PROCESS FOR PREPARATION OF RIBOCICLIB, ITS ACID ADDITION SALTS

AND THEIR SOLID FORMS

FIELD OF INVENTION

The present application relates to a process for the preparation ribociclib of formula (I) and its acid addition salts.

The present application also relates to amorphous form of ribociclib succinate and process for preparation thereof. The present application further relates to amorphous solid dispersion of ribociclib succinate, with one or more pharmaceutically acceptable carrier.

BACKGROUND OF INVENTION

US8415355B2 (hereinafter the US'355 patent) 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.

The US9193732B2 discloses the polymorphic forms of succinate salt of ribociclib, characterized by XRD, DSC, TGA, post-DVS XRD, post-DVS DSC and post-DVS TGA figures (hereinafter referred as the US' 732 patent). Another US application US2016039832A1 discloses both anhydrous and hydrated forms of succinate salt of ribociclib (hereinafter referred as the US' 832 application). Further the Chinese application CN105085533A discloses a crystalline form I of mono-succinate salt of ribociclib, characterized by XRD peaks (hereinafter referred as the CN' 533 application).

In general, polymorphism refers to the ability of a substance to exist as two or more crystalline phases that have different spatial arrangements and/or conformations of molecules in their crystal lattices. Thus, "polymorphs" refer to different crystalline forms of the same pure substance in which the molecules have different spatial arrangements of the molecules, atoms, and/or ions forming the crystal. Different polymorphs may have different physical properties such as melting points, solubilities, etc. The variation in solid forms may appreciably influence the pharmaceutical properties, such as bioavailability, handling properties, dissolution rate, and stability, and in turn such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorphic form. For these reasons, regulatory authorities require drug manufacturing companies to put efforts into identifying all polymorphic forms, e.g., crystalline, amorphous, solvates, stable dispersions with a pharmaceutically acceptable carriers, etc., of new drug substances.

The existence and possible numbers of polymorphic forms for a given compound cannot be predicted, and there are no "standard" procedures that can be used to prepare polymorphic forms of a substance. This is well-known in the art, as reported, for example, by A. Goho, "Tricky Business," Science News, Vol. 166(8), August 2004.

It has been disclosed earlier that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to crystalline forms [Konne T., Chem pharm Bull., 38, 2003(1990)]. Typically, the more crystalline the pharmaceutical agent, the lower is its bioavailability or vice varsa, reducing the degree of crystallinity has a positive effect on bioavailability. Amorphous material generally offers interesting properties such as higher dissolution rate and solubility than crystalline forms, typically resulting in improved bioavailability. An amorphous form of cefuroxime axetil is a good example for exhibiting higher bioavailability than the crystalline form.

Hence, there remains a need for alternate solid forms of ribociclib succinate and processes for preparing them.

SUMMARY OF INVENTION

First aspect of the present application relates to a process for the preparation of ribociclib of formula (I) or pharmaceutically acceptable salts thereof, comprising steps of:

(a) reacting compound of formula (IV) with compound of formula (V) to provide compound of formula (III)

(b) converting compound of formula (III) to compound of formula (II)

(c) converting compound of formula (II) to ribociclib of formula (I) in presence of a suitable reagent; and

(d) optionally converting ribociclib of formula (I) to pharmaceutically acceptable salts thereof;

wherein, P is an amino protecting group and X is a halogen.

Second aspect of the present application relates to a process for the preparation of compound of formula (III) comprising reacting compound of formula (IV) with compound of formula (V)

(IV) (V) (III)

wherein, P is an amino protecting group and X is a halogen.

Third aspect of the present application relates to a process for the preparation of ribociclib of formula (I) or pharmaceutically acceptable salts thereof, comprising steps of:

(a) reacting compound of formula (Ilia) with dimethylamine and sodium cyanide or potassium cyanide in presence of an oxidizing agent to provide compound of formula (Ila)

(b) treating compound of formula (Ila) with an acid to provide ribociclib of formula (I); and

(Ila) (I)

(c) optionally converting ribociclib of formula (I) to pharmaceutically acceptable salts thereof.

Fourth aspect of the present application relates to a compound of formula (III)

wherein, P is an amino protecting group.

Fifth aspect of the present application relates acid addition salt of Ribociclib wherein the acid is selected from a group of isethionic acid, oxalic acid, phosphoric acid, tartaric acid, acetic acid, trifluoroacetic acid, hydrobromic acid, citric acid, ^-toluenesulfonic acid.

Sixth aspect of the present application relates to amorphous form of ribociclib.

Seventh aspect of the present application relates to amorphous form of ribociclib succinate.

Eighth aspect of the present application relates to process for preparing amorphous form of ribociclib or ribociclib succinate comprising

(a) mixing ribociclib or ribociclib succinate and a suitable solvent,

(b) removing the solvent of step (a) by any suitable technique, and

(c) optionally drying amorphous ribociclib or ribociclib succinate.

Ninth aspect of the present application relates to amorphous solid dispersion of ribociclib with one or more pharmaceutically acceptable carrier.

Tenth aspect of the present application relates to amorphous solid dispersion of ribociclib succinate with one or more pharmaceutically acceptable carrier.

Eleventh aspect of the present application relates to process for preparation of amorphous solid dispersion of ribociclib or ribociclib succinate with one or more pharmaceutically acceptable carrier comprising

(a) dissolving ribociclib or ribociclib succinate and a pharmaceutically acceptable carrier in suitable solvent or mixture thereof;

(b) isolating amorphous solid dispersion of ribociclib or ribociclib succinate with a pharmaceutically acceptable carrier;

(c) optionally drying the amorphous solid dispersion of ribociclib or ribociclib succinate. Twelfth aspect of the present application relates to process for preparation of amorphous solid dispersion of ribociclib or ribociclib succinate with one or more pharmaceutically acceptable carrier comprising mixing amorphous ribociclib or ribociclib succinate with one or more pharmaceutically acceptable carrier. BRIEF DESCRIPTION OF THE DRAWING

Figure 1: The PXRD pattern of amorphous form of ribociclib obtained by the process of example 15.

Figure 2: The PXRD pattern of amorphous ribociclib succinate obtained by the process of example 16.

Figure 3: The PXRD pattern of amorphous solid dispersion of ribociclib and hydroxypropyl methylcellulose acetate succinate (1 : 1 w/w), obtained by the process of example 17.

