Novel polymorph of ribociclib dihydrochloride dihydrate and method of preparation

Abstract

The present invention refers to a crystalline form of Ribociclib dihydrochloride (dihydrate) designated as Form A and a process for its preparation, a pharmaceutical composition comprising it, and its use for the the treatment of breast cancer.

Description

[0001] NOVEL POLYMORPH OF RIBOCICLIB DIHYDROCHLORIDE DIHYDRATE AND METHOD OF PREPARATION

[0002] Technical Field

[0003] The present invention relates to a novel crystalline polymorphic form of Ribociclib dihydrochloride dihydrate designated as Form A and a process for its preparation.

[0004] The invention further relates to pharmaceutical compositions comprising Form A and use of

[0005] Form A in the treatment of breast cancer.

[0006] Background Art

[0007] Ribociclib is chemically known as 7-cyclopentyl-N,N-dimethyl-2-((5-piperazin-l-yl)pyridin- 2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6 carboxamide and represented by the following structural formula:

[0008] Ribociclib

[0009] Ribociclib is currently marketed under the brand name KISQALI®. KISQALI® film-coated tablet contains ribociclib as its succinate salt. Ribociclib is an orally administered, reversible and highly selective CDK (Cyclin-dependent-kinase) 4 / 6 inhibitor. It is proposed for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer.

[0010] International (PCT) publication No. WO 2010020675 Al first disclosed Ribociclib and its pharmaceutically acceptable salts thereof. Its synthesis is specifically described in WO 2010020675 Al, Example 74. Further the application discloses pharmaceutical preparation of Ribociclib and therapeutic application thereof. No details on the solid state of the final form are disclosed in this document.

[0011] International (PCT) publication No. WO 2012064805 Al disclosed succinate salt of Ribociclib and polymorphic forms of succinate salt of Ribociclib as in a non-hydrated form and in a hydrated form.

[0012] U.S. Patent Application No. 20170342075 discloses crystalline Form I of mono- succinate salt of Ribociclib. This application also discloses Hemi-succinate Form A.

[0013] European Patent Application No. 3156406 Al discloses crystalline forms of Ribociclib free base amorphous form.

[0014] Several salts of Ribociclib including various crystalline forms are disclosed.

[0015] International (PCT) publication No. WO 2016091221 Al discloses the salt of Ribociclib, comprising adipate, maleic acid salt and glycolate.

[0016] International (PCT) publication No. WO 2018051280 discloses the salt of Ribociclib, comprising isethionic acid, oxalic acid, phosphoric acid, tartaric acid, acetic acid, trifluoroacetic acid, hydrobromic acid, citric acid and p-toluenesulfonic acid.

[0017] The discovery of a new salt of an active ingredient or a new polymorph thereof provides an opportunity to improve its characteristics, increasing the possibilities available to a formulation specialist when developing a new pharmaceutical form, a drug with a particular release profile or a specific dissolution degree.

[0018] Based on these considerations, there still appears a need for new salts of Ribociclib and new polymorphs thereof having further improved physical and / or chemical properties. Hence it was thought worthwhile by the inventors of the present application to explore pharmaceutically novel polymorphs of Ribociclib dihydrochloride dihydrate with good chemical purity and improved stability characteristics, which may further improve the characteristics of Ribociclib in finished medicinal product.

[0019] Summary of the invention

[0020] The object of the present invention is to provide a new polymorphic form of Ribociclib dihydrochloride dihydrate and process for the preparation of this novel polymorphic form of Ribociclib dihydrochloride dihydrate.

[0021] Another object of the present invention is to provide pharmaceutical compositions comprising new polymorphic form of Ribociclib dihydrochloride dihydrate.

[0022] Technical Problem Active pharmaceutical ingredients are individual components that are used as a part of a finished pharmaceutical drug or medicinal product, where they provide the pharmacological activity.

[0023] Research and development projects in the pharmaceutical industry mainly aim to investigate different possible salts, polymorphs and processes to produce active pharmaceutical ingredients.

