DESC:SOLID FORMS OF RUXOLITINIB TARTRATE AND PROCESS THEREOF

FIELD OF THE INVENTION
Aspects of the present application relate to solid state form of Ruxolitinib Tartrate. Specific aspects relate to crystalline Form RT1 of Ruxolitinib Tartrate and process for its 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.
Salts of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile prepared with maleic acid, sulphuric acid and phosphoric acid are disclosed in WO2008157208A1.
International Patent Application Publication Nos. WO 2017008772A1, WO2016063294A2, WO2016026975A1, WO2016074650A1, WO 2016026974A1 and WO2017125097A1, reported various salts of Ruxolitinib.
Different salt forms of the same pharmaceutically active moiety differ in their physical properties such as melting point, solubility, etc. These properties may appreciably influence pharmaceutical properties such as dissolution rate and bioavailability. A pharmaceutically acceptable salt is not only defined by its chemical composition but also by the so-called polymorphism. In addition, polymorphism is very common among pharmaceutical substances. It is commonly defined as the ability of any substance to exist in two or more crystalline phases that have a different arrangement and/or conformation of the molecules in the crystal lattice. Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule, like Ruxolitinib or salts thereof, may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis - "TGA", or differential scanning calorimetry - "DSC"), powder X-ray diffraction (PXRD) pattern, infrared absorption and solid state NMR spectrum. One or more of these techniques may be used to characterize a particular polymorph and to distinguish different polymorphic forms of a compound.
Different solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different solid state forms and solvates may provide a basis for improving certain aspects of the API, such as its formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different solid state forms may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different solid state forms and solvates of an active pharmaceutical ingredient may also give 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.
Pharmaceutical stability is believed to depend on simultaneous influence of various factors, of which some important factors are the sizes of the crystals, shape of the crystals, water content, residual solvents and impurities. Towards this end, it has been the endeavor of pharmaceutical scientists to provide novel salts and/or novel stable polymorphs of salts of drug substances, which would have the strengths of the crystalline forms, viz. thermodynamic stability, and those of the amorphous form, viz. enhanced solubility, rapid onset of action and an enhanced bioavailability.
Discovering new polymorphic forms and solvates of a pharmaceutical product can provide materials having, inter alia, desirable processing properties, such as ease of handling, ease of processing, chemical and polymorphic stability upon storage and processing, and ease of purification or are useful as advantageous intermediate crystal forms that facilitate conversion to other solid state forms (including other solvates) of said pharmaceutical product.
New polymorphic forms and solvates of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf- life. Lastly, new polymorphic forms may be prepared with improved reliability and reproducibility compared to other forms, for example, in terms of crystallinity or polymorphic purity.
The intestinal tract obeys different pH ranges, which vary from pH 1 to 2 of the empty stomach, pH 3-5 for stomach filled with chyme, to pH 5-7.5 of the colon. A dissolution screening test regime for solid state forms of an active ingredient may be set up for example at pH 1.2, pH 4.5 and pH 6.8 in order to cover a broad range of the gastro-intestinal tract.
Solubility studies showed good solubility for Ruxolitinib phosphate at pH 1.2, but considerably less solubility at higher pH points. Ruxolitinib maleate exhibited less solubility at pH 1.2 in comparison with Ruxolitinib phosphate and in addition a distinct pH dependency at pH 4.5 and 6.8. Ruxolitinib sulfate gave a moderate solubility with less pH dependency.
In order to provide a modified release formulation, such as delayed release, prolonged release, sustained release, repeated action release, extended release, controlled release, it is of favor when the solid state forms of an active ingredient show moderate solubility. This may be of advantage, when a so-called matrix system is used. For such systems, the active ingredient is embedded in an appropriate polymer, for example hydroxy propyl methyl cellulose, and release of the active ingredient is diffusion controlled over a period of time.
It is of favor if salts of active ingredients show comparable solubilities through all pH ranges of the gastro-intestinal tract when used in a modified release formulation in order to be available for permeation into the body through the entire passage of the gastro-intestinal passage. This passage may take a few hours.
Object of the present invention is to provide crystalline form of Ruxolitinib Tartrate, which gives moderate solubility for all pH ranges, while the salt is still pharmaceutically acceptable & formulation compatible physicochemical properties.

