WO2019092752A2

WO2019092752A2 - Novel salt of lenalidomide and polymorphic forms thereof

Info

Publication number: WO2019092752A2
Application number: PCT/IN2018/050741
Authority: WO
Inventors: Venkata Rama Rao Alla; Chandrashekar Ramarao; Mukesh Padmakar SHEWALKAR; Sampath AMUDALA
Original assignee: Avra Laboratories Pvt. Ltd.
Priority date: 2017-11-13
Filing date: 2018-11-13
Publication date: 2019-05-16
Also published as: WO2019092752A3

Abstract

This invention discloses a novel pharmaceutical salt of Lenalidomide. More particularly, the invention discloses crystalline Trifluroacetic acid salt of Lenalidomide; polymorphic forms thereof and process for preparation thereof. The invention further discloses pharmaceutical composition comprising crystalline Trifluroacetic acid salt of Lenalidomide in association with one or more pharmaceutical excipients.

Description

NOVEL SALT OF LENALIDOMIDE AND POLYMORPHIC FORMS

THEREOF"

Related Applications:

This application is Complete Cognate Application of the Provisional Patent Application No. 201741040454 filed on 13^th November, 2017 and Provisional Patent Application No. 201841006631 filed on 21^st February, 2018.

Technical filed:

This invention relates to novel pharmaceutical salt of Lenalidomide. More particularly, the invention relates to Trifluroacetic acid salt of Lenalidomide; polymorphic forms thereof and process for preparation thereof. The invention further relates to pharmaceutical composition comprising Trifluroacetic acid salt of Lenalidomide in association with one or more pharmaceutical excipients.

Background and prior art:

Lenalidomide is chemically known as 3-(4-amino-l-oxo-l,3-dihydro-2H-isoindol- 2-yl)piperidine-2,6-dione and structurally represented below.

The first therapeutic use of Lenalidomide, a Thalidomide analogue, was for the treatment of multiple myeloma. Subsequently, the therapeutic efficacy of Lenalidomide has been established in the hematological disorders known as the myelodysplasia syndromes. Lenalidomide was approved by the U.S. Food and Drug Administration for treating patients with low or intermediate- 1 risk MDS with 5q with or without additional cytogenetic abnormalities. Lenalidomide is currently marketed under the trade name REVLIMID® by Celgene. Lenalidomide was first disclosed in US5635517. The aqueous solubility of Lenalidomide is very low. Therefore continued search for suitable polymorphic forms with improved physical characteristics results in various patents/patent applications for various crystalline, amorphous polymorphic forms of Lenalidomide as well as solvate forms.

WO 2005/023192 disclose polymorphic forms of Lenalidomide, designated as forms A, B, C, D, E, F, G, and H.

US9108945 discloses an anhydrous unsolvated crystalline form of Lenalidomide (Form-I) having weight loss of up to 0.13% between 25 and 225° C. by thermogravimetric analysis and characterized by its Powder XRD having peaks at 10.175±0.2, 11.269±0.2, 15.772±0.2, 16.277±0.2, 17.646±0.2, 20.099±0.2, 24.098±0.2, 25.230±0.2, 25.987±0.2, 28.320±0.2, and 32.595±0.2 degrees 2Θ .

WO2012127493 discloses a Lenalidomide N-methylpyrrolidone solvate which is characterized by peaks in the powder x-ray diffraction spectrum having 20 angle positions at about 8.5, 14.0, 14.5, 15.6, 16.1, 17.1, 17.6, 19.6, 21.6, 22.8 and 25.3 ± 0.2 degrees.

US20110237802 disclose DMF and DMSO solvates of Lenalidomide. Amorphous Lenalidomide was disclosed in WO 2009/114601.

Different pharmaceutical salts of drug substances exhibit different physical properties; however can influence pharmaceutically relevant properties, such as solubility, dissolution rate, stability and subsequent efficacy thereby significantly influence the commercial acceptance of such salts.

