WO2018163114A1

WO2018163114A1 - Amorphous panobinostat and its lactate salt

Info

Publication number: WO2018163114A1
Application number: PCT/IB2018/051544
Authority: WO
Inventors: Sriram RAMPALLI; Lav Kumar UPALLA; Veera Venkatarao DAKARAPU; Chandra Sekhar DANGUDUBIYYAM; Purohit PRASHANT; Purandhar CHILUVURU
Original assignee: Shilpa Medicare Limited
Priority date: 2017-03-10
Filing date: 2018-03-09
Publication date: 2018-09-13

Abstract

The present invention relates to an amorphous form of Panobinostat Lactate hydrate. In particular, the present invention relates to processes for the preparation of amorphous form of Panobinostat Lactate. More particular the present invention relates to the pharmaceutical composition comprising an amorphous Panobinostat Lactate and one or more of pharmaceutically acceptable carriers, excipients or diluents used for the treatment of Multiple myeloma. The present invention relates to an amorphous form of Panobinostat and its process for the preparation thereof.

Description

AMORPHOUS PANOBINOSTAT AND ITS LACTATE SALT

FIELD OF THE INVENTION

The present invention relates to an amorphous form of Panobinostat Lactate. In particular, the present invention relates to processes for the preparation of amorphous form of Panobinostat Lactate. More particular the present invention relates to the pharmaceutical composition comprising an amorphous Panobinostat Lactate and one or more of pharmaceutically acceptable carriers, excipients or diluents used for the treatment of Multiple myeloma. The present invention particularly relates to amorphous Panobinostat lactate hydrate.

BACKGROUND OF THE INVENTION

The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.

Panobinostat Lactate is chemically known as 2-Hydroxypropanoic acid, compound with 2-(E)-N-hydroxy-3-[4-4[[[2-(2-methyl-lH-indol-3-yl)ethyl]amino]methyl]phenyl]-2- propenamide (1 : 1) having Formula (1).

Formula (I)

Panobinostat Lactate is indicated for the treatment of Multiple myeloma, patients have received at least 2 prior regimens, including bortezomib and an immunomodulatory agent. It is available under the trade name of FARYDAK^® and its Capsules are supplied in 10, 15, and 20 mg base strengths for oral administration.

Valuable pharmacological properties are attributed to this compound; thus, it can be used, for example, as a histone deacetylase inhibitor useful in therapy for diseases which respond to inhibition of histone deacetylase activity. Knowledge of the potential polymorphic forms of N- hydroxy-3-[4-[[[2-(2-methy!-l H-indol-3-yl)ethyl]amino]- mclh 1 ] phenyl ] -2E-2-propenamide 2- Hydroxypropanoic acid is useful in the development of a suitable dosage form. Once chosen, it is important that a polymorphic form can be reproducibly prepared and remain unchanged for prolonged time periods in the dosage form developed. It is also desirable to have a process for producing N-hydroxy-3-[4-[[[2-(2-methyl-l H-indoi-3-yl)ethyl]amino]methyl]phenyl]-2E-2- propenamide 2-Hydroxypropanoic acid in high purity since the presence of impurities may produce undesired toxicological effects. Remiszewski et al in US6552065 provides no information at all about possible crystal modifications and amorphous of N-hydroxy-3-[4-[[[2-(2-methyl-l H-indol-3-yl)ethyl]amino] methyl]phenyl]-2E-2-propenamide or its Lactate (2-Hydroxypropanoic acid) salts.

Acemoglu et al in US 7989494 discloses crystalline Form A (anhydrous) and crystalline Form H_A (Monohydrate) and crystalline Form S_A ( Monomethanol solvate) of the DL-lactate salt of Panobinostat and other salts thereof. Further, this patent also disclosed that the salts of compounds disclosed in US '494 are sticky amorphous materials or amorphous gels.

There is no disclosure found about the process for the preparation of an amorphous form of Panobinostat Lactate and its characterization as well as physiochemical properties and its stability.

