably acetone.
The solution may be formed by heating the mixture at a temperature of about 30°C to about reflux temperature, preferably about 40°C to about 100°C. The acid addition salt can be isolated by any known techniques such as cooling the solution to precipitation, crystallization, solvent precipitation, spray drying, freeze drying, agitated thin film evaporator (ATFE) and the like.
Tofacitinib Saccharine salt prepared according to such procedure exhibits a powder X-ray diffraction pattern substantially in accordance with Figure. 6.
In another embodiment, the present invention provides a process for preparing acid addition salts of Tofacitinib, wherein the acid addition salt, comprising
a) providing a solution of Tofacitinib and Cholic acid in one or more solvents and
b) isolating the Tofacitinib Cholic acid salt.
The suitable solvent used is selected from the group consisting of water, methanol, ethanol, acetone, THF, acetonitrile, ethyl acetate, IPE and mixtures thereof, preferably acetone.
The solution may be formed by heating the mixture at a temperature of about 30°C to about reflux temperature, preferably about 40°C to about 100°C. The acid addition salt can be isolated by any known techniques such as cooling the solution to precipitation, crystallization, solvent precipitation, spray drying, freeze drying, agitated thin film evaporator (ATFE) and the like.
Tofacitinib Cholic acid salt prepared according to such procedure exhibits a powder X-ray diffraction pattern substantially in accordance with Figure 7.
Tofacitinib Cholic acid salt prepared according to such procedure exhibits a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 8.
In another embodiment, the present invention provides a process for preparing acid addition salts of Tofacitinib, wherein the acid addition salt, comprising
a) providing a solution of Tofacitinib and Aspartic acid in one or more solvents and
b) isolating the Tofacitinib Aspartic acid salt.
The suitable solvent used is selected from the group consisting of water, methanol, ethanol, acetone, THF, acetonitrile, ethyl acetate, IPE and mixtures thereof, preferably acetone.
The solution may be formed by heating the mixture at a temperature of about 30°C to about reflux temperature, preferably about 40°C to about 100°C. The acid addition salt can be isolated by any known techniques such as cooling the solution to precipitation, crystallization, solvent precipitation, spray drying, freeze drying, agitated thin film evaporator (ATFE) and the like.
Tofacitinib Aspartic acid salt prepared according to such procedure exhibits a powder X-ray diffraction pattern substantially in accordance with Figure. 9.
In another embodiment, the present invention provides novel acid addition salts of Tofacitinib, having a chemical purity of 96% or more as measured by HPLC, preferably 99% or more, more preferably 99.5% or more.
In another embodiment, the novel acid addition salts of Tofacitinib of the present invention can be used as intermediate or as starting material for the preparation of other pharmaceutically acceptable acid salts of Tofacitinib, for example Tofacitinib citrate but not limited.
In another embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of acid addition salts of Tofacitinib of the present invention with at least one pharmaceutically acceptable carrier or other excipients.
The pharmaceutical composition can be useful for rheumatoid arthritis (RA) and is being studied for treatment of psoriasis, inflammatory bowel disease, and other immunological diseases, as well as for the prevention of organ transplant rejection, xeno transplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn’s disease, Alzheimer’s disease, leukemia and other indications, where immunosuppression would be desirable.
Pharmaceutical acceptable salts in accordance with present invention can be embodied for example in form of tablet, capsules, injectables, syrups, orally dissolvable, sublingual, pellets, in granules and suppositories or their combined forms. Pharmaceutical composition in accordance with present invention can be suitable for immediate release or delayed release or modified release of Tofacitinib salts of the present invention. Solid pharmaceutical compositions can be for example coated with aim of increasing pelletability or regulating the disintegration or absorption.
Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification.
The invention is further defined by reference to the following examples describing in detail the preparation of the composition and methods of use of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
The embodiments and illustrated examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to limit its scope any way.

Examples:
Example 1: Preparation of Tofacitinib gentisic acid salt
5 gm of Tofacitinib free base residue in 25 ml of acetone and 2.39 gm of gentisic acid was stirred at ambient temperature. Distill off solvent completely to obtain Tofacitinib gentisic acid salt.
Example 2: Preparation of Tofacitinib glyoxylic acid salt
5 gm of Tofacitinib free base residue in 25 ml of acetone was heated up to 40.0-45.0OC till clear solution was observed. Add glyoxylic acid solution (1.47 gm of glyoxylic acid in 25 ml of acetone). Stirred for 30 minutes at same temperature and cool down to ambient temperature. Stirred for 30 minutes. Filtered the mass and washed with acetone. Dried the Tofacitinib glyoxylic acid salt.
Example 3: Preparation of Tofacitinib cyclamic acid salt
5 gm of Tofacitinib free base residue in 25 ml of acetone and 2.86 gm of cyclamic acid was stirred at ambient temperature. Distill off solvent completely to obtain Tofacitinib cyclamic acid salt.
Example 4: Preparation of Tofacitinib pyruvic acid salt
5 gm of Tofacitinib free base residue in 25 ml of acetone and 1.4 gm of pyruvic acid was stirred at ambient temperature. Distill off solvent completely to obtain Tofacitinib pyruvic acid salt.
Example 5: Preparation of Tofacitinib saccharine salt
5 gm of Tofacitinib free base residue in 25 ml of acetone and 2.9 gm of saccharine was stirred at ambient temperature. Distilled off solvent completely under vacuum to obtain Tofacitinib saccharine salt.
Example 6: Preparation of Tofacitinib cholic acid salt
5 gm of Tofacitinib free base residue in 25 ml of methanol was stirred with cholic acid solution (6.5 gm of cholic acid acid in 15 ml of acetone). Stirred for one hour at ambient temperature. Distilled off solvent completely under vacuum to obtain Tofacitinib cholic acid salt.

Example 7: Preparation of Tofacitinib aspartic acid salt
5 gm of Tofacitinib free base residue in 300 ml of water and 2.1 gm of aspartic acid was heated to 80.0OC. Distilled off solvent completely under vacuum to obtain Tofacitinib aspartic acid salt.
Example 8: Preparation of Tofacitinib free base residue
Taken 100 gm of Tofacitinib citrate, 700 ml of Purified water, 1500 ml of Methylene chloride in RB flask. Adjusted the reaction mass pH to 8.0 with Sodium carbonate solution. Stirred for 30 minutes. Separated the organic layer, dry the organic layer over Sodium sulphate. Distill off organic layer completely and to get 57 gm of Tofacitinib free base residue.
It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be constructed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the specification appended hereto.