Figure 4: The PXRD pattern of amorphous solid dispersion of ribociclib and polyvinylpyrrolidone K-90 (1 :4 w/w), obtained by the process of example 18.

Figure 5: The PXRD pattern of amorphous solid dispersion of ribociclib and Eudragit (1 :4 w/w), obtained by the process of example 19.

Figure 6: The PXRD pattern of amorphous solid dispersion of ribociclib and copovidone (1 :4 w/w), obtained by the process of example 20.

Figure 7: The PXRD pattern of amorphous solid dispersion of ribociclib and a mixture of hydroxypropyl methylcellulose acetate succinate and syloid (1 : 1 : 1 w/w), obtained by the process of example 21.

Figure 8: The PXRD pattern of amorphous solid dispersion of ribociclib and syloid (1 : 1 w/w), obtained by the process of example 22.

Figure 9: The PXRD pattern of amorphous solid dispersion of ribociclib succinate and hydroxypropyl methylcellulose acetate succinate (1 :4 w/w), obtained by the process of example 23.

Figure 10: The PXRD pattern of amorphous solid dispersion of ribociclib succinate and polyvinylpyrrolidone K-90 (1 :4 w/w), obtained by the process of example 24.

Figure 11: The PXRD pattern of amorphous solid dispersion of ribociclib succinate and Eudragit (1 :4 w/w), obtained by the process of example 25.

Figure 12: The PXRD pattern of amorphous solid dispersion of ribociclib succinate and copovidone (1 :4 w/w), obtained by the process of example 26.

Figure 13: The PXRD pattern of amorphous solid dispersion of ribociclib succinate and a mixture of Eudragit and syloid (1 : 1 : 1 w/w), obtained by the process of example 27.

Figure 14: The PXRD pattern of amorphous solid dispersion of ribociclib succinate and syloid (1 : 1 w/w), obtained by the process of example 28.

DETAILED DESCRIPTION OF INVENTION

First aspect of the present application relates to a process for the preparation of ribociclib of formula (I) or pharmaceutically acceptable salts thereof, comprising steps of: (a) reacting compound of formula (IV) with compound of formula (V) to provide compound of formula (III)

(b) converting compound of formula (III) to compound of formula (II)

(III) (II)

(c) converting compound of formula (II) to ribociclib of formula (I) in presence of a suitable reagent; and

(II) (I)

(d) optionally converting ribociclib of formula (I) to pharmaceutically acceptable salts thereof;

wherein, P is an amino protecting group and X is a halogen.

In embodiments of step (a), reaction between compound of formula (IV) and compound of formula (V) is carried out in an inert organic solvent including but not limited to polar aprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; alcoholic solvent such as methanol, isopropanol and the like; ketone solvent such as acetone, methyl isobutyl ketone and the like; ether solvent such as methyl t-butyl ether, tetrahydrofuran and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvent such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like and mixtures thereof. Specifically, the solvent may be ketone solvent. More specifically, the ketone solvent may be methyl isobutyl ketone. The reaction between compound of formula (IV) and compound of formula (V) may be carried out in presence of a palladium catalyst including but not limited to tetrakis(triphenylphosphine)palladium(0), palladium(II)acetate, tris(dibenzylideneacetone)-dipalladium(0), bis(triphenylphosphine)-palladium (Il)dichloride, and the like. Specifically, the palladium catalyst may be palladium (II) acetate. The reaction between compound of formula (IV) and compound of formula (V) may be carried out in presence of a base including but not limited to sodium tert-but oxide, lithium bis(trimethylsilyl)amide, potassium carbonate, cesium carbonate and the like. Specifically, the base may be cesium carbonate. The reaction between compound of formula (IV) and compound of formula (V) may be carried out in presence of a ligand including but not limited to l, l'-bis(diphenylphosphino)ferrocene (dppf), 2,2'-Bis(diphenylphosphino)-l,l'-binaphthyl (BINAP) and the like. Specifically, the ligand may be BINAP. The reaction of step a) may be carried out at a temperature of about 20 °C to about boiling point of the solvent.

In one embodiment, compound of formula (IV) may specifically be,

(IVa)

The compound of formula (IVa) may be prepared by a process known in the art. Specifically, the compound of formula (IVa) may be prepared by a process as described in WO2012064805A1.

In one embodiment, the compound of formula (III) may be isolated from the reaction mixture by any known technique in the art. In another embodiment the compound of formula (III) may be purified by any known method in the art. Specifically the compound of formula (III) may be crystallized from a suitable solvent or mixture thereof. In another embodiment the compound of formula (III) may be purified and the pure compound of formula (III) may be used in the next step. Specifically, the compound of formula (III) may be isolated by filtration.

In embodiments of step (b), compound of formula (III) may be converted to compound of formula (II) comprising reacting compound of formula (III) with dimethyl amine and sodium cyanide or potassium cyanide in presence of an oxidizing agent. The oxidizing agent, may include but not limited to selenium dioxide, manganese dioxide, oxone, pyridinium chlorochromate, cerium ammonium nitrate, 2,3-dichloro-5,6-dicyano-l,4-benzoquinone and the like. Specifically, the oxidizing agent may be manganese dioxide. The reaction of step (b) may be carried out in an inert organic solvent including but not limited to polar aprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; alcoholic solvent such as methanol, isopropanol and the like; ketone solvent such as acetone, methyl isobutyl ketone and the like; ether solvent such as methyl t-butyl ether, tetrahydrofuran and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvent such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like and mixtures thereof. Specifically, the solvent may be a polar aprotic solvent. More specifically, the polar aprotic solvent may be DMF. The reaction of step (b) may be carried out at a temperature of about 0 °C to about boiling point of the solvent. Specifically, the reaction of step (b) may be carried out at a temperature of about 5 °C to about 40 °C.

In one embodiment, the compound of formula (II) may be isolated from the reaction mixture by any known technique in the art. In another embodiment the compound of formula (II) may be purified by any known method in the art. Specifically, the compound of formula (II) may be crystallized from a suitable solvent or mixture thereof. In another embodiment, the compound of formula (II) may be purified and the pure compound of formula (II) may be used in the next step. In yet another embodiment, the isolated compound (II) may be used in the next step without purification.

In embodiments of step (c), compound of formula (II) may be treated with a suitable reagent to provide ribociclib of formula (I). A person skilled in the art may be able to choose a suitable reagent depending upon the protection group used in compound of formula (II). Specifically the suitable reagent may be selected from reagents as known in Greene et al., Protecting groups in organic chemistry, Third Edition, 1999.