The different physical properties exhibited by 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 more rapidly when comprised of one polymorph than when comprised of another polymorph), mechanical changes (e.g., capsules crumble on storage as a kinetically favored crystalline form converts to thermodynamically more stable crystalline form) or both (e.g., capsules of one polymorph are more susceptible to breakdown at high humidity). An amorphous form generally prov ides better solubility and bioavailabil ity than the crystalline form and may be useful for formulations which can have better stability, solubility and compressibility etc which are important for formulation and product manufacturing.

Therefore, it is desirable to have a stable amorphous form of drug with high purity to meet the needs of regulatory agencies and highly reproducible processes for its preparation.

In view of the above, it is therefore, desirable to provide an efficient, more economical, less hazardous and eco-friendly process for the preparation of amorphous form of Panobinostat Lactate. The amorphous form provided herein is stable under ordinary stability conditions with respect to purity and storage.

SUMMARY OF THE INVENTION

The main aspect of the present invention is to provide an amorphous form of Panobinostat Lactate.

In another aspect, there is provided an amorphous form of solid Panobinostat Lactate wherein the amorphous Panobinostat Lactate is hydrate.

In another aspect, there is provided a process for the preparation of an amorphous form of Panobinostat Lactate, wherein the amorphous form is prepared by milling Panobinostat Lactate for sufficient time.

In another aspect, there is provided an amorphous solid dispersion of Panobinostat Lactate and a polymer.

In another aspect, there is provided an amorphous solid dispersion of Panobinostat Lactate wherein the amorphous solid dispersion of Panobinostat Lactate is prepared by a process comprising grinding a solid-solid mixture of Panobinostat Lactate and a polymer. In another aspect, there is provided a process for preparing an amorphous solid dispersion of Panobinostat Lactate, wherein the step of grinding a solid-solid mixture of Panobinostat Lactate and a polymer comprises grinding a solid-solid mixture of crystalline Panobinostat Lactate and a polymer.

In another aspect, there is provided a process for the preparation of an amorphous form of Panobinostat Lactate, the process comprising:

(a) suspending or dissolving Panobinostat in a solvent or mixture of solvents;

(b) adding Lactic acid;

(c) removing the solvent from the solution as obtained in step (b); and

(d) isolating amorphous Panobinostat Lactate.

In another aspect, there is provided a stable amorphous form of Panobinostat Lactate wherein the stability is measured by an absence of conversion of the amorphous form of Panobinostat Lactate to a crystalline form of Panobinostat Lactate after the amorphous Panobinostat Lactate is exposed to a relative humidity of at 25 °C ± 2 °C/60% RH ± 5% RH for a period of at least six months.

In another aspect, there is provided an amorphous solid dispersion of Panobinostat Lactate and a polymer, wherein the amorphous solid dispersion of Panobinostat Lactate is prepared by a process comprising grinding a solid-solid mixture of Panobinostat Lactate and a polymer under controlled humidity.

In another aspect, there is provided a pharmaceutical composition comprising an amorphous form of Panobinostat Lactate and one or more pharmaceutically acceptable carriers, excipients or diluents.

In another aspect, there is provided a pharmaceutical composition further comprising at least one polymer selected from hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methyl cellulose, methacrylic acid copolymers, and polyvinyl pyrrolidone.

In another aspect, the present invention further related to amorphous Panobinostat In another aspect of the present invention relates to a process for the preparation of an amorphous form of Panobinostat, the process comprising:

a) suspending or dissolving Panobinostat in a solvent or mixture of solvents;

b) removing the solvent from the solution as obtained in step (a); and

c) isolating amorphous Panobinostat.

DESCRIPTION OF THE DRAWINGS

FIG. 1 discloses the x-ray diffractogram (XRD) o the amorphous form of Panobinostat Lactate. FIG. 2 discloses the x-ray di ffractogram (XRD) f the amorphous form of Panobinostat.

FIG. 3 discloses the Thermo Gravametric analysis (TGA) of the amorphous form of Panobinostat Lactate.

DETAILED DESCRIPTION OF THE INVENTION

The above and other objects of the present invention are achieved by the process of the present invention, which leads to amorphous Panobinostat Lactate suitable for pharmaceutical use and having greater stability. The invention provides a process for preparing amorphous form of Panobinostat Lactate.

The present invention particularly provides an amorphous form of solid Panobinostat Lactate wherein the amorphous Panobinostat Lactate is hydrate.

