DESC:The following specification describes particularly the invention and in the manner in which it is to be performed:

SOLID DISPERSIONS OF ZANUBRUTINIB.
INTRODUCTION
Aspects of the present application relate to solid dispersions of Zanubrutinib. Specific aspects relate to amorphous solid dispersions of Zanubrutinib and preparative processes thereof.
The drug compound having the adopted name “Zanubrutinib” has chemical name: (S)-7-(1-acryloylpiperidin-4-yl)-2-(4­phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide of formula (I) as below.

Formula (I)
Zanubrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor developed and marketed by BeiGene Co Ltd as BRUKINSA™ oral capsule for the treatment for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy in U.S. Moreover, this indication is approved under accelerated approval based on overall response rate.
The US 9447106 B2 patent first disclosed Zanubrutinib generically and specifically and its use thereof for the treatment of mantle cell lymphoma (MCL). US 9447106 B2 further discloses a general procedure for the preparation of Zanubrutinib in Example-11.
Subsequently, the US 20190169201A1 patent application discloses a crystalline form of Zanubrutinib characterized by XRD, MP, DSC and TGA. Also covers crystalline form of Zanubrutinib intermediate.
The US 20190169201A1 patent application discloses alternate procedure for the preparation of Zanubrutinib and its intermediates. It also discloses the process for the preparation of crystalline form (Form A) of Zanubrutinib comprises the steps of dissolving Zanubrutinib in DCM, swapping to solvent ??, recrystallizing from ??/???? to obtain Zanubrutinib crystalline form (Form A).
The US 20190169201A1 patent application further discloses that Zanubrutnib was found to be an amorphous form prepared from the process exemplified in US9447106B2, which was further confirmed by the X-Ray Powder Diffraction pattern of FIG. 7?.
The solid forms of Zanubrutinib are not viable at industrially scale and there remains a need for alternate solid forms and their preparative processes.

SUMMARY
In an aspect, the present application provides a solid dispersion of Zanubrutinib, together with atleast one pharmaceutically acceptable excipient.

In another aspect, the present application provides an amorphous solid dispersion of Zanubrutinib, together with atleast one pharmaceutically acceptable excipient.

In another aspect, the present application provides a process for the preparation of solid dispersions comprising Zanubrutinib one or more pharmaceutically acceptable excipient said process comprising
a) providing a solution of Zanubrutinib and one or more pharmaceutically acceptable carriers in a suitable solvent or mixture of solvents; and
b) isolating amorphous solid dispersion comprising Zanubrutinib and one or more pharmaceutically acceptable carriers.

In another aspect, the present application provides a process for the preparation of amorphous solid dispersions comprising Zanubrutinib one or more pharmaceutically acceptable excipient said process comprising
a) providing a solution of Zanubrutinib and one or more pharmaceutically acceptable carriers in a suitable solvent or mixture of solvents; and
b) isolating amorphous solid dispersion comprising Zanubrutinib and one or more pharmaceutically acceptable carriers.

In another aspect the present application provides stable amorphous
Zanubrutinib.
In another aspect the present application provides a pharmaceutical composition comprising Zanubrutinib, obtained according the processes of above aspects and at least one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWING
Figures 1 to 4 are the illustrative X-ray powder diffraction patterns of amorphous solid dispersions of Zanubrutinib prepared by the methods of Example 1 to 4.

DETAILED DESCRIPTION
In an aspect, the present application provides a solid dispersion of Zanubrutinib, together with atleast one pharmaceutically acceptable excipient. In embodiments, the solid dispersion of Zanubrutinib is in amorphous state.