[0024] Salt formation in general is vitally important in drug substance synthesis as well as overall pharmaceutical development and manufacture.

[0025] Salt forms of drug substances have significant effects on physicochemical properties of the drug influencing its quality, safety, and performance.

[0026] Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule, may give rise to a variety of crystalline forms having distinct crystal structures and physical properties like melting point, thermal behaviours, X-ray powder diffraction (XRPD) pattern, Infrared absorption fingerprint, Raman absorption fingerprint, and solid state (13C) NMR spectrum. One or more of these tecniques may be used to distinquish different polymorphic forms of a compound. Difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid.

[0027] The relationship between polymorphic forms of pharmaceutically active ingredient and pharmaceutical product is well known in the pharmaceutical industry. Pharmaceutical formulation is affected by polymorphic form of the pharmaceutically active ingredient.

[0028] Discovery of new salts and polymorphic forms of an active pharmaceutical ingredient provides a new opportunity to improve the performance characteristics of pharmaceutical finished product, therefore, development of new salts and polymorphic forms are always encouraged.

[0029] According to the need, studies have been done to develop novel polymorph of Ribociclib having advantageous properties which are useful and suitable for the preparation of various pharmaceutical compositions.

[0030] Solution to Problem

[0031] In an embodiment invention relates to novel solid form of Ribociclib dihydrochloride dihydrate.

[0032] This new polymorph of Ribociclib, besides being stable, meets the pharmaceutical requirements such as storage, shelf life, solubility and high purity. Description of embodiments

[0033] The present invention relates to novel polymorph of Ribociclib, namely Ribociclib dihydrochloride Form A.

[0034] A first aspect of the present invention relates to a novel polymorphic form of Ribociclib dihydrochloride . This new form herein after is referred as crystalline Form A of Ribociclib.

[0035] Form A of Ribociclib dihydrochloride is dihydrate. Form A is characterized by an XRPD pattern having characteristic peaks at 10.1 ± 0.2, 18.82 ± 0.2 and 21.28 ± 0.2 degree 2-theta. Furthermore, Form A of Ribociclib dihydrochloride can be characterized by an XRPD pattern with characteristic peaks at 4.51 ± 0.2, 8.80 ± 0.2, 14.16 ± 0.2, 19.98 ± 0.2, 20.86 ± 0.2, 22.05 ± 0.2, 24.88± 0.2, 26.60 ± 0.2 and 29.11 ± 0.2 degree 2-theta.

[0036] Table 1 provides the corresponding 2-theta values, and the relative intensity of crystalline Form A of Ribociclib dihydrochloride dihydrate.

[0037] Table 1. Characteristic 2-theta values of Ribociclib dihydrochloride dihydrate (Form A) Form A is characterized by an XRPD pattern, as shown in Figure 2.

[0038] Form A is also characterized by an Infrared (IR) spectrum, as shown in Figure 6 and characterized by differential scanning calorimetry (DSC) thermogram, as shown in Figure 18.

[0039] A second aspect of the present invention relates to a process for preparing novel polymorphic Form A of Ribociclib dihydrochloride dihydrate.

[0040] Form A of Ribociclib dihydrochloride dihydrate according to the present invention may be obtained by: a) mixing Ribociclib intermediate (formula 1) in a suitable solvent and / or solvent mixture, b) adding hydrochloric acid and / or its solution into the Ribociclib intermediate solution at step (a) c) heating and stirring the reaction solution at step (b) at a suitable temperature, d) cooling the solution to 0 °C, e) filtering and isolating the obtained solid, f) washing the obtained solid as pure crystalline Ribociclib dihydrochloride dihydrate designated as Form A with a suitable organic solvent.

[0041] Wherein suitable solvent in step (a) is selected from, tetrahydrofuran, water, methanol, ethanol, 2-propanol, acetonitrile.

[0042] The suitable temperature used in step (c) is selected from room temperature to reflux temperature of the solvent used.

