DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No. IN 201941035093 filed on August 30, 2019.
FIELD OF THE INVENTION:
The present invention relates to Ribociclib Succinate monohydrate and its preparation process.

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

US 8415355B2 disclosed Ribociclib and it’s pharmaceutically acceptable salts thereof.
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 20170342075A1 disclosed crystalline mono-succinate form I Ribociclib characterized by XRD peaks.

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

PCT application WO 2018051280A1 disclosed amorphous Ribociclib Succinate, amorphous Ribociclib and amorphous solid dispersion of Ribociclib.

The inventors of the present invention have developed novel crystalline form of Ribociclib Succinate which is stable and suitable for formulation development.

OBJECT AND SUMMARY OF THE INVENTION:

The main object of the present invention is to provide Ribociclib Succinate monohydrate.

In one aspect, the present invention is to provide a crystalline form of Ribociclib Succinate monohydrate is designated as Form M13.

In yet another aspect, the present invention is to provide Ribociclib Succinate monohydrate is characterized by powder X-ray diffraction pattern having peaks at 4.7, 13.0, 19.9 and 22.0 ±0.2° degrees 2?.

In yet another aspect, the Ribociclib Succinate monohydrate is characterized by the powder X-ray diffraction pattern as illustrated in Figure 1.

In yet another embodiment, the present invention relates to a process for the preparation of Ribociclib Succinate mononydate comprising the steps of:
a) suspending Ribociclib, Succinic acid in an organic solvent and water,
b) heating and cooling the reaction mass,
c) isolating Ribociclib Succinate monohydrate.

In yet another embodiment, the present invention relates to a process for the preparation of Ribociclib Succinate monohydrate comprising the steps of:

a) suspending Ribociclib, Succinic acid in an organic solvent,
b) heating and cooling the reaction mass,
c) isolating the solid,
d) drying the solid, and
e) isolating Ribociclib Succinate monohydrate.

Brief description of the figures:
Figure 1: Illustrates the Powder X-ray Diffraction (PXRD) pattern of Ribociclib Succinate monohydate, designated as Form M13.
Figure 2: Illustrates the Differential Scanning Calorimetry (DSC) of Ribociclib Succinate monohydate designated as form M13.
Figure 3: Illustrates the Thermal Gravimetric Analysis (TGA) of Ribociclib Succinate monohydate designated as form M13.

DETAILED DESCRIPTION:

The present invention relates to Ribociclib Succinate monohydrate.

In one embodiment, the Ribociclib Succinate monohydrate is designated as Form M13.

In another embodiment, the present invention relates to Ribociclib Succinate monohydrate is characterized by powder X-ray diffraction pattern having peaks at 13.0, 19.9 and 22.0 ±0.2° degrees 2?.

In yet another embodiment, the present invention relates to Ribociclib Succinate monohydrate characterized by powder X-ray diffraction pattern having further peaks at 4.7, 12.3, 12.6, 16.2, 18.3, 18.5, 19.6, 20.9, 21.3 and 21.6 ±0.2° degrees 2?.

In yet another embodiment, the Ribociclib Succinate monohydrate is characterized by the powder X-ray diffraction pattern as illustrated in Figure 1.

In yet another embodiment, the Ribociclib Succinate monohydrate is characterized by Differential Scanning Calorimetry (DSC) showing an endotherm at 187.12 °C, illustrated in Figure 2.

In yet another embodiment, the Ribociclib Succinate monohydrate is characterized by Thermal gravimetric analysis (TGA) showing a weight loss of 3.552%, illustrated in Figure 3.

In yet another embodiment, the present invention relates to a process for the preparation of Ribociclib Succinate monohydrate comprising the steps of:
a) suspending Ribociclib, Succinic acid in an organic solvent and water,
b) heating and cooling the reaction mass,
c) isolating Ribociclib Succinate monohydrate.

