RIBOCYCLIB DIHYDROCHLORIDE DIHYDRATE: A NEW POLYMORPHOUS AND PREPARATION METHOD

Abstract

RIBOCYCLIB DIHYDROCHLORIDE DIHYDRATE: A NEW POLYMORPHOUS AND PREPARATION METHOD The present invention relates to a crystalline form of Ribocyclib dihydrochloride (dihydrate), designated Form A, to the process of its preparation, to a pharmaceutical composition containing it, and to its use in the treatment of breast cancer.

Description

1 TARIFF A NEW POLYMORPHOUS OF RIBOSICLIB DIHYDROCHLORIDE DIHYDRATE AND PREPARATION METHOD Technical Area The present invention is a novel crystalline form of Ribocyclib dihydrochloride dihydrate, designated Form A. It relates to the polymorphic form and the process of its preparation. The invention also relates to pharmaceutical compounds containing Form A and to Form A in the treatment of breast cancer. It is also related to its usage. State of the Art Ribocyclib is chemically 7-cyclopentyl-N,N-dimethyl-2-((5-piperazine-1-yl)pyridine-2-yl)amino)-10 It is known as 7H-pyrrolo[2,3-d]pyrimidine-6 ​​carboxamide and has the following structural formula: It is shown: Ribosiklib Ribocyclib is currently marketed under the trade name KISQALI®. KISQALI® is a film-coated 15 The tablet contains ribociclib as the succinate salt. Ribociclib is an orally administered, reversible drug. It is a highly selective CDK (cyclin-dependent kinase) 4 / 6 inhibitor. Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. It is recommended in the treatment of cancer. International (PCT) publication No. WO 2010020675 A1, describes Ribocyclib and its pharmaceutical 20 for the first time. He described the salts that can be accepted as such. Its synthesis is in Sample 74 of WO 2010020675 A1. It is described in detail. Furthermore, the application includes the pharmaceutical preparation of Ribocycline and... It also describes its therapeutic application. This document refers to the solid state of the final form. No details have been disclosed. International (PCT) publication No. WO 2012064805 A1, Ribocyclib succinate salt and Ribocyclib 25 He described the polymorphic forms of the succinate salt in its anhydrous and hydrated forms. 2 U.S. Patent Application No. 20170342075, Crystalline Form of Ribociclib Monosuccinate Salt This document explains Form I. This application also explains Hemi-succinate Form A. European Patent Application No. 3156406 A1, crystalline amorphous form of ribocyclib free base. It describes their forms. Various salts of ribocycline, including different crystalline forms, have been described. 5 International (PCT) publication No. WO 2016091221 A1, containing adipate, maleic acid salt and glycolate. This describes ribocyclib salt. International (PCT) publication No. WO 2018051280, isethionic acid, oxalic acid, phosphoric acid, tartaric acid, acetic acid, trifluoroacetic acid, hydrobromic acid, citric acid, and p-toluenesulfonic acid It describes the ribocyclib salt, which contains 10. The discovery of a new salt of an active substance or a new polymorph thereof leads to an improvement in its properties. This provides an opportunity for improvement and a new pharmaceutical form with a specific release profile. formulation when developing a drug that has or has a specific degree of solubility It increases the opportunities available to the specialist. Based on these assessments, further improved physical and / or chemical properties 15 There is still a need for new ribocyclib salts and their new polymorphs. This is seen. Therefore, by the inventors of the present application, in the final medicinal product Better chemical purity and improved stability that could further enhance the properties of ribocycline. pharmaceutically novel Ribocyclib dihydrochloride dihydrate polymorphs with similar properties It was thought that further research would be beneficial. 20 Summary of the Invention The aim of the present invention is to produce a novel polymorphic form of Ribocyclib dihydrochloride dihydrate and this The goal is to provide a process for preparing the new polymorphic form. Another objective of the present invention is to create a novel polymorphic form of Ribocyclib dihydrochloride dihydrate. The aim is to provide pharmaceutical compounds containing 25 ingredients. Technical Problem Active pharmaceutical ingredients, as part of a finished pharmaceutical drug or medicinal product. These are the individual components used, which provide the pharmacological activity here. Research and development projects in the pharmaceutical industry focus on the main active pharmaceutical ingredients. It aims to investigate different possible salts, polymorphs, and processes for their production. 