WO2019111160A1

WO2019111160A1 - Crystalline forms of ribociclib succinate

Info

Publication number: WO2019111160A1
Application number: PCT/IB2018/059641
Authority: WO
Inventors: Anu Arya; Chandra Has Khanduri
Original assignee: Sun Pharmaceutical Industries Ltd
Current assignee: Sun Pharmaceutical Industries Ltd
Priority date: 2017-12-04
Filing date: 2018-12-04
Publication date: 2019-06-13
Anticipated expiration: 2020-06-04

Abstract

The present invention relates to crystalline Forms S1 and S2 of ribociclib succinate, processes for their preparation, a pharmaceutical composition comprising these crystalline forms, and their use for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.

Description

CRYSTALLINE FORMS OF RIBOCICLIB SUCCINATE

Field of the Invention

The present invention relates to crystalline Forms S 1 and S2 of ribociclib succinate, processes for their preparation, pharmaceutical compositions comprising these crystalline forms, and their use for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.

Background of the Invention

Ribociclib succinate chemically is 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), represented by Formula I.

Formula I

Ribociclib is a kinase inhibitor which is approved in United States as ribociclib succinate for use in combination with an aromatase inhibitor, as an initial endocrine -based therapy for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2) -negative advanced or metastatic breast cancer.

U.S. Patent No. 8,415,355 describes a process for the preparation of ribociclib. U.S. Patent No. 9,193,732 discloses crystalline forms of ribociclib succinate and processes thereof.

PCT Publication No. W02016/0091221 discloses crystalline Form A of ribociclib hemi-succinate and crystalline Form I of ribociclib monosuccinate and their processes.

There is a need in the art to develop new polymorphic forms of ribociclib succinate. Summary of the Invention

The present invention relates to crystalline Forms S 1 and S2 of ribociclib succinate, processes for their preparation, pharmaceutical compositions comprising these crystalline forms, and their use for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. The crystalline Forms S 1 and S2 of ribociclib succinate of the present invention are stable.

Brief Description of the Drawings

Figure 1 depicts an X-Ray Powder Diffraction (XRPD) pattern of crystalline Form Sl of ribociclib succinate.

Figure 2 depicts a Differential Scanning Calorimetry (DSC) thermogram of crystalline Form Sl of ribociclib succinate.

Figure 3 depicts an Infra-red (IR) spectrum of crystalline Form Sl of ribociclib succinate.

Figure 4 depicts Thermogravimetric analysis (TGA) of crystalline Form Sl of ribociclib succinate.

Figure 5 depicts an X-Ray Powder Diffraction (XRPD) pattern of crystalline Form S2 of ribociclib succinate.

Figure 6 depicts a Differential Scanning Calorimetry (DSC) thermogram of crystalline Form S2 of ribociclib succinate.

Figure 7 depicts an Infra-red (IR) spectrum of crystalline Form S2 of ribociclib succinate.

Detailed Description of the Invention

The term“about,” as used herein, refers to any value which lies within the range defined by a number up to ±10% of the value.

The term“ambient temperature,” as used herein, refers to the temperature in the range of 25 °C to 35°C.

The term“contacting,” as used herein, refers to dissolving, slurrying, stirring, suspending, or combinations thereof.

A first aspect of the present invention provides a crystalline Form Sl of ribociclib succinate. In an embodiment, the crystalline Form S 1 of ribociclib succinate is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at d-spacing’s of about 6.8, 4.7, 4.4, 4.2, 3.9 A, and further characterized by additional peaks at d-spacing’s of about 8.1, 6.5, 4.2, 4.0, and 3.0 A. In further embodiments, the present invention provides for crystalline form Sl in the form of hydrates, non-hydrates or mixtures thereof.

In an embodiment, the crystalline Form S 1 of ribociclib succinate is characterized by a differential scanning calorimetry (DSC) thermogram having an endothermic peak at about 212.2°C.

In a preferred embodiment, the crystalline Form S 1 of ribociclib succinate is characterized by an XRPD pattern substantially as depicted in Figure 1, a DSC thermogram substantially as depicted in Figure 2, an IR absorption spectrum substantially as depicted in Figure 3, or a TGA substantially as depicted in Figure 4.