In one embodiment, the compound of formula (I) may be isolated from the reaction mixture by any known technique in the art. In another embodiment the compound of formula (I) may be purified by any known method in the art. Specifically the compound of formula (I) may be crystallized from a suitable solvent or mixture thereof. In another embodiment the compound of formula (I) may be purified and the pure compound of formula (I) may be used in the next step. In yet another embodiment, the isolated compound (I) may be used in the next step without purification.

Optionally, in embodiments of step (d), ribociclib of formula (I) may be converted to pharmaceutically acceptable salts thereof. Second aspect of the present application relates to a process for the preparation of compound of formula (III) comprising reacting compound of formula (IV) with compound of formula (V) to provide compound of formula (III)

(IV) (V) (III)

wherein, P is an amino protecting group.

Specifically, the present application relates to the process for the preparation of compound of formula (Ilia) comprising reacting compound of formula (IVa) with compound of formula (Va) to provide compound of formula (Ilia)

(IVa) (Va) (Ilia)

The compound of formula (Va) may be prepared by a process known in the art. Specifically, the compound of formula (Va) may be prepared by a process as described in WO2010020675A1.

Third aspect of the present application relates to a process for the preparation of ribociclib of formula (I) or pharmaceutically acceptable salts thereof, comprising steps of:

(a) reacting compound of formula (Ilia) with dimethyl amine and sodium cyanide or potassium cyanide in presence of an oxidizing agent to provide compound of formula (Ila)

(Ilia) (Ila)

(b) treating compound of formula (Ila) with an acid to provide ribociclib of formula (I); and

(c) optionally, converting ribociclib of formula (I) to pharmaceutically acceptable salts thereof.

In embodiments of step (b), compound of formula (II) may be treated with an acid to provide ribociclib of formula (I). Acid used for the reaction of step (b) may include but not limited to hydrochloric acid, hydrobromic acid, triflouroacetic acid and the like. Specifically, an acid may be hydrochloric acid. The reaction of step (c) may be carried out in presence of an aromatic hydrocarbon solvent. Specifically, the aromatic hydrocarbon solvent may be toluene. The reaction of step (c) may be carried out at a temperature of about 0 °C to about boiling point of the solvent. Specifically, the reaction of step (c) may be carried out at a temperature of about 5 °C to about 27 °C.

Fourth aspect of the present application relates to a compound of formula (III)

(Ill)

wherein, P is an amino protecting group.

Specifically, P may be any amino protecting group including but not limited to tert- butyloxycarbonyl (Boc), carboxybenzyl (CBZ), acetyl, benzyl, trityl and the like.

More specifically, the present application relates to a compound of formula (Ilia)

(Ilia)

Fifth aspect of the present application relates acid addition salt of Ribociclib wherein the acid is selected from a group of isethionic acid, oxalic acid, phosphoric acid, tartaric acid, acetic acid, trifluoroacetic acid, hydrobromic acid, citric acid, ^-toluenesulfonic acid.

The present application further relates to the process for the preparation of acid addition salt of ribociclib comprising:

(a) dissolving ribocilib in a suitable solvent or mixture thereof;

(b) optionally filtering the un-dissolved particles;

(c) adding an acid to the solution of step (b);

(d) isolating acid salt of ribociclib form the solution of step (c); and

(e) optionally, drying the isolated product at suitable temperature. Ribociclib may be dissolved in a suitable solvent or mixture thereof. The suitable solvent include, but not limited to, alcohol solvent such as methanol, isopropanol and the like; ketone solvent such as acetone, methyl isobutyl ketone and the like; ether solvent such as diethyl ether, tetrahydrofuran and the like; ester solvent such as ethyl acetate, n-butyl acetate and the like; water and mixture thereof. Specifically, the solvent is an alcohol solvent. More specifically, the alcohol solvent is isopropanol. Ribociclib may be dissolved in a suitable solvent or mixture thereof at room temperature or by heating a suspension of ribociclib in a suitable solvent or mixture thereof at its boiling point. Specifically, crude ribociclib may be dissolved in a suitable solvent or mixture thereof at room temperature. The solution may be optionally filtered to remove any un-dissolved particles. In one embodiment, the desired acid may be added to the solution of ribociclib in a suitable solvent or mixture thereof directly. In another embodiment, a solution containing the desired acid in a suitable solvent or mixture thereof may be added to the solution of ribociclib in a suitable solvent or mixture thereof. In yet another embodiment, the reverse addition may also be performed wherein the solution of ribociclib in a suitable solvent or mixture thereof may be added to the acid or a solution of acid in a suitable solvent or mixture thereof. The reaction mass containing the desired acid and ribociclib in a suitable solvent or mixture thereof may be stirred for a period sufficient to form the desired product at a temperature between about 0 °C to about the boiling point of the solvent. Specifically, the reaction mass may be stirred for about 5 minutes to about 2 hours at the boiling temperature of the solvent. More specifically, the reaction mass may be stirred for 30 minutes at the boiling temperature of the solvent. After the reaction is over, the acid salt of ribociclib may be isolated from the reaction mass by any method known in the art. Specifically, the reaction mass may be cooled up to about 25-35 °C. The precipitated solid may be isolated by filtration. Optionally, the wet solid may be dried. Drying may be suitably carried out using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, specifically at temperatures less than about 80 °C and more specifically less than about 60 °C. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 30 minutes to about 24 hours, or longer.

Sixth aspect of the present application relates to amorphous form of ribociclib.

One embodiment of the present application relates to amorphous form of ribociclib characterized by a PXRD pattern substantially as illustrated in the pattern of Figure 1. Seventh aspect of the present application relates to amorphous form of ribociclib succinate.

One embodiment of the present application relates to amorphous form of ribociclib succinate characterized by a PXRD pattern substantially as illustrated in the pattern of Figure 2.

Eighth aspect of the present application relates to process for preparing amorphous form of ribociclib or ribociclib succinate comprising

(a) mixing ribociclib or ribociclib succinate and a suitable solvent,

(b) removing the solvent of step (a) by any suitable technique, and

(c) optionally drying amorphous ribociclib or ribociclib succinate.

Any crystalline form of ribociclib or mixture thereof may be used as starting material for preparing amorphous form of ribociclib. Any crystalline form of ribociclib succinate or mixture thereof may be used as starting material for preparing amorphous form of ribociclib succinate.

