WO2017221163A1

WO2017221163A1 - Novel salts and polymorphic forms of panobinostat

Info

Publication number: WO2017221163A1
Application number: PCT/IB2017/053685
Authority: WO
Inventors: Mahender Rao Siripragada; Irfan Vohra; Chirag Parikh; Mayur BUDDH; Akash Joshi; Ananda Babu Thirunavakarasu; Pinky PARIKH
Original assignee: Alembic Pharmaceuticals Ltd
Current assignee: Alembic Pharmaceuticals Ltd
Priority date: 2016-06-21
Filing date: 2017-06-21
Publication date: 2017-12-28
Anticipated expiration: 2018-12-21

Abstract

The present invention provides novel crystalline polymorphic form of DL-lactate salt of Panobinostat of Formula-I. This invention also provides process for preparation of crystalline forms of Panobinostat DL-lactate. Further, the present invention relates to a novel pharmaceutically acceptable salts and solid forms of Panobinostat.

Description

Novel Salts and Polymorphic Forms of Panobinostat.

RELATED APPLICATION

This application claims the benefit of priority of our Indian patent application numbers IN201621021159 filed on June 21, 2016 and IN201621030984 filed on September 12, 2016 which are incorporated herein by reference.

FIELD OF THE INVENTION

Formula-I

BACKGROUND OF THE INVENTION

Panobinostat, which is chemically known as 2-(E)-N-hydroxy-3-[4[[[2-(2-methyl-lH- indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide, has the following structural formula:

Panobinostat is formulated in the form of its DL-lactate salt and marketed under the name FARYDAK. FARYDAK is a histone deacetylase inhibitor, in combination with bortezomib and dexamethasone, indicated treatment of patients with multiple myeloma who have received at least 2 prior regimens, including Bortezomib and an immunomodulatory agent. Panobinostat, its salts, their preparation and solid state forms thereof are described in WO2002022577, WO2007146715, WO2007146716, WO2007146717 and WO2007146718. WO2007146716 describes Panobinostat DL-lactate salt polymorphic form A, form HA and form SA.

The different physical properties exhibited by salts and polymorphs affect important pharmaceutical parameters such as storage, stability, compressibility, density and dissolution rates (important in determining bioavailability). Stability differences may result from changes in chemical reactivity (e.g., differential hydrolysis or oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph), mechanical changes (e.g., tablets crumble on storage as a kinetically favoured crystalline form converts to thermodynamically more stable crystalline form) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity).

There is always a need for a novel polymorphic forms and/or salt of drug substances, which have improved stable, shelf life, solubility, formulation properties, and processing properties suitable for development of drug formulations. The screening of novel polymorphic forms is useful for better understanding and controlling the possibility of contamination during a drug's manufacture or storage by other polymorphic forms.

SUMMARY OF THE INVENTION

The present invention relates to novel polymorphic forms of Panobinostat DL-lactate form Al-1 and form Al-2.

More specifically, the present invention relates to benzyl alcohol solvate of Panobinostat DL-lactate, referred herein as form Al- 1 and monohydrate of Panobinostat DL-lactate, referred herein as form Al-2.

The present invention also relates to preparation of Panobinostat DL-lactate form Al-1 and form Al-2.

Further, the present invention relates to a novel pharmaceutically acceptable salts and solid forms of Panobinostat.

The salts according to the present invention are adipate, benzenesulfonate, mandelate, benzoate, tartrate, hydrobromide, hydrochloride, edetate, esylate, fumarate, gluceptate, glucinate, glutamate, hydrocynapthoate, lactobionate, mandelate, methylnitrate, mucate, napsylate, nitrate, pantothenate, stearate, tannate, teoclate, alginate, amiosahcylate, citrate, aspartate, camphorate, diglyconate, disuccinate, hydroiodide, methylenebis(salicylate), pectinate, persulfate, picrate, propionate, thiocyanate, phosphate, hippurate, isoethanoate, ascorbate, stearate, xinofoate, napsylate, formate, pyruvate, barbiturate, hexanoate and tosylate.

