WO2017221169A1 - Premixes of deutetrabenazine - Google Patents

Premixes of deutetrabenazine Download PDF

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Publication number
WO2017221169A1
WO2017221169A1 PCT/IB2017/053695 IB2017053695W WO2017221169A1 WO 2017221169 A1 WO2017221169 A1 WO 2017221169A1 IB 2017053695 W IB2017053695 W IB 2017053695W WO 2017221169 A1 WO2017221169 A1 WO 2017221169A1
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Prior art keywords
deutetrabenazine
premix
talc
copovidone
magnesium stearate
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PCT/IB2017/053695
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French (fr)
Inventor
Tushar Nandkumar DESPANDE
Dnyaneshwar Tukaram Singare
Yogesh Dadaji Pawar
Yuvraj Atmaram Chavan
Purna Chandra Ray
Girij Pal Singh
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Lupin Limited
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Publication of WO2017221169A1 publication Critical patent/WO2017221169A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds

Definitions

  • the present invention provides premises of deutetrabenazine with polyvinylpyrrolidone K-30, copovidone, talc and magnesium stearate and their polymorphs.
  • Deutetrabenazine (1 ) is a deuterated analog of tetrabenazine which has improved pharmacokinetic properties when compared to the non-deuterated drug.
  • New Drug Application fNDA for deutetrabenazine has been accepted by the U .S. Food. and Drug Administration.
  • FDA New Drug Application
  • Increased levels of deuterioni incorporation may produce a detectable Deuterium Kinetic Isotope Effect (DK1E) that could affect the pharmacokinetic, pharmacologic and/or toxicologic profiles of in the drug
  • Deutetrabenazine (I) has the following structure.
  • the present invention provides novel premises of deutetrabenazine, novel crystalline form of premtxes of deutetrabenazine and process for preparation thereof DESCRIPTION OF DRAWING
  • Figure 1 X-ray powder diffraction pattern of deutetrabenazine premixed with copovi done
  • 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 magnes iu m stearate .
  • 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 optica! microscopy and the like. Prernixes are not simple or manual, mixtures of powdered ingredients.
  • stable herein means deutetrabenazine that substantially does not convert to any other solid form and fulfil! the standard stability criteria given in USP/EP monograph.
  • the present invention provides stable premix of deuteirabenaz ' me comprising deutetrabenazine arid at least one pharmaceutically acceptable excipient selected from copovidone, polyvinylpyrrolidone K.-30; talc, and magnesium stearate.
  • the present invention provides novel amorphous form of deutetrabenazine prem ixed with copovidone.
  • the novel amorphous form of deutetrabenazine premixed with, copovidone is characterized by X-ray powder diffraction pattern of Figure 1 .
  • 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.
  • 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.
  • the present invention provides a process for the preparation of deutetrabenazine premixed with and one or more pharmaceutically acceptable excipient comprising the steps of: mixing deutetrabenazine in one or more organic solvent,
  • the organic solvent is selected from benzene, toluene, xylene, hexane, heptane, cyclohexane, cycloheptane, methanol, ethanol, n-butanol, t-butanol, acetone, 2-butanone, methyl isobiityl ketone, ethyl acetate, isopropyi acetate, ethyl ether, methyl t-buty!
  • ether di-isopropyl ether
  • dichloromethane ethylene dichloride, dimethyl fbrmainide, dimethyl sulfoxide, tetrahydrofuran, acetonitn ' le, isopropyi nitri le and chloroform and mixtures thereof.
  • the pharmaceutically acceptable excipient or excipient include, but not limi ted to mannitol, lactose, fructose, sorbitol, xylitol, maJtodextrin, dextrates, dextrins, iactitol, inositol trehalose, trehalose, maltose, raffinose, .alpha.-, .beta.- and . gamma.
  • - cyelodextrins gum arable, sodium alginate, propylene glycol alginate., agar, gelatin, tragacanth, xanthan guni, starch, lectins, urea, chitosan, cbitosan gkitamate, hydroxypropyl beta.-cyeiodexirin chi tosan., hydroxypropy Imeihylcelluiose (HPMC), hydroxypropylceUuiose (HPC), methylcelluiose (MC), cellulose acetate phihalale (CAP), hydroxypropylmethylcellulose phthalate (HPMC-P), hydroxy!propyl methylcelluiose acetate succinate (HPMC-AS), carboxymethyiethylcelfulose (CMEC), carboxymethyl cellulose, sodium carboxymethyl cellulose, celiulose acetate butyrate, hydroxyethyl
  • aminoalkyi methaerylate 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), polyethyieneglycols of various molecular weights, polyethyle.ne-/polypropylene- /polyethylene-oxide block copolymers, polymethaciylates, poiyvinylaicohol (PV'A) and co-polymers thereof with PVP or with other polymers, polyacrylates, hyproroellose phthalates, polyhydric alcohols, polyethylene glycols, polyethylene oxides, polyoxyethy!ene derivatives, organic amines such as aikyl amines (primary, secondary
  • corn starch and potato starch pregelatini2ed starches; lactose, sucrose, glucose, reduced maltose, mannitol, sorbitol, xylitol, trehalose, powdered cellulose, microcrystalUne cellulose, dicalcium phosphate, tricalcium phosphate, crystalline ceJlulose/carmeliose sodium, hydroxypropyl cellulose, magnesium a!uminometasilieate.
  • 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 tnetbylcelluloses, pregelatinized starches or the like; disinregrants such as hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, croscarmeliose sodium, a starch, methylcellolose.
  • binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl tnetbylcelluloses, pregelatinized starches or the like
  • disinregrants such as hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, croscarmel
  • talc light anhydrous silicic acid, calcium stearate, zinc stearate, magnesium oxide, sodium iaiiryl sulfate, sodium stearyl fumarate, magnesium aluminometasilieate 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, gfycyrrhizinic 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, poiyoxyethylene 60 nydrogenated castor oil, sorbitan nionostearate.
  • sorbitan monopalmitate or the like complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymetlryl celluloses, hydroxypropyl methy lcel luloses, ethylceiluioses. methylcel!uloses. various grades of methyl methacryiates. 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 deufetrabenazine premised with and one or more excipient comprises the steps of mixing deutetrahenazme 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 iyophilization.
  • the present invention provides a stable deutetrabenazine preniix having enhanced flow property, stability that can be easily formulated into pharmaceutical compositions.
  • the deutetrabenazine preniix of the present invention can be formulated into various pharmaceutical compositions like powder, granules, capsules, tablets, pellets etc.
  • the pharmaeeutical 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 preniix 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 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. ExainpJe-2:

