DESC:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

“PROCESS FOR PREPARATION OF DEUTETRABENAZINE AND SALT THEREOF”

Glenmark Life Sciences Limited
Glenmark Pharmaceuticals Limited
an Indian Company, registered under the Indian company’s Act 1957 and having its registered office at
Glenmark House,
HDO- Corporate Bldg, Wing-A,
B. D. Sawant Marg, Chakala,
Andheri (East), Mumbai- 400 099

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

FIELD OF THE INVENTION
[0001] The present invention relates to salts of deutetrabenazine and process for its preparation.

BACKGROUND OF THE INVENTION
[0002] Deutetrabenazine, also 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, is represented by the structure of formula I.
I
[0003] Deutetrabenazine is a vesicular monoamine transporter 2 (VMAT2) inhibitor indicated for the treatment of chorea associated with Huntington’s disease.

SUMMARY OF THE INVENTION
[0004] The present invention provides a crystalline deutetrabenazine hydrochloride.
[0005] In one embodiment the present invention provides a process for the preparation of crystalline deutetrabenazine hydrochloride, the process comprising:
(a) providing deutetrabenazine in a solvent to form a mixture.
(b) adding hydrochloric acid, optionally in the presence of a solvent, to the mixture obtained in step (a);
(c) obtaining deutetrabenazine hydrochloride from the mixture of step (b); and
(d) isolating the deutetrabenazine hydrochloride.
[0006] In one embodiment the present invention provides a crystalline deutetrabenazine hydrobromide.
[0007] In one embodiment the present invention provides a process for preparation of crystalline form of deutetrabenazine hydrobromide, the process comprising:
(a) providing deutetrabenazine in a solvent to form a mixture.
(b) adding hydrobromic acid, optionally in the presence of a solvent, to the mixture obtained in step (a);
(c) obtaining deutetrabenazine hydrobromide from the mixture of step (b); and
(d) isolating the deutetrabenazine hydrobromide.

BRIEF DESCRIPTION OF THE DRAWINGS
[0008] Figure 1 is the characteristic XRPD of deutetrabenazine hydrochloride as obtained in Example 3
[0009] Figure 2 is the TGA thermogram of deutetrabenazine hydrochloride as obtained in Example 3
[0010] Figure 3 is the DSC thermogram of deutetrabenazine hydrochloride as obtained in Example 3
[0011] Figure 4 is the proton NMR spectrum of deutetrabenazine hydrochloride as obtained in Example 3
[0012] Figure 5 is the characteristic XRPD of deutetrabenazine hydrobromide as obtained in Example 4
[0013] Figure 6 is the DSC thermogram of deutetrabenazine hydrobromide as obtained in Example 4
[0014] Figure 7 is the TGA thermogram of deutetrabenazine hydrobromide as obtained in Example 4

DETAILED DESCRIPTION OF THE INVENTION
[0015] The present invention provides a crystalline deutetrabenazine hydrochloride.
[0016] In the present application, the term “room temperature” means a temperature of about 25°C to about 30°C.
[0017] In one embodiment, the present invention provides a crystalline deutetrabenazine hydrochloride characterized by an X-ray powder diffraction (XRPD) spectrum as depicted in Figure 1.
[0018] In one embodiment, the present invention provides a crystalline deutetrabenazine hydrochloride characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at 8.91, 12.19, 12.99, 18.60, 19.10, 20.73, 22.53, 24.53, 25.49, 26.39, 27.64, 30.31±0.2 2?.
[0019] In one embodiment, the present invention provides a crystalline deutetrabenazine hydrochloride characterized by TGA thermogram, showing a weight loss of about 0.2 weight% to about 0.8 weight% up to 100°C determined over the temperature range of 0°C to 250°C and heating rate 10°C/min.
[0020] In one embodiment, the present invention provides a crystalline deutetrabenazine hydrochloride characterized by TGA thermogram, showing a weight loss of about 0.3 weight% to about 0.7 weight% up to 100°C determined over the temperature range of 0°C to 250°C and heating rate 10°C/min which is substantially in accordance with Figure 2.
[0021] In one embodiment, the present invention provides a crystalline deutetrabenazine hydrochloride characterized by DSC thermogram having one endothermic with peak temperature at about 216±5°C.
[0022] In one embodiment, the present invention provides a crystalline deutetrabenazine hydrochloride characterized by DSC thermogram having one endothermic peak with onset at about 212±5°C with peak temperature at about 216±5°C.
[0023] In one embodiment, the present invention provides a crystalline deutetrabenazine hydrochloride characterized by DSC thermogram having one endothermic peak with onset at about 212±2°C with peak temperature at about 216±2°C which is substantially in accordance with Figure 3.
[0024] In one embodiment, the present invention provides a crystalline deutetrabenazine hydrochloride characterized by proton 1H NMR having peak reflections at d 12.37 (br,1H), d 6.69 (s,1H), d 3.47 (m,2H), d 3.27 (d,1H), d 3.14 (d,1H), d 2.84-2.67 (m,2H), d 2.56 (d,1H), d 2.5-2.29 (m,4H), d 2.09 (d,2H), d 1.68-1.61 (d,2H), d 0.85-0.95 (m,6H).
[0025] In one embodiment, the present invention provides a crystalline deutetrabenazine hydrochloride characterized by data selected from the group consisting of: an X-ray powder diffraction (XRPD) pattern as depicted in Figure 1, a TGA thermogram as depicted in Figure 2; a DSC thermogram as depicted in Figure 3; 1H NMR as depicted in Figure 4 and any combination thereof.
[0026] In one embodiment, the present invention provides a process for the preparation of crystalline deutetrabenazine hydrochloride, the process comprising:
(a) providing deutetrabenazine in a solvent to form a mixture.
(b) adding hydrochloric acid, optionally in the presence of a solvent, to the mixture obtained in step (a);
(c) obtaining deutetrabenazine hydrochloride from the mixture of step (b); and
(d) isolating the deutetrabenazine hydrochloride.
[0027] In step (a) of the process for the preparation of crystalline deutetrabenazine hydrochloride, deutetrabenazine is mixed in a solvent to form a mixture.
[0028] In one embodiment, the solvent includes, but is not limited to haloalkanes such as dichloromethane, chloroform, ethylene dichloride and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, tert-butyl alcohol, n-pentyl alcohol, n-octyl alcohol and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dimethoxyethane, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; hydrocarbons such as heptane, hexane, pentane, cyclohexane, toluene, xylene, and the like; dimethyl sulfoxide; dimethylformamide; dimethyl acetamide, water; or mixtures thereof.
[0029] In step (b) of the process for the preparation of deutetrabenazine hydrochloride, hydrochloric acid, optionally in the presence of a solvent, is added to the mixture obtained in step (a).
[0030] In one embodiment, the solvent used includes but is not limited to alcohols such as butanol, methanol, n-propyl propanol and isopropyl alcohol, isobutyl alcohol, tert-butyl alcohol, n-pentyl alcohol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone or mixture thereof.
[0031] In one embodiment, the hydrochloric acid used may be an aqueous hydrochloric acid or a solvent containing hydrochloric acid or in gaseous form.
[0032] In one embodiment, the solvent used includes but is not limited to alcohols such as butanol, methanol, n-propyl propanol and isopropyl alcohol, isobutyl alcohol, tert-butyl alcohol, n-pentyl alcohol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone or mixture thereof.
[0033] The reaction may be carried out at a temperature in the range from about 10°C to about 100°C. The stirring time may range from about 30 minutes to about 10 hours, or longer.
[0034] In step (c) of the process for the preparation of crystalline deutetrabenazine hydrochloride, crystalline deutetrabenazine hydrochloride is obtained from the mixture of step (b), the process comprising:
(i) optionally cooling and stirring the mixture obtained in step (b); or
(ii) removing the solvent from the mixture obtained in step (b); or
(iii) treating the mixture of step (b) with an anti-solvent and optionally, cooling and stirring the obtained mixture.
[0035] In (i) of the above process, crystalline deutetrabenazine hydrochloride is obtained by optionally cooling and stirring the mixture obtained in step (b). The stirring time may range from about 30 minutes to about 10 hours, or longer. The temperature may range from about 0°C to about 35°C.
[0036] In (ii) of the above process, crystalline deutetrabenazine hydrochloride is obtained by removing the solvent from the mixture obtained in step (b). Removal of solvent may be accomplished by substantially complete evaporation of the solvent or concentrating the mixture, cooling the mixture if required and filtering the obtained solid. The mixture may be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720mm Hg. The mixture may also be completely evaporated as discussed supra, adding a second solvent, optionally cooling and stirring the obtained mixture and filtering the obtained solid.
[0037] The second solvent includes but is not limited to haloalkanes such as dichloromethane, chloroform, ethylene dichloride and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, tert-butyl alcohol, n-pentyl alcohol, n-octyl alcohol and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dimethoxyethane, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; hydrocarbons such as heptane, hexane, pentane, cyclohexane, toluene, xylene, and the like; dimethyl sulfoxide; dimethylformamide; dimethyl acetamide; water; or mixtures thereof.
[0038] In (iii) of the above process, crystalline deutetrabenazine hydrochloride is obtained by adding an anti-solvent to the mixture obtained in step (b) and optionally, cooling and stirring the obtained mixture. The stirring time may range from about 30 minutes to about 10 hours, or longer. The temperature may range from about 0°C to about 50°C.
[0039] The anti-solvent is selected such that crystalline deutetrabenazine hydrochloride is precipitated out from the solution.
[0040] The anti-solvent includes but is not limited to haloalkanes such as dichloromethane, chloroform, ethylene dichloride and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, tert-butyl alcohol, n-pentyl alcohol, n-octyl alcohol and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dimethoxyethane, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; hydrocarbons such as heptane, hexane, pentane, cyclohexane, toluene, xylene, and the like; dimethyl sulfoxide; dimethylformamide; dimethyl acetamide; water; or mixtures thereof.
[0041] In (d) of the process for the preparation of crystalline deutetrabenazine hydrochloride, the crystalline deutetrabenazine hydrochloride is isolated by any method known in the art. The method, may involve any of techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like, complete evaporation in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum, or concentrating the mixture, cooling the mixture if required and filtering the obtained solid by gravity or by suction, centrifugation, and the like.
[0042] In one embodiment, the present invention provides a crystalline deutetrabenazine hydrobromide characterized by an X-ray powder diffraction (XRPD) spectrum as depicted in Figure 5.
[0043] In one embodiment, the present invention provides a crystalline deutetrabenazine hydrobromide characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at 8.78, 11.18, 12.08, 13.72, 16.04, 17.64, 20.58, 21.00, 21.88, 22.06, 22.36, 23.43, 24.28, 24.53, 25.14, 25.89, 26.23, 26.61, 27.43, 27.97, 28.55 31.71±0.2 2?.
[0044] In one embodiment, the present invention provides a crystalline deutetrabenazine hydrobromide characterized by TGA thermogram, showing a weight loss of about 2.2 weight% to about 2.8 weight% up to 100°C determined over the temperature range of 0°C to 250°C and heating rate 10°C/min.
[0045] In one embodiment, the present invention provides a crystalline deutetrabenazine hydrobromide characterized by TGA thermogram, showing a weight loss of about 2.3 weight% to about 2.7 weight% up to 100°C determined over the temperature range of 0°C to 250°C and heating rate 10°C/min which is substantially in accordance with Figure 7.
[0046] In one embodiment, the present invention provides a crystalline deutetrabenazine hydrobromide characterized by DSC thermogram having one endothermic peak with peak temperature at about 211±5°C.
[0047] In one embodiment, the present invention provides a crystalline deutetrabenazine hydrobromide characterized by DSC thermogram having one endothermic peak with onset at about 208°C±5°C with peak temperature at about 211±5°C.
[0048] In one embodiment, the present invention provides a crystalline deutetrabenazine hydrobromide characterized by DSC thermogram having one endothermic peak with onset at about 208±2°C with peak temperature at about 211±2°C which is substantially in accordance with Figure 6.
[0049] In one embodiment, the present invention provides a crystalline deutetrabenazine hydrobromide characterized by data selected from the group consisting of: an X-ray powder diffraction (XRPD) pattern as depicted in Figure 5, a TGA thermogram as depicted in Figure 7; a DSC thermogram as depicted in Figure 6; and any combination thereof.
[0050] In one embodiment, the present invention provides a process for the preparation of crystalline deutetrabenazine hydrobromide, the process comprising:
(a) providing deutetrabenazine in a solvent to form a mixture.
(b) adding hydrobromic acid, optionally in the presence of a solvent, to the mixture obtained in step (a);
(c) obtaining deutetrabenazine hydrobromide from the mixture of step (b); and
(d) isolating the deutetrabenazine hydrobromide.
[0051] In step (a) of the process for the preparation of crystalline deutetrabenazine hydrobromide, deutetrabenazine is mixed in a solvent to form a mixture.
[0052] In one embodiment, the solvent includes, but is not limited to haloalkanes such as dichloromethane, chloroform, ethylene dichloride and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, tert-butyl alcohol, n-pentyl alcohol, n-octyl alcohol and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dimethoxyethane, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; hydrocarbons such as heptane, hexane, pentane, cyclohexane, toluene, xylene, and the like; dimethyl sulfoxide; dimethylformamide; dimethyl acetamide, water; or mixtures thereof.
[0053] In step (b) of the process for the preparation of deutetrabenazine hydrobromide, hydrobromic acid, optionally in the presence of a solvent, is added to the mixture obtained in step (a).
[0054] In one embodiment, the solvent used includes but is not limited to alcohols such as butanol, methanol, n-propyl propanol and isopropyl alcohol, isobutyl alcohol, tert-butyl alcohol, n-pentyl alcohol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone or mixture thereof.
[0055] In one embodiment, the hydrobromic acid used may be an aqueous hydrobromic acid or a solvent containing hydrobromic acid or in gaseous form.
[0056] In one embodiment, the solvent used includes but is not limited to alcohols such as butanol, methanol, n-propyl propanol and isopropyl alcohol, isobutyl alcohol, tert-butyl alcohol, n-pentyl alcohol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone or mixture thereof.
[0057] The reaction may be carried out at a temperature in the range from about 10°C to about 100°C. The stirring time may range from about 30 minutes to about 10 hours, or longer.
[0058] In step (c) of the process for the preparation of crystalline deutetrabenazine hydrobromide, crystalline deutetrabenazine hydrobromide is obtained from the mixture of step (b), the process comprising:
(i) optionally cooling and stirring the mixture obtained in step (b); or
(ii) removing the solvent from the mixture obtained in step (b); or
(iii) treating the mixture of step (b) with an anti-solvent and optionally, cooling and stirring the obtained mixture.
[0059] In (i) of the above process, crystalline deutetrabenazine hydrobromide is obtained by optionally cooling and stirring the mixture obtained in step (b). The stirring time may range from about 30 minutes to about 10 hours, or longer. The temperature may range from about 0°C to about 35°C.
[0060] In (ii) of the above process, crystalline deutetrabenazine hydrobromide is obtained by removing the solvent from the mixture obtained in step (b). Removal of solvent may be accomplished by substantially complete evaporation of the solvent or concentrating the mixture, cooling the mixture if required and filtering the obtained solid. The mixture may be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720mm Hg. The mixture may also be completely evaporated as discussed supra, adding a second solvent, optionally cooling and stirring the obtained mixture and filtering the obtained solid.
[0061] The second solvent includes but is not limited to haloalkanes such as dichloromethane, chloroform, ethylene dichloride and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, tert-butyl alcohol, n-pentyl alcohol, n-octyl alcohol and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dimethoxyethane, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; hydrocarbons such as heptane, hexane, pentane, cyclohexane, toluene, xylene, and the like; dimethyl sulfoxide; dimethylformamide; dimethyl acetamide; water; or mixtures thereof.
[0062] In (iii) of the above process, crystalline deutetrabenazine hydrobromide is obtained by adding an anti-solvent to the mixture obtained in step (b) and optionally, cooling and stirring the obtained mixture. The stirring time may range from about 30 minutes to about 10 hours, or longer. The temperature may range from about 0°C to about 50°C.
[0063] The anti-solvent is selected such that crystalline deutetrabenazine hydrobromide is precipitated out from the solution.
[0064] The anti-solvent includes but is not limited to haloalkanes such as dichloromethane, chloroform, ethylene dichloride and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, tert-butyl alcohol, n-pentyl alcohol, n-octyl alcohol and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dimethoxyethane, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; hydrocarbons such as heptane, hexane, pentane, cyclohexane, toluene, xylene, and the like; dimethyl sulfoxide; dimethylformamide; dimethyl acetamide; water; or mixtures thereof.
[0065] In (d) of the process for the preparation of crystalline deutetrabenazine hydrobromide, the crystalline deutetrabenazine hydrobromide is isolated by any method known in the art. The method, may involve any of techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like, complete evaporation in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum, or concentrating the mixture, cooling the mixture if required and filtering the obtained solid by gravity or by suction, centrifugation, and the like.
[0066] In one embodiment, the present invention provides salts of deutetrabenazine, wherein the salts of deutetrabenazine include salt with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, acetic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, lactic acid, mandelic acid, salicylic acid, citric acid, malonic acid, malic acid.
[0067] In one embodiment, the present invention provides a process for the preparation of salt of deutetrabenazine, the process comprising:
(a) providing deutetrabenazine in a solvent to form a mixture.
(b) adding acid, optionally in the presence of a solvent, to the mixture obtained in step (a);
(c) obtaining salt of deutetrabenazine from the mixture of step (b); and
(d) isolating the salt of deutetrabenazine.
[0068] The salt of deutetrabenazine includes salt with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, acetic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, lactic acid, mandelic acid, salicylic acid, citric acid, malonic acid, malic acid.
[0069] The reaction may be carried out in a solvent selected from esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; halogenated hydrocarbons such as dichloromethane, chloroform, ethylene dichloride, and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; water; or mixtures thereof.
[0070] In one embodiment, the deutetrabenazine hydrochloride is converted to deutetrabenazine by subjecting deutetrabenazine hydrochloride with a base.
[0071] In one embodiment, the deutetrabenazine hydrochloride is crystalline.
[0072] In one embodiment, the deutetrabenazine hydrobromide is converted to deutetrabenazine by subjecting deutetrabenazine hydrobromide with a base.
[0073] In one embodiment, the deutetrabenazine hydrobromide is crystalline.
[0074] A suitable base includes but is not limited to an alkali or an alkaline earth metal hydroxide, an alkali or an alkaline earth metal carbonate and the like, an alkali or an alkaline earth metal bicarbonate for example sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like.
[0075] In one embodiment, the present invention provides pharmaceutical compositions comprising deutetrabenazine or salt or solvate thereof obtained by the processes herein described, having a D90 particle size of less than about 250 microns, preferably less than about 150 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns and most preferably less than about 10 microns.
[0076] In one embodiment, the present invention provides pharmaceutical compositions comprising deutetrabenazine or salt or solvate thereof obtained by the processes herein described, having a D50 particle size of less than about 250 microns, preferably less than about 150 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns and most preferably less than about 10 microns.
[0077] The particle size disclosed here can be obtained by, for example, any milling, grinding, micronizing or other particle size reduction method known in the art to bring the solid state deutetrabenazine or salt or solvate thereof into any of the foregoing desired particle size range.
[0078] The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.

