DESC:FIELD OF THE INVENTION
The present invention relates to crystalline Ribociclib succinate polymorph Form C and process for preparation thereof.

BACKGROUND OF THE INVENTION
Ribociclib, chemically known as 7-Cyclopentyl-N,N-dimethyl-2-{[5-(1-piperazinyl)-2-pyridinyl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (Formula I) is a moderate to strong CYP3A4 inhibitor used for the treatment of certain kinds of breast cancer.

Ribociclib is sold under the brand name Kisqali®. Ribociclib is the only CDK4/CDK6 inhibitor with a proven benefit on overall survival across all three phase III trials of the MONALEESA clinical program with different endocrine therapy partners, regardless of menopausal status or line of therapy. Ribociclib is used in form of its succinate salt.

US8415355B2 discloses Ribociclib and its pharmaceutically acceptable salts as selective inhibitors of CDK4 over other cyclin dependent kinases.

US9193732 discloses succinate salt of 7-Cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo [2,3-d]pyrimidine-6-carboxylic acid dimethylamide (Formula II) in the form of non-hydrate, hydrate forms, or mixtures thereof and to the process for preparation thereof. US’732 disclose a process for preparation of said succinate salt of Ribociclib as shown in scheme 1 below:

US20230042479A1
US20230042479A1 discloses crystalline form(s) of succinate salt(s) of 7-Cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d] pyrimidine-6-carboxylic acid dimethylamide in the form of Modification E, F, HA, or HB. The crystalline form of Modification E characterized by an X-ray powder diffraction pattern with peaks at 11.0°+/-0.2°, 13.0°+/-0.2°, and 17.2°+/-0.2° (CuKa I=1.5406 Å). The process of preparing the crystalline form of Modification E includes (a) providing a solution of succinic acid in a first organic solvent at a second temperature ranging between about 70°C and about 85°C, (b) providing a solution of free base of Ribociclib in a second organic solvent at a third temperature ranging between about 60°C and about 85°C, (c) transferring the solution of free base of Ribociclib to a crystallization vessel;(d) adding the solution of succinic acid to said crystallization vessel at a fourth temperature ranging between about 60° C. and about 85° C, (e) immediately after the addition in (d) is complete, adding seed crystals of pure Modification E to obtain a turbid mixture; (f) cooling the turbid mixture to a fifth temperature ranging between about 0°C and about 20°C to obtain Modification E; (g) optionally separating Modification E from the mixture and optionally rinsing the filtered solid with an organic solvent; and (h) optionally drying Modification E obtained from step (g). The pharmaceutical composition disclosed in US’479 comprises about 90% of crystalline form of Modification E. US’479 disclose Modification F which is an anhydrous Ribociclib hemisuccinate; Modification HB which is a Ribociclib succinate dehydrate, Modification HA is a hydrated form of Ribociclib hemisuccinate (e.g., hemihydrate, or monohydrate, or a hydrate with a ratio of ribociclib:water ranging between 2:1 and 1:1 or between 3:1 and 2:1, or between 3:2 and 2:1).

Ribociclib succinate has been classified according to the BCS as a poorly soluble drug. Further, conversion of one polymorphic form in to another polymorphic form is generally unfavorable in pharmaceutical dosage forms often resulting in different hygroscopicity, dissolution and pharmacokinetic properties consequently having adverse effect on its bioavailability. Active agents having different interchangeable polymorphs may further lead to regulatory and commercial disadvantages since they very often do not fulfill the requirements of the corresponding regulation authorities such as the FDA and EMEA. Hence, there exists a need to provide stable crystalline form of Ribociclib succinate salt.
Developing new polymorphic forms of a pharmaceutically useful compound can provide an opportunity to improve the performance characteristics of a pharmaceutical product such as stability, shelf life, dissolution profile, bioavailability, etc.

The present inventors envisaged that there is a scope to provide new polymorph form of Ribociclib succinate with improved stability, the process thereof which remains the objective of the present invention.

SUMMARY OF THE INVENTION
In accordance with the above, the present invention provides a novel crystalline form of Ribociclib succinate with improved stability and process for preparation thereof.