30 3 In general, salt formation occurs in the synthesis of drug active ingredients as well as in general pharmaceuticals. It is also vital in development and production. Salt forms of pharmaceutical active ingredients affect the quality, safety, and performance of the drug. It has significant effects on its physicochemical properties. Polymorphism, that is, the emergence of different crystal forms, is the process by which some molecules and molecular 5 This is a characteristic of complexes. A single molecule has different melting points, thermal behaviors, and X-ray powder characteristics. XRPD pattern, infrared absorption fingerprint, Raman absorption fingerprint and different physical properties and different crystal structures such as solid-state (13C) NMR spectrum It can give various crystalline forms. This is used to distinguish different polymorphic forms of a compound. One or more of these techniques can be used. 10 Different crystalline forms have different physical properties. The difference lies in the orientation of adjacent molecules or complexes within a bulk solid and in the intermolecular relationship. It results from their interactions. The relationship between the polymorphic forms of a pharmaceutically active compound and the pharmaceutical product is called drug. It is well known in the industry. Pharmaceutical formulation, of the pharmaceutically active compound. It is affected by its polymorphic form. 15 The discovery of novel salts and polymorphic forms of an active pharmaceutical compound leads to the development of finished pharmaceuticals. This presents a new opportunity to improve the performance characteristics of the product; therefore, new salts... And the development of polymorphic forms is always encouraged. Useful and suitable for the preparation of various pharmaceutical compounds as needed. Studies on the development of a new Ribosiklib polymorph with advantageous properties 20 It has been done. Solution to the problem In one application, the invention relates to a novel solid form of ribocyclib dihydrochloride dihydrate. This new Ribosiklib polymorph is not only stable but also offers improved storage, shelf life, solubility, and It also meets pharmaceutical requirements such as high purity. 25 Description of the applications of the invention The present invention relates to a novel polymorph of ribocyclib, namely ribocyclib dihydrochloride Form A. It is related. The first aspect of the present invention is a novel polymorphic form of ribocyclib dihydrochloride. It is related. This new form will henceforth be referred to as Ribociclib crystalline Form A. Ribociclib 30 Form A of dihydrochloride is the dihydrate. Form A has degrees 2- of 10.1 ± 0.2, 18.82 ± 0.2 and 21.28 ± 0.2. 4 It is characterized by an XRPD pattern with characteristic peaks in theta values. Also... Ribocyclib dihydrochloride Form A had the following values: 4.51 ± 0.2, 8.80 ± 0.2, 14.16 ± 0.2, 19.98 ± 0.2, 20.86 ± Characteristic 2-theta values ​​of 0.2, 22.05 ± 0.2, 24.88 ± 0.2, 26.60 ± 0.2 and 29.11 ± 0.2 degrees It can also be characterized by an XRPD pattern with peaks. Table 1 shows the 2-theta 5-cell ratio corresponding to the crystalline Form A of ribocyclib dihydrochloride dihydrate. It provides the values ​​and relative density. Table 1. Characteristic 2-theta values ​​of ribocyclib dihydrochloride dihydrate (Form A). 2-Theta (±0.2°) Relative Intensity (%) 4.51 16 8.80 4 10.14 28 14.16 4 18.82 22 19.98 13 20.86 16 21.28 100 22.05 17 24.88 8 26.60 15 29.11 12 33.35 4 Form A is characterized by an XRPD pattern, as shown in Figure 2. Form A is also characterized by an Infrared (IR) spectrum, as shown in Figure 6, and 10 As shown in Figure 18, this can also be determined using a differential scanning calorimetry (DSC) thermogram. It is characterized. The second aspect of the present invention is the novel polymorphic Form A of Ribocyclib dihydrochloride dihydrate. It relates to a process for its preparation. According to the present invention, Form A of Ribociclib dihydrochloride dihydrate is obtained as follows: can be done: a) Ribociclib intermediate in a suitable solvent and / or solvent mixture Mixing (formula 1), 5 b) Add hydrochloric acid and / or its equivalent to the Ribociclib intermediate solution in step (a) adding the solution, c) Heating the reaction solution in step (b) to a suitable temperature and mixing, d) cooling the solution to 0 °C, 10 e) Filtration and isolation of the resulting solid, f) The resulting pure crystalline Ribocyclib dihydrochloride dihydrate, referred to as Form A. Washing the solid with a suitable organic solvent. Suitable solvents for step (a) are tetrahydrofuran, water, methanol, ethanol, 2-propanol, and acetonitrile. is selected from among them. 15 (c) The appropriate temperature used in step (c) is the reflection of the solvent used from room temperature. It is selected from the range up to the temperature. Suitable solvents in step (f); tetrahydrofuran, ethyl acetate, dichloromethane, chloroform, acetonitrile and acetone are chosen. The third aspect of the present invention relates to the crystalline anhydrous form of ribocyclib succinate. 