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

The present application claims priority from Indian provisional application no. 202041013253 filed on Mar 26, 2020 and Indian provisional application no. 202041016109 filed on Apr 14, 2020 both of which are incorporated in their entirety.
FIELD OF THE INVENTION
Aspects of the present application relate to solid state forms of Ruxolitinib phosphate. Specific aspects relate to crystalline forms of Ruxolitinib phosphate and their process for the preparation.
BACKGROUND OF THE INVENTION
Ruxolitinib is useful as inhibitor of the Janus Kinase family of protein tyrosine kinases (JAKs) for treatment of inflammatory diseases, myeloproliferative disorders, and other diseases and is represented by below chemical structure.

Ruxolitinib phosphate is approved and marketed as JAKAFI (USA) / JAKAVI (Europe) oral tablets for the treatment of as the myelofibrosis, polycythaemia vera (PV) and steroid-refractory acute graft-versus-host disease (GVHD).
WO2007070514A1 first discloses Ruxolitinib, its preparation and use in the treatment of diseases related to activity of Janus kinases including immune-related diseases, skin disorders, myeloid proliferative disorders, cancer, and other diseases.
WO2008157208A2 discloses the phosphate salt of Ruxolitinib and its crystalline form. However, the PXRD pattern of crystalline Ruxolitinib phosphate was disclosed only during the prosecution of corresponding US patent application. Further, the CMHP assessment report of elucidates that, crystalline Ruxolitinib phosphate present in marketed product, JAKAVI is anhydrous.
The existence and possible numbers of polymorphic forms for a given compound cannot be predicted, and there are no “standard” procedures that can be used to prepare polymorphic forms of a substance. This is well-known in the art, as reported, for example, by A. Goho, “Tricky Business,” Science News, Vol. 166(8), August 2004. Hence, there remains a need for an alternate and viable solid state form of Ruxolitinib phosphate.
SUMMARY OF THE INVENTION
In an aspect, the present application provides a crystalline Form S2 of Ruxolitinib phosphate, characterized by a PXRD pattern comprising the peaks at about 14.23, 16.54, 18.23, 26.14 and 28.52° ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form S3 of Ruxolitinib phosphate, characterized by a PXRD pattern comprising the peaks at about 11.51, 15.38 and 20.11° ± 0.2° 2?.
In an aspect, the present application provides a crystalline Form S4 of Ruxolitinib phosphate, characterized by a PXRD pattern comprising the peaks at about 3.68, 15.01, 16.37, 18.41, 18.81, 22.67 and 27.15° ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline Form S2 of Ruxolitinib phosphate, comprising the step of combining Ruxolitinib phosphate with formic acid.
In another aspect, the present application provides a process for the preparation of crystalline Form S3 of Ruxolitinib phosphate, comprising the step of heating crystalline Form S2 of Ruxolitinib phosphate.
In another aspect, the present application provides a process for the preparation of crystalline Form S4 of Ruxolitinib phosphate, comprising the step of combining Ruxolitinib phosphate with benzyl alcohol.
In another aspect, the present application provides pharmaceutical compositions comprising a crystalline Ruxolitinib phosphate, selected from the group consisting of Form S2, Form S3, Form S4 or mixtures thereof, together with atleast one pharmaceutically acceptable excipient.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction pattern of crystalline Form S2 of Ruxolitinib phosphate, prepared by the method of Example No 1.
Figure 2 is an illustrative X-ray powder diffraction pattern of crystalline Form S3 of Ruxolitinib phosphate, prepared by the method of Example No 2.
Figure 3 is an illustrative X-ray powder diffraction pattern of crystalline Form S4 of Ruxolitinib phosphate, prepared by the method of Example No 3.
DETAILED DESCRIPTION OF THE INVENTION
In an aspect, the present application provides a crystalline Form S2 of Ruxolitinib phosphate, characterized by a PXRD pattern comprising the peaks at about 14.23, 16.54, 18.23, 26.14 and 28.52° ± 0.2° 2?. In an embodiment, the crystalline Form S2 is characterized by one or more additional peaks at about 4.09, 12.06, 13.73, 15.47 and 20.72° ± 0.2° 2?. In an embodiment, the application provides crystalline Form S2, characterized by a PXRD pattern of figure 1.