In embodiments of step (a), suitable solvents include, but are not limited to ketone solvent such as acetone, ethyl methyl ketone, 2-butanone, methyl isobutyl ketone and the like; ether solvent such as tetrahydrofuran, dioxane and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; halogenated hydrocarbon solvent such as dichloromethane, chloroform and the like; alcohol solvent such as methanol, ethanol, propanol, isopropanol and the like; water; mixtures thereof. Specifically, the solvent is selected from a group of alcohol solvent such as methanol, ethanol, propanol, isopropanol, tert-butanol and the like. In another embodiment, the solvent is a mixture of an alcohol solvent and a halogenated hydrocarbon solvent. Specifically, the solvent is a mixture of methanol and dichloromethane.

In one embodiment of step (a), the mixing of ribociclib or ribociclib succinate and a suitable solvent may be performed at a temperature of about 5°C to about the boiling point of the solvent. In another embodiment, ribociclib or ribociclib succinate may be dissolved in a suitable solvent at a temperature of about 5°C to about boiling point of the solvent.

In another embodiment of step (a), the solution of ribociclib or ribociclib succinate may be filtered to remove any un-dissolved particles or extraneous matter.

In one embodiment of step (b), suitable techniques that may be used for the removal of solvent include but are not limited to rotational distillation using a device such as Buchi Rotavapor, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization), Rotary cone vacuum dryer (RVPD), melt crystallization and the like, optionally under reduced pressure. One specific embodiment of the present application relates to spray-drying or freeze-drying technique, to provide amorphous form of ribociclib or ribociclib succinate. Alternatively, an anti-solvent may be added to the solution of ribociclib or ribociclib succinate of step (a) to precipitate amorphous form of ribocilcib or ribociclib succinate and the precipitated solid may be isolated by any methods known in the art, such as filtration. The suitable anti-solvent may be any organic solvent known in the art in which ribociclib or ribociclib succinate is insoluble or slightly soluble or water or a mixture thereof.

The resulting solid may be collected by using techniques such as by scraping, or by shaking the container, or other techniques specific to the equipment used.

The isolated solid may be optionally further dried to afford amorphous form of ribociclib or ribociclib succinate. Drying may be suitably carried out using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, specifically at temperatures less than about 80 °C and more specifically less than about 60 °C. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 30 minutes to about 24 hours, or longer.

The dried product may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of the product. Equipment that may be used for particle size reduction includes but not limited to ball mill, roller mill, hammer mill, and jet mill.

The amorphous form of ribociclib or ribociclib succinate that is substantially free of any crystalline form is hereby referred to as 'pure amorphous' form of ribociclib or ribociclib succinate. Pure amorphous form of ribociclib does not contain more than about 10 % of any crystalline form of ribociclib. Specifically, pure amorphous form of ribociclib does not contain more than about 5 % of any crystalline form of ribociclib. More specifically, pure amorphous form of ribociclib does not contain more than about 3 % of any crystalline form of ribociclib. Most specifically, pure amorphous form of ribociclib does not contain more than about 1% of any crystalline form of ribociclib. Fig. 1 illustrates XRPD pattern of pure amorphous form of ribociclib obtained by a process of example 15. Pure amorphous form of ribociclib succinate does not contain more than about 10 % of any crystalline form of ribociclib succinate. Specifically, pure amorphous form of ribociclib succinate does not contain more than about 5 % of any crystalline form of ribociclib succinate. More specifically, pure amorphous form of ribociclib succinate does not contain more than about 3 % of any crystalline form of ribociclib succinate. Most specifically, pure amorphous form of ribociclib succinate does not contain more than about 1% of any crystalline form of ribociclib. Fig. 2 illustrates XRPD pattern of pure amorphous form of ribociclib Succinate obtained by a process of example 16.

It was found that the amorphous ribociclib or ribociclib succinate is stable and has excellent physico-chemical properties. The amorphous form of ribociclib or ribociclib succinate of the present application may be easily formulated into a pharmaceutical composition along with suitable pharmaceutically acceptable excipients.

Another aspect of the present application provides pharmaceutical composition comprising amorphous form of ribociclib or ribociclib succinate, with one or more pharmaceutically acceptable excipients. Pharmaceutical composition comprising amorphous form of ribociclib or ribociclib succinate of the present application may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as, but not limited to, syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze dried compositions. Pharmaceutical composition may be in the forms of immediate release, delayed release, or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations; and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using any one or more of techniques such as direct blending, dry granulation, wet granulation, extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated.

Ninth aspect of the present application relates to amorphous solid dispersion of ribociclib with one or more pharmaceutically acceptable carrier.

Another aspect of the present application relates to amorphous solid dispersion of ribociclib characterized by a PXRD pattern substantially as illustrated in the pattern of Figure 3 or Figure 4 or Figure 5 or Figure 6 or Figure 7 or Figure 8.

Tenth aspect of the present application relates to amorphous solid dispersion of ribociclib succinate with one or more pharmaceutically acceptable carrier.

Another aspect of the present application relates to amorphous solid dispersion of ribociclib succinate characterized by a PXRD pattern substantially as illustrated in the pattern of Figure 9 or Figure 10 or Figure 11 or Figure 12 or Figure 13 or Figure 14. Eleventh aspect of the present application relates to process for preparation of amorphous solid dispersion of ribociclib or ribociclib Succinate with one or more pharmaceutically acceptable carrier comprising

(a) dissolving ribociclib or ribociclib Succinate and a pharmaceutically acceptable carrier in suitable solvent or mixture thereof;

(b) isolating amorphous solid dispersion of ribociclib or ribociclib Succinate with a pharmaceutically acceptable carrier;

(c) optionally drying the amorphous solid dispersion of ribociclib or ribociclib Succinate. Any crystalline form of ribociclib or mixture thereof may be used as starting material for preparing amorphous solid dispersion of ribociclib. Any crystalline form of ribociclib succinate or mixture thereof may be used as starting material for preparing amorphous solid dispersion of ribociclib succiante.

In embodiments of step (a), suitable solvents include, but are not limited to ketone solvent such as acetone, ethyl methyl ketone, 2-butanone, methyl isobutyl ketone and the like; ether solvent such as tetrahydrofuran, dioxane and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; halogenated hydrocarbon solvent such as dichloromethane, chloroform and the like; alcohol solvent such as methanol, ethanol, propanol, isopropanol and the like; mixtures thereof. Specifically, the solvent is selected from a group of alcohol solvent such as methanol, ethanol, propanol, isopropanol, tert-butanol and the like. In another embodiment, the solvent is methanol.