A second aspect of the present invention provides a process for the preparation of the crystalline Form Sl of ribociclib succinate comprising contacting ribociclib succinate with a solvent.

Ribociclib succinate, to be used as a starting material, for the preparation of the crystalline Form S 1 of ribociclib succinate may be obtained by methods known in the literature such as those disclosed in U.S. Patent No. 9,193,732.

In an embodiment, water may be added with the solvent.

In another embodiment, seeding may be carried out with crystal seed of the crystalline Form Sl of ribociclib succinate.

Crystalline Form Sl of ribociclib succinate is prepared by contacting ribociclib succinate with a solvent. The solvent is selected from alcohols, sulfoxides, ketones, nitriles, aromatic hydrocarbons, ethers, water mixtures thereof. The solvent may also be selected from mixture of these solvents with water. Examples of alcohols include ethanol, n-propanol, iso-propanol, n-butanol, sec-butanol, tert-butanol, and n-pentanol. In a preferred embodiment, the solvent is selected from mixture of alcohol and water. In yet another preferred embodiment, the solvent is selected from alcohols, water, and mixtures thereof. An example of sulfoxide is dimethylsulfoxide. Examples of ketones include acetone, methyl ethyl ketone, and methyl isobutyl ketone. An example of nitrile is acetonitrile. Examples of aromatic hydrocarbon include toluene and xylene. Examples of ethers include methyl tert- butyl ether, tetrahydrofuran, l,4-dioxane, ethyl methyl ether, diethyl ether, diisopropyl ether, and anisole.

In one embodiment, ribociclib succinate is contacted with an alcohol solvent. In another embodiment, ribociclib succinate is contacted with n-propanol. In a preferred embodiment, ribocilcib succinate is contacted with a mixture of n-propanol and water. In another embodiment, ribociclib succinate is contacted with iso-propanol. In a preferred embodiment, ribociclib succinate is contacted with a mixture of iso-propanol and water. In another embodiment, ribociclib succinate is contacted with ethanol. In a preferred embodiment, ribociclib succinate is contacted with a mixture of ethanol and water. In another embodiment, ribociclib succinate is contacted with sec-butanol. In a preferred embodiment, ribociclib succinate is contacted with a mixture of sec-butanol and water. In another embodiment, ribociclib succinate is contacted with n-butanol. In a preferred embodiment, ribociclib succinate is contacted with a mixture of n-butanol and water. In another embodiment, ribociclib succinate is contacted with tert-butanol. In a preferred embodiment, ribociclib succinate is contacted with a mixture of tert-butanol and water. In another embodiment, ribociclib succinate is contacted with a sulfoxide solvent. In another embodiment, ribociclib succinate is contacted with dimethylsulfoxide. In another embodiment, ribociclib succinate is contacted with a mixture of a sulfoxide and a nitrile solvent. In a preferred embodiment, ribociclib succinate is contacted with a mixture of dimethylsulfoxide and acetonitrile. In another embodiment, ribociclib succinate is contacted with a ketone solvent. In another embodiment, ribociclib succinate is contacted with acetone. In a preferred embodiment, ribociclib succinate is contacted with a mixture of acetone and water. In another embodiment, ribociclib succinate is contacted with methyl ethyl ketone. In a preferred embodiment, ribociclib succinate is contacted with a mixture of methyl ethyl ketone and water. In another embodiment, ribociclib succinate is contacted with methyl isobutyl ketone. In a preferred embodiment, ribociclib succinate is contacted with a mixture of methyl isobutyl ketone and water. In another embodiment, ribociclib succinate is contacted with anisole. In a preferred embodiment, ribociclib succinate is contacted with a mixture of anisole and water. In another embodiment, ribociclib succinate is contacted with a nitrile solvent. In another embodiment, ribociclib succinate is contacted with acetonitrile. In a preferred embodiment, ribociclib succinate is contacted with a mixture of acetonitrile and water. In another embodiment, ribociclib succinate is contacted with an aromatic hydrocarbon solvent. In another embodiment, ribociclib succinate is contacted with toluene. In a preferred embodiment, ribociclib succinate is contacted with a mixture of toluene and water. In another embodiment, ribociclib succinate is contacted with an ether solvent. In another embodiment, ribociclib succinate is contacted with tetrahydrofuran. In a preferred embodiment, ribociclib succinate is contacted with a mixture of tetrahydrofuran and water.

