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

SOLID FORMS OF ENTINOSTAT

INTRODUCTION
Aspects of the present application relate to solid forms of Entinostat and pharmaceutical compositions thereof.
The drug compound having the adopted name “Entinostat” has chemical name: Pyridin-3-ylmethyl-N-[[4-[(2-aminophenyl)carbamoyl] phenyl]methyl]carbamate as below.

Entinostat is an oral synthetic benzamide derivative and the lead in a series of HDAC inhibitors, for the potential treatment of cancer, particularly breast cancer. The US FDA has granted breakthrough therapy designation to Entinostat for the treatment of locally recurrent or metastatic ER-positive breast cancer, when added to exemestane in postmenopausal women whose disease had progressed following non-steroidal aromatase inhibitor therapy.
US 6174905 B1 discloses Entinostat and a salt thereof, its pharmaceutical composition and its use in the treatment of a malignant tumor including colorectal cancer, ovarian cancer, oral cancer, lung carcinoma, breast carcinoma, prostate carcinoma and melanoma.
Further, US 6174905 B1 exemplified the preparation of Entinostat by reacting 4-aminomethyl-N-[2-(N-tertbutoxycarbonyl) aminophenyl]benzamide with 3-pyridinemethanol in the presence of N,N'-carbonyldiimidazole. The compound obtained by this process was extracted into chloroform and concentrated to give crystals of Entinostat, which were then recrystallized from ethanol to give crystalline Entinostat with melting at 159-160°C.

US 6320078 B1 describes the synthesis and isolation of Entinostat by reacting 4-[N-(pyridin-3-ylmethoxycarbonyl)aminomethyl]benzoic acid with 1,2-phenylenediamine to obtain the Entinostat followed by its purification through silica gel column chromatography Entinostat with same melting range of 159-160°C as described in US 6174905 B1. A similar methodology for the synthesis of Entinostat is described in J Med Chem. 1999, 42(15), 3001-3 via a three- step procedure in 50.96% overall yield.

US RE45499 describes amorphous and crystalline forms of Entinostat, wherein the crystalline forms are designated as polymorph A, B and C. US RE45499 states that the prior art processes produces crystalline polymorph A of Entinostat (with melting at 159-160°C), which is not the thermodynamically stable form. Further, it indicates that it was not possible to establish a reliable manufacturing process for polymorph A as pure polymorphic phase and with high chemical purity at larger scale. US RE45499 does not describe the process for the preparation of polymorph C and amorphous form of Entinostat.
In addition to the modest overall yields, the prior art procedures have other disadvantages, such as a tedious method for the preparation of a carboxylic acid or its acid chloride and requiring the use of column chromatography for purification. Further, there remains a need for alternate solid forms of Entinostat and processes thereof, which may lead to selection as final drug substance for pharmaceutical product development. Therefore, it is desirable to have an alternate form of a drug to meet the needs of drug development which is stable and also a reproducible process there along with a need for an efficient and high yield production of Entinostat.

SUMMARY
In an aspect, the present application provides a crystalline form of Entinostat, characterized by a PXRD pattern comprising the peaks at about 4.32, 4.71, 8.63, 15.86, 16.56 and 17.30 ±0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline form of Entinostat, characterized by a PXRD pattern comprising the peaks at about 4.32, 4.71, 8.63, 15.86, 16.56 and 17.30 ±0.2° 2? comprising the steps of:
a) combining Entinostat with a solvent selected from the group comprising of methyl tert. butyl ether, ethyl acetate or mixture thereof.
b) Stirring the mixture of step a)
c) Isolating crystalline form of Entinostat.
In another aspect, the present application provides a pharmaceutical composition comprising crystalline form of Entinostat, characterized by a PXRD pattern comprising the peaks at about 4.32, 4.71, 8.63, 15.86, 16.56 and 17.30 ±0.2° 2? 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 of Entinostat prepared by the method of Example No 2
Figure 1 is an illustrative X-ray powder diffraction pattern of crystalline form of Entinostat prepared by the method of Example No 3

DETAILED DESCRIPTION
In an aspect, the present application provides a crystalline form of Entinostat, characterized by a PXRD pattern comprising the peaks at about 4.32, 4.71, 8.63, 15.86, 16.56 and 17.30 ±0.2° 2?. In an embodiment, the present application provides a crystalline form of Entinostat characterized by a powder X-ray diffraction (PXRD) pattern, substantially as illustrated by Figures 1 or 2.

