DESC:FIELD OF INVENTION
The present invention provides stable premixes of deutetrabenazine with eudragit.

BACKGROUND OF THE INVENTION
Deutetrabenazine (I) is a deuterated analog of tetrabenazine, it has been approved by the FDA as Austedo® for the treatment of chorea associated with Huntington disease and Tardive dyskinesia. Deutetrabenazine (I) is chemically known as (RR, SS)-1, 3, 4, 6, 7, 11b-hexahydro-9, 10-di (methoxy-d3)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one and represented by the following structure.

The PCT applications WO 2010044981 and WO 2014047167 discloses deutetrabenazine (I), its preparation and solid dosage. The present invention provides stable premixes of deutetrabenazine with eudragit, its novel polymorph and process for preparation thereof.

DESCRIPTION OF DRAWING
Figure 1 – X-ray powder diffraction pattern of deutetrabenazine premix with eudragit.
Figure 2- Infrared absorption spectrum of deutetrabenazine premix with eudragit.

SUMMARY OF THE INVENTION
The present invention provides stable premix of deutetrabenazine comprising deutetrabenazine and eudragit. The present invention provides novel polymorphs of deutetrabenazine premix with eudragit. The present invention further provides process for preparation of these premixes.

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 eudragit. Eudragit is commercially available in different forms and grades. Eudragit is available as aqueous dispersions, organic solutions, granules and powders as Eudragit® L, S, FS, E, NE, RL and RS polymers.

In the second embodiment, the present invention provides amorphous form of deutetrabenazine premix with eudragit S100. The amorphous form of deutetrabenazine premix with eudragit S100 is characterized by X-ray powder diffraction pattern of figure 1. The amorphous form of deutetrabenazine premix with eudragit S100 is characterized by Infrared absorption spectrum of figure 2.

The present invention provides deutetrabenazine premix with eudragit having spectra consisting of:

i) X-ray powder diffraction pattern of figure 1; and
ii) Infrared absorption spectrum of figure 2.

In the third embodiment, the present invention provides a process for the preparation of deutetrabenazine premix with eudragit comprising the steps of:

i) mixing deutetrabenazine in one or more organic solvent,
ii) adding eudragit,
iii) stirring the mixture and
iv) isolating the premix.

The solvent can be selected from organic polar or non-polar solvent, water or mixtures thereof. Polar solvent can be selected from alcohols like methanol, ethanol, butanol, propanol; nitriles like acetonitrile, propionitrile, butyronitrile; ethers like tetrahydrofuran, dioxane, dimethoxyethane; esters like ethyl acetate, ethyl acetoacetate, butyl acetate, propyl acetate; ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone; ether solvents such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1 ,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane and the like; nitrile solvents such as acetonitrile, propionitrile, isobutyronitrile and the like ; other polar solvents like dimethylacetamide, dimethylformamide, dimethyl sulfoxide, water and mixtures thereof. Non-polar solvent can be selected from hydrocarbon solvent such as hexane, heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; chlorinated hydrocarbons like chloroform, dichloro methane, ethylene dichloride; or mixtures thereof.

The process for the preparation of deutetrabenazine premix with eudragit 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 eudragit 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. Deutetrabenazine which is used for preparation of premix of the present invention can be prepared by the methods known in the literature.

Eudragit premixes offers valuable advantages in formulations such as protection of actives sensitive to gastric fluids, increase in drug effectiveness, good storage stability, taste and odor masking, moisture protection, customized release profiles and cost effective processing. The present invention also 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 and pellets for immediate or delayed release, by various methods known in the art. The deutetrabenazine premix formulation of the present invention can be utilized for the treatment of chorea associated with Huntington disease and Tardive dyskinesia 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 infrared absorption spectrum was obtained using a Perkin Elmer Precisely Spectrum 400 instrument using KBr pellet method.

Example 1: preparation of deutetrabenazine eudragit premix.

To a mixture of deutetrabenazine (3.0 g), dichloromethane (50 ml) and methanol (70 ml), eudragit S100 (3.0 g) was added and the mixture was stirred. The solvent was removed by concentration and the residue was isolated to give the title compound, which depicted X-ray powder diffraction pattern of Figure 1.
,CLAIMS:
1. A premix of deutetrabenazine comprising deutetrabenazine and eudragit.

2. An amorphous form of deutetrabenazine premix with eudragit S100.

3. An amorphous form of deutetrabenazine premix with eudragit S100 of claim 2, having spectra consisting of:
iii) X-ray powder diffraction pattern of figure 1; and
iv) Infrared absorption spectrum of figure 2.

4. A process for the preparation of deutetrabenazine premix with eudragit comprising the steps of:
v) mixing deutetrabenazine in one or more organic solvent,
vi) adding eudragit,
vii) stirring the mixture and
viii) isolating the premix.

5. The process of claim 4, wherein the organic solvent is alcohol, nitrile, ether, ester, ketone or hydrocarbon solvent.

6. The process of claim 5, wherein the organic solvent is methanol, ethanol, butanol, propanol, acetonitrile, propionitrile, butyronitrile, tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate, ethyl acetoacetate, butyl acetate, propyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane, hexane, heptane, cyclohexane, petroleum ether, benzene, toluene, xylene, chloroform, dichloro methane, ethylene dichloride or mixtures thereof.

7. The process of claim 4, wherein the organic solvent is dimethylacetamide, dimethylformamide or dimethyl sulfoxide.