In an aspect, the present invention provides crystalline Ribociclib succinate Form C characterized by PXRD having peaks at 8.79, 10.91, 12.93, 13.68, 19.9 and 24.78 ±2?? as shown in Figure 1.

The crystalline Ribociclib succinate Form C of the present invention is further characterized by PXRD having peaks at 7.80, 12.30, 14.95, 15.60, 21.05, 21.36, 21.95 and 22.94±2??.

In another aspect, the crystalline Ribociclib succinate Form C of the present invention is characterized by Differential Scanning Calorimetry (DSC) with an endotherm having an onset temperature at about 209.94?C and a peak at about 212.59?C.

In another aspect, the crystalline Ribociclib succinate Form C of the present invention is characterized by Thermo gravimetric analysis (TGA) exhibiting a weight loss of about 0.1% up to 240?C as shown in Figure 3.

In an aspect, the present invention discloses crystalline Ribociclib succinate Form C characterized by 13CSSNMR spectrum having characteristic peaks at 30.7, 32.1, 45.81, 48.66, 111.8, 132.28, 139.58, 153.89, 173.25 and 182.23 PPM as shown in Figure 4.

In an aspect, the present invention relates to Ribociclib succinate Form C characterized by Raman spectrum having characteristic peaks at 1549.49, 1497.76, 1340.35, 1312.26, 1253.19, 1053.32, 677.2 cm-1 as shown in Figure 5.

In yet another aspect, the present invention provides a process for preparation of Ribociclib succinate Form- C comprising;
i. Providing a solution of Ribociclib in an organic solvent and optionally heating the mixture to a temperature of 70-80ºC , maintaining the mixture at same temperature for 30-40mins;
ii. Optionally filtering the reaction mass and heating to a temperature of 70-80ºC until clear solution is obtained;
iii. Preparing the solution of succinic acid in an organic solvent at a temperature of 65-75ºC;
iv. Adding slowly the succinic acid solution of step (ii) to the solution of step (i) and heating the mix to a temperature of 70-80ºC and maintaining the temperature for 1-2 hours, cooling and filtering to obtain the desired product.

In an alternate aspect, the process step comprises seeding with Ribociclib succinate Form -C seed material prior to addition of succinic acid solution to the solution of the free base of step (i).
Accordingly, the process step comprises;
i. Providing a solution of Ribociclib in an organic solvent and heating the mixture to a temperature of 70-80ºC, maintaining the mixture at same temperature for 30-40mins until clear solution is obtained;
ii. Adding Ribociclib succinate Form C seed material to the solution of step (i) and stirring at 65-75ºC;
iii. Preparing the solution of succinic acid in an organic solvent at a temperature of 65-75ºC;
iv. Adding slowly the succinic acid solution of step (iii) to the solution of step (i) and heating the mix to a temperature of 70-80ºC and maintaining the temperature for 1-2 hours, cooling and filtering to obtain the desired product.

In another aspect, the present invention is directed to a pharmaceutical composition comprising Ribociclib succinate Form-C along with pharmaceutically acceptable excipients.

DESCRIPTION OF DRAWINGS
Figure 1: Depicts PXRD of Ribociclib succinate Form C.
Figure 2: Depicts DSC of Ribociclib succinate Form C
Figure 3: Depicts TGA of Ribociclib succinate Form C
Figure 4: Depicts 13CSSNMR of Ribociclib succinate Form-C.
Figure 5: Depicts Raman spectra of Ribociclib succinate Form-C.
Figure 6: Depicts comparative powder dissolution data of Ribociclib succinate Form C vs Form A in 0.01N HCl media.
Figure 7: Depicts comparative powder dissolution data of Ribociclib succinate Form C vs Form A in water media.

DETAILED DESCRIPTION OF THE INVENTION
The features of the present invention is described below in the various preferred and optional embodiments, however, should not be construed as limiting the scope of the invention.

Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.

Unless stated to the contrary, any of the words “contains”, “containing”, "including," "includes," "comprising," and "comprises" mean "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention.

Further, words like “a”, “an”, “at least” and “the” should be construed to not only cover singular quantities but also plural quantities of the elements immediately following them.