In another aspect, the present application provides a process for the preparation of crystalline form of Entinostat, characterized by a PXRD pattern comprising the peaks at about 4.32, 4.71, 8.63, 15.86, 16.56 and 17.30 ±0.2° 2?, comprising the steps of:
a) combining Entinostat with a solvent selected from the group comprising of methyl tert. butyl ether, ethyl acetate or mixture thereof.
b) stirring the mixture of step a)
c) isolating crystalline form of Entinostat.
In an embodiment, Entinostat that used in step a) of this aspect may be either in crystalline form or amorphous form and it may be purified by methods known in the art such as recrystallization, acid-base treatment or chromatography, before using.
In an embodiment, step a) may be carried out by combining Entinostat with a solvent selected from the group comprising of methyl tert. butyl ether, ethyl acetate or mixture thereof.
In an embodiment, Entinostat may be combined with a solvent at any suitable temperatures, such as at about 0°C to about the reflux temperature of the solvent or mixture thereof. In an embodiment, the mixture of Entinostat and solvent may be either a heterogeneous or homogeneous phase.
In an embodiment, step b) of this aspect may be carried out by stirring the mixture of step a). Mixture of step a) may be stirred for sufficient time to complete formation of crystalline Entinostat. In an embodiment, the mixture of Entinostat and solvent may be stirred for atleast 0.5 hour or more.
In an embodiment, the mixture of Entinostat and solvent may be stirred at suitable temperature for the formation of crystalline form of Entinostat. In an embodiment, the mixture may be stirred at temperature between 0°C and 50°C. Preferably between 15°C and 40°C.
In an embodiment, step c) of this aspect may be carried out by the isolation of crystalline form of Entinostat by any methods known in the art or procedures described in the present application. In an embodiment, crystalline Entinostat may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
In an embodiment, isolated crystalline form of Entinostat may be dried in a suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C or any other suitable temperatures. Drying can be carried out at temperatures and times sufficient to achieve desired quality of product. Drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
Entinostat that may be used in the previous aspect of the invention as starting material may be in any solid form either in crystalline or amorphous form.
Entinostat that may be used as starting material in the present application may be prepared according to any methods known in the art or according to the procedures described or exemplified in the present application.
Entinostat may prepared according to a process comprising the steps of
a) reacting a 4-(aminomethyl)benzoic acid of formula (II) or its active derivatives with Pyridin-3-yl methanol of formula (III) to obtain 4-(((pyridin-3-ylmethoxy)carbonylamino)methyl) benzoic acid of formula (IV) or derivatives thereof.

b) treating 4-(((pyridin-3-ylmethoxy)carbonylamino)methyl) benzoic acid of formula (IV) or derivatives thereof of step a) with 1,2-phenylene diamine to obtain Entinostat.