EXAMPLES

[0079] EXAMPLE 1: Preparation of 9,10-dihydroxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one.
To a stirred suspension of 6, 7 Dihydroxy-3, 4 Dihydroisoquinoline (50g) in methanol (150mL) was added potassium carbonate (34.97g) at about room temperature. The reaction mixture was stirred at about room temperature followed by addition of water (150 mL) and of 2-Acetyl-NNN, 4-tetramethyl-1-pentan-aminium iodide (82.53g) at about 30°C. The reaction mixture was stirred at about 65°C and cooled to ambient temperature. Water (150 mL) was added in to reaction mixture and stirred for about 4h to about 5h. The solid obtained was filtered and dried for about 12 h at about 55°C.
Yield: 50g
1H NMR (DMSO): d 8.75 (s,1H), d 8.64 (s,1H), d 6.47-6.44 (s,2H), d 3.37 (m,1H), d 2.86-2.40 (m,6H), d 2.78 (m,1H), d 2.67 (m,1H), d 2.65 (m,1H), d 2.46 (m,1H), d 2.41 (m,1H), d 1.66 (m,2H), d 0.83-0.93 (m,6H).
Mass: M/Z = 290 (M+H)
[0080] EXAMPLE 2: preparation of 9,10-dihydroxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one.
3-[(dimethylamino)methyl]-5-methylhexan-2-one (52.47g), and 3,4-dihydroisoquinoline-6,7-diol (50g) were dissolved in a mixed solution of water and methanol (300mL) with a one-to-one volume ratio. The reaction mixture was stirred and heated under reflux at about 95°C for about 30h and the solvent was removed under reduced pressure. The residue obtained was washed with methylene chloride and concentrated in vacuum. The crude product obtained was purified by crystallization with methanol to give of 9,10-dihydroxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one. Yield: 35g
[0081] EXAMPLE 3: Preparation of deutetrabenazine hydrochloride
9,10-dimethyl-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (100g), was added in deuterated methanol (124.5g) and THF (500 mL) under nitrogen atmosphere at about room temperature. The reaction is stirred followed by the addition of triphenylphosphine (273.86g) and a solution of diisopropyl azodicarboxylate [prepared by dissolving 209.5g in 200 ml of THF]. The reaction mixture was stirred at about room temperature for about 3h. The residue obtained was dissolved in toluene and water, the solution was stirred for about 30min. The suspension was washed with aqueous sodium bisulfate solution (5%) and extracted in to methylene chloride, the pH was adjusted between 9.0 to 10 using aqueous ammonia solution. The organic layer was concentrated under vacuum, the residue mass obtained dissolved in tert-butyl methyl ether (120mL), hydrogen chloride-2-propanol solution was added at about 25°C, and the reaction mixture was stirred for about 1h to about 3h at about room temperature. The solid obtained was filtered and dried for about 12h at about 55°C to give the deutetrabenazine hydrochloride. Yield: 27g
1H NMR (DMSO): d 12.37 (br, 1H), d 6.69 (s, 1H), d 3.47 (m, 2H), d 3.27 (d, 1H), d 3.14 (d, 1H), d 2.84-2.67 (m, 2H), d 2.56 (d, 1H), d 2.5-2.29 (m, 4H), d 2.09 (d, 2H), d 1.68-1.61 (d, 2H), d 0.85-0.95 (m, 6H).
Mass: M/Z = 325.34 (M+H)
DSC analysis of deutetrabenazine hydrochloride shows endothermic peak at about 216°C.
TGA analysis of deutetrabenazine hydrochloride shows a weight loss of about 0.53% weight% up to 100°C determined over the temperature range of 0°C to 250°C and heating rate 10°C/min.
Table 1: XRD peaks of Deutetrabenazine hydrochloride
Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]
8.91 9.91 100.00 26.39 3.37 59.40
11.37 7.77 15.65 26.84 3.32 13.09
12.19 7.25 30.99 27.64 3.22 18.92
12.99 6.81 98.56 28.11 3.17 2.01
13.96 6.34 13.14 28.68 3.11 7.54
14.36 6.16 19.82 28.97 3.08 2.23
14.65 6.04 11.33 29.56 3.02 10.02
15.54 5.70 9.30 30.31 2.94 10.96
16.13 5.49 1.20 31.13 2.87 2.94
17.53 5.05 2.88 31.35 2.85 3.64
17.85 4.96 14.28 32.07 2.79 3.66
18.60 4.77 19.24 32.56 2.74 2.64
19.10 4.64 13.30 33.02 2.71 0.93
19.26 4.60 7.44 34.18 2.62 0.50
20.46 4.33 6.79 34.99 2.56 2.21
20.73 4.28 41.06 35.45 2.53 3.11
21.16 4.19 14.40 36.12 2.48 2.30
22.28 3.99 36.27 36.51 2.46 1.49
22.53 3.94 34.75 37.76 2.38 2.49
23.56 3.77 31.34 38.78 2.32 3.28
24.17 3.68 3.83 39.65 2.27 1.20
24.53 3.62 22.78 40.29 2.23 1.87
24.76 3.59 12.66 40.70 2.21 2.12
25.49 3.49 18.67 41.90 2.15 1.52
26.12 3.41 19.19 42.73 2.11 2.44