Similarly, polymorphism is defined as the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice. Although, different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. however, these properties will disappear once the compound is dissolved. Further, these physical properties can influence pharmaceutically relevant properties of the solid form, such as handling properties; dissolution rate and stability thereby significantly influence the processing, shelf life, therapeutic efficacy and thus commercial acceptance of a polymorph.

It is therefore important to investigate novel salt forms of Lenalidomide and polymorphic forms thereof to determine its stability, solubility, dissolution profile and flow properties of these salt forms.

Therefore, there remains a need in the art to provide novel pharmaceutical salts of Lenalidomide that has more solubility, dissolution rate and stability in addition to processing and handling properties.

Objective of the invention:

It is an objective of the present invention to provide Trifluroacetic acid salt of Lenalidomide that has more solubility, dissolution rate and stability.

It is another objective of the invention to provide novel crystalline polymorphic forms of Trifluroacetic acid salt of Lenalidomide that has more solubility, dissolution rate and stability in addition to processing and handling properties thereby meeting the industrial requirements and market acceptance.

Summary of the invention:

In accordance with the above objectives, the present invention discloses a novel Trifluroacetic acid (TFA) salt of Lenalidomide of formula I, which is stable and exhibits more intrinsic dissolution to that of existing forms. In one preferred aspect, Trifluroacetic acid (TFA) salt of Lenalidomide of formula I is crystalline in nature. In another aspect, the invention provides process for preparation of the novel Trifluroacetic acid (TFA) salt of Lenalidomide by reacting Lenalidomide with Trifluroacetic acid at ambient temperature to obtain Trifluroacetic acid (TFA) salt of Lenalidomide.

It was observed serendipitously by the present inventors that it is possible to obtain different crystalline forms of Trifluroacetic acid (TFA) salt of Lenalidomide of Formula I when the reaction mass consisting of Trifluroacetic acid (TFA) salt of Lenalidomide of Formula I is treated with different solvents.

Accordingly, the present invention encompasses various crystalline polymorphic forms of Trifluroacetic acid (TFA) salt of Lenalidomide viz., Form I; Form II; Form III; Form IV and Form V. The invention also encompasses mixtures of these forms. In further embodiments, this invention provides methods of making, isolating and characterizing these polymorphs.

In yet another aspect, the invention provides pharmaceutical compositions comprising therapeutically effective amount of crystalline Trifluroacetic acid (TFA) salt of Lenalidomide in association with one or more pharmaceutical carriers. These compositions may be formulated into oral solid dosage forms such as tablets and capsules; liquid dosage forms such as syrups and solutions and injectable dosage forms, using suitable excipients by conventional methods.

In a further aspect, the invention provides methods of using the TFA salt of Lenalidomide according to the invention for treatment of hematological disorders, which method comprises administering a therapeutically effective amounts of TFA salt of Lenalidomide or its crystalline polymorphic forms optionally in association with one or more pharmaceutical excipients to a subject in need thereof. Description of drawing:

Fig 1 depicts PXRD of Trifluroacetic acid (TFA) salt of Lenalidomide resulted from Ethanol and DCM solvent system, referred as polymorphic form I

Fig 2 depicts PXRD Trifluroacetic acid (TFA) salt of Lenalidomide resulted from DCM as solvent, as well as resulted from Toluene referred as polymorphic form II

Fig 3 depicts PXRD Trifluroacetic acid (TFA) salt of Lenalidomide resulted from Ethyl acetate as solvent, referred as polymorphic form III

Fig 4 depicts PXRD Trifluroacetic acid (TFA) salt of Lenalidomide resulted from MTBE as solvent referred as polymorphic form IV

Fig 5 depicts PXRD Trifluroacetic acid (TFA) salt of Lenalidomide resulted from Acetonitrile as solvent referred as polymorphic form V

Detailed description of the invention:

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be fully understood and appreciated.