SUMMARY OF THE INVENTION
The present invention provides a crystalline Ruxolitinib tartrate, processes for the preparation thereof, and pharmaceutical compositions and formulations comprising the solid state form of Ruxolitinib tartrate, and processes for the preparation of the pharmaceutical compositions and formulations. Specifically, present invention provides crystalline Form RT1 of Ruxolitinib tartrate and its process.
The present invention also provides the use of said solid state form of Ruxolitinib tartrate for the manufacture of pharmaceutical compositions and formulations. Accordingly, the present invention further provides a pharmaceutical composition comprising said solid state form of Ruxolitinib tartrate of the present invention. The pharmaceutical composition may additionally comprise at least one pharmaceutically acceptable excipient to form a pharmaceutical formulation that can, for example, be administered to patients in need of such treatment.
The present invention comprises a process for preparing the above-mentioned pharmaceutical formulations. The process comprises combining the solid state form of Ruxolitinib tartrate with at least one pharmaceutically acceptable excipient.
The solid state form as defined herein as well as the pharmaceutical compositions and formulations of Ruxolitinib tartrate can be used as medicaments, particularly for the treatment of cancer, myelofibrosis, polycythemia vera, essential Thrombocythemia, hematological malignancies and psoriasis. The present invention also provides a method of treating cancer, myelofibrosis, polycythemia vera, essential Thrombocythemia hematological malignancies and psoriasis comprising administering a therapeutically effective amount of the solid state form of Ruxolitinib tartrate of the present invention, or a therapeutically effective amount of at least one of the pharmaceutical compositions or formulations of the present invention comprising said solid state form of Ruxolitinib tartrate of the present invention to a patient in need thereof.
The present invention also provides the use of said solid state form of Ruxolitinib tartrate, or at least one of the above pharmaceutical compositions and/or formulations for the manufacture of a medicament for treating cancer, myelofibrosis, polycythemia vera, essential Thrombocythemia, hematological malignancies and psoriasis.
Further, depending on which other solid state form it is compared with, the solid form of Ruxolitinib Tartrate of the present invention may have advantageous properties selected from at least one of: chemical or polymorphic purity, increased crystallinity, flowability, solubility, dissolution rate, bioavailability, morphology or crystal habit, specific surface and bulk/tap density, stability - such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and/or storage stability, a lower degree of hygroscopicity, low content of residual solvents and advantageous processing and handling characteristics such as compressibility, and bulk density.

BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is an illustration of powder X-ray diffraction (“PXRD”) pattern of Ruxolitinib Tartrate prepared according to example 1.
Fig. 2 is an illustration of DSC thermogram of Ruxolitinib Tartrate prepared according to example 1.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a crystalline form of Ruxolitinib Tartrate, processes for the preparation thereof, and pharmaceutical compositions and formulations comprising the solid state form of Ruxolitinib Tartrate, and processes for the preparation of the pharmaceutical compositions and formulations.
In the first embodiment, the present application provides a crystalline form of Ruxolitinib Tartrate.
In the second embodiment, the present application provides a crystalline form RT1 of Ruxolitinib Tartrate that can be characterized by its PXRD pattern, as illustrated in Figure 1.
In the third embodiment, the present application provides a crystalline Form RT1 of Ruxolitinib Tartrate, characterized by a PXRD pattern comprising the peaks at about 8.85, 15.19 and 20.45 ± 0.2° 2?. Further comprising, additional peaks at about 4.36, 7.54, 13.95 19.38 and 22.18 ± 0.2° 2?.
In the fourth embodiment, the present application provides a process for the preparation of crystalline Ruxolitinib Tartrate, comprising:
a) providing a mixture of Ruxolitinib free base or its salt in a suitable solvent;
b) adding L-Tartaric acid or a source of Tartrate anion to the mixture of step a);
c) isolating and recovering the crystalline Ruxolitinib Tartrate from the mixture of step b); and
d) drying the said crystalline form.
The mixture comprising Ruxolitinib free base or its salt in step a) may be a suspension or a solution. The mixture of step a) may be obtained, for example, by providing free base or a salt of Ruxolitinib of any form in a solvent. The said base or salt may be obtained by a previous step of the process which can be a final reaction and/or purification. If it is intended to obtain a clear solution of Ruxolitinib free base or its salt, the reaction mixture can be heated to dissolution temperature that can be any temperature as long as the stability of the Ruxolitinib free base or its salt is not compromised and a substantially clear solution is obtained. For example, the dissolution temperature may range from about 20°C to about the reflux temperature of the solvent.