[0043] Wherein suitable solvent in step (f) is selected from, tetrahydrofuran, ethyl acetate, dichloromethane, chloroform, acetonitrile, acetone.

[0044] A third aspect of the present invention relates to crystalline anhydrous form of Ribociclib succinate.

[0045] This form is characterized by an XRPD pattern, as shown in Figure 1.

[0046] This form is also characterized by an IR spectrum, as shown in Figure 5 and characterized by a DSC thermogram, as shown in Figure 17.

[0047] A fifth aspect of the present invention relates to a process for preparing of Ribociclib succinate involving of Ribociclib freebase. The degree of purity of the active ingredient and the resulting possible changes of the efficacy, further important properties for the pharmaceutical processing can be affected in an adverse manner.

[0048] The process of the present invention affords Ribociclib dihydrochloride dihydrate in high purity and high yield. The Ribociclib dihydrochloride dihydrate is obtained having purity greater than 99% by area percentage in high performance liquid chromatography (HPLC).

[0049] Stability plays an important role in the drug development process. Stability of a pharmaceutical product may be defined as the capability of that particular formulation, in a specific container or closure system, to remain within its chemical, physical, microbiological, therapeutic and toxicological specifications to assure its attributed quality, e.g., identity, purity, strength etc. until drug expiry.

[0050] Stability of a pharmaceutical product is strongly influenced by changes in solid-state form of the drug substance. The changes in solid state form of the drug substance may be resulted from the conditions of manufacturing process. Examples of processing that may cause polymorphic changes including grinding, milling, heating, and applying compression. Manufacturing conditions that include a solvent (e.g., wet granulation, polymorphs in solution, and polymorphs in suspension) may facilitate changes in the solid-state form of drug substance. These variations comprising polymorphic transformations, hydrate / solvate formations and dehydration / desolvation reactions in the solid-state form of the drug substance, may cause stability problems in finished pharmaceutical products. Therefore, crystalline stability of the drug substance has a critical role on satisfying the essentialities of qualified pharmaceutical product and stable polymorphs of drug substance should be used in pharmaceutical formulations.

[0051] For this aspect, crystalline stability of Ribociclib dihydrochloride dihydrate Form A was investigated under the following conditions: a sample was kept in an open flask at 90 °C for 10 days. The crystalline stability referred here, is the stability of a polymorphic form of drug substance with respect to polymorph transformations, hydration, dehydration, or amorphization through time under these conditions.

[0052] The crystalline stability of Ribociclib dihydrochloride dihydrate Form A was investigated and determined by X-ray powder diffraction method. Results showed that any polymorphic transformation to another crystal form or any degradation in crystalline Ribociclib dihydrochloride dihydrate Form A did not occur. Crystalline Ribociclib dihydrochloride dihydrate Form A showed crystalline stability under dry heating at 90 °C for 10 days. The chemical stability of crystalline Ribociclib dihydrochloride dihydrate Form A is also important and its can be predicted from short-term storage under accelerated conditions at high temperature and humidity. A study was conducted to show that Ribociclib dihydrochloride dihydrate Form A is more stable than reference polymorph of Ribociclib succinate. Reference polymorph of Ribociclib succinate defined in Fig.6 of W02012 / 064805 and designated Form I according to the present invention.

[0053] The XRPD pattern of Ribociclib succinate crystalline Form I is displayed in Figure 1.

[0054] In the present invention, samples of obtained crystalline Ribociclib dihydrochloride dihydrate and Ribociclib succinate crystalline Form I were kept under dry heating in open flask at 90 °C for 10 days in an oven, in stability chambers to test chemical stability. The chemical stability of the samples was determined by HPLC method.