The present invention discloses a novel Trifluroacetic acid salt of Lenalidomide of formula I, which is structurally depicted below:

Formula I

In another aspect, the invention provides process for preparation of the novel Trifluroacetic acid (TFA) salt of Lenalidomide by reacting Lenalidomide with Trifluroacetic acid at ambient temperature under stirring for about 2 to lOhrs. The reaction mass is concentrated to obtain residue containing Trifluroacetic acid salt of Lenalidomide.

In one preferred embodiment, the Trifluroacetic acid (TFA) salt of Lenalidomide of formula I is crystalline in nature.

Accordingly, purified crystals of Trifluroacetic acid salt of Lenalidomide can be obtained by treating the residue with organic solvent.

Thus the present invention encompasses these crystalline polymorphic forms of formula I which are designated as Form 1, Form II, Form III, Form IV and Form V. All these forms exhibits characteristic peaks when subjected to PXRD.

The PXRD of the crystalline polymorphs is conducted on Bruker AXS, X-ray Powder Diffractometer equipment using condition as 40KV/30mA, Range (2Θ) = 2-50° (normal / full scan), step width = 0.0053 °, step time = 13.9 sec.

Accordingly, the invention provides a process for preparation of the crystalline form I of Trifluroacetic acid salt of Lenalidomide which process comprises;

a) reacting Lenalidomide with trifluroacetic acid under stirring in presence of ethanol at ambient temperature conditions followed by concentrating the reaction mass to obtain residue; and

b) adding dichloromethane under stirring at ambient temperature conditions to precipitate and isolate the crystalline form I of Trifluroacetic acid salt of Lenalidomide. In a further aspect, the Trifluroacetic acid (TFA) salt of Lenalidomide Form I thus obtained from combination of ethanol and dichloromethane solvents is analyzed by PXRD, for its crystal characteristics. The PXRD shows characteristic peaks at 8.4, 8.8, 9.3, 12.1, 14.6, 15.1, 15.5, 20.4, 21.4, 22.1, 22.5, 23.1, 23.4, 24, 24.4, 24.7 degrees 2Θ, as shown in figure 1.

In another embodiment, the invention provides process for preparation of novel crystalline form II of Trifluroacetic acid (TFA) salt of Lenalidomide which comprises;

a) reacting Lenalidomide with trifluroacetic acid under stirring followed by concentration of the reaction mass to obtain a residue; b) adding Dichloromethane or toluene under ambient temperature

conditions and

c) isolating the crystalline form II of Trifluroacetic acid salt of

Lenalidomide.

The PXRD of this crystalline form having characteristic peaks at 5.2, 5.4, 8.3, 10.6, 10.8, 13.9, 13.8, 18, 18.7, 20.2, 20.7, 21.3, 21.7, 26.1, 27 degrees 2Θ±0.2. The PXRD of the crystalline form thus obtained from both toluene and dichloromethane is substantially as shown in figure 2.

In further embodiment, the invention provides process for preparation of novel crystalline form III of Trifluroacetic acid (TFA) salt of Lenalidomide which process comprises;

a) reacting Lenalidomide with trifluroacetic acid under stirring followed by concentration of the reaction mass to obtain a residue; b) adding ethylacetate under ambient temperature conditions; and c) isolating the crystalline form III of Trifluroacetic acid salt of Lenalidomide. This crystalline form obtained from Ethyl acetate having PXRD characteristic peaks at 5.4, 10.9, 12.8, 13.2, 13.8, 14.5, 15.6, 15.9, 16.3, 16.8, 17.3, 18.1, 18.8,

19.6, 21, 21.2, 24.5, 24.7, 27, 28.2, 29.5 degrees 2Θ±0.2. The PXRD of the crystalline form III is substantially as shown in figure 3.

