Crystalline forms of lenalidomide

Abstract

The present invention provides for novel co-crystals of lenalidomide. The present invention particularly provides for novel cocrystals of lenalidomide with Resorcinol, Methyl paraben and Saccharin. The present invention also provides for the processes for the production of cocrystals of lenalidomide with Resorcinol, Methyl paraben and Saccharin. The present invention further provides for processes for the preparation of crystalline anhydrous lenalidomide Form IV.

Claims

1. A lenalidomide Saccharin co-crystal of Formula Vc, ##STR00028## characterised by an XPRD pattern comprising major peaks at approximately 14.99±0.2, 16.05±0.2, 19.14±0.2, 20.14±0.2, 22.53±0.2, 25.17±0.2 and 25.78±0.2, degrees 2θ.

2. The lenalidomide Saccharin co-crystal of claim 1, characterised by a DSC having an endotherm at around 185° C. and the DSC pattern in accordance with FIG. 8.

3. A process for the preparation of a lenalidomide Saccharin co-crystal of Formula Vc of claim 1, the process comprising the following steps, reducing a Nitro intermediate of Formula II ##STR00029##  using a hydrogenation catalyst in a solvent selected from an organic solvent, an aqueous solvent, and a combination thereof at a temperature ranging between 25 and 70° C. to obtain a reaction mixture containing lenalidomide of Formula I ##STR00030## in situ treating of lenalidomide of Formula I with conformer Saccharin in an amount ranging between 0.5 and 10 equivalents ##STR00031## obtaining crystalline lenalidomide Saccharin co-crystal of Formula Vc.

4. The process for preparation of crystalline lenalidomide Saccharin co-crystal of claim 3 of Formula Vc, wherein the organic solvent is selected from N,N,Dimethyl acetamide a C.sub.1-C.sub.3 alcohol, and a combination thereof.

5. The process for preparation of crystalline lenalidomide Saccharin co-crystal of claim 4 of Formula Vc, wherein the C.sub.1-C.sub.3 alcohol is methanol.

Description

BRIEF DESCRIPTION OF THE FIGURES

(1) In order that the disclosure may be readily understood and put into practical effect, reference will now be made to exemplary embodiments as illustrated with reference to the accompanying figures. The figures together with a detailed description below, are incorporated in and form part of the specification, and serve to further illustrate the embodiments and explain various principles and advantages, in accordance with the present disclosure wherein:

(2) FIG. 1: Illustrates the .sup.1H NMR pattern of the crystalline Lenalidomide-Resorcinol co-crystal of Formula Va.

(3) FIG. 2: Illustrates the DSC thermogram of the crystalline Lenalidomide-Resorcinol co-crystal of Formula Va.

(4) FIG. 3: Illustrates the PXRD of crystalline Lenalidomide-Resorcinol co-crystal of Formula Va.

(5) FIG. 4: Illustrates the .sup.1H NMR pattern of the crystalline Lenalidomide-Methyl Paraben co-crystal of Formula Vb.

(6) FIG. 5: Illustrates the DSC thermogram of the crystalline Lenalidomide-Methyl Paraben co-crystal of Formula Vb.

(7) FIG. 6: Illustrates the PXRD of the crystalline Lenalidomide-Methyl Paraben co-crystal of Formula Vb.

(8) FIG. 7: Illustrates the .sup.1H NMR pattern of the crystalline Lenalidomide-Saccharin co-crystal of Formula Vc.

(9) FIG. 8: Illustrates the DSC thermogram of the crystalline Lenalidomide-Saccharin co-crystal of Formula Vc.

(10) FIG. 9: Illustrates the PXRD of the crystalline Lenalidomide-Saccharin co-crystal of Formula Vc.

(11) FIG. 10: Illustrates the PXRD of the crystalline anhydrous lenalidomide Form IV.

