DESC:CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of the earlier filing date of Indian provisional patent application no IN 201841036689 filed on September 28, 2018.

FIELD OF THE INVENTION:
The present invention relates to novel polymorphs of Ribociclib and it’s Succinate salt.

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 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 polymorphs of Ribociclib and it’s Succinate salt.

In one aspect, the present invention is to provide a crystalline form of Ribociclib Succinate designated as Form M7.

In yet another aspect, the crystalline Ribociclib Succinate Form M7 is characterized by powder X-ray diffraction pattern having peaks at 5.3, 7.9, 9.5, 10.6, 11.0, 11.8, 12.3, 13.5, 14.6, 15.3, 16.0, 16.8, 18.7, 19.2, 19.5, 20.1, 21.4, 21.9, 22.7, 23.3, 23.6, 24.1, 24.8, 25.9, 26.2, 26.7, 27.2, 28.6, 29.4, 30.1, 30.8, 31.5, 32.0, 33.0, 33.5, 35.4, 36.2, 36.9, 37.7, 38.5, 39.1, 41.0, and 41.8 ± 0.2° degrees 2?.

In yet another aspect, the crystalline Ribociclib Succinate Form M7 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 Succinate Form M7 comprising the steps of:
a) dissolving Ribociclib Succinate in an organic solvent or mixture of solvents,
b) optionally seeding with crystalline Ribociclib succinate Form M7,
c) isolating crystalline Ribociclib Succinate Form M7.
In yet another aspect, the present invention is to provide a novel crystalline form of Ribociclib Succinate designated as Form M8.

In yet another aspect, the crystalline Ribociclib Succinate Form M8 is characterized by powder X-ray diffraction pattern having peaks at 5.1, 6.8, 8.2, 9.0, 10.0, 10.6, 11.3, 11.9, 12.3, 12.7, 13.7, 14.5, 15.6, 16.5, 17.2, 17.8, 18.5, 19.3, 19.8, 20.4, 21.7, 22.0, 22.8, 23.1, 24.6, 25.2, 26.5, 26.8, 27.2, 28.1, 29.3, 29.9, 30.8, 31.2, 32.1, 33.1, 33.8, 34.7, 36.3, 38.4, 39.7 and 41.1 ± 0.2° degrees 2?.

In yet another aspect, the crystalline Ribociclib Succinate Form M8 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 Succinate Form M8 comprising the steps of:
a) heating crystalline Ribociclib Succinate Form M7,
b) isolating crystalline Ribociclib Succinate Form M8.

In yet another aspect, the present invention is to provide a novel crystalline form of Ribociclib designated as Form M1.

In yet another aspect, the crystalline Ribociclib Form M1 is characterized by powder X-ray diffraction pattern having peaks at 4.7, 6.4, 6.7, 8.9, 10.5, 11.8, 12.9, 13.5, 14.1, 14.6, 15.3, 16.4, 17.2, 18.4, 19.0, 19.5, 20.0, 20.7, 21.2, 21.8, 23.0, 23.8, 26.8, 27.8, 30.4, 31.7, 33.2, 36.1, and 40.1 ± 0.2° degrees 2?.

In yet another aspect, the crystalline Ribociclib Form M1 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 Form M1 comprising the steps of:
a) adding Ribociclib Succinate to a precooled aqueous base,
b) isolating crystalline Ribociclib Form M1.

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

In yet another aspect, the crystalline Ribociclib Form M2 is characterized by powder X-ray diffraction pattern having peaks at 4.7, 6.5, 7.6, 8.2, 8.9, 9.7, 10.3, 11.4, 11.8, 12.2, 12.8, 13.7, 15.4, 16.1, 16.5, 17.1, 18.8, 20.0, 20.8, 21.2, 22.0, 22.6, 23.8, 24.5, 25.3, 26.5, 28.2, 29.9, 31.4, and 40.1 ± 0.2° degrees 2?.

In yet another aspect, the crystalline Ribociclib Form M2 is characterized by powder X-ray diffraction pattern as given in Figure 4.

In yet another aspect, the present invention is to provide a process for the preparation of crystalline Ribociclib Form M2 comprising the steps of:
a) drying Ribociclib Form M1,
b) isolating crystalline Ribociclib Form M2.

Brief description of the figures:

Figure 1: Illustrates the powder X-ray diffraction (PXRD) pattern of crystalline Ribociclib Succinate Form M7.
Figure 2: Illustrates the powder X-ray diffraction (PXRD) pattern of crystalline Ribociclib Succinate Form M8.
Figure 3: Illustrates the powder X-ray diffraction (PXRD) pattern of crystalline Ribociclib Form M1.
Figure 3: Illustrates the powder X-ray diffraction (PXRD) pattern of crystalline Ribociclib Form M2.

DETAILED DESCRIPTION:

The present invention relates to novel crystalline forms of Ribociclib and it’s salts.

In one embodiment, the present invention relates to a crystalline form of Ribociclib Succinate designated as Form M7.

In yet another embodiment, the crystalline Ribociclib Succinate Form M7 is characterized by powder X-ray diffraction pattern having peaks at 5.3, 7.9, 9.5,10.6, 11.0, 11.8, 12.3, 13.5, 14.6, 15.3, 16.0, 16.8, 18.7, 19.2, 19.5, 20.1 21.4, 21.9, 22.7, 23.3, 23.6, 24.1, 24.8, 25.9, 26.2, 26.7, 27.2, 28.6 29.4, 30.1, 30.8, 31.5, 32.0, 33.0, 33.5, 35.4, 36.2, 36.9, 37.7, 38.5, 39.1, 41.0, and 41.8 ± 0.2° degrees 2?.

In yet another embodiment, the crystalline Ribociclib Succinate Form M7 is characterized by the 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 Succinate Form M7 comprising the steps of:
a) dissolving Ribociclib Succinate in an organic solvent or mixture of solvents,
b) optionally seeding with crystalline Ribociclib succinate Form M7,
c) isolating crystalline Ribociclib Succinate Form M7.

According to the present invention, Ribociclib succinate may be dissolved in organic solvents selected from dimethyl sulfoxide, tetrahydrofuran, acetone, methanol, ethanol, 1-butanol, 2-butanol, 1-propanol, Isopropyl alcohol, ethyl acetate, n-butyl acetatate, n-propyl acetate, isopropyl acetate, acetonitrile, dimethylformamide or mixtures thereof. The clear solution may be cooled to 25±5°C and then placed in a precooled bath maintained at -5 to -10°C. The solid formed may be filtered and dried to obtain crystalline Ribociclib Succinate Form M7.

According to another embodiment, Ribociclib succinate may be dissolved in organic solvents selected from dimethyl sulfoxide, tetrahydrofuran, acetone, methanol, ethanol, 1-butanol, 2-butanol, 1-propanol, Isopropyl alcohol, ethyl acetate, n-butyl acetatate, n-propyl acetate, isopropyl acetate, acetonitrile, dimethylformamide or mixtures thereof. The reaction mass may initially cooled to 25±5°C followed by further cooling to about -5 to -10°C and added with a Ribociclib succinate Form M7 seed material. The solid formed may be filtered and dried under vacuum to obtain crystalline Ribociclib Succinate Form M7.

According to another embodiment, the seed material may be added at 35±5°C and further cooled to 25±5°C and the solid formed may be filtered and dried under vacuum to obtain crystalline Ribociclib Succinate Form M7.

In yet another embodiment, the present invention relates to a crystalline form of Ribociclib Succinate designated as Form M8.

In yet another embodiment, the crystalline Form M8 of Ribociclib Succinate is characterized by powder X-ray diffraction pattern having peaks at 5.1, 6.8, 8.2, 9.0, 10.0, 10.6, 11.3, 11.9, 12.3, 12.7, 13.7, 14.5, 15.6, 16.5, 17.2, 17.8, 18.5, 19.3, 19.8, 20.4, 21.7, 22.0, 22.8, 23.1, 24.6, 25.2, 26.5, 26.8, 27.2, 28.1, 29.3, 29.9, 30.8, 31.2 32.1, 33.1, 33.8. 34.7, 36.3 , 38.4, 39.7 and 41.1 ± 0.2° degrees 2?.

In yet another embodiment, the crystalline Ribociclib Succinate Form M8 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 Succinate Form M8 comprising the steps of:
a) heating crystalline Ribociclib Succinate Form M7,
b) isolating crystalline Ribociclib Succinate Form M8.

According to the present invention, Ribociclib succinate form M7 may be heated in a vacuum tray dryer at about 120-130°C for 2-3hours to obtain crystalline Ribociclib succinate Form M8.

In yet another embodiment, the present invention relates to crystalline form of Ribociclib designated as Form M1.

In yet another embodiment, the crystalline Ribociclib Form M1 is characterized by powder X-ray diffraction pattern having peaks at 4.7, 6.4, 6.7, 8.9, 10.5, 11.8, 12.9, 13.5, 14.1, 14.6, 15.3, 16.4, 17.2, 18.4, 19.0, 19.5, 20.0, 20.7, 21.2, 21.8, 23.0, 23.8, 26.8, 27.8, 30.4, 31.7, 33.2, 36.1, and 40.1 ± 0.2° degrees 2?.

In yet another embodiment, the crystalline Ribociclib Form M1 is characterized by 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 Form M1 comprising the steps of:
a) adding Ribociclib Succinate to a precooled aqueous base,
b) isolating crystalline Ribociclib Form M1.

According to the present invention, Ribociclib succinate may be added to a precooled aqueous base solution wherein the base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide. The resultant solid may be filtered and dried under vacuum to obtain crystalline Ribociclib Form M1.

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

In yet another aspect, the crystalline Form M2 of Ribociclib is characterized by powder X-ray diffraction pattern having peaks at 4.7, 6.5, 7.6, 8.2, 8.9, 9.7, 10.3, 11.4, 11.8, 12.2, 12.8, 13.7, 15.4, 16.1, 16.5, 17.1, 18.8, 20.0, 20.8, 21.2, 22.0, 22.6, 23.8, 24.5, 25.3, 26.5, 28.2, 29.9, 31.4, and 40.1 ± 0.2° degrees 2?.

In yet another embodiment, the crystalline Ribociclib Form M2 is characterized by powder X-ray diffraction pattern as given in Figure 4.

In yet another embodiment, the present invention relates to a process for the preparation of crystalline Ribociclib Form M2 comprising the steps of:
a) drying crystalline Ribociclib Form M1,
b) isolating crystalline Ribociclib Form M2.

According to the present invention, Ribociclib Form M1 may be dried under vacuum at a temperature of about 110 to 135°C and slowly cooled to about 30°C to obtain crystalline Ribociclib Form M2.

In yet another embodiment, the present invention relates to a pharmaceutical composition comprising crystalline Ribociclib forms M1 or M2 or crystalline Ribociclib succinate forms M7 or M8 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:
Process for the preparation of Ribociclib succinate Form M7
Example 1:
Ribociclib succinate (0.1g) was dissolved in a mixture of dimethyl sulfoxide (2mL) and tetrahydrofuran (1mL) at 80±5°C. The clear solution was cooled to 25±5°C in 5min and then placed in a precooled bath maintained at -5 to -10°C and stirred for 5hours. The resulting reaction mass was filtered and dried under vacuum at 50°C for 2h. The solid obtained was identified as crystalline Ribociclib succinate Form M7.

Example 2:
Ribociclib succinate (0.5g) was dissolved in a mixture of dimethylsulfoxide (4mL) and tetrahydrofuran (4 mL) at 80±5°C and maintained under strirring for 30min. The resulting clear solution was slowly cooled to 25±5°C in 20min and maintained under stirring at 25±5°C for 30min. The clear solution was further cooled to -5 to -10°C in 15min, added crystalline Ribociclib Succinate Form M7 seeds (5mg) and stirred for 3h at -5 to -10°C. The product obtained was filtered, suck-dried for 30min and then dried under vacuum at 50°C for 12h. The solid obtained was identified as crystalline Ribociclib succinate Form M7.

Example 3:
Ribociclib succinate (0.5g) was suspended in dimethyl sulfoxide (2ml) at 25±5°C. Heated the reaction mass to 80±5°C and stirred for 30min to get clear solution. The resulting clear solution was slowly cooled to 35±5°C and added seeds of crystalline Ribociclib succinate Form M7 (5mg) at 35±5°C and then cooled to 25±5°C and stirred for 1-2h at 25±5°C. Filtered the reaction mass and suck-dried for 30min. The solid obtained was identified as crystalline Ribociclib succinate Form M7.

Process for the preparation of Ribociclib succinate Form M8
Example 4:
Crystalline Ribociclib succinate Form M7 (200mg) obtained in examples 1-3 above was heated in a vacuum tray dryer at 120-130°C for 2-3h. The solid obtained was identified as crystalline Ribociclib succinate Form M8.

Process for the preparation of Crystalline form of Ribociclib
Example 5:
Aqueous sodium hydroxide solution prepared by dissolving 290mg of sodium hydroxide in 50mL of water was precooled at 15±5°C and charged Ribociclib succinate (2g) and stirred the reaction mass for 1h at 20±5°C. Filtered the reaction mass and dried under vacuum at 50°C for 1h. The solid obtained was identified as Ribociclib crystalline Form M1.

Example 6:
Crystalline Ribociclib Form M1 was dried at 130°C under vacuum for 1h and followed by slow cooling to 30°C. The resulting solid was identified as crystalline Ribociclib Form M2.

,CLAIMS:1. Crystalline Ribociclib Form M1 characterized by powder X-ray diffraction pattern having peaks at 6.4, 6.7, 15.5, 16.4, 17.2, 18.4, 21.8 and 23.0 ± 0.2° degrees 2?.

2: The crystalline Ribociclib Form M1 as claimed in claim 1, is prepared comprising the steps of:
a) adding Ribociclib Succinate to a precooled aqueous base,
b) isolating crystalline Ribociclib Form M1.

3. The process as claimed in claim 2, wherein the base is selected from sodium hydroxide, sodium carbonate, potassium hydroxide or potassium carbonate.

4. Crystalline Ribociclib Form M2 characterized by powder X-ray diffraction pattern having peaks at 11.8, 12.2, 12.8, 17.9, 18.8, 20.0, 20.8, 21.2, 22.0, 22.6 and 26.5 ± 0.2° degrees 2?.

5. The crystalline Ribociclib Form M2 as claimed in claim 4, is prepared comprising the steps of:
a) drying crystalline Ribociclib Form M1,
b) isolating crystalline Ribociclib Form M2.
wherein the drying is carried at 130°C followed by cooling to 30°C

6. Crystalline Ribociclib Succinate Form M7 characterized by powder X-ray diffraction pattern having peaks at 13.5, 16.0, 16.8, 18.7, 19.2, 19.5, 21.9 and 24.8 ± 0.2° degrees 2?.

7. The crystalline Ribociclib Succinate Form M7 as claimed in claim 6, is prepared comprising the steps of:
d) dissolving Ribociclib Succinate in an organic solvent or mixture of solvents,
e) optionally seeding with crystalline Ribociclib Succinate Form M7,
f) isolating crystalline Ribociclib Succinate Form M7.

8. The process as claimed in to claim 7, wherein the organic solvent is selected from Dimethyl sulfoxide, tetrahydrofuran, acetone, methanol, ethanol, 1-butanol, 2-butanol, 1-propanol, IPA, ethyl acetate, n-butyl acetatate, n-propyl acetate, isopropyl acetate, acetonitrile, DMF or mixtures thereof and seeding is carried at -5 to -10°C or 35±5°C.

9. Crystalline Ribociclib Succinate Form M8 characterized by powder X-ray diffraction pattern having peaks at 10.0, 16.5, 17.8, 20.4, 20.8 and 21.7 ± 0.2° degrees 2?.

10. The crystalline Ribociclib Succinate Form M8 as claimed in claim 9, is prepared comprising the steps of:
a) heating crystalline Ribociclib Succinate Form M7,
b) isolating crystalline Ribociclib Succinate Form M8.
wherein the heating is carried at about 120-130°C for 2-3hours.