In one embodiment of step (a), dissolving ribociclib or ribociclib succinate in suitable solvent may be performed at a temperature of about 5°C to about the boiling point of the solvent. In another embodiment, ribociclib or ribociclib succinate may be dissolved in a suitable solvent at a temperature of about 5°C to about boiling point of the solvent.

In another embodiment of step (a), the solution of ribociclib or ribociclib succinate may be filtered to remove any un-dissolved particles or extraneous matter.

The pharmaceutically acceptable carrier may be any suitable carrier reported in the literature. Specifically, the pharmaceutically acceptable carrier includes, but not restricted to methyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl cellulose, polysaccharides, heteropolysaccharides (pectins), poloxamers, poloxamines, ethylene vinyl acetates, polyethylene glycols, dextrans, polyvinyl alcohols, propylene glycols, polyvinylacetates, phosphatidylcholines (lecithins), miglyols, polylactic acid, polyhydroxybutyric acid, polyvinylpyrrolidones (PVP), silicon dioxide (syloid), copovidone, methacrylic acid, polymethacrylate, mixtures of two or more thereof, copolymers thereof and derivatives thereof. More specifically, the pharmaceutically acceptable carrier may be selected from a group of hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, copovidone, polyvinylpyrrolidones (PVP), Eudragit and syloid.

The ratio (weight/weight) of ribociclib and pharmaceutically acceptable carrier in amorphous solid dispersion of the present application may be about 5:95, or about 10:90, or about 15:85, or about 20:80, or about 25:75, or about 30:70, or about 35:65, or about 40:60, or about 45:55, or about 50:50 and vice versa.

Isolation of amorphous solid dispersion of ribociclib or ribociclib succinate may involve one or more methods including removal of solvent by techniques known in the art e.g. evaporation, distillation, filtration of precipitated solid and the like, cooling, concentrating the reaction mass, and the like. Stirring or other alternate methods such as shaking, agitation, and the like, may also be employed for the isolation. One of the embodiments relate to addition of an anti-solvent to the solution of step (a) to precipitate amorphous solid dispersion of ribociclib or ribociclib succinate with one or more pharmaceutically acceptable carrier. Distillation of the solvent may be conducted at atmospheric pressure or above, or under reduced pressures and at a temperatures less than about 120°C, less than about 100°C, less than about 90°C, or any other suitable temperatures. Any temperature and vacuum conditions can be used as long as there is no increase in the impurity levels of the product due to decomposition.

Suitable techniques which can be used for the distillation include, but not limited to, distillation using a rotary evaporator device such as a Buchi Rotavapor, spray drying, agitated thin film drying ("ATFD"), and the like. Specifically, techniques providing a rapid solvent removal may be utilized to provide the desired amorphous solid dispersion of ribociclib or ribociclib succinate with one or more pharmaceutically acceptable carrier. More specifically, distillation using a rota-vapor device such as a Buchi Rotavapor or a spray drying technique may be used for the isolation of amorphous solid dispersion of ribociclib or ribociclib succinate with one or more pharmaceutically acceptable carrier.

The solid may be collected using techniques such as by scraping, or by shaking the container, or other techniques specific to the equipment used.

The isolated solid may be optionally further dried to afford amorphous solid dispersion of ribociclib or ribociclib succinate. Drying may be suitably carried out using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, at temperatures less than about 120°C, less than about 100°C, less than about 80°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 30 minutes to about 24 hours, or longer.

Twelfth aspect of the present application relates to process for preparation of amorphous solid dispersion of ribociclib or ribociclib succinate with one or more pharmaceutically acceptable carrier comprising mixing amorphous ribociclib or ribociclib succinate with one or more pharmaceutically acceptable carrier.

The mixing may be carried out by any known methods in the art. Specifically, the mixing may be carried out by blending. Blending of amorphous ribociclib and one or more pharmaceutically acceptable carrier may be carried out in a suitable equipment known in the art. Specifically, blending may be carried out in a V-blender, double cone blender, rotatory cone vacuum drier (RCVD). The blending may further comprise unit operations such as Rapid Mix Granulation (RMG), milling, co-milling, grinding and the like. Alternatively, the mixing of amorphous ribociclib with one or more pharmaceutically acceptable carrier may be carried out by physical blending. Physical blending may be carried out by blending amorphous ribociclib with one or more pharmaceutically acceptable carrier in a petri-dish or mortar pestle.

The obtained amorphous solid dispersion of ribociclib or ribociclib succinate may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of the amorphous solid dispersions. Equipment that may be used for particle size reduction include, but not limited to, ball, roller, and hammer mills, jet mills and the like.

It was found that the amorphous solid dispersion of ribociclib or ribociclib succinate of the present application is stable and has excellent physico-chemical properties. The amorphous solid dispersion of ribociclib or ribociclib succinate of the present application may be easily formulated into a pharmaceutical composition comprising ribociclib along with one or more pharmaceutically acceptable excipients.

Another aspect of the present application provides pharmaceutical composition comprising amorphous solid dispersion of ribociclib or ribociclib succinate, with one or more pharmaceutically acceptable excipients. Pharmaceutical composition comprising amorphous solid dispersion of ribociclib or ribociclib succinate of the present application may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as, but not limited to, syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze dried compositions. Pharmaceutical composition may be in the forms of immediate release, delayed release, or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations; and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using any one or more of techniques such as direct blending, dry granulation, wet granulation, extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated.

DEFINITIONS

The following definitions are used in connection with the present application unless the context indicates otherwise.

"Halogen" is defined as non-metallic elements found in group VII of the periodic table and is selected from fluorine, bromine, chlorine and iodine.

"Amino protecting group" is defined as any amino protecting group including but not limited to tert-butyloxycarbonyl (Boc), carboxybenzyl (CBZ), acetyl, benzyl, trityl and the like.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner.

The terms "about," "general, 'generally," and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.

A name used herein to characterize a crystalline form should not be considered limiting with respect to any other substance possessing similar or identical physical and chemical characteristics, but rather it should be understood that these designations are mere identifiers that should be interpreted according to the characterization information also presented herein. All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, the terms "comprising" and "comprises" mean the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range between two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.

The term "optional" or "optionally" is taken to mean that the event or circumstance described in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.