In an embodiment, at least one pharmaceutically acceptable excipient of this aspect may be selected from the group consisting of polyvinyl pyrrolidone, povidone K-30, povidone K-60, Povidone K-90, polyvinylpyrrolidone vinylacetate, co-povidone NF, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene–polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit or Eudragit-RLPO), hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), hydroxypropylmethyl cellulose, hydroxypropyl cellulose SSL(HPC-SSL), hydroxypropyl cellulose SL(HPC-SL), hydroxypropyl cellulose L (HPC-L), hydroxyethyl cellulose, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxymethylethylcelluloseand the like; cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, and the like; water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and the like; polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like; organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and guanidine or its derivatives, or any other excipient at any aspect of present application. The use of mixtures of more than one of the pharmaceutical excipients to provide desired release profiles or for the enhancement of stability is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, and mixtures are all within the scope of this invention without limitation. Solid dispersions of the present application also include the solid dispersions obtained by combining Zanubrutinib with a suitable non-polymeric excipient by employing techniques known in the art or procedures described or exemplified in any aspect of the instant application.
In another aspect, the present application provides an amorphous solid dispersions of Zanubrutinib, together with atleast one pharmaceutically acceptable excipient.
In an embodiment, amorphous solid dispersion of Zanubrutinib with at least one pharmaceutically acceptable excipient are characterized by a powder X-ray diffraction (PXRD) pattern, substantially as illustrated by Figures 1 to 4.
In another aspect, the present application provides an amorphous solid dispersion of Zanubrutinib with Copovidone. In embodiments, the amorphous solid dispersion of Zanubrutinib with Copovidone is characterized by a powder X-ray diffraction (PXRD) pattern, substantially as illustrated by Figure 1.
In another aspect, the present application provides an amorphous solid dispersion of Zanubrutinib with HPMC. In embodiments, the amorphous solid dispersion of Zanubrutinib with HPMC is characterized by a powder X-ray diffraction (PXRD) pattern, substantially as illustrated by Figure 2.
In another aspect, the present application provides an amorphous solid dispersion of Zanubrutinib with HPC. In embodiments, the amorphous solid dispersion of Zanubrutinib with HPC is characterized by a powder X-ray diffraction (PXRD) pattern, substantially as illustrated by Figure 3.
In another aspect, the present application provides an amorphous solid dispersion of Zanubrutinib with HPMC-AS. In embodiments, the amorphous solid dispersion of Zanubrutinib with HPMC-AS is characterized by a powder X-ray diffraction (PXRD) pattern, substantially as illustrated by Figure 4.
In another aspect, the present application provides a process for the preparation of solid dispersions comprising Zanubrutinib one or more pharmaceutically acceptable excipient said process comprising
a) providing a solution of Zanubrutinib and one or more pharmaceutically acceptable carriers in a suitable solvent or mixture of solvents; and
b) isolating amorphous solid dispersion comprising Zanubrutinib and one or more pharmaceutically acceptable carriers.
In embodiments, the solid dispersion of this aspect is amorphous solid dispersion of Zanubrutinib.
In embodiments, Zanubrutinib may be combined with atleast one pharmaceutically acceptable excipient, under heating or mechanical stress to obtain molten mixture of components. In embodiments, the molten mixture may be optionally cooled to obtain solid dispersion of Zanubrutinib with atleast one pharmaceutically acceptable excipient. In embodiments, Zanubrutinib may be combined with atleast one pharmaceutically acceptable excipient in a suitable equipment such as hot melt extruder, twin screw extruder or the like.
In embodiments, Zanubrutinib may be combined with pharmaceutically acceptable excipient in the presence of a suitable solvent. In embodiments, the suitable solvent may be selected from the group consisting of methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol, dichloromethane, tetrahydrofuran, 1-4-dioxane, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide N,N-dimethylacetamide, N-methyl-2-pyrrolidone, ethylene glycol, water and mixtures thereof.
In embodiments, at least one pharmaceutically acceptable excipient of this aspect may be selected from the group of excipients of the previous aspect.
In embodiments, combining Zanubrutinib may be carried out by dissolving Zanubrutinib and at least one pharmaceutically acceptable excipient simultaneously or separately in same or different solvents.
In embodiments, a solution of Zanubrutinib and the excipient may be prepared at any suitable temperature, such as about 0 °C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
In embodiments, a solution of Zanubrutinib and the excipient may be filtered to make it clear and free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
In embodiments, the solvent from the solution of Zanubrutinib and the excipient may be removed. In embodiments, removal of solvent may be carried out by methods known in the art or any procedure disclosed in the present application. In preferred embodiments, removal of solvent may include, but not limited to: solvent evaporation or sublimation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Büchi® Rotavapor®, spray drying, freeze drying (Lyophilization), agitated thin film drying and the like.
In preferred embodiment, the solvent may be removed under reduced pressures, at temperatures of less than about 100°C, less than about 80°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80°C, or any other suitable temperatures.
In embodiments, the isolation of the solid dispersion of Zanubrutinib with excipient involves recovering the solid obtained after removal of the solvent. The solid obtained may be recovered using techniques such as by scraping, or by shaking the container, or triturating with a solvent to make slurry followed by filtration, or other techniques specific to the equipment used.
In embodiments, the solid dispersion of Zanubrutinib and excipient obtained may be optionally dried before or after isolating the solid.
The solid dispersion of Zanubrutinib obtained may be optionally combined with at least one additional pharmaceutically acceptable excipient to obtain a premix or admixture of solid dispersion of Zanubrutinib to enhance the flow properties of solid dispersion.
In an embodiment, solid dispersion of Zanubrutinib may be combined with additional excipient using a technique known in art or according to the previous aspects of the present application.
The solid dispersion of Zanubrutinib isolated may be dried in a suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
In another aspect, the present application provides a process for the preparation of amorphous solid dispersions of Zanubrutinib, together with atleast one pharmaceutically acceptable excipient, comprising the step of combining Zanubrutinib with atleast one pharmaceutically acceptable excipient, optionally in the presence a suitable solvent. The step of combining Zanubrutinib with pharmaceutically acceptable excipient may carried out according to the process of the previous aspect.