Optionally, the solution, prior to any solids formation, can be filtered to remove any undissolved solids and/or solid impurities prior to the removal of the solvent. Any filtration system and techniques known in the art can be used.

All ranges recited herein include the endpoints, including those that recite a range "between" two values. Terms such as "about", "generally", "substantially," and 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 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. As used herein, the term "controlled humidity" refers to a relative humidity in the range of 50±10%. In particular, the controlled humidity includes grinding process performed under controlled humidity followed by drying under controlled humidity for the preparation of an amorphous form of Panobinostat Lactate.

As used herein, the term "grinder" includes mixers, mills, blenders, and micronizers, or a combination thereof. The terms "grinding", "milling", "mixing", and "blending^" and the like are interchangeable for achiev ing the homogeneous solid-solid mixture.

As used herein, the term "ball milling" as used herein means a process wherein shear forces are applied to a starting material by means of so-called milling balls located in a milling vessel. Typically and preferably, the milling vessel is rotated, wherein the milling balls collide with each other and with the API particles provided as the starting material. The ball mill preferred, may be planetary ball mill with model No. PM 100 and make of Retsch, Germany.

As used herein, the term "stable Panobinostat Lactate" includes an amorphous Panobinostat Lactate measured by an absence of conversion of the amorphous form of Panobinostat Lactate to a crystalline form of Panobinostat Lactate after the amorphous Panobinostat Lactate is exposed to a relative humidity of 75% at 40° C. or 60% at 25° C for a period of at least three months.

As used herein, the term "solid dispersion" means any solid composition having at least two components. In certain embodiments, a solid dispersion as disclosed herein includes r uiuumus u

As used herein the term "immobilize" with reference to the immobilization of the Panobinostat Lactate in the polymer matrix, means that molecules of the Panobinostat Lactate interact with molecules of the polymer in such a way that the molecules of the Panobinostat Lactate are held in the aforementioned matrix and prevented from crystal nucleation due to lack of mobility. In another aspect, there is provided an amorphous form of Panobinostat Lactate.

In another aspect, there is provided an amorphous form of Panobinostat Lactate, wherein the amorphous Panobinostat Lactate is hydrate.

In another aspect, there is provided an amorphous form of Panobinostat Lactate, wherein the amorphous form is prepared by milling Panobinostat Lactate for sufficient time. In general, the step of milling Panobinostat Lactate comprises milling crystalline Panobinostat Lactate.

In another aspect, the amorphous form of Panobinostat Lactate is stable and has not detectable quantity of the crystalline form of Panobinostat Lactate after the amorphous form of Panobinostat Lactate is exposed to a relative humidity of 75% at 40° C. or 60% at 25° C. for a period of at least three months.

In another aspect, the amorphous solid dispersion of Panobinostat Lactate is prepared by a process comprising grinding a solid-solid mixture of Panobinostat Lactate and a polymer. In another, the step of grinding a solid-solid mixture of Panobinostat Lactate and a polymer comprises grinding a solid-solid mixture of crystalline Panobinostat Lactate and a polymer.

In another aspect, the polymer may be a non-ionic polymer or an ionic polymer. The polymer comprises of hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulose, methacrylic acid copolymers, and polyvinylpyrrolidone. In particular, polyvinylpyrrolidone of different grades comprises of K-15, K-30, K-60, K-90 and K-120 which may be used for the preparation of amorphous composition. More particular, hydroxypropylmethyl cellulose acetate succinate and polyvinylpyrrolidone K-30 may be used. In another aspect, the solid-solid mixture of Panobinostat Lactate and a polymer may be m i l led by grinding action between two surfaces. Such milling has been traditionally carried out in pharmacy practice by compounding using a pestle and mortar or a common mixer grinder. According to the invention, milling machines that work on substantially the same principle may be used in the present process. Examples of such milling machines include various makes of ball mills, roller mills, gyratory mills, multi-mills, Jet-mills, and the like.

In another aspect, a mill such as a Micros Super Fine Mill, Multi-Mill Sr. No. G.1.132, Ret sch (Planetary ball mill), Jet-Mill from Midas Micronizer M-100 Aerosol (No. 154/07-08 or a common mixer grinder can be used. Alternatively another commercially available milling machine can be used.