[0082] EXAMPLE 4: Preparation of deutetrabenazine hydrobromide
To a stirred suspension of deutetrabenazine (50g) in water (250mL) at about 25°C, 48% aqueous HBr (100mL) was added and the reaction mixture was stirred for about 4h at about room temperature. The solid obtained was filtered, washed with water and dried at about 55°C for about 12h to about 14 h, to give the deutetrabenazine hydrobromide. Yield: 34g.
DSC analysis of deutetrabenazine hydrobromide shows endothermic onset peak at about 208°C, and peak temperature at about 211°C.
TGA analysis of deutetrabenazine hydrobromide shows a weight loss of about 2.50 weight% up to 100°C determined over the temperature range of 0°C to 250°C and heating rate 10°C/min.
Table 2: XRD peaks of Deutetrabenazine hydrobromide
Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]
8.78 10.06 63.06 25.89 3.44 57.95
11.18 7.91 92.89 26.23 3.39 61.53
12.08 7.32 100.00 26.61 3.34 32.58
12.73 6.95 69.72 27.43 3.25 20.67
13.72 6.45 30.20 27.97 3.18 10.94
14.12 6.27 41.87 28.55 3.12 26.63
14.54 6.08 78.14 28.89 3.08 7.48
15.40 5.75 14.41 29.27 3.05 26.32
16.04 5.52 35.87 29.99 2.97 16.89
17.64 5.02 21.56 30.76 2.90 12.68
18.13 4.89 51.69 31.09 2.87 6.75
18.86 4.70 39.87 31.71 2.82 17.83
19.87 4.46 13.47 32.68 2.74 10.64
20.58 4.31 22.14 34.96 2.56 6.93
21.00 4.22 43.59 35.87 2.50 5.15
21.88 4.06 35.27 36.33 2.47 4.99
22.06 4.02 39.56 37.62 2.39 8.53
22.36 3.97 63.87 39.98 2.25 8.25
23.43 3.79 73.29 40.44 2.23 9.14
24.28 3.66 59.75 41.88 2.15 6.73
24.53 3.62 43.21 42.95 2.10 7.06
25.14 3.54 46.40 44.69 2.02 10.83

WE CLAIM
1. A crystalline form of deutetrabenazine hydrochloride.
2. The crystalline form of deutetrabenazine hydrochloride as claimed in claim 1, characterized by an X-ray powder diffraction (XRPD) peaks at 8.91, 12.19, 12.99, 18.60, 19.10, 20.73, 22.53, 24.53, 25.49, 26.39, 27.64, 30.31±0.2 2?.
3. The crystalline form of deutetrabenazine hydrochloride as claimed in claim 1, characterized by TGA thermogram, showing a weight loss of about 0.2 weight% to about 0.8 weight% up to 100°C determined over the temperature range of 0°C to 250°C and heating rate 10°C/min.
4. The crystalline form of deutetrabenazine hydrochloride as claimed in claim 1, characterized by DSC thermogram having one endothermic peak with peak temperature at about 216±5°C.
5. A process for preparation of crystalline form of deutetrabenazine hydrochloride, the process comprising:
(a) providing deutetrabenazine in a solvent to form a mixture.
(b) adding hydrochloric acid, optionally in the presence of a solvent, to the mixture obtained in step (a);
(c) obtaining deutetrabenazine hydrochloride from the mixture of step (b); and
(d) isolating the deutetrabenazine hydrochloride.
6. A crystalline form of deutetrabenazine hydrobromide.
7. The crystalline form of deutetrabenazine hydrobromide as claimed in claim 6, characterized by an X-ray powder diffraction (XRPD) peaks at 8.78, 11.18, 12.08, 13.72, 16.04, 17.64, 20.58, 21.00, 21.88, 22.06, 22.36, 23.43, 24.28, 24.53, 25.14, 25.89, 26.23, 26.61, 27.43, 27.97, 28.55 31.71±0.2 2?.
8. The crystalline form of deutetrabenazine hydrobromide as claimed in claim 6, characterized by TGA thermogram, showing a weight loss of about 2.2 weight% to about 2.8 weight% up to 100°C determined over the temperature range of 0°C to 250°C and heating rate 10°C/min.
9. The crystalline form of deutetrabenazine hydrobromide as claimed in claim 6, characterized by DSC thermogram having one endothermic peak with peak temperature at about 211±5°C.
10. A process for preparation of crystalline form of deutetrabenazine hydrobromide, the process comprising:
(a) providing deutetrabenazine in a solvent to form a mixture.
(b) adding hydrobromic acid, optionally in the presence of a solvent, to the mixture obtained in step (a);
(c) obtaining deutetrabenazine hydrobromide from the mixture of step (b); and
(d) isolating the deutetrabenazine hydrobromide.