In yet another embodiment, the invention provides process for preparation of novel crystalline form IV of Trifluroacetic acid (TFA) salt of Lenalidomide which process comprises;

a) reacting Lenalidomide with trifluroacetic acid under stirring followed by concentration of the reaction mass to obtain a residue;

b) adding Methyl tert-butyl ether (MTBE) under ambient temperature conditions; and

c) isolating the crystalline form IV of Trifluroacetic acid salt of Lenalidomide.

The PXRD of the crystalline form IV obtained from MTBE exhibits characteristic peaks at 5.4, 8.3, 10.4, 10.8, 12.8, 13.2, 13.6, 14.5, 15.8, 16.3, 16.7, 18, 18.7, 19.4,

19.7, 20.1, 20.4, 20.7, 21.2, 21.8, 23, 24.3, 25.6, 25.9, 26.9 degrees 2Θ±0.2. The PXRD of the crystalline form IV is substantially as shown in figure 4.

In yet another embodiment, the invention provides process for preparation of novel crystalline form V of Trifluroacetic acid (TFA) salt of Lenalidomide which process comprises;

b) adding acetonitrile under ambient temperature conditions; and c) isolating the crystalline form V of Trifluroacetic acid salt of Lenalidomide.

The PXRD of the crystalline form V obtained from acetonitrile exhibits characteristic peaks at 5.6, 6.1, 11.4, 124, 14, 14.7, 15.8, 16.6, 17.2, 17.9, 18.7, 19.7, 20.3, 21.2, 23.1, 25.9, 26.5, 27.1, 28.2, 29.1 degrees 2Θ±0.2. The PXRD of this novel crystalline form V is substantially as shown in figure 5.

Accordingly, in another embodiment the present invention encompasses various crystalline polymorphic forms of Trifluroacetic acid (TFA) salt of Lenalidomide referred as above- a) Crystalline polymorphic form I of Trifluroacetic acid (TFA) salt of Lenalidomide analyzed by PXRD having characteristic peaks at 8.4, 8.8, 9.3, 12.1, 14.6, 15.1, 15.5, 20.4, 21.4, 22.1, 22.5, 23.1, 23.4, 24, 24.4, 24.7 degrees 2Θ±0.2, substantially as shown in figure 1; b) Crystalline polymorphic form II of Trifluroacetic acid (TFA) salt of Lenalidomide analyzed by PXRD having characteristic peaks at 5.2, 5.4, 8.3, 10.6, 10.8, 13.9, 13.8, 18, 18.7, 20.2, 20.7, 21.3, 21.7, 26.1, 27 degrees 2Θ±0.2, substantially as shown in figure 2; c) Crystalline polymorphic form III of Trifluroacetic acid (TFA) salt of Lenalidomide analyzed by PXRD having characteristic peaks at 5.4, 10.9, 12.8, 13.2, 13.8, 14.5, 15.6, 15.9, 16.3, 16.8, 17.3, 18.1, 18.8, 19.6, 21, 21.2, 24.5, 24.7, 27, 28.2, 29.5 degrees 2Θ±0.2, substantially as shown in figure

3; d) Crystalline polymorphic form IV of Trifluroacetic acid (TFA) salt of Lenalidomide analyzed by PXRD having characteristic peaks at 5.4, 8.3, 10.4, 10.8, 12.8, 13.2, 13.6, 14.5, 15.8, 16.3, 16.7, 18, 18.7, 19.4, 19.7, 20.1, 20.4, 20.7, 21.2, 21.8, 23, 24.3, 25.6, 25.9, 26.9 degrees 2Θ±0.2, substantially as shown in figure 4; and e) Crystalline polymorphic form V of Trifluroacetic acid (TFA) salt of Lenalidomide analyzed by PXRD having characteristic peaks at 5.6, 6.1, 11.4, 124, 14, 14.7, 15.8, 16.6, 17.2, 17.9, 18.7, 19.7, 20.3, 21.2, 23.1, 25.9,

26.5, 27.1, 28.2, 29.1 degrees 2Θ±0.2, is referred herein after as form V.