In an embodiment, the amount of solvent is 30 fold to 60 fold (v/w) with respect to ribociclib succinate. In another embodiment, the amount of solvent is 35 fold to 60 fold (v/w) with respect to ribociclib succinate. In another embodiment, the amount of solvent is 45 fold to 55 fold (v/w) with respect to ribociclib succinate. In another embodiment, the amount of solvent is 50 fold to 55 fold (v/w) with respect to ribociclib succinate.

In an embodiment, the amount of water is 0.1 fold to 0.5 fold (v/w) with respect to ribociclib succinate. In another embodiment, the amount of water is 0.2 fold to 0.45 fold (v/w) with respect to ribociclib succinate. In a preferred embodiment, the amount of water is 0.15 fold to 0.35 fold (v/w) with respect to ribociclib succinate.

In an embodiment, the volume ratio of solvent to water is between 100: 1 to 20: 1.

In another embodiment, the volume ratio of solvent to water is between 50: 1 to 25: 1. In another embodiment, the volume ratio of solvent to water is between 40: 1 to 33 : 1.

Ribociclib succinate is contacted with the solvent at ambient temperature to the reflux temperature of the solvent. In one embodiment, ribociclib succinate is contacted with the solvent at a temperature of about 65°C to about 80°C. In another embodiment, ribociclib succinate is contacted with the solvent at a temperature of about 70°C to about 78°C. In a preferred embodiment, ribociclib succinate is contacted with the solvent at reflux temperature .

Ribociclib succinate is contacted with the solvent for about 2 hours to about 10 hours. In an embodiment, ribociclib succinate is contacted with the solvent for about 2.5 hours to about 7 hours. In a preferred embodiment, ribociclib succinate is contacted with the solvent for about 2.5 hours to about 4.5 hours.

The solution of ribociclib succinate in the solvent is further stirred at ambient temperature for about 2 hours to 24 hours. In one embodiment, the solution of ribociclib succinate in the solvent is stirred for about 2 hours to about 20 hours. In a preferred embodiment, the solution of ribociclib succinate in the solvent is stirred for about 2 hours to about 16 hours. Isolation of the crystalline Form S 1 of ribociclib succinate may optionally be carried out by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization.

Crystalline Form S 1 of ribociclib succinate may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, suck drying, air drying, or agitated thin film drying.

Drying may be carried out using any suitable method, such as, drying under reduced pressure, air drying, or vacuum tray drying. In a preferred embodiment, drying is carried out at high temperature under reduced pressure. In another embodiment, air drying is carried out. In another embodiment, vacuum tray drying is carried out. In another embodiment, drying is carried out at a temperature of about 45°C to about 70°C. In another embodiment, drying is carried out at a temperature of about 50°C to about 60°C.

In a preferred embodiment, drying is carried out at a temperature of about 50°C to about 55°C.

Drying is carried out for a period of about 5 hours to about 16 hours. In one embodiment, drying is carried out for about 16 hours. In a preferred embodiment, drying is carried out for about 10 hours. In yet another preferred embodiment, drying is carried out for about 9 hours. In yet another preferred embodiment, drying is carried out for about 12 hours. In another embodiment, drying is carried out for about 6.5 hours. In another embodiment, drying is carried out for about 6 hours. In another embodiment, drying is carried out for about 5 hours.

The dried material may optionally be micronized. In one embodiment, micronization is carried out using ball mill. In another embodiment, micronization is carried out using colloid mill. In another embodiment, micronization is carried out using grinding mill. In another embodiment, micronization is carried out using air jet mill. In another embodiment, micronization is carried out using roller mill. In another embodiment, micronization is carried out using impact mill.

A third aspect of the present invention provides a process for the preparation of a crystalline Form S 1 of ribociclib succinate comprising contacting ribociclib free base with succinic acid in the presence of a solvent. Ribociclib free base, to be used as a starting material, for the preparation of crystalline Form S 1 of ribociclib succinate may be obtained by methods known in the literature such as those disclosed in U.S. Patent No. 8,415,355.

