DESC:INTRODUCTION
Aspects of the present application relates to formic acid salt of Deutetrabenazine, crystalline forms of formic acid salt of Deutetrabenazine, process for the preparation thereof and pharmaceutical composition thereof.
Deutetrabenazine or d6-tetrabenazine is a deuterated analog of tetrabenazine. The drug compound having the adopted name “Deutetrabenazine” has chemical name: (RR, SS)-1, 3, 4, 6, 7, 11b-hexahydro-9, 10-di(methoxy-d3)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one. Deutetrabenazine is a racemic mixture containing the following structures:

RR-Deutetrabenazine SS-Deutetrabenazine
AUSTEDOTM (Deutetrabenazine) is a vesicular monoamine transporter 2 (VMAT2) inhibitor for oral administration. AUSTEDOTM was approved as oral tablets (6 mg, 9 mg, and 12 mg) by USFDA on 3 April 2017 for the treatment of chorea associated with Huntington’s disease. In August 2017 it was also approved for the treatment of tardive dyskinesia in adults.
US8524733B1 discloses Deutetrabenazine or a pharmaceutically acceptable salt thereof, method for the treatment of chronic hyperkinetic movement disorders and pharmaceutical composition thereof.
US9550780B2 discloses crystalline Form I and crystalline Form II of Deutetrabenazine.
WO2017221169A1 discloses premixes of deutetrabenazine with polyvinylpyrrolidone K-30, copovidone, talc and magnesium stearate.
The occurrence of different crystal forms, i.e., polymorphism, is a property of some compounds. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties, such as PXRD patterns, IR absorption spectra, melting points (MP), TGA curves, DSC curves, and solubilities. Polymorphs are different solids having the same molecular structure, yet having distinct physical properties when compared to other polymorphs of the same structure.
The discovery of new polymorphs and solvates of a pharmaceutical active compound provides an opportunity to improve the performance of a drug product in terms of its bioavailability or release profile in vivo, or it may have improved stability or advantageous handling properties. Polymorphism is an unpredictable property of any given compound. This subject has been reviewed in recent articles, including A. Goho, “Tricky Business,” Science News, August 21, 2004. In general, one cannot predict whether there will be more than one form for a compound, how many forms will eventually be discovered, or how to prepare any previously unidentified form.
There remains a need to provide the new polymorphic form of Deutetrabenazine which can be used in the pharmaceutical composition.

SUMMARY OF THE INVENTION
The aspect of the application provides crystalline formic acid salt of Deutetrabenazine.
The another aspect of the application provides crystalline forms of formic acid salt of Deutetrabenazine designated as Form SD1, Form SD2, and Form SD3 and processes for their preparation.
In one aspect, the application provides a crystalline form of formic acid salt of Deutetrabenazine, herein designated as Form SD1, characterized by a PXRD pattern having X-ray powder diffraction peaks selected from the following at about 7.93°, 11.44° and 24.33°± 0.2° 2?. The crystalline Form SD1 may be further characterized by X-ray powder diffraction peaks at about 17.41°, 18.22°, and 25.01°± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline form SD1 of formic acid salt of Deutetrabenazine, characterized by a PXRD pattern having peaks at about 7.93°, 11.44° and 24.33°± 0.2° 2?; comprising,
a) providing the solution of Deutetrabenazine in formic acid;
b) cooling the solution obtained in step (a); and
c) isolating the crystalline form SD1 of formic acid salt of Deutetrabenazine.
In another aspect, the present application provides a process for the preparation of crystalline form SD1 of formic acid salt of Deutetrabenazine, characterized by a PXRD pattern having peaks at about 7.93°, 11.44° and 24.33°± 0.2° 2?; comprising,
a) providing the solution of Deutetrabenazine in formic acid;
b) adding the anti-solvent to the solution obtained in step (a); and
c) isolating the crystalline form SD1 of formic acid salt of Deutetrabenazine.
In another aspect, the application provides a crystalline form of formic acid salt of Deutetrabenazine, herein designated as Form SD2, characterized by a PXRD pattern having X-ray powder diffraction peaks selected from the following at about 7.83°, 11.32° and 24.24°± 0.2° 2?. The crystalline Form SD2 may be further characterized by X-ray powder diffraction peaks at about 15.82 ° and 24.91°± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline form SD2 of formic acid salt of Deutetrabenazine, characterized by a PXRD pattern having peaks at about 7.83°, 11.32° and 24.24°± 0.2° 2?; by drying Form SD1.
In another aspect, the application provides a crystalline form of formic acid salt of Deutetrabenazine, herein designated as Form SD3, characterized by a PXRD pattern having X-ray powder diffraction peaks selected from the following at about 10.38° and 19.20°± 0.2° 2?. The crystalline Form SD3 may be further characterized by X-ray powder diffraction peaks at about 22.90° and 25.90°± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline form SD3 of formic acid salt of Deutetrabenazine, characterized by a PXRD pattern having peaks at about 10.38° and 19.20° ± 0.2° 2?; comprising,
a) providing the solution of Deutetrabenazine in mixture of formic acid and n-Heptane;
b) cooling the solution obtained in step (a); and
c) isolating the crystalline form SD3 of formic acid salt of Deutetrabenazine.
In another aspect, the present application provides a pharmaceutical composition comprising the crystalline forms SD1, SD2 and SD3 of formic acid salt of Deutetrabenazine together with at least one pharmaceutically acceptable excipient.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction pattern of the crystalline form SD1 of formic acid salt of Deutetrabenazine.
Figure 2 is an illustrative X-ray powder diffraction pattern of the crystalline form SD2 of formic acid salt of Deutetrabenazine.
Figure 3 is an illustrative X-ray powder diffraction pattern of the crystalline form SD3 of formic acid salt of Deutetrabenazine.