In additional embodiment, equilibrium solubility experiments were conducted in a 100 mL conical flask at room temperature. A solid sample of 260 mg was stirred in 25 mL of dissolution medium (HC1 buffer, pH 1.8, with sodium lauryl sulphate) using a mechanical stir rod. Aliquots were filtered using 0.2μπι nylon syringe filters and immediately diluted 1 mL to 50 with dissolution medium. The Trifluroacetic acid (TFA) salt of Lenalidomide and the polymorphic forms thereof according to the invention of the present invention exhibits greater solubility to that of existing forms.

The solubility of the various novel crystalline polymorphic forms TFA salts of Lenalidomide of the present invention is observed to be in the range of 8.5mg/ml to 11 26mg/mL which is far greater than the Form I and Form B of Lenalidomide viz., 3.15mg/ml and 3.28 respectively as reported in US9108945.

The solubility results of polymorphic form I to V of TFA salt of Lenalidomide are given below.

Sr. No Form Solubility

1 Lenalidomide TFA salt Form I ~10.2mg/mL

2 Lenalidomide TFA salt Form II ~9.75mg/mL

3 Lenalidomide TFA salt Form III ~9.15gm/mL

4 Lenalidomide TFA salt Form IV ~8.75mg/mL

5 Lenalidomide TFA salt Form V ~9.95mg/mL

6 Lenalidomide Form I 3.15mg/ml

7 Lenalidomide Form B 3.28mg/ ml The greater solubility of the polymorphic forms I to form V of trifluro acetic acid salt of Lenalidomide over the Form I and Form B of the Lenalidomide free base consequently translate into improved bioavailability of the drug upon ingestion.

It is also observed that all the polymorphic forms of TFA salt of Lenalidomide of the present invention are stable and not interconverted upon standing over a period of 6 months. Therefore, in the light of the stability and high aqueous solubility of these polymorphic forms; the consistency in therapeutic efficacy upon administration of these forms will be considerably increased.

In yet another embodiment, the invention provides comparative evaluation study of acute toxicity of Lenalidomide Trifluroacetate and Lenalidomide free base by fixed dose method as per NCI guidelines. Accordingly, the study was conducted in Balb/c Mice as test subjects in order to derive the data with the test compounds for predicting the human response by strictly adhering to the regulatory guidelines NCI for testing the chemicals for acute oral toxicity by fixed dose method. These animals are widely used for pre-clinical toxicological studies for anticancer compounds. According to this study, mice of both the genders having uniform weight and age were used for acute toxicity testing to determine the effect of a single dose on the test subjects. In acute toxicological testing, the test product is administered at different dose levels, and the effect is observed for 14 days. The fixed dose procedure (FDP) is used to assess the nonlethal toxicity rather than the lethal dose. The Lenalidomide Trifluroacetate (test compound I) is administered to the mice at fixed dose levels of 100, 200 and 400mg/kg and mice is observed for a specified period of 14 days to notice the difference in the body weight, to assess the toxicity of the test compound.

Accordingly, a comparative acute oral toxicity test was conducted in male and female mice using Lenalidomide Trifluroacetate (test compound I) of the present invention vis-a-vis the known Lenalidomide free base (test compound 2) at fixed dose levels of lOOmg/Kg body weight; 200mg/KG body weight and 400mg/Kg body weight for testing the nonlethal toxicity of the these test product, i.e., TFA salt of Lenalidomide of formula I vis-a-vis the known marketed product, i.e., Lenalidomide free base. The results of difference in body weight for the observed period of 14 days are shown below in tables 1 and 2.