The process parameter includes adding a solid-solid mixture of Panobinostat Lactate and hydroxypropylmethyl cellulose acetate succinate in a grinder. A specific grinder used can be small-scale to large-scale mixer grinder which can easily prepare the homogeneous mixture of two solids. For example purpose, Quadro dry mixing apparatus for providing lump-free homogenous blending to ensure proper mixing. The varieties of mills and mixers provided in Perry's Chemical Engineers' I landbook Seventh Edition by Robert 11. Perry and Don W. Green can be used based on suitability are incorporated herein by reference in its entirety.

This grinding apparatus may consists of a water cooled jacketed bowl with the inside surface made of a suitable material such as Zirconium oxide, stainless steel, tungsten carbide, or aluminum oxide. Depending on the size of the grinder, the speed of rotation of the main shaft

ctiiu me ciic^ii v c vuiuiiic lilt gi ii iuing ^Γι ΠΙυω v ai y . i nt uitwi v i v i uiiiv^ iv^ grinding chamber may be in the range from about 0.45 liters to about 30 liters. For low Capacity mills (such as 0, capacity 0.45 liters; or 5, capacity 4.8 liters), the speed of rotation of the main shaft is typically in the range from about 200 rpm to about 2000 rpm. In general aspect, the grinder may be a typical milling apparatus. This milling apparatus may be typically charged with feed material such that from about 10% to 30% of the effective volume of the grinding chamber is occupied. Examples o methods of transferring materials well known in the art include manual transfer, gravity feed, pneumatic conveying (using a high velocity air stream), and vacuum transfer. Such methods, well known in the art, may be used with the process of this invention to charge the feed material into the grinding volume available between the bowl and the sub-shafts. For obtaining homogeneous solid-solid mixture, the Panobinostat Lactate and hydroxypropylmethyl cellulose acetate succinate may be mixed in a wide range of ratios.

The period of mill ing using the mil l may vary depending on the size of the mill, the speed of rotation of the main shaft, the type of feed material, and the quantity of feed material. The effects of these variables are well known in the art and the invention may be worked over a range of these variables. Typically, the period of milling ranges from about 15 minutes to 300 minutes. In general, the Panobinostat Lactate is subjected to grinding involving attrition of the particles and machine surfaces.

In some aspects, the Panobinostat Lactate may be dispersed within a matrix formed by a polymer in its solid state such that it is immobilized in its amorphous form. The polymer may prevent intramolecular hydrogen bonding or weak dispersion forces between two or more drug molecules of Panobinostat Lactate. The solid dispersion provides for a large surface area, thus further allowing for improved dissolution and bioavailability of Panobinostat Lactate.

In some aspects, the ratio of the amount of weight of Panobinostat Lactate within the solid dispersion to the amount by weight of the polymer therein is from about 1 : 1 to about 1 : 10. The composition of Panobinostat Lactate with polymer, particularly hydroxypropylmethyl cellulose acetate succinate or polyvinylpyrrolidone may be prepared by using about 1 : 1 to about 1 : 10 polymers with respect to Panobinostat Lactate.

In another aspect, there is provided a process for the preparation of an amorphous solid dispersion of Panobinostat Lactate and a polymer, the process comprising mixing Panobinostat Lactate with a polymer in one or more solvents and obtaining the amorphous solid dispersion of Panobinostat Lactate by the removal of the solvent. The compound Panobinostat Lactate and a polymer (for example hydroxypropylmethyl cellulose acetate succinate or pol y v i n y 1 p rro 1 i done K-30) may be dissolved in one or more solvents selected from methanol, ethanol, isopropanol, acetone, ethyl acetate or mixture thereof with water. The amorphous solid dispersion may be obtained by the removal of the solvent. The removal of the 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 thereby leaving the amorphous solid dispersion precipitated in a matrix formed by the polymer.

In another aspect, the present invention provides a process for the preparation of an amorphous form of Panobinostat Lactate, the process comprising:

(a) suspending or dissolving Panobinostat in a solvent or mixture of solvents;

(b) adding Lactic acid;

(c) removing the solvent from the solution as obtained in step (b); and

(d) isolating amorphous Panobinostat Lactate.

