DESC:FIELD OF THE INVENTION

The present disclosure generally relates to the field of pharmaceutical sciences and specifically relates to novel salts of deutetrabenazine. The present disclosure more specifically relates to deutetrabenazine salts namely saccharinate salt, monofumarate salt and hemifumarate salt, its polymorphs and processes for the preparation thereof.

BACKGROUND OF THE INVENTION
Deutetrabenazine 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 is shown below in Formula-I:

Deutetrabenazine (I) is a deuterated analog of tetrabenazine which has improved pharmacokinetic properties when compared to the non-deuterated drug. Deutetrabenazine has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of chorea associated with Huntington disease.

Deutetrabenazine (I) is disclosed in the United States Pat. No. US 8524733. The United States Pat. No US 9550780 discloses deutetrabenazine crystalline polymorphs, form-I and form-II.

PCT patent publication WO 2017221169 discloses deutetrabenazine premix comprising deutetrabenazine and at least one pharmaceutically acceptable excipient selected from polyvinylpyrrolidone K-30, copovidone, talc and magnesium stearate.

There remains a need in the art for new salt forms of deutetrabenazine having increased a solubility. There also remains a need in the art for polymorphic forms of deutetrabenazine new salts having improved properties of increased solubility while at the same time exhibiting chemical stability.
OBJECT AND SUMMARY OF THE INVENTION
The principle object of the present invention is to provide deutetrabenazine salts namely saccharinate salt, monofumarate salt and hemifumarate salt, its polymorphs and processes for the preparation thereof.

Another aspect of the present invention is to provide polymorphic forms of deutetrabenazine saccharinate salt designated as crystalline form M1, form M2 and amorphous form.

Another aspect of the present invention is to provide polymorphic forms of deutetrabenazine monofumarate salt designated as crystalline form M1 and form M2.

Another aspect of the present invention is to provide polymorphic form of deutetrabenazine hemifumarate salt designated as crystalline form M1.

Another aspect of the present invention is to provide process for the preparation of crystalline form-M1 of deutetrabenazine saccharinate salt comprising the steps of:
a) dissolving deutetrabenazine and saccharine in a polar solvent
b) isolating crystalline form-M1 of deutetrabenazine saccharinate salt.
Another aspect of the present invention is to provide process for the preparation of crystalline form-M2 of deutetrabenazine saccharinate salt comprising the steps of:
a) dissolving deutetrabenazine and saccharine in a mixture of solvents
b) isolating crystalline form-M2 of deutetrabenazine saccharinate salt.

Another aspect of the present invention is to provide process for the preparation of amorphous form of deutetrabenazine saccharinate salt comprising the steps of:
a) dissolving deutetrabenazine and saccharine in an alcohol solvent
b) adding an anti-solvent
c) isolating amorphous form of deutetrabenazine saccharinate salt
Another aspect of the present invention is to provide process for the preparation of crystalline form-M1 of deutetrabenazine monofumarate salt comprising the steps of:
a) dissolving deutetrabenazine and fumaric acid in an alcohol solvent
b) adding an anti-solvent
c) isolating crystalline form-M1 of deutetrabenazine monofumarate salt.
Another aspect of the present invention is to provide process for the preparation of crystalline form-M1 of deutetrabenazine monofumarate salt comprising the steps of:
a) dissolving deutetrabenazine and fumaric acid in an alcohol solvent
b) adding an anti-solvent
c) seeding crystalline form-M1 of deutetrabenazine monofumarate salt.
d) isolating crystalline form-M1 of deutetrabenazine monofumarate salt.
Another aspect of the present invention is to provide process for the preparation of crystalline form-M2 of deutetrabenazine monofumarate salt comprising the steps of:
a) dissolving crystalline form-M1 of deutetrabenazine monofumarate salt in a mixture of solvents
b) isolating crystalline form-M2 of deutetrabenazine monofumarate salt.
Another aspect of the present invention is to provide process for the preparation of crystalline form-M1 of deutetrabenazine hemifumarate salt comprising the steps of:
a) dissolving deutetrabenazine and fumaric acid in an alcohol solvent
b) adding an anti-solvent
c) seeding deutetrabenazine hemifumarate salt.
d) isolating crystalline form-M1 of crystalline form-M1 of deutetrabenazine hemifumarate salt.