Influence on body weight with the Test Compound-I ( Lenalidomide

Tnfluroacetate)

Table 1

+ indicates increase in body weig

- indicates decrease in body weight

As is evident from the above, the toxicity of Lenalidomide Tnfluroacetate even at a test dose of 400mg/Kg body weight on the test subjects appears to be negligible as a minimum of 80% subjects have gained body weight of about 2 to 12% over a period of 14 days which indicates that the Lenalidomide Trifluroacetate of the present invention is non-toxic even at a maximum test dose of 400mg/Kg body weight. Influence on body weight - Test Compound-II (Lenalidomide)

Table 2

+ indicates increase in body weight

- indicates decrease in body weight

As is evident from the above, the toxicity of Lenalidomide at a test dose of 400mg/Kg body weight on the test subjects is also appears to be negligible as minimum of 90% subjects have gained body weight of about 2 to 9% over a period of 14 days.

However, it is further clear from the above tables 1 and 2 that the tolerability of Lenalidomide Trifluroacetate in mice at a maximum dose of 400mg/KG body weight is better than that of the prior art Lenalidomide in view of the maximum increase of about 12% body weight of the mice administered Lenalidomide Trifluroacetate over the mice administered lenalidomide, wherein, the maximum increase in body weight is only about 9%.

Therefore, the Lenalidomide Trifluroacetate of the present invention is much safer than the Lenalidomide or at least comparable.

In view of the foregoing, it is evident that the Lenalidomide Trifluroacetate having very good safety profile and 3 times greater solubility over the Lenalidomide of the prior art conclusively proves that Lenalidomide Trifluroacetate, if administered, provides enhanced therapeutic efficacy over the prior art product, Lenalidomide.

According to another embodiment, the present invention provides pharmaceutical compositions comprising novel TFA salt of Lenalidomide in therapeutically effective amounts along with one or more pharmaceutical carriers/ excipients.

Accordingly, the pharmaceutical compositions of present invention may comprise any one specific polymorphic form of TFA salt of Lenalidomide selected from polymorphic forms I to V according to the present invention along with one or more pharmaceutical excipients/carriers to attain desired therapeutic efficacy.

Alternately, the pharmaceutical compositions of present invention may comprise mixture of one or more polymorphic forms of TFA salt of Lenalidomide selected from polymorphic forms I to V according to the present invention along with one or more pharmaceutical excipients/carriers to attain desired therapeutic efficacy.

The TFA salt of Lenalidomide according to the invention can be formulated into oral dosage forms such as tablets, capsules, oral liquids such as syrups and suspensions or injectable dosage forms using suitable pharmaceutical excipients. In yet another aspect, the invention provides methods of using the TFA salt of Lenalidomide according to the invention for treatment of hematological disorders, which method comprises administering a therapeutically effective amounts of TFA salt of Lenalidomide or the crystalline polymorphic forms I to V according to the invention optionally in association with one or more pharmaceutical excipients to a subject in need thereof.

The excipients are the conventional excipients which can be selected from the group consisting of binders, diluents, distintegrants, lubricants, polymers, gelatin, fillers etc.

In another embodiment, the invention provides methods of using the TFA salt of Lenalidomide according to the invention for the preparation of medicament for treatment of hematological disorders. Such methods of use involve preparation of variety of dosage forms of TFA salt of Lenalidomide optionally in association with one or more pharmaceutical excipients.

Other features and embodiments of the invention will become apparent by the following examples which are given for illustration of the invention rather than limiting its intended scope. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art.

Examples:

Example 1

Preparation of TFA salt of Lenalidomide:

Lenalidomide free base (10 g, leq.0.038 mole) and TFA (50 mL, 5 V) were stirred at 25-30° C for 4 hrs. Ethanol (200 mL, 20 V) was added then stirred for at 25-30° C for 1 hr. The solvent was evaporated and the residue was taken into DCM (200 mL, 20 V) to precipitate the salt. The salt thus obtained (14.2gm) was collected by filtration. PXRD of the TFA salt of Lenalidomide thus obtained is shown as Fig. l . Yield: 98%

Purity by HPLC: 99.45% Example 2

Preparation of TFA salt of Lenalidomide using DCM:

Lenalidomide free base (9g, 0.034mole) and TFA (45mL, 5V) were stirred at 25- 30° C for 5Hrs. TFA was concentrated and the residue was stirred with DCM (612mL, 68V) at 25-30° C for 12Hrs. The obtained solid (12.4g) was collected by filtration. The PXRD of the TFA salt of Lenalidomide thus obtained is shown as Fig.2.

