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

INTRODUCTION
Aspects of the present application relates to amorphous solid dispersions of Deutetrabenazine, process for the preparation thereof and pharmaceutical composition of amorphous solid dispersions of Deutetrabenazine.
Deutetrabenazine or d6-tetrabenazine is a deuterated analog of tetrabenazine. The drug compound having the adopted name “Deutetrabenazine” has chemical name: (RR, SS)-1, 3, 4, 6, 7, 11b-hexahydro-9, 10-di(methoxy-d3)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one. Deutetrabenazine is a racemic mixture containing the following structures:

RR-Deutetrabenazine SS-Deutetrabenazine
AUSTEDOTM (deutetrabenazine) is a vesicular monoamine transporter 2 (VMAT2) inhibitor for oral administration. AUSTEDOTM was approved as oral tablets (6 mg, 9 mg, and 12 mg) by USFDA on 3 April 2017 for the treatment of chorea associated with Huntington’s disease. In August 2017 it was also approved for the treatment of tardive dyskinesia in adults.
US8524733B1 discloses Deutetrabenazine or a pharmaceutically acceptable salt thereof, method for the treatment of chronic hyperkinetic movement disorders and pharmaceutical composition thereof.
US9550780B2 discloses crystalline Form I and crystalline Form II of Deutetrabenazine. WO2017221169A1 discloses premixes of deutetrabenazine with polyvinylpyrrolidone K-30, copovidone, talc and magnesium stearate. The premixes disclosed in WO2017221169A1 contain crystalline peaks.
There remains a need for alternate solid forms of Deutetrabenazine and preparative processes thereof. Particularly, an amorphous form of a drug may exhibit a higher bioavailability than its crystalline counterparts, which leads to the selection of the amorphous form as the final drug substance for pharmaceutical dosage form development. Additionally, the solubility of crystalline form is lower than its amorphous form in some instances, particularly aqueous solubility, which may result in the difference in their in-vivo bioavailability. Therefore, it is desirable to have an amorphous form of a drug to meet the needs of drug development which is stable and also a reproducible process for their preparation. Hence, it is desirable to provide a stable amorphous solid dispersion Deutetrabenazine.
SUMMARY
In an aspect, the present application provides amorphous solid dispersion of Deutetrabenazine together with at least one pharmaceutically acceptable excipient selected from hydroxypropyl methylcellulose phthalate, polyvinylpyrrolidone-K 90 and ethyl cellulose.
In another aspect, the present application provides a process for the preparation of amorphous solid dispersion of Deutetrabenazine, comprising the steps of:
a) providing a solution of Deutetrabenazine and at least one pharmaceutically acceptable excipient in a suitable solvent or a mixture thereof;
b) removing the solvent from the solution obtained in step a); and
c) isolating the amorphous solid dispersion of Deutetrabenazine;
d) optionally combining amorphous solid dispersion of Deutetrabenazine obtained in step c) with at least one additional pharmaceutically acceptable excipient.
In another aspect, the present application provides a pharmaceutical composition comprising amorphous solid dispersion of Deutetrabenazine together with at least one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction pattern of Deutetrabenazine with hydroxypropyl methylcellulose phthalate (HPMC Phthalate HP 55) prepared by the method of Example No 1.
Figure 2 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Deutetrabenazine with polyvinylpyrrolidone-K 30 prepared by the method of Example No 2.
Figure 3 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Deutetrabenazine with copovidone VA 64 prepared by the method of Example No 3.
Figure 4 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Deutetrabenazine with polyvinylpyrrolidone-K 90 prepared by the method of Example No 4.
Figure 5 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Deutetrabenazine with ethyl cellulose prepared by the method of Example No 5.
DETAILED DESCRIPTION
In an aspect, the present application provides amorphous solid dispersion of Deutetrabenazine together with at least one pharmaceutically acceptable excipient selected from hydroxypropyl methylcellulose phthalate, polyvinylpyrrolidone-K 90 and ethyl cellulose.
In an embodiment, the present application provides amorphous solid dispersion of Deutetrabenazine together with at least one pharmaceutically acceptable excipient characterized by a powder X-ray diffraction (PXRD) pattern, substantially as illustrated by Figures 1,2,3,4,5.