The present invention discloses a novel crystalline form of Ribociclib succinate which is stable both at low temperature and under accelerated conditions and comparable dissolution profile with Ribociclib succinate Form A.

In an embodiment, the present invention relates to a novel crystalline Ribociclib succinate Form C characterized by PXRD having peaks at 8.79, 10.91, 12.93, 13.68, 19.9 and 24.78 ±2?? as shown in Figure 1.

The crystalline Ribociclib succinate Form C of the present invention is further characterized by PXRD having peaks at 7.80, 12.30, 14.95, 15.60, 21.05, 21.36, 21.95 and 22.94±2??.

In another embodiment, the crystalline Ribociclib succinate Form C is characterized by Differential Scanning Calorimetry (DSC) with an endotherm having an onset temperature at about 209.94?C and a peak at about 212.59?C. as shown in Figure 2.

In yet another embodiment, the crystalline Ribociclib succinate Form C is characterized by Thermogravimetric analysis (TGA) exhibiting a weight loss of about 0.1% up to 240?C as shown in Figure 3.
In an embodiment, the present invention relates to crystalline Ribociclib succinate Form C characterized by 13CSSNMR spectrum having characteristic peaks at 30.7, 32.1, 45.81, 48.66, 111.8, 132.28, 139.58, 153.89, 173.25 and 182.23 PPM as shown in Figure 4.

In an aspect, the present invention relates to Ribociclib succinate Form C characterized by Raman spectrum having characteristic peaks at 1549.49, 1497.76, 1340.35, 1312.26, 1253.19, 1053.32, 677.2 cm-1 as shown in Figure 5.

In another embodiment, the present invention discloses a process for preparation of Ribociclib succinate Form-C comprising;
i. Providing a solution of Ribociclib in an organic solvent and heating the mixture to a temperature of 70-80ºC, maintaining the mixture at same temperature for 30-40mins;
ii. Optionally filtering the reaction mass of step (i) and heating to a temperature of 70-80ºC until clear solution is obtained;
iii. Preparing the solution of succinic acid in an organic solvent at a temperature of 65-75ºC;
iv. Adding slowly the succinic acid solution of step (ii) to the solution of step (i) and heating the mix to a temperature of 70-80ºC and maintaining the temperature for 1-2 hours, cooling and filtering to obtain the desired product.

According to the above process, Ribociclib base was dissolved in a suitable solvent and the mixture was heated to a temperature ranging between 70-80?C and the mixture was maintained at said temperature for 30-40 minutes until a clear solution was obtained. The reaction mass was optionally filtered and the filtered reaction mass was further heated to a temperature of 70-80ºC until clear solution was obtained. In a separate flask the solution of succinic acid was prepared in a suitable solvent at a temperature of 65-75ºC followed by slow addition to the clear solution of Ribociclib base. The mixture was heated to a temperature of 70-80ºC and maintained the temperature for about 1-2 hours. The reaction mass was cooled to room temperature and stirred at room temperature for about 1 hr. The resultant material was filtered and washed with 10ml of suitable solvent, dried to get Ribociclib succinate Form C.

In an alternate embodiment, the process step comprises seeding with Ribociclib succinate Form -C seed material prior to addition of succinic acid solution to the solution of the free base of step (i).
Accordingly, the process step comprises;
i. Providing a solution of Ribociclib in an organic solvent and heating the mixture to a temperature of 70-80ºC , maintaining the mixture at same temperature for 30-40mins until clear solution is obtained;
ii. Adding Ribociclib succinate Form C seed material to the solution of step (i) and stirring at 65-75ºC;
iii. Preparing the solution of succinic acid in an organic solvent at a temperature of 65-75ºC;
iv. Adding slowly the succinic acid solution of step (iii) to the solution of step (i) and heating the mix to a temperature of 70-80ºC and maintaining the temperature for 1-2 hours, cooling and filtering to obtain the desired product.