BRIEF DESCRIPTION OF THE DRAWINGS
Further aspects of the present disclosure together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of embodiments of the disclosure which are shown in the accompanying drawing figures wherein:

Figure 1 shows the powder X-ray diffraction pattern of crystalline form-M1 of deutetrabenazine saccharinate salt.
Figure 2 shows the powder X-ray diffraction pattern of crystalline form-M2 of deutetrabenazine saccharinate salt
Figure 3 shows the powder X-ray diffraction pattern of amorphous of deutetrabenazine saccharinate salt.
Figure 4 shows the powder X-ray diffraction pattern of crystalline form-M1 of deutetrabenazine monofumarate salt.
Figure 5 shows the powder X-ray diffraction pattern of crystalline form-M2 of deutetrabenazine monofumarate salt.
Figure 6 shows the powder X-ray diffraction pattern of crystalline form-M1 of deutetrabenazine hemifumarate salt.

DETAILED DESCRIPTION OF THE INVENTION

The principle object of the present invention is to provide deutetrabenazine salts namely saccharinate salt, monofumarate salt and hemifumarate salt, its polymorphs and processes for the preparation thereof.

Powder X-ray diffraction (PXRD)
The said polymorph of the present invention is characterized by X-ray powder diffraction pattern. Thus X-ray powder diffraction patterns of said polymorph of the invention were measured on PANalytical X’Pert PRO powder X-ray diffractometer equipped with a goniometer of ?/? configuration and X’Celerator detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 2? range of 2.0°-50.0° with 0.030° step size and 50 seconds step time.

One aspect of the present invention provides novel salt of deutetrabenazine namely saccharinate salt, monofumarate salt and hemifumarate salt.

Another aspect of the present invention provides polymorphic forms of deutetrabenazine salts namely saccharinate salt, monofumarate salt and hemifumarate salt.

Another aspect of the present invention provides crystalline form-M1 of deutetrabenazine saccharinate salt.

According to this embodiment, crystalline Form M1 of deutetrabenazine saccharinate salt may be characterized by a powder X-ray diffraction having characteristic peaks at about 2? angles of 6.6, 7.4, 13.1, 15.7, 16.2, 17.3, 20.6, 21.5 and 25.5 (±) 0.2°.

According to this embodiment, crystalline Form M1 of deutetrabenazine saccharinate salt may be further characterized by a powder X-ray diffraction having characteristic peaks at about 2? angles of 6.6, 7.4, 7.7, 8.9, 9.7, 10.4, 11.6, 12.0, 13.1, 14.2, 15.0, 15.7, 16.2, 17.3, 18.2, 19.0, 20.6, 21.1, 21.5, 22.1, 22.8, 23.7, 24.3, 25.5, 27.7 and 32.3 (±) 0.2°.

Crystalline Form M1 of deutetrabenazine saccharinate salt may be further characterized by the PXRD pattern in Figure 1. It is believed that crystalline form-M1 of deutetrabenazine saccharinate salt is a tetrahydrofuran solvate of deutetrabenazine saccharinate salt.

Another aspect of the present invention is to provide process for the preparation of crystalline form-M1 of deutetrabenazine saccharinate salt comprising the steps of:
a) dissolving deutetrabenazine and saccharine in a polar solvent
b) isolating crystalline form-M1 of deutetrabenazine saccharinate salt.
According to the present embodiment, the term “polar solvent,” unless otherwise indicated, refers to ethereal solvents or mixtures thereof.
as used herein, ether solvent include, but are not limited to 1,4-dioxane, tetrahydrofuran, and mixtures thereof.
In some embodiments of the present invention deutetrabenazine and saccharine may be dissolved in tetrahydrofuran under the heating, heating may be carried out at a temperature of about 50°C to 80°C In some embodiments of the present invention, a temperature of about 40°C to about 80°C was found to be particularly useful for dissolving deutetrabenazine and saccharine in tetrahydrofuran. As used herein, the term “about” means 10% above or below the value recited.
The above obtained clear solution may be cooled to 20°C to 30°C and maintained under stirring for about 24 hours. The reaction mass may be further cooled to 5°C to 10°C and maintained under stirring for about 30 to 60 minutes.
Next, according to the present embodiment, the solvent may be removed by known techniques which may include, but are not limited to, evaporation, distillation, spray drying and filtration
The isolation of crystalline form-M1 of deutetrabenazine saccharinate salt may be carried out by methods well known in the art, for example, by isolation of the precipitate by filtration followed by suck-drying.