[0055] Table 2 shows the stability results of Ribociclib dihydrochloride dihydrate and Ribociclib succinate crystalline Form I. Table 2. Stability test results of Ribociclib dihydrochloride dihydrate (Form A) versus

[0056] Ribociclib succinate crystalline Form I

[0057] * Comparative crystalline form defined in Fig.6 of W02012 / 064805

[0058] Ribociclib dihydrochloride dihydrate Form A samples stayed stable under all conditions without any change in the impurity profile and without increase in the impurity amounts. It can be concluded that there is difference between Ribociclib dihydrochloride dihydrate Form A and Ribociclib succinate Form I in terms of stability. Total impurities were detected in higher amounts in Ribociclib succinate crystalline Form I. Ribociclib dihydrochloride dihydrate Form A is more physically and chemically stable under normal and accelerated stability conditions.

[0059] The result indicates that crystalline Ribociclib dihydrochloride dihydrate Form A has good stability and it was also found to be more stable than Ribociclib succinate crystalline Form I.

[0060] A sixth aspect of the present invention relates to pharmaceutical compositions comprising crystalline Ribociclib dihydrochloride dihydrate Form A along with a pharmaceutically acceptable carrier.

[0061] Ribociclib dihydrochloride salt was obtained from 3 different solvents and the same crystalline Form A was obtained in all of them.

[0062] Brief description of the drawings:

[0063] Figure 1 shows the X-ray powder diffraction (XRPD) pattern of crystalline Ribociclib succinate designated Form I (reference crystalline form)

[0064] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of crystalline Ribociclib dihydrochloride dihydrate Form A obtained by example 1

[0065] Figure 3 shows the X-ray powder diffraction (XRPD) pattern of crystalline Ribociclib dihydrochloride dihydrate Form A obtained by example 2

[0066] Figure 4 shows the X-ray powder diffraction (XRPD) pattern of crystalline Ribociclib dihydrochloride dihydrate Form A obtained by example 3

[0067] Figure 5 shows the attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectrum of crystalline Ribociclib succinate designated Form I (reference crystalline form)

[0068] Figure 6 shows the attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectrum of crystalline Ribociclib dihydrochloride dihydrate Form A obtained by example 1

[0069] Figure 7 shows the attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectrum of crystalline Ribociclib dihydrochloride dihydrate Form A obtained by example 2

[0070] Figure 8 shows the attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectrum of crystalline Ribociclib dihydrochloride dihydrate Form A obtained by example 3

[0071] Figure 9 shows the nuclear magnetic resonance NMR) spectrum of Ribociclib succinate designated Form I (reference crystalline form) Figure 10 shows the13C nuclear magnetic resonance (13C NMR) spectrum of Ribociclib succinate designated Form I (reference crystalline form)

[0072] Figure 11 shows the ’ H nuclear magnetic resonance ( ’H NMR) spectrum of Ribociclib dihydrochloride dihydrate Form A obtained by example 1

[0073] Figure 12 shows the13C nuclear magnetic resonance (13C NMR) spectrum of Ribociclib dihydrochloride dihydrate Form A obtained by example 1

[0074] Figure 13 shows the ’ H nuclear magnetic resonance ( ’H NMR) spectrum of Ribociclib dihydrochloride dihydrate Form A obtained by example 2

[0075] Figure 14 shows the13C nuclear magnetic resonance (13C NMR) spectrum of Ribociclib dihydrochloride dihydrate Form A obtained by example 2

[0076] Figure 15 shows the ’ H nuclear magnetic resonance ( ’H NMR) spectrum of Ribociclib dihydrochloride dihydrate Form A obtained by example 3

[0077] Figure 16 shows the13C nuclear magnetic resonance (13C NMR) spectrum of Ribociclib dihydrochloride dihydrate Form A obtained by example 3

[0078] Figure 17 shows the differential scanning calorimetry (DSC) thermogram of Ribociclib succinate designated Form I (reference crystalline form)

[0079] Figure 18 shows the differential scanning calorimetry (DSC) thermogram of Ribociclib dihydrochloride dihydrate Form A obtained by example 1

[0080] Figure 19 shows the differential scanning calorimetry (DSC) thermogram of Ribociclib dihydrochloride dihydrate Form A obtained by example 2

[0081] Figure 20 shows the differential scanning calorimetry (DSC) thermogram of Ribociclib dihydrochloride dihydrate Form A obtained by example 3