(12) The method of analysis of the compounds represented in the figures as above are as below:

(13) PXRD Analysis

(14) About 300 mg of powder sample was taken onto the sample holder and was tightly packed on the sample holder uniformly by means of glass slide and Powder X-ray diffraction was recorded on Bruker D8 Advance diffractometer (Bruker-AXS, Karlsruhe, Germany) using Cu-Kα X-radiation (k=1.5406 Å) at 40 kV and 30 mA powder. X-ray diffraction patterns were collected over the 20 range 3-50° at a scan rate of 1°/min.

(15) DSC Analysis

(16) DSC was performed on a Mettler Toledo DSC 822e module. 4-6 mg of sample was placed in crimped but vented aluminium sample pans. The temperature range was from 30-250° C. @ 10° C./min. Samples were purged by a stream of nitrogen flowing at 80 mL/min.

(17) IR Anlaysis

(18) IR was performed on a Fisher Scientific (NICOLET-iS50-FTIR). About 5 mg of sample was spread over the region of diamond ATR sampling station and collected the sample spectrum between 4000 cm−1 to 400 cm−1 to obtain a spectrum of suitable intensity (above 60% transmission at 2000 cm−1).

DETAILED DESCRIPTION OF THE INVENTION

(19) The embodiments of the present invention are further described using specific examples herein after. The examples are provided for better understanding of certain embodiments of the invention and not, in any manner, to limit the scope thereof. Possible modifications and equivalents apparent to those skilled in the art using the teachings of the present description and the general art in the field of the invention shall also form the part of this specification and are intended to be included within the scope of it.

(20) Schemes:

(21) ##STR00023##

General Example-1

(22) To a hydrogenator were added Formula II, a suitable solvent and a hydrogenation catalyst. The reaction mass was stirred under H.sub.2 atmosphere at a suitable temperature for a suitable amount of time. After completion of the reaction the reaction mass was cooled, filtered and the product as obtained in solution is subjected to charcoalisation followed by treatment with a suitable coformer R [wherein R is selected from Resorcinol, Methyl Paraben & Saccharin], stirred at a suitable temperature for a suitable amount of time and isolated crystalline lenalidomide cocrystal of Formula V. The crystalline lenalidomide cocrystal of Formula V was dissolved in a suitable first solvent, heated to a suitable temperature and cooled to a suitable temperature followed by addition of a second solvent. The reaction mass was stirred for a suitable duration and isolated crystalline anhydrous lenalidomide Form IV.

(23) As explained above the crystalline anhydrous lenalidomide Form IV is conveniently prepared using any of the coformers selected from Resorcinol, Methyl Paraben & Saccharin.

Example 1a: [Using Crystalline Lenalidomide Saccharin Cocrystal]

(24) ##STR00024##
Step-A:

(25) To a suspension of Formula-II (50.0 g, 0.173 mol) in N,N-Dimethyl acetamide (250 mL, 5.0 vol.), 10% Pd/C (5.0 g, 0.1% w/w) was added into a hydrogenator. The mass was stirred at 25±5° C. under H.sub.2 gas (90 psi) atmosphere. After completion of the reaction (Monitored through HPLC), the mass was filtered through celite, washed with N,N-Dimethyl acetamide (100 mL, 2.0 vol). The resulting filtrate subjected for Charcoal (5.0 g, 0.1% w/w) treatment, filtered through celite bed at 55±5° C., washed with N,N-Dimethyl acetamide (100 mL, 2.0 vol) to obtain Formula-I as a solution in DMAc (480 g).

(26) Step-B:

(27) To a solution of Formula-I in N,N-Dimethyl acetamide (480 g, 0.166 mol, Obtained from Step-A), Formula-IIIc (106.6 g, 0.582 mol) was added. The mass was concentrated under reduced pressure to a syrupy mass. It was contacted with MeOH (431 mL, 10.0 vol) at 25±5° C., filtered, and dried under reduced pressure at 55±5° C. to obtain a Formula-Vc as an off white solid (71.0 g).