The present invention relates to Panobinostat Adipate; more specifically, its amorphous form and crystalline form and preparation thereof.

The present invention relates to Panobinostat formate; more specifically, its amorphous form, and crystalline form and preparation thereof.

The present invention relates to Panobinostat S-(+)-mandelate, its amorphous form and preparation thereof.

The present invention is also directed to a method of treating disease which responds to an inhibition of histone deacetylase activity comprising the step of administrating Panobinostat DL-lactate salt of present invention.

The invention is further directed to pharmaceutical compositions comprising:

a) a solid form of Panobinostat free base or salt thereof of the present invention; and

b) at least one pharmaceutically acceptable carrier, diluent, vehicle or excipient.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig 1 shows the X-ray powder diffraction ("PXRD") pattern of crystalline Panobinostat DL- lactate form Al-1

Fig 2 shows the Differential Scanning Calorimetry (DSC) of Panobinostat DL-lactate form Al- 1 Fig 3 shows the X-ray powder diffraction ("PXRD") pattern of Panobinostat DL-lactate form Al- 2.

Fig 4 shows the Differential Scanning Calorimetry (DSC) of Panobinostat DL-lactate form Al-2 Fig 5 shows the Thermo gravimetric analyses (TGA) of Panobinostat DL-lactate form Al-1 Fig 6 shows the X-ray powder diffraction ("PXRD") pattern of amorphous Panobinostat DL- lactate

Fig 7 shows the X-ray powder diffraction ("PXRD") crystalline form of Panobinostat adipate Fig 8 shows the X-ray powder diffraction ("PXRD") amorphous form of Panobinostat adipate Fig 9 shows the X-ray powder diffraction ("PXRD") crystalline form of Panobinostat formate Fig 10 shows the X-ray powder diffraction ("PXRD") amorphous form of Panobinostat formate Fig 11 shows the X-ray powder diffraction ("PXRD") amorphous form of Panobinostat S(+)mandelate

DETAILED OF THE INVENTION

In an embodiment invention relates to a novel pharmaceutically acceptable salts and solid forms of Panobinostat. The solid form can be amorphous or crystalline form.

In an embodiment the present invention relates to benzyl alcohol solvate of Panobinostat DL-lactate form Al- 1.

In one embodiment invention relates to benzyl alcohol solvate of Panobinostat DL-lactate polymorph form Al-1 characterized with an XRPD pattern showing at least one characteristic peak (2theta±0.2) at 9.78, 10.73 and 22.65; and further characterized by having XRPD peaks (2theta±0.2) at 7.86, 9.78, 10.73, 13.54, 13.99, 14.29, 15.61, 15.80, 16.11, 16.88, 18.62, 18.73, 19.12, 19.65, 19.92, 20.83, 21.42, 21.96, 22.65, 23.18, 24.27, 24.55, 25.02, 26.28, 26.85, 27.31, 28.07, 28.70, 29.08, 29.89, 31.08, 31.54, 32.36, 34.73 and 36.11. Benzyl alcohol solvate of Panobinostat DL-lactate form Al- 1 can alternatively characterized by an XPRD pattern having 2 theta values as shown in fig- 1.

In specific embodiment the present invention relates to a crystalline benzyl alcohol solvate of Panobinostat DL-lactate, wherein the molar ratio of Panobinostat DL-lactate to benzyl alcohol is approximately 1 :0.3-1: 1.1; more specifically, crystalline Panobinostat DL-lactate benzyl alcohol solvate 1:0.5. The crystalline solvates of the present invention may have advantages relative to other known forms of Panobinostat DL-lactate including chemical stability, polymorphic stability and/or varying solubility.

In certain embodiments, crystalline form Al-1 of Panobinostat DL-lactate benzyl alcohol solvate may be characterized by thermal analysis. A representative DSC plot for crystalline form Al-1 of Panobinostat DL-lactate benzyl alcohol solvate is shown in fig. 2. In certain embodiments, crystalline form Al-1 of Panobinostat DL-lactate benzyl alcohol solvate is characterized by a DSC plot comprising an endothermic event with an onset temperature of about 168.78° C. In certain embodiments, crystalline form Al-1 of Panobinostat DL-lactate benzyl alcohol solvate may be characterized by TGA shown in Fig 5.