20 This form is characterized by an XRPD pattern, as shown in Figure 1. This form is also characterized by an IR spectrum, as shown in Figure 5, and in Figure 17. It is also characterized by a DSC thermogram, as shown. The fifth aspect of the present invention is Ribosiklib succinate, which contains the free base of Ribosiklib. It relates to a process for its preparation. 25 The degree of purity of the active ingredient and the potential resulting effects on efficacy. The changes negatively impacted other important aspects of pharmaceutical processing. can be affected. The process of the present invention involves the production of high-purity and high-yield ribocyclib dihydrochloride dihydrate. Ribociclib dihydrochloride dihydrate provides 30% efficiency in high-performance liquid chromatography (HPLC). 6 It is obtained with a purity of over 99% in terms of area percentage. Stability plays a crucial role in the drug development process. The stability of a pharmaceutical product depends on specific characteristics. Within a container or closure system, the relevant formulation's chemical, physical, and microbiological characteristics, remaining within therapeutic and toxicological specifications, and maintaining its attributed quality, for example, identity, Purity, potency, and the ability to maintain these qualities until the drug's expiration date are considered as 5. definable. The stability of a pharmaceutical product depends on changes in the solid-state form of the active drug substance. It is strongly affected. Changes in the solid-state form of the drug's active ingredient and the manufacturing process. This can result from various conditions. Processes that can cause polymorphic changes include milling. Examples include the application of heating and pressure. Production conditions involving a solvent (e.g., age 10) granulation, polymorphs in solution and polymorphs in suspension), of the active drug substance It can facilitate changes in the solid-state form. The active ingredient of the drug in its solid-state form. polymorphic transformations, hydrate / solvate formations, and dehydration / desolvation reactions These changes, which include these modifications, can lead to stability problems in finished pharmaceutical products. Therefore, Crystalline stability of the drug active ingredient meets 15 of the requirements for qualified pharmaceutical products. It plays a critical role in meeting the demand and in the active ingredient of the drug in pharmaceutical formulations. Stable polymorphs should be used. In this respect, the crystalline stability of Ribociclib dihydrochloride dihydrate Form A is under the following conditions. It was investigated under the following conditions: a sample was kept in a reaction flask at 90 °C for 10 days. Here The crystalline stability referred to is the polymorphic 20 of the drug active substance over time under these conditions. Transformations, such as hydration, dehydration, or amorphous transformations, indicate its stability. Crystalline stability of ribocyclib dihydrochloride dihydrate Form A, X-ray powder diffraction. This method was used to investigate and determine the results. The results show that crystalline Ribocyclib dihydrochloride dihydrate... No polymorphic transformation of Form A to another crystalline form has occurred. or has shown that no degradation occurs in Form A. Crystalline 25 Ribocyclib dihydrochloride dihydrate Form A exhibits crystalline stability under dry heating at 90 °C for 10 days. has shown. The chemical stability of crystalline ribocyclib dihydrochloride dihydrate Form A is also important, and This is predictable with short-term storage under accelerated conditions of high temperature and humidity. Ribociclib dihydrochloride dihydrate Form A is 30% different from the reference polymorph of Ribociclib succinate. A study was conducted to demonstrate that it is more stable. Figure 6 of WO2012 / 064805 describes the reference polymorph of ribociclib succinate and 7 According to the current invention, it is referred to as Form I. The XRPD pattern of ribociclib succinate crystalline Form I is shown in Figure 1. In the present invention, the obtained crystalline Ribociclib dihydrochloride dihydrate and Ribociclib succinate Crystalline Form I samples were incubated in an oven at 90 °C for 10 days to test chemical stability. The samples were kept in stability chambers under dry heating for 5 days. The chemical stability of the samples was 5 It was determined by HPLC method. Table 2 shows the stability of Ribociclib dihydrochloride dihydrate and Ribociclib succinate crystalline form I. It shows the results. Table 2. 