(EXTRACTED FROM WIPO)(TABLES ARE NOT COPIED)
PHARMACEUTICAL COMPOSITION OF IVOSIDENIB

Technical Field of Invention

The present subject matter relates to solid oral pharmaceutical composition of drug that are inhibitors of mutant isocitrate dehydrogenase 1 or their pharmaceutically acceptable salt thereof as an active ingredient and at least one excipient, and process for preparation for the same.

Background of Invention

Isocitrate dehydrogenase 1 (IDH1) is also known as IDH mutations of IDH1 present in certain cancer cells catalyze the NAPH-dependent reduction of a-ketoglutarate to R (-)-2-hydroxyglutarate (2HG). The production of 2HG is believed to contribute to the formation and progression of cancer. The inhibition of mutant IDH1 therefore is a potential therapeutic treatment for cancer. One such example of compound that inhibits mutant IDH1 is ivosidenib. Chemical name of ivosidenib is (2S)-N- { ( IS)- 1 -(2-chlorophenyl)-2-[(3, 3-difluorocyclobutyl)-amino]-2-oxoethyl }- 1 -(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5oxopyrrolidine-2-carboxamide. The compound is identified by following structure:

Ivosidenib has been approved by United States Food & Drug Administration under the brand TIBSOVO® for the treatment of newly-diagnosed acute myeloid leukemia (AML) with a susceptible IDH1 mutation and for the treatment of relapsed or refractory AML with a susceptible IDH1 mutation. It is as provided as 250 mg tablets with a recommended dose of 500 mg orally once a day. As per United States Food & Drug Administration records, the compound belongs to BCS class II.

Ivosidenib, its process and therapeutic uses have been disclosed in US patent number US 9,474,779.

US patent number US 9,968,595 discloses certain crystalline polymorphs of ivosidenib, solid dispersion formulations of ivosidenib with polymers such as hydroxypropylmethylcellulose acetate succinate (HPMCAS) and polyvinyl acetate phthalate (PVAP), and methods of preparing such formulations. According to said disclosure, solid dispersions have improved solubility and enhance the exposure of the therapeutically active compound relative to neat crystalline forms of the therapeutically active compounds.

PCT publications WO 2020/010058 and WO 2019/104318 disclose other crystalline polymorphic forms of ivosidenib.

There is a need for alternative formulation approaches to obtain a product that may be bioequivalent to the commercial formulation with comparable dissolution and/or pharmacokinetic profile.

Summary of Invention

The subject matter of the present application relates to a solid oral pharmaceutical composition comprising ivosidenib or a pharmaceutically acceptable salt thereof as an active ingredient, and at least one pharmaceutically acceptable excipient, wherein said composition provides dissolution and/or pharmacokinetic (PK) profile that is comparable to the commercial composition of ivosidenib. The present subject matter further relates to a method of preparing such composition and use of such composition for the treatment of cancers such as newly-diagnosed acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase- 1 (IDH1) mutation, relapsed or refractory acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase- 1 (IDH1) mutation, cholangiocarcinoma, low grade glioma, and chondrosarcomas.

In one aspect, the present subject matter relates to a solid oral pharmaceutical composition comprising a solid dispersion comprising ivosidenib or pharmaceutically acceptable salt thereof, a polymer, and optionally one or more other pharmaceutically acceptable excipients.

In one aspect, the present subject matter relates to a solid oral pharmaceutical composition comprising ivosidenib or pharmaceutically acceptable salt thereof, a polymer, and optionally one or more other pharmaceutically acceptable excipients, wherein said composition is free of substantially free of solid dispersion.

In another aspect, the present subject matter relates to a solid oral pharmaceutical composition comprising ivosidenib or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, wherein said composition is non-solid dispersion composition that comprises ivosidenib in substantially amorphous form.

In some aspects, the present subject matter relates to a method of producing a solid oral pharmaceutical composition comprising a solid dispersion comprising ivosidenib or pharmaceutically acceptable salt thereof, a polymer, and optionally one or more other pharmaceutically acceptable excipients. Such methods include those that are well known in the art such as solvent evaporation techniques including spray drying, hot melt extrusion etc.

In some aspects, the present subject matter relates to a method of producing a solid oral pharmaceutical composition comprising ivosidenib or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient wherein said composition is non-solid dispersion composition. Such methods include, but not limited to direct compression, dry granulation such as slugging or roller compaction, wet granulation methods such as high-shear granulation (or rapid mixer granulation) or top spray granulation using fluidized bed processor, other granulation techniques such as twin screw granulation, etc., or one or more combinations thereof. In some aspects alternate spray drying methods also may be employed for preparing said non-solid dispersion composition.

In one aspect, said compositions described above are prepared using a crystalline form of ivosidenib as the input form.

In another aspect, said compositions described above are prepared using stable amorphous form of ivosidenib as the input form.

In one aspect, said compositions described above have a dissolution profile comparable to the commercial formulation when tested at in 900 mL of pH 6.8 Phosphate buffer with 0.6% SDS using Apparatus II at 50 rpm.

In another aspect, said compositions have a PK profile comparable to the commercial formulation at fasted and/or fed conditions.

Detailed description:

Description provided herein is not meant to be limited. Embodiments and different ways to practice the subject matter of the present application are expressly included and variations in those embodiments is considered part of the present subject matter.

Majority of the promising active pharmaceutical agents are characterized by poor water solubility which results in several difficulties during the formulation development of oral solid dosage forms of these agents. Different formulation strategies are available to enhance the dissolution properties without modifying the structure of the poorly soluble drug. One of the most common physical modifications is the formation of solid dispersion wherein a drug is molecularly dispersed in a polymeric matrix, and is in substantially amorphous form, that results in higher dissolution and increasing bioavailability of the drug.

Numerous technologies have been discovered in last few decades for the preparation of solid dispersions. Mostly solid dispersions products are prepared by the solvent-based methods, which is a particularly good choice in the case of thermo sensitive active agents. The majority of the marketed products are prepared by spray drying since it is a simple and effective technique. However, removal of residual solvents is a huge challenge in solvent-based techniques. Further, there are strict quality requirements related to the limit of the residual solvents, especially the organic solvents.

Improved solubility and dissolution of ivosidenib are reported in US 9,968,595 as described earlier. However, during the course of experimentation, it was found that a non-solid dispersion composition of ivosidenib could also provide desired improved dissolution comparable to the commercial composition.

The present subject matter relates to a solid oral pharmaceutical composition comprising ivosidenib or its pharmaceutically acceptable salt and at least one excipient.

Definitions:

The terms “composition”, “pharmaceutical composition” or “formulation” or “dosage form” or “pharmaceutical dosage form” are synonymously used in the present specification and may be in the form of, e.g., tablet, capsule, granule, powder etc. The term "tablet" refers to tablet without a coating or tablet with one or more coatings. Furthermore, the term “tablet” comprises tablets having one, two, three or even more layers and press-coated tablets, wherein each of the before mentioned types of tablets may be without or with one or more coatings.

Unless otherwise indicated, all numbers used herein to express quantities, dimensions, and so forth used should be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numbers or numerical parameters set forth herein are approximations that may vary depending upon the desired properties sought to be obtained.

As used herein, the singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to “a process” includes one or more process, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth. Similarly, the term “a polymer’ as used herein includes one or more polymers.

As used in certain contexts of the present specification, the terms ’’drug”, “active agent”, “active pharmaceutical ingredient (API)” are interchangeably used with the term “ivosidenib”, and these terms encompass free base a pharmaceutically acceptable salt or hydrate thereof.

The term "dispersion" refers to a disperse system in which one substance, the dispersed phase, is distributed, in discrete units, throughout a second substance.

The term “solid dispersion” as used herein refers to a dispersion of a drug in an inert polymer matrix at solid state, wherein interaction between the drug and the polymer occurs at the molecular level. Generally solid dispersion comprise drug in substantially amorphous form. The solid dispersion may further contain other components such as surfactants or other pharmaceutical excipients.

The term “substantially amorphous” as used herein refers to a composition wherein majority of the drug is in the form of amorphous compound, e.g. at least 50%, preferably at least 75%, more preferably at least 90% of the drug is in the amorphous form.

The term "amorphous solid dispersion" generally refers to a solid dispersion of two or more components, usually a therapeutically active compound and polymer but possibly containing other components such as surfactants or other pharmaceutical excipients, where the therapeutically active compound is in the amorphous phase.

The terms “free of solid dispersion” or “non-solid dispersion” or “non-solid dispersion composition” are interchangeably used herein in the present subject matter, and refer to a composition wherein the composition is substantially free of solid dispersion or substantially avoids solid dispersion formation of the drug (or ivosidenib), or wherein the drug (or ivosidenib) is not in the form of solid dispersion in said composition. In an aspect, said non-solid dispersion composition may be equivalent to a physical mixture that does not contain the molecular level interaction between the drug and the polymer at solid state. In one embodiment, a non-solid dispersion, or a composition free of solid dispersion exhibits distinct melting peaks of the drug and the polymer when characterized by DSC unlike solid dispersion which generally exhibits a single peak of molecularly mixed system.

The term “stable” as used herein refers to a composition comprising drug or drug substance, which retains its amorphous form or remains substantially amorphous without conversion to crystalline form, at least for a period of three months or six months under the temperature and relative humidity conditions of 40°C ± 2°C/75% RH ± 5% RH, wherein said amorphous form is represented by substantial absence of sharp characteristic peaks in X-ray diffractrogram (XRD) analysis. Further, the total amount of impurities at the end of three months or six months under the temperature and relative humidity conditions of 40°C ± 2°C/75% RH ± 5% RH, may not exceed 10% w/w. More preferably the total amount of impurity is < 8% w/w or <5% w/w at the end of three months or six months under conditions specified above. Further, said stable composition retains at least about 90% w/w of the drug under said conditions.

The term “crystalline form” as used herein refers to a solid having a highly regular chemical structure. In particular, a crystalline free base or salt form may be produced as one or more crystalline forms such as ‘form 1 ’ and/or ‘form 2’ wherein the said ‘form 1 ’ and ‘form 2’ may be defined in any of the ways described in US patent number US 9,968,595. In an embodiment, crystalline nature of a compound or a composition is represented by the presence of sharp characteristic peaks in X-ray diffractrogram (XRD) analysis.

As used herein, the term "amorphous" refers to a solid material having no regular structure. Method for determination of crystalline or amorphous form are well known in the art. In an embodiment, amorphous nature of a compound or a composition is represented by the absence of sharp peaks in XRD analysis.

The term “substantially free of’ as used herein refers to not more than (NMT) 25% w/w of the total composition, or NMT 20%, or NMT 10%, or NMT 5%, based the total weight of the composition, or completely absent in said composition.

In one aspect, the present subject matter relates to a solid oral pharmaceutical composition comprising ivosidenib or a pharmaceutically acceptable salt thereof as an active ingredient, a polymer, and optionally one or more other pharmaceutically acceptable excipients, wherein said composition comprises ivosidenib in the form of a solid dispersion.

In one embodiment, said composition comprising ivosidenib in the form of solid dispersion is prepared by methods that are well known in the art such as solvent evaporation techniques including spray drying, hot melt extrusion etc. Solvent evaporation techniques comprise the dissolution of drug and one or more polymers in a solvent or solvent mixture to form a homogeneous solution, followed

by the removal of the solvent or solvent mixture using drying methods such as, spray drying, vacuum drying, tray drying, lyophilization, and other drying procedures known in the art. Hot melt extrusion comprises molecular level dispersion of the drug into a polymer matrix at a temperature above the glass transition temperature (Tg) of the polymer, followed by solidifying the mixture by cooling.

In an aspect, the present subject matter relates to a solid oral pharmaceutical composition comprising ivosidenib or a pharmaceutically acceptable salt thereof, a polymer, and optionally one or more other pharmaceutically acceptable excipients, wherein said composition is free of solid dispersion.

In some aspects, the present subject matter relates to a solid oral pharmaceutical composition comprising ivosidenib or a pharmaceutically acceptable salt thereof, a polymer, and optionally one or more other pharmaceutically acceptable excipients, wherein said composition is free of solid dispersion, and wherein said composition comprises ivosidenib in substantially amorphous form.

In some embodiments, said composition free of solid dispersion is prepared by methods including, but not limited to, direct compression, dry granulation such as slugging or roller compaction, wet granulation such as high-shear granulation (or rapid mixer granulation), top spray granulation using fluidized bed processor etc., or other granulation techniques such as twin screw granulation, alternate spray drying methods, or one or more combinations thereof.

The methods used in the preparation of a composition free of solid dispersion as described above are conventional methods well known in the art for the preparation of solid dosage forms and a skilled artisan would understand that these do not lead to formation of solid dispersion.

In some aspects, the present subject matter relates to a solid oral pharmaceutical composition comprising a solid dispersion comprising ivosidenib or a pharmaceutically acceptable salt thereof, one or more polymers, and optionally one or more other pharmaceutically acceptable excipients.

In some aspects, the present subject matter relates to a solid oral pharmaceutical composition comprising ivosidenib or a pharmaceutically acceptable salt thereof, one or more polymers, and optionally one or more other pharmaceutically acceptable excipients, wherein said composition is free of solid dispersion.

