DESC:FIELD OF INVENTION
The present invention provides premixes of deutetrabenazine with polyvinylpyrrolidone K-30, copovidone, talc and magnesium stearate and their polymorphs.
BACKGROUND OF THE INVENTION
Deutetrabenazine (I) is a deuterated analog of tetrabenazine which has improved pharmacokinetic properties when compared to the non-deuterated drug. Currently the New Drug Application (NDA) for deutetrabenazine has been accepted by the U.S. Food and Drug Administration (FDA) for the treatment of chorea associated with Huntington disease. Increased levels of deuterium incorporation may produce a detectable Deuterium Kinetic Isotope Effect (DKIE) that could affect the pharmacokinetic, pharmacologic and/or toxicologic profiles of in the drug. Deutetrabenazine (I) has the following structure.

The patent US 8,524,733 discloses deutetrabenazine (I) and the patent application US 2014/0341994 discloses crystalline forms I and II of deutetrabenazine (I) and also the solid dosage form composition of deutetrabenazine (I).
The present invention provides novel premixes of deutetrabenazine, novel crystalline form of premixes of deutetrabenazine and process for preparation thereof.

DESCRIPTION OF DRAWING
Figure 1 – X-ray powder diffraction pattern of deutetrabenazine premixed with copovidone.
Figure 2 – X-ray powder diffraction pattern of deutetrabenazine premixed with polyvinylpyrrolidone K-30.
Figure 3 – X-ray powder diffraction pattern of deutetrabenazine premixed with magnesium stearate.
Figure 4 – X-ray powder diffraction pattern of deutetrabenazine premixed with talc.

SUMMARY OF THE INVENTION
The present invention provides stable premix of deutetrabenazine comprising deutetrabenazine and at least one pharmaceutically acceptable excipient selected from copovidone, polyvinylpyrrolidone K-30, talc and magnesium stearate. The present invention provides novel amorphous forms of deutetrabenazine premixed with polyvinylpyrrolidone K-30 and deutetrabenazine premixed with copovidone. The present invention also provides novel crystalline forms of deutetrabenazine premixed with talc and deutetrabenazine premixed with magnesium stearate. The present invention further provides process for preparation of the same.

DETAILED DESCRIPTION OF THE INVENTION
The term "premix" is used herein to describe combinations of deutetrabenazine and at least one pharmaceutically acceptable excipient, wherein individual particles of the components cannot be distinguished using techniques such as optical microscopy and the like. Premixes are not simple or manual mixtures of powdered ingredients.

The term "stable" herein means deutetrabenazine that substantially does not convert to any other solid form and fulfill the standard stability criteria given in USP/EP monograph.

In the first embodiment, the present invention provides stable premix of deutetrabenazine comprising deutetrabenazine and at least one pharmaceutically acceptable excipient selected from copovidone, polyvinylpyrrolidone K-30, talc and magnesium stearate.

In the second embodiment the present invention provides novel amorphous form of deutetrabenazine premixed with copovidone. The novel amorphous form of deutetrabenazine premixed with copovidone is characterized by X-ray powder diffraction pattern of Figure 1.
In the third embodiment the present invention provides novel amorphous form of deutetrabenazine premixed with polyvinylpyrrolidone K-30. The novel amorphous form of deutetrabenazine premixed with polyvinylpyrrolidone K-30 is characterized by X-ray powder diffraction pattern of Figure 2.
In the fourth embodiment the present invention provides novel crystalline form of deutetrabenazine premixed with magnesium stearate. The novel crystalline form of deutetrabenazine premixed with magnesium stearate is characterized by X-ray powder diffraction pattern of Figure 3.
In the fifth embodiment the present invention provides novel crystalline form of deutetrabenazine premixed with talc. The novel crystalline form of deutetrabenazine premixed with talc is characterized by X-ray powder diffraction pattern of Figure 4.

In the sixth embodiment the present invention provides a process for the preparation of deutetrabenazine premixed with and one or more pharmaceutically acceptable excipient comprising the steps of:
i) mixing deutetrabenazine in one or more organic solvent,
ii) adding the excipient,
iii) stirring the mixture and
iv) isolating.
The organic solvent is selected from benzene, toluene, xylene, hexane, heptane, cyclohexane, cycloheptane, methanol, ethanol, n-butanol, t-butanol, acetone, 2-butanone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, ethyl ether, methyl t-butyl ether, di-isopropyl ether; dichloromethane, ethylene dichloride, dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, isopropyl nitrile and chloroform and mixtures thereof.