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

Step-b involves aqueous lactic acid added to the solution obtained in step-a. Lactic acid addition involves slow addition, wherein slow addition involves the drop wise addition (or) direct charging/adding in a single lot at a temperature ranging from 25-30°C. Step c) involves removing the solvent from the solution obtained in step b). 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 (lyophi lization). flash evaporation, and vacuum distillation.

In another aspect, the present invention provides a process for the preparation of an amorphous form of Panobinostat Lactate having water content in the range between 3. 1 to 4.9 % w/w, the process comprising:

a) suspending or dissolving Panobinostat in a solvent or mixture of solvents;

b) adding Lactic acid; and

c) removing the solvent from the solution as obtained in step (b);

d) optionally co-distilled with the same or other solvent or mixture of solvents; and e) isolating amorphous Panobinostat Lactate.

Panobinostat Lactate obtained as per the present invention is hydrate, particularly monohydrate having water content in the range between 3.1 to 4.9 % w/w.

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

Step-b involves aqueous lactic acid added to the solution obtained in step-a. Lactic acid addition involves slow addition, wherein slow addition involves the drop wise addition (or) direct charging/adding in a single lot at a temperature ranging from 25-30°C. Step c) involves removing the solvent from the solution obtained in step b). 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 (Syophilization), flash evaporation, and vacuum distillation.

Co-distillation involves solvents, wherein solvent in step d) comprises one or more of methanol, ethanol. isopropanol. 2-propanol, 1 -butanol. and t-butyl alcohol, trifluoroethanol ketones selected from acetone, butanone, and methyl ethyl ketone, 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 and/or mixture thereof; acetonitrile; and polar aprotic solvents selected from dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, Tetrahydrofuran, Dioxane, Dimethoxyethane, Acetonitrile, Toluene, xylene and water and mixtures thereof.

In another aspect, there is provided a process for the preparation of an amorphous form of Panobinostat, the process comprising:

a) suspending or dissolving Panobinostat in a solvent or mixture of solvents;

b) removing the solvent from the solution as obtained in step (a); and

c) isolating amorphous Panobinostat.

The solvents that may be used in step a) comprises one or more of alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1 -butanol, and t-butyl alcohol, trifluoroethanol and/or mixture thereof; ketones selected from acetone, butanone, and methyl ethyl ketone, methyl isobutyl ketone and/or mixture thereof; esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate, chlorinated hydrocarbons selected from methylene dichloride, ethylene dichloride, and chlorobenzene and/or mixture thereof; acetonitrile; and polar aprotic solvents selected from dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, Tetrahydrofuran, Dioxane, Dimethoxyethane^ Acetonitrile, Toluene, xylene and water mixtures thereof. Step b) involves removing the solvent from the solution obtained in 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 fi lm drying ("ATFD"), freeze drying (lyophilization), flash evaporation, and vacuum distillation.

In another embodiment the present invention further relates to solid dispersion of Panobinostat amorphous using the process as described in the foregoing description for amorphous Panobinostat lactate.

The present invention is further illustrated by the following example which is provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modification and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLE 1

Preparation of amorphous Panobinostat Lactate hydrate

500 mg of N-hydroxy-3-[4-[[[2-(2-methyl-l Hindol-3-yl)ethyl]amino]methyl]phenyl]-2E-2- propenamide (Panobinostat free base) was suspended in 10.0 ml of Acetone then stirred for 10 min. 1M Solution of Aqueous DL- Lactic acid (1.36 ml) was diluted with 2.5 ml of Acetone this solution was added to the above suspension at 25-30°C as drop wise. Suspension became clear solution, maintained for lh at ambient temperature then cool to 0-5°C and maintain for lh.

Slowly allowed to room temperature and maintain for 18h then distill the Acetone & water under vacuum at 45-50°C up to get foaming solid. Dried the obtained foaming solid at 45-50°C for 5-

6h. XRD was recorded as amorphous form.