In general, a diffraction angle (2Θ) in powder X-ray diffractometry may have an error in the range of ± 0.2°. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ± 0.2°. Accordingly, the present application includes not only crystals whose peak diffraction angles in powder X-ray diffractometry completely coincide with each other, but also crystals whose peak diffraction angles coincide with each other with an error of about ± 0.2°. Therefore, in the present specification, the phrase "having a diffraction peak at a diffraction angle (2Θ±0.2 ) of 19.6 " means "having a diffraction peak at a diffraction angle (2Θ) of 19.4 to 19.8 . Although the intensities of peaks in the x-ray powder diffraction patterns of different batches of a compound may vary slightly, the peaks and the peak locations are characteristic for a specific polymorphic form. The relative intensities of the XRD peaks can vary depending on the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed. Moreover, instrument variation and other factors can affect the 2-theta values.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner. EXAMPLES

Example 1: Preparation of (2-chloro-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-6- yl)methanol (IVa)

To a solution of 3-(2-chloro-4-(cyclopentylamino)pyrimidin-5-yl)prop-2-yn-l-o l (27 g) in tetrahydrofuran (270 mL) was added a solution of tetra butyl ammonium fluoride in tetrahydrofuran (1M , 268 mL) at 25-30 °C and stirred for 10 minutes at the same temperature. The reaction mass was then heated to 60 °C and stirred for 4 hours at the same temperature. The reaction mass was then cooled to 25-30 °C and evaporated under reduced pressure at 45 °C. Residue obtained from the evaporation was dissolved in 2-propanol (270 mL) and stirred for 15 minutes at 25-30 °C. Water (270 mL) was added to the above solution and again stirred for 30 minutes at 20 °C. Resulting solid compound was then filtered, washed with water (2 x 30 mL) followed by n- hexane (100 mL) and methyl tert-butyl ether (100 mL), dried for 16 hours at 50 °C to afford the title compound.

Yield: 20 2 g; Purity by HPLC: 95 25 %

Example 2: Preparation of terf-butyl 4-(6-((7-cyclopentyl-6-(hydroxymethyl)-7H- pyrrolo [2,3-d] pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l-carboxylate (Ilia)

To a mixture of (2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)meth anol (IVa) (4.5 g) and tert-butyl 4-(6-aminopyridin-3-yl)piperazine-l-carboxylate (Va) (4.97 g) in methyl isobutyl ketone (36 mL) was added palladium (II) acetate (0.08 g) and 2,2'- bis(diphenylphosphino)-l, l'-binaphthyl (0.44 g) at 25-30 °C. The reaction mass was then heated to 40 °C. Cesium carbonate (8.73 g) was added to the above reaction mass portion wise at 40 °C. The reaction mass was heated to 100 °C and stirred for 3 hours. The reaction mass was cooled to 70 °C. Water (36 mL) was added to the above reaction mass at 70 °C and again cooled to 50 °C. n-Heptane (54 mL) was added to the above reaction mass drop wise at 50 °C. The reaction mass was again cooled to 20 °C and stirred for 2 hours at the same temperature. Resulting solid compound was then filtered, washed with ^-Heptane (2 ^χ 10 mL) and dried for 4 hours at 50 °C to afford title compound.

Yield: 5 2 g; Purity by HPLC: 97 01 %

Example 3: Preparation of terf-butyl 4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H- pyrrolo [2,3-d] pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l-carboxylate (Ila)

To a solution of tert-butyl 4-(6-((7-cyclopentyl-6-(hydroxymethyl)-7H-pyrrolo[2,3- d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l-carboxylate (IHa) (2.0 g) in dimethylformamide (24 mL) was added sodium cyanide (0.04 g) at 25-30 °C and cooled to 15 °C. A solution of dimethyl amine in tetrahydrofuran (2.0 M, 8 mL) was added to the above reaction mass at 15 °C and stirred for 15 minutes. Activated manganese (IV) oxide (8.45 g) was added to the above reaction mass portion wise at 15-20 °C and stirred for 16 hours at 25- 30 °C. The reaction mass was filtered through celite bed and washed with ethyl acetate (3 ^χ 30 mL). Filtrate was evaporated under reduced pressure at 50 °C to obtain the crude product. The crude product was dissolved in ethyl acetate (150 mL) and washed with aqueous ferrous sulphate solution (100 mL, 10 % w/w) followed by water (2 x 30 mL) and brine solution (50 mL). Organic layer was dried over sodium sulfate and evaporated under reduced pressure. A mixture of ethyl acetate and hexane mixture (1 :4, 20 mL) was added to the above residue and again stirred for 30 minutes at 25-30 °C. Precipitated solid product was filtered, washed with hexane (2 x 10 mL) and dried for 4 hours at 45 °C to afford the title compound.

Yield: 1 7 g; Purity by HPLC: 93 08 %

Example 4: Preparation of ribociclib free base (I)

A solution of tert-butyl 4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3- d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l-carboxylate (Ila) (50 g) in toluene (300 mL) was cooled to 10 °C. Hydrochloric acid (6N, 100 mL) was added to the above solution in drop wise at 15 °C. The reaction mass was stirred for 1 hour at 25-30 °C. Hydrochloric acid (IN, 200 mL) was added to the above reaction mass at 25-30 °C and stirred for 10 minutes at the same temperature. The reaction mass was then filtered and washed with toluene (1 x 50 mL) followed by hydrochloric acid (IN, 50 mL). Organic layer was separated and aqueous layer was cooled to 15 °C. pH of aqueous layer was adjusted to pH=12.0-12.5 using saturated solution of sodium hydroxide (50% w/w) and stirred for 1 hour at 15-20 °C. The resulted precipitate was then filtered, washed with water (3 ^χ 80 mL) and dried at 50 °C for 6 hours to provide the title compound.

Yield: 35.1 g; Purity by HPLC: 99.31 %

Example 5: Preparation of isethionic acid salt of ribociclib

Ribociclib (1.0 g) was dissolved in isopropanol (30 mL) and heated to 80 °C and stirred for 10 minutes at the same temperature. A solution of isethionic acid (0.304 g) dissolved in isopropanol (5 mL) was added to the above solution at 80 °C. The reaction mass was stirred at 80 °C for 30 minutes. The reaction mass was cooled to 25 °C to 35 °C and stirred for 16 hours. The precipitated solid was filtered and washed with «-hexane (2 x 5 mL). The wet solid was dried in hot air oven at 50 °C for 16 hours to provide the title compound.