The pharmaceutically acceptable excipient or excipient include, but not limited to mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol, inositol, trehalose, trehalose, maltose, raffinose, .alpha.-, .beta.- and .gamma.-cyclodextrins, gum arabic, sodium alginate, propylene glycol alginate, agar, gelatin, tragacanth, xanthan gum, starch, lectins, urea, chitosan, chitosan glutamate, hydroxypropyl beta.-cyclodextrin chitosan, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), methylcellulose (MC), cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose phthalate (HPMC-P), hydroxylpropyl methylcellulose acetate succinate (HPMC-AS), carboxymethylethylcellulose (CMEC), carboxymethyl cellulose, sodium carboxymethyl cellulose, cellulose acetate butyrate, hydroxyethyl cellulose, ethyl cellulose, co-(lactic/glycolic)copolymers, poly(orthoester), polyvinyl chloride, polyvinyl acetate, ethylene vinyl acetate, carbopols, silicon elastomers, polyacrylic polymers, polyvinylacetal diethylaminoacetate, aminoalkyl methacrylate copolymer E, aminoalkyl methacryl copolymer RS, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, and carboxylvinyl polymer, polyvinylpyrrolidones (homopolymers or copolymers of N-vinyl pyrrolidone), polyethyleneglycols of various molecular weights, polyethylene-/polypropylene-/polyethylene-oxide block copolymers, polymethacrylates, polyvinylalcohol (PVA) and co-polymers thereof with PVP or with other polymers, polyacrylates, hypromellose phthalates, polyhydric alcohols, polyethylene glycols, polyethylene oxides, polyoxyethylene derivatives, 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; diluents such as starches and derivative thereof, e.g. dextrin, pullulan, corn starch and potato starch pregelatinized starches; lactose, sucrose, glucose, reduced maltose, mannitol, sorbitol, xylitol, trehalose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, crystalline cellulose/carmellose sodium, hydroxypropyl cellulose, magnesium aluminometasilicate, silica excipients like silicon dioxide, syloid, light anhydrous silicic acid or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches or the like; disintegrants such as hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, croscarmellose sodium, a starch, methylcellulose, sodium alginate, sodium carboxymethyl starch, carmellose calcium, carmellose sodium, crystalline cellulose and crystalline cellulose/carmellose sodium, sodium starch glycolate, pregelatinized starches, copovidone, crospovidones, colloidal silicon dioxide or the like; lubricants such as stearic acid, magnesium stearate, talc, light anhydrous silicic acid, calcium stearate, zinc stearate, magnesium oxide, sodium lauryl sulfate, sodium stearyl fumarate, magnesium aluminometasilicate or the like; flavoring agents such as sucrose, aspartame, mannitol, dextran, saccharin, menthol, citric acid, tartaric acid, malic acid, ascorbic acid, sweet hydrangea leaves, fennel, ethanol, fructose, xylitol, glycyrrhizinic acid, purified sucrose, L-glutamine, cyclodextrin, peppermint, methyl salicylate or the like; surfactants such as sodium lauryl sulfate, polysolvate 80, sucrose fatty acid ester, polyoxyl 40 stearate, polyoxyethylene 60 hydrogenated castor oil, sorbitan monostearate, sorbitan monopalmitate or the like; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes or the like. Other pharmaceutically acceptable carriers that can be used include, but are not limited to, film formers, plasticizers, colorants, viscosity enhancers, preservatives, antioxidants, or the like.

The process for the preparation of deutetrabenazine premixed with and one or more excipient comprises the steps of mixing deutetrabenazine in one or more organic solvent and stirring it for 10-15 minutes to form a mixture or a solution, followed by addition of the excipient and stirring at a temperature of 0 to 80°C for a time period of 5 minutes to two hours and isolating the deutetrabenazine premix. Isolation can be achieved by various methods such as concentration, removal of solvent by evaporation, distillation, crash cooling, flash evaporation, drying on rotavapor, spray drying, thin film drying, freeze drying, and lyophilization.
The present invention provides a stable deutetrabenazine premix having enhanced flow property, stability that can be easily formulated into pharmaceutical compositions. The deutetrabenazine premix of the present invention can be formulated into various pharmaceutical compositions like powder, granules, capsules, tablets, pellets etc. The pharmaceutical composition of the invention can be formed by various methods known in the art such as by dry granulation, wet granulation, melt granulation, direct compression, double compression, extrusion spheronization, layering and the like, preparation of compositions such as tablets, capsules, pellets are well known in the art. The deutetrabenazine premix formulation of the present invention can be utilized for the treatment of chorea associated with Huntington disease in a subject in need of such treatment.