Another aspect of the present invention provides crystalline form-M2 of deutetrabenazine saccharinate salt.

According to this embodiment, crystalline Form M2 of deutetrabenazine saccharinate salt may be characterized by a powder X-ray diffraction having characteristic peaks at about 2? angles of 7.4, 8.6, 10.0, 11.2, 14.5, 16.9, 18.4, 21.9 and 24.0 (±) 0.2°.

According to this embodiment, crystalline Form M2 of deutetrabenazine saccharinate salt may be further characterized by a powder X-ray diffraction having characteristic peaks at about 2? angles of 4.1, 6.4, 7.4, 8.6, 10.0, 11.2, 12.5, 14.5, 15.2, 16.9, 17.5, 18.4, 19.0, 19.7, 20.4, 21.9, 22.7, 23.4, 24.0, 24.6, 25.2, 26.1, 27.1, 28.5, 29.2, 30.1, 31.7, 32.8 and 37.2(±) 0.2°.

Crystalline Form M2 of deutetrabenazine saccharinate salt may be further characterized by the PXRD pattern in Figure 2. It is believed that crystalline form-M2 of deutetrabenazine saccharinate salt is a toluene solvate of deutetrabenazine saccharinate salt.

Another aspect of the present invention is to provide process for the preparation of crystalline form-M2 of deutetrabenazine saccharinate salt comprising the steps of:
a) dissolving deutetrabenazine and saccharine in a mixture of solvents
b) isolating crystalline form-M2 of deutetrabenazine saccharinate salt.
According to the present embodiments deutetrabenazine and saccharine may be dissolved in a mixture of solvents under the heating. The heating may be carried out at a temperature of about 50°C to 80°C
Within the context of this embodiment, solvent may be selected from hydrocarbon solvent, chlorinated solvent and mixtures thereof. The hydrocarbon solvents include, but are not limited to, toluene, hexane, heptane and mixtures thereof, chlorinated solvent include, but are not limited to dichloromethane, dichloroethane, chloroform and mixtures thereof. Within the specific context of this embodiment, a mixture of toluene and dichlormethane may be used as the solvent mixture for dissolving deutetrabenazine and saccharine.
In some embodiments of the present invention, a temperature of about 40°C to about 80°C was found to be particularly useful for dissolving deutetrabenazine and saccharine in toluene and dichlormethane mixture. As used herein, the term “about” means 10% above or below the value recited.
The above obtained clear solution may be cooled to 20°C to 30°C and maintained under stirring for about 10 -20 hours.
Next, according to the present embodiment, the solvent may be removed by known techniques which may include, but are not limited to, evaporation, distillation, spray drying and filtration
The isolation of crystalline form-M2 of deutetrabenazine saccharinate salt may be carried out by methods well known in the art, for example, by isolation of the precipitate by filtration followed by suck-drying.

Another aspect of the present invention provides amorphous form of deutetrabenazine saccharinate salt.
Amorphous form of deutetrabenazine saccharinate salt may be further characterized by the PXRD pattern in Figure 3.
Another aspect of the present invention is to provide process for the preparation of amorphous form of deutetrabenazine saccharinate salt comprising the steps of:
a) dissolving deutetrabenazine and saccharine in an alcohol solvent
b) adding an anti-solvent
c) isolating amorphous form of deutetrabenazine saccharinate salt
According to this embodiment, deutetrabenazine and saccharine may be dissolved in alcohol solvent. As used herein, alcohol solvents include, but are not limited to, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, t-butanol, 1-pentanol, 2-methyl-2-butanol or mixtures thereof;
In some embodiments of the present invention deutetrabenazine and saccharine may be dissolved particularly in methanol solvent under heating, heating may be carried out at a temperature of about 40°C to about reflux. In some embodiments of the present invention, a temperature of about 50°C to about 80°C was found to be particularly useful for dissolving deutetrabenazine and saccharine in methanol solvent. As used herein, the term “about” means 10% above or below the value recited.
Further, the above resulted solution may be cooled to a temperature of about 20°C to about 30°C.
Next, according to this embodiment, an anti-solvent solvent may be added to above resulted solution, anti-solvent solvent for example, a hydrocarbon solvent, an ethereal solvent or mixtures thereof. Specific examples of hydrocarbon solvent include but not limited to toluene, heptane, hexane, cylohexane, ethereal solvent include but not limited to 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran or a mixture thereof. Within the context of this embodiment an anti-solvent methyl tert-butyl ether is preferably used.
The above obtained reaction mass may be maintained under stirring for about 10-20 hours.
Next, according to this embodiment, the solvent may be removed to isolate amorphous form of deutetrabenazine saccharinate salt.
Next, according to the present embodiment, the solvent may be removed by known techniques which may include, but are not limited to, evaporation, distillation, spray drying and filtration
The isolation of amorphous form of deutetrabenazine saccharinate salt. may be carried out by methods well known in the art, for example, by isolation of the precipitate by filtration followed by suck-drying.
Another aspect of the present invention provides crystalline form-M1 of deutetrabenazine monofumarate salt.

According to this embodiment, crystalline Form M1 of deutetrabenazine monofumarate salt may be characterized by a powder X-ray diffraction having characteristic peaks at about 2? angles of 7.6, 8.8, 10.2, 11.4, 17.2, 18.6, 19.9, 22.2, 24.4, 24.9, 27.4 and 28.7 (±) 0.2°.
According to this embodiment, crystalline Form M1 of deutetrabenazine monofumarate salt may be further characterized by a powder X-ray diffraction having characteristic peaks at about 2? angles of 5.7, 7.6, 8.8, 10.2, 11.4, 12.8, 14.7, 15.5, 17.2, 17.8, 18.1, 18.6, 19.2, 19.4, 19.9, 20.6, 20.7, 21.2, 22.2, 22.8, 23.1, 23.6, 24.2, 24.9, 26.5, 27.4, 28.7, 29.5 and 31.1 (±) 0.2°.

Crystalline Form M1 of deutetrabenazine monofumarate salt may be further characterized by the PXRD pattern in Figure 4. It is believed that crystalline form-M1 of deutetrabenazine monofumarate s salt is an anhydrous form of deutetrabenazine monofumarate salt.