Suitable polymers that may be used are known in the art and include, but not limited to, polyvinylpyrrolidones (PVPs); polyethylene glycols (PEGs); polyvinyl alcohols (PVA); polyvinyl esters such as polyvinyl acetate phthalate (PVAP); cellulose derivatives (e.g., hydroxypropylmethylcellulose also known as hypromellose (HPMC), hydroxypropylmethylcellulose phthalate, also known as hypromellose phthalate (HPMCP), hydroxypropylmethylcellulose acetate

succinate, also known as hypromellose acetate succinate, (HPMCAS), hydroxypropylcellulose (HPC), ethylcellulose, or cellulose acetate phthalate); poly (D, L-lactide) (PLA), poly (D,L-lactide, co-glycolide acid (PLGA); polyvinyl caprolactam-polyvinyl, and acetate -polyethyleneglycol copolymer, methylacrylate/methacrylic acid copolymeracrylates, such as polymethacrylate (e.g., Eudragit®); cyclodextrins (e.g., .beta. -cyclodextrin); polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (e.g., Soluplus); copovidone; cellulose acetate phthalate (CAP), carboxymethylcellulose (CMC) or a salt thereof (e.g., a sodium salt such as (CMC-Na); cellulose acetate trimellitate (CAT), and methylcellulose acetate phthalate (MCAP); and combinations thereof. In some embodiments, the amount of polymer(s) based on total weight of the composition may be about 10% to about 60% or from about 15% to about 55% or from about 20% to about 50% or from about 25% to about 45% or from about 30% to about 40% or from about 25% to about 40% or from about 25% to about 35% or from about 20% to about 30%. In some embodiments the amount of polymer may be about 15% or about 16% or about 17% or about 18% or about 19% or about 20% or about 21% or about 22% or about 23% or about 24% or about 25% or about 26% or about 27% or about 28% or about 29% or about 30% or about 31% or about 32% or about 33% or about 34% or about 35% or about 36% or about 37% or about 38% or about 39% or about 40%, based on the total weight of the composition.

In some aspects, the present subject matter relates to a solid oral pharmaceutical composition comprising a solid dispersion comprising: ivosidenib or a pharmaceutically acceptable salt thereof; one or more polymers comprising comprising cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, or hydroxypropyl methylcellulose acetate succinate, acrylates, methylacrylate/methacrylic acid copolymers (e.g., Eudragit®), poloxamers, polyvinylpyrrolidones, vinylpyrrolidone/vinyl acetate copolymers, polyethylene oxide, polyethylene glycol, polyvinyl caprolactam-polyvinyl acetate -polyethylene glycol graft copolymer, or combinations thereof; and optionally one or more other pharmaceutically acceptable excipients.

In some aspects, the present subject matter relates to a solid oral pharmaceutical composition comprising: ivosidenib or a pharmaceutically acceptable salt thereof; one or more polymers comprising cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, or hydroxypropyl methylcellulose acetate succinate, acrylates, methylacrylate/methacrylic acid copolymers (e.g., Eudragit®), poloxamers, polyvinylpyrrolidones, vinylpyrrolidone/vinyl acetate

copolymers, polyethylene oxide, polyethylene glycol, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, or combinations thereof; and optionally one or more other pharmaceutically acceptable excipients; wherein said composition is free of solid dispersion.

In some aspects, the present subject matter relates to a solid oral pharmaceutical composition comprising a solid dispersion comprising ivosidenib, hydroxypropyl methylcellulose acetate succinate, and optionally one or more other pharmaceutically acceptable excipients.

In some aspects, the present subject matter relates to a solid oral pharmaceutical composition comprising ivosidenib, hydroxypropyl methylcellulose acetate succinate, and optionally one or more other pharmaceutically acceptable excipients, wherein said composition is free of solid dispersion.

In some aspects, the present subject matter relates to a solid oral pharmaceutical composition comprising a solid dispersion comprising ivosidenib or a pharmaceutically acceptable salt thereof, one or more polymers selected from acrylates, methylacrylate/methacrylic acid copolymers (e.g., Eudragit®), and optionally one or more other pharmaceutically acceptable excipients.

In some aspects, the present subject matter relates to a solid oral pharmaceutical composition comprising ivosidenib or a pharmaceutically acceptable salt thereof, one or more polymers selected from acrylates, methylacrylate/methacrylic acid copolymers (e.g., Eudragit®), and optionally one or more other pharmaceutically acceptable excipients, wherein said composition is free of solid dispersion.

In some aspects, the present subject matter relates to a solid oral pharmaceutical composition comprising a solid dispersion comprising: ivosidenib or a pharmaceutically acceptable salt thereof; one or more polymers selected from poloxamers, polyvinylpyrrolidones, vinylpyrrolidone/vinyl acetate copolymers, polyethylene oxide, polyethylene glycol, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; and optionally one or more other pharmaceutically acceptable excipients.

In some aspects, the present subject matter relates to a solid oral pharmaceutical composition comprising: ivosidenib or a pharmaceutically acceptable salt thereof; one or more polymers selected from poloxamers, polyvinylpyrrolidones, vinylpyrrolidone/vinyl acetate copolymers, polyethylene oxide, polyethylene glycol, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; and optionally one or more other pharmaceutically acceptable excipients, wherein said composition is free of solid dispersion.

In some embodiments, said solid dispersion described above is prepared by the methods including those that are well known in the art such as solvent evaporation techniques including spray drying, hot melt extrusion etc.

In some embodiments, said composition free of solid dispersion described above is prepared by the methods such as direct compression, dry granulation such as slugging or roller compaction, wet granulation methods such as high-shear granulation (or rapid mixer granulation) or top spray granulation (using fluidized bed processor), other granulation techniques such as twin screw granulation, etc., or one or more combinations thereof. In some aspects alternate spray drying methods also may be employed for preparing said composition free of solid dispersion.

In some embodiments, said compositions described above are prepared using a crystalline form of ivosidenib as the input form.

In some embodiments, said compositions described above are prepared using amorphous form of ivosidenib as the input form. In some embodiments said amorphous form is a stable form.

The pharmaceutically acceptable excipients useful in the composition of the present subject matter are selected from typically used pharmaceutical excipients such as polymers, fillers, disintegrants, lubricants, binders, glidants, surfactants, pH adjusters, coating agents, colorants, or combinations thereof.

Suitable fillers that may be used are known in the art and include, but not limited to, lactose, dextrose, dextrin, mannitol, maltodextrin, isomalt, sorbitol, sucrose, dextrates, sugar spheres, xylitol, fmctose, lactitol, maltitol, erythritol, maltose, raffinose, polydextrose, trehalose, microcrystalline cellulose, calcium carbonate, calcium sulphate, dibasic calcium phosphate, chitin, chitosan, kaolin, ethylcellulose, magnesium carbonate, magnesium oxide, sodium bicarbonate, sodium carbonate, powdered cellulose, pregelatinized starch, di- and tri-basic calcium phosphate, starch and combinations thereof. The formulation of present subject matter comprises at least one filler. In some embodiments the filler may be at least one of lactose and microcrystalline cellulose. In some embodiments the filler may be other than lactose and microcrystalline cellulose. In some embodiments, the amount of filler(s) based on total weight of formulation may be from about 5% to about 60% or from about 10% to about 60% or from about 20% to about 55% or from about 20% to about 50% or from about 25% to about 40% or from about 25% to about 30% or from about 5% to about 40% or from about 10% to about 30% based on the total weight of the composition. In some embodiments, the amount of filler(s) may be from about 5% to about 10% or from about 10% to about

20% or from about 20% to about 30% based on the total weight of the composition. In some embodiments, the amount of filler(s) may be about 10% or about 11% or about 12% or about 13% or about 14% or about 15% or about 16% or about 17% or about 18% or about 19% or about 20% or about 21% or about 22% or about 23% or about 24% or about 25% or about 26% or about 27% or about 28% or about 29% or about 30% or about 31% or about 32% or about 33% or about 34% or about 35% based on total weight of composition.