If Ruxolitinib salt is employed in step a) as an input material then it will be different salt from the finally obtained Ruxolitinib Tartrate of step c) and step d).
Solvents employed include, but are not limited to: alcohols, such as, for example, methanol, ethanol, or 2-propanol; esters, such as, for example, ethyl acetate, isopropyl acetate, or t-butyl acetate; ketones such as acetone or methyl isobutyl ketone; ethers, such as, for example, diisopropyl ether, methyl tert-butyl ether, diethyl ether, 1,4-dioxane, THF, or methyl THF; halogenated hydrocarbons, such as, for example, dichloromethane, dichloroethane, chloroform, or the like; hydrocarbons, such as, for example, toluene, xylene, or cyclohexane; nitriles such as acetonitrile; dipolar aprotic solvents such as dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide or like; water; or any mixtures thereof.
Appropriate solvents or non-solvents may be determined by solubility tests in various solvents.
In a preferred embodiment acetonitrile-water are employed.
Step b) involves addition of L-tartaric acid or source of tartrate anion to the mixture of step a).
Suitable solvents are same as that employed in step a) & are inert to the reaction conditions. Non-dissolved particles from a mixture of step b) can be removed suitably by filtration, centrifugation, decantation, or other techniques, such as passing the solution through paper, glass fiber, a particulate bed, or a membrane material.
The reaction can be efficiently completed at room temperature or ambient temperature or if required reaction mass can be heated to elevated temperatures or up to about the reflux temperatures, and maintained for a time from about 10 minutes to about 5 hours or longer. Suitable temperatures for crystallization are from about 0°C to about 50°C, from about 10 to about 30°C, or any other temperatures may be used. Suitable times for crystallization will vary, and can be from about 10 minutes to about 10 hours, or longer.
Step c) involves isolation and recovery of crystalline Ruxolitinib Tartrate from the reaction mixture. The isolation of salts of crystalline Ruxolitinib Tartrate may be induced by using conventional techniques known in the art. For example, useful techniques include but are not limited to, concentrating, cooling, stirring, shaking, combining with an anti-solvent, adding seed crystals, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying including ATFD, freeze-drying, or the like. The solid that is obtained may carry a small proportion of occluded mother liquor containing a higher percentage of impurities and, if desired, the solid may be washed with a suitable solvent to wash out the mother liquor. Evaporation as used herein refers to distilling of solvent almost completely at atmospheric pressure or under reduced pressure. Flash evaporation as used herein refers to distilling of solvent by using a technique includes but is not limited to tray drying, spray drying, fluidized bed drying, thin film drying under reduced pressure, or thin film drying at atmospheric pressure. The recovery of crystalline Ruxolitinib Tartrate can be done by decantation, centrifugation, gravity filtration, suction filtration and like.
The crystalline Ruxolitinib Tartrate of the present invention if desired can be purified by re-crystallization from an appropriate re-crystallization solvent or mixture of solvents by methods customary to one of skill in the art. If required, the process further comprises, at a suitable stage, removing or separating any undesired material or impurities, and finally, optionally, the salts may be washed and/or dried.
The resulting solid may be further dried. Drying may be suitably carried out by using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve a desired purity of the product, such as, for example, from about 1 hour to about 15 hours, or longer.
Once obtained, crystals of crystalline Ruxolitinib Tartrate may be used as the nucleating agent or “seed” crystals for subsequent crystallizations of salts of crystalline Ruxolitinib Tartrate from solutions.
In a preferred embodiment, crystalline form of Ruxolitinib Tartrate obtained by above process is Form RT1.
The crystalline Ruxolitinib Tartrate of the present application may be characterized by means of Powder X-ray Diffraction Pattern (PXRD). Other techniques, such as solid state NMR, Fourier Transform Infrared (FTIR), differential scanning calorimetry (DSC) may also be used.
Ruxolitinib employed as a starting material for preparation of crystalline Ruxolitinib Tartrate can be obtained by any processes known in the art, including processes disclosed in US7598257, US8722693 and US8410265 which are incorporated herein by reference in their entireties, as well as by other processes known in the art.
The compound of this application is best characterized by the X-ray powder diffraction pattern determined in accordance with procedures that are known in the art. PXRD data reported herein was obtained using CuK? radiation, having the wavelength 1.5406 Å and were obtained using a PANalytical X’Pert PRO instruments. For a discussion of these techniques see J. Haleblain, J. Pharm. Sci. 1975 64:1269-1288, and J. Haleblain and W. McCrone, J. Pharm. Sci. 1969 58:911-929.
Generally, a diffraction angle (2?) in powder X-ray diffractometry may have an error in the range of ± 0.2o. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ± 0.2o. Accordingly, the present application includes not only crystals whose peak diffraction angles in powder X-ray diffractometry completely coincide with each other, but also crystals whose peak diffraction angles coincide with each other with an error of about ± 0.2o. Therefore, in the present specification, the phrase "having a diffraction peak at a diffraction angle (2? ± 0.2o) of 7.9?" means "having a diffraction peak at a diffraction angle (2?) of 7.7? to 8.1?”. Although the intensities of peaks in the x-ray powder diffraction patterns of different batches of a compound may vary slightly, the peaks and the peak locations are characteristic for a specific polymorphic form. Alternatively, the term "about" means within an acceptable standard error of the mean, when considered by one of ordinary skill in the art. The relative intensities of the PXRD peaks can vary depending on the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed. Moreover, instrument variation and other factors can affect the 2-theta values. Therefore, the term "substantially" in the context of PXRD is meant to encompass that peak assignments can vary by plus or minus about 0.2 degree. Moreover, new peaks may be observed or existing peaks may disappear, depending on the type of the machine or the settings (for example, whether a Ni filter is used or not).
Optionally crystalline Ruxolitinib Tartrate of the present invention can be subjected to particle size reduction by conventional techniques like jet-milling, micronization and like to obtain suitable particle size distribution. The D10, D50, and D90 values are useful ways for indicating a particle size distribution. D90 refers to at least 90 volume percent of the particles having a size smaller than the said value. Likewise, D10 refers to 10 volume percent of the particles having a size smaller than the said value. D50 refers to 50 volume percent of the particles having a size smaller than the said value. Methods for determining D10, D50, and D90 include laser diffraction, such as using equipment from Malvern Instruments Ltd. of Malvern, Worcestershire, United Kingdom.
In the fifth embodiment, the present application provides a pharmaceutical composition comprising crystalline Ruxolitinib Tartrate and one or more pharmaceutically acceptable excipients.
Such further excipients and adjuvants are known to the person skilled in the art and may include one or more fillers; diluents, for example microcrystalline cellulose, lactose, mannitol, dibasic calcium phosphate, pregelatinized starch and the like; binders such as PVP, HPMC, HPC and the like; disintegrants, for example, sodium starch glycolate, crospovidone, croscarmellose sodium and the like; lubricants, for example, magnesium stearate, sodium stearyl fumarate and the like; sweeteners, for example, sucrose, saccharin and the like; flavoring agents, for example, peppermint, methyl salicylate, orange flavoring and the like; colorants; preservatives; buffers; and/or other excipients depending on the dosage form used.
The pharmaceutical compositions of the present invention are generally administered orally to patients, which include, but are not limited to, mammals, for example, humans, in the form of, for example, a hard or soft gelatin capsule, a tablet, a caplet, pills, granules or a suspension. The pharmaceutical dosage form can be prepared by methods known in the art, such as direct compression or wet granulation or direct compression. The compression of the blend to tablet cores can be carried out using a conventional tabletting machine or a rotary compression machine. The tablet cores may vary in shape and can be, for example, round, oval, oblong, cylindrical or any other suitable shape. The cores may also vary in size depending on the concentration of the therapeutic agent.
The pharmaceutical dosage form according to the present invention may be is coated with one or more coating materials or uncoated. The coating materials are not particularly limited and are known to the person skilled in the art.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the application in any manner.

DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise. Polymorphs are different solids sharing the same molecular formula, yet having distinct physical properties when compared to other polymorphs of the same formula. The abbreviation “MC” mean moisture content. Moisture content can be conveniently measured, for example, by the Karl Fischer method.
“Crystalline form” as used herein refers to a solid state wherein the crystalline content with in the said solid state is at least about 50% or at least about 55% or at least about 60% or at least about 65% or at least about 70% or at least about 75% or at least about 80% or at least about 85% or at least about 90% or at least about 95% or at least about 96% or at least about 97% or at least about 98% or at least about 99% or about 100%.
