DESC:FIELD OF THE INVENTION:
The invention relates to polymorph of Ribociclib citrate salt and pharmaceutical compositions thereof. The present invention also relates to preparation method thereof. In particular, the invention relates to Ribociclib citrate dihydrate.
BACKGROUND OF THE INVENTION:
The chemical name of Ribociclib is 7-cyclopentyl-N,N-dimethyl-2-[[5-(l-piperazinyl)-2-pyridinyl]amino]-7H-pyrrolo-[2,3-d]pyrimidine-6-carboxamide (CAS Number: 1211441-98-3).

Ribociclib (LEE011; Novartis) is a cyclin-dependent kinase 4/6 inhibitor (CDK4/6). Ribociclib drug product (Kisqali®) was approved by FDA and EMA in 2017 and is commercially available as film coated, immediate release tablets containing 200 mg of Ribociclib free base. Kisqali® is approved for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with (i) an aromatase inhibitor as initial endocrine-based therapy or (ii) fulvestrant as initial endocrine-based therapy or following disease progression on endocrine therapy in postmenopausal women or in men. FDA expanded the use of Kisqali® co-packaged with Femara® (letrozole). Kisqali® Femara® Co-Pack is indicated as initial endocrine-based therapy for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.
US 8,415,355 assigned to Novartis/Astex Pharma, covers Ribociclib or a pharmaceutically acceptable salts thereof. The US'355 patent also discloses a process for the preparation of Ribociclib.
US 9,193,732 assigned to Novartis discloses hydrated and non-hydrated form of Ribociclib mono-succinate.
US 11,155,545 discloses mesylate, acetate, oxalate, tosylate, sulfate, phosphate, hydrochloride, malate, maleate and succinate salts of Ribociclib.
WO 2018051280 discloses isethionic acid, oxalic acid, phosphoric acid, tartaric acid, acetic acid, trifluoroacetic acid, hydrobromic acid, citric acid, p-toluenesulfonic acid salts of Ribociclib.
Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, improving the dissolution profile, or improving stability (polymorph as well as chemical stability) and shelf-life.
In general, polymorphism refers to the ability of a substance to exist as two or more crystalline phases that have different spatial arrangements and/or conformations of molecules in their crystal lattices. Thus, "polymorphs" refer to different crystalline forms of the same pure substance in which the molecules have different spatial arrangements of the molecules, atoms, and/or ions forming the crystal. Different polymorphs may have different physical properties such as melting point, solubility, etc. The variation in solid forms may appreciably influence the pharmaceutical properties, such as bioavailability, handling properties, dissolution rate, and stability, and in turn such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorphic form. For these reasons, regulatory authorities require drug manufacturing companies to put efforts into identifying all polymorphic forms, e.g., crystalline, amorphous, solvates, stable dispersions with a pharmaceutically acceptable carriers, etc., of new drug substances.
The existence and possible numbers of polymorphic forms for a given compound cannot be predicted, and there are no "standard" procedures that can be used to prepare polymorphic forms of a substance. This is well-known in the art, as reported, for example, by A. Goho, "Tricky Business," Science News, Vol. 166(8), August 2004.
Considering the importance of Ribociclib in the pharmaceutical field, there always remains a need for obtaining different polymorph of Ribociclib salts for use in providing improved drug products containing Ribociclib and commercially amenable processes for their manufacture. Accordingly, the discovery of different polymorph of Ribociclib salt that possesses desired properties remains vital to drug development. Thus, disclosed herein, are different polymorphs of Ribociclib salt that may be used in the pharmaceutical compositions for the treatment of proliferative diseases such as cancer.
SUMMARY OF THE INVENTION:
An aspect of the invention is to provide Ribociclib citrate dihydrate.
In another aspect, the present invention provides a process for the preparation of Ribociclib citrate dihydrate comprising:
(a) contacting of Ribociclib base and citric acid or Ribociclib citrate in a suitable solvent(s); and
(b) isolating crystalline form of Ribociclib citrate dihydrate.
In still another aspect, the present invention provides a process for preparation of Ribociclib citrate dihydrate comprising of contacting Ribociclib base with citric acid in water.
BRIEF DESCRIPTION OF DRAWINGS:
Figure-1: Illustrates the PXRD pattern of crystalline Form A of Ribociclib citrate dihydrate.
Figure-2: Illustrates the single-crystal X-ray diffraction (SCXRD) pattern of crystalline Form A of Ribociclib citrate dihydrate.
Figure-3: Illustrates the PXRD pattern of Ribociclib citrate salt obtained according to reference example-1.