Yield: 500 mg EXAMPLE-02

Preparation of amorphous Panobinostat Lactate hydrate

100 mg of N-hydroxy-3-[4-[[[2-(2 -methyl- l Hindol-3-yl) ethyl] amino] methyl] phenyl]-2E-2- propenamide was suspended in 2.0 ml of Methyl Ethyl ketone then stirred for 10 min. 85% of DL-l.actic acid (33.0mg) was diluted with 0.5 ml of Methyl Ethyl ketone this solution was added to the above suspension at ambient temperature as drop wise. Maintained this suspension for lh at ambient temperature then heat to 45-50°C and maintain for 4h. Di lute the solution with 1 .0 ml of water to get clear the suspension and stirred for l h at 25-30°C. Distilled the Methyl Ethyl ketone & Water under vacuum at 45-50°C up to get foaming solid. Dried the obtained foaming solid at 45-50°C for 5-6h.XRD was recorded as amorphous form.

Yield: 64 mg

EXAMPLE-03

Preparation of amorphous Panobinostat Lactate hydrate

100 mg of N-hydroxy-3-[4-[ [[2-(2-methyl- l I lindol-3-yl) ethyl] amino] methyl] phenyl]-2E-2- propenamide was suspended in 2.0 ml of Tirfluroethanol then stir for 10 min. 85% of DI . -Lactic acid (33.0 mg) was diluted with 0.5 ml of Tirfluroethanol this solution was added to the above suspension at ambient temperature as drop wise. Maintained this suspension for l h at ambient temperature then maintain for lh at ambient temperature then cool to 0-5°C and maintained for l h. Slowly allow to room temperature and maintained for 18h then distilled the Tirfluroethanol & water under vacuum at 45-50°C up to get foaming solid. Dried the obtained foaming solid at 45-50°C for 5-6h.XRD was recorded as amorphous form.

Yield: 100 mg EXAMPLE-04

Preparation of amorphous Panobinostat Lactate hydrate

200 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lHindol-3 -yl) ethyl] amino] methyl] phenyl]-2E-2- propenamide was suspended in 1 .5 ml of water then stir for 10 min. 85% of DL-Lactic acid (66.0 mg) was diluted with 0.5 ml of Water this solution is added to the above suspension at ambient temperature as drop wise. Maintained this suspension for 2h at ambient temperature. Then distilled the water under vacuum at 45-50°C up to get foaming solid. Dried the obtained foaming solid at 45-50°C for 2-3h.XRD was recorded as amorphous form.

Yield: 200 mg EXAMPLE-05

Preparation of amorphous Panobinostat

l OOmg of N-hydroxy-3-[4-[[[2-(2-methyl-l H indol-3 -yl) ethyl] amino] methyl] phenyl]-2E-2- propenamide (Panobinostat free base) is dissolved in 10 ml. of Methanol and filter through 0.4μ filter paper then distill the Methanol of the filtrate volumes at 45°C under vacuum to foaming solid. Dry the foaming solid at 45°C under vacuum for 5h. XRD is recorded as amorphous form Yield: 70 mg

EXAMPLE-06

Purification of Panobinostat free base

5.0 g of N-hydroxy-3-[4-[[[2-(2-methyl-l Hindol-3-yl)ethyl]amino]methyl]phenyl]-2E-2- propenamide (Panobinostat free base) was suspended in 50.0 ml of Methanol, heated to 60-65 °C then to the suspension was added a solution of Fumaric acid (2.0 g) in Methanol (50.0 mL) at 60-65 °C, obtained clear solution maintained for 30 min at 60-65 °C. Allowed to 25-30 °C and maintained for 2 h at 25-30 °C then filtered under vacuum at 25-30°C. Wet compound was taken in 37.5 mL of Methanol, to this suspension was added TEA (2.45 g) then maintained for 2 hours at 25-30 °C. Solid were collected on filtration at 25-30 °C. Obtained wet compound was dried under vacuum at 35-40 °C for 10-12 h.