In one embodiment the invention provides a process for preparation of benzyl alcohol solvate of Panobinostat DL-lactate form Al-1 comprises;

a) providing a solution of Panobinostat DL-lactate in benzyl alcohol optionally in presence of suitable solvent; and

b) isolating the benzyl alcohol solvate of Panobinostat DL-lactate from the solution.

Providing a solution of Panobinostat DL-lactate in benzyl alcohol solvent means the solution of Panobinostat DL-lactate may be obtained by dissolving Panobinostat DL-lactate in benzyl alcohol solvent, or such a solution may be obtained directly from a chemical synthesis mixture in which Panobinostat DL-lactate is formed. Providing a solution of Panobinostat DL- lactate in benzyl alcohol optionally involves use of other suitable solvents capable of dissolving Panobinostat DL-lactate. Then optionally, filtering the solvent solution to remove any extraneous matter; and finally isolating by removing the solvent from the solution to afford Panobinostat DL-lactate benzyl alcohol solvate. Removal of solvent is accomplished by, for example, filtering the solid, substantially complete evaporation of the solvent, concentrating the solution and filtering the solid.

Wherein suitable solvent is selected from water, methanol, ethanol, isopropanol, 2- propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, toluene, xylene, methylene dichloride, ethylene dichloride, chlorobenzene, acetonitrile, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran (THF), 1,4- dioxane, 2-methoxyethanol, N,N-dimethylformamide, Ν,Ν-dimethylacetamide, N- methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine, formic acid, acetic acid, propionic acid, hexane, heptanes, cyclohexane, cycloheptane and cyclooctane or mixtures thereof.

In certain embodiments, crystalline form Al-1 may be characterized by its stability profile. In certain embodiments, form Al-1 material is stable, e.g., its XRPD pattern remains substantially unchanged, upon exposure to elevated temperature, upon exposure to elevated humidity, upon exposure to one or more solvents, and/or upon compression. Form Al-1 is substantially nonhygroscopic. In certain embodiments, form Al-1 is stable with respect to humidity. Certain embodiments herein provide form Al-1 of Panobinostat DL-lactate which is substantially pure.

In another embodiment the present invention relates to monohydrate of Panobinostat DL- lactate form Al-2.

In one embodiment invention relates to Panobinostat DL-lactate monohydrate polymorph form Al-2 characterized with an XRPD pattern showing at least one characteristic peak (2theta±0.2) at 6.57, 7.85 and 23.90, and further characterized by having XRPD peaks (2theta±0.2) at 3.28, 6.17, 6.58, 7.84, 8.65, 9.82, 11.48, 12.11, 12.45, 13.15, 14.00, 14.78, 15.70, 16.02, 16.50, 16.82, 17.73, 18.67, 19.66, 20.70, 21.10, 21.90, 22.41, 22.73, 23.19, 23.89, 24.34, 25.14, 26.18, 26.52, 27.05, 27.89, 28.19, 29.16, 29.97, 31.69, 32.68, 33.55, 35.00, 38.14, 39.05.

In one embodiment invention relates to Panobinostat DL-lactate monohydrate polymorph form Al-2 characterized by an XPRD pattern having 2theta values as shown in fig-3.

In certain embodiments, crystalline form Al-2 of Panobinostat DL-lactate monohydrate may be characterized by thermal analysis. A representative DSC plot for crystalline form Al-2 of Panobinostat DL-lactate monohydrate is shown in fig. 4. In certain embodiments, crystalline form Al-2 of Panobinostat DL-lactate monohydrate is characterized by a DSC plot comprising two endothermic event with an onset temperature at about 89.60⁰ C and 132.53° C.