The present invention is further illustrated by the following representative examples and does not limit the scope of the invention.
EXAMPLES
The X-ray powder diffraction pattern was recorded at room temperature using PANalytical X’Pert PRO diffractogram with Cu Ka radiation (? = 1.54060 Å), running at 45 kV and 40 mA.
The rotavapor used for concentration is Buchi-R-215 with about 100 revolutions per minute.
Example 1:
To a mixture of dichloromethane (25.0 ml) and deutetrabenazine (1.0 g), copovidone NF (0.1 g) was added. The mixture was stirred at 35-40°C for 10-15 min. The reaction mass was concentrated under vacuum, degased and solid was unloaded. Yield: 1.07 g.
Example-2:

To a mixture of dichloromethane (25.0 ml) and deutetrabenazine (1.0 g), polyvinylpyrrolidone K-30 (0.1 g) was added. The mixture was stirred at 35-40°C for 10-15 min. The reaction mass was concentrated under vacuum, degased and solid was unloaded. Yield: 1.10 g.
Example-3:

To a mixture of dichloromethane (20.0 ml) and deutetrabenazine (1.0 g), talc (0.1 g) was added. The mixture was stirred at 35-40°C for 10-15 min. The reaction mass was concentrated under vacuum, degased and solid was unloaded. Yield: 0.80 g.
Example-4:

To a mixture of dichloromethane (20.0 ml) and deutetrabenazine (1.0 g), magnesium stearate (0.1 g) was added. The mixture was stirred at 35-40°C for 10-15 min. The reaction mass was concentrated under vacuum, degased and solid was unloaded. Yield: 0.71 g.
,CLAIMS:1. A stable deutetrabenazine premix comprising deutetrabenazine and at least one pharmaceutically acceptable excipient selected from polyvinylpyrrolidone K-30, copovidone, talc and magnesium stearate.

2. The deutetrabenazine premix with copovidone of claim 1, wherein the premix is in amorphous form.

3. The deutetrabenazine premix with copovidone of claim 2, wherein the amorphous form is characterized by X-ray powder diffraction pattern of Figure 1.

4. The deutetrabenazine premix with polyvinylpyrrolidone K-30 of claim 1, wherein the premix is in amorphous form.

5. The deutetrabenazine premix with polyvinylpyrrolidone K-30 of claim 4, wherein the amorphous form is characterized by X-ray powder diffraction pattern of Figure 2.

6. The deutetrabenazine premix with magnesium stearate of claim 1, wherein the premix is in crystalline form.

7. The deutetrabenazine premix with magnesium stearate of claim 6, wherein the crystalline form is characterized by X-ray powder diffraction pattern of Figure 3.

8. The deutetrabenazine premix with talc of claim 1, wherein the premix is in crystalline form.

9. The deutetrabenazine premix with talc of claim 8, wherein the crystalline form is characterized by X-ray powder diffraction pattern of Figure 4.

10. A process for the preparation of deutetrabenazine premixed with and one or more pharmaceutically acceptable excipient comprising the steps of:
v) mixing deutetrabenazine in an organic solvent,
vi) adding the pharmaceutically acceptable excipient,
vii) stirring the mixture and
viii) isolating the premix.

11. A process according to claim 6 wherein, organic solvent is selected from benzene, toluene, xylene, hexane, heptane, cyclohexane, cycloheptane, methanol, ethanol, n-butanol, t-butanol, acetone, 2-butanone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, ethyl ether, methyl t-butyl ether, di-isopropyl ether; dichloromethane, ethylene dichloride, dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, isopropyl nitrile and chloroform and mixtures thereof.

12. A process according to claim 11 wherein, excipient is selected from polyvinylpyrrolidone K-30, copovidone, talc and magnesium stearate.