Yield: 95% Example 3

Preparation of TFA salt of Lenalidomide using Toluene:

Lenalidomide free base (5g, 0.019mole) and TFA (25mL, 5V) were stirred at 25- 30° C for 5Hrs. TFA was concentrated and the residue was stirred with Toluene (300mL, 60V) at 25-30° C for 48Hrs. The obtained solid (7g) was collected by filtration. The PXRD of the TFA salt of Lenalidomide thus obtained is corresponding Fig.2.

Yield: 97%

Example 4

Preparation of TFA salt of Lenalidomide using Ethyl acetate:

Lenalidomide free base (5g, 0.019mole) and TFA (25mL, 5V) were stirred at 25-

30° C for 4 Firs. TFA was concentrated and the residue was stirred with Ethyl acetate (50mL, 10V) at 25-30° C for 0.5Hr. The obtained solid (7g) was collected by filtration. PXRD of the TFA salt of Lenalidomide thus obtained is shown as

Fig.3.

Yield: 97% Example 5

Preparation of TFA salt of Lenalidomide using MTBE:

Lenalidomide free base (5g, 0.019mole) and TFA (25mL, 5V) were stirred at 25- 30° C for 4 Hrs. TFA was concentrated and the residue was stirred with MTBE (lOOmL, 20V) at 25-30° C for IHr. The obtained solid (6.8g) was collected by filtration. PXRD of the TFA salt of Lenalidomide thus obtained is shown as Fig.4. Yield: 94%

Example 6

Preparation of TFA salt of Lenalidomide using Acetonitrile:

Lenalidomide free base (5g, 0.019mole) and TFA (25mL, 5V) were stirred at 25- 30° C for 4 Hrs. TFA was concentrated and the residue was stirred with Acetonitrile (150mL, 30V) at 25-30° C for 0.5Hr. The obtained solid (5.8g) was collected by filtration. PXRD of the TFA salt of Lenalidomide thus obtained is shown as Fig.5. Yield: 80%

Example 7

Formulation for a 10 mg capsule

Drug Percent by weight Quantity (mg/tablet)

TFA salt of Lenalidomide 40% lOmg

polymorphic form I

Pregel starch 59% 14.75

Mg Stearate 1% 0.25

Total 100% 25mg

Claims

We claim,

1. Crystalline Trifluroacetic acid salt of Lenalidomide with high aqueous solubility and stability.

2. The crystalline form of the Trifluroacetic acid salt of Lenalidomide as claimed in claim 1, designated as Form I which is characterized by a powder X-Ray diffraction pattern (PXRD) having peaks at 8.4, 8.8, 9.3, 12.1, 14.6, 15.1, 15.5, 20.4, 21.4, 22.1, 22.5, 23.1, 23.4, 24, 24.4, 24.7 degrees 2Θ±0.2.

3. A process for preparation of the crystalline form I of Trifluroacetic acid salt of Lenalidomide as claimed in claim 2, wherein, the said process comprises; a) reacting Lenalidomide with trifluroacetic acid under stirring in presence of ethanol at ambient temperature conditions followed by concentrating the reaction mass to obtain residue; and

b) adding dichloromethane under stirring at ambient temperature conditions to isolate the crystalline form I of Trifluroacetic acid salt of Lenalidomide.

4. The crystalline form of the Trifluroacetic acid salt of Lenalidomide as claimed in claim 1, designated as Form II which is characterized by a powder X-Ray diffraction pattern (PXRD) having peaks at 5.2, 5.4, 8.3, 10.6, 10.8, 13.9, 13.8, 18, 18.7, 20.2, 20.7, 21.3, 21.7, 26.1, 27 degrees 2Θ±0.2.