In one embodiment the present invention relates to preparation of Panobinostat DL- lactate monohydrate form Al-2 comprising

a) adding DL-lactic acid in to mixture of Panobinostat base and water at a suitable temperature; b) optionally seeding with form Al-2; and

c) isolating Panobinostat DL-lactate monohydrate form Al-2.

In certain embodiments, isolating is performed by removing the solvent from the solution to afford Panobinostat DL-lactate monohydrate. Removal of solvent is accomplished by, for example, filtering the solid, substantially complete evaporation of the solvent, concentrating the solution and filtering the solid.

In certain embodiments, crystalline form Al-2 may be characterized by its stability profile. In certain embodiments, form Al-2 material is stable, e.g., its XRPD pattern remains substantially unchanged, upon exposure to elevated temperature, upon exposure to elevated humidity, upon exposure to one or more solvents, and/or upon compression. Form Al-2 is substantially nonhygroscopic. In certain embodiments, form Al-2 is stable with respect to humidity. Certain embodiments herein provide form Al-2 of Panobinostat DL-lactate which is substantially pure.

In an embodiment the present invention relates to amorphous Panobinostat DL-lactate.

In an embodiment amorphous Panobinostat DL-lactate characterized having XRPD pattern as Fig 6.

In an embodiment the present invention relates to Panobinostat adipate salt.

In an embodiment the invention provides a process for preparation of panobinostat adipate salt or its polymorph comprises adding adipic acid or adipic acid in a suitable solvent to a solution of Panobinostat in a suitable solvent and isolating the Panobinostat adipate.

In an embodiment the present invention relates to crystalline form of Panobinostat adipate.

In one embodiment invention relates to crystalline form of Panobinostat adipate characterized with an XRPD pattern showing characteristics peaks (2theta±0.2) at 11.9, 13.80,

14.80, 15.69, 16.69, 20.9, 21.49, 22.79, 23.35, 28.12 and further characterized by having XRPD peaks (2theta±0.2) at 6.34, 8.037, 9.58, 11.29, 12.73, 12.96, 15.06, 16.96, 17.7, 19.16, 19.78,

21.81, 22.17, 23.21, 24.03, 25.29, 25.77, 26.26, 26.79, 27.42, 29.27, 30.34, 31.10, 34.64, 32.80, 33.47, 34.57, 36., 21, 37., 224, 38.36, 38.75, 39.30.

In one embodiment invention relates to crystalline form of Panobinostat adipate characterized having XRPD pattern as shown in Fig. 7.

In an embodiment the present invention relates to amorphous Panobinostat adipate.

In an embodiment amorphous Panobinostat adipate characterized having XRPD pattern as Fig 8.

In an embodiment the present invention relates to Panobinostat formate salt.

In an embodiment the invention provides a process for preparation of Panobinostat formate salt or its polymorph comprises adding formic acid in a suitable solvent to a solution of Panobinostat in a suitable solvent and isolating the Panobinostat formate. In an embodiment the present invention relates to crystalline form of Panobinostat formate.

In one embodiment invention relates to crystalline form of Panobinostat formate characterized with an XRPD pattern showing characteristics peaks (2theta±0.2) at 10.9, 12.80, 19.5, 20.1 land 21.46 further characterized by having XRPD peaks (2theta±0.2) at 7.60, 8.51, 9.73, 10.29, 10.94, 12.84, 13.31, 13.75, 14.36, 15.72, 16.47, 17.03, 17.43, 18.05, 18.89, 19.57, 20.11, 21.46, 22.97, 23.66, 24.60, 25.95, 26.77, 30.62, 31.13, 32.26, 35.23 and 36.93.

In an embodiment the present invention relates to crystalline form of Panobinostat formate characterized having XRPD pattern shown in Fig 9.

In an embodiment the present invention relates to Panobinostat formate amorphous form.

In an embodiment amorphous Panobinostat formate characterized having XRPD pattern as Fig 10.

In an embodiment the present invention relates to Panobinostat S(+)mandelate amorphous form.

In an embodiment amorphous Panobinostat S(+)mandelate characterized having XRPD pattern as Fig 11.