In another aspect, the present application provides a crystalline Form S3 of Ruxolitinib phosphate, characterized by a PXRD pattern comprising the peaks at about 11.51, 15.38 and 20.11° ± 0.2° 2?. In an embodiment, the crystalline Form S3 is characterized by one or more additional peaks at about 4.15, 14.61, 16.88, 20.75, 21.13 and 26.18° ± 0.2° 2?. In an embodiment, the application provides crystalline Form S3, characterized by a PXRD pattern of figure 2.
In an aspect, the present application provides a crystalline Form S4 of Ruxolitinib phosphate, characterized by a PXRD pattern comprising the peaks at about 3.68, 15.01, 16.37, 18.41, 18.81, 22.67 and 27.15° ± 0.2° 2?. In an embodiment, the crystalline Form S4 is characterized by one or more additional peaks at about 14.25, 17.19, 22.24, 23.67, 25.31 and 26.32° ± 0.2° 2?. In an embodiment, the application provides crystalline Form S4, characterized by a PXRD pattern of figure 3.
In another aspect, the present application provides a process for the preparation of crystalline Form S2 of Ruxolitinib phosphate, comprising the step of combining Ruxolitinib phosphate with formic acid.
In embodiments, Ruxolitinib phosphate used in this aspect may be obtained by any methods known in the art or any process comprising the reaction of Ruxolitinib with phosphoric acid under suitable conditions to form phosphate salt of Ruxolitinib.
In embodiments, combining Ruxolitinib phosphate with formic acid may be carried out through the formation of a homogeneous solution or a heterogeneous mixture, under suitable temperature at about 0°C to reflux temperature the solvent or reaction mixture thereof.
In an embodiment, combining Ruxolitinib phosphate with formic acid may be carried out by dissolving Ruxolitinib phosphate in formic acid, optionally by heating. In embodiments, the solution containing Ruxolitinib phosphate in formic acid may be cooled to suitable temperature to crystallize form S2.
In an embodiment, the solvent from the solution containing Ruxolitinib phosphate in formic acid may be removed by evaporation or sublimation of the solvent, optionally under reduced pressure at about 0°C to reflux temperature of inert organic solvent or mixtures thereof.
In an embodiment, the solution containing Ruxolitinib phosphate in formic acid may be contacted with a suitable anti-solvent, to crystallize form S2. Anti-solvent is solvent in which the Ruxolitinib phosphate is insoluble or low soluble. Suitable anti-solvent may include, but not limited to diethyl ether, methyl tert. butyl ether, diisopropyl ether or the likes.
In embodiments, Ruxolitinib phosphate may be combined with formic acid by suspending Ruxolitinib phosphate in formic acid to form a slurry or suspension, optionally under heating.
In embodiments, Ruxolitinib phosphate may be combined with formic acid for sufficient time to obtain crystalline form S2 of Ruxolitinib phosphate.
In embodiments, Ruxolitinib phosphate may be combined with formic acid at suitable temperature to obtain crystalline form S2 of Ruxolitinib phosphate. In preferred embodiments, Ruxolitinib phosphate may be combined with formic acid at suitable temperature of about 0°C to reflux temperature to obtain crystalline form S2.
In embodiments, the crystalline form S2 of Ruxolitinib phosphate may be isolated by separating the solids from the solvent through suitable techniques known in the art such as filtration, decantation and the like.
In embodiments, Ruxolitinib phosphate may be combined through grinding or milling the Ruxolitinib phosphate in the presence of formic acid. In embodiments, Ruxolitinib phosphate may be ground in a suitable equipment such as mortar-pestle, milled in a ball mill or the like. In embodiments, Ruxolitinib phosphate may be ground for sufficient time and at suitable temperature to obtain crystalline Form S2.
In embodiments, the isolated solids may be dried under suitable drying conditions such as aerial drying, drying under vacuum or inert gas at a suitable temperature of about 25°C or above.
In embodiments, the crystalline Form S2 of Ruxolitinib phosphate obtained by the process of this aspect may be characterized by a PXRD pattern comprising the peaks at about 14.23, 16.54, 18.23, 26.14, 28.52° ± 0.2° 2?. In an embodiment, the application provides crystalline Form S2, characterized by a PXRD pattern of figure 1.