Another aspect of the present invention is to provide process for the preparation of crystalline form-M1 of deutetrabenazine monofumarate salt comprising the steps of:
a) dissolving deutetrabenazine and fumaric acid in an alcohol solvent
b) adding an anti-solvent
c) isolating crystalline form-M1 of deutetrabenazine monofumarate salt.
According to this embodiment, deutetrabenazine and fumaric acid may be dissolved in alcohol solvent. As used herein, alcohol solvents include, but are not limited to, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, t-butanol, 1-pentanol, or mixtures thereof;
In some embodiments of the present invention deutetrabenazine and fumaric acid may be dissolved particularly in methanol solvent under heating, heating may be carried out at a temperature of about 25°C to about reflux. In some embodiments of the present invention, a temperature of about 25°C to about 30°C was found to be particularly useful for dissolving deutetrabenazine and fumaric acid in methanol solvent. As used herein, the term “about” means 10% above or below the value recited.
Further, the above resulted solution may be maintained under stirring at 25 to 30°C for about 36-48 hours.
Next, according to this embodiment, an anti-solvent solvent may be added to above resulted solution, anti-solvent solvent for example, a hydrocarbon solvent, an ethereal solvent or mixtures thereof. Specific examples of hydrocarbon solvent include but not limited to toluene, heptane, hexane, cylohexane, ethereal solvent include but not limited to 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran or a mixture thereof. Within the context of this embodiment an anti-solvent methyl tert-butyl ether is preferably used.
Next, according to this embodiment, the solvent may be removed to isolate form-M1 of deutetrabenazine monofumarate salt
The isolation of crystalline form-M1 of deutetrabenazine monofumarate salt may be carried out by methods well known in the art, for example, by isolation of the precipitate by filtration followed by suck-drying.
Another aspect of the present invention is to provide process for the preparation of crystalline form-M1 of deutetrabenazine monofumarate salt comprising the steps of:
a) dissolving deutetrabenazine and fumaric acid in a alcohol solvent
b) adding an anti-solvent
c) seeding crystalline form-M1 of deutetrabenazine monofumarate salt.
d) isolating crystalline form-M1 of deutetrabenazine monofumarate salt.
According to this embodiment, deutetrabenazine and fumaric acid may be dissolved in alcohol solvent. As used herein, alcohol solvents include, but are not limited to, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, t-butanol, 1-pentanol, 2-methyl-2-butanol or mixtures thereof;
In some embodiments of the present invention deutetrabenazine and fumaric acid may be dissolved particularly in methanol solvent under heating, heating may be carried out at a temperature of about 50°C to about 80°C. In some embodiments of the present invention, a temperature of about 60°C to about 70°C was found to be particularly useful for dissolving deutetrabenazine and fumaric acid in methanol solvent. As used herein, the term “about” means 10% above or below the value recited.
Next, according to this embodiment, an anti-solvent may be added to above resulted solution, anti-solvent solvent for example, a hydrocarbon solvent, an ethereal solvent or mixtures thereof. Specific examples of hydrocarbon solvent include but not limited to toluene, heptane, hexane, cylohexane, ethereal solvent include but not limited to 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran or a mixture thereof. Within the context of this embodiment an anti-solvent methyl tert-butyl ether is preferably used.
Next, according to this embodiment, the seed of crystalline form-M1 of deutetrabenazine monofumarate salt may be added to the above resulted reaction mass.
Further, the above resulted reaction mass may be maintained under stirring at 25 to 30°C for about 10-20 hours.
Next, according to this embodiment, the solvent may be removed to isolate form-M1 of deutetrabenazine monofumarate salt
The isolation of crystalline form-M1 of deutetrabenazine monofumarate salt. may be carried out by methods well known in the art, for example, by isolation of the precipitate by filtration followed by suck-drying.
Another aspect of the present invention provides crystalline form-M2 of deutetrabenazine monofumarate salt.

According to this embodiment, crystalline Form M2 of deutetrabenazine monofumarate salt may be characterized by a powder X-ray diffraction having characteristic peaks at about 2? angles of 4.3, 8.7, 13.3, 26.9 and 32.1 (±) 0.2°.

According to this embodiment, crystalline Form M2 of deutetrabenazine monofumarate salt may be further characterized by a powder X-ray diffraction having characteristic peaks at about 2? angles of 4.3, 7.3, 8.7, 9.2, 11.1, 11.7, 13.3, 13.5, 13.9, 14.5, 15.2, 16.7, 17.5, 18.5, 19.2, 20.1, 20.8, 23.4, 24.0, 26.6, 26.9, 27.7, 29.4, 31.5 and 32.1 (±) 0.2°.

Crystalline Form M2 of deutetrabenazine monofumarate salt may be further characterized by the PXRD pattern in Figure 5. It is believed that crystalline form-M2 of deutetrabenazine monofumarate salt is a toluene solvate of deutetrabenazine monofumarate salt.

Another aspect of the present invention is to provide process for the preparation of crystalline form-M2 of deutetrabenazine monofumarate salt comprising the steps of:
a) dissolving crystalline form-M1 of deutetrabenazine monofumarate salt in a mixture of solvents
b) isolating crystalline form-M2 of deutetrabenazine monofumarate salt.
According to the present embodiments, crystalline form-M1 of deutetrabenazine monofumarate may be dissolved in a mixture of solvents under the heating. The heating may be carried out at a temperature of about 50°C to 80°C
Within the context of this embodiment, solvent may be selected from hydrocarbon solvent, alcohol solvent and mixtures thereof. The hydrocarbon solvents include, but are not limited to, toluene, hexane, heptane and mixtures thereof, alcohol solvent include, but are not limited to methanol, ethanol, propanol, isopropanol, butanol and mixtures thereof. Within the context of this embodiment toluene and methanol solvent mixture is preferably used.
In some embodiments of the present invention, a temperature of about 40°C to about 80°C was found to be particularly useful for dissolving crystalline form-M1 of deutetrabenazine monofumarate in toluene and methanol solvent mixture. As used herein, the term “about” means 10% above or below the value recited.
The above obtained clear solution may be cooled to 20°C to 30°C and maintained under stirring for about 36-48 hours. The reaction mass may be further cooled to 5°C to 10°C and maintained under stirring for about 10 to 15 hours.
Next, according to the present embodiment, the solvent may be removed by known techniques which may include, but are not limited to, evaporation, distillation, spray drying and filtration
The isolation of crystalline form-M2 of deutetrabenazine monofumarate salt may be carried out by methods well known in the art, for example, by isolation of the precipitate by filtration followed by suck-drying.