In another embodiment, seeding may be carried out with crystal seed of Form Sl .

Crystalline Form S 1 of ribociclib succinate is prepared by contacting ribociclib free base with succinic acid in the presence of a solvent. The solvent is selected from alcohols, water, and mixtures thereof. Examples of alcohols include ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, tert-butanol, and n-pentanol.

In an embodiment, ribociclib free base is contacted with an alcohol solvent. In a preferred embodiment, ribociclib free base is contacted with iso-propanol. In another preferred embodiment, ribociclib free base is contacted with a mixture of iso-propanol and water.

In an embodiment, the amount of solvent is 30 fold to 60 fold (v/w) with respect to ribociclib free base. In another embodiment, the amount of solvent is 35 fold to 60 fold (v/w) with respect to ribociclib free base. In another embodiment, the amount of solvent is 45 fold to 55 fold (v/w) with respect to ribociclib free base. In another embodiment, the amount of solvent is 50 fold to 55 fold (v/w) with respect to ribociclib free base.

Ribociclib free base is contacted with the solvent at ambient temperature to a temperature of about 66°C to about 80°C. In an embodiment, ribociclib free base is contacted with the solvent at ambient temperature. In another embodiment, ribociclib free base is contacted with the solvent at a temperature of about 70°C to about 75°C.

Ribociclib free base is contacted with the solvent for about 10 minutes to about 60 minutes. In another embodiment, ribociclib free base is contacted with the solvent for about 20 minutes to about 40 minutes. In another embodiment, ribociclib free base is contacted with the solvent for about 25 minutes to about 30 minutes.

The solution of ribociclib free base in the solvent is further treated with succinic acid at a temperature of about 65°C to about 80°C. In an embodiment, the solution of ribociclib free base in the solvent is treated with succinic acid at a temperature of about 70°C to about 75°C.

The solution of ribociclib free base with succinic acid is further stirred at ambient temperature for about 2 hours to about 20 hours. In a preferred embodiment, the solution of ribociclib free base with succinic acid is stirred for about 3 hours. In another preferred embodiment, the solution of ribociclib free base with succinic acid is stirred for about 6 hours. In another preferred embodiment, the solution of ribociclib free base with succinic acid is stirred for about 16 hours.

Isolation of crystalline Form S 1 of ribociclib succinate may optionally be carried out by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization.

Drying may be carried out using any suitable method, such as, drying under reduced pressure, air drying, or vacuum tray drying. In one embodiment, drying is carried out at high temperature under reduced pressure. In another embodiment, air drying is carried out. In another embodiment, vacuum tray drying is carried out. In another embodiment, drying is carried out at a temperature of about 45°C to about 70°C. In another embodiment, drying is carried out at a temperature of about 50°C to about 60°C. In another embodiment, drying is carried out at a temperature of about 50°C to about 55°C.

Drying is carried out for a period of about 5 hours to about 16 hours. In one embodiment, drying is carried out for about 16 hours. In another embodiment, drying is carried out for about 10 hours. In another embodiment, drying is carried out for about 9 hours. In another embodiment, drying is carried out for about 6.5 hours. In another embodiment, drying is carried out for about 6 hours. In another embodiment, drying is carried out for about 5 hours.

Crystalline form Sl of ribociclib succinate is non-hygroscopic in nature. Crystalline form Sl of ribociclib succinate has a purity of more than 98% as determined by High Performance Liquid Chromatography.

A fourth aspect of the present invention provides a crystalline Form S2 of ribociclib succinate.

In an embodiment, the crystalline Form S2 of ribociclib succinate is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at d-spacings of about 4.8, 4.7, 4.2, and 4.0 A, and further characterized by additional peaks at d-spacings of about 9.5, 4.4, 3.9, 3.8, and 3.5 A.

In an embodiment, the crystalline Form S2 of ribociclib succinate is characterized by a differential scanning calorimetry (DSC) thermogram having endothermic peaks at about 88.4°C, 149. l°C, and l85.7°C.

Crystalline Form S2 of ribociclib succinate is characterized by an XRPD pattern substantially as depicted in Figure 5, a DSC thermogram substantially as depicted in Figure 6, or an IR absorption spectrum substantially as depicted in Figure 7.

A fifth aspect of the present invention provides a process for the preparation of a crystalline Form S2 of ribociclib succinate comprising contacting ribociclib succinate with methanol.

Ribociclib succinate, to be used as a starting material, for the preparation of crystalline Form S2 of ribociclib succinate may be obtained by methods known in the literature such as those disclosed in U.S. Patent No. 9,193,732.

In an embodiment, water may be added with methanol.

In another embodiment, seeding may be carried out with crystal seed of Form S2.

Ribociclib succinate is contacted with methanol at ambient temperature to a temperature of about 65°C to 80°C. In an embodiment, ribociclib succinate is contacted with methanol at a temperature of about 70°C to about 75 °C.

The solution of ribociclib succinate in methanol is further stirred at ambient temperature for about one hour to about 15 hours. In one embodiment, the solution of ribociclib succinate in methanol is stirred for about 6 hours. In another embodiment, the solution of ribociclib succinate in methanol is stirred for about 4 hours. In another embodiment, the solution of ribociclib succinate in methanol is stirred for about 2 hours. In another embodiment, the solution of ribociclib succinate in methanol is stirred for about one hour.

Isolation of crystalline Form S2 of ribociclib succinate may optionally be carried out by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization.

Crystalline Form S2 of ribociclib succinate may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, suck drying, air drying, or agitated thin film drying.

Drying may be carried out using any suitable method, such as, drying under reduced pressure, air drying, or vacuum tray drying. In a preferred embodiment, drying is carried out at high temperature under reduced pressure. In another embodiment, air drying is carried out. In another embodiment, vacuum tray drying is carried out. In a preferred embodiment, drying is carried out at a temperature of about 35°C to about 60°C under reduced pressure. In another embodiment, drying is carried out at a temperature of about 40°C to about 45 °C under reduced pressure.

Drying is carried out for a period of about 5 hours to about 16 hours. In a preferred embodiment, drying is carried out for about 12 hours. In another embodiment, drying is carried out for about 9 hours. In another embodiment, drying is carried out for about 6 hours. In another embodiment, drying is carried out for about 4 hours.

A sixth aspect of the present invention provides a pharmaceutical composition comprising crystalline Forms Sl or S2 of ribociclib succinate, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

A seventh aspect of the present invention provides a method of treating postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising crystalline Forms Sl or S2 of ribociclib succinate. While the present invention has been described in terms of its specific aspects and embodiments, certain modifications and equivalents will be apparent to those skilled in the art, and are intended to be included within the scope of the present invention.

Methods

XRPD of the sample was determined by using a PANalytical^® instrument; Model X’pert PRO; Detector: X’celerator^®.

DSC of the sample was recorded using a Mettler-Toledo^® 82 le instrument or Shematzu; DTG-60-A instrument.

TGA was recorded using a TA Q-500 instrument.

IR of the samples was recorded using a PerkinElmer^® instrument, potassium bromide pellet method.

The following examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.

EXAMPLES

Example 1: Preparation of crystalline Form SI of ribociclib succinate

Method A: Ribociclib succinate (200 mg) was added to a mixture of iso-propanol (10 mL) and water (100 pL) to obtain a slurry. The slurry was heated at 70°C for 2 hours to obtain a reaction mixture. The reaction mixture was stirred at ambient temperature for 16 hours to obtain a solid. The solid obtained was collected by filtration and then dried at 50°C under vacuum for 12 hours to obtain the title compound.

Yield: 165 mg

Method B: Ribociclib succinate (400 mg) was added to a mixture of ethanol (4 mL) and water (100 pL) to obtain a slurry. The slurry was heated at 70°C for 2 hours to obtain a reaction mixture. The reaction mixture was stirred at ambient temperature for 5 hours to obtain a solid. The solid obtained was collected by filtration and then dried at 50°C under vacuum for 5 hours to obtain the title compound.

Yield: 340 mg

Method C: Ribociclib succinate (400 mg) was added to a mixture of sec-butanol (4 mL) and water (150 pL) to obtain a slurry. The slurry was heated at 70°C for 4 hours to obtain a reaction mixture. The reaction mixture was stirred at ambient temperature for 2 hours to obtain a solid. The solid obtained was collected by filtration and then dried at 50°C under vacuum for 6.5 hours to obtain the title compound.