In another aspect, Zanubrutinib amorphous form was prepared by following the process reported in US9447106B2. After purification of Zanubrutinib the resultant solution was concentrated and mixture of ethyl acetate and MTBE (10% EtOAc-MTBE) was added, suspension was stirred for 1 hour and amorphous Zanubrutinib was isolated and dried at about 50 °C.
Amorphous Zanubrutinib found to be stable atleast 9 months at ambient temperature.
In another aspect, the present application provides a solid dispersion of Zanubrutinib, obtained according to the processes of the present application, having a chemical purity of atleast 99% or atleast 99.5% by HPLC.

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 application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

Definitions
The term "about" when used in the present application preceding a number and
referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example "about 10" should be construed as meaning within the range of 9 to 11 , preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.
EXAMPLES

Example-1: Preparation of amorphous solid dispersion of Zanubrutinib with copovidone.
Zanubrutinib (250 mg) and copovidone (125 mg) were dissolved in methanol (10 mL) at 30°C. The mixture was stirred at the same temperature for 15 minutes and the resultant solution was filtered to make it particle free. The clear solution was evaporated at 45 °C under reduced pressure to obtain the title compound. PXRD: Amorphous (Figure 1).

Example-2: Preparation of amorphous solid dispersion of Zanubrutinib with HPMC.
Zanubrutinib (250 mg) and HPMC (125 mg) were dissolved in methanol (10 mL) at 30°C. The mixture was stirred at the same temperature for 15 minutes and the resultant solution was filtered to make it particle free. The clear solution was evaporated at 45°C under reduced pressure to obtain the title compound. PXRD: Amorphous (Figure 2).

Example-3: Preparation of amorphous solid dispersion of Zanubrutinib with L-HPC.
Zanubrutinib (250 mg) and L-HPC (125 mg) were dissolved in methanol (10 mL) at 30°C. The mixture was stirred at the same temperature for 15 minutes and the resultant solution was filtered to make it particle free. The clear solution was evaporated at 45°C under reduced pressure to obtain the title compound. PXRD: Amorphous (Figure 3).

Example-4: Preparation of amorphous solid dispersion of Zanubrutinib with HPMC AS.
Zanubrutinib (250 mg) and HPMC AS (125 mg) were dissolved in methanol (15 mL) at 30°C. The mixture was stirred at the same temperature for 15 minutes and the resultant solution was filtered to make it particle free. The clear solution was evaporated at 45°C under reduced pressure to obtain the title compound. PXRD: Amorphous (Figure 4).
,CLAIMS:CLAIMS

1. Amorphous solid dispersion comprising Zanubrutinib and one or more pharmaceutically acceptable excipient.

2. The solid dispersion according to claim 1, wherein the pharmaceutically acceptable excipient selected from copovidone, HPMC, L-HPC, HPMC-AS.

3. A process for the preparation of amorphous solid dispersions comprising Zanubrutinib one or more pharmaceutically acceptable excipient said process comprising

a) providing a solution of Zanubrutinib and one or more pharmaceutically acceptable carriers in a suitable solvent or mixture of solvents; and
b) isolating amorphous solid dispersion comprising Zanubrutinib and one or more pharmaceutically acceptable carriers.

4. The process according to claim 3, wherein the solvent is selected from water, alcohol, ether, ketone, acetate, N,N-dimethylacetamide, N-methyl-2-pyrrolidone.

5. The process according to claim 3, wherein the solvent is selected from water, methanol, 2-propanol, 2-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone.