CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the priority of earlier Indian provisional patent application no. 201641002806, filed on January 25, 2016, which is incorporated herein in its entirety by reference.

FIELD OF THE INVENTION

The present disclosure relates generally to active pharmaceutical ingredients and more specifically to anamorphous solid dispersion of palbociclib with pharmaceutically acceptable excipients. The present disclosure also provides processes for the preparation thereof.

BACKGROUND OF THE INVENTION

Palbociclib (PD-0332991)is a potent and selective inhibitor of CDK4 and CDK6. Palbociclib is marketed in the United States as IBRANCE® by Pfizer. Chemically, palbociclib is known as 6-acetyl-8-cyclopentyl-5-methyl-2-{ [5-(piperazin-l-yl)pyridin-2yl]amino}pyrido[2,3- d]pyrimidin-7(8H)-one and has a chemical structure represented by formula- 1 below.

Formula- 1

Palbociclib and pharmaceutically acceptable salts thereof are disclosed in International Publication No. WO 2003/062236 and U.S. Patent Nos. 6,936,612; 7,208,489; and 7,456, 168, which describe the preparation of formula-1 as its hydrochloride salt. International Publication No. WO 2005/005426 and U.S. Patent Nos. 7,345, 171 and 7,863,278 describe the preparation of the free base and various mono- and di-acid addition salts of formula- 1, including polymorphic forms of the isethionate salt of palbociclib.

International Publication No. WO2014/128588A1 describes crystalline forms of palbociclib, such as polymorphic form- A and form-B.

Due to their highly organized, lattice-like structures, crystalline solids are sometimes difficult to dissolve. Chemically, the energy required to break the intermolecular forces in a crystal lattice (thus allowing dissolution of the API) is typically more than required to break the intermolecular forces in amorphous or non-crystalline forms of the same API. It is well known that, for a number of active ingredients, the amorphous form of said active ingredient exhibits different dissolution profiles and, in some cases, different bioavailability when compared to the crystalline form of the same active ingredient. (Econno T., Chem. Pharm. Bull., 1990; 38: 2003-2007).

Therefore, it is desirable to prepare the amorphous form of an active ingredient that meets the standards of various pharmaceutical regulatory agencies in a highly reproducible manner.

In view of the above, there is still a need in the art for a stable, commercially viable form of palbociclib. Thus, the present disclosure provides an amorphous solid dispersion of palbociclib that is stable and easy to prepare on a commercial scale.

SUMMARY OF THE INVENTION In one aspect, the present invention provides an amorphous solid dispersion of palbociclib.

In another aspect, the present invention provides a process for the preparation of amorphous solid dispersion of palbociclib.

In one embodiment, anamorphous solid dispersion of palbociclib may be prepared by a process that includes the steps of: a) dissolving palbociclib in an organic solvent; b) adding a pharmaceutically acceptable excipient; and c) isolating amorphous solid dispersion of palbociclib.

Within the context of this embodiment, the solvent may be, for example, an alcohol solvent, dichloromethane, or mixtures thereof.

Examples of suitable alcohol solvents include methanol, ethanol, isopropanol, n-butanol, 2- methyl- 1-propanol, 3 -methyl- 1-butanol, 1-pentanol, and mixtures thereof.

Examples of suitable pharmaceutically acceptable excipients include polymeric excipients, for example, copolymers of N-vinyl-2-pyrrolidone and vinyl acetate, povidone, 2- hydroxypropyl-P-cyclodextrin (HPpCD), hydroxypropyl methylcellulose, and mixtures thereof. In some embodiments, a copolymer of N-vinyl-2-pyrrolidone and vinyl acetate with a mass ratio of 60:40N-vinyl-2-pyrrolidone:vinyl acetate or a povidone with a K value of 30 is used.

Within the context of this embodiment, the amorphous solid dispersion of palbociclib may be isolated by removal of the solvent.

Suitable methods for removing the solvent include for example distillation, spray drying, lyophilization, or combinations thereof.

In another aspect, the present invention provides a pharmaceutical composition comprising an amorphous solid dispersion of palbociclib together with one or more additional pharmaceutically acceptable excipients.

BRIEF DESCRIPTION OF THE FIGURES The present disclosure together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of embodiments of the disclosure which are shown in the accompanying drawing figures wherein:

Figure 1 shows a powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion of palbociclib. DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that the description of the present disclosure has been simplified to illustrate elements that are relevant for a clear understanding of the invention, while eliminating, for purposes of clarity, other elements that may be well known. In one aspect, the present disclosure provides an amorphous solid dispersion of palbociclib. Within the context of the present invention, the amorphous solid dispersion of palbociclib may contain palbociclib and one or more pharmaceutically acceptable excipient. In some embodiments, polymeric excipients are particularly useful.

The solid dispersions disclosed herein may be characterized as amorphous by powder x-ray diffraction (PXRD). Therefore, samples of the amorphous solid dispersion of palbociclib, prepared by methods disclosed herein, were analyzed by PXRD on a Bruker D8 Discover powder diffractometer equipped with goniometer of Θ/2Θ configuration and LYNX EYE detector. The Cu-anode X-ray tube was operated at 40 kV and 30 mA. The experiments were conducted over the 2Θ range of 2.0 ⁰ - 50.0 °, 0.030 ⁰ step size, and 0.4 seconds step time.

The amorphous solid dispersion of palbociclib may be characterized as amorphous by PXRD, for example, by the PXRD pattern shown in Figure 1.

In another aspect, the present disclosure provides a process for the preparation of an amorphous solid dispersion of palbociclib. In one embodiment, anamorphous solid dispersion of palbociclib may be prepared by a process that includes the steps of:

a) dissolving palbociclib in an organic solvent;

b) adding a pharmaceutically acceptable excipient; and

c) isolating an amorphous solid dispersion of palbociclib. According to this embodiment, palbociclib may be dissolved an organic solvent. Within the context of this embodiment, the solvent may be an alcohol solvent, dichloromethane, or mixtures thereof. Examples of suitable alcohol solvents include methanol, ethanol, isopropanol, n-butanol, 2-methyl-l-propanol, 3-methyl-l-butanol, and 1-pentanol. Next, a pharmaceutically acceptable excipient may be added to the solution. The pharmaceutically acceptable excipient may be, for example, polysaccharides, polyvinyl pyrrolidone, polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinylpyrrolidone-vinyl acetate copolymers, Ci-C ₆ polyalkylene glycols (e.g., polypropylene glycol, polyethylene glycol), copolymers of polyethylene glycol and polypropylene glycol (e.g., the families of block copolymers based on ethylene oxide and propylene oxide sold under the PLURONIC ^® trade name), and mixtures thereof. Suitable polysaccharides include, for example, microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC), croscarmellose, carboxymethyl cellulose (CMC) and salts thereof, methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), optionally substituted a-cyclodextrins, optionally substituted β-cyclodextrins (e.g., hydroxypropyl β-cyclodextrin), optionally substituted γ- cyclodextrins (e.g., hydroxypropyl y-cyclodextrin)and mixtures thereof. As used herein, the term "substituted" with respect to cyclodextrin means the addition of side chain groups such as hydroxyl, hydroxypropyl, and other Ci-C ₆ alkyl and Ci-C ₆ hydroxyalkyl.

In particularly useful embodiments, copolymers of N-vinyl-2-pyrrolidone and vinyl acetate, for examples, those with a mass ratio of 60:40 (e.g., Plasdone S-630), povidones, for example, those with a K-value of about 30 (e.g., PVP K30), optionally substituted β- cyclodextrins (e.g., 2-hydroxypropyl-P-cyclodextrin (HPpCD)), hydroxypropyl methylcellulose (HPMC), or combinations thereof are used.

Within the context of this embodiment of the present disclosure, the pharmaceutically acceptable excipient may be combined with the solution of palbociclib from about 5 % w/w (pharmaceutically acceptable excipient/total composition mass) to about 90 % w/w, which may be about 5% w/w, 10% w/w, 15% w/w, 20% w/w, 25% w/w, 30% w/w, 35% w/w, 40% w/w, 45% w/w, 50% w/w, 55% w/w, 60% w/w, 65% w/w, 70% w/w, 75% w/w, 80% w/w, 85% w/w, 90% w/w, or between any of the aforementioned w/w percentages, including the ranges of about 5%-90%, 5%-80%, 5%-70%, 5%-60%, 5%-50%, 5%-40%, 5%-30%, 5%- 20%, 5%-10%, 10%-90%, 10%-80%, 10%-70%, 10%-60%, 10%-50%, 10%-40%, 10%-30%, 10%-20%, 20%-90%, 20%-80%, 20%-70%, 20%-60%, 20%-50%, 20%-40%, 20%-30%, 30%-90%, 30%-80%, 30%-70%, 30%-60%, 30%-50%, 30%-40%, 40%-90%, 40%-80%, 40%-70%, 40%-60%, 40%-50% w/w, 50%-90%, 50%-80%, 50%-70%, 50%-60%, 60%- 90%, 60%-80%,60%-70%, 70%-90%, 70%-80%, and 80%-90%. Next, an amorphous solid dispersion of palbociclib may be isolated. This may be carried out by methods well known in the art, for example, by removing the solvent to isolate an amorphous solid dispersion of palbociclib. Solvent removal may be carried out, for example, by distillation, spray drying, lyophilization, or other similar processes. Optionally, before isolation of the amorphous solid dispersion, the solution may be filtered to remove any undissolved materials from the solution.