Accordingly, the alternate process of the present invention comprises dissolving Ribociclib base in a suitable solvent and heating the mixture to a temperature ranging between 70-80?C and maintaining the mixture at said temperature for 30-40 minutes until a clear solution was obtained. This was followed by seeding the reaction mixture with Ribociclib succinate Form C seed material and stirring at 65-75ºC. Preparing the solution of succinic acid in an organic solvent in another flask at a temperature of 65-75ºC and adding slowly said succinic acid solution to the clear solution of Ribociclib base and heating the mixture to a temperature of 70-80ºC and maintaining the temperature for 1-2 hours, cooling filtering to obtain the desired product.

The solvent used in the process of the present invention is selected from water, lower alcohols (C1-C5), ketones, ethers or esters alone or mixture thereof.

The crystalline Ribociclib succinate Form C prepared by the present process is in anhydrous form

In an embodiment, the crystalline Ribociclib succinate Form C prepared by the present process is free from other polymorphic impurities, wherein said crystalline Ribociclib succinate Form C is obtained in powder form with HPLC purity >99.8%.

In an embodiment, the stability of crystalline Ribociclib succinate Form C of the present invention was evaluated as shown in the table 1 below. The crystalline Ribociclib succinate Form C was stable as a pale brown powder for a period of six months when stored at 25°C/60%RH with the water content of 0.37%w/w.

In another embodiment, the crystalline Ribociclib succinate Form C was observed to be stable as a pale brown powder for a period of six months when stored at accelerated conditions of 40°C/75%RH with the water content of 0.5%w/w.

In yet another embodiment, the crystalline Ribociclib succinate Form C was observed to be stable as a pale brown powder for a period of six months when stored at 2-8?C with the water content of 0.3%w/w.

The crystalline Ribociclib succinate Form C of the present invention obtained by the present process is found to be a very stable crystal lattice which is adequately stable to handle and store for longer time without any significant or measurable change in its morphology and physicochemical characteristics evident from its dissolution profile.

The crystalline Ribociclib succinate Form C of the present invention exhibited comparable dissolution with crystalline Ribociclib succinate Form A in 0.01N HCl media as shown in the table 2 and Fig 6.

The crystalline Ribociclib succinate Form C of the present invention exhibited comparable dissolution with crystalline Ribociclib succinate Form A in water media as shown in the table 3 and Fig 7.

Thus the present invention provides a stable crystalline Ribociclib succinate Form C which offers advantages in terms of storage, shelf life and favorable impurity profile.

Solubility is one of the important parameters to achieve desired concentration of drug in systemic circulation for achieving required pharmacological response. Poorly water soluble drugs often require high doses in order to reach therapeutic plasma concentrations after oral administration. Drug solubility thereby its oral bio-availability remains one of the most challenging aspects of drug development process especially for oral-drug delivery system. The poor solubility and low dissolution rate of poorly water soluble drugs in the aqueous gastrointestinal fluids often cause insufficient bioavailability.

The present crystalline Ribociclib succinate Form C which is stable, free of process related impurities and having comparable dissolution profile to the known Ribociclib succinate Form A inherently, increases the solubility of said crystalline form, which plays a major role for enhancement of drug dissolution rate in solid oral dosage forms.

In yet another embodiment, the present invention is directed to a pharmaceutical composition comprising Ribociclib succinate Form-C along with pharmaceutically acceptable excipients.

In another embodiment, the present invention provides the use of the Ribociclib succinate Form-C or its pharmaceutical composition for inhibiting cyclin dependent kinases.

In another embodiment, the present invention relates to a method of treating a disease which responds to an inhibition of cyclin dependent kinases, (in particular, cyclin dependent kinases selected from CDK1, CDK2, CDK3, CDK4, CDK5, CDK6 and CDK9) comprising the step of administering to a subject in need of such treatment a therapeutically effective amount of Ribociclib succinate Form-C.

Specific embodiments of the invention will now be demonstrated by reference to the following examples. It should be understood that these examples are disclosed solely by way of illustrating the invention and should not be taken in any way to limit the scope of the present invention.