Abstract

The present invention provides stable premix of deutetrabenazine comprising deutetrabenazine and at least one pharmaceutically acceptable excipient selected from copovidone, polyvinyl pyrrolidone K-30, talc and magnesium stearate and their polymorphs and preparations thereof.

Description

PREMISES OF DEUTETRABENAZINE
FIELD OF INVENTION
The present invention provides premises of deutetrabenazine with polyvinylpyrrolidone K-30, copovidone, talc and magnesium stearate and their polymorphs.
BACKGROUND OF THE INVENTION
Deutetrabenazine (1 ) is a deuterated analog of tetrabenazine which has improved pharmacokinetic properties when compared to the non-deuterated drug. Currently the New Drug Application fNDA) 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 deuterioni incorporation may produce a detectable Deuterium Kinetic Isotope Effect (DK1E) that could affect the pharmacokinetic, pharmacologic and/or toxicologic profiles of in the drug, Deutetrabenazine (I) has the following structure.
Figure imgf000003_0001
The patent US 8.524,733 discloses deutetrabenazine (1) and the. patent, application US 2014/0341994 discloses crystalline forms I and II of deutetrabenazine (f) and also the solid dosage form composition of deutetrabenazine {]}.
The present invention provides novel premises of deutetrabenazine, novel crystalline form of premtxes of deutetrabenazine and process for preparation thereof DESCRIPTION OF DRAWING
Figure 1 - X-ray powder diffraction pattern of deutetrabenazine premixed with copovi done- 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 magnes iu m stearate .
Figure 4 - X-ray posvder diffraction pattern of deutetrabenazine premixed with iak. SUMMARY OF THE INVENTION
The present invention provides stable premix of deutetrabenazine comprising deutetrabenazine and at least one pharmaceutically acceptable excipient selected front eopovidone, 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 eopovidone. 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 optica! microscopy and the like. Prernixes 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 fulfil! the standard stability criteria given in USP/EP monograph. In the first embodiment, the present invention provides stable premix of deuteirabenaz'me comprising deutetrabenazine arid 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 prem ixed 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 crystall ine form of deutetrabenazine premixed with magnesium stearate. The novel crystall ine 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: mixing deutetrabenazine in one or more organic solvent,
adding the excipient.
iii ) stirring the m ixture 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 isobiityl ketone, ethyl acetate, isopropyi acetate, ethyl ether, methyl t-buty! ether, di-isopropyl ether; dichloromethane, ethylene dichloride, dimethyl fbrmainide, dimethyl sulfoxide, tetrahydrofuran, acetonitn'le, isopropyi nitri le and chloroform and mixtures thereof.
The pharmaceutically acceptable excipient or excipient include, but not limi ted to mannitol, lactose, fructose, sorbitol, xylitol, maJtodextrin, dextrates, dextrins, iactitol, inositol trehalose, trehalose, maltose, raffinose, .alpha.-, .beta.- and . gamma. - cyelodextrins, gum arable, sodium alginate, propylene glycol alginate., agar, gelatin, tragacanth, xanthan guni, starch, lectins, urea, chitosan, cbitosan gkitamate, hydroxypropyl beta.-cyeiodexirin chi tosan., hydroxypropy Imeihylcelluiose (HPMC), hydroxypropylceUuiose (HPC), methylcelluiose (MC), cellulose acetate phihalale (CAP), hydroxypropylmethylcellulose phthalate (HPMC-P), hydroxy!propyl methylcelluiose acetate succinate (HPMC-AS), carboxymethyiethylcelfulose (CMEC), carboxymethyl cellulose, sodium carboxymethyl cellulose, celiulose acetate butyrate, hydroxyethyl cellulose, ethyl cellulose, co-ί lactic/glycoHc )copolymers, po]y(orthoester), polyvinyl chloride, polyvinyl acetate, ethylene vinyl acetate, carbopols, silicon elastomers, po!yacrylic polymers, polyvinylacetal diethylaminoacetatc. aminoalkyi methaerylate 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), polyethyieneglycols of various molecular weights, polyethyle.ne-/polypropylene- /polyethylene-oxide block copolymers, polymethaciylates, poiyvinylaicohol (PV'A) and co-polymers thereof with PVP or with other polymers, polyacrylates, hyproroellose phthalates, polyhydric alcohols, polyethylene glycols, polyethylene oxides, polyoxyethy!ene derivatives, organic amines such as aikyl amines (primary, secondary, and tertiary), aromatic amines, alicyciic 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 pregelatini2ed starches; lactose, sucrose, glucose, reduced maltose, mannitol, sorbitol, xylitol, trehalose, powdered cellulose, microcrystalUne cellulose, dicalcium phosphate, tricalcium phosphate, crystalline ceJlulose/carmeliose sodium, hydroxypropyl cellulose, magnesium a!uminometasilieate. 