In another aspect, the present application provides a process for the preparation of amorphous solid dispersion of Deutetrabenazine, comprising the steps of:
a) providing a solution of Deutetrabenazine and at least one pharmaceutically acceptable excipient in a suitable solvent or a mixture thereof;
b) removing the solvent from the solution obtained in step a); and
c) isolating the amorphous solid dispersion of Deutetrabenazine;
d) optionally combining amorphous solid dispersion of Deutetrabenazine obtained in step c) with at least one additional pharmaceutically acceptable excipient.
In an embodiment, suitable solvent at step a) may be selected from halogenated hydrocarbons, C1-C6 alcohols, C3-C6 ketones, C5-C8 aliphatic or aromatic hydrocarbons, C3-C6 esters, C2-C6 aliphatic or cyclic ethers, C2-C6 nitriles, water or mixtures thereof.
In preferred embodiment, the suitable solvent may be selected from the group consisting of dichloromethane, methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran, water and mixtures thereof.
In an embodiment, at least one pharmaceutically acceptable excipient of this aspect may be selected from hydroxypropyl methylcellulose phthalate, polyvinylpyrrolidone-K 90 and ethyl cellulose.
In addition to the pharmaceutically acceptable excipients provided in the examples described in this application, any other suitable excipient can also be used for preparation of amorphous solid dispersion.
In an embodiment, the other suitable pharmaceutically acceptable excipient of this aspect may be selected from the group consisting of polyvinyl pyrrolidone, povidone K-60, hydroxypropyl cellulose, hydroxypropyl cellulose SSL(HPC-SSL), hydroxypropyl cellulose SL(HPC-SL), hydroxypropyl cellulose L (HPC-L), hydroxypropylmethyl cellulose, methyl cellulose 15 cps, prosolv HD 40, syloid, syloid 244 NF, polyvinylpyrrolidone vinylacetate, 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, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, 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; homopolymers and copolymers of N-vinyl lactams, cellulose esters, cellulose ethers, high molecular weight polyalkylene oxides, polyacrylamides, vinyl acetate polymers, graft copolymers of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate, oligo- and polysaccharides and mixtures thereof 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.
Any physical form of Deutetrabenazine may be utilized for providing the solution of Deutetrabenazine in step a). Deutetrabenazine that may be used as the input for the process of the present invention may be obtained by the processes described in the art. For example Deutetrabenazine may be prepared by the processes described in US8524733B1, US9550780B2, WO2015084622A1, WO2011153157A2 and WO2017182916A1.
In an embodiment, providing a solution at step a) may be carried out by taking the reaction mixture containing Deutetrabenazine directly or by dissolving Deutetrabenazine and at least one pharmaceutically acceptable excipient in a suitable solvent simultaneously or by dissolving components in a suitable solvent separately to form individual solutions and combining those solutions later.
In an embodiment, a solution of Deutetrabenazine and the excipient may be prepared at any suitable temperatures, 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 an embodiment, a solution of Deutetrabenazine and the excipient may be filtered to make it clear, 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 an embodiment, removal of solvent at step b) 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 under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using buchi rotavapor, spray drying, freeze drying, agitated thin film drying, filtration 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 60°C, less than about 40°C, or any other suitable temperatures.
In an embodiment, the isolation of an amorphous solid dispersion of Deutetrabenazine and excipient at step c) involves recovering the solid obtained in step b). The solid obtained from step b) may be recovered using techniques such as by scraping, or by shaking the container, or adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used.
Amorphous solid dispersion of Deutetrabenazine obtained at step c) may be optionally combined with at least one additional pharmaceutically acceptable excipient at step d).
In an embodiment, amorphous solid dispersion of Deutetrabenazine may be combined with additional excipient using a technique known in art or by the procedures disclosed in the present application.
In preferred embodiment, amorphous solid dispersion of the present application may be combined with additional excipient either by physical blending of both the solid components or by suspending both the components in a suitable solvent and conditions, such that both the components remain unaffected. Blending may be carried out using techniques known in art such as rotatory cone dryer, fluidized bed dryer or the like optionally under reduced pressure / vacuum or inert atmosphere such nitrogen at suitable temperature and sufficient time to obtain uniform composition of amorphous solid dispersion of Deutetrabenazine with pharmaceutically acceptable excipient and at least one additional pharmaceutically acceptable excipient.
