DESC:FIELD OF THE INVENTION
The present invention relates to novel stable crystalline and solvate polymorphic forms of Ribociclib of formula (I).

The present invention further relates to amorphous mono succinate and methods of preparing the same as well as pharmaceutically acceptable salts thereof.

The present invention mainly relates to novel stable crystalline polymorphic forms of Ribociclib free base and its mono succinate, said crystalline or amorphous forms may be commercially viable and lead to consistently produce as the stable material as per the processes according to the present invention.

BACKGROUND OF THE INVENTION
Ribociclib is chemically known as 7-Cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo [2,3-d]pyrimidine-6-carboxylic acid dimethylamide.
7-Cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo [2,3-d]pyrimidine-6-carboxylic acid dimethylamide or Ribociclib is an orally available cyclin-dependent kinase (CDK) inhibitor targeting cyclin D1/CDK4 and cyclin D3/CDK6 cell cycle pathway, with potential antineoplastic activity. Ribociclib specifically inhibits CDK4 and 6, thereby inhibiting retinoblastoma (Rb) protein phosphorylation. Inhibition of Rb phosphorylation prevents CDK-mediated G1-S phase transition, thereby arresting the cell cycle in the G1 phase, suppressing DNA synthesis and inhibiting cancer cell growth. Overexpression of CDK4/6, as seen in certain types of cancer, causes cell cycle deregulation.
Ribociclib mono succinate salt was approved by USFDA in March 13, 2017 and is marketed under the brand name Kisqali® and is indicated for the treatment of for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.
Ribociclib mono succinate is a light yellow to yellowish brown crystalline powder. The molecular formula for Ribociclib mono succinate is C23H30N8O•C4H6O4 and the molecular weight is 552.64 g/mol (Free base: 434.55 g/mol).

As per EMEA scientific discussion the active substance is a slightly hygroscopic yellow to brown crystalline powder, soluble in acidic aqueous media, becoming less soluble as pH increases.
Polymorphism has been observed for Ribociclib mono succinate. Production of the correct polymorphic form is ensured by an XRPD method in the active substance specification. As described under the stability section, Ribociclib mono succinate form A has been demonstrated to be stable and not to convert into other polymorphic forms under long term and accelerated stability studies when stored in the proposed packaging.

Ribociclib is specifically anticipated in US 8415355. The compound Ribociclib has valuable pharmacological properties and can be used, for example(1) as inhibitors of cyclin dependent kinases, in particular CDK1, CDK2, CDK3, CDK4, CDK5, CDK6 and CDK9; and (2) as modulators and/or inhibitors of glycogen synthesis kinase-3(GSK-3). The process for the preparation of Ribociclib is delineated below.

This patent has not provided any insight about the impurity concern as well as solid state and purity of the final product of Ribociclib. The process appears cumbersome and involves the formation of large number of impurities.

John et al in US 9193732 disclose a process for the preparation of Ribociclib and the succinate salt thereof. In addition this patent also describes the solid state characteristics of anhydrous Ribociclib mono succinate salt as well as monohydrate thereof.

The process for the preparation of Ribociclib mono succinate was schematically represented as below:
However, when following the proposed route of synthesis the obtained ribociclib shows certain disadvantages with regard to its purity and or solid state.

Chen et al in US20170342075 disclosed different salt forms like crystalline form of hemi succinate salt of Form A, mono succinate salt of Form I and crystalline Form A of adipate, maleate and glycolate salts of Ribociclib. Further this patent application does not disclose any specific process for the preparation of Ribociclib.

Frank et al, in EP 3156406 discloses crystalline Ribociclib free base Form 1, Form 4, Form 6, Form 7 and Form 8. Further this patent application does not disclose any salt forms of Ribociclib and its preparation thereof.
The conversion of one polymorphic form into another polymorphic form can be unfavorable in pharmaceutical dosage forms such as tablets, often resulting in different hygroscopicity, dissolution and pharmacokinetic properties. As a result thereof, the bioavailability of the active agent might be undesirably unpredictable. Consequently, active agents having different interchangeable polymorphs may lead to regulatory and commercial disadvantages since they very often do not fulfill the requirements of the corresponding regulation authorities such as the FDA and EMEA.