Another aspect of the present invention provides crystalline form-M1 of deutetrabenazine hemifumarate salt.

According to this embodiment, crystalline Form M1 of deutetrabenazine hemifumarate salt may be characterized by a powder X-ray diffraction having characteristic peaks at about 2? angles of 7.9, 8.4, 11.5, 12.6, 16.8, 18.9, 20.6, 23.0 23.9 and 25.3 (±) 0.2°.

According to this embodiment, crystalline Form M1 of deutetrabenazine hemifumarate salt may be further characterized by a powder X-ray diffraction having characteristic peaks at about 2? angles of 7.9, 8.4, 8.9, 10.3, 11.5, 12.6, 15.0, 15.7, 16.3, 16.8, 18.1, 18.9, 19.5, 20.6, 21.1, 21.6, 23.0, 23.9, 24.1, 24.7, 25.3 and 26.3 (±) 0.2°.

Crystalline Form M1 of deutetrabenazine monofumarate salt may be further characterized by the PXRD pattern in Figure 6. It is believed that crystalline form-M1 of deutetrabenazine hemifumarate salt is an anhydrous form of deutetrabenazine hemifumarate salt.

Another aspect of the present invention is to provide process for the preparation of crystalline form-M1 of deutetrabenazine hemifumarate salt comprising the steps of:
a) dissolving deutetrabenazine and fumaric acid in an alcohol solvent
b) adding an anti-solvent
c) seeding deutetrabenazine hemifumarate salt.
d) isolating crystalline form-M1 of crystalline form-M1 of deutetrabenazine hemifumarate salt.
According to this embodiment, deutetrabenazine and fumaric acid may be dissolved in alcohol solvent. As used herein, alcohol solvents include, but are not limited to, methanol, ethanol, propanol, isopropanol, n-butanol, 2-butanol, t-butanol, 1-pentanol, or mixtures thereof;
In some embodiments of the present invention deutetrabenazine and fumaric acid may be dissolved particularly in methanol solvent under heating, heating may be carried out at a temperature of about 50°C to about 80°C. In some embodiments of the present invention, a temperature of about 60°C to about 70°C was found to be particularly useful for dissolving deutetrabenazine and fumaric acid in methanol solvent. As used herein, the term “about” means 10% above or below the value recited.
Next, according to this embodiment, an anti-solvent solvent may be added to above resulted solution, anti-solvent solvent for example, a hydrocarbon solvent, an ethereal solvent or mixtures thereof. Specific examples of hydrocarbon solvent include but not limited to toluene, heptane, hexane, cylohexane, ethereal solvent include but not limited to 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran or a mixture thereof. Within the context of this embodiment an anti-solvent methyl tert-butyl ether is preferably used.
Further, the above resulted reaction mass may be cooled to 25 to 30°C maintained under stirring.
Next, according to this embodiment, the seed of deutetrabenazine hemifumarate salt may be added to the above resulted reaction mass.
Further, the above resulted reaction mass may be maintained under stirring at 25 to 30°C for about 10-20 hours.
Next, according to this embodiment, the solvent may be removed to isolate form-M1 of deutetrabenazine hemifumarate salt
The isolation of crystalline form-M1 of deutetrabenazine hemifumarate salt may be carried out by methods well known in the art, for example, by isolation of the precipitate by filtration followed by drying.
In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.