c) optionally, purifying Entinostat obtained in step (b) to provide pure Entinostat.
In an embodiment, starting compounds of formula (II) and (III) may be obtained according to methods known in the art or from the commercially available sources.
Step a) may be carried out by reacting a 4-(aminomethyl)benzoic acid of formula (II) with Pyridin-3-yl methanol of formula (III) in the presence a suitable coupling agent to convert alcohols and amines into carbamates such as 1,1-carbonyldiimidazole (CDI), or the like.
Step a) may be carried out by reacting a 4-(aminomethyl)benzoic acid of formula (II) with Pyridin-3-yl methanol of formula (III) in the presence a suitable base which include, but not limited to hydroxides such as sodium hydroxide, potassium hydroxide; metal carbonates such sodium carbonate, potassium carbonate; or the like.
Step a) may be carried out in a suitable inert solvent. Suitable solvents that may be used include, but are not limited to: alcohols such as for examples, methanol, ethanol, isopropyl alcohol, 1-propanol, 1-butanol, 2-butanol, or the like; hydrocarbons such as for examples, toluene, xylene, hexanes, heptanes, cyclohexane or the like; halogenated hydrocarbons such as for example dichloromethane, ethylene dichloride, chloroform, or the like; ethers such as for examples diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, dioxane or the like; polar aprotic solvents such as for examples, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, N-methylpyrrolidone or the like; water; and mixtures thereof, and any other suitable solvent.
Step a) may be carried out at a temperature ranging from about 10°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about 20°C to the reflux temperature of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, a period of for about 1 to about 24 hours or longer.
Optionally the product of step (a) i.e., compound of Formula IV or its salts may be isolated as solid or used directly for the next step from the reaction mixture itself after the reaction is complete in step (a), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction or the like. The salts of compound of Formula IV obtained compound in step (a) may be optionally further purified by recrystallization or by slurring in a suitable solvent or by column chromatography or any other suitable technique.
The product of step (a) i.e., the compound of Formula IV or its salts may be optionally further dried at suitable temperatures and atmospheric or reduced pressures, for about 1-50 hours, or longer, using any types of drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer or the like. In an embodiment, the compound of Formula IV or its salts can be used directly in the next step without drying.
Step b) may be carried out by treating 4-(((pyridin-3-ylmethoxy)carbonylamino)methyl) benzoic acid of formula (IV) or derivatives thereof of step a) with 1,2-phenylene diamine to obtain Entinostat.
In an embodiment, 4-(((pyridin-3-ylmethoxy)carbonylamino) methyl)benzoic acid of formula (IV) may be treated with 1,2-phenylene diamine in the presence of suitable coupling agents.
The suitable coupling agent includes but are not limited to 1,1-carbonyldiimidazole (CDI), N,N'-Dicyclohexylcarbodiimide (DCC), N, N’-diisopropylcarbodiimide (DIC), N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide (EDC) or a salt thereof, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-tetrafluoroborate(TBTU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-hexafluorophosphate(HBTU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-hexafluoro phosphate(HATU),(benzothazol-1-yloxy)-tris-(dimethylamino)-phosphonium-hexafluoro-phosphate (BOP), (benzothazol-1-yloxy)-thpyrrolidinophosphonium-hexafluorophosphate (PyBOP), cyanuric chloride, 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methyl morpholinium chloride (DMTMM) or the like or any mixture thereof.
Optionally the Step b) reaction may be carried out in the presence of a neutralizing agent such as trifluoroacetic acid (TFA).
Step b) may be carried out in a suitable inert solvent. Suitable solvents that may be used include, but are not limited to: alcohols such as for examples, methanol, ethanol, isopropyl alcohol, 1-propanol, 1-butanol, 2-butanol, or the like; hydrocarbons such as for examples, toluene, xylene, hexanes, heptanes, cyclohexane or the like; halogenated hydrocarbons such as for example dichloromethane, ethylene dichloride, chloroform, or the like; ethers such as for examples diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, dioxane or the like; polar aprotic solvents such as for examples, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, N-methylpyrrolidone or the like; water; and mixtures thereof, and any other suitable solvent.
Step b) reaction may be carried out at a temperature ranging from about 10°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about 20°C to the reflux temperature of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, a period of for about 1 to about 24 hours or longer.
The product of step (b) may be optionally further dried at suitable temperatures and atmospheric or reduced pressures, for about 1-50 hours, or longer, using any types of drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer or the like.
Step c) of this aspect may be carried out by, Optionally purifying the product of step b). Purification of Entinostat obtained in step b) may be purified according to method known in the art or procedures described in any aspect or exemplified in the instant application.
In an embodiment, purification of Entinostat obtained in step b) may be carried out by recrystallizing or slurring in a suitable solvent or mixture of solvents or by column chromatography or any other suitable technique or combinations thereof. In an embodiment, suitable solvent may be selected from the group comprising methyl tert. butyl ether, ethyl acetate or mixtures thereof.
In another aspect, the present application provides a pharmaceutical composition comprising crystalline form of Entinostat, characterized by a PXRD pattern comprising the peaks at about 4.32, 4.71, 8.63, 15.86, 16.56 and 17.30 ±0.2° 2? together with atleast one pharmaceutically acceptable excipient.
In an embodiment, atleast 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 or Eudragit-L100), 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 application. 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.
In another aspect, the present application provides Entinostat, its crystalline form or pharmaceutical composition comprising Entinostat having a chemical purity of atleast 99% by HPLC or atleast 99.5% by HPLC or atleast 99.9% by HPLC.
