DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No. IN 201941034699 filed on August 28, 2019.
FIELD OF THE INVENTION:
The present invention relates to novel crystalline forms of Ribociclib Hemi Succinate.

BACKGROUND OF THE INVENTION:
Ribociclib Succinate, chemically known as Butanedioic acid—7-cyclopentyl-N,N
dimethyl-2-{[5-(piperazin-1-yl) pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-
carboxamide (1/1) and represented by Formula-I is approved for the inhibition of cyclin D1/CDK4 and CDK6. It is similar to Palbociclib both structurally and pharmacologically,
acting as a selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6.

Formula I

Ribociclib and it’s pharmaceutically acceptable salts thereof was first claimed in US 8415355B2 patent. This patent also disclosed a process for the preparation of Ribociclib.

US 9193732B2 disclosed the polymorphic forms of succinate salt of Ribociclib, characterized by XRD, DSC, TGA, post-DVS XRD, post-DVS DSC and post-DVS TGA figures and non-hydrate form, hydrate form and mixtures.

US 9868739 B2 disclosed both anhydrous and hydrated forms of succinate salt of Ribociclib.

US 20170342075 disclosed crystalline form I of mono-succinate salt of Ribociclib, characterized by XRD peaks. This application also disclosed Hemi-succinate Form A, adipate salt Form A, Maleate salt Form A and Glycolic acid salt Form A.

EP application EP 3156406A1 claimed crystalline forms of Ribociclib free base and amorphous form.

PCT application WO 2018051280 claimed Salts of Ribociclib such as isethionic acid, oxalic acid, phosphoric acid, tartaric acid, acetic acid, trifluoroacetic acid, hydrobromic acid, citric acid, p-toluenesulfonic acid and disclosed different salts, amorphous form of Ribociclib and amorphous solid dispersion of Ribociclib.

The inventors of the present invention have developed novel polymorphic forms of Ribociclib and it’s Hemi Succinate salt which are stable and suitable for formulation development.

OBJECT AND SUMMARY OF THE INVENTION:

The main object of the present invention is to provide novel crystalline forms of Ribociclib Hemi Succinate.

In one aspect, the present invention is to provide a crystalline form of Ribociclib Hemi Succinate designated as Form M1.

In yet another aspect, the crystalline Ribociclib Hemi Succinate Form M1 is characterized by powder X-ray diffraction pattern having peaks at 12.0, 15.1, 18.4, 21.6, 21.9, 22.2 and 22.9 ± 0.2° degrees 2?.

In yet another aspect, the crystalline Ribociclib Hemi Succinate Form M1 is characterized by powder X-ray diffraction pattern as given in Figure 1.

In yet another aspect, the present invention is to provide a process for the preparation of crystalline Ribociclib Hemi Succinate Form M1 comprising the steps of:
a) dissolving Ribociclib in an organic solvent,
b) optionally adding a seed,
c) adding succinic acid, and
d) isolating crystalline Ribociclib Hemi Succinate Form M1.

In yet another aspect, the present invention is to provide a crystalline form of Ribociclib Hemi Succinate designated as Form M2.

In yet another aspect, the crystalline Ribociclib Hemi Succinate Form M2 is characterized by powder X-ray diffraction pattern having peaks at 11.8, 12.9, 13.9, 16.4, 18.2, 20.0, 21.3 and 22.0 ± 0.2° degrees 2?.

In yet another aspect, the crystalline Ribociclib Hemi Succinate Form M2 is characterized by powder X-ray diffraction pattern as given in Figure 2.

In yet another aspect, the present invention is to provide a process for the preparation of crystalline Ribociclib Hemi Succinate Form M2 by exposing crystalline Ribociclib Hemi Succinate Form M1 to about 90% Relative Humidity for about 24 hours to obtain crystalline Ribociclib Hemi Succinate Form M2.

In yet another aspect, the present invention is to provide a crystalline form of Ribociclib Hemi Succinate designated as Form M3.

In yet another aspect, the crystalline Ribociclib Hemi Succinate Form M3 is characterized by powder X-ray diffraction pattern having peaks at 4.6, 12.6, 13.6, 16.0, 17.9, 18.2, 19.5, 21.5 and 22.1 ± 0.2° degrees 2?.

In yet another aspect, the crystalline Ribociclib Hemi Succinate Form M3 is characterized by the powder X-ray diffraction pattern as given in Figure 3.

In yet another aspect, the present invention is to provide a process for the preparation of crystalline Ribociclib Hemi Succinate Form M3 by heating crystalline Ribociclib Hemi Succinate Form M2 to variable temperature of about 30 to 150°C followed by cooling to about 30°C to obtain crystalline Ribociclib Hemi Succinate Form M3.