10% of Ribociclib dihydrochloride dihydrate (Form A) and Ribociclib succinate crystalline Form I. stability test results Experiment Acceptance Criteria Ribocyclib dihydrochloride (dihydrate) Ribocyclic succinate (anhydrous) Beginning Reaction in the balloon 10 at 90 °C day Beginning Reaction in the balloon 10 at 90 °C day X-ray Diffraction Pattern Form A Form A *Form I *Form I Relating to Compounds (HPLC) Any One impurity NMT 0.10% (each (for impurities) < 0.10% < 0.10% < 0.10% < 0.10% Total impurity NMT 1.0% 0.12% 0.43% 0.46% 5.96% * Comparative crystalline form as defined in Figure 6 of WO2012 / 064805. Ribocyclib dihydrochloride dihydrate Form A samples showed no impurity profile under all conditions. It remained stable without any changes or increase in impurity levels. In terms of stability, Ribociclib dihydrochloride dihydrate Form A and Ribociclib succinate Form I 15 It can be concluded that there is a difference between them. Total impurities, Ribocyclib succinate crystalline. Higher amounts were detected in Form I. Ribocyclib dihydrochloride dihydrate Form A, It is physically and chemically more stable under normal and accelerated stability conditions. The result shows that crystalline Ribocyclib dihydrochloride dihydrate Form A has good stability. 8 Furthermore, studies have shown that ribocyclib succinate is more stable than the crystalline form I. The sixth aspect of the present invention is the crystalline structure combined with a pharmaceutically acceptable carrier. This relates to pharmaceutical formulations containing ribocyclib dihydrochloride dihydrate Form A. Ribocyclib dihydrochloride salt was obtained from 3 different solvents and contained the same in all of them. Crystalline Form A was obtained. 5 Brief description of the figures: Figure 1 shows X-ray of crystalline Ribociclib succinate, referred to as Form I (reference crystalline form). This shows the x-ray dust diffraction (XRPD) pattern. Figure 2 shows the X-ray of crystalline Ribociclib dihydrochloride dihydrate Form A obtained from sample 1. It shows the powder diffraction (XRPD) pattern. 10 Figure 3 shows the X-ray of crystalline Ribociclib dihydrochloride dihydrate Form A obtained from sample 2. It shows the powder diffraction (XRPD) pattern. Figure 4 shows the X-ray image of crystalline Ribociclib dihydrochloride dihydrate Form A obtained from sample 3. It shows the powder diffraction (XRPD) pattern. Figure 5 shows 15 of crystalline Ribociclib succinate, referred to as Form I (reference crystalline form). attenuated total reflection Fourier transform infrared (ATR-FTIR) spectrum It shows Figure 6 shows crystalline Ribociclib dihydrochloride dihydrate Form A obtained from sample 1. attenuated total reflection Fourier transform infrared (ATR-FTIR) spectrum shows 20 Figure 7 shows crystalline Ribociclib dihydrochloride dihydrate Form A obtained from sample 2. attenuated total reflection Fourier transform infrared (ATR-FTIR) spectrum It shows Figure 8 shows crystalline Ribociclib dihydrochloride dihydrate Form A obtained from sample 3. attenuated total reflection Fourier transform infrared (ATR-FTIR) spectrum 25 It shows Figure 9 shows the 1H nuclear form of Ribociclib succinate, referred to as Form I (reference crystalline form). It shows the magnetic resonance (1H NMR) spectrum. Figure 10 shows the 13C nuclear form of Ribociclib succinate, referred to as Form I (reference crystalline form). It shows the magnetic resonance (13C NMR) spectrum. 30 9 Figure 11 shows the 1H nuclear of Ribocyclib dihydrochloride dihydrate Form A obtained from sample 1. It shows the magnetic resonance (1H NMR) spectrum. Figure 12 shows the 13C nuclear of Ribocyclib dihydrochloride dihydrate Form A obtained from sample 1. It shows the magnetic resonance (13C NMR) spectrum. Figure 13 shows the 1H nuclear 5 of Ribocyclib dihydrochloride dihydrate Form A obtained from sample 2. It shows the magnetic resonance (1H NMR) spectrum. Figure 14 shows the 13C nuclear of Ribocyclib dihydrochloride dihydrate Form A obtained from sample 2. It shows the magnetic resonance (13C NMR) spectrum. Figure 15 shows the 1H nuclear of Ribocyclib dihydrochloride dihydrate Form A obtained from sample 3. It shows the magnetic resonance (1H NMR) spectrum. 