Yield: 345 mg

Method D: Ribociclib succinate (400 mg) was added to a mixture of n-butanol (4 mL) and water (150 pL) to obtain a slurry. The slurry was heated at 70°C for 2.5 hours to obtain a reaction mixture. The reaction mixture was stirred at ambient temperature for 15 hours to obtain a solid. The solid obtained was collected by filtration and then dried at 50°C under vacuum for 6.5 hours to obtain the title compound.

Yield: 300 mg

Method E: Ribociclib succinate (400 mg) was added to a mixture of tert-butanol (4 mL) and water (200 pL) to obtain a slurry. The slurry was heated at 70°C for 5 hours to obtain a reaction mixture. The reaction mixture was stirred at ambient temperature for 15 hours to obtain a solid. The solid obtained was collected by filtration and then dried at 50°C under vacuum for 6.5 hours to obtain the title compound.

Yield: 300 mg

Method F : Ribociclib succinate (400 mg) was added to a mixture of n-propanol (5 mL) and water (150 pL) to a obtain slurry. The slurry was heated at 70°C for 2.5 hours to obtain a reaction mixture. The reaction mixture was stirred at ambient temperature for 4 hours to obtain a solid. The solid obtained was collected by filtration and then dried at 50°C under vacuum for 9 hours to obtain the title compound.

Yield: 330 mg

Method G: Ribociclib succinate (300 mg) was added to dimethyl sulfoxide (2.1 mL) and stirred at 75°C for 5 minutes to 7 minutes to obtain a reaction mixture. The reaction mixture was filtered to remove any solid particle and stirred at ambient temperature for 5 minutes. Acetonitrile (15 mL) was added to the reaction mixture and stirred at ambient temperature for 4 hours to obtain a solid. The solid obtained was collected by filtration and then dried at 50°C under vacuum for 6 hours to obtain title compound.

Yield: 230 mg

Method H: Ribociclib succinate (400 mg) was added to a mixture of acetone (5 mL) and water (100 pL) to obtain a slurry. The slurry was heated at 70°C for 4 hours to obtain a reaction mixture. The reaction mixture was stirred at ambient temperature for 15 hours to obtain a solid. The solid obtained was collected by filtration and then dried at 50°C under vacuum for 6.5 hours to obtain the title compound.

Yield: 300 mg

Method I: Ribociclib succinate (400 mg) was added to a mixture of methyl ethyl ketone (5 mL) and water (150 pL) to obtain a slurry. The slurry was heated at 70° C for 2.5 hours to obtain a reaction mixture. The reaction mixture was stirred at ambient temperature for 4 hours to obtain a solid. The solid obtained was collected by filtration and then dried at 50°C under vacuum for 9 hours to obtain the title compound.

Yield: 320 mg

Method J: Ribociclib succinate (400 mg) was added to a mixture of methyl isobutyl ketone (5 mL) and water (200 pL) to obtain a slurry. The slurry was heated at 70°C for 4.5 hours, then at 65°C for 2.5 hours to obtain a reaction mixture. The reaction mixture was stirred at ambient temperature for 15 hours to obtain a solid. The solid obtained was collected by filtration and then dried at 50°C under vacuum for 10 hours to obtain the title compound.

Yield: 310 mg

Method K: Ribociclib succinate (400 mg) was added to a mixture of acetonitrile (5 mL) and water (100 pL) to obtain slurry. The slurry was heated at 70°C for 4 hours to obtain a reaction mixture. The reaction mixture was stirred at ambient temperature for 1 hour to obtain a solid. The solid obtained was collected by filtration and then dried at 50°C under vacuum for 6.5 hours to obtain the title compound.

Yield: 345 mg

Method L: Ribociclib succinate (400 mg) was added to a mixture of toluene (5 mL) and water (150 pL) to obtain a slurry. The slurry was heated at 70°C for 4.5 hours to obtain a reaction mixture. The reaction mixture was stirred at ambient temperature for 15 hours to obtain a solid. The solid obtained was collected by filtration and then dried at 50°C under vacuum for 10 hours to obtain the title compound.