In another aspect, the present application provides a process for the preparation of crystalline Form S3 of Ruxolitinib phosphate, comprising the step of heating crystalline Form S2 of Ruxolitinib phosphate.
In embodiments, Ruxolitinib phosphate or its crystalline form S2 used in this aspect may be obtained by any methods known in the art or procedures described or exemplified in the present application, comprising the reaction of Ruxolitinib with phosphoric acid under suitable conditions to form phosphate salt of Ruxolitinib.
In embodiments, crystalline form S2 of Ruxolitinib phosphate may be heated under suitable conditions such as heating under atmospheric conditions such as aerial drying, heating under vacuum or inert gas at a suitable temperature of about 25 °C or above.
In an embodiment, crystalline form S2 may be heated in an open container under at suitable temperature for sufficient time to convert into crystalline form S3. In an embodiment, crystalline form S2 may be heated under controlled humidity conditions.
In embodiments, the crystalline form S2 may be heated in suitable equipment such as hot air oven, vacuum oven, humidifiers or calorimeters under reduced pressure or inert gas atmospheric conditions such as nitrogen.
In embodiments, the crystalline form S2 may be heated for atleast one hour or longer.
In embodiments, the crystalline Form S3 of Ruxolitinib phosphate obtained by the process of this aspect may be characterized by a PXRD pattern comprising the peaks at about 11.51, 15.38 and 20.11° ± 0.2° 2?. In embodiments, crystalline Form S3 may be characterized by a PXRD pattern of figure 2.
In another aspect, the present application provides a process for the preparation of crystalline Form S4 of Ruxolitinib phosphate, comprising the step of combining Ruxolitinib phosphate with benzyl alcohol.
In embodiments, Ruxolitinib phosphate used in this aspect may be obtained by any methods known in the art or any process comprising the reaction of Ruxolitinib with phosphoric acid under suitable conditions to form phosphate salt of Ruxolitinib.
In embodiments, combining Ruxolitinib phosphate with benzyl alcohol may be carried out through the formation of a homogeneous solution or a heterogeneous mixture, under suitable temperature at about 0°C to reflux temperature the solvent or reaction mixture thereof.
In an embodiment, combining Ruxolitinib phosphate with benzyl alcohol may be carried out by dissolving Ruxolitinib phosphate in benzyl alcohol, optionally by heating. In embodiments, the solution containing Ruxolitinib phosphate in benzyl alcohol may be cooled to suitable temperature to crystallize Form S4.
In an embodiment, the solvent from the solution containing Ruxolitinib phosphate in benzyl alcohol may be removed by evaporation or sublimation of the solvent, optionally under reduced pressure at about 0°C to reflux temperature.
In an embodiment, the solution containing Ruxolitinib phosphate in benzyl alcohol may be contacted with a suitable anti-solvent, to crystallize Form S4. Anti-solvent is solvent in which the Ruxolitinib phosphate is insoluble or low soluble. Suitable anti-solvent may include, but not limited to diethyl ether, methyl tert. butyl ether, diisopropyl ether or the likes.
In embodiments, Ruxolitinib phosphate may be combined with benzyl alcohol by suspending Ruxolitinib phosphate in benzyl alcohol to form a slurry or suspension, optionally under heating.
In embodiments, Ruxolitinib phosphate may be combined with benzyl alcohol for sufficient time to obtain crystalline Form S4 of Ruxolitinib phosphate.
In embodiments, Ruxolitinib phosphate may be combined with benzyl alcohol at suitable temperature to obtain crystalline Form S4 of Ruxolitinib phosphate. In preferred embodiments, Ruxolitinib phosphate may be combined with benzyl alcohol at suitable temperature of about 0°C to reflux temperature to obtain crystalline Form S4.
In embodiments, the crystalline Form S4 of Ruxolitinib phosphate may be isolated by separating the solids from the solvent through suitable techniques known in the art such as filtration, decantation and the like.
In embodiments, Ruxolitinib phosphate may be combined through grinding or milling the Ruxolitinib phosphate in the presence of benzyl alcohol. In embodiments, Ruxolitinib phosphate may be ground in a suitable equipment such as mortar-pestle, milled in a ball mill or the like. In embodiments, Ruxolitinib phosphate may be ground for sufficient time and at suitable temperature to obtain crystalline Form S4.
In embodiments, the isolated solids may be dried under suitable drying conditions such as aerial drying, drying under vacuum or inert gas at a suitable temperature of about 25°C or above.
In embodiments, the crystalline Form S4 of Ruxolitinib phosphate obtained by the process of this aspect may be characterized by a PXRD pattern comprising the peaks at about 3.68, 15.01, 16.37, 18.41, 18.81, 22.67 and 27.15° ± 0.2° 2?. In an embodiment, the application provides crystalline Form S4, characterized by a PXRD pattern of figure 3.
In another aspect, the present application provides pharmaceutical compositions comprising a crystalline Ruxolitinib phosphate, selected from the group consisting of Form S2, Form S3, Form S4 or mixtures thereof, together with atleast one pharmaceutically acceptable excipient.
In another aspect, the present application provides crystalline form of Ruxolitinib phosphate selected from the group consisting of Form S2, Form S3, Form S4 or mixtures thereof, according to instant application and pharmaceutical compositions thereof, wherein the chemical purity of Ruxolitinib phosphate may be more than 99% by HPLC or more than 99.5% by HPLC or more than 99.9% by HPLC.
In an embodiment, Ruxolitinib phosphate of present invention has average particle size of particles between 1 to 100 µm, less than 90 µm, less than 80 µm, less than 60 µm, less than 50 µm, less than 40 µm, less than 30 µm, less than 20 µm, less than 10 µm, less than 5 µm or any other suitable particle sizes. In another embodiment, Ruxolitinib phosphate of present invention may have particle size distribution: D10 of particles smaller than 20 µm, smaller than 15 µm, smaller than 10 µm, or smaller than 5 µm; D50 of particles smaller than 100 µm, smaller than 90 µm, smaller than 80 µm, smaller than 70 µm, smaller than 60 µm, smaller than 50 µm, smaller than 40 µm, smaller than 30 µm, smaller than 20 µm, smaller than 10 µm; D90 of particles smaller than 200 µm, smaller than 175 µm, smaller than 150 µm, smaller than 140 µm, smaller than 130 µm, smaller than 120 µm, smaller than 110 µm, smaller than 100 µm, smaller than 90 µm, smaller than 80 µm, smaller than 70 µm, smaller than 60 µm, smaller than 50 µm, smaller than 40 µm, smaller than 30 µm, smaller than 20 µm, smaller than 10 µm.
Particle size distributions of Ruxolitinib phosphate particles may be measured using any techniques known in the art. For example, particle size distributions of Ruxolitinib phosphate particles may be measured using microscopy or light scattering equipment, such as, for example, a Malvern Master Size 2000 from Malvern Instruments Limited, Malvern, Worcestershire, United Kingdom. As referred herein, the term “D10” in the context of the present invention is 10% of the particles by volume are smaller than the D10 value and 90% particles by volume are larger than the D10 value. “D50” in the context of the present invention is 50% of the particles by volume are smaller than the D50 value and 50% particles by volume are larger than the D50 value. “D90” in the context of the present invention is 90% of the particles by volume are smaller than the D90 value and 10% particles by volume are larger than the D90 value.
In an embodiment, Ruxolitinib phosphate of present invention can be micronized or milled using conventional techniques to get the desired particle size to achieve desired solubility profile to suit to pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball milling, roller milling and hammer milling. Milling or micronization may be performed before drying, or after the completion of drying of the product.
In another embodiment, the present invention provides pharmaceutical compositions comprising Ruxolitinib phosphate prepared according to method disclosed herein alone or in combination with other drugs. Further the present invention provides a process of preparing a pharmaceutical composition comprising alone or in combination with other drugs. Conveniently various pharmaceutically acceptable excipients can be employed in a process according to the present invention.
In another embodiment, at least one pharmaceutically acceptable excipient of this aspect may be selected from the group consisting of polyvinyl pyrrolidone, povidone K-30, povidone K-60, Povidone K-90, polyvinylpyrrolidone vinylacetate, co-povidone NF, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene–polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit or Eudragit-RLPO), hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), hydroxypropylmethyl cellulose, hydroxypropyl cellulose SSL(HPC-SSL), hydroxypropyl cellulose SL(HPC-SL), hydroxypropyl cellulose L (HPC-L), hydroxyethyl cellulose, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxymethylethylcelluloseand the like; cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, and the like; water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and the like; polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like; organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and guanidine or its derivatives, or any other excipient at any aspect of present invention. A thorough discussion of pharmaceutically acceptable excipients is presented in Remington's Pharmaceutical Sciences (17th ed., Mack Publishing Company) and Remington: The Science and Practice of Pharmacy (21st ed., Lippincott Williams & Wilkins), which are hereby incorporated by reference.
The use of mixtures of more than one of the pharmaceutical excipients to provide desired release profiles or for the enhancement of stability is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, and mixtures are all within the scope of this invention without limitation.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.
Definitions
The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example "about 10" should be construed as meaning within the range of 9 to 11 , preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.

EXAMPLES
Example-1: Preparation of crystalline form S2 of Ruxolitinib phosphate
Ruxolitinib phosphate (3 g) was dissolved in formic acid (5 mL) at 30 ? and filtered the solution to make it particle free. Methyl tert.butyl ether (30 mL) was added to the solution slowly at 30 ? and the mixture was stirred at the same temperature for 15 minutes. The solid was filtered and washed with methyl tert.butyl ether (20 mL) to obtain the title compound. XRPD: Crystalline Form S2.

Example-2: Preparation of crystalline Form S3 of Ruxolitinib phosphate
Crystalline Form S2 of Ruxolitinib phosphate obtained at example 1 was dried in vacuum tray drier at 70 ? for 1 hour to obtain the title compound. XRPD: Crystalline Form S3.

Example-3: Preparation of crystalline Form S4 of Ruxolitinib phosphate
Ruxolitinib phosphate (3 g) was dissolved in benzyl alcohol (50 mL) at 70 ? and filtered the solution to make it particle free. Methyl tert.butyl ether (200 mL) was added to the solution slowly at 30 ? and the mixture was stirred at the same temperature for 30 minutes. The solid was filtered and washed with methyl tert.butyl ether (50 mL) to obtain the title compound. XRPD: Crystalline Form S4.
,CLAIMS:We Claim:
1. A process for the preparation of crystalline Form S2 of Ruxolitinib phosphate, comprising the step of combining Ruxolitinib phosphate with formic acid.
2. The process as claimed in claim-1, wherein the crystalline Form S2 of Ruxolitinib phosphate is characterized by a PXRD pattern comprising the peaks at about 14.23, 16.54, 18.23, 26.14 and 28.52° ± 0.2° 2?.
3. The process as claimed in claim-1, wherein the crystalline Form S2 of Ruxolitinib phosphate is characterized by a PXRD pattern of figure 1.
4. A process for the preparation of crystalline Form S3 of Ruxolitinib phosphate, comprising the step of heating crystalline Form S2 of Ruxolitinib phosphate.
5. The process as claimed in claim-4, wherein the crystalline Form S3 of Ruxolitinib phosphate is characterized by a PXRD pattern comprising the peaks at about 11.51, 15.38 and 20.11° ± 0.2° 2?.
6. The process as claimed in claim-4, wherein the crystalline Form S3 of Ruxolitinib phosphate is characterized by a PXRD pattern of figure 2.
7. A process for the preparation of crystalline Form S4 of Ruxolitinib phosphate, comprising the step of combining Ruxolitinib phosphate with benzyl alcohol.
8. The process as claimed in claim-7, wherein the crystalline Form S3 of Ruxolitinib phosphate is characterized by a PXRD pattern comprising the peaks at about 3.68, 15.01, 16.37, 18.41, 18.81, 22.67 and 27.15° ± 0.2° 2?.
9. The process as claimed in claim-7, wherein the crystalline Form S4 of Ruxolitinib phosphate is characterized by a PXRD pattern of figure 3.
10. A pharmaceutical compositions comprising a crystalline Ruxolitinib phosphate, selected from the group consisting of Form S2, Form S3, Form S4 or mixtures thereof, together with atleast one pharmaceutically acceptable excipient.