In view of the above it is pertinent to note that there exists an inherent need to develop stable crystalline form of Ribociclib and its salts having further improved physical and/or chemical properties besides high purity levels. Hence it was thought worthwhile by the inventors of the present application to explore novel process/crystallization process for the preparation of Ribociclib mono succinate, which may further improve the characteristics of drug Ribociclib and in developing the substantially pure stable crystalline forms of Ribociclib mono succinate consistently obtainable and amenable to scale-up.

As polymorphism has been given importance in the recent literatures owing to its relevance to the drugs having oral dosage forms due to its apparent relation to dose preparation/suitability in composition steps/bioavailability and other pharmaceutical profiles, stable polymorphic form of a drug has often remained the clear choice in composition due to various reason of handling, mixing and further processing including bioavailability and stability.

Exploring new polymorphic form for developing stable and pure forms of Ribociclib mono succinate which are amenable to scale up for pharmaceutically active useful compounds in the preparation of Ribociclib may thus provide an opportunity to improve the drug performance characteristics of products such as purity and solubility. Hence, inventors of the present application report a new polymorphic form, which is a stable and substantially pure form of Ribociclib mono succinate, which may be industrially amenable and usable for preparing the corresponding pharmaceutical compositions.

In view of above and overcome the prior art problems the present inventors had now developed a new polymorphic forms of Ribociclib and its salts. It was apparent to develop a process/or crystallization process resulting in the product, which is complying with the ICH requirements of quality parameters. Ribociclib mono succinate crystalline material was obtained by the process of the present invention is chemically stable and has been found with good dissolution properties.

OBJECTIVE OF THE INVENTION
The main object of the invention relates to new stable amorphous forms of Ribociclib mono succinate

Yet another object of the present invention relates a process for the preparation of stable amorphous forms of Ribociclib mono succinate

Yet another object of the present invention relates to crystalline and solvate forms of Ribociclib free base, which is stable and substantially pure form, which may be industrially amenable and useful for preparing corresponding pharmaceutical compositions.

Yet another object of the present invention relates to a process for the preparation of crystalline and solvate forms of Ribociclib free base.

SUMMARY OF THE INVENTION
Aspects of the present invention relates to the stable amorphous forms of Ribociclib mono succinate

Another aspect of the present invention relates to process for the preparation of amorphous Ribociclib mono succinate comprising the steps of:
a) dissolving Ribociclib mono succinate in a solvent; and
b) isolating amorphous Ribociclib mono succinate

Yet another object of the present invention relates to crystalline and solvate forms of Ribociclib free base, which is stable and substantially pure form, which may be industrially amenable and useful for preparing corresponding pharmaceutical compositions.

Yet another object of the present invention relates to a process for the preparation of crystalline and solvate forms of Ribociclib free base.

BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is an example of X-ray powder diffraction (“XRPD”) pattern of amorphous Ribociclib mono succinate obtained according the present invention.
Fig. 2 is an example of X-ray powder diffraction (“XRPD”) pattern of crystalline Ribociclib base obtained according the present invention.

DETAILED DESCRIPTION OF THE INVENTION
Although several polymorphs of Ribociclib mono succinate have been identified and well known in the literature, each polymorphic form can be distinguished using several different analytical parameters, alone or in combination, such as, but not limited to, powder X-ray diffraction pattern peaks or combinations of two or more peaks. However, the present inventors now developed a new stable amorphous polymorphic form, which are different from the prior-art polymorphic forms disclosed in the literature.

In one embodiment of the present invention relates to new stable amorphous forms of Ribociclib mono succinate

Yet another embodiment of the present invention relates a process for the preparation of stable amorphous forms of Ribociclib mono succinate

In another embodiment of the present invention relates to amorphous Ribociclib mono succinate characterized by X-ray powder diffraction pattern as disclosed in Fig 1.

Amorphous Ribociclib mono succinate, wherein process for the preparation of Amorphous Ribociclib mono succinate comprising the steps of:
a) dissolving Ribociclib mono succinate in a solvent; and
b) isolating amorphous Ribociclib mono succinate
wherein solvent selected from alcohol used is selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1- pentanol, 2,2,2-trifluoroethanol and 2-pentanol, water or mixture thereof; isolating amorphous form of Ribociclib mono succinate is by solvent evaporation technique such as distillation using a rotational evaporator, freeze drying (lyophilization), spray drying and agitated thin film drying (ATFD) are used.

The Amorphous Ribociclib mono succinate obtained by this process is stable and free of process related impurities.