DETAILED DESCRIPTION OF THE INVENTION:
In an embodiment, the present invention provides Ribociclib citrate dihydrate.
In a preferred embodiment, the Ribociclib citrate dihydrate according to the invention is at least partially crystalline, preferably essentially crystalline, designated as Form A.
In another preferred embodiment, the Ribociclib citrate dihydrate according to the invention is at least partially amorphous, preferably essentially amorphous.
In another preferred embodiment, crystalline form A of Ribociclib citrate dihydrate which is characterized by its powder x-ray diffraction pattern as depicted in Figure-1.
In another preferred embodiment, crystalline form A of Ribociclib citrate dihydrate is characterized by its powder x-ray diffraction pattern peaks at about 5.23, 10.53, 12.88, 16.83, 18.26, 20.99 + 0.2o degree two theta.
In another preferred embodiment, crystalline form A of Ribociclib citrate dihydrate is further characterized by its powder x-ray diffraction pattern peaks at about 5.23, 8.66, 10.53, 11.68, 15.85, 12.88, 16.83, 18.26, 19.0, 19.58, 20.6, 20.99, 22.5, 22.8, 23.5, 24.59, 26.0 + 0.2o degree two theta.
In another preferred embodiment, crystalline form A of Ribociclib citrate dihydrate is characterized by a single crystal as depicted in Figure-2.
Below table provides the experimental data and structural refinement parameters for the crystal structure analysis of crystalline Form A of Ribociclib citrate salt.
Identification code B.No. A824-A
Empirical formula (C23H31N8O)+, (C6H7O7)-,2(H2O)
Formula weight 662.70
Temperature 294(2) K
Wavelength 0.71073 Å
Crystal system Triclinic
Space group P1
Unit cell dimensions a = 9.0796(3) Å a = 101.5535(8) °.
b = 11.0627(3) Å ß = 100.0233(8) °.
c = 17.6287(5) Å ? = 108.1414(7) °.
Volume 1594.56(8) Å3
Z 2
Density (calculated) 1.380 Mg/m3
Absorption coefficient 0.106 mm-1
F (000) 704
Crystal size 0.230 x 0.210 x 0.180 mm3
? range for data collection 2.435 to 30.549°
Index ranges -12<=h<=12, -15<=k<=15, -25<=l<=24
Reflections collected 31231
Independent reflections 9515 [R(int) = 0.0291]
Completeness to ? = 25.242° 99.5 %
Absorption correction Semi-empirical from equivalents
Max. and min. transmission 0.7461 and 0.6846
Refinement method Full-matrix least-squares on F2
Data / restraints / parameters 9515 / 12 / 470
Goodness-of-fit on F2 1.036
Final R indices [I>2?(I)] R1 = 0.0516, wR2 = 0.1309
R indices (all data) R1 = 0.0832, wR2 = 0.1526
Largest diff. peak and hole 0.313 and -0.277 e.Å-
Measurement 3Bruker D8 QUEST PHOTON-III Detector
Software Used SHELXTL-PLUS

In still another embodiment of the present invention, the Ribociclib free base used can be obtained by the known methods that include direct use of a reaction mixture containing Ribociclib base that is obtained in the course of its synthesis, or in any polymorphic form obtained by following any of the known process in prior art.
In yet another embodiment of the present invention, Ribociclib base may optionally be subjected to acid-base treatment before subjecting to citrate salt preparation. Suitable acid can be selected from acetic acid, formic acid, hydrochloric acid and like. Suitable base can be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium tert-butoxide, sodium tert-butoxide, triethyl amine, diisopropylamine and like. For example, Ribociclib base in water can be treated with suitable acid such as acetic acid, followed by washing with suitable water immiscible solvent(s) such as DCM (dichloromethane), toluene, ethyl acetate and like. Aqueous layer containing product is further treated with suitable base such as sodium hydroxide or aqueous solution of base. The precipitates formed are filtered, optionally washed with suitable solvent and dried to obtain pure Ribociclib base.
In another embodiment, the invention relates to a process of preparation of Ribociclib citrate dihydrate comprising:
(a) contacting of Ribociclib base and citric acid or Ribociclib citrate in a suitable solvent(s); and
(b) isolating crystalline form of Ribociclib citrate dihydrate.
In still another embodiment, the invention relates to a process of preparation of Ribociclib citrate dihydrate comprising:
(a) providing a solution of Ribociclib citrate in a suitable solvent(s) ); and
(b) isolating crystalline form of Ribociclib citrate dihydrate.