EXAMPLES

Example 1: Preparation of Deutetrabenazine Saccharinate salt crystalline form M1
Deutetrabenazine (500mg) and Saccharine (283mg) were dissolved in tetrahydrofuran (5mL) at 70±5°C, then cooled to 25±5°C and maintained under stirring at 25±5°C for 24h. The reaction mass was further cooled to 7±3°C, stirred for 30min, filtered and suck-dried. The solid obtained was identified as crystalline Form M1 of Deutetrabenazine saccharinate salt. Yield: 630mg

Example 2: Preparation of Deutetrabenazine Saccharinate salt crystalline form M2
Deutetrabenazine (200mg) and saccharin (113mg) were dissolved in a mixture of toluene (3mL) and dichloromethane (2mL) at 70±5°C, then cooled to 25±5°C and maintained under stirring for 15h. The reaction mass was filtered and suck-dried. The solid obtained was identified as crystalline Form M2 of Deutetrabenazine saccharinate salt Yield: 250mg

Example 3: Preparation of amorphous form of Deutetrabenazine Saccharinate salt
Deutetrabenazine (100mg) and Saccharin (56.63mg) were dissolved in methanol (0.6 mL) at 70±5°C. The clear solution was cooled to 25±5°C, added methyl tertiary butyl ether (2 mL) at 25±5°C and stirred the reaction mass at 25±5°C for 10h. The product obtained was filtered and suck-dried. The solid obtained was identified as amorphous form of Deutetrabenazine saccharinate salt. Yield: 120mg.

Example 4: Preparation of amorphous form of Deutetrabenazine Saccharinate salt
Deutetrabenazine (500mg) and Saccharin (283mg) were suspended in methanol (3 mL) and heated to 70±5°C to obtain clear solution. To the clear solution added methyl tertiary butyl ether (10 mL) at 70±5°C, then cooled to 25±5°C and maintained under stirring for 15h. The reaction mass was then distilled under vacuum at 55±5°C to get foamy solid. The solid obtained was identified as amorphous form of Deutetrabenazine saccharinate salt Yield: 600mg.

Example 5: Preparation of Deutetrabenazine Monofumarate salt crystalline form M1
Deutetrabenazine (100mg) and fumaric acid (36mg) were dissolved in methanol (1mL) at 70°C. The clear solution was maintained under stirring at 25±5°C for 48h. Then added methyl tertiary butyl ether (0.5mL) to the reaction mass and the resulting solid was identified as crystalline Form M1 of Deutetrabenazine monofumarate salt. Yield: 90mg

Example 6: Preparation of Deutetrabenazine Monofumarate salt crystalline form M1
Deutetrabenazine (500mg) and fumaric acid (180mg) were dissolved in methanol (3mL) at 70±5°C. Then added methyl tertiary butyl ether (1.5mL) at 70±5°C. To the clear solution added seeds of Form M1 at 70±5°C and cooled to 25±5°C. The reaction mass was maintained under stirring at 25±5°C for 15h. The product obtained was filtered and dried under vacuum at 40°C for 1h. The solid obtained was identified as crystalline Form M1 of Deutetrabenazine monofumarate salt. Yield: 400mg

Example 7: Preparation of Deutetrabenazine Monofumarate salt crystalline form M2
Deutetrabenazine Form M1 (200mg) was dissolved in a mixture of toluene (5mL) and methanol (1mL) at 70±5°C. The clear solution was then cooled to 25±5°C and stirred the reaction mass at 25±5°C for 48h. Further stirred at 5±3°C for 12h. The reaction mass was filtered and suck-dried. The solid obtained was identified as crystalline Form M2 of Deutetrabenazine monofumarate salt. Yield: 130mg

Example 8: Preparation of Deutetrabenazine hemifumarate salt crystalline form M1
Deutetrabenazine (500mg) and fumaric acid (90mg) were dissolved in methanol (1mL) at 70±5°C. Then added methyl tertiary butyl ether (3mL) at 25±5°C. To the clear solution added seeds of Deutetrabenazine hemifumarate salt (3mg) at 25±5°C and cooled to 25±5°C. Stirred the reaction mass at 25±5°C for 15h. The product obtained was filtered and dried under vacuum at 40°C for 1h. The solid obtained was identified as crystalline Form M1 of Deutetrabenazine hemifumarate salt. Yield: 520mg