[0082] Figure 21 shows the thermogravimetric analysis (TGA) of Ribociclib succinate designated Form I (reference crystalline form)

[0083] Figure 22 shows the thermogravimetric analysis (TGA) of Ribociclib dihydrochloride dihydrate

[0084] Form A obtained by example 1

[0085] Figure 23 shows the thermogravimetric analysis (TGA) of Ribociclib dihydrochloride dihydrate

[0086] Form A obtained by example 2

[0087] Figure 24 shows the thermogravimetric analysis (TGA) of Ribociclib dihydrochloride dihydrate Form A obtained by example 3 Instrumental parameters:

[0088] NMR:

[0089] 1H NMR and13C NMR analyses were performed on a 400 MHz NMR spectrometer (JEOL Ltd., Tokyo, Japan) using deuterated dimethyl sulfoxide (DMSO-de) as a solvent.

[0090] FTIR:

[0091] Samples were measured as neat by ATR (attenuated total reflectance) on Shimadzu FTIR Spectrometer IR Prestige-21 (Shimadzu Corporation, Kyoto, Japan) in the range of 600 - 4000 cm-1with 20 scans and 4 cm-1resolution.

[0092] DSC:

[0093] Differential scanning calorimetry (DSC) thermograms were obtained using a differential scanning calorimeter (TA instruments DSC 250, USA) by using following instrument parameters: Start temperature: room temperature, final temperature: 350 °C, heating rate: 10 °C / min.

[0094] TGA:

[0095] Thermogravimetric analysis (TGA) thermograms were obtained by using a thermogravimetric analzer (TA instruments TGA 550, USA) by using the following instrument parameters: Start temperature: 25 °C, final temperature: 1000 °C, heating rate: 10 °C / min, isothermal: 120 min.

[0096] PXRD Method of Analysis:

[0097] X-Ray powder diffractograms were measured using a Shimadzu LabX XRD-6100 X-ray diffractometer (Shimadzu Corporation, Japan) by using following instrument parameters:

[0098] The measurement conditions were as follows:

[0099] Radiation: Cu (1.5406 A)

[0100] Filter for KP: Nickel

[0101] Voltage: 40.0 kV

[0102] Current: 30.0 mA

[0103] Auto slit: not used

[0104] Divergence slit: 1.0°

[0105] Scatter slit: 1.0°

[0106] Receiving slit: 0.30 mm with a Graphite monochromator

[0107] Drive axis: Theta-2Theta Scan range: 3.00 - 40.00'

[0108] Scan mode: continuous scan

[0109] Scan speed: 1.0° / min

[0110] Sampling pitch: 0.02°

[0111] Following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention.

[0112] EXAMPLES

[0113] Preparation of Ribociclib intermediate -1

[0114] Tert-butyl 4-(6-aminopyridin-3-yl)piperazine-l-carboxylate (4.75 g, 17 mmol, 1 eq) was added in tetrahydrofuran (20 mL). The mixture was cooled to 0-5 °C and stirred for 10 min. Then LiHMDS (lithium bis(trimethylsilyl)amide) (68 mL, 68 mmol, 4 eq) was added to the mixture. It was stirred until reaction temperature was stabilized at 0 °C. Afterwards, (2-chloro-7- cyclopentyl-A,A-dimethyl-7H-pyrrolo[2,3- / ]pyrimidine-6-carboxamide) (5.00 g, 17 mmol, 1 eq) was added to the mixture and stirred for 1 h at 0 °C. Then it was keep stirring for 16 h at room temperature. After completion of stirring, NH4CI (aq) (45 mL) was added to the mixture drop by drop at 0 °C and stirred for 10 min. Afterwards, the mixture was taken into the separating funnel. The aqueous phase was seperated, organic phase was evaporated and the residue was obtained. Methanol (65 mL) was added to the residue and mixture was stirred for 1 h at 70 °C. Then it was cooled to 0 °C and stirred for 1 h. The mixture was filtered, washed with methanol and wet product was obtained. Ethyl acetate (30 mL) and 2-propanol (30 mL) were added to wet product. Mixture was stirred for 1 h at 60 °C and then stirred for 1 h at 10- 15 °C. Afterwards, the mixture was filtered, washed with ethyl acetate and 2-propanol (1:1) mixture. Obtained product was dried in vacuo at 70 °C. Ribociclib intermediate- 1 was defined as an off-light pink crystalline solid (3.96 g, 79%, HPLC purity: 99.74%, water content (KF): 0.26%, anhydrous, MW:534.65 g / mol).