5. A process for preparation of the crystalline form II of Trifluroacetic acid salt of Lenalidomide as claimed in claim 4, wherein the said process comprises;

b) adding Dichloromethane or toluene under ambient temperature conditions and

c) isolating the crystalline form II of Trifluroacetic acid salt of Lenalidomide.

6. The crystalline form of the Trifluroacetic acid salt of Lenalidomide as claimed in claim 1, designated as Form III which is characterized by a powder X-Ray diffraction pattern (PXRD) having peaks at 5.4, 10.9, 12.8, 13.2, 13.8, 14.5, 15.6, 15.9, 16.3, 16.8, 17.3, 18.1, 18.8, 19.6, 21, 21.2, 24.5,

24.7, 27, 28.2, 29.5 degrees 2Θ±0.2.

7. A process for preparation of the crystalline form III of Trifluroacetic acid salt of Lenalidomide as claimed in claim 6, wherein the said process comprises;

b) adding ethyl acetate under ambient temperature conditions; and c) isolating the crystalline form III of Trifluroacetic acid salt of Lenalidomide.

8. The crystalline form of the Trifluroacetic acid salt of Lenalidomide as claimed in claim 1, designated as Form IV which is characterized by a powder X-Ray diffraction pattern (PXRD) having peaks at 5.4, 8.3, 10.4,

10.8, 12.8, 13.2, 13.6, 14.5, 15.8, 16.3, 16.7, 18, 18.7, 19.4, 19.7, 20.1, 20.4, 20.7, 21.2, 21.8, 23, 24.3, 25.6, 25.9, 26.9 degrees 2Θ±0.2.

9. A process for preparation of the crystalline form IV of Trifluroacetic acid salt of Lenalidomide as claimed in claim 8, wherein the said process comprises;

b) adding MTBE under ambient temperature conditions; and

10. The crystalline form of the Trifluroacetic acid salt of Lenalidomide as claimed in claim 1, designated as Form V which is characterized by a powder X-Ray diffraction pattern (PXRD) having peaks at 5.6, 6.1, 11.4, 124, 14, 14.7, 15.8, 16.6, 17.2, 17.9, 18.7, 19.7, 20.3, 21.2, 23.1, 25.9, 26.5, 27.1, 28.2, 29.1 degrees 2Θ±0.2.

11. A process for preparation of the crystalline form V of Trifluroacetic acid salt of Lenalidomide as claimed in claim 10, wherein the said process comprises; a) reacting Lenalidomide with trifluroacetic acid under stirring followed by concentration of the reaction mass to obtain a residue;

12. The process as claimed in claims 3, 5, 7, 9 and 11, wherein the ambient temperature is 25-30° C.

13. The process as claimed in claims 3, 5, 7, 9 and 11, wherein the solvent can be added directly to the reaction mass of step a) or in step b).

14. A pharmaceutical composition comprising crystalline Trifluroacetic acid salt of Lenalidomide as claimed in claim 1, in therapeutically effective amounts in association with one or more pharmaceutical carriers/excipients.

15. The pharmaceutical composition as claimed in claim 14, wherein, the composition comprises one or more crystalline forms of Trifluroacetic acid salt of Lenalidomide as claimed in claims 2, 4, 6, 8, and 10 in association with one or more pharmaceutical carriers/excipients.

16. A Method for treating a subject suffering with hematological disorders, which method comprises administering a therapeutically effective amounts of crystalline TFA salt of Lenalidomide optionally in association with one or more pharmaceutical excipients to a subject in need thereof.

17. The Method for treating a subject as claimed in claim 16, which method comprises administering a therapeutically effective amounts of one or more crystalline polymorphic forms I to V of TFA salt of Lenalidomide optionally in association with one or more pharmaceutical excipients to a subject in need thereof.