In another embodiment of the present invention, providing a solution of Ribociclib citrate in step (a) includes contacting Ribociclib citrate in a suitable solvent(s) or contacting of Ribociclib base and citric acid in a suitable solvent(s).
In another embodiment of the present invention, the step (a) involves dissolving Ribociclib base and citric acid in a suitable solvent(s), if needed involves stirring, heating and the combination thereof.
In an embodiment of the invention, providing a solution of Ribociclib citrate in step (a) includes direct use of a reaction mixture containing Ribociclib citrate that is obtained in the course of its synthesis or dissolving Ribociclib citrate in a suitable solvent(s) or mixing of Ribociclib base and citric acid in a suitable solvent(s).
As used herein the term “suitable solvent(s)” is water which may optionally contain 5 – 10% water miscible organic solvent(s).
As used herein the term "water miscible solvent(s)" is selected from methanol, ethanol, propanol, acetone, acetonitrile, dimethylacetamide (DMAc), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), sulfolane, THF, 2me-THF and the like.
In another embodiment of the present invention, the invention provides a process for preparation of Ribociclib citrate dihydrate comprising contacting Ribociclib base with citric acid in water.
In another embodiment of the present invention, the invention provides a process for preparation of Ribociclib citrate dihydrate wherein the reaction is carried out at a temperature in the range of 15 to 40 °C.
In an embodiment of the present invention, the isolation in step (b) is performed by any conventional methods such as cooling, filtration or combination thereof.
In an embodiment of the present invention, the isolation in step (b) further comprises optionally washing with a suitable solvent(s) and drying.
In an embodiment, the present invention provides crystalline form A of Ribociclib citrate dihydrate having purity of greater than 99 %, more preferably greater than 99.5 %.
In an embodiment, the present invention provides a crystalline form A of Ribociclib citrate dihydrate is having water content of about 4.0 to 7.0 %.
In another embodiment, Ribociclib citrate of present invention can also be prepared by dissolving Ribociclib base in suitable solvent, to the clear solution optionally a small amount of an antioxidant such as, but not limited to, citric acid, ascorbic acid, triphenylphosphine, 2,6-di-tert-butyl-4-methylphenol (BHT), butylated hydroxyanisole, a mixture of 2-tert-butylhydroxy anisole and 3-tert-butylhydroxy anisole (BHA), ethyl gallate (EtG) and propyl gallate (PrG) is added, followed by the addition of citric acid. Said Ribociclib citrate can be isolated by any of the conventional means.
Wherever applicable in the example of the present invention, the reaction solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material like N-acetyl-L-cysteine, SilaMetS thiol to remove metallic impurity, color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
The isolated compound according to the present invention may be recovered by methods including decantation, centrifugation, evaporation, gravity filtration, suction filtration, or any other technique for the recovery of solids under pressure or under reduced pressure. The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100° C., less than about 80° C., less than about 60° C., less than about 50° C., less than about 30° C., or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the compound is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller and hammer milling, and jet milling.
In an embodiment, the present invention provides crystalline form A of Ribociclib citrate dihydrate having a primary particle size of from about 5 µm to about 600 µm, preferably from about 10 µm to about 300 µm, or more preferably from about 15 µm to about 200 µm. In further embodiment, the present invention provides crystalline form A of Ribociclib citrate dihydrate having particle size of D(90) not more than 600 µm, not more than 300 µm or not more than 200 µm. In further embodiment, the present invention provides crystalline form A of Ribociclib citrate dihydrate having particle size of D (50) not more than 100 µm, not more than 50 µm or not more than 20 µm. In further embodiment, the present invention provides crystalline form A of Ribociclib citrate dihydrate having particle size of D(10) not more than 50 µm, not more than 20 µm or not more than 5 µm.
The Ribociclib citrate dihydrate as described herein possess a number of advantageous properties such as higher solubility, improved filterability and flow properties due to particle morphology/aspect ratio, and lower hygroscopicity.
Further, Ribociclib citrate dihydrate offers distinct advantages in formulating the pharmaceutical compositions due to their superior stability and reduced hygroscopicity compared to existing salts. Their enhanced stability ensures consistent potency and shelf-life durability, crucial for maintaining the efficacy and safety of active pharmaceutical ingredients over extended periods and under diverse environmental conditions. By being less hygroscopic, these salts mitigate moisture-related degradation risks during dosage form preparation and storage period, simplifying the manufacturing processes and reducing the need for stringent moisture control measures. This not only optimizes production efficiency but also enhances product reliability and quality assurance. Furthermore, their improved stability and pharmaceutical composition development flexibility, support enhanced bioavailability of APIs potentially improving therapeutic outcomes and patient adherence.
In another embodiment, the invention also includes a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form A of Ribociclib citrate dihydrate, as described herein and at least one pharmaceutically acceptable excipient.
In yet another embodiment of the invention, the present disclosure further encompasses processes for manufacturing of pharmaceutical compositions comprising Ribociclib citrate dihydrate and at least one pharmaceutically acceptable excipient.
In still another embodiment of the invention, the Ribociclib citrate dihydrate according to the invention as well as the pharmaceutical compositions of the Ribociclib citrate dihydrate may be used as medicaments, particularly for the treatment cancer, more particularly, for the treatment breast cancer.
The present disclosure also provides methods of treating breast cancer comprising administering a therapeutically effective amount of the Ribociclib citrate dihydrate of the present disclosure and at least one pharmaceutically acceptable excipient, to a subject suffering from breast cancer, or otherwise in need of the treatment.
In one embodiment, the pharmaceutical composition according to the disclosure may contain pharmaceutically acceptable excipients commonly used in pharmaceutical dosage forms, particularly those for oral administration for example, solubilizers, diluents, fillers, binders, adsorbents, disintegrants, glidants, anticaking agents, plasticizers, antioxidants, film forming polymers, anti-adherents, lubricants, flavouring agents, sweeteners, colorants, coating agents, preservatives, and combinations thereof.
In one embodiment, the pharmaceutical composition may be in the form of capsules, tablets, solutions, suspensions, syrups, or lozenges. The pharmaceutical compositions includes film coated tablets, layered tablets, chewable tablets, disintegrating tablets, buccal tablets, granules, powders, powder for oral solution, microparticles, capsules, caplets, sachets, pellets, spheroids, mini-tablets, beads, microcapsules and pills.
Diluents play a vital role in increasing the bulk of a pharmaceutical dosage form, also improving the content uniformity, thus ensuring ease in manufacturing process of the pharmaceutical dosage form. In this specification the terms “diluent” and “diluents” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable pharmaceutical diluent according to the present subject matter can be selected from the group of, but not limited to, microcrystalline cellulose, microfine cellulose, anhydrous lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate anhydrous, tribasic calcium phosphate, kaolin, sucrose, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, powdered cellulose, sodium chloride, sorbitol, talc, and the like. Diluents in the dosage form ranges from 0% to 90.0% by weight, preferably from 20% to 70% by weight.