10 Figure 16 shows the 13C nuclear of Ribocyclib dihydrochloride dihydrate Form A obtained from sample 3. It shows the magnetic resonance (13C NMR) spectrum. Figure 17 shows the differential of Ribociclib succinate, referred to as Form I (reference crystalline form). This shows the scanning calorimetry (DSC) thermogram. Figure 18 shows the differential 15 of Ribociclib dihydrochloride dihydrate Form A obtained from sample 1. This shows the scanning calorimetry (DSC) thermogram. Figure 19 shows the differential of Ribociclib dihydrochloride dihydrate Form A obtained from sample 2. This shows the scanning calorimetry (DSC) thermogram. Figure 20 shows the differential of Ribociclib dihydrochloride dihydrate Form A obtained from sample 3. Shows scanning calorimetry (DSC) thermogram 20 Figure 21 shows Ribociclib succinate, referred to as Form I (reference crystalline form). It shows thermogravimetric analysis (TGA). Figure 22 shows the thermogravimetric analysis of Ribociclib dihydrochloride dihydrate Form A obtained from sample 1. It shows the analysis (TGA). Figure 23 shows the thermogravimetric 25 of Ribociclib dihydrochloride dihydrate Form A obtained from sample 2. It shows the analysis (TGA). Figure 24 shows the thermogravimetric analysis of Ribociclib dihydrochloride dihydrate Form A obtained from sample 3. It shows the analysis (TGA). Device parameters: NMR: 1H NMR and 13C NMR analyses were performed using deuterated dimethyl sulfoxide (DMSO-d6) as the solvent. using a 400 MHz NMR spectrometer (JEOL Ltd., Tokyo, Japan) It has been accomplished. 5 FTIR: Samples were analyzed using a Shimadzu FTIR Spectrometer IR Prestige-21 (Shimadzu Corporation, Kyoto, (Japan) with ATR (attenuated total reflectance), in the range of 600 – 4000 cm–1, 20 Measured in pure form using scanning and a resolution of 4 cm–1. DSC: 10 Differential scanning calorimetry (DSC) thermograms are obtained using the following instrument parameters: obtained using a differential scanning calorimeter (TA Instruments DSC 250, USA) The following specifications were used: Initial temperature: room temperature, final temperature: 350 °C, heating rate: 10 °C / min. TGA: Thermogravimetric analysis (TGA) thermograms are obtained using the following instrument parameters: 15 Obtained using a thermogravimetric analysis device (TA Instruments TGA 550, USA): Initial Temperature: 25 °C, final temperature: 1000 °C, heating rate: 10 °C / min, isothermal: 120 min. PXRD Analysis Method: X-ray powder diffractograms were obtained from a Shimadzu LabX using the following instrument parameters. Measured with an XRD-6100 X-ray diffractometer (Shimadzu Corporation, Japan): 20 The measurement conditions are as follows: Radiation: Cu (1.5406 Å) Filter for Kβ: Nickel Voltage: 40.0 kV Current: 30.0 mA 25 Auto split: unused Divergence gap: 1.0° Scattering gap: 1.0° Receiver slit: 0.30 mm, with graphite monochromator. Movement axis: Theta-2Theta 30 11 Scanning range: 3.00 – 40.00° Scanning mode: continuous scanning Scanning speed: 1.0° / min Sampling interval: 0.02° The following examples are designed to enable a person skilled in the art to apply the invention. The examples provided are for illustrative purposes only and are intended to limit the scope of the invention. It should not be interpreted. EXAMPLES Preparation of Ribociclib Intermediate-1 Tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (4.75 g, 17 mmol, 1 eq), 10 Tetrahydrofuran (20 mL) was added. The mixture was cooled to 0-5 °C and stirred for 10 minutes. Then LiHMDS (lithium bis(trimethylsilyl)amide) (68 mL, 68 mmol, 4 eq) was added to the mixture. was stirred until the reaction temperature stabilized at 0 °C. Then (2-chloro-7- cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide) (5.00 g, 17 mmol, 1 eq) It was added to the mixture and stirred at 0°C for 1 hour. Then it was left at room temperature for 16 hours. Stirring was continued. After stirring was complete, NH4Cl (aq) (45 mL) was added to the mixture. It was added dropwise at °C and stirred for 10 minutes. Then the mixture was transferred to a separating funnel. The aqueous phase was separated, the organic phase was evaporated, and the residue was obtained. Methanol (65 mL) was added to the residue. It was added and the mixture was stirred at 70 °C for 1 hour. Then it was cooled to 0 °C and stirred for 1 hour. The mixture was stirred. The mixture was filtered, washed with methanol, and the wet product was obtained. Ethyl acetate 20 was added to the wet product. (30 mL) and 2-propanol (30 mL) were added. The mixture was left at 60 °C for 1 hour and then at 10-15 °C for 1 hour. The mixture was stirred for an hour. Afterwards, the mixture was filtered and washed with a mixture of ethyl acetate and 2-propanol (1:1). The resulting product was dried under vacuum at 70 °C. Ribociclib intermediate-1, light pale pink. crystalline solid (3.96 g, 79%, HPLC purity: 99.74%, water content (KF): 0.26%, anhydrous, MA: 534.65 It was defined as (g / mol). 