In another embodiment, the present invention provides Amorphous Ribociclib mono succinate obtained by the present invention is free of other polymorphic impurities, wherein said crystalline form is present in a solid form greater than 99.9 %by weight.

In another embodiment of the present invention relates to crystalline Ribociclib free base.

In another embodiment the present invention further relates to process for the preparation of crystalline Ribociclib base comprises dissolving in a solvent selected from alcohol (C1-5) at 25-30 °C. Reaction mass was stirred for 5 to 30 minutes and filtered directly into a buchi rotavapor flask. Rotavaporization was performed at 40-60°C with step-wise decrease of pressure from 916 mbar to 50 mbar for 120 minutes to yield crystalline Ribociclib base having PXRD pattern as disclosed in Figure 2.

In another embodiment of the present invention relates to solvates of Ribociclib, wherein solvate is selected from 2-Methoxy ethanol solvate and DMSO solvate.

In another embodiment of the present invention further relates to process for the preparation of solvates of Ribociclib, wherein solvate is selected from 2-Methoxy ethanol solvate and DMSO solvate comprises reacting ribociclib base with specified solvent at 25-30°C. The obtained reaction mass was stirred for 30 minutes to 1 hour 30 minutes at 40-70°C. The obtained reaction mass was cooled to 25-30°C and again stirred the reaction mass for 30 minutes to 1 hour 30 minutes at 25-30°C. Filtered and washed with specified solvent to yield corresponding solvate. Dried the material at 55-60°C under vacuum for 12-15 hours.

Any form of Crude or Pure Ribociclib mono succinate obtained by any process may be used for preparing any of the Crystalline or amorphous Ribociclib mono succinate forms disclosed in the present invention. Ribociclib mono succinate forms disclosed in the present invention may have one or more advantageous and desirable properties compared to the known Crystalline Ribociclib mono succinate forms, which are not limited to better stability, hygroscopicity, high solubility and high purity leading to improved storage and distribution.

The process related impurities, including degradation products and other medium dependent impurities like residual solvent, that appear in the impurity profile of the Ribociclib mono succinate can be substantially removed by the process of the present invention resulting in the formation pure Ribociclib mono succinate. A substantially pure product i.e. crystalline Ribociclib mono succinate having purity more than 99.9% (by HPLC) can be obtained in high yield by the process of the present invention.

The Ribociclib mono succinate described herein may be characterized by X-ray powder diffraction pattern (XRPD) and IR absorption spectra and Thermal techniques such as differential scanning calorimetric (DSC) Analysis and TGA and solid state NMR. The samples of Ribociclib mono succinate were analyzed by XRPD on a Bruker AXS D8 Advance Diffractometer using X-ray source - Cu Ka radiation using the wavelength 1.5418 Å. DSC was done on a Perkin Elmer instrument. Illustrative example of analytical data for the Ribociclib mono succinate obtained in the Examples is set forth in the Figures 1-2.

The Ribociclib or its mono succinate salt used in the present invention is prepared by any of the conventional processes disclosed in the prior art.

The crude Ribociclib or its mono succinate salt obtained from the above stage may be purified by treating the compound of the formula (I) or a reaction mixture or a solvated form thereof is treated with an acid selected from methane sulphonic acid, sulphuric acid, trifluoro-methanesulphonic acid, difluoromethanesulphonic acid, dichloroacetic acid, glucornic acid, gluconic acid, glycols and glycol ethers; to form a salt of the compound of the formula (I) which precipitates from the solution containing the solvated compound of the formula (I), the salt of the compound of the formula (I) is then treated with an aqueous basic solution to precipitate the pure form of compound of the formula (I), preferably at a temperature of from 15° C. to 45° C., most preferably from 25° C. to 35° C. If required, repeat again the acidification followed by basification to obtained desired purity, which is greater than 99.5 %.

The Ribociclib or its mono succinate salt is dissolved in a solvent selected from solvent selected from alcohol (C1-3) or Ketones (C3-6) or organic solvents (C1-8 alkanes, dimethyl formamide) or halogenated organic solvents (Methylene dichloride, Ethylene dichloride) or Ethers (Methyl tertiary butyl ether, tetrahydrofuran) or sulphoxides (dimethyl sulphoxide) or esters (Ethyl acetate, benzyl acetate, isoamyl acetate) or water or mixtures thereof. To the obtained solution acid was added at a temperature ranging from -10 to 30°C for 30 min to 2 hrs to yield wet product, which was dried under vacuum at 50-55°C for 2hrs to yield Ribociclib or its acid salt.