Brief description of the figures:

Figure 1: Illustrates the powder X-ray diffraction (PXRD) pattern of crystalline Ribociclib Hemi Succinate Form M1.
Figure 2: Illustrates the powder X-ray diffraction (PXRD) pattern of crystalline Ribociclib Hemi Succinate Form M2.
Figure 3: Illustrates the powder X-ray diffraction (PXRD) pattern of crystalline Ribociclib Hemi Succinate Form M3.

DETAILED DESCRIPTION:

The present invention relates to novel crystalline forms of Ribociclib Hemi Succinate.

In one embodiment, the present invention relates to a crystalline form of Ribociclib Hemi Succinate designated as Form M1.

In yet another embodiment, the crystalline Ribociclib Hemi Succinate Form M1 is characterized by powder X-ray diffraction pattern having peaks at 12.0, 15.1, 18.4, 21.6, 21.9, 22.2 and 22.9 ± 0.2° degrees 2?.

In yet another embodiment, the crystalline Ribociclib Hemi Succinate Form M1 is characterized by powder X-ray diffraction pattern as given in Figure 1.

In yet another embodiment, the present invention relates to a process for the preparation of crystalline Ribociclib Hemi Succinate Form M1 comprising the steps of:
a) dissolving Ribociclib in an organic solvent,
b) optionally adding a seed,
c) adding succinic acid, and
d) isolating crystalline Ribociclib Hemi Succinate Form M1.

According to the present invention, Ribociclib may be taken in an organic solvent selected from alcohols like methanol, ethanol or Isopropyl alcohol and heated to 80±5°C to obtain a clear solution. To the clear solution may be added succinic acid solution prepared by dissolving succinic acid in isopropanol and maintain at 80±5°C for about an hour followed by cooling to about 50±5°C and maintain for about 20 hours. The resultant solid may be filtered and dried to obtain crystalline Ribociclib Hemi Succinate Form M1.

According to the present invention, Ribociclib may be taken in an organic solvent selected from alcohols like methanol, ethanol or Isopropyl alcohol and heated to 80±5°C to obtain a clear solution. To the clear solution, seed of crystalline Ribociclib Hemi Succinate Form M1 may be added followed by addition of succinic acid solution prepared by dissolving succinic acid in isopropanol and maintain at 80±5°C for about an hour. The resultant reaction mass may be cooled to about 50±5°C and maintain for about 20 hours. The resultant solid may be filtered and dried to obtain crystalline Ribociclib Hemi Succinate Form M1.

In yet another embodiment, the present invention relates to a crystalline form of Ribociclib Hemi Succinate designated as Form M2.

In yet another aspect, the crystalline Ribociclib Hemi Succinate Form M2 is characterized by powder X-ray diffraction pattern having peaks at 11.8, 12.9, 13.9, 16.4, 18.2, 20.0, 21.3 and 22.0 ± 0.2° degrees 2?.

In yet another embodiment, the crystalline Ribociclib Hemi Succinate Form M2 is characterized by powder X-ray diffraction pattern as given in Figure 2.

In yet another embodiment, the present invention relates to a process for the preparation of crystalline Ribociclib Hemi Succinate Form M2 by exposing crystalline Ribociclib Hemi Succinate Form M1 to 90% Relative Humidity for about 24 hours to obtain crystalline Ribociclib Hemi Succinate Form M2.

In yet another embodiment, the present invention relates to a crystalline form of Ribociclib Hemi Succinate designated as Form M3.

In yet another embodiment, the crystalline Ribociclib Hemi Succinate Form M3 is characterized by powder X-ray diffraction pattern having peaks at 4.6, 12.6, 13.6, 16.0, 17.9, 18.2, 19.5, 21.5 and 22.1 ± 0.2° degrees 2?.

In yet another embodiment, the crystalline Ribociclib Hemi Succinate Form M3 is characterized by the powder X-ray diffraction pattern as given in Figure 3.

In yet another embodiment, the present invention relates to a process for the preparation of crystalline Ribociclib Hemi Succinate Form M3 by heating crystalline Ribociclib Hemi Succinate Form M2 to variable temperature of about 30 to 150°C followed by cooling to about 30°C to obtain crystalline Ribociclib Hemi Succinate Form M3.

In yet another embodiment, the present invention relates to a pharmaceutical composition comprising crystalline Ribociclib Hemi Succinate form M1 or M2 or M3 and a pharmaceutically acceptable excipient.

The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in anyway.