,CLAIMS:1. A pharmaceutically acceptable salt of Deutetrabenazine of formula (I)

wherein the salt is selected from saccharinate, monofumarate and hemifumarate.
2. The pharmaceutically acceptable salt of Deutetrabenazine as claimed in clam 1 selected from:
a) crystalline Form M1 of deutetrabenazine saccharinate salt characterized by a powder X-ray diffraction pattern having peaks at 6.6, 7.4, 13.1, 15.7, 16.2, 17.3, 20.6, 21.5 and 25.5 (±) 0.2°;
b) crystalline Form M2 of deutetrabenazine saccharinate salt characterized by a powder X-ray diffraction pattern having peaks at 7.4, 8.6, 10.0, 11.2, 14.5, 16.9, 18.4, 21.9 and 24.0 (±) 0.2°;
c) amorphous form of deutetrabenazine saccharinate salt characterized by the PXRD pattern as shown in Figure 3.
d) crystalline Form M1 of deutetrabenazine monofumarate salt characterized by a powder X-ray diffraction pattern having peaks at .6, 8.8, 10.2, 11.4, 17.2, 18.6, 19.9, 22.2, 24.4, 24.9, 27.4 and 28.7 (±) 0.2°;
e) crystalline Form M2 of deutetrabenazine monofumarate salt characterized by a powder X-ray diffraction pattern having peaks at 4.3, 8.7, 13.3, 26.9 and 32.1 (±) 0.2°;
f) crystalline Form M1 of deutetrabenazine hemifumarate salt characterized by a powder X-ray diffraction pattern having peaks at 7.9, 8.4, 11.5, 12.6, 16.8, 18.9, 20.6, 23.0 23.9 and 25.3 (±) 0.2°.
3. A process for the preparation of crystalline Form M1 of deutetrabenazine saccharinate salt comprising the steps of:
a) dissolving deutetrabenazine and saccharine in a polar solvent; and
b) isolating crystalline form-M1 of deutetrabenazine saccharinate salt;
wherein the polar solvent is selected from 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, and mixtures thereof.

4. A process for the preparation of crystalline Form M2 of deutetrabenazine saccharinate salt comprising the steps of:
a) dissolving deutetrabenazine and saccharine in a mixture of solvents; and
b) isolating crystalline form-M2 of deutetrabenazine saccharinate salt.

5. The process according to claim 4, wherein the solvent is selected from toluene, hexane, heptane, dichloromethane, dichloroethane, chloroform and mixtures thereof.

6. A process for the preparation of amorphous form of deutetrabenazine saccharinate salt comprising the steps of:
a) dissolving deutetrabenazine and saccharine in an alcohol solvent;

b) adding an anti-solvent; and

c) isolating amorphous form of deutetrabenazine saccharinate salt.

7. A process for the preparation of crystalline form-M1 of deutetrabenazine monofumarate salt comprising the steps of:
a) dissolving deutetrabenazine and fumaric acid in an alcohol solvent;

b) adding an anti-solvent; and

c) isolating crystalline form-M1 of crystalline form-M1 of deutetrabenazine monofumarate salt.

8. A process for the preparation of crystalline form-M1 of deutetrabenazine monofumarate salt comprising the steps of:
a) dissolving deutetrabenazine and fumaric acid in an alcohol solvent;

b) adding an anti-solvent;

c) seeding deutetrabenazine monofumarate salt; and

d) isolating crystalline form-M1 of crystalline form-M1 of deutetrabenazine monofumarate salt.

9. A process for the preparation of crystalline form-M1 of deutetrabenazine hemifumarate salt comprising the steps of:
a) dissolving deutetrabenazine and fumaric acid in an alcohol solvent;

b) adding an anti-solvent;

c) seeding deutetrabenazine hemifumarate salt; and

d) isolating crystalline form-M1 of crystalline form-M1 of deutetrabenazine hemifumarate salt.

10. The process according to claim 6, 7, 8 and 9, wherein the alcohol solvent is selected from the group comprising of methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, t-butanol, 1-pentanol, 2-methyl-2-butanol or mixtures thereof; anti-solvent is selected from the group comprising of toluene, heptane, hexane, cylohexane, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran or a mixture thereof.