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.
The term “inert solvent” when used in the present application is a solvent that does not react with the reactants or reagent s under conditions that cause the chemical reaction indicated to take place.
The terms “crystalline form of Entinostat" and “crystalline Entinostat” indicate that the Entinostat is present in substantially crystalline state in the composition (e.g. solid dispersion, adsorbate or pharmaceutical composition). "Substantially" crystalline denotes that 60 %, preferably 85 % or 90 %, more preferably all of the Entinostat being present is crystalline.
An “alcohol” is an organic compound containing a carbon bound to a hydroxyl group. “C1-C6 alcohols” 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, phenol, glycerol, or the like.
An “aliphatic hydrocarbon” is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds. A liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called“aromatic.” Examples of “C5-C8aliphatic or aromatic hydrocarbons” include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, or any mixtures thereof.
An “ester” is an organic compound containing a carboxyl group -(C=O)-O- bonded to two other carbon atoms. “C3-C6esters” include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like.
An “ether” is an organic compound containing an oxygen atom –O- bonded to two other carbon atoms. “C2-C6 ethers” include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like.
A “halogenated hydrocarbon” is an organic compound containing a carbon bound to a halogen. Halogenated hydrocarbons include, but are not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the like.
A “ketone” is an organic compound containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “C3-C6 ketones” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, or the like.
A “nitrile” is an organic compound containing a cyano -(C=N) bonded to another carbon atom. “C2-C6Nitriles” include, but are not limited to, acetonitrile, propionitrile, butanenitrile, or the like.
EXAMPLES
Example-1: Preparation of 4-(((pyridin-3-ylmethoxy)carbonylamino) methyl)benzoic acid.
A mixture of carbonyldiimidazole (321.8g) in dimethyl formamide (1000 mL) was cooled to 8°C and a solution of Pyridin-3-yl methanol (216.4 g) in dimethyl formamide (500 mL) was slowly added to it. 4-(aminomethyl)benzoic acid (250 g) was combined with 1 N sodium hydroxide solution (1500 mL) at 29°C and the above mixture was added by dropwise addition. Stirred the reaction mixture for 16 hours and quenched the reaction mixture with saturated brine solution (250 mL) at 27°C. The reaction mixture was cooled to 8°C and adjusted the pH to 5 – 6 with concentrated HCl. Stirred the reaction mixture for 1 hour at 10°C. Filtered the reaction mixture and washed with cold water (2 x 1250 mL) and methanol (2 x 250 mL). The solid was dried at 45°C for 8 hours to obtain the title compound as white solid. Yield: 450 g; Purity by HPLC: 98.73%
Example-2: Preparation of Entinostat
A mixture of 4-(((pyridin-3-ylmethoxy)carbonylamino)methyl)benzoic acid (100 g) and dimethyl sulfoxide (1200 mL) was combined with carbonyldiimidazole (67.96 g) at 29°C. The reaction mixture was stirred for 3 hours at the same temperature. 1,2-phenylene diamine (67.87 g) was added and cooled the reaction mixture to 20°C. Trifluoro acetic acid (91.6 g) was added slowly and stirred the reaction mixture for 5 hours at 28°C. The reaction mixture was poured into ice water (6000 mL) and stirred for 40 minutes at 28°C. Filtered the solid and washed with water (1500 mL) and then with methyl tert. butyl ether (600 mL). The solid was dried in hot air oven at 50°C for 10 hours and purified by column chromatography using 60-120 silica mesh and ethyl acetate; 1% methanol-ethyl acetate, 2% methanol-ethyl acetate and 3% methanol-ethyl acetate as eluents and the pure fractions were combined and evaporated the solvent under reduced pressure to obtain pale yellow solid. Solid was combined with methyl tert. Butyl ether (500 mL) and stirred for 0.5 hour at 28°C. Filtered the solid and washed with methyl tert. butyl ether (200 mL). The solid was dried at 50°C for 6 hours in hot air oven to obtain title compound as off-white solid. Yield: 105 g and Purity by HPLC: 99.67%
Example-3: Preparation of Entinostat
A mixture of 4-(((pyridin-3-ylmethoxy)carbonylamino)methyl)benzoic acid (40 g) and tetrahydrofuran (800 mL) was combined with carbonyldiimidazole (24.92 g) at 29°C. Heated the reaction mixture to 60°C and stirred for 3 hours at the same temperature. The reaction mixture was cooled to 30°C and 1,2-phenylene diamine (13.59 g), Trifluoro acetic acid (14 g) were added. Stirred the reaction mixture for 16 hours at 30°C and then evaporated the solvent completely under reduced pressure at 50°C. Water (200 mL) and ethyl acetate (200 mL) were added to the reaction mixture and separated the organic layer. Extracted the aqueous layer with ethyl acetate (2 x 160 mL) and the combined organic layer was washed with water (200 mL) and then with brine solution (200 mL). Separated the organic layer and dried over sodium sulfate. Evaporated the solvent completely under reduced pressure at 50°C to obtain the crude product and purified by column chromatography using 60-120 silica mesh and ethyl acetate as eluent to obtain off-white solid. Solid was combined with methyl tert. Butyl ether (360 mL) and ethyl acetate (40 mL) and stirred for 1 hour at 28°C. Filtered the solid and washed with methyl tert. butyl ether (80 mL). The solid was dried at 45°C for 6 hours in hot air oven to obtain title compound as off-white solid. Yield: 22.50 g and Purity by HPLC: 99.56%
,CLAIMS:We Claim:
1. A crystalline form of Entinostat, characterized by a PXRD pattern comprising the peaks at 4.32, 4.71, 8.63, 15.86, 16.56 and 17.30 ±0.2° 2?.
2. A process for the preparation of crystalline form of Entinostat, characterized by a PXRD pattern comprising the peaks at 4.32, 4.71, 8.63, 15.86, 16.56 and 17.30 ±0.2° 2? comprising the steps of:
a) combining Entinostat with a solvent selected from the group comprising of methyl tert. butyl ether, ethyl acetate or mixture thereof.
b) stirring the mixture of step a)
c) isolating crystalline form of Entinostat.
3. A pharmaceutical composition comprising crystalline form of Entinostat, characterized by a PXRD pattern comprising the peaks at 4.32, 4.71, 8.63, 15.86, 16.56 and 17.30 ±0.2° 2? together with atleast one pharmaceutically acceptable excipient.