(28) Step-C:

(29) A mixture of Formula-Vc (20.0 g, 0.032 mol) in N,N-Dimethyl acetamide (80.0 mL, 4.0 vol) was heated to 45-50° C., cooled to 25-30° C. Methanol (200 mL, 10.0 vol) was added. and the solid formed was filtered and dried at 80° C. under vacuum to obtain a Formula-I as an off-white solid.

(30) ##STR00025##

General Example-2

(31) To a hydrogenator were added the Formula II, a suitable solvent and a hydrogenation catalyst. The reaction was stirred under H.sub.2 atmosphere at a suitable temperature for a suitable amount of time. After completion of the reaction the reaction mass was cooled, filtered and the product as obtained in solution is subjected to charcoalisation. The charcoalised solution is treated with a suitable coformer R [wherein R is selected from Resorcinol, Methyl Paraben & Saccharin, stirred at a suitable temperature for a suitable amount of time and the lenalidomide cocrystal of Formula Vas obtained was taken to next step without isolation. The solution of lenalidomide cocrystal of Formula V is heated to a suitable temperature and cooled to room temperature followed by addition of a second solvent. The reaction mass was stirred for a suitable duration and isolated crystalline anhydrous lenalidomide Form IV.

(32) As explained above the crystalline anhydrous lenalidomide Form IV is conveniently prepared using any of the coformers selected from Resorcinol, Methyl Paraben & Saccharin.

Example-2a

(33) Step-a:

(34) To a suspension of Formula-II (100 g, 0.345 mol.) in N, N-Dimethyl acetamide (500 mL, 5.0 vol.) was added 10% Pd/C (10.0 g, 0.1% w/w) into a hydrogenator. This reaction mass was stirred at 60±5° C. under H2 atmosphere for 3 h. After completion of the reaction indicated by the HPLC, mass was cooled to 25±5° C., filtered through Celite® bed, washed with N,N-Dimethyl acetamide (200 mL, 2.0 vol.). Filtrate was transferred into a reactor, charcoalised and the mass was filtered through Celite® bed at 45±5° C., washed with N,N-Dimethyl acetamide (200 mL, 2.0 vol.) to obtain Formula-I in DMAc as a yellow colour solution.

(35) Step-b:

(36) To a solution of Formula-I in N,N-Dimethyl acetamide (0.194 mol. obtained as in step-a) was contacted with saccharin as coformer of Formula-IIIc (125.67 g, 0.686 mol.). This mass was concentrated under reduced pressure to obtain a syrupy mass (Formula-Vc). This mass was treated with Methanol (1018 mL, 20.0 vol.), then stirred for 1 h at 25±5° C., filtered, washed with Methanol (101.74 mL, 2.0 vol.) and dried under reduced pressure at 60±5° C. for 16 h to obtain Formula-I as an off-white solid (36.5 g, 71.75%). The solid obtained was optionally treated with methanol (20.0 vol) at 25-30° C. and filtered. Compound was dried under reduced pressure at 60±5° C. for 16 h to obtain crystalline anhydrous lenalidomide Form IV of Formula-I as an off white solid.

Example-2b

(37) Step-a:

(38) To a suspension of Formula-II (100 g, 0.345 mol.) in N,N-Dimethyl acetamide (500 mL, 5.0 vol.) was added 10% Pd/C (10.0 g, 0.1% w/w) into a hydrogenator. This reaction mass was stirred at 60±5° C. under H.sub.2 atmosphere for 3 h. After completion of the reaction indicated by the HPLC, mass was cooled to 25±5° C., filtered through Celite® bed, washed with N,N-Dimethyl acetamide (200 mL, 2.0 vol.). Filtrate was transferred into a reactor, charcoalised and the mass was filtered through Celite® bed at 45±5° C., washed with N,N-Dimethyl acetamide (200 mL, 2.0 vol.) to obtain Formula-I in Dimethyl acetamide as a yellow colour solution.