Binders play a vital role in ensuring the agglomeration and cohesion of the granules to each other and promoting appropriate compactibility and free-flowing properties. In this specification, the terms “binder” and “binders” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable pharmaceutical binder according to the present subject matter can be selected form the group of, but not limited to acacia, alginic acid, carbomer, carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, liquid glucose, magnesium aluminium silicate, maltodextrin, methylcellulose, povidone, pregelatinized starch, sodium alginate, starch, copovidone, ethyl cellulose, polyethylene glycol, and the like. Binders in the dosage form ranges from 0% to 15.0% by weight.
Disintegrants play a vital role in pharmaceutical compositions to enhance the dissolution and bioavailability, thus improving the drug activity. In this specification the terms “disintegrant” and “disintegrants” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable pharmaceutical disintegrants according to the present subject matter can be selected from, but not limited to alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, methyl cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate, starch, low-substituted hydroxypropyl cellulose, methyl cellulose, chitosan, glycine and the like. Disintegrants in the dosage form ranges from 0.1% to 30.0% by weight.
Glidants play a vital role in improving the powder flowability of a pharmaceutical composition. In this specification the terms “glidant” and “glidants” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable pharmaceutical glidants according to the present subject matter can be selected from, but not limited to colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, tribasic calcium phosphate, colloidal silica, calcium silicate, silicon hydrogel, and the like. Glidants in the dosage form ranges from 0% to 5.0% by weight
Lubricants play vital role in reducing friction and inn preventing sticking during manufacturing process of pharmaceutical dosage form. In this specification, the terms “lubricant”, “lubricants” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable pharmaceutical lubricants according to the present subject matter can be selected from, but not limited to, aluminium stearate, glyceryl behenate, glyceryl dibehenate, mixture of behenate esters of glycerine (e.g. a mixture of glyceryl dibehenate, tribehenin and glyceryl behenate), myristic acid, palmitic acid, silica, colloidal silica, corn starch, magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate, calcium silicate, magnesium silicate, and the like. Lubricants in the dosage form ranges from 0.5% to 5.0% by weight.
Solid and liquid pharmaceutical compositions can also be dyed using pharmaceutically acceptable colorants, to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
In liquid pharmaceutical compositions of the present invention, Ribociclib citrate dihydrate of the present disclosure and at least one pharmaceutically acceptable excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerine.
Liquid pharmaceutical compositions can contain emulsifying agents to uniformly disperse, throughout the composition, active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that can be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.
Liquid pharmaceutical compositions of the present invention can also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, and xanthan gum.
Solubilizer plays vital role in uniformly dispersing the drug and dissolving in the solution. Suitable solubilizers include, citric acid, tartaric acid, glutaric acid, lactic acid, ascorbic acid, glycolic acid, mevalonic acid, malic acid, tartronic acid, maleic acid, fumaric acid, malonic acid, succinic acid, and the like.
Flavoring agents and flavor enhancers tend to make the dosage form more palatable to the patients. Common flavoring agents and flavor enhancers for pharmaceutical dosage forms that can be included are maltol, vanillin, ethyl vanillin, menthol, ethyl maltol, strawberry, lemon, grape, cherry, and orange, and the like.
Sweetening agents are used to improve palatability of the pharmaceutical compositions. Suitable sweeteners such as glucose, sucralose, maltitol, sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve the taste.
Preservatives are used to prevent the growth of bacteria and/or fungi in the liquid composition. Suitable preservatives such as parabens (methyl, ethyl, propyl, and butyl), paraben sodium salt, potassium sorbate, sorbic acid, alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyl anisole, and ethylenediamine tetraacetic acid can be added at levels safe for ingestion to improve storage stability.
According to the present invention, a liquid composition can also contain buffer such as gluconic acid, lactic acid, citric acid, or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used can be readily determined based upon experience and consideration of standard procedures and reference works in the field.
The active ingredient and excipients can be formulated into compositions and dosage forms according to methods known in the art.
A pharmaceutical composition for tableting or capsule filling can be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water that causes the powders to clump into granules. Granulates are screened and/or milled, then dried, and then screened and/or milled to the desired particle size. They can then be tableted, or other excipients can be added prior to tableting, such as a glidant and/or a lubricant.
A tableting composition can be prepared conventionally by dry blending. For example, the blended composition of the actives and excipients can be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules can subsequently be compressed into a tablet.
As an alternative to dry granulation, a blended composition can be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate, and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.
A capsule filling of the present invention can comprise any of the aforementioned blends and granulates that were described with reference to tableting, but they are not subjected to a final tableting step.
A powder for oral solution can be prepared using Ribociclib citrate dihydrate and excipients such as diluent, solubilizer, sweetener, preservative, anti-adherent, glidant, flavor, water and combinations thereof; by the process of step by step blending together Ribociclib citrate dihydrate with other excipients and the resultant powder is reconstituted to obtain said powder for oral solution.
A pharmaceutical composition of Ribociclib citrate dihydrate can be administered. Ribociclib citrate dihydrate is formulated for administration to a mammal, preferably a human, by injection. Ribociclib citrate dihydrate can be formulated, for example, as a viscous liquid solution or suspension, preferably a clear solution, for injection. The compositions can contain one or more solvents. A suitable solvent can be selected by considering the solvent's physical and chemical stability at various pH levels, viscosity (which would allow for syringeability), fluidity, boiling point, miscibility, and purity. Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP, and Castor oil USP. Additional substances can be added to the composition such as buffers, solubilizers, and antioxidants, among others. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed.
The X-ray powder diffraction (XRPD) spectrum according to the present invention was measured on a PANalytical X'Pert PRO X- Ray Diffractometer. The parameters of the X-ray powder diffraction method of the present invention were as follows:
X-ray Reflection: Cu, Ka
Ka1 (Å): 1.54060; Ka2 (Å): 1.54443
Ka2 / Ka1 intensity ratio: 0.50
Voltage: 45 (kV), Current: 40 (mA)
Scan range: from 2.5084 degree to 40.0 degree