In an embodiment, amorphous solid dispersion of the present application may be combined with additional excipient by evaporating the suspension or solution of amorphous solid dispersion of Deutetrabenazine and additional excipient.
In an embodiment, pharmaceutically acceptable additional excipient may be same or different from the excipient used in the preparation of amorphous solid dispersion of Deutetrabenazine. Additional excipient may include, but not limited to an inorganic oxide such as SiO2, TiO2, ZnO2, ZnO, Al2O3 and zeolite; a water insoluble polymer is selected from the group consisting of cross- polyvinyl pyrrolidinone, cross-linked cellulose acetate phthalate, cross-linked hydroxypropyl methyl cellulose acetate succinate, microcrystalline cellulose, polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer, cross-linked carboxymethyl cellulose, sodium starch glycolat, and cross-linked styrene divinyl benzene or any other excipient at any aspect of present application.
Amorphous solid dispersion of Deutetrabenazine isolated at step c) or d) 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, 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 an aspect, the present application provides pharmaceutical composition comprising amorphous solid dispersion of Deutetrabenazine with at least one pharmaceutically acceptable excipient.
In embodiments, the present application provides adsorbates, wherein Deutetrabenazine is associated with a suitable substrate. Suitable substrate may be a particulate and/or porous substrate, wherein this substrate has an outer and/or inner surface onto which the API may be adsorbed. This means that if the substrate has pores, these pores are filled by the Deutetrabenazine and the substrate remains unaffected, it does not, at least not essentially, change during and / or after the adsorption. In embodiments, the suitable substrate is selected from the excipients at any aspect of present application.
Amorphous solid dispersion of Deutetrabenazine may be obtained alternatively either by employing a melt-extrusion technique.
Amorphous solid dispersion of Deutetrabenazine obtained according to the present invention is substantially pure amorphous unlike the premix/solid dispersions known in the literature.
The present application provides amorphous solid dispersion of Deutetrabenazine, or its pharmaceutical composition comprising Deutetrabenazine having a chemical purity of at least 99% by HPLC or at least 99.5% by HPLC or at least 99.9% 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.
The term "solid dispersion" when used in the present application, denotes a state where most of the Deutetrabenazine, preferably 90%, 95% or all of the Deutetrabenazine of the solid dispersion, is homogeneously molecularly dispersed in a solid polymer matrix. Preferably solid dispersion, relates to a molecular dispersion where the API (active pharmaceutical ingredient) and polymer molecules are uniformly but irregularly dispersed in a non-ordered way. In other words, in a solid dispersion, the two components (polymer and API) form a homogeneous one-phase system, where the particle size of the API in the solid dispersion is reduced to its molecular size. In a preferred embodiment, in the solid dispersion according to the present invention no chemical bonds can be detected between the API and the polymer. In order to arrive at such a solid dispersion, preferably solid solution, it is required to have a substantial amount of API dissolved in a suitable solvent at least at one time point during preparation of said solid dispersion.
The term "adsorbate" when used in the present application, specifies that the Deutetrabenazine is, preferably evenly, and preferably homogeneously, distributed on the inner and/or outer surface of the particulate substrate.
An “alcohol” is an organic compound containing a carbon bound to a hydroxyl group. “C1-C6 alcohols” include, but are not limited to, methanol, ethanol, 2-nitroethanol,2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, or the like.
An “aliphatic hydrocarbon” is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds. A liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called“aromatic.” Examples of “C5-C8aliphatic or aromatic hydrocarbons” include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, or any mixtures thereof.
An “ester” is an organic compound containing a carboxyl group -(C=O)-O- bonded to two other carbon atoms. “C3-C6esters” include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like.
An “ether” is an organic compound containing an oxygen atom –O- bonded to two other carbon atoms. “C2-C6 ethers” include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like.
A “halogenated hydrocarbon” is an organic compound containing a carbon bound to a halogen. Halogenated hydrocarbons include, but are not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the like.
A “ketone” is an organic compound containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “C3-C6 ketones” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, or the like.
A “nitrile” is an organic compound containing a cyano -(C=N) bonded to another carbon atom. “C2-C6Nitriles” include, but are not limited to, acetonitrile, propionitrile, butanenitrile, or the like.