25 Preparation of ribocyclib free base (monohydrate) 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), acetonitrile (50 mL) was added. 32% concentrated HCl (3.66 mL, 37.4 mmol, 4 eq) was added dropwise to the mixture. was added. Then the mixture was heated to 40ºC and stirred for 2 hours. Stirring 30 After completion, 50% NaOH (aq) (10 mL) was added to the mixture, cooled to 0 °C and 1 The mixture was stirred for an hour. Then the mixture was filtered and washed with 2-propanol. The resulting wet product... 12 Distilled water (75 mL) was added. The mixture was stirred at room temperature for 1 hour, filtered, and 2- Washed with propanol. The resulting product was dried under vacuum at 70 °C. Ribocyclib free. Some, off-white crystalline solid (3.5 g, 83%, HPLC purity: 99.57%, water content (SCF): 7.74%, MA: It was defined as 452.5 g / mol. Comparative Example: Preparation of Crystalline Form I Ribocyclib succinate 5 In the comparative example, crystalline Form I Ribociclib succinate was prepared, and the prepared Ribocyclib succinate WO has the same crystal structure as described in 2012 / 064805A1. Ribociclib free base (7-cyclopentyl-N,N-dimethyl-2-((5-piperazin-1-yl)pyridin-2-yl)amino)-7H- pyrrolo[2,3-d]pyrimidine-6 ​​carboxamide hydrate) (5 g, 11.5 mmol, 1 eq), 2-propanol (100 mL) It was added to the mixture. It was heated to 65 °C. Then succinic acid was added to the mixture (1.6 g, 13.2 10 (1.2 eq, mmol). After addition, it was heated to 80 °C and stirred for 2 hours. Afterwards, it was reduced to 0 °C. It was cooled and stirred for 2 hours. Then it was filtered and washed with 2-propanol. The resulting product Dried under vacuum at 70 °C. Ribocyclib succinate, off-white crystalline solid (5.01 g, 82%). HPLC purity was defined as 99.64%, water content (SCF) as 0.8%, anhydrous, MA: 552.6 g / mol. EXAMPLE-1: Preparation of Ribocyclib Dihydrochloride Dihydrate Form A 15 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), Tetrahydrofuran (50 mL) was added. 32% concentrated HCl (2.66 mL, 27.9 mmol, 3 eq) was added to the mixture. It was added drop by drop. Then the mixture was heated to 40ºC and stirred for 6 hours. Stirring After completion, it was cooled to 0 °C, acetone (25 mL) was added and stirred for 1 hour. Then 20 It was then filtered and washed with acetone. The resulting product was dried under vacuum at 70 °C. Ribocyclib dihydrochloric acid dihydrate, yellow crystalline solid (4.6 g, 90%, HPLC purity: 99.8%, water) The content (KF) was defined as 6.78%, dihydrate, MA: 543.5 g / mol. EXAMPLE-2: Preparation of Ribocyclib Dihydrochloric Acid Dihydrate Form A Ribociclib intermediate-1 (tert-butyl 4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-25 d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate) (5 g, 9.35 mmol, 1 eq), acetonitrile (50 mL) was added. 32% concentrated HCl (2.66 mL, 27.9 mmol, 3 eq) was added to the mixture drop by drop. was added. Then the mixture was heated to 40ºC and stirred for 4 hours. Stirring After completion, it was cooled to 0 °C, acetone (25 mL) was added and stirred for 1 hour. Then... It was then filtered and washed with acetone. The resulting product was dried under vacuum at 70 °C. 30 Ribocyclib dihydrochloric acid dihydrate, yellow crystalline solid (4.85 g, 95%, HPLC purity: 99.77%, water) The content was defined as (KF): 6.7%, dihydrate, MA: 543.5 g / mol). 13 EXAMPLE-3: Preparation of Ribocyclib Dihydrochloric Acid Dihydrate Form A 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), methanol (85 mL) was added. 32% concentrated HCl (2.66 mL, 27.9 mmol, 3 eq) was added dropwise to the mixture. was added. Then the mixture was heated to 40ºC and stirred for 2 days. Stirring After completion, it was cooled to 0 °C, acetone (250 mL) was added, and stirred for 2 hours. It was then filtered and washed with acetone. The resulting product was dried under vacuum at 70 °C. Ribocyclib dihydrochloric acid dihydrate, yellow crystalline solid (4.1 g, 81%, HPLC purity: 99.7%, water) The content (KF): 6.89%, dihydrate, MA: 543.5 g / mol was defined as 10.

Claims

14 REQUESTS 1. Characteristic diffraction patterns in the X-ray diffraction pattern (2θ angular degrees ± 0.2°) Ribocyclib dihydrochloride, designated as Form A, has concentrations of 4.51°, 10.14°, 21.28°, and 22.05°. Crystalline form of dihydrate.

2. According to claim 1, the X-ray powder diffraction pattern of Ribociclib 5 is as shown in Figure 2. dihydrochloride dihydrate crystalline Form A.

3. According to Claim 1, Ribocyclib dihydrochloride has an IR spectrum pattern as shown in Figure 6. Dihydrate crystalline Form A.

4. According to Claim 1, Ribocyclib's NMR spectra are as shown in Figures 11-12. dihydrochloride dihydrate crystalline Form A. 10 5. According to claim 1, the DSC thermogram pattern of Ribocyclib is as shown in Figure 18. dihydrochloride dihydrate crystalline Form A.

6. According to Claim 1, Ribocyclib's TGA thermogram pattern is as shown in Figure 22. dihydrochloride dihydrate crystalline Form A.

7. Synthesis of crystalline Form A of Ribociclib dihydrochloride dihydrate according to Claim 1 or 2, 15 a process that includes the following steps: a) Ribociclib intermediate (formula 1) in a suitable solvent and / or solvent mixture mixing, b) hydrochloric acid and / or its solution, Ribociclib intermediate in step (a). adding to the solution, 20 c) Heating and stirring the reaction solution from step (b) at a suitable temperature, d) cooling the solution to 0 °C, e) Filtration and isolation of the resulting solid, f) the obtained pure crystalline Ribocyclib dihydrochloride dihydrate, which is called Form A. Washing the solid with a suitable organic solvent. 25 8. Crystalline form of Ribocyclib dihydrochloride dihydrate according to any of claims 1-3. A of which is a pharmaceutical compound containing ribocyclib dihydrochloride dihydrate or Its use in preparing the formulation.

9. Crystalline form of Ribocyclib dihydrochloride dihydrate according to any of claims 1 to 4. A treatment for breast cancer that involves the administration of a therapeutically effective amount of A. A drug used for treatment.

10. Crystalline form of Ribocyclib dihydrochloride dihydrate according to any of claims 1 to 5. Breast cancer treatment involves the administration of a therapeutically effective amount of A. method. 5 11. Crystalline form of Ribocyclib dihydrochloride dihydrate according to any of claims 1 to 6. The use of A in the preparation of a drug for the treatment of breast cancer.

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