Processes for the preparation of Ribociclib succinate Form –C

Example 1:
Charged Ribociclib (20 g) and IPA (800 ml) into the round bottomed flask. The resulted suspension was heated to 78-80°C and the reaction mass was maintained at same temperature for 30-40 min. The reaction mass was clarified through filter paper and the clear MLR was collected. Above MLR was taken into round bottomed flask and heated to 70°C. In a separate flask 5.82 gm of succinic acid was dissolved in 100ml of IPA at 65°C. Succinic acid solution was slowly added to above Ribociclib reaction mass. The resultant suspension was heated to 70°C and the reaction mass was maintained at same temperature for 1-2 hr. The reaction mass was cooled to room temperature and stirred at room temperature for 1 hr. The resultant material was filtered and washed with 10 ml of IPA, dried at 55°C for 4-6 hrs to get Ribociclib succinate Form –C.
Yield: 23.0g

Example 2:
Charged Ribociclib (50 g) and IPA (2000 ml) into the round bottomed flask. The resulted suspension was heated to 70°C and the reaction mass was maintained at same temperature for 30-40 min for clear dissolution. 0.1gm of Ribociclib succinate form C seed material was added and stirred at 65-70°C for 2-3 min. In a separate flask 14.92 gm of succinic acid was dissolved in 254 ml of IPA at 40°C. Succinic acid solution was slowly added to the above Ribociclib reaction mass. The resultant suspension was heated to 70°C and the reaction mass was maintained at same temperature for 2-3 hrs. The reaction mass was cooled to room temperature and stirred at room temperature for 1 hr. The resultant material was filtered and washed with 50 ml of IPA, dried at 60°C for 1 hr to get Ribociclib succinate Form –C.
Yield: 60.0g

Example 3:
Charged Ribociclib (370 g) and Ethanol (2960ml, 8 vol) into the reactor. In a separate flask 105.4gm of succinic acid was dissolved in 1406 ml of Ethanol and 74ml of water mixture (3.8:02 ratio, 4 vol) at room temperature (RT). Succinic acid solution was slowly added to the above Ribociclib reaction mass at RT. 1.85gms of Ribociclib succinate form C seed material was added and stirred at RT. The resultant suspension was heated to 73±3°C and the reaction mass was maintained at same temperature for 2-3 hrs. The reaction mass was cooled to room temperature and stirred at room temperature for 1 hr. The resultant material was filtered and washed with 370 ml of Ethanol, dried at 60°C for 8-10 hrs to get Ribociclib succinate Form –C.
Dry weight=432.0g

Example 4: Stability study of Ribociclib succinate Form C

Table 1:
Ribociclib succinate form C - 6 months stability
Limits Description Water content (% w/w) XRD Purity by HPLC
Initial Pale brown colour Powder 0.18 Form C 99.86
40°C/75%RH (6 months) Pale brown colour Powder 0.5 Form C 99.84
25°C/60%RH (6 months) Pale brown colour Powder 0.37 Form C 99.85
2-8°C (6 months) Pale brown colour Powder 0.3 Form C 99.86

Example 5: Comparative dissolution data of Ribociclib succinate Form C with crystalline Form A

SOLUBILITY PROCESS:
900 mg of sample was added to 900 ml of selected media and stirred in a dissolution apparatus at 37? for 1 hour. At specified time intervals, approximately 5 ml of the solution was taken and filtered through a 0.45 µm filter. The filtrate was then analysed spectrophotometrically using HPLC to determine the concentration of Ribociclib succinate.
Results:
The comparative powder dissolution data of Ribociclib succinate Form C vs Form A in 0.01N HCl media is depicted in Table 2 and Figure 6.
Table 2
Dissolution media: 0.01N HCL (Volume 900 ml),
Apparatus: USP -II, Paddle, RPM: 50
Powder dissolution: Form A vs Form C
Time (min) Form A Form C T/ R
5 0.914 0.88 0.96
10 0.899 0.837 0.93
15 0.887 0.85 0.96
20 0.896 0.885 0.98
30 0.911 0.857 0.94
45 0.881 0.875 0.99
60 0.901 0.881 0.97

The comparative powder dissolution data of Ribociclib succinate Form C vs Form A in water media is depicted in Table 3 and figure 7.
Table 3
Dissolution media: water (Volume 900 ml),
Apparatus: USP -II, Paddle, RPM: 50
Powder dissolution: Form A vs Form C
Time (min) Form A Form C T/ R
5 0.689 0.71 1.03
10 0.741 0.733 0.99
15 0.774 0.787 1.01
20 0.778 0.824 1.05
30 0.861 0.834 0.97
45 0.89 0.875 0.98
60 0.862 0.857 0.99