In an embodiment the present invention relates to Panobinostat tosylate salt.

In an embodiment the invention provides a process for preparation of Panobinostat tosylate salt comprises adding toluene sulfonic acid or toluene sulfonic acid in a suitable solvent to a solution of Panobinostat in a suitable solvent and isolating the Panobinostat tosylate salt.

The amorphous form may be a substantially pure form free from any crystalline forms of Panobinostat.

In an embodiment the invention provides a process for preparation of amorphous form of Panobinostat salt comprises

a) providing a solution of Panobinostat base and a suitable acid in one or more solvents and b) obtaining an amorphous form of Panobinostat salt by the removal of solvent.

The suitable acid is selected from DL-lactic acid, adipic acid, formic acid, S-(+)-mandelic acid.

The solvents that may be used in step a) of amorphous preparation comprises one or more of alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, and t-butyl alcohol; ketones selected from acetone, butanone, and methyl isobutyl ketone; esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate, chlorinated hydrocarbons selected from methylene dichloride, ethylene dichloride, and chlorobenzene; acetonitrile; and polar aprotic solvents selected from dimethylformamide, dimethylacetamide, N- methylpyrrolidone, dimethyl sulfoxide, and mixtures thereof.

Step b) involves isolation of an amorphous form of Panobinostat from the solution of step a). The isolation may be affected by removing the solvent. The techniques which may be used for the removal of solvent comprises one or more of evaporation by rotational distillation, evaporation under reduced pressure, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization), flash evaporation, and vacuum distillation.

Alternatively, the isolation can be effected by addition of an anti-solvent to the solution obtain in step a), optionally by concentrating the solution obtained in the step.

The anti-solvents comprises one or more of hydrocarbons selected from hexanes, n- heptane, n-pentane, cyclohexane, and methylcyclohexane; aromatic hydrocarbons selected from toluene, xylene, and ethylbenzene; ethers selected diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1 ,4-dioxane, and 2-methoxy ethanol.

The suitable temperature used in present invention is selected from 0°C to reflux temperature of the solvent used.

The suitable solvents used in present invention are selected from alcohols (such as 1 - butanol, 2-butanol, ethanol, 2-ethoxyethanol, ethylene glycol, isopropanol, methanol, 2- methoxyethanol, 3-methyl-l -butanol, 1 -pentanol and 1 -propanol), amides (such as N,N- dimethylacetamide, N,N -dimethylformamide and formamide), carbonates (such as ethylene carbonate and propylene carbonate), carbon sulfide, carboxylic acids (such as acetic acid, trichloroacetic acid and trifluoroacetic acid), esters (such as butyl acetate, ethyl acetate, ethyl formate, isobutyl acetate, isopropyl acetate, methyl acetate and propyl acetate), ethers (such as anisole, bis {2- methoxyethyl)ether, diethyl ether, diisopropyl ether, 1 ,2-dimethoxyethane, 1 , 1 - dimethoxymethane, 2,2-dimethoxypropane, diphenyl ether and methyl ie f-butyl ether), halogenated hydrocarbons (such as carbon tetrachloride, chlorobenzene, chloroform, 1 ,2- dichloroethane, 1 ,1 -dichloroethene, 1 ,2-dichloroethene, dichlorome thane, trichloroethane, trichloroethene, and trifluoromethylbenzene), heterocycles (such as dioxane, N-methyl pyrrolidone, 2-methyl tetrahydrofuran, pyridine and tetrahydrofuran), hydrocarbons (such as benzene, cumene, cyclohexane, cyclopentane, heptane, hexane(s), isooctane, methylcyclohexane, octane, pentane, petroleum ether, tetralin, toluene and xylene), ketones (such as acetone, butanone, methyl butyl ketone, methyl ethyl ketone, methyl methyl isobutyl ketone and isopropyl ketone), nitriles (such as acetonitrile), nitro compounds (such as nitrobenzene and nitromethane), phosphoramides (such as hexamethylphosphoramide), sulfones (such as sulfolane), sulfoxides (such as dimethyl sulfoxide), water and mixtures thereof.