The obtained Ribociclib acid salt is dissolved in a solvent selected from solvent selected from alcohol (C1-4) or Ketones (C3-6) or organic solvents (C1-8 alkanes, dimethyl formamide, toluene, xylene) or halogenated organic solvents (Methylene dichloride, Ethylene dichloride) or Ethers (Methyl tertiary butyl ether, tetrahydrofuran, Di-isopropyl ether ) or sulphoxides (dimethyl sulphoxide) or esters (Ethyl acetate, benzyl acetate, isoamyl acetate) or water or mixtures thereof at a temperature ranging from 25-30°C and stirred for 30min to get clear solution. The obtained solution was treated with an alkaline solution, wherein alkaline solution used is prepared using a base selected from organic base such as triethylamine, methylamine, pyridine, imidazole, benzimidazole; or inorganic base selected from carbonates such as sodium carbonate, potassium carbonate, calcium carbonate, ammonium carbonate; hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, barium hydroxide, magnesium hydroxide, lithium hydroxide, zinc hydroxide; bicarbonates such as sodium bicarbonate, potassium bicarbonate, ammonium bicarbonate, calcium bicarbonate, magnesium bicarbonate; in a solvent selected from organic solvent or water. The reaction mass was stirred for 30 min to 4 hrs depending on the acid used. After completion of the reaction, the reaction mass was cooled to a temperature ranging from 0-10°C and maintained the reaction mass under stirring for 30min to 4 hrs. The precipitated product was filtered, washed with organic solvent or a mixture of organic solvent or mixture of organic solvent and water to get wet cake, which was dried under vacuum at 50-85°C for 3 hrs to 6hrs to yield pure Ribociclib.

The obtained pure Ribociclib was analyzed, if it is not matching with the desired purity; again repeat the process by treating the Ribociclib with acid to prepare the corresponding salt, followed by treating with an alkali solution to obtain substantially pure Ribociclib having a purity of greater than 99.5% and meeting the ICH guidelines.

The process related impurities that appear in the impurity profile of the Ribociclib (I) may be substantially removed by the process of the present invention resulting in the formation of substantially Ribociclib (I), which meets the ICH guidelines.

The merit of the process according to the present invention resides in that product isolated after drying is stable and having a purity of greater than 99.5% purity by HPLC, which was not disclosed in any of the prior-art. The product obtained as per the present invention is highly pure than the any of the prior-art products obtained. Till now no publication discloses a purity of greater than 99.5%.

Solubility is one of the important parameters to achieve desired concentration of drug in systemic circulation for achieving required pharmacological response. Poorly water soluble drugs often require high doses in order to reach therapeutic plasma concentrations after oral administration. Low aqueous solubility is the major problem encountered with formulation development of new chemical entities as well as generic formulation development. Most of the drugs are either weakly acidic or weakly basic having poor aqueous solubility. The improvement of drug solubility thereby its oral bio-availability remains one of the most challenging aspects of drug development process especially for oral-drug delivery system. The poor solubility and low dissolution rate of poorly water soluble drugs in the aqueous gastrointestinal fluids often cause insufficient bioavailability. The enhancement in the purity of Ribociclib or its succinate salt and crystalline arrangement of novel polymorphic forms (as disclosed in the present invention) which is free of process related impurities inherently, increases the solubility of Ribociclib or its succinate salt, which plays a major role for enhancement of drug dissolution rate in solid oral dosage forms.

Drying may be also be performed by any conventional process not limited to spray drying or distillation to remove the solvent. Drying may be performed under reduced pressure conditions also. Reduced pressure conditions may be suitably utilized by person skilled in the art in order to obtain the dried material. The drying may be performed at a temperature ranging from 50-85°C for a time ranging from 5 to 10 hours depending upon the physical attributes of the end product obtained i.e. Pure Ribociclib or its succinate salt, which is obtained according to the present invention is having purity greater than 99.5%.

In another embodiment of the present invention the substantially pure Ribociclib or its succinate salt obtained by the processes of the present application may be taken as such in crystalline form for manufacture of solid dosage forms like tablets, capsules and/or for manufacture of oral liquids.