Yield: 0 9 g; Purity by HPLC: 99 36 % Example 6: Preparation of oxalic acid salt of ribociclib

Ribociclib (1.0 g) was dissolved in isopropanol (30 mL) and heated to 80 °C and stirred for 10 minutes at the same temperature. A solution of oxalic acid (0.217 g) dissolved in isopropanol (5 mL) was added to the above solution at 80 °C. The reaction mass was stirred at 80 °C for 30 minutes. The reaction mass was cooled to 25 °C to 35 °C and stirred for 16 hours. The precipitated solid was filtered and washed with «-hexane (2 x 5 mL). The wet solid was dried in hot air oven at 50 °C for 16 hours to provide the title compound.

Yield: 1 0 g; Purity by HPLC: 98.37 %

Example 7: Preparation of tartaric acid salt of ribociclib

Ribociclib (1.5 g) was dissolved in isopropanol (45 mL) and heated to 80 °C and stirred for 10 minutes at the same temperature. A solution of tartaric acid (0.544 g) dissolved in isopropanol (7.5 mL) was added to the above solution at 80 °C. The reaction mass was stirred at 80 °C for 30 minutes. The reaction mass was cooled to 25 °C to 35 °C and stirred for 16 hours. The precipitated solid was filtered and washed with «-hexane (2 ^χ 7.5 mL). The wet solid was dried in hot air oven at 50 °C for 16 hours to provide the title compound.

Yield: 1.5 g; Purity by HPLC: 99.40 %

Example 8: Preparation of phosphoric acid salt of ribociclib

Ribociclib (1.5 g) was dissolved in isopropanol (45 mL) and heated to 80 °C and stirred for 10 minutes at the same temperature. A solution of phosphoric acid (0.35 g) dissolved in isopropanol (7.5 mL) was added to the above solution at 80 °C. The reaction mass was stirred at 80 °C for 30 minutes. The reaction mass was cooled to 25 °C to 35 °C and stirred for 16 hours. The precipitated solid was filtered and washed with «-hexane (2 ^χ 7.5 mL). The wet solid was dried in hot air oven at 50 °C for 16 hours to provide the title compound.

Yield: 0 8 g; Purity by HPLC: 99 25 %

Example 9: Preparation of acetic acid salt of ribociclib

Ribociclib (1.5 g) was dissolved in isopropanol (45 mL) and heated to 80 °C and stirred for 10 minutes at the same temperature. A solution of acetic acid (0.217 g) dissolved in isopropanol (7.5 mL) was added to the above solution at 80 °C. The reaction mass was stirred at 80 °C for 30 minutes. The reaction mass was cooled to 25 °C to 35 °C and stirred for 16 hours. The precipitated solid was filtered and washed with «-hexane (2 ^χ 7.5 mL). The wet solid was dried in hot air oven at 50 °C for 16 hours to provide the title compound.

Yield: 0 8 g; Purity by HPLC: 99 05 % Example 10: Preparation of hydrobromic acid salt of ribociclib

Ribociclib (1.5 g) was dissolved in isopropanol (45 mL) and heated to 80 °C and stirred for 10 minutes at the same temperature. An aqueous solution of hydrobromic acid (0.45 mL, 47 %) dissolved in isopropanol (7.5 mL) was added to the above solution at 80 °C. The reaction mass was stirred at 80 °C for 30 minutes. The reaction mass was cooled to 25 °C to 35 °C and stirred for 16 hours. The precipitated solid was filtered and washed with «-hexane (2 ^χ 7.5 mL). The wet solid was dried in hot air oven at 50 °C for 16 hours to provide the title compound.

Yield: 0 8 g; Purity by HPLC: 99 38 %

Example 11: Preparation of trifluoroacetic acid salt of ribociclib

Ribociclib (1.5 g) was dissolved in isopropanol (45 mL) and heated to 80 °C and stirred for 10 minutes at the same temperature. A solution of trifluoroacetic acid (0.413 g) dissolved in isopropanol (7.5 mL) was added to the above solution at 80 °C. The reaction mass was stirred at 80 °C for 30 minutes. The reaction mass was cooled to 25 °C to 35 °C and stirred for 16 hours. The precipitated solid was filtered and washed with «-hexane (2 ^χ 7.5 mL). The wet solid was dried in hot air oven at 50 °C for 16 hours to provide the title compound.

Yield: 1 3 g; Purity by HPLC: 99 66 %

Example 12: Preparation of citric acid salt of ribociclib

Ribociclib (1.5 g) was dissolved in isopropanol (45 mL) and heated to 80 °C and stirred for 10 minutes at the same temperature. A solution of citric acid (0.696 g) dissolved in isopropanol (7.5 mL) was added to the above solution at 80 °C. The reaction mass was stirred at 80 °C for 30 minutes. The reaction mass was cooled to 25 °C to 35 °C and stirred for 16 hours. The precipitated solid was filtered and washed with «-hexane (2 ^χ 7.5 mL). The wet solid was dried in hot air oven at 50 °C for 16 hours to provide the title compound.

Yield: 1 7 g; Purity by HPLC: 98 65 %

Example 13: Preparation of sulfuric acid salt of ribociclib

Ribociclib (1.5 g) was dissolved in isopropanol (45 mL) and heated to 80 °C and stirred for 10 minutes at the same temperature. A solution of sulfuric acid (0.355 g) dissolved in isopropanol (7.5 mL) was added to the above solution at 80 °C. The reaction mass was stirred at 80 °C for 30 minutes. The reaction mass was cooled to 25 °C to 35 °C and stirred for 16 hours. The precipitated solid was filtered and washed with «-hexane (2 ^χ 7.5 mL). The wet solid was dried in hot air oven at 50 °C for 16 hours to provide the title compound.

Yield: 1 72 g; Purity by HPLC: 99 38 % Example 14: Preparation of / oluenesulfonic acid salt of ribociclib

Ribociclib (1.5 g) was dissolved in isopropanol (45 mL) and heated to 80 °C and stirred for 10 minutes at the same temperature. A solution of ^-toluenesulfonic acid (0.689 g) dissolved in isopropanol (7.5 mL) was added to the above solution at 80 °C. The reaction mass was stirred at 80 °C for 30 minutes. The reaction mass was cooled to 25 °C to 35 °C and stirred for 16 hours. The precipitated solid was filtered and washed with «-hexane (2 ^χ 7.5 mL). The wet solid was dried in hot air oven at 50 °C for 16 hours to provide the title compound.