Suitable disintegrants that may be used are known in the art and include, but not limited to, sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidones such as crospovidone, polacrilin potassium, cross-linked alginic acid, sodium alginate, chitosan, pregelatinized starch, hydroxypropyl cellulose, methyl cellulose, gums such as gellan gum and xanthan gum, calcium silicate sodium starch glycolate, cross-linked PVP, alginic acid, croscamellose sodium and combinations thereof. In some embodiments the disintegrant may be at least one of sodium starch glycolate and croscamellose sodium. In some embodiments the disintegrant may be other than sodium starch glycolate and croscamellose sodium. In some embodiments, the amount of disintegrant(s) based on total weight of formulation may be from about 1% to about 40% or from about 1% to about 30% or from about 1% to about 20% or from about 1% to about 15% or from about 1% to about 10% or from about 1% to about 8% or from about 1% to about 5% or from about 3% to about 7% or from about 4% to about 6% based on the total weight of the composition. In some embodiments the amount of disintegrant(s) may be about 1% or about 2% or about 3% or about 4% or about 5% or about 6% or about 7% or about 8% or about 9% or about 10% or about 11% or about 12% or about 13% or about 14% or about 15% based on total weight of composition.

Suitable lubricants that may be used are known in the art and include, but not limited to, magnesium stearate, calcium stearate, stearic acid, myristic acid, palmitic acid, hydrogenated vegetable oils, tribehenin, polyethylene glycol, glyceryl behenate, glyceryl dibehenate, glyceryl monostearate, glyceryl palmitostearate, a mixture of benenate esters of glycerine, myristic acid, sodium stearyl fumarate, sodium lauryl sulfate and combinations thereof. In some embodiments, the formulation comprises at least one or both of sodium stearyl fumarate and magnesium stearate. In some embodiments, amount of lubricant(s) based on total weight of formulation may be from about 0.2% to about 5% or from about 0.2% to about 4% or from about 0.2% to about 3% or from about 0.2% to about 2% based on the total weight of the composition. In some embodiment, the amount of lubricant(s) may be about 0.2% or about 0.3% or about 0.4% or about 0.5% or about 0.6% or about 0.7% or about 0.8% or about 0.9% or about 1% or about 1.1% or about 1.2% or about 1.3%

or about 1.4% or about 1.5% or about 1.6% or about 1.7% or about 1.8% or about 1.9% or about 2% or about 3% or about 4% based on the total weight of the composition.

Suitable binders that may be used are known in the art and include, but not limited to, pregelatinized starch, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose copovidone, acacia, alginate, alginic acid, candelilla wax, carnuba wax, liquid glucose, sucrose, tragacanth, polyethylene glycol, polyvinyl alcohol, polymethacrylates, corn starch, erythrosine sodium, gelatin, glyceryl monostearate, sodium carboxymethyl cellulose and povidone. In some aspects, the binder is copovidone, povidone, pregelatinized starch, and combinations thereof. In some further aspects, the binder is copovidone. The amount of binder(s) based on total weight of composition may be from about 1% to about 10% or from about 2% to about 8% or from about 3% to about 7% or from about 4% to about 6% based on the total weight of the composition. In some embodiments the amount of binder(s) may be about 3% or about 4% or about 5% or about 6% based on the total weight of the composition.

Suitable surfactants that may be used are known in the art and include, but not limited to, sodium, potassium, ammonium salts of long chain alkyl sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2-ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate. Cationic surfactants include quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene and coconut amine. Examples of nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG- 150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates, polyoxyethylene octylphenylether, PEG- 1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, poloxamer 401, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide. Examples of amphoteric surfactants include sodium N-dodecyl-P-alanine, sodium N-lauryl-P-iminodi propionate, myristoamphoacetate, lauryl betaine and lauryl sulfobetaine. In some embodiments, the amount of surfactant(s) based on total weight of formulation may be from about 0.5% to about 5% or about 0.5% to about 4% or about 0.5% to about 3% or about 0.5% to about 2% or about 0.5% to about 1% based on the total weight of the composition. In some embodiments the amount of surfactant(s) may be about 0.5% or about 0.6% or about 0.7% or about 0.8% or about 0.9% or about 1% or about 1.1% or

about 1.2% or about 1.3% or about 1.4% or about 1.5% or about 1.6% or about 1.7% or about 1.8% or about 1.9% or about 2%, based on the total weight of the composition.

Suitable glidants that may be used include, but not limited to, calcium phosphate tribasic, dibasic calcium phosphate, calcium silicate, cellulose, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, silicon dioxide, starch, talc, sodium stearyl fumarate and combinations thereof. In some embodiments, the amount of glidant(s) based on total weight of composition may be from about 0.2% to about 10% or from about 0.2% to about 8% or from about 0.2% to about 5% or from about 0.2% to about 4% or from about 0.2% to about 3% or from about 0.2% to about 2% based on the total weight of the composition. In some embodiments, the amount of glidant(s) may be about 0.2% or about 0.3% or 0.4% or about 0.5% or about 0.6% or about 0.7% or about 0.8% or about 0.9% or about 1% or about 1.1% or about 1.2% or about 1.3% or about 1.4% or about 1.5% or about 1.6% or about 1.7% or about 1.8% or about 1.9% or about 2% or about 2.5% or about 3% or about 3.5% or about 4% or about 4.5% or about 5%, based on the total weight of the composition.

Suitable coating materials may include commercial coating compositions such as various grades of Opadry such as Opadry® YS- 1-7003, Opadry® YS-1- 18202, Opadry® II White 85F 18422 or Opadry II 33K105003 Blue. In some embodiments, amount of coating based on total weight of composition is from about 1% to about 8% or about 2% to about 7% or about 3% to about 6% or about 4% to about 5%. The film coating may be applied using conventional methods. A coating can be used to provide protection against, for example, moisture ingress or degradation by light, to color the formulation, or to modify or control the release of the active pharmaceutical ingredient from the formulation. The coating composition as described herein may include conventional additives, such as plasticizers, pigments, colorants, stabilizing agents and glidants.