In another embodiment of the present invention the substantially pure crystalline or amorphous form of Ribociclib or its succinate salt obtained by the processes of the present application may be manufactured as the amorphous form by processing with polymers like hydroxypropyl methylcellulose acetate succinate (HPMC-AS).

In another embodiment, the substantially pure crystalline or amorphous form of Ribociclib or its succinate salt obtained by the processes of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. In these compositions, the active product is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerin, propylene glycol or liquid paraffin.

In one embodiment of the present invention, it also includes premix comprising one or more pharmaceutically acceptable excipients in the range of 1 to 50% w/w with the substantially pure crystalline or amorphous form of Ribociclib or its succinate salt, while retaining the crystalline nature of the premix.

The compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

Pharmaceutically acceptable excipients used in the compositions comprising substantially pure crystalline or amorphous form of Ribociclib or its succinate salt obtained as per the present application process- include, but are not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, di-calcium phosphate, tri-calcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

Pharmaceutically acceptable excipients used in the compositions derived from substantially pure crystalline or amorphous form of Ribociclib or its succinate salt of the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLES
Example-1
Preparation of Ribociclib DMSO solvate:
Ribociclib base (0.5 g, 0.00115mol) charged into a reaction flask containing DMSO (4.0 mL) at 25-30°C. Reaction mass temperature heated to 55-60°C. Stirred the reaction mass for 1.0 hour at 55-60°C. Reaction mass cooled to 25-30°C and stirred for 1.0 hour at 25-30°C. Filtered and washed with DMSO (1.0 mL). Dried the material at 55-60°C under vacuum for 12-15 hours.
Yield: 0.27 g.

Example-2
Process for the preparation of crystalline Ribociclib base:
Ribociclib base (0.5 g, 0.00115 mol) was charged into a reaction flask containing methanol (100 ml) at 25-30 °C. Reaction mass was stirred for 5 minutes and filtered directly into a buchi rotavapor flask. Rotavaporization was performed at 60 °C with step-wise decrease of pressure from 916 mbar to 50 mbar for 120 minutes to yield crystalline Ribociclib base having PXRD pattern as disclosed in Figure 2.
Yield: 0.4 g

Example-3
Preparation of Ribociclib 2-Methoxy ethanol solvate:
Ribociclib base (0.5 g, 0.00115mol) charged into a reaction flask containing 2-Methoxy ethanol (4.0 mL) at 25-30°C. Reaction mass temperature heated to 55-60°C. Stirred the reaction mass for 1.0 hour at 55-60°C. Reaction mass cooled to 25-30°C and stirred for 1.0 hour at 25-30°C. Filtered and washed with 2-Methoxy ethanol (1.0 mL). Dried the material at 55-60°C under vacuum for 12-15 hours.
Yield: 0.13 g.

Example-4
Process for the preparation of amorphous Ribociclib mono succinate:
Ribociclib mono succinate (500 mg) obtained from any of the prior art process was charged into a reaction flask containing methanol (50 ml) at 25-30° C. The reaction mass was stirred for 5 minutes and filtered directly into a buchi rotavapor flask. Rotavaporization was performed at 60° C with step-wise decrease of pressure from 916 mbar to 50 mbar for 120 minutes to yield amorphous Ribociclib mono succinate having PXRD pattern as disclosed in Figure 1.

Yield: 350 mg

While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the summary, description and examples are for illustrative purpose only of the core of the invention and non-limiting in their scope. Furthermore, as many changes may be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.
,CLAIMS:1) Amorphous Ribociclib mono succinate.

2) Amorphous Ribociclib mono succinate, wherein process for the preparation of Amorphous Ribociclib mono succinate comprising the steps of:
a) dissolving Ribociclib mono succinate in solvent; and
b) isolating amorphous Ribociclib mono succinate

3) Amorphous Ribociclib mono succinate according to claim 11, wherein solvent selected from alcohol such as methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1- pentanol, 2,2,2-trifluoroethanol and 2-pentanol. Methoxy ethanol, ethoxy methanol, water or mixtures thereof.

4) Amorphous Ribociclib mono succinate according to claim 11, wherein isolating amorphous form of Ribociclib mono succinate is by solvent evaporation technique such as distillation using a rotational evaporator, freeze drying (lyophilization), spray drying and agitated thin film drying (ATFD) are used.

5) Amorphous or crystalline Ribociclib mono succinate according to preceding claims, used in the pharmaceutical composition