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 tnetbylcelluloses, pregelatinized starches or the like; disinregrants such as hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, croscarmeliose sodium, a starch, methylcellolose. sodium alginate, sodium carboxymethyl starch, canneliose calcium, carraellose sodium, crystalline cellulose and crystalline ceilulose/carmellose sodium, sodium starch glyco!ate. pregelatinized starches, copovidone, crospovidones, colloidal silicon dioxide or the [ike; lubricants such as stearic acid, magnesium stearate. talc, light anhydrous silicic acid, calcium stearate, zinc stearate, magnesium oxide, sodium iaiiryl sulfate, sodium stearyl fumarate, magnesium aluminometasilieate 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, gfycyrrhizinic 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, poiyoxyethylene 60 nydrogenated castor oil, sorbitan nionostearate. sorbitan monopalmitate or the like; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymetlryl celluloses, hydroxypropyl methy lcel luloses, ethylceiluioses. methylcel!uloses. various grades of methyl methacryiates. 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 deufetrabenazine premised with and one or more excipient comprises the steps of mixing deutetrahenazme 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 iyophilization.
The present invention provides a stable deutetrabenazine preniix having enhanced flow property, stability that can be easily formulated into pharmaceutical compositions. The deutetrabenazine preniix of the present invention can be formulated into various pharmaceutical compositions like powder, granules, capsules, tablets, pellets etc. The pharmaeeutical 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 preniix 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 PANaiyticai X'Pert PRO diffractograra with Cu Kα radiation (λ = 1.54060 A), 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. ExainpJe-2:
To a mixture of dichlororaethane (25.0 ml) and deutetrabenazine {1.0 g), polyvinylpyiTolidone K-30 (O. i g) was added. The mixture was stirred at 35-4(PC for 10- 15 nun. The reaction mass was concentrated under vacuum, degased and solid was unloaded. Yield; 1.1 0 g.
Examp!e-3:
To a mixture of dichloromethane (20.0 ml) and deutetrabenazine ( 1.0 g), talc (O. i 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: O.SO g,
Example-4:
To a mixture of dichloromethane (20.0 mi) 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 pharmaceuticaHy 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 farm. 3. The deutetrabenazine premix with copovidone of claim 2, wherein the amorphous form is characterized by X-ray powder diffraction pattern of Figure I . 4. The deutetrabertazine 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 di ffraction pattern of Figure 2, 6. The deutetrabenazine premix with magnesium stearate of claim 1 , wherein the premix is in crystalli ne form. 7. The deutetrabenazine premix with magnesium stearate of claim 6, wherein the crystal line form is characterized by X-ray powder diffraction pattern of Figure 3. 8. The deutetrabenazine premix with talc of claim I , 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 premised with and one or more pharmaceutically acceptable excipient comprising the steps of: i) mixing deutetrabenazine in an organic solvent
ii) adding the pharmaceutically acceptable excipient,
iii) stirring the mixture and
iv) isolating the prermx.
1 1. A process according to claim 6 wherein, organic solvent is selected, from benzene, toluene, xylene, hexane, heptane, cyclohexane, cycioheptane, methanol, ethanol. n-butanoJ, t-butanol, acetone, 2-botanone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, ethyl ether, methyl i-butyi ether, di-isopropyl ether; dtchloromethane, ethylene d iehioride, dimethyl forraamide, dimethyl sulfoxide, tetrahydrofuran, acetonitriie, isopropyl nitrile and chloroform and .mixtures thereof. 12. A process accordi ng to claim Ϊ 1 wherein, excipient is selected from polyvinylpyrrolidone K-30, copovidone, talc and magnesium stearate.
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