Dated this 28th day of August, 2019

(Signed)____________________
DR. MADHAVI KARNIK
SENIOR GENERAL MANAGER-IPM
GLENMARK LIFE SCIENCES LIMITED
,CLAIMS:WE CLAIM
1. A crystalline form of deutetrabenazine hydrochloride.
2. The crystalline form of deutetrabenazine hydrochloride as claimed in claim 1, characterized by an X-ray powder diffraction (XRPD) peaks at 8.91, 12.19, 12.99, 18.60, 19.10, 20.73, 22.53, 24.53, 25.49, 26.39, 27.64, 30.31±0.2 2?.
3. The crystalline form of deutetrabenazine hydrochloride as claimed in claim 1, characterized by TGA thermogram, showing a weight loss of about 0.2 weight% to about 0.8 weight% up to 100°C determined over the temperature range of 0°C to 250°C and heating rate 10°C/min.
4. The crystalline form of deutetrabenazine hydrochloride as claimed in claim 1, characterized by DSC thermogram having one endothermic peak with peak temperature at about 216±5°C.
5. A process for preparation of crystalline form of deutetrabenazine hydrochloride, the process comprising:
(a) providing deutetrabenazine in a solvent to form a mixture.
(b) adding hydrochloric acid, optionally in the presence of a solvent, to the mixture obtained in step (a);
(c) obtaining deutetrabenazine hydrochloride from the mixture of step (b); and
(d) isolating the deutetrabenazine hydrochloride.
6. A crystalline form of deutetrabenazine hydrobromide.
7. The crystalline form of deutetrabenazine hydrobromide as claimed in claim 6, characterized by an X-ray powder diffraction (XRPD) peaks at 8.78, 11.18, 12.08, 13.72, 16.04, 17.64, 20.58, 21.00, 21.88, 22.06, 22.36, 23.43, 24.28, 24.53, 25.14, 25.89, 26.23, 26.61, 27.43, 27.97, 28.55 31.71±0.2 2?.
8. The crystalline form of deutetrabenazine hydrobromide as claimed in claim 6, characterized by TGA thermogram, showing a weight loss of about 2.2 weight% to about 2.8 weight% up to 100°C determined over the temperature range of 0°C to 250°C and heating rate 10°C/min.
9. The crystalline form of deutetrabenazine hydrobromide as claimed in claim 6, characterized by DSC thermogram having one endothermic peak with peak temperature at about 211±5°C.
10. A process for preparation of crystalline form of deutetrabenazine hydrobromide, the process comprising:
(a) providing deutetrabenazine in a solvent to form a mixture.
(b) adding hydrobromic acid, optionally in the presence of a solvent, to the mixture obtained in step (a);
(c) obtaining deutetrabenazine hydrobromide from the mixture of step (b); and
(d) isolating the deutetrabenazine hydrobromide.


Dated this 28th day of August, 2019

(Signed)____________________
DR. MADHAVI KARNIK
SENIOR GENERAL MANAGER-IPM
GLENMARK LIFE SCIENCES LIMITED