[0115] Preparation of Ribociclib freebase (Monohydrate)

[0116] Ribociclib intermediate- 1 (tert-butyl 4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H- pyrrolo[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl) piperazine- 1 -carboxylate) (5 g, 9.35 mmol, 1 eq) was added in acetonitrile (50 mL). 32% con. HC1 (3.66 mL, 37.4 mmol, 4 eq) was added to mixture drop by drop. Afterwards mixture was heated to 40 °C and stirred for 2 h. After completion of stirring, 50% NaOH (aq) (10 mL) was added to the mixture, cooled to 0 °C and stirred for 1 h. Then the mixture was filtered and washed with 2-propanol. Distilled water (75 mL) was added to obtained wet product. Mixture was stirred for 1 h at room temperature, filtered and washed with 2-propanol. Obtained product was dried in vacuo at 70 °C. Ribociclib free base was defined as an off-white crystalline solid (3.5 g, 83%, HPLC purity: 99.57%, water content (KF): 7.74%, MW:452.5 g / mol)

[0117] Comparative Example: Preparation of Ribociclib succinate in crystalline Form I

[0118] In the comparative example, Ribociclib succinate in crystalline Form I was prepared, and the prepared Ribociclib succinate had the same crystalline structure as disclosed in WO 2012 / 064805A1.

[0119] Ribociclib free base (7-cyclopentyl-N,N-dimethyl-2-((5-piperazin-l-yl)pyridin-2-yl)amino)- 7H-pyrrolo[2,3-d]pyrimidine-6 carboxamide hydrate) (5 g, 11.5 mmol, 1 eq) was added in 2- propanol (100 mL). It was heated to 65 °C. Then succinic acid was added to mixture (1.6 g, 13.2 mmol, 1.2 eq). After the addition, it was heated to 80 °C and stirred for 2 h. Afterwards, it was cooled to 0 °C and stirred for 2 h. Then it was filtered and washed with 2-propanol. Obtained product was dried in vacuo at 70 °C. Ribociclib succinate was defined as an off-white crystalline solid (5.01 g, 82%, HPLC purity: 99.64%, water content (KF): 0.8%, anhydrous, MW:552.6 g / mol).

[0120] EXAMPLE- 1: Preparation of Ribociclib dihydrochloric acid dihydrate Form A

[0121] Ribociclib intermediate- 1 (tert-butyl 4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H- pyrrolo[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl) piperazine- 1 -carboxylate) (5 g, 9.35 mmol, 1 eq) was added in tetrahydrofuran (50 mL). 32% con. HC1 (2.66 mL, 27.9 mmol, 3 eq) was added to mixture drop by drop. Afterwards, mixture was heated to 40 °C and stirred for 6 h. After completion of stirring, it was cooled to 0 °C, acetone (25 mL) was added and stirred for 1 h. Then it was filtered and washed with acetone. Obtained product was dried in vacuo at 70 °C. Ribociclib dihydrochloric acid dihydrate was defined as a yellow crystalline solid (4.6 g, 90%, HPLC purity: 99.8%, water content (KF): 6.78%, dihydrate, MW:543.5 g / mol).