In some embodiments, isolation of amorphous solid dispersion of palbociclib is carried out by spray drying using a solution feed rate of about 5 mL/min and an inlet temperature of about 70 °C to 85°C. Within the context of the present invention, the amorphous solid dispersions of palbociclib disclosed herein may be combined with one or more pharmaceutically acceptable excipients to create a pharmaceutical composition. For example, the amorphous solid dispersion of palbociclib may be combined with a lubricant, a glidant, a filler, a bulking agent, a binder, an anti-adherant, a disintegrants, a sweetener, a sorbent, artificial colorings or flavorings, or any mixtures thereof. One of skill in the art would recognize a variety of excipients and combinations thereof that would be useful for preparing a pharmaceutical composition.

In some embodiments, the amorphous solid dispersions of palbociclib prepared by methods disclosed herein may be useful in formulating a dosage form, for example, a tablet or a capsule. The tablet or capsule may contain any of the aforementioned pharmaceutically acceptable excipients, for example, microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate, gelatin, and mixtures thereof. The tablets or capsules may be coated with a shell or film that may contain gelatin, titanium dioxide, and artificial colorings such as, for example, red iron oxide, yellow iron oxide, and inks that may contain shellac, titanium dioxide, ammonium hydroxide, propylene glycol, and simethicone.

Dosage forms containing the amorphous solid dispersion of palbociclib prepared by methods disclosed herein may be useful in the treatment of metastatic breast cancer alone or when used in combination with other active ingredients, such as letrozole or fulvestrant. In some embodiments, the amorphous solid dispersion of palbociclib prepared by methods disclosed herein may exhibit long term stability. The stability of several samples of amorphous solid dispersions of palbociclib containing palbociclib and povidone with a Revalue of 30 (PVP K30) were determined by storing the samples at 40°C/75% relative humidity (RH), at 25 °C/60% relative humidity (RH), and at 5+3°C for 6 months. Table 1 below shows data collected on amorphous solid dispersions palbociclib with 50% w/w PVP- 30 prepared according to the processes disclosed herein. In certain particularly effective embodiments, the amorphous solid dispersion of palbociclib and PVP-30 displayed no change in PXRD pattern over six months under those storage conditions. Table 1

In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure. EXAMPLES

Example 1: Preparation of solid dispersion of Palbociclib with Plasdone S-630 (50% w/w)

Palbociclib (2.0g) was dissolved in a mixture of methanol (50mL) and dichloromethane (50mL) at 40-45°C. Plasdone S-630 (2.0g) was added to this clear solution which was stirred at the same temperature for 15-30minutes to get a clear solution. The clear solution was filtered through a Hyflo bed to remove any undissolved particulate and the filtrate was washed with a 1: 1 mixture of methanol and dichloromethane (20mL). The clear filtrate was then cooled to 25-30°C and subjected to spray-drying in a laboratory Spray Dryer (Model Buchi-290) with a solution feed rate of 5mL/min and an inlet temperature of 75°C with 100% aspiration to yield an amorphous solid dispersion of palbociclib with Plasdone S-630.

Example 2: Preparation of solid dispersion of Palbociclib with PVP K30 (50% w/w)

Palbociclib (5.0g) was dissolved in a mixture of methanol (125mL) and dichloromethane (125 mL) at 40-45°C. PVP K30 (5.0g) was added to this clear solution which was then stirred at the same temperature for 15-30minutes to get a clear solution. The clear solution was filtered through a Hyflo bed to remove any undissolved particulate and the filtrate was washed with a 1: 1 mixture of methanol and dichloromethane (50mL). The clear filtrate was then cooled to 25-30°C and subjected to spray drying in a laboratory Spray Dryer (Model Buchi-290) with a solution feed rate of 5mL/min and an inlet temperature at 75°C with 100% aspiration to yield an amorphous solid dispersion of palbociclib with PVP K30.