EXAMPLES:
Example 1: Process for the preparation of Crystalline Ribociclib Hemi Succinate Form M1 without seeding.
Charged Ribociclib (1g) and Iso propyl alcohol (30mL) at 25±2°C to a round bottom flask. Heated the reaction mass to 80±5°C and stirred for 15minutes at 80±5°C to get clear solution. Added Succinic acid solution (prepared by dissolving succinic acid (0.3g) in Iso propyl alcohol (25ml) at 70±5°C) slowly for 20 min at 80±5°C. Stirred the reaction mass for 1h at 80±5°C. The reaction mass was cooled to 50±5°C and stirred for 20h at 50±5°C. The reaction mass was filtered, suck-dried for 30minutes and further dried the material under vacuum at 40°C for 16 h. The solid obtained was identified as crystalline Ribociclib Hemi Succinate Form M1.
Yield: 0.83g

Example 2: Process for the preparation of Crystalline Ribociclib Hemi Succinate Form M1 with seeding.
Charged Ribociclib (1g) and Iso propyl alcohol (30mL) at 25±2°C to a round bottom flask. Heated the reaction mass to 80±5°C and stirred for 15minutes to get clear solution. Added crystalline Ribociclib Hemi Succinate Form M1 (5mg) seeds at 80±5°C. Added Succinic acid solution (prepared by dissolving succinic acid (300mg) in Iso propyl alcohol (25ml) at 70±5°C) slowly for 20 min at 80±5°C. Stirred the reaction mass for 30minutes at 80±5°C. The reaction mass was cooled to 30±5°C and stirred for 20h at 30±5°C. The reaction mass was filtered, suck-dried for 30minutes and further dried the material under vacuum at 40°C for 16 h. The solid obtained was identified as crystalline Ribociclib Hemi Succinate Form M1.
Yield: 0.95g

Example 3: Process for the preparation of Crystalline Ribociclib Hemi Succinate Form M2.
Crystalline Ribociclib Hemi Succinate Form M1 (300mg) was placed in a petri dish and exposed to 90% Relative Humidity for 24 h. The product obtained was identified as crystalline Ribociclib Hemi succinate Form M2.
Yield: 300mg

Example 1: Process for the preparation of crystalline Ribociclib Hemi Succinate Form M3
Crystalline Ribociclib Hemi Succinate Form M2 (60mg) was heated using variable temperature powder XRD tool on Bruker D8 X-Ray Diffractometer from 30-150°C and slowly cooled to 30°C. The resulting solid was identified as crystalline Ribociclib Hemi succinate Form M3.
Yield: 50mg
,CLAIMS:
1. Crystalline Ribociclib Hemi Succinate Form M1 characterized by powder X-ray diffraction pattern having peaks at 12.0, 15.1, 18.4, 21.6, 21.9, 22.2 and 22.9 ± 0.2° degrees 2?.

2: The crystalline Ribociclib Hemi Succinate Form M1 as claimed in claim 1, is prepared comprising the steps of:
a) dissolving Ribociclib in an organic solvent,
b) optionally adding a seed,
c) adding succinic acid, and
d) isolating crystalline Ribociclib Hemi Succinate Form M1.

3. The process as claimed in claim 2, wherein the organic solvent is selected from alcohols like methanol, ethanol or Isopropyl alcohol.

4. The process as claimed in claim 2, wherein the reaction mixiture is heated to 80±5°C and cooled to 50±5°C

5. Crystalline Ribociclib Hemi Succinate Form M2 characterized by powder X-ray diffraction pattern having peaks at 11.8, 12.9, 13.9, 16.4, 18.2, 20.0, 21.3 and 22.0 ± 0.2° degrees 2?.

6. The crystalline Ribociclib Hemi Succinate Form M2 as claimed in claim 5, is prepared comprising the steps of:

a) exposing crystalline Ribociclib Hemi Succinate Form M1 to 90% Relative Humidity.
b) isolating crystalline Ribociclib Hemi Succinate Form M2.

7. Crystalline Ribociclib Hemi Succinate Form M3 characterized by powder X-ray diffraction pattern having peaks at 4.6, 12.6, 13.6, 16.0, 17.9, 18.2, 19.5, 21.5 and 22.1 ± 0.2° degrees 2?.

8. The crystalline Ribociclib Hemi Succinate Form M3 as claimed in claim 7, is prepared comprising the steps of:
a) heating crystalline Ribociclib Hemi Succinate Form M2 to variable temperatures.
b) cooling the mixture.
c) isolating crystalline Ribociclib Hemi Succinate Form M3.

9. The process as claimed in claim 8, wherein the variable temperature is 30 to 150°C and cooling is 30-35°C.

10. A pharmaceutical composition comprising crystalline Ribociclib Hemi Succinate selected from M1, M2 or M3 and a pharmaceutically acceptable excipient.