The invention is further exemplified by the following non-limiting examples, which are illustrative representing the preferred modes of carrying out the invention. The invention's scope is not limited to these specific embodiments only but should be read in conjunction with what is disclosed anywhere else in the specification together with those information and knowledge which are within the general understanding of the person skilled in the art.
EXAMPLES:
Example-1: Preparation of Ribociclib citrate dihydrate:
To a stirred solution of citric acid (46.5 g) in water (1000 ml) at about 25-30°C, Ribociclib base (100.0g) was added along with stirring. Reaction mass was stirred for about 4 hours at room temperature. The product obtained was filtered and dried. (Water content: ~ 5.45 %); content of Ribociclib Nitroso amine is BQL (LOQ: 0.046 ppm by LCMS)

Example-2: Preparation of Ribociclib citrate dihydrate:
Ribociclib citrate (50.0 g) obtained in reference example-1 and water (1000 ml) was stirred at about 25-30°C for several hours, filtered and dried to obtain product. (Water content: ~ 5.40 %)
Example-3: Preparation of Ribociclib citrate dihydrate:
To a stirred solution of citric acid (51 g) in water (900 ml) at about 27±3°C, Ribociclib base (100.0g) was added along with stirring. Reaction mass was stirred, during stirring reaction mass became clear and product precipitated during stirring at about 27±3°C. The product obtained was filtered, washed with water (200 ml) and dried to obtain product.
Example-4: Preparation of Ribociclib citrate dihydrate:
To a stirred solution of citric acid (50 g) in water (900 ml) and acetone (50 ml) at about 27±3°C, Ribociclib base (100.0g) was added along with stirring. The Reaction mass was stirred, during which it became clear, and the product precipitated immediately. The product obtained was filtered, washed with water (200 ml) and dried to obtain product.
Reference Example-1: Preparation of Ribociclib citrate
To a stirred solution of Ribociclib base (100.0g) in isopropanol (3600 ml) at 75-80°C was added solution of citric acid (46.5 g) in isopropanol (800 ml) along with stirring. After completion of reaction, the reaction mixture was cooled to 20°C, filtered and dried to obtain product. Content of Ribociclib Nitroso amine is ~1-2 ppm.