According to the present invention, Ribocicilb and succinic acid may be suspended in an organic solvent selected from alcohols such as methanol, ethanol, isopropanol, isobutanol, Isoamyl alcohol. or esters such as ethyl acetate, butyl acetate, isobutyl acetate, isopropyl acetate and water. The resultant suspension may be heated to about 45 to 55°C and maintained for about 2 to 3 hours followed by cooling to about 20 to 30 °C and maintained for about 15 to 20 hours. The solid obtained may be filtered and dried to obtain Ribociclib Succinate monohydrate.

In yet another embodiment, the present invention relates to a process for the preparation of Ribociclib Succinate monohydrate comprising the steps of:

a) suspending Ribociclib, Succinic acid in an organic solvent,
b) heating and cooling the reaction mass,
c) isolating the solid,
d) drying the solid, and
e) isolating Ribociclib Succinate monohydrate.

According to the present invention, Ribocicilb and succinic acid may be suspended in an organic solvent selected from alcohols such as methanol, ethanol, isopropanol, isobutanol or Isoamyl alcohol. The resultant suspension may be heated to about 45 to 55°C and maintained for about an hour followed by cooling to about 20 to 30°C and maintained for about 15 to 18 hours. The reaction mass may be filtered for solid isolation. [This solid is identified as Ribociclib succinate Form M11 by PXRD]. The solid obtained may be subjected to humid drying at 40 to 50°C by water diffusion method for about 24 to 72 hours to obtain Ribociclib Succinate monohydrate.

According to the present invention humid drying is carried using vaccum tray drier by water diffusion method.

According to the present invention, the Ribociclib Succinate is characterized by monohydrate Coulometry analysis showing water content of 3.05% which corresponds to Monohydrate.

In yet another embodiment, the present invention relates to a pharmaceutical composition comprising Ribociclib Succinate monohydate and a pharmaceutically acceptable excipient.

Instrumentation Details
Powder X-ray Diffraction (PXRD)
The PXRD measurements were carried out using PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of ?/? configuration and X'Celerator detector. The Cu- anode X-ray tube is operated at 40kV and 30mA. The experiments were conducted over the 2? range of 2.0º-50.0°, 0.03° step size and 50 seconds step time.

Differential Scanning Calorimetry (DSC)
The DSC measurements were carried out on DSCQ2000 of TA instruments. The experiments were performed at a heating rate of 10.0°C/min over a temperature range of 30°C-250°C purging with nitrogen at a flow rate of 50ml/min. Standard aluminum crucibles covered by lids with three pin holes were used.

Thermo Gravimetric Analysis (TGA)
TGA was recorded using the instrument TGAQ5000 IR of TA instruments. The experiments were performed at a heating rate of 10.0°C/min over a temperature range of 30°C-200°C purging with nitrogen at a flow rate of 25ml/min.

Indicative stability
In yet another embodiment, the physical and chemical stability of Ribociclib Succinate Form M13 was determined by storing the samples at 40°C/75% relative humidity (RH) and 25°C/60% relative humidity (RH) for six months. The samples were analyzed by PXRD and purity by HPLC. The results are shown in Table 1. The Ribociclib Succinate Form M13 was found to be physically and chemically stable 25°C/60% relative humidity (RH) and 40°C/75% relative humidity (RH) conditions up to six months.
Table 1
Conditions/ Polymorph Ribociclib Succinate
Form M13
PXRD HPLC purity
at 25°C/60% RH
Initial Crystalline form 99.8
1 months Stable 99.8
2 months Stable 99.7
3 months Stable 99.8
6 months Stable 99.7
at 40°C/75% RH
Initial Crystalline form 99.8
1 months Stable 99.8
2 months Stable 99.7
3 months Stable 99.7
6 months Stable 99.6