In another embodiment the novel form or salt of Panobinostat disclosed herein for use in the pharmaceutical compositions of the present invention, wherein 90 volume -percent of the particles (D90) have a size of less than or equal to about 500 microns, specifically less than or equal to about 300 microns, more specifically less than or equal to about 200 microns, still more specifically less than or equal to about 100 microns, and most specifically less than or equal to about 15 microns.

The melting points are measured using Differential Scanning Calorimetry (DSC). The equipment is a TA-Instruments DSC-Q1000 calibrated at 10°/min to give the melting point as onset value. About 2 mg of sample is heated 10°/min in a loosely closed pan under nitrogen flow.

X-Ray powder diffractograms were measured on a PANalytical X'Pert PRO X-Ray Diffractometer using CuKal radiation. The samples were measured in reflection mode in the 2Θ- range 2.5-40° using an X' accelerator detector.

Thermo gravimetric analysis (TGA) used for estimation of solvent/water content of dried material is performed using a TA-instruments TGA-Q500 about 10 mg sample is heated 10°/min in an open pan under nitrogen flow.

The invention is further exemplified by the following non-limiting examples, which are illustrative representing the preferred modes of carrying out the invention. The invention's scope is not limited to these specific embodiments only but should be read in conjunction with what is disclosed anywhere else in the specification together with those information and knowledge which are within the general understanding of the person skilled in the art. EXAMPLES

Example 1: Preparation of (2E)-3-(4-formylphenyl)prop-2-enoic acid

Ν,Ν-Dimethyl acetamide, water, p-Bromo benzaldehyde (100 g), potassium carbonate, tetra-n- butylammonium bromide and palladium acetate were charged in reaction flask at ambient temperature and allowed to stirred for few minutes. Mixture of prop-2-enoic acid (50.60 g) in water was added to above reaction mixture at ambient temperature and allowed to stir for few minutes. The reaction mixture was heated to 85±2°C, allowed to stir for few hours and cooled to 57±3°C. Water was added to reaction mixture and filtered the catalyst. Filtrate was washed with isopropyl acetate and then acetic acid was added to aqueous layer, Precipitated product is filtered and dried. Yield: 88.0gm

Example 2: Preparation of methyl (2E)-3-(4-formyl phenyl)prop-2-enoate

(2E)-3-(4-formylphenyl)prop -2-enoic acid (100 g) was added to a stirred solution of methanol, followed by addition of thionyl chloride at ambient temperature. Reaction mixture was heated to 45±3°C and stirred for few hours. Solvent was evaporated and water was added to reaction mass and allowed to stir for few minutes. Reaction mass was cooled, filtered and dried. Yield: 105.0gm

Example 3: Preparation of methyl (2E)-3-[4-({[2-(2-methyl- lH-indol-3- yl)ethyl]amino}methyl)phenyl] prop-2-enoate hydrochloride

Methyl (2E)-3-(4-formyl phenyl) prop-2-enoate (lOOg) and 2-(2-methyl-lH-indol-3-yl) ethanamine (96.20 g) were added to stirred solution of methanol at ambient temperature and allowed to stirred for few hours. Reaction mixture was cooled and followed by addition of dichloromethane. Solution of sodium borohydride in water was added to above reaction mixture and stirred for few hours. Reaction mixture was extracted with dichloromethane and distilled out partial solvent from organic layer. IPA.HC1 was added to obtain dichloromethane solution to get hydrochloride salt of methyl (2E)-3-[4-({ [2-(2-methyl- lH-indol-3- yl)ethyl] amino }methyl)phenyl] prop-2-enoate. Filtered the solid and dried. Yield: 175.0 gm Example 4: Preparation of Panobinostat