Yield: 330 mg Method M: Ribociclib succinate (400 mg) was added to a mixture of anisole (5 mL) and water (150 pL) to obtain a slurry. The slurry was heated at 70°C for 4.5 hours to obtain a reaction mixture. The reaction mixture was stirred at ambient temperature for 15 hours to obtain a solid. The solid obtained was collected by filtration and then dried at 50°C under vacuum for 10 hours to obtain the title compound.

Yield: 300 mg

Method N: Ribociclib succinate (400 mg) was added to a mixture of tetrahydrofiiran (5 mL) and water (150 pL) to obtain a slurry. The slurry was heated at 70°C for 2.5 hours to obtain a reaction mixture. Tetrahydrofiiran (5 mL) and water (50 pL) were again added to the reaction mixture and stirred at 65°C for 4 hours to obtain a solid. The solid obtained was collected by filtration and then dried at 50°C under vacuum for 9 hours to obtain the title compound.

Yield: 300 mg

Method O: Ribociclib succinate (5 g) was added to iso-propanol (300 mL) and stirred at 75°C for 4.5 hours to obtain a reaction mixture. The reaction mixture was stirred at ambient temperature for 12 hours to obtain a solid. The solid obtained was collected by filtration and then dried at 50°C under vacuum for 9 hours to obtain the title compound.

Yield: 4.2 g

Method P: Ribociclib free base (500 mg) was added to iso-propanol (30 mL) and stirred at 75°C for 25 minutes to obtain a reaction mixture. Iso-propanol (2.5 mL) with succinic acid (150 mg) was added to the reaction mixture and stirring was continued at 75° C for 4 hours. Iso-propanol (10 mL) was again added to the reaction mixture and the mixture was stirred at ambient temperature for 12 hours to obtain a solid. The solid obtained was collected by filtration and then dried at 50°C under vacuum for 10 hours to obtain the title compound.

Yield: 435 mg

Method Q: Ribociclib free base (10 g) was added to iso-propanol (550 mL) and stirred at 75°C for 25 minutes to obtain a solution. A solution of succinic acid (3 g) in iso-propanol (70 mL) was added to the solution to obtain a reaction mass. The reaction mass obtained was stirred at 75°C for 30 minutes. Water (2.5 mL) and seeds [Form Sl, 200 mg] were added to the reaction mass. The reaction mass was further stirred at 75°C for 3.5 hours and at ambient temperature for one hour to obtain a solid. The solid obtained was collected by filtration and then dried at 50°C under vacuum for 9 hours to obtain the title compound. The product was analyzed by XRD and the XRD pattern disclosed all the characteristic peaks of form S 1.

Yield: 12.40 g

Method R: Ribociclib free base (40 g) was added to a mixture of water (10 mL) and iso propanol (2200 mL) at 53°C to 60°C. The reaction mixture was heated to 75°C to 80°C. A solution of succinic acid (12 g) in iso-propanol (200 mL) was added. Seed crystals of crystalline Form Sl of ribociclib succinate (800 mg) were added. The reaction mixture was refluxed for 3 hours, and then cooled to 45 °C. The solid obtained was collected by filtration, washed with iso-propanol (200 mL), and dried at 55°C to 60°C under vacuum for 12 hours to obtain the crystalline Form S l of ribociclib succinate.

Yield: 43 g

Table 1 provides the d-spacing values (A), the corresponding 20 values, and the relative intensity of crystalline Form S 1 of ribociclib succinate as prepared by Method R.

Table 1

Crystalline Form S l of ribociclib succinate is characterized by an XRPD pattern substantially as depicted in Figure 1, a DSC thermogram substantially as depicted in Figure 2, an IR absorption spectrum substantially as depicted in Figure 3, or a TGA substantially as depicted in Figure 4.

