PREPARATION

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of earlier Indian provisional patent application IN 201841007796 filed on March 01, 2018 which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present disclosure generally relates to the field of pharmaceutical sciences and specifically relates to a polymorphic form of deutetrabenazine. The present disclosure more specifically relates to a novel polymorphic form of deutetrabenazine designated as crystalline Form Ml and a process for its preparation.

BACKGROUND OF THE INVENTION

Deutetrabenazine is chemically known as (RR, SS)-l, 3, 4, 6, 7, 1 lb-hexahydro-9, 10- di(methoxy-d3)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-on e and is shown below in Formula (I):

Deutetrabenazine (I) is a deuterated analog of tetrabenazine having 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. 8,524,733. United States Pat. No. 9,550,780 discloses deutetrabenazine crystalline polymorph form-I and form-II.

International patent publication no. WO2017/221169 discloses a deutetrabenazine premix comprising deutetrabenazine and at least one pharmaceutically acceptable excipient.

SUMMARY OF THE INVENTION

In one aspect, the present disclosure provides crystalline Form Ml of deutetrabenazine.

In one embodiment, crystalline Form Ml of deutetrabenazine may be characterized by a powder X-ray diffraction pattern having peaks at 8.2, 11.4, 13.8, 19.8, 20.6, 23.2, 24.7, 26.0 and 26.5 (±) 0.2 °20. In another embodiment, crystalline Form Ml of deutetrabenazine may be characterized by a PXRD pattern having peaks at 6.4, 8.2, 10.2, 11.4, 12.0, 13.8, 19.8, 20.6, 22.2, 23.2, 24.7, 26.0, and 26.5 (±) 0.2 °20. In another embodiment, crystalline Form Ml of deutetrabenazine may be characterized by the PXRD pattern as shown in Figure 4.

In another embodiment, crystalline Form Ml of deutetrabenazine may be characterized by an FT-Raman spectrum having peaks at 3079, 3049, 2909, 1699, and 1293 ± 1 cm ¹ . In one embodiment, crystalline Form Ml of deutetrabenazine may be characterized by a FT- Raman spectrum as shown in Figure 1.

In one embodiment, crystalline Form Ml of deutetrabenazine may be characterized by a DSC curve as shown in Figure 2. Crystalline Form Ml of deutetrabenazine may be characterized by a DSC curve having an endotherm between about l l l°C and about l29°C.

In one embodiment, crystalline Form Ml of deutetrabenazine may be characterized by the TGA curve as shown in Figure 3.

In another aspect, crystalline Form Ml of deutetrabenazine may be prepared by a process that includes the steps of: a. dissolving deutetrabenazine in a solvent; and b. removing the solvent to isolate deutetrabenazine crystalline Form Ml

The solvent may be, for example, an ether solvent, alcohol solvent, water, or mixtures thereof. Examples of suitable ether solvents include l,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, anisole, and mixtures thereof. Examples of suitable alcohol solvents include methanol, ethanol, 1 -propanol, isopropanol, 1 -butanol, 2-butanol, isobutyl alcohol, tert-butanol, isopentyl alcohol, l-pentanol, 2-pentanol, and mixtures thereof.

The solvent may be removed by evaporation, distillation, spray drying, lyophilization, agitated thin film drying, or any combination thereof. Crystalline Form Ml of deutetrabenazine may be formulated into a pharmaceutical composition, optionally including a pharmaceutically acceptable excipient.

In some embodiments, crystalline Form Ml of deutetrabenazine may have a deuterium enrichment of no less than about 90%.

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

Figure 1 shows the FT-Raman spectra of crystalline Form Ml of deutetrabenazine; Figure 2 shows the DSC plot of crystalline Form Ml of deutetrabenazine;

Figure 3 shows the TGA and DTA plots of crystalline Form Ml of deutetrabenazine; and

Figure 4 shows the powder X-ray diffraction pattern of crystalline Form Ml of deutetrabenazine . DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that the figures and descriptions of the present invention have been simplified to illustrate elements that are relevant for a clear understanding of the invention. The detailed description will be provided herein below with reference to the attached drawings.

The present invention provides crystalline deutetrabenazine having a polymorphic form not yet reported, as well as methods of its preparation. Designated as Form Ml, it may be characterized and distinguished from other polymorphic forms of deutetrabenazine by a variety of analytical methods, including, but not limited to, Fourier transform Raman spectroscopy (FT-Raman), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and powder X-ray diffraction (PXRD). Samples of deutetrabenazine prepared by methods disclosed herein were analyzed by these analytical methods according to the parameters outlined for each below.

Instrumentation Fourier Transform Raman (FT-Raman) spectroscopy

Samples of deutetrabenazine Form Ml were analyzed by FT-Raman (Thermo Fisher Scientific, Waltham, MA, USA) equipped with a He-Ne Laser (1064 nm) in the range of 3600cm ¹ to lOOcm ¹ .