EXAMPLES
Example-1: Preparation of amorphous solid dispersion of Deutetrabenazine with hydroxypropyl methylcellulose phthalate
Deutetrabenazine (500 mg), hydroxypropyl methylcellulose phthalate HP-55 (500 mg), dichloromethane (60 mL) were charged into a rotavapor flask at 25°C. The reaction mass was stirred for 5 minutes at 25°C. The reaction mass was stirred for 15 minutes at 35-45°C. The reaction mass was evaporated under vacuum at 45°C for over 10 minutes. The PXRD pattern of the isolated material is represented as Figure-1.

Example-2: Preparation of amorphous solid dispersion of Deutetrabenazine with polyvinylpyrrolidone-K30
Deutetrabenazine (500 mg), polyvinylpyrrolidone-K30 (500 mg), dichloromethane (30 mL) were charged into a rotavapor flask at 25°C. The reaction mass was stirred for about 20 minutes at 30-45°C. The reaction mass was evaporated under vacuum at 45°C for over 15 minutes. The PXRD pattern of the isolated material is represented as Figure-2.

Example-3: Preparation of amorphous solid dispersion of Deutetrabenazine with copovidone VA 64
Deutetrabenazine (500 mg), copovidone VA 64 (500 mg) and dichloromethane (30 mL) were charged into a rotavapor flask at 25°C. The reaction mass was stirred for 15 minutes at 25-32°C. The reaction mass was stirred for 2 minutes at 30-40°C. The reaction mass was evaporated under vacuum at 44°C for over 3 minutes. The PXRD pattern of the isolated material is represented as Figure-3.

Example-4: Preparation of amorphous solid dispersion of Deutetrabenazine with polyvinylpyrrolidone-K90
Deutetrabenazine (500 mg), polyvinylpyrrolidone-K90 (500 mg), and dichloromethane (30 mL) were charged into rotavapor flask at 25°C. The reaction mass was stirred for about 5 minutes at 25-35°C. The reaction mass was further stirred for 10 minutes at 35-45°C. The reaction mass was evaporated under vacuum at 45°C for over 2 minutes. The PXRD pattern of the isolated material is represented as Figure-4

Example-5: Preparation of amorphous solid dispersion of Deutetrabenazine with ethyl cellulose
Deutetrabenazine (500 mg), ethyl cellulose 10cps (500 mg) and dichloromethane (30 mL) were charged into a rotavapor flask at 25°C. The reaction mass was stirred for 5 minutes at 25°C. The reaction mass was further stirred for 30 minutes at 35°C-45°C. The reaction mass was evaporated under vacuum at 45-48°C for over 50 minutes. The PXRD pattern of the isolated material is represented as Figure-5.
,CLAIMS:We claim:
1. Amorphous solid dispersion of Deutetrabenazine comprising deutetrabenazine and at least one pharmaceutically acceptable excipient selected from hydroxypropyl methylcellulose phthalate, polyvinylpyrrolidone-K 90 and ethyl cellulose.
2. Amorphous solid dispersion of Deutetrabenazine with hydroxypropyl methylcellulose phthalate of claim 1, wherein the amorphous form is characterized by X-ray powder diffraction pattern of Figure 1.
3. Amorphous solid dispersion of Deutetrabenazine with polyvinylpyrrolidone-K 90 of claim 1, wherein the amorphous form is characterized by X-ray powder diffraction pattern of Figure 4.
4. Amorphous solid dispersion of Deutetrabenazine with ethyl cellulose of claim 1, wherein the amorphous form is characterized by X-ray powder diffraction pattern of Figure 5.
5. A process for the preparation of amorphous solid dispersion of Deutetrabenazine, comprising the steps of:
a) providing a solution of Deutetrabenazine and at least one pharmaceutically acceptable excipient in a suitable solvent or a mixture thereof;
b) removing the solvent from the solution obtained in step a); and
c) isolating the amorphous solid dispersion of Deutetrabenazine;
6. A process as claimed in claim 5 wherein, the solvent is selected from dichloromethane, methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran, water and mixtures thereof.
7. A process as claimed in claim 5 wherein, excipient is selected from hydroxypropyl methylcellulose phthalate, polyvinylpyrrolidone-K 90 and ethyl cellulose.
8. Pharmaceutical composition comprising amorphous solid dispersion of Deutetrabenazine as claimed in any of claims 1 to 4 and a suitable pharmaceutically acceptable excipient.