(39) Step-b:

(40) Compound of Formula-I in N,N-Dimethyl acetamide (0.0194 mol, obtained as in step-a) was concentrated under reduced pressure to a transparent syrupy mass. Formula IIIc (0.039 mol, 2.0 equiv) was added to the mass and charged N,N-Dimethyl acetamide (5.0 mL, 1.0 vol). This mass was stirred for 6-12 h at 25-30° C., methanol (10 vol) was added, stirred for 1 h at 25-30° C., filtered and dried at 45-50° C. under vacuum to obtain Formula-I as an off-white solid.

Example-2c

(41) Step-a:

(42) Performed as per step-a of Example-2b.

(43) Step-b:

(44) A solution of Formula-I in N,N-Dimethyl acetamide (0.388 mol) was added with Saccharin of Formula IIIc (1.356 mol). This solution was concentrated under reduced pressure to a transparent syrupy mass. This mass was added to Methanol (10.0 vol) at 25±5° C., then stirred for 1 h at 25±5° C. and filtered. It was dried under reduced pressure at 60±5° C. for 16 h to obtain Formula-I as an off-white solid.

Example-2d

(45) Step-a:

(46) Performed as per step-A&B of Example-1a.

(47) Step-b:

(48) A slurry of Formula-Vc (150 g, 0.239 mol.) in N,N-Dimethyl acetamide (2.5 vol.) was heated to 55±5° C. under stirring to obtain a clear solution. This solution was cooled to 25±5° C. It was added to Methanol (10.0 vol.), stirred for 1.5 h at 25±5° C., filtered and washed with Methanol (2.0 vol.). Compound was dried under reduced pressure at 60±5° C. for 16 h to obtain Formula-I as an off-white solid (38.50 g).

(49) ##STR00026##

Example 3a

(50) To a suspension of compound of Formula II (7.00 g), Water (105 mL, 15 vol), Methane sulfonic acid (3.92 mL) and Pd/C (10% loading, 50% wet, 0.70 g), hydrogen gas (90 psi) was purged at 25-30° C. The progress of the reaction was monitored by HPLC. After the completion of the reaction, the mass was filtered, washed with water (20 mL). pH of the filtrate was adjusted to by adding triethylamine (9.0 mL). The slurry obtained was washed with water (2×35 mL) followed by the addition of compound of Formula IIIa (4.58 g). The mass was heated between 65 and 70° C. for 5-6 h. It was cooled between 60 and 70° C., filtered and dried at 45-50° C. under reduced pressure to obtain Lenalidomide-Resorcinol co-crystal of Formula Va as a crystalline solid. It was characterized by .sup.1H NMR, DSC, FT-IR, PXRD and TGA.

Example 3b

(51) To a suspension of compound of Formula I (10.0 g) in water (100 mL, 10 vol) was added compound of Formula IIIa (6.37 g, 1.50 equiv). The reaction mixture was heated between 65 and 70° C. for 5 to 6 h. It was then filtered under hot condition and dried under vacuum at 45-50° C. to obtain Lenalidomide-Resorcinol co-crystal of Formula Va as a crystalline solid.

Example 3c

(52) To a suspension of compound of Formula I (1.0 g) in Ethyl acetate (10 mL, 10 vol) was added compound of Formula IIIa (1.70 g, 4.0 equiv). The reaction mixture was stirred between 25 and 30° C. for 5 to 6 h. It was then filtered and dried under vacuum at 45-50° C. to obtain Lenalidomide-Resorcinol co-crystal of Formula Va as a crystalline solid.

(53) ##STR00027##

Example-4

(54) A slurry of Formula-Va (5.0 g, 0.0192 mol obtained as per the procedure mentioned in Example-3a) in N,N-Dimethyl acetamide (20.0 mL, 4.0 vol.) was heated to 65±5° C. under stirring to obtain a clear solution. Solution was cooled to 25±5° C., this mass was contacted with Methanol (50.0 mL, 10.0 vol.) at 25±5° C. and filtered. Compound was dried under vacuum at 60±5° C. for 16 h to obtain Formula-I as crystalline anhydrous lenalidomide Form IV an off white solid (3.50 g, 70%).