Yield: 2.5 g EXAMPLE-07

Purification of Panobinostat free base

5.0g of N-hydroxy-3-[4-[[[2-(2-methyl-l Hindol-3-yl)ethyl]amino]methyl]phenyl]-2E-2- propenamide (Panobinostat free base) was suspended in Methanol (45.0 mL), to the suspension was added a solution of sulfuric acid (1.40 g) in Methanol (5.0 mL) at 10-15 °C, then maintained the resultant solution for 10-15 min. Triethylamine (5.79 g) was added to the solution at 0-5 °C and maintained for 2 h at 25-30 °C. Filtered the precipitated compound and suck dry for 15-30 min at 25-30 °C and unloaded the wet compound and dried under vacuum at 35-40°C for 10-12h. Yield: 4.3 g EXAMPLE-OS

Preparation of amorphous Panobinostat lactate hydrate

20.0 g of N-hydroxy-3-[4-[[[2-(2-methyl-l Hindol-3-yl)ethyl]amino]methyl]phenyl]-2E-2- propenamide (Panobinostat free base) was suspended in Methanol (400.0 ml ), to the suspension was added a solution of Lactic acid (42 ml .) in Methanol ( 100.0 ml .) at 25-30 °C, during 30 min. Suspension became clear solution. Filtered the solution and concentrated under vacuum at 35- 40°C and co-distilled with Methanol (100 niL) and dried for 1 hour. MTBE (200 ml.) was charged and stirred for 1 hour at 25-30°C. Filtered the solid under vacuum and solid was dried at 25-30°C for 24 hours.

Yield: 23 g

MC : 4.33 % w/w

While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the summary, description and examples are for illustrative purpose only of the core of the invention and non-limiting in their scope. Furthermore, as many changes may be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.

Claims

CLAIMS:

1. An amorphous form of Panobinostat Lactate having water content in the range between 3.1 to 4.9 % w/w.

2. An amorphous form of Panobinostat Lactate according to claim 1 , wherein the amorphous Panobinostat I .actate is hydrate.

3. A process for the preparation of an amorphous form of Panobinostat Lactate having water content in the range between 3. 1 to 4.9 % w/w, the process comprising:

a) suspending or dissolving Panobinostat in a solvent or mixture of solvents;

b) adding Lactic acid; and

c) removing the solvent from the solution as obtained in step (b);

4. A process for the preparation of an amorphous form of Panobinostat Lactate according to claim 3, wherein the solvent in step a) comprises one or more of alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1 -butanol, and t-butyl alcohol, trifluoroethanol; ketones selected from acetone, butanone, and methylethylketone, methyl isobuty! 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, Tetrahydrofuran, Dioxane, Dimethoxyethane, Acetonitrile, Toluene, xylene and water and mixtures thereof.

5. A process for the preparation of an amorphous form of Panobinostat Lactate according to claim 3, wherein the removal of the solvent comprises one or more of evaporation, evaporation by rotational distillation device, evaporation under reduced pressure, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization), flash evaporation, and vacuum distillation.

6. A process for the preparation of an amorphous form of Panobinostat Lactate according to claim 3, wherein the solvent in step d) comprises one or more solvents comprises one or more of methanol, ethanol, isopropanol, 2-propanol, 1 -butanol, and t-butyl alcohol, trifluoroethanol ketones selected from acetone, butanone, and methyl ethyl ketone, 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 and/or mixture thereof; acetonitrile; and polar aprotic solvents selected from dimethyl formamide. dimethyiacetamide, N-methylpyrrolidone, dimethyl sulfoxide, Tetrahydrofuran, Dioxane, Dimethoxyethane, Acetonitrile, Toluene, xylene and water and mixtures thereof.

7. An amorphous form of Panobinostat.

8. A process for the preparation of an amorphous form of Panobinostat, the process comprising: a) suspending or dissolving Panobinostat in a solvent or mixture of solvents;

b) removing the solvent from the solution as obtained in step (a); and

c) isolating amorphous Panobinostat.

9. A process for the preparation of an amorphous form of Panobinostat according to claim 8, wherein the solvent comprises one or more of alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1 -butanol, and t-butyl alcohol, trifluoroethanol; ketones selected from acetone, butanone, and methylethyl ketone, 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, dimethyiacetamide, N-methylpyrrolidone, dimethyl sulfoxide, Tetrahydrofuran, Dioxane, Dimethoxyethane, Acetonitrile, Toluene, xylene and water and mixtures thereof.

10. A process for the preparation of an amorphous form of Panobinostat according to claim 8, wherein the removal of the solvent comprises one or more of evaporation, evaporation by rotational distillation device, evaporation under reduced pressure, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization), flash evaporation, and vacuum distillation.