It will be understood that the above description is intended to be illustrative and not restrictive. The embodiments will be apparent to those in the art upon reviewing the above description. The scope of the invention should therefore, be determined not with reference to the above description but should instead be determined by the appended claims along with full scope of equivalents to which such claims are entitled.
,CLAIMS:1. Crystalline Ribociclib succinate Form C characterized by X-ray powder diffraction pattern comprising characteristic peaks at 8.79, 10.91, 12.93, 13.68, 19.9 and 24.78 ±2??.

2. The Crystalline Ribociclib succinate Form C as claimed in claim 1, having the X-ray powder diffraction pattern comprising characteristic peaks at 7.80, 12.30, 14.95, 15.60, 21.05, 21.36, 21.95 and 22.94±2??.

3. The Crystalline Ribociclib succinate Form C as claimed in claim 1, characterized by Differential Scanning Calorimetry (DSC) with an endotherm having an onset temperature at about 209.94?C and a peak at about 212.59?C.

4. The Crystalline Ribociclib succinate Form C as claimed in claim 1, characterized by Thermogravimetric analysis (TGA) exhibiting a weight loss of about 0.1% up to 240?C.

5. The Crystalline Ribociclib succinate Form C as claimed in claim 1, characterized by13CSSNMR having characteristic peaks at 30.7, 32.1, 45.81, 48.66, 111.8, 132.28, 139.58, 153.89, 173.25 and 182.23 PPM.

6. The Crystalline Ribociclib succinate Form C as claimed in claim 1, characterized by Raman spectrum having characteristic peaks at 1549.49, 1497.76, 1340.35, 1312.26, 1253.19, 1053.32, 677.2 cm-1.

7. The Crystalline Ribociclib succinate Form C as claimed in claim 1, wherein said Crystalline Ribociclib succinate Form C is in anhydrous form.

8. The Crystalline Ribociclib succinate Form C as claimed in claim 1, prepared by the process comprising;
i. Providing a solution of Ribociclib in an organic solvent and heating the mixture to a temperature of 70-80ºC, maintaining the mixture at same temperature for 30-40mins;
ii. Optionally filtering the reaction mass of step (i) and heating to a temperature of 70-80ºC until clear solution is obtained;
iii. Preparing the solution of succinic acid in an organic solvent at a temperature of 65-75ºC;
iv. Adding slowly the succinic acid solution of step (iii) to the solution of step (i) and heating the mix to a temperature of 70-80ºC and maintaining the temperature for 1-2 hours, cooling and filtering to obtain the desired product.

9. The Crystalline Ribociclib succinate Form C as claimed in claim 8, wherein the solvent is selected from water, lower alcohols (C1-C5), ketones, ethers or esters alone or mixture thereof.

10. The Crystalline Ribociclib succinate Form C as claimed in claim 8, wherein the process may comprise seeding with Ribociclib succinate Form C seed material.

11. The Crystalline Ribociclib succinate Form C as claimed in claim 8, the process comprising;
i. Providing a solution of Ribociclib in an organic solvent and heating the mixture to a temperature of 70-80ºC, maintaining the mixture at same temperature for 30-40mins until clear solution is obtained;
ii. Adding Ribociclib succinate Form C seed material to the solution of step (i) and stirring at 65-75ºC;
iii. Preparing the solution of succinic acid in an organic solvent at a temperature of 65-75ºC;
iv. Adding slowly the succinic acid solution of step (iii) to the solution of step (i) and heating the mix to a temperature of 70-80ºC and maintaining the temperature for 1-2 hours, cooling and filtering to obtain the desired product.

12. The Crystalline Ribociclib succinate Form C as claimed in claim 11, wherein the solvent is selected from water, lower alcohols (C1-C5), ketones, ethers or esters alone or mixture thereof.

13. A pharmaceutical composition comprising Ribociclib succinate Form-C as claimed in any one of the preceding claims along with pharmaceutically acceptable excipients.