To ethylene glycol methyl (2E)-3-[4-({ [2-(2-methyl- lH-indol-3-yl)ethyl] amino} methyl )phenyl] prop-2-enoate hydrochloride (lOOg), and hydroxyl amine hydrochloride (45 gm) were added at ambient temperature followed by addition of n-propanol. Reaction mixture was cooled at -6°C and solution of potassium hydroxide in ethylene glycol was added slowly at this temperature, stirred at -6°C till completion of reaction. After completion of reaction, . water was added to reaction mixture and pH adjusted by dilute HCl. Reaction mass was stirred at 23±3°C, filtered the solid. The wet solid was stirred with methanol in presence of urea, heated to reflux for 1 hour. Cooled it and filtered it. After drying the material again stirred with THF and dimethyl formamide, heated to 67"C for 1 hour, cooled to room temperature, filtered it and dried to give pure title compound. Yield: 77.0gm

Example 5: Preparation of Panobinostat DL-lactate form Al-1

Panobinostat base (lOOg), THF and DL-lactic acid were added to water at ambient temperature. Reaction mixture was heated to 42±3°C and stirred till clear solution obtained. Activated carbon was added to reaction mixture, stirred and filtered. Benzyl alcohol was added to reaction mass at 42±3°C to get solid Panobinostat DL-lactate benzyl alcohol solvate. Filtered the solid and dried it. Yield: i iO.Ogm. XRPD: Fig 1, DSC: Fig 2

Example-6: Preparation of Panobinostat DL-lactate monohydrate form Al-2:

DL- Lactic acid (4.0 g) was added to the mixture of Panobinostat base (10.0 g) and water (100.0 ml) at ambient temperature. Reaction mass was heated at 57°C for 1 hour. Cooled the reaction mass and collected the precipitate by filtration. Washed with water and dried the material to obtain title compound. Yield: 11.0 gm. Water content: 4.38 %. XRPD: Fig 3, DSC: Fig 4

Example-7: Preparation of Panobinostat adipate Amorphous:

Panobinostat base (2.0 g) and adipic acid (1.05 eq.) are dissolve in methanol (20.0 ml). The clear solution was evaporated to obtain solid. XPRD of the solid gives pure amorphous form of Panobinostat adipate. Example-8: Preparation of crystalline Panobinostat adipate

Panobinostat Adipate (2.0 g) was refluxed in IPA (20.0 ml) for 24 hrs. The reaction was cooled at ambient temperature and the solid was filtered. Obtained solid was characterized by XPRD as Panobinostat Adipate crystalline form. Example- 9: Preparation of crystalline Panobinostat formate

Panobinostat base (2.0 g) and formic acid (1.05 eq.) was added to the DM water (20 ml). The suspension was stirred for 24 hrs. The solid was filtered. Obtained solid was characterized by XPRD as Panobinostat formate crystalline form.

Example- 10: Preparation of Panobinostat formate amorphous

Panobinostat base (2.0 g) and formic acid (1.05 eq.) is dissolve in methanol (20.0 ml). A clear solution is evaporated to obtain solid. Obtained solid was characterized by XPRD as Amorphous form of Panobinostat formate.

Example- 11: Preparation of Panobinostat S-(+)-mandelate amorphous

Panobinostat base (2.0 g) and S-(+)-mandelic acid (1.05 eq.) is dissolve in methanol (20.0 ml). A clear solution is evaporated dryness to obtain solid. Obtained solid was characterized by XPRD as amorphous form of Panobinostat S-(+)-mandelate.

Example-12: Preparation of Panobinostat DL-lactate amorphous:

Panobinostat base (2.0 g) and DL- lactic acid (0.85 g) are dissolved in methanol (20.0 ml). The clear solution was evaporated to obtain solid. XPRD of the solid gives pure amorphous form of Panobinostat DL-lactate.

Claims

Claims:

1. Benzyl alcohol solvate of Panobinostat DL-lactate.

2. Crystalline form Al- 1 of benzyl alcohol solvate of Panobinostat DL-lactate having an X-ray powder diffractogram comprising at least one peak at diffraction 2-theta angle (2theta±0.2) selected from 9.78, 10.73 and 22.65.