Differential Scanning Calorimetry (DSC) Samples of deutetrabenazine Form Ml were analyzed on a differential scanning calorimeter (TA Q1000, TA Instruments, New Castle, DE, USA). The experiments were performed at a heating rate of 30.0°C/min over a temperature range of 30°C-200°C purging with nitrogen at a flow rate of 50 mL/min. Standard aluminum crucibles covered by lids with three pin holes were used. Thermogravimetric Analysis (TGA)

Samples of deutetrabenazine Form Ml were analyzed on a vapor sorption analyzer (TA Q5000, TA Instruments). The experiments were performed at a heating rate of l0.0°C/min over a temperature range of 30°C-300°C, purging with nitrogen at a flow rate of 25 mL/min.

Powder X-rav diffraction (PXRD)

Samples of deutetrabenazine Form Ml were analyzed on a PANalytical X’Pert PRO powder X-ray diffractometer equipped with a goniometer of Q/Q configuration and X’Celerator detector. The Cu-anode X-ray tube was operated at 40 kV and 30 mA. The experiments were conducted over the 20 range of 2.0°-50.0° with 0.030° step size and 50 seconds step time.

In one aspect, the present invention provides crystalline Form Ml of deutetrabenazine.

In one embodiment, crystalline Form Ml of deutetrabenazine may be characterized by an FT-Raman spectrum having characteristic peaks at about 3079, 3049, 2909, 1699, and 1293 ± 1 cm ¹ . In another embodiment, crystalline Form Ml of deutetrabenazine may be further characterized by the FT-Raman spectral data shown in Figure 1. In yet another embodiment, crystalline Form Ml of deutetrabenazine may be characterized by the DSC curve shown in Figure 2. In yet another embodiment, crystalline Form Ml of deutetrabenazine may be characterized by the TGA curve shown in Figure 3.

In one embodiment, crystalline Form Ml of deutetrabenazine may be characterized by PXRD pattern having characteristic peaks at 20 angles of 8.2, 11.4, 13.8, 19.8, 20.6, 23.2, 24.7, 26.0, and 26.5 (±) 0.2°. In another embodiment, crystalline Form Ml of deutetrabenazine may be further characterized by a powder X-ray diffraction having characteristic peak at 20 angles of 6.4, 8.2, 10.2, 11.4, 12.0, 13.8, 19.8, 20.6, 22.2, 23.2, 24.7, 26.0, and 26.5 (±) 0.2°. In yet another embodiment, crystalline Form Ml of deutetrabenazine may be further characterized by the PXRD pattern shown in Figure 4. In another aspect, the present invention provides a method for preparing crystalline Form Ml of deutetrabenazine.

In one embodiment, crystalline Form Ml of deutetrabenazine may be prepared by a process that includes: a) dissolving deutetrabenazine in a solvent; and

b) removing the solvent to isolate deutetrabenazine crystalline Form Ml.

Deutetrabenazine may be first dissolved in a solvent. The starting deutetrabenazine may be any polymorphic form or amorphous. The solvent may be, for example, an ether solvent, an alcohol solvent, water, or mixtures thereof. Examples of suitable ether solvents include, but are not limited to, l,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, anisole, and mixtures thereof. Examples of suitable alcohol solvents include, but are not limited to, methanol, ethanol, propanol, isopropanol, butanol, and mixtures thereof. In some embodiments, deutetrabenazine is dissolved in a mixture of l,4-dioxane and water. This may be carried out at a suitable temperature, for example, at a temperature of about 25°C to 30°C.

Optionally, after dissolving, the solution may be filtered to remove any undissolved particulates (e.g., through Flyflo®).

Next, the solvent may then be removed to isolate deutetrabenazine crystalline Form Ml. This may be carried out by well-known techniques such as, evaporation, distillation, spray drying, lyophilization, agitated thin film drying, or combinations thereof. In some embodiments, lyophilization is used to remove the solvent.

Crystalline Form Ml of disclosed herein may be incorporated into a pharmaceutically acceptable dosage form, for example, an oral dosage form such as a tablet or capsule. In particularly useful embodiments, deutetrabenazine is formulated into a tablet. In particularly useful embodiments, tablets contain 6 mg to 12 mg deutetrabenazine, which includes 6 mg, 9 mg, and 12 mg deutetrabenazine. The tablet or capsule may have additional pharmaceutically acceptable excipients, such as microcrystalline cellulose 101 or 102 (including or additional to any that may be part of a solid dispersion), lactose monohydrate, croscarmellose sodium, sodium stearyl fumarate, silicon dioxide, polyvinyl alcohol, polyethylene glycol, talc, as well as artificial colorings, such as iron oxide red, iron oxide yellow, and titanium dioxide.

Pharmaceutical dosage forms that incorporate deutetrabenazine polymorph disclosed herein may be useful in treatment of a VMAT2 -mediated disease.

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 crystalline Form Ml of deutetrabenazine

Deutetrabenazine (5g) was dissolved in mixture of l,4-dioxane (90 mL) and water (30 mL) at 25±5°C. The resulting clear solution was filtered through diatomaceous earth (Hyflo®) to remove any undissolved particulates and the filtrate was lyophilized using a Labocon lyophilizer (Model: LFD-BT-104) to yield deutetrabenazine Form Ml . Yield: 4.4 g.