Dated this: 16th August 2024
Dr. S. Ganesan
Alembic Pharmaceutical Ltd.

CLAIMS:WE CLAIM:

1. Ribociclib citrate dihydrate.

2. The Ribociclib citrate dihydrate according to claim 1, which is characterized by XRPD signals, measured with Cu ka radiation, at about 5.23, 10.53, 12.88, 16.83, 18.26, 20.99 + 0.2o degree two theta.

3. The Ribociclib citrate dihydrate according to claim 1, which is characterized by its powder x-ray diffraction pattern as depicted in Figure-1.

4. A process for preparation of Ribociclib citrate dihydrate comprising
(a) contacting of Ribociclib base and citric acid or Ribociclib citrate in a suitable solvent(s); and ,
(b) isolating crystalline form of Ribociclib citrate dihydrate.

5. The process as claimed in claim 4, wherein step (a) is carried out at a temperature in the range of 15 to 40 °C.

6. The process as claimed in step (a) of claim 4, wherein suitable solvent(s) is water.

7. The process as claimed in step (a) of claim 4, wherein suitable solvent(s) is water and water miscible organic solvent(s), selected from methanol, ethanol, propanol, acetone, acetonitrile, dimethylacetamide (DMAc), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), sulfolane, THF and 2me-THF.

8. A process for preparation of Ribociclib citrate dihydrate comprising of contacting Ribociclib base with citric acid in water at a temperature in the range of 15 to 40 °C.

9. A process for preparation of a pharmaceutical composition comprising combining Ribociclib citrate dihydrate and at least one pharmaceutically acceptable excipient.

10. Use of Ribociclib citrate dihydrate according to any one of claims 1 to 3 in the preparation of a medicament.

Dated this: 16th August 2024
Dr. S. Ganesan
Alembic Pharmaceutical Ltd.