In some aspects, the present subject matter relates to methods for preparing a composition free of solid dispersion, said comprising ivosidenib or pharmaceutically acceptable salt thereof, a polymer, and one or more other pharmaceutically acceptable excipients, wherein the excipients include polymers, fillers, disintegrants, lubricants, binders, glidants, surfactants, pH adjusters, coating agents, colorants, or combinations thereof.

In some aspects, the present subject matter relates to a method of producing a solid oral pharmaceutical composition comprising ivosidenib or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient wherein said composition is free of solid dispersion. Such method includes, but not limited to, direct compression, dry granulation such as slugging or

roller compaction, wet granulation such as high-shear granulation (or rapid mixer granulation) or top spray granulation using eg: fluidized bed processor, other granulation techniques such as twin screw granulation, etc., alternate spray drying methods, and or one or more combinations thereof.

In one embodiment, a method for preparing said non-solid dispersion composition (i.e., composition ‘free of solid dispersion’ as defined herein) of ivosidenib or a pharmaceutically acceptable salt thereof comprises direct compression process. Direct compression is well known method in the art for the preparation of tablets and comprises the steps of dispensing, sieving, blending ivosidenib, polymer(s), and other excipients, lubrication and compression into tablets. Direct compression is the most straightforward manufacturing option, with the fewest manufacturing steps, making it the easiest to control and least expensive. Apart from process simplicity, the key advantages of direct compression include reduced costs for manufacture.

In one embodiment, a method for preparing said non-solid dispersion composition of ivosidenib or a pharmaceutically acceptable salt thereof comprises dry granulation process such as slugging or roller compaction. Dry granulation process is well known method in the art and comprises the steps of dispensing, sieving, blending of ivosidenib, polymer(s), and other intragranular excipients in formation of granules by slugging/roller compaction of the blended material, followed by blending the obtained granular material with extragranular material, lubrication and final compression into tablets.

In one embodiment, a method for preparing said non-solid dispersion composition of ivosidenib or a pharmaceutically acceptable salt comprises conventional wet granulation using eg: high-shear granulation (or rapid mixer granulation) or top spray granulation using eg: fluidized bed processor. These wet granulation methods comprise the steps of dispensing, sieving, blending, formation of granules using a binder solution comprising water or organic solvents, a binder, a surfactant, or combinations thereof, followed by blending with extragranular material, lubrication and final compression into tablets. In conventional wet granulation method, process of size enlargement occurs in which fine powder particles are agglomerated or brought together into larger, strong and relatively permanent structure using a suitable granulating fluid such as water, isopropanol or ethanol or combinations thereof. The granulating fluid can be used alone or as a solvent containing binder or granulating agent. Powder mixing, in conjunction with the cohesive properties of the granulating agent, enables the formation of granules. The characteristics and performance of the final product, greatly depends on the extent to which the powder particles interact with each other to form aggregates.

In top spray granulation powder ingredients are fluidized and a binder solution or suspension is sprayed onto the fluidized particles, creating liquid bridges which form agglomerates from the powder. As soon as the desired size of the agglomerates is achieved, spraying is stopped and the liquid evaporated.

In one embodiment, said wet granulation methods comprise ivosidenib, polymer(s) and other excipients in dry blend of the intragranular portion, wherein said dry blend is granulated by adding/spraying a binder solution comprising water, a binder, and optionally a surfactant, or combinations thereof.

In one embodiment, said wet granulation methods comprise polymer(s) and other excipients in the dry blend of the intragranular portion, wherein said dry blend is granulated by adding/spraying a binder solution comprising water, a binder, and optionally a surfactant, or combinations thereof, wherein ivosidenib is dispersed in said binder solution.

In one embodiment, said wet granulation methods may comprise polymer(s) and excipients in the dry blend of the intragranular portion, wherein said dry blend is processed by adding/spraying ivosidenib solution in an organic solvent (such as Methanol/IPA/DCM/Acetone/combinations thereof) followed by granulation/top-spray granulation using a binder solution comprising water, a binder, and optionally a surfactant, or combinations thereof.

In one embodiment, said wet granulation methods may comprise excipients other than polymer(s) in the dry blend of the intragranular portion, wherein said dry blend is granulated by adding/spraying ivosidenib solution in an organic solvent (such as Methanol/IPA/DCM/Acetone/combinations thereof), followed by granulation/top-spray granulation using a binder solution comprising water, a binder, and optionally a surfactant, or combinations thereof, and wherein said polymer(s) is present in the extragranular portion.

In another embodiment, said wet granulation methods may comprise polymer(s) and excipients in the dry blend of the intragranular portion, wherein said dry blend is granulated by adding/spraying a binder solution comprising ivosidenib in an organic solvent (such as Methanol/IPA/DCM/ Acetone/ combinations thereof), a binder, and optionally a surfactant, or combinations thereof.

In another embodiment, said wet granulation methods may comprise excipients other than polymer(s) in the dry blend of the intragranular portion, wherein said dry blend is granulated by adding/spraying a binder solution comprising ivosidenib in an organic solvent (such as Methanol/IPA/DCM/Acetone/ combinations thereof), a binder, and optionally a surfactant, or combinations thereof, and wherein said polymer(s) is present in extragranular portion.

In one embodiment, said material obtained by any of the above wet granulation methods is further subjected to slugging or roller compaction, followed by blending with extragranular material, lubrication, and final compression.

In one embodiment, a method for preparing said non-solid dispersion composition of ivosidenib or a pharmaceutically acceptable salt comprises other granulation techniques such as twin screw granulation. Twin screw granulation is performed by mixing and granulating the blend comprising ivosidenib, polymer(s) and optionally other excipients in a twin screw granulator at a temperature well below the glass transition temperature of polymer. In an embodiment said temperature is about 30° to about 70°C. In another embodiment, said temperature is about 40°C to about 70°C. In another embodiment, said temperature is about 30° to about 55°C. In another embodiment, said temperature is about 35°C to about 55°C. In another embodiment, the temperature does not exceed 90°C. Twin screw granulation is an alternative process to the traditional granulation techniques for better mixing and densification to improve flow with the help of a twin screw. Ivosidenib has poor flow and low bulk density. Ivosidenib drug substance in combination with polymer (such as HPMCAS / Eudragit) and optionally other excipients may be passed through a barrel with twin screw of the granulator at a temperature of about 30°C to about 70°C or about 40°C to about 70°C or about 30°C to about 55°C or 35° to about 55°C or less than about 90°C. In some embodiments, said twin screw granulation process is different from hot melt extrusion (HME) process. Hot melt extrusion process is a continuous pharmaceutical process that involves pumping polymeric materials with a rotating screw at temperatures above their glass transition temperature (Tg) and sometimes above the melting temperature (Tm) to achieve molecular level mixing of the active compounds and polymers. This molecular mixing converts the components into an amorphous product with a uniform shape and density, thereby increasing the dissolution profile of the poorly water-soluble drug. On the other hand, said twin screw granulation process employs temperatures well below (or not higher than) the glass transition temperature, hence the resultant product does not have properties equivalents to those of hot melt extruded product.

In one embodiment, said material obtained by the above twin screw granulation method is further subjected to slugging or roller compaction, followed by blending with extragranular material, lubrication and final compression into tablets.

In one embodiment, a method for preparing said non-solid dispersion composition comprises alternate spray drying methods wherein ivosidenib and other excipients such as surfactants and/or binders, excluding polymer(s), are mixed in purified water and spray dried, wherein said spray-dried material is further blended with polymer(s) and other excipients and subjected to slugging/roller compaction, followed by blending with extra granular material, lubrication and final compression into tablets.

In one embodiment, a method for preparing said non-solid dispersion composition comprises one or more combinations of: direct compression, dry granulation such as slugging or roller compaction, wet granulation such as high-shear granulation (or rapid mixer granulation) or top spray granulation using fluidized bed processor, other granulation techniques such as twin screw granulation, and alternate spray drying methods etc.

In one embodiment, a method for preparing solid dispersion composition of ivosidenib or a pharmaceutically acceptable salt thereof made comprises solvent evaporation process including spray drying. Solvent evaporation comprises the dissolution of the ivosidenib and one or more polymers in a suitable solvent or solvent mixture to form a homogeneous solution, followed by the removal of the solvent or solvent mixture using drying methods such as, spray drying, vacuum drying, tray drying, top-spray over a carriers or other excipient blend, lyophilization, and other drying procedures known in the art. Spray drying involves the atomisation of a liquid feed into very small droplets within a hot drying gas leading to flash drying of the droplets into solid particles. The particles are then separated from the drying gas, using a cyclone and/or a filter bag, as a final spray dried product. The feed can be a solution, a suspension or an emulsion and the resulting product can be classified as a powder, granules or agglomerates.

In one embodiment, said material obtained by the above solvent evaporation process is further subjected to slugging or roller compaction, followed by blending with extragranular material, lubrication, and final compression.

In one embodiment, a method for preparing solid dispersion composition of ivosidenib or a pharmaceutically acceptable salt thereof comprises Hot Melt Extrusion (HME) process. HME

comprises molecular level dispersion of ivosidenib into a polymer matrix at a temperature above the glass transition temperature (Tg) of the polymer, followed by solidifying the mixture by cooling. In this process ivosidenib is molecularly dispersed into polymeric matrix to form a solid dispersion.

In one embodiment, said material obtained by the above HME process is further subjected to slugging or roller compaction, followed by blending with extragranular material, lubrication, and final compression.

In some embodiments, the present subject matter relates to solid oral pharmaceutical composition of ivosidenib or its pharmaceutically acceptable salt thereof, wherein said composition is prepared using amorphous form of ivosidenib as the input form. In another embodiment, said composition is free of solid dispersion or is a non-solid dispersion composition. In an embodiment, said amorphous form is a stable form.

In some embodiments, the present subject matter relates to solid oral pharmaceutical composition of ivosidenib or its pharmaceutically acceptable salt thereof, wherein said composition is prepared using a crystalline form of ivosidenib as the input form. In some embodiments, crystalline form 1 and/or crystalline form 2 may be used for preparation of solid oral pharmaceutical composition of ivosidenib. In an embodiment said composition comprises solid dispersion. In another embodiment, said composition free of solid dispersion or is a non-solid dispersion composition.

For the purpose of the present subject matter, pharmaceutical composition may comprise ivosidenib in the base form or as a pharmaceutically acceptable salt, or as mixture thereof.

In some embodiments, the pharmaceutical composition of the present subject matter comprises ivosidenib in an amorphous form.

In some embodiments, the pharmaceutical composition of the present subject matter comprises ivosidenib in a crystalline form.

In one embodiment, the pharmaceutical composition of the present subject matter comprises ivosidenib or a pharmaceutically acceptable salt thereof, and one or more polymers as part of a solid dispersion or an amorphous solid dispersion. In some embodiments, the solid dispersion comprises ivosidenib or a pharmaceutically acceptable salt thereof, and one or more polymers. In some embodiments, the solid dispersion comprises ivosidenib or a pharmaceutically acceptable salt thereof, one or more polymers, and one or more surfactants.

In some embodiments, the pharmaceutical composition of the present subject matter comprises ivosidenib or a pharmaceutically acceptable salt thereof, and one or more polymers, wherein said composition is not a solid dispersion composition. In some embodiments, the pharmaceutical composition of the present subject matter comprises ivosidenib or a pharmaceutically acceptable salt thereof, one or more polymers, one or more surfactant(s), and other excipients such as fillers, binders, disintegrants, wherein said composition is not a solid dispersion composition or is substantially free of solid-dispersion.

Though solid dispersion is known to be an effective strategy to improve the solubility, dissolution rate and oral bioavailability of poorly water soluble drugs such as ivosidenib, in some embodiments of the present subject matter, it was found that a composition free of solid dispersion or a non-solid dispersion composition comprising ivosidenib or a pharmaceutically acceptable salt thereof, and one or more polymers, may have similar dissolution and/or PK profile compared to a solid dispersion composition comprising ivosidenib or a pharmaceutically acceptable salt thereof, and one or more polymers.

In some embodiments, the input form of ivosidenib is amorphous form that is stable and is retained as substantially amorphous form during and after the formulation process and in the final composition.

In some embodiments, the pharmaceutical composition of ivosidenib or a pharmaceutically acceptable salt thereof remains stable at least for a period of 3 months under the conditions of 40°C ± 2°C/75% RH ± 5% RH. In some embodiments said composition remains stable at least for a period of 6 months. In some embodiments said composition remains stable at least for a period of 12 months. In an embodiment said composition is free of solid dispersion or a non-solid dispersion composition. In another embodiment, said composition comprises ivosidenib in the form of a solid dispersion.

Solid state characterization to determine the presence or absence of solid dispersion may be carried out by known techniques in the art such as differential scanning calorimetry (DSC), thermo gravimetric analysis (TGA) and powder X-ray diffractrogram (XRD). Further solubility and dissolution profile evaluation may also be used to determine the presence or absence of solid dispersion or amorphous solid dispersion.

In some embodiments of the present subject matter, comparative characterization of differential scanning calorimetry (DSC), thermo gravimetric analysis (TGA), powder X-ray diffractrogram (XRD), solubility and dissolution of: input API; physical mixture of active pharmaceutical ingredient and suitable polymer; and product of API and suitable polymer processed by any of the aforementioned methods; may be used to determine presence or absence of solid dispersion or amorphous solid dispersion.

In some embodiments, presence of distinct peaks of API and polymer seen in differential scanning calorimetry (DSC) of the product of API and suitable polymer processed by any of the aforementioned methods, may indicate the absence of solid dispersion. In some embodiments, presence of a single peak seen in differential scanning calorimetry (DSC) of the processed blend comprising API and polymer and optionally other excipients or final composition, may indicate the presence of solid dispersion.

In some embodiments, the non-solid dispersion composition or the composition free of solid dispersion, of the present subject matter comprising ivosidenib or a pharmaceutically acceptable salt thereof, a polymer(s), and optionally one or more pharmaceutically acceptable excipients, is characterized by the presence of distinct peaks of API and polymer when analyzed by differential scanning calorimetry (DSC).

In some embodiments, solid dispersion composition of the present subject matter comprising ivosidenib or a pharmaceutically acceptable salt thereof, a polymer, and optionally one or more other pharmaceutically acceptable excipients, is characterized by the presence of single peak when analyzed by differential scanning calorimetry (DSC).

In some embodiments the pharmaceutical composition of the present subject matter comprises active ingredient ivosidenib in an amount of from about 200 mg to about 500 mg. In some embodiments, said composition comprises ivosidenib in an amount of about 250 mg or about 500mg. In some embodiments, the amount of ivosidenib based on total weight of formulation is about 10% to about 60% or from about 20% to about 60% or from about 20% to about 55% or from about 20% to about 50% or from about 25% to about 40% or from about 25% to about 30%. In some embodiments the amount of ivosidenib is about 25% or about 26% or about 27% or about 28% or about 29% or about 30% or about 31% or about 32% or about 33% or about 34% or about 35%.

Examples:

Some aspects of the present subject matter can be further illustrated by following examples:

Table 1: Compositions by Direct Compression/Dry Granulation

Manufacturing Process: The material of Examples 1 and 2 as shown in the above table are processed by direct compression wherein the ingredients are sifted, blended, lubricated and compressed into tablet and film coated. Alternatively the material is also processed by dry granulation using slugging or roller compaction wherein intragranular portion includes API, polymer and other excipients followed by blending with extragranular material, lubrication and final compression into tablets or alternatively filling into capsules. The tablets obtained may be further coated by film-coating material.

Table 2: Compositions by Solvent Evaporation/Hot melt Extrusion

Manufacturing Process: Ivosidenib and hypromellose acetate succinate (HPMCAS) of example 3 / polymer(s) listed in example 4 were dissolved in suitable solvent(s) (Methanol/IPA/DCM/Acetone) and spray dried or top sprayed on to a carrier in fluid bed processor to prepare an intermediate. Alternatively, ivosidenib and polymer(s) listed in example 5 were mixed and processed using hot melt extrusion or melt granulation, followed by blending the extruded material with HPMCAS. The intermediate spray dried material/top- sprayed material/ HME material was further processed by dry granulation such as slugging or roller compaction followed by blending with extragranular material, lubrication and final compression into tablets or alternatively filling into capsules. The tablets obtained may be further coated by film-coating material.

Table 3: Compositions by Wet Granulation Method (RMG/Top Spray using FBP)

Manufacturing Process: Ivosidenib, HPMCAS and other intragranular excipients (such as one or more of: microcrystalline cellulose, SLS, and croscarmellose sodium) were mixed and granulated using aqueous binder solution comprising PVP alone or PVP and SLS, using rapid mixer granulator (RMG) or by top-spraying the binder solution onto the dry blend in a fluid bed processor (FBP). The granulated material thus obtained is further blended with extragranular material (such as one or more of: microcrystalline cellulose, croscarmellose sodium, and silicon dioxide) followed by lubrication and final compression into tablets or alternatively filled into capsules. The excipient amounts mentioned in the examples are inclusive of their multiple applications in different processing steps involved till final compression. The tablets obtained may be further coated by film-coating material.

Table 4: Compositions by Twin Screw Granulation

by B , using HMPCAS MF grade are denoted by C.

$ Eudragit EPO/ Poloxamer 407/ Kolliphor PI 88/ Polyethylene oxide (MW ~ 100,000)/ Polyvinylpyrrolidones - Vinylpyrrolidone: vinyl acetate 6:4 (MW 45,000-70,000)/ Polyvinylpyrrolidones (MW 44,000-54,000)/ Polyethylene glycol/ Soluplus/ Hydroxypropyl methylcellulose phthalate.

Manufacturing Process: Ivosidenib, HPMCAS/ Methacrylic acid ethyl acrylate co polymer/ other Polymer as listed in the above examples, and optionally other excipients (such as one or more of: silicon dioxide; croscarmellose sodium; and sodium lauryl sulfate); were blended and passed through twin screw granulator at a temperature of about 30°C to about 70°C, or about 30°C to about 55°C, or at a temperature not exceeding about 90°C. The granulated material thus obtained, including other excipients (such as one or more of: microcrystalline cellulose, silicon dioxide, and magnesium stearate), are further processed by dry granulation such as slugging or roller compaction, followed by blending with extragranular material (such as one or more of: microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, silicon dioxide, and magnesium stearate), lubrication and final compression into tablets or alternatively filled into capsules. The excipient amounts mentioned in the examples are inclusive of their multiple applications in different processing steps involved till the final compression. The tablets obtained may be further coated by film-coating material.

Table 5: Other compositions by Top Spray Granulation using Fluid Bed Processor

Manufacturing Process: The compositions of Examples 12 and 13 are prepared by a top-spray granulation process wherein ivosidenib is dissolved in the non-aqueous binder solution comprising organic solvent(s) (Methanol/IPA/DCM/Acetone) and wherein polymer(s) such as HPMCAS/Eudragit L100 55 is either present in the intragranular portion (Example 12) or in the extragranular portion (Example 13). The listed intragranular (dry mix) materials are mixed in FBP, followed by the top-spray of non-aqueous binder solution of ivosidenib over said dry mix. The granulated material thus obtained is mixed with the extragranular material followed by lubrication and final compression into tablets or alternatively filled into capsules. The composition of Example 14 is prepared by a top-spray granulation process wherein ivosidenib is dispersed in the aqueous binder solution comprising PVP, water, and optionally SLS, and wherein polymer(s) such as HPMCAS/Eudragit L10055 is present in the intragranular portion. The listed intragranular (dry mix) materials are mixed in FBP, followed by the top-spray of the aqueous binder dispersion of ivosidenib over said dry mix. The granulated material thus obtained is further subjected to dry granulation (slugging/roller compaction) followed by blending with the extragranular material, lubrication and final compression into tablets or alternatively filled into capsules. The compositions of Example 15 and 16 are prepared by a top-spray granulation process wherein ivosidenib is present in the intragranular (dry mix) portion, wherein said intragranular portion is granulated using aqueous binder solution comprising PVP, SLS and water. The granulated material thus obtained is further subjected to dry granulation (slugging/roller compaction) followed by blending with the extragranular material, lubrication and final compression into tablets or alternatively filled into capsules. The composition of Example 17 is prepared by a top-spray granulation process wherein aqueous dispersion of ivosidenib and SLS in water is first sprayed onto the intragranular (dry mix) portion in the FBP, followed by the top spray of aqueous binder solution comprising PVP and water. The granulated material thus obtained is further subjected to dry granulation (slugging/roller compaction) followed by blending with the extragranular material, lubrication and final compression into tablets or alternatively filled into capsules. The tablets obtained may be further coated by film-coating material.

Table 6: Compositions by Alternate Spray Drying

Manufacturing Process: The compositions of Examples 18 and 19 are prepared by spray-drying of the aqueous dispersion comprising ivosidenib, polyvinyl pyrolidone, sodium lauryl sulfate and water. The spray dried material thus obtained, including other excipients (such as one or more of HPMCAS / Eudragit L10055, microcrystalline cellulose, croscarmellose sodium, and silicon dioxide and magnesium stearate) is further subjected to dry granulation (slugging/roller compaction), followed by blending with the extragranular material (such as one or more of: microcrystalline cellulose, croscarmellose sodium, and silicon dioxide), lubrication with eg magnesium stearate, and final compression into tablets or alternatively filled into capsules. The tablets obtained may be further coated by film-coating material. The composition of Example 20 is prepared in the similar manner except that polyvinyl pyrolidone is not a part of spray dried dispersion but present in the intragranular (dry granulation) portion.

Table 7: Dissolution data of some of the examples 1-20 are provided in the below table.

Dissolution conditions: pH 6.8 Phosphate buffer with 0.6% SDS/Apparatus IE 900 mL/ 50 rpm.

Table 8: Stability data for some examples are provided in the below table

The above description discloses several aspects and embodiments directed to compositions and methods of the present subject matter. This subject matter is susceptible to modifications in the methods and compositions, as well as alterations in the equipment. Such modifications will become apparent to those skilled in the art from a consideration of this disclosure or practice of the subject matter disclosed herein. Consequently, it is not intended that this subject matter be limited to the specific embodiments or aspects disclosed herein, but that it cover all modifications and alternatives coming within the true scope and spirit of the present subject matter.

Claims

1. A solid oral pharmaceutical composition comprising a solid dispersion comprising ivosidenib or a pharmaceutically acceptable salt thereof, a polymer, and optionally one or more other pharmaceutically acceptable excipients.

2. The composition of claim 1, wherein said polymer comprise cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, or hydroxypropyl methylcellulose acetate succinate, acrylates, methylacrylate/methacrylic acid copolymers (e.g., Eudragit®), poloxamers, polyvinylpyrrolidones, vinylpyrrolidone/vinyl acetate copolymers, polyethylene oxide, polyethylene glycol, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, or combinations thereof.

3. The composition of claim 1, wherein said polymer comprises hydroxypropyl methylcellulose acetate succinate.

4. The composition of claim 1, wherein said polymer comprises acrylates or methylacrylate/methacrylic acid copolymers (e.g., Eudragit®).

5. The composition of claim 1, wherein said polymer comprises poloxamers, polyvinylpyrrolidones, vinylpyrrolidone/vinyl acetate copolymers, polyethylene oxide, polyethylene glycol, or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

6. The composition of claim 1, wherein said composition comprises ivosidenib in substantially amorphous form.

7. The composition of claim 1, wherein said composition is prepared by using a crystalline form of ivosidenib as the input form.

8. The composition of claim 1, wherein said composition is prepared by using amorphous form of ivosidenib as the input form.

9. The composition of claim 1, wherein said pharmaceutically acceptable excipients comprise polymers, fillers, disintegrants, lubricants, binders, glidants, surfactants, pH adjusters, coating agents, colorants, or combinations thereof.

10. The composition of claim 1, wherein said solid dispersion is prepared by a solvent evaporation techniques such as spray drying, hot melt extrusion, or any other method known in the art.

11. The composition of claim 1, wherein said composition remains stable at least for a period of 3 months under the conditions of 40°C ± 2°C/75% RH ± 5% RH.

12. The composition of claim 11, wherein said composition retains its amorphous form or remains substantially amorphous without conversion to crystalline form.

13. The composition of claim 11, wherein the total amount of impurities in said composition at the end of three months is less than 5% w/w.

14. A solid oral pharmaceutical composition comprising ivosidenib or a pharmaceutically acceptable salt thereof, a polymer, and optionally one or more other pharmaceutically acceptable excipients, wherein said composition is free of solid dispersion.

15. The composition of claim 14, wherein said polymer comprises cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, or hydroxypropyl methylcellulose acetate succinate, acrylates, methylacrylate/methacrylic acid copolymers (e.g., Eudragit®), poloxamers, polyvinylpyrrolidones, vinylpyrrolidone/vinyl acetate copolymers, polyethylene oxide, polyethylene glycol, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, or combinations thereof.

16. The composition of claim 14, wherein said polymer comprises hydroxypropyl methylcellulose acetate succinate.

17. The composition of claim 14, wherein said polymer comprises acrylates or methylacrylate/methacrylic acid copolymers (e.g., Eudragit®).

18. The composition of claim 14, wherein said polymer comprises poloxamers, polyvinylpyrrolidones, vinylpyrrolidone/vinyl acetate copolymers, polyethylene oxide, polyethylene glycol, or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

19. The composition of claim 14, wherein said composition comprises ivosidenib in substantially amorphous form.

20. The composition of claim 14, wherein said composition is prepared by using a crystalline form of ivosidenib as the input form.

21. The composition of claim 14, wherein said composition is prepared by using amorphous form of ivosidenib as the input form.

22. The composition of claim 14, wherein said pharmaceutically acceptable excipients comprise polymers, fillers, disintegrants, lubricants, binders, glidants, surfactants, pH adjusters, coating agents, colorants, or combinations thereof.

23. The composition of claim 14, wherein said composition is prepared by direct compression, dry granulation such as slugging or roller compaction, wet granulation such as high-shear granulation (or rapid mixer granulation) or top spray granulation, other granulation techniques such as twin screw granulation, alternate spray drying methods, or combinations thereof.

24. The method of claim 23, wherein said twin screw granulation is performed by mixing and granulating the blend comprising ivosidenib, polymer(s) and optionally other excipients at a temperature well below the glass transition temperature of polymer.

25. The method of claim 24, wherein said temperature is about 30°C to about 70°C, or about 40°C to about 70°C, or about 30°C to about 55°C, or about 35° to about 55°C, or less than about 90°C.

26. The method of claim 14, wherein said composition remains stable at least for a period of 3 months or six months under the conditions of 40°C ± 2°C/75% RH ± 5% RH.

27. The composition of claim 26, wherein said composition retains its amorphous form or remains substantially amorphous without conversion to crystalline form.

28. The composition of claim 26, wherein the total amount of impurities in said composition at the end of three months, is less than 5% w/w.