Yield: 0 9 g; Purity by HPLC: 99 65 %

EXAMPLE 15: Preparation of amorphous form of ribociclib

Ribociclib (3 g) was dissolved in a mixture of methanol-dichloromethane (20%, 450 mL) at 27 °C. The solution was filtered to make it particle-free. The solution was spray-dried under the following conditions to provide the title compound:

Inlet temperature: 70°C; Outlet temperature: 51°C; Aspirator%: 70%; Flow rate: 6 mL/min (20%); Nitrogen Pressure: 5 Kg.

EXAMPLE 16: Preparation of amorphous form of ribociclib succinate

Ribociclib succinate (3 g) was dissolved in a mixture of methanol-dichloromethane (20%, 450 mL) at 27 °C. The solution was filtered to make it particle-free. The solution was spray- dried under the following conditions to provide the title compound.

Inlet temperature: 70°C, Outlet temperature: 51 °C, Aspirator%: 70%, Flow rate: 6 mL/min (20%), Nitrogen Pressure: 5 Kg.

Example 17: Preparation of amorphous solid dispersion of ribociclib and hydroxypropyl methylcellulose acetate succinate (1:1 w/w)

Ribociclib (1 g) and hydroxypropyl methylcellulose acetate succinate (1 g) was dissolved in methanol (170 mL) at 27 °C. The solution was filtered to make it particle-free. The filtrate was evaporated in a rotavapor under the following conditions to provide the title compound. RPM: 250, Temperature: 70 °C, Vacuum Set Point: 1 torn

Example 18: Preparation of amorphous solid dispersion of ribociclib and polyvinylpyrrolidone K-90 (1:4 w/w)

Ribociclib (0.25 g) and polyvinylpyrrolidone K-90 (1 g) was dissolved in methanol (100 mL) at 27 °C. The solution was filtered to make it particle-free. The filtrate was evaporated in a rotavapor under the following conditions to provide the title compound.

RPM: 250, Temperature: 70 °C, Vacuum Set Point: 1 torn Example 19: Preparation of amorphous solid dispersion of ribociclib and Eudragit (1:4 w/w)

Ribociclib (0.25 g) and Eudragit (1 g) was mixed with methanol (100 mL) at 27 °C. The mixture was sonicated for 15 minutes to provide a clear solution. The solution was filtered to make it particle-free. The filtrate was evaporated in a rotavapor under the following conditions to provide the title compound.

RPM: 250, Temperature: 70 °C, Vacuum Set Point: 1 torn

Example 20: Preparation of amorphous solid dispersion of ribociclib and copovidone (1:4 w/w)

Ribociclib (0.25 g) and Eudragit (1 g) was mixed with methanol (100 mL) at 27 °C. The mixture was sonicated for 15 minutes to provide a clear solution. The solution was filtered to make it particle-free. The filtrate was evaporated in a rotavapor under the following conditions to provide the title compound.

RPM: 250, Temperature: 70 °C, Vacuum Set Point: 1 torn

Example 21: Preparation of amorphous solid dispersion of ribociclib and a mixture of hydroxypropyl methylcellulose acetate succinate and syloid (1:1:1 w/w)

The amorphous solid dispersion of ribociclib and hydroxypropyl methylcellulose acetate succinate (1 : 1) (250 mg), as prepared in Example 3, was mixed with syloid (125 mg) in a mortar pestle and grinded for 5 minutes to provide the desired compound.

Example 22: Preparation of amorphous solid dispersion of ribociclib and syloid (1:1 w/w)

Amorphous ribociclib (250 mg), as prepared in Example 1, was mixed with syloid (250 mg) in a mortar pestle and grinded for 10 minutes to provide the title compound.

Example 23: Preparation of amorphous solid dispersion of ribociclib succinate and hydroxypropyl methylcellulose acetate succinate (1:4 w/w)

Ribociclib succinate (0.25 g) and hydroxypropyl methylcellulose acetate succinate (1 g) was dissolved in methanol (100 mL) at 27 °C. The solution was filtered to make it particle-free. The filtrate was evaporated in a rotavapor under the following conditions to provide the desired compound.

RPM: 250, Temperature: 70 °C, Vacuum Set Point: 1 torn Example 24: Preparation of amorphous solid dispersion of ribociclib succinate and polyvinylpyrrolidone K-90 (1:4 w/w)

Ribociclib succinate (0.25 g) and polyvinylpyrrolidone K-90 (1 g) was dissolved in methanol (100 mL) at 27 °C. The solution was filtered to make it particle-free. The filtrate was evaporated in a rotavapor under the following conditions to provide the title compound.

RPM: 250, Temperature: 70 °C, Vacuum Set Point: 1 torn

Example 25: Preparation of amorphous solid dispersion of ribociclib succinate and Eudragit (1:4 w/w)

Ribociclib succinate (0.25 g) and Eudragit (1 g) was mixed with methanol (100 mL) at 27 °C. The mixture was sonicated for 15 minutes to provide a clear solution. The solution was filtered to make it particle-free. The filtrate was evaporated in a rotavapor under the following conditions to provide the title compound.

RPM: 250, Temperature: 70 °C, Vacuum Set Point: 1 torn

Example 26: Preparation of amorphous solid dispersion of ribociclib succinate and copovidone (1:4 w/w)

Ribociclib succinate (0.25 g) and copovidone (1 g) was mixed with methanol (100 mL) at 27 °C. The mixture was sonicated for 15 minutes to provide a clear solution. The solution was filtered to make it particle-free. The filtrate was evaporated in a rotavapor under the following conditions to provide the desired compound.

RPM: 250, Temperature: 70 °C, Vacuum Set Point: 1 torn

Example 27: Preparation of amorphous solid dispersion of ribociclib succinate and a mixture of Eudragit and syloid (1:4:1 w/w)

The amorphous solid dispersion of ribociclib succinate and Eudragit (1 : 1) (200 mg), as prepared in Example 11, was mixed with syloid (40 mg) in a mortar pestle and grinded for 5 minutes to provide the desired compound.

Example 28: Preparation of amorphous solid dispersion of ribociclib succinate and syloid (1:1 w/w)

Amorphous ribociclib succinate (250 mg), as prepared in Example 2, was mixed with syloid (250 mg) in a mortar pestle and grinded for 10 minutes to provide the title compound.