3. Crystalline form Al-1 according to claim 2, further characterized having an X-ray powder diffractogram comprising peaks at diffraction 2-theta angle (2theta±0.2) selected from 15.61, 18.62, 19.19, 19.65, 24.27 and 24.55.

4. Crystalline form Al-1 according to claim 2, characterized by a DSC plot comprising an endothermic event with an onset temperature of about 168.78ο C.

5. Crystalline form Al-1 according to claim 2, characterized having an X-ray powder diffractogram as shown in Fig 1.

6. Process for preparation of novel crystalline form Al-1 of benzyl alcohol solvate of Panobinostat DL-lactate comprises:

a) providing a solution of Panobinostat DL-lactate in benzyl alcohol optionally in presence of suitable solvent;

b) isolating the benzyl alcohol solvate of Panobinostat DL-lactate .

7. The process for preparation according to claim 4, wherein suitable solvent is selected from water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2- pentanol, amyl alcohol, ethylene glycol, glycerol, acetone, butanone, 2-pentanone, 3- pentanone, methyl butyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, toluene, xylene, methylene dichloride, ethylene dichloride, chlorobenzene, acetonitrile, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran (THF), 1,4-dioxane, 2-methoxyethanol, N,N- dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine, formic acid, acetic acid, propionic acid, hexane, heptanes, cyclohexane, cycloheptane and cyclooctane or mixtures thereof.

8. Crystalline form Al-2 of monohydrate of Panobinostat DL-lactate having an X-ray powder diffractogram comprising at least one peak at diffraction 2-theta angle (2theta±0.2) selected from 6.58, 7.84, and 23.89.

9. Crystalline form Al-2 according to claim 8, further characterized having an X-ray powder diffractogram comprising peaks at diffraction 2-theta angle (2theta±0.2) selected from 9.82, 13.15, 15.70, 19.66, 22.41 and 23.89

10. Crystalline form Al-2 according to claim 8, characterized by a DSC plot comprising an endothermic event with an onset temperature at about 89.60 ° C and 132.53° C.

11. Crystalline form Al-2 according to claim 8, characterized having an X-ray powder diffractogram as shown in Fig 3.

12. Process of preparation of novel crystalline form Al-2 of monohydrate of Panobinostat DL- lactate comprising:

a) adding DL-lactic acid in to mixture of Panobinostat base and water;

b) optionally seeding with form Al-2; and

c) isolating Panobinostat DL-lactate monohydrate form Al-2.

13. Panobinostat acid addition salt, wherein the acid is selected from adipic acid, formic acid, S- (+)-mandelic acid.

14. Panobinostat acid addition salt according to claim 13, wherein Panobinostat acid addition salts are in amorphous or crystalline forms.

15. Amorphous Panobinostat adipate.

16. Amorphous Panobinostat formate.

17. Amorphous S-(+)-mandalate.

18. Amorphous Panobinostat DL-lactate.

19. A process for preparation of amorphous form of Panobinostat acid additional salt comprising the steps of

a) providing a solution of Panobinostat base and a suitable acid in one or more solvents and b) obtaining an amorphous form of Panobinostat acid additional salt by the removal of solvent.

20. The process for preparation according to claim 19, wherein suitable acid is selected from DL- lactic acid, adipic acid, formic acid, S-(+)-mandelic acid.

21. Crystalline form of Panobinostat adipate characterized having an X-ray powder diffractogram as shown in fig 7.

22. Crystalline form of Panobinostat formate characterized having an X-ray powder diffractogram as shown in fig 9.

23. A process for preparation of Panobinostat adipate salt or its crystalline form comprises adding adipic acid or adipic acid in a suitable solvent to a solution of Panobinostat in a suitable solvent and isolating the Panobinostat adipate.

24. A process for preparation of Panobinostat formate salt or its crystalline form comprises adding formic acid in a suitable solvent to a solution of Panobinostat in a suitable solvent and isolating the Panobinostat formate.

25. A pharmaceutical compositions comprising:

a) a solid form of Panobinostat salt as claimed in proceeding claims; and