[0122] EXAMPLE-2: Preparation of Ribociclib dihydrochloric acid dihydrate Form A

[0123] Ribociclib intermediate- 1 (tert-butyl 4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H- pyrrolo[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl) piperazine- 1 -carboxylate) (5 g, 9.35 mmol, 1 eq) was added in acetonitrile (50 mL). 32% con. HC1 (2.66 mL, 27.9 mmol, 3 eq) was added to mixture drop by drop. Afterwards, mixture was heated to 40 °C and stirred for 4 h. After completion of stirring, it was cooled to 0 °C, acetone (25 mL) was added and stirred for 1 h. Then it was filtered and washed with acetone. Obtained product was dried in vacuo at 70 °C. Ribociclib dihydrochloric acid dihydrate was defined as a yellow crystalline solid (4.85 g, 95%, HPLC purity: 99.77%, water content (KF): 6.7%, dihydrate, MW:543.5 g / mol). EXAMPLE-3: Preparation of ribociclib dihydrochloric acid dihydrate Form A

[0124] Ribociclib intermediate- 1 (tert-butyl 4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H- pyrrolo[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl) piperazine- 1 -carboxylate) (5 g, 9.35 mmol, 1 eq) was added in methanol (85 mL). 32% con. HC1 (2.66 mL, 27.9 mmol, 3 eq) was added to mixture drop by drop. Afterwards, mixture was heated to 40 °C and stirred for 2 days. After completion of stirring, it was cooled to 0 °C, acetone (250 mL) was added and stirred for 2 h.

[0125] Then it was filtered and washed with acetone. Obtained product was dried in vacuo at 70 °C. Ribociclib dihydrochloric acid dihydrate was defined as a yellow crystalline solid (4.1 g, 81%, HPLC purity: 99.7%, water content (KF): 6.89%, dihydrate, MW:543.5 g / mol).

Claims

CLAIMS1. A crystalline form of Ribociclib dihydrochloride dihydrate designated Form A wherein the characteristic diffraction lines (29 in angular degrees ± 0.2°) in the X-ray diffraction pattern thereof: 4.51°, 10.14°, 21.28°and 22.05°.

2. The crystalline Form A of Ribociclib dihydrochloride dihydrate according to claim 1, wherein the X-ray powder diffraction pattern is as shown in FIG. 2.

3. The crystalline Form A of Ribociclib dihydrochloride dihydrate according to claim 1, where in the IR spectrum pattern is as shown in FIG. 6.

4. The crystalline Form A of Ribociclib dihydrochloride dihydrate according to claim 1, where in NMR spectrums are as shown in FIG. 11-12.

5. The crystalline Form A of Ribociclib dihydrochloride dihydrate according to claim 1, where in the DSC thermogram pattern is as shown in FIG. 18.

6. The crystalline Form A of Ribociclib dihydrochloride dihydrate according to claim 1, where in the TGA thermogram pattern is as shown in FIG. 22.

7. A process for the synthesis of crystalline Form A of Ribociclib dihydrochloride dihydrate according to claim 1 or 2 comprising: a) mixing Ribociclib intermediate (formula 1) in a suitable solvent and / or solvent mixture, b) adding hydrochloric acid and / or its solution into the Ribociclib intermediate solution at step (a) c) heating and stirring the reaction solution at step (b) at a suitable temperature, d) cooling the solution to 0 °C, e) filtering and isolating the obtained solid, f) washing the obtained solid as pure crystalline Ribociclib dihydrochloride dihydrate designated as Form A with a suitable organic solvent.

8. Use of crystalline Form A of of Ribociclib dihydrochloride dihydrate according to any one of claims 1-3 in the preparation of a pharmaceutical composition or a formulation comprising Ribociclib dihydrochloride dihydrate.

9. A medicament for the treatment of breast cancer comprising administering a therapeutically effective amount of crystalline Form A of Ribociclib dihydrochloride dihydrate of any oneof the claims 1 to 4.

10. A method of treating breast cancer comprising administering a therapeutically effective amount of crystalline Form A of Ribociclib dihydrochloride dihydrate of any one of the claims 1 to 5.

11. The use of crystalline Form A of Ribociclib dihydrochloride dihydrate according to any one of the claims 1 to 6 in the manufacture of a medicament for the treatment of breast cancer.

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