A crystal form may be referred to herein as being characterized by graphical data "substantially as depicted" in a Figure. Such data include, for example, powder X-ray diffractograms, infrared spectra and DSC thermograms. The graphical data potentially provides additional technical information to further define the respective solid state form which can not necessarily or easily be described by reference to numerical values for peak positions and/or relative intensities. In any event, the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to factors such as variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown solid state form and confirm whether the two sets of graphical data are characterizing the same solid state form or two different solid state forms.
Where this document refers to a material, such as in this instance, crystalline Ruxolitinib Tartrate, and their solid state forms thereof by reference to patterns, spectra or other graphical data, it may do so by qualifying that they are "substantially" shown or as depicted in a Figure, or by one or more data points. By "substantially" used in such a context, it will be appreciated that patterns, spectra and other graphical data can be shifted in their positions, relative intensities and/or values due to a number of factors known to those of skill in the art.
In addition, where a reference is made to a figure, it is permissible to, and this document includes and contemplates, the selection of any number of data points illustrated in the figure which uniquely define that solid state form, within any associated and recited margin of error, for purposes of identification.
As used herein, the term "isolated" corresponds to product or solid state form thereof that is physically separated from the reaction mixture in which it is formed.
All percentages and ratios used herein are by weight of the total composition, unless the context indicates otherwise. All temperatures are in degrees Celsius unless specified otherwise and all measurements are made at 25oC and normal pressure unless otherwise designated. The present disclosure can comprise the components discussed in the present disclosure as well as other ingredients or elements described herein.
As used herein, "comprising" means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise.
All ranges recited herein include the endpoints, including those that recite a range "between" two values.
Terms such as "about," "generally," "substantially," or the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify, as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
When a molecule or other material is identified herein as "pure", it generally means, unless specified otherwise, that the material is 99% pure or more, as determined by methods conventional in art such as high performance liquid chromatography (HPLC) or optical methods. In general, this refers to purity with regard to unwanted residual solvents, reaction byproducts, impurities, and unreacted starting materials. "Substantially" pure means, the same as "pure except that the lower limit is about 98% pure or more and likewise, "essentially" pure means the same as "pure" except that the lower limit is about 95% pure.
As used herein, the term "room temperature" refers to a temperature of from about 20oC to about 35oC, from about 25oC to about 35oC, from about 25oC to about 30oC, or for example, about 25oC.
As used herein, the term "overnight" refers to a time interval from about 14 hours to about 24 hours, or about 14 hours to about 20 hours, for example, about 16 hours.
The "polymer" or “carrier” or “excipient” as used herein interchangeably refers to any substance or mixture of substances which are pharmaceutically acceptable inactive ingredients.
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.

EXAMPLES
Example 1: Preparation of Crystalline Ruxolitinib Tartrate
A flask was charged with Ruxolitinib free base (3 g), acetonitrile (30 mL) at room temperature for dissolution. To this mixture, solution of L-Tartaric acid (1.5 g) in water (5mL) was added. The resulting mixture was stirred at room temperature for about an hour. The obtained solid was filtered and washed with MTBE (20 mL) followed by vacuum drying at 40oC to afford the title compound.
,CLAIMS:We Claim,
Claim 1: A Crystalline form RT1 of Ruxolitinib Tartrate, characterized by a PXRD pattern comprising the peaks at about 8.85, 15.19 and 20.45 ± 0.2° 2?.
Claim 2: The Crystalline form as claimed in Claim 1 further characterized by a PXRD pattern comprising the peaks at about 4.36, 7.54, 8.85, 13.95, 15.19, 19.38, 22.18 and 20.45 ± 0.2° 2?.
Claim 3: The Crystalline form as claimed in Claim 2, characterized by its PXRD pattern, as illustrated in Figure 1.
Claim 4: A process for the preparation of crystalline Form RT1 of Ruxolitinib Tartrate, comprising:
a) providing a mixture of Ruxolitinib free base or its salt in a suitable solvent;
b) adding L-Tartaric acid or a source of Tartrate anion to the mixture of step a);
c) isolating and recovering the crystalline Ruxolitinib Tartrate from the mixture of step b); and
d) drying the said crystalline form.
Claim 5: A pharmaceutical composition comprising Ruxolitinib Tartrate and a pharmaceutically acceptable excipient.