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WO2025041004A1 - Polymorphe de sel de ribociclib - Google Patents

Polymorphe de sel de ribociclib Download PDF

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Publication number
WO2025041004A1
WO2025041004A1 PCT/IB2024/057882 IB2024057882W WO2025041004A1 WO 2025041004 A1 WO2025041004 A1 WO 2025041004A1 IB 2024057882 W IB2024057882 W IB 2024057882W WO 2025041004 A1 WO2025041004 A1 WO 2025041004A1
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WO
WIPO (PCT)
Prior art keywords
ribociclib
citrate dihydrate
citrate
water
preparation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/IB2024/057882
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English (en)
Inventor
Sanjiv Tomer
Ramesh Kumar -
Kamlesh Kanzariya
Vaibhav Patel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Alembic Pharmaceuticals Ltd
Original Assignee
Alembic Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Alembic Pharmaceuticals Ltd filed Critical Alembic Pharmaceuticals Ltd
Publication of WO2025041004A1 publication Critical patent/WO2025041004A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/265—Citric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention relates to polymorph of Ribociclib citrate salt and pharmaceutical compositions thereof.
  • the present invention also relates to preparation method thereof.
  • the invention relates to Ribociclib citrate dihydrate.
  • Ribociclib 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.
  • HR hormone receptor
  • HER2 human epidermal growth factor receptor 2
  • 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.
  • HR hormone receptor
  • HER2 human epidermal growth factor receptor 2
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • An aspect of the invention is to provide Ribociclib citrate dihydrate.
  • the present invention provides a process for the preparation of crystalline form of Ribociclib citrate dihydrate comprising:
  • the present invention provides a process for preparation of Ribociclib citrate dihydrate comprising of contacting Ribociclib base with citric acid in water.
  • 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.
  • SCXRD single-crystal X-ray diffraction
  • Figure-3 Illustrates the PXRD pattern of Ribociclib citrate salt obtained according to reference example- 1.
  • the present invention provides Ribociclib citrate dihydrate.
  • the Ribociclib citrate dihydrate according to the invention is at least partially crystalline, preferably essentially crystalline, designated as Form A.
  • the Ribociclib citrate dihydrate according to the invention is at least partially amorphous, preferably essentially amorphous.
  • crystalline form A of Ribociclib citrate dihydrate which is characterized by its powder x-ray diffraction pattern as depicted in Figure- 1.
  • 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 + 0.2° degree two theta.
  • 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 + 0.2° degree two theta.
  • crystalline form A of Ribociclib citrate dihydrate is characterized by a single crystal as depicted in Figure-2.
  • Table-2 provides the experimental data and structural refinement parameters for the crystal structure analysis of crystalline Form A of Ribociclib citrate salt.
  • 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.
  • 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.
  • 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.
  • the invention relates to a process of preparation of crystalline form of Ribociclib citrate dihydrate comprising:
  • the invention relates to a process of preparation of crystalline form of Ribociclib citrate dihydrate comprising:
  • 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).
  • the step (a) involves dissolving Ribociclib base and citric acid in a suitable solvent(s), if needed involves stirring, heating and the combination thereof.
  • 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).
  • suitable solvent(s) is water which may optionally contain 5 - 10% water miscible organic solvent(s).
  • 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.
  • the invention provides a process for preparation of Ribociclib citrate dihydrate comprising contacting Ribociclib base with citric acid in water.
  • 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.
  • the isolation in step (b) is performed by any conventional methods such as cooling, filtration or combination thereof.
  • the isolation in step (b) further comprises optionally washing with a suitable solvent(s) and drying.
  • the present invention provides crystalline form A of Ribociclib citrate dihydrate having purity of greater than 99 %, more preferably greater than 99.5 %.
  • the present invention provides a crystalline form A of Ribociclib citrate dihydrate is having water content of about 4.0 to 7.0 %.
  • 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 -tertbutylhydroxy 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.
  • 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.
  • 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.
  • 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.
  • the present invention provides crystalline form A of Ribociclib citrate dihydrate having a primary particle size of from about 5 pm to about 600 pm, preferably from about 10 pm to about 300 pm, or more preferably from about 15 pm to about 200 pm. In further embodiment, the present invention provides crystalline form A of Ribociclib citrate dihydrate having particle size of D(90) not more than 600 pm, not more than 300 pm or not more than 200 pm. In further embodiment, the present invention provides crystalline form A of Ribociclib citrate dihydrate having particle size of D (50) not more than 100 pm, not more than 50 pm or not more than 20 pm. In further embodiment, the present invention provides crystalline form A of Ribociclib citrate dihydrate having particle size of D(10) not more than 50 pm, not more than 20 pm or not more than 5 pm.
  • 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.
  • 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.
  • 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.
  • their improved stability and pharmaceutical composition development flexibility support enhanced bioavailability of APIs potentially improving therapeutic outcomes and patient adherence.
  • 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.
  • the present disclosure further encompasses processes for manufacturing of pharmaceutical compositions comprising Ribociclib citrate dihydrate and at least one pharmaceutically acceptable excipient.
  • 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.
  • 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.
  • 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.
  • the terms “diluent” and “diluents” are intended to be interpreted in the context of pharmaceutical formulation science.
  • Suitable pharmaceutical diluent 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.
  • the terms “binder” and “binders” are intended to be interpreted in the context of pharmaceutical formulation science.
  • Suitable pharmaceutical binder 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.
  • 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.
  • glidanf 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.
  • lubricant lubricants
  • 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.
  • glyceryl dibehenate, tribehenin and glyceryl behenate myristic acid, palmitic acid, silica, colloidal silica, com 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.
  • 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.
  • a viscosity enhancing agent 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.
  • 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.
  • 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.
  • compositions and dosage forms 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.
  • 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.
  • 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.
  • 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, antiadherent, 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.
  • excipients such as diluent, solubilizer, sweetener, preservative, antiadherent, glidant, flavor, water and combinations thereof
  • 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:
  • Scan range: from 2.5084 degree to 40.0 degree
  • 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 %)

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Abstract

La présente invention concerne un polymorphe de sel de citrate de ribociclib et des compositions pharmaceutiques de celui-ci. La présente invention concerne également un procédé de préparation associé. En particulier, l'invention concerne le citrate de ribociclib dihydraté.
PCT/IB2024/057882 2023-08-18 2024-08-14 Polymorphe de sel de ribociclib Pending WO2025041004A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN120329307A (zh) * 2025-06-18 2025-07-18 瑞博(苏州)制药有限公司 Lee011中间体的新晶型及其制备方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018051280A1 (fr) * 2016-09-15 2018-03-22 Dr. Reddy’S Laboratories Limited Procédé de préparation de ribociclib, ses sels d'addition d'acides
WO2020152629A1 (fr) * 2019-01-23 2020-07-30 Novartis Ag Nouvelles formes cristallines d'un sel de succinate de diméthylamide d'acide 7-cyclopentyl-2-(5-pipérazin-1-yl-pyridin-2-ylamino)-7h-pyrrolo[2,3-d]pyrimidine-6-carboxylique

Patent Citations (2)

* Cited by examiner, † Cited by third party
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