The crystalline form S l was found to be stable for 6 months when subjected to a stability testing_at various temperature and relative humidity' (RH) conditions, for example, at 25±2°C/ 60±5%RH, 30±2°C/ 55±5%RH, and 40÷2°C/ 75±5% RH. Stability testing in the present invention was carried out using triple pouch packing i.e., inner pouch (low- density polyethylene (LDPE) twisted and tied), middle pouch (poiyester/LDPE heat sealed under vacuum with silica gel sachet) and outer pouch (polyester film/aluminum foil/LDPE heat sealed). The results are depicted in Table 3

Table 3: Stability Data of crystalline Form SI of Ribociclib Succinate

Method A: Ribociclib succinate (400 mg) was added to methanol (6 mL) to obtain a slurry. The slurry was heated at 75°C for 2 hours to obtain a reaction mixture. The reaction mixture was stirred at ambient temperature for one hour to obtain a solid. The solid obtained was collected by filtration and then dried at 40°C under vacuum for 9 hours to obtain the title compound.

Yield: 310 mg

Table 2 provides the d-spacing values (A), the corresponding 2Q values, and the relative intensity of crystalline Form S2 of ribociclib succinate as prepared by method A.

Table 2

Method B: Ribociclib succinate (400 mg) was added to methanol (6 mL) to obtain slurry. The slurry was heated at 45°C for 12 hours to obtain a solid. The solid obtained was collected by fdtration and then dried at 40°C under vacuum for 9 hours to obtain the title compound.

Yield: 320 mg

Claims

We Claim:

1. A crystalline Form S 1 of ribociclib succinate, characterized by an XRPD pattern having peaks at d-spacings of about 6.8, 4.7, 4.4, 4.2, and 3.9 A..

2. The crystalline form of claim 1, characterized by an XRPD pattern as depicted in Figure 1.

3. The crystalline form of claim 1, characterized by a DSC thermogram having an endothermic peak at about 2 l2.2°C.

4. The crystalline form of claim 1, characterized by a DSC thermogram as depicted in Figure 2.

5. The crystalline form of claim 1, characterized by a TGA as depicted in Figure 4.

6. A process for the preparation of a crystalline Form Sl of ribociclib succinate comprising the step of: contacting ribociclib succinate with a solvent selected from alcohols, sulfoxides, ketones, nitriles, aromatic hydrocarbons, ethers, and mixtures thereof.

7. The process according to claim 6, wherein the amount of solvent is 30 fold to 60 fold (v/w) with respect to ribociclib succinate and is carried out at ambient temperature to a temperature of about 80°C.

8. The process according to claim 6, wherein ribociclib succinate is contacted with a mixture of a solvent and water.

9. The process according to claim 8, wherein the amount of water is 0.1 fold to 0.5 fold (v/w) with respect to ribociclib succinate.

10. A process for the preparation of a crystalline Form Sl of ribociclib succinate comprising contacting ribociclib free base with succinic acid in the presence of a solvent selected from alcohols, water, and mixtures thereof.

11. A process for the preparation of a crystalline Form S 1 of ribociclib succinate comprising contacting ribociclib free base with succinic acid in the presence of a isopropanol and water.

12. The process according to claim 10, wherein the amount of solvent is 30 fold to 60 fold (v/w) with respect to ribociclib free base and is carried out at ambient temperature to a temperature of about 80°C.

13. A pharmaceutical composition comprising crystalline Form Sl of ribociclib succinate, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

14. A method of treating postmenopausal women with hormone receptor (HR)- positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising crystalline Form S 1 of ribociclib succinate.

15. A crystalline Form S2 of ribociclib succinate, characterized by an X-ray powder diffraction (XRPD) pattern having peaks at d-spacings of about 4.8, 4.7, 4.2, and 4.0 A.

16. The crystalline Form S2 of ribociclib succinate of claim 15, characterized by an XRPD pattern as depicted in Figure 5.

17. The crystalline Form S2 of ribociclib succinate of claim 15, characterized by a DSC thermogram having endothermic peaks at about 88.4°C, 149. l°C, and 185.7°C.

18. The crystalline Form S2 of ribociclib succinate of claim 15, characterized by a DSC thermogram as depicted in Figure 6.

19. A process for the preparation of a crystalline Form S2 of ribociclib succinate comprising contacting ribociclib succinate with methanol.

20. The process according to claim 19, wherein the preparation is carried out by contacting ribociclib succinate with methanol at ambient temperature to a temperature of about 80°C.

21. A pharmaceutical composition comprising crystalline Form S2 of ribociclib succinate, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

22. A method of treating postmenopausal women with hormone receptor (HR)- positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising crystalline Form S2 of ribociclib succinate.