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

EXAMPLES:
Processes for the preparation of novel crystalline form M13 of Ribociclib Succinate (Monohydrate)
Example 1:
Ribociclib free base (0.5g), succinic acid (0.142g) and isobutanol (10mL) were charged into a round bottom flask. The suspension was stirred for 15 min at 25±5°C. The suspension was heated to 50±2°C and stirred for 1h at 50±2°C. The suspension was cooled to 25-30°C and stirred for 16h at 25±5°C. The reaction mass was filtered and identified as Ribociclib succinate Form M11 by PXRD. The wet material was further subjected to humid drying at 40-50°C for 24-72h in Vacuum tray dryer by water diffusion method. The solid obtained was identified as Ribociclib succinate monohydrate designated as crystalline Form M13 of Ribociclib Succinate. Yield=0.5g

Example 2:
Ribociclib free base (1g), succinic acid (0.285g), ethyl acetate (15mL) and water (165mg) were charged into a round bottom flask at 25±2°C. The suspension was stirred for 10 min at 25±2°C. The suspension was heated to 50±2°C and stirred for 80minutes at 50±2°C. The suspension was cooled to 25±2°C and stirred for 20 hours at 25±2°C. The reaction mass was filtered and washed with ethyl acetate (1mL). The wet material was further dried at 40-45°C under vacuum for 15h. The solid obtained was identified as Ribociclib succinate monohydrate designated as crystalline Form M13 of Ribociclib Succinate. Yield: 0.9g

Example 3:
Ribociclib free base (5g), succinic acid (1.43g), ethyl acetate (75mL) and water (828mg) were charged into a round bottom flask at 25±2°C. The suspension was stirred for 10 min at 25±2°C. The suspension was heated to 50±2°C and stirred for 2h at 50±2°C. The suspension was cooled to 25±2°C and stirred for 17h at 25±2°C. The reaction mass was filtered and washed with ethyl acetate (2.5mL). The wet material was further dried at 40±2°C under vacuum for 15h. The solid obtained was identified as Ribociclib succinate monohydrate designated as crystalline Form M13 of Ribociclib Succinate. Yield: 5.2g

,CLAIMS:1. Crystalline Ribociclib Succinate monohydrate.
2. The Crystalline Ribociclib Succinate monohydrate as claimed in claim 1, is designated as Form M13 and characterized by powder X-ray diffraction pattern having peaks at 4.7, 12.3, 13.0, 12.6, 16.2, 18.3, 18.5, 19.6, 19.9, 20.9, 21.3, 21.6 and 22.0 ±0.2° degrees 2?.
3. The Ribociclib Succinate monohydate as claimed in claim 2, is prepared comprising the steps of:
a) suspending Ribociclib, Succinic acid in an organic solvent and water,
b) heating and cooling the reaction mass,
c) isolating Ribociclib Succinate monohydate.

4. The process as claimed in claim 3, wherein the organic solvent is selected from alcohols such as methanol, ethanol, isopropanol, isobutanol, Isoamyl alcohol. or esters such as ethyl acetate, butyl acetate, isobutyl acetate, isopropyl acetate and water or mixtures thereof.

5. The process as claimed in claim 3, wherein the reaction mixiture is heated to 45 to 55°C and cooled to 20 to 30 °C

6. The Ribociclib Succinate monohydate as claimed in claim 1, is prepared comprising the steps of:
a) suspending Ribociclib, Succinic acid in an organic solvent,
b) heating and cooling the reaction mass,
c) isolating the solid,
d) drying the solid, and
e) isolating Ribociclib Succinate monohydrate.

7. The process as claimed in claim 6, wherein the organic solvent is selected from alcohols such as methanol, ethanol, isopropanol, isobutanol, Isoamyl alcohol. or esters such as ethyl acetate, butyl acetate, isobutyl acetate, isopropyl acetate and water.

8. The process as claimed in claim 6, wherein the drying is carried in a humid drying at 40-50°C for 24-72h.

8. The Ribociclib Succinate monohydrate as claimed in claim 1 has water content of 3.05%.

9. The Ribociclib Succinate monohydate as claimed in claim 1, is characterized by Differential Scanning Calorimetry (DSC) showing an endotherm at 187.12 °C.

10. A pharmaceutical composition comprising Ribociclib succinate monohydate and a pharmaceutically acceptable salt.