DETAILED DESCRIPTION
In one aspect of the application provides crystalline formic acid salt of Deutetrabenazine.
In another aspect, the application provides a crystalline form of formic acid salt of Deutetrabenazine, herein designated as Form SD1, characterized by a PXRD pattern having X-ray powder diffraction peaks selected from the following at about 7.93°, 11.44° and 24.33°± 0.2° 2?. The crystalline Form SD1 may be further characterized by X-ray powder diffraction peaks at about 17.41°, 18.22°, and 25.01°± 0.2° 2?. PXRD pattern of crystalline form SD1 of Deutetrabenazine is substantially depicted in FIG.1.
In another aspect, the present application provides a process for the preparation of crystalline form SD1 of formic acid salt of Deutetrabenazine, characterized by a PXRD pattern having peaks at about 7.93°, 11.44° and 24.33°± 0.2° 2?; comprising,
a) providing the solution of Deutetrabenazine in formic acid;
b) cooling the solution obtained in step (a); and
c) isolating the crystalline form SD1 of formic acid salt of Deutetrabenazine.
In embodiments, Deutetrabenazine can be dissolved in formic acid to provide a solution.
In an embodiment, the precipitation of crystalline form SD1 of formic acid salt of Deutetrabenazine can be obtained by cooling the solution obtained in step a). In embodiments, the solution obtained in step a) can be cooled to room temperature to -10°C. In embodiments, the slurry comprising precipitated crystalline form SD1 of formic acid salt of Deutetrabenazine can be maintained at any suitable temperatures, such as from about room temperature to about 0°C. In embodiments, the slurry comprising precipitated crystalline form SD1 of formic acid salt of Deutetrabenazine can be maintained for about 10 minutes to about 10 hours, or longer.
In embodiments, crystalline Form SD1 of formic acid salt of Deutetrabenazine can be isolated using any techniques, such as decantation, filtration by gravity or suction, centrifugation, or the solvent can be evaporated from the mass to obtain the desired product, and optionally the solid can be washed with a solvent, such as the solvent used for the crystallization to reduce the amount of entrained impurities in the product. In embodiments, crystalline form SD1 of formic acid salt of Deutetrabenazine can be isolated by filtration.
In embodiments, crystalline form SD1 of formic acid salt of Deutetrabenazine that is isolated may be dried at suitable temperatures such as room temperature to about 80°C under atmospheric or reduced pressures, for about 10 minutes to about 50 hours, or longer, using any types of drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
In another aspect, the application provides a process for the preparation of crystalline form SD1 of formic acid salt of Deutetrabenazine, characterized by a PXRD pattern having peaks at about 7.93°, 11.44° and 24.33°± 0.2° 2?; comprising,
a) providing the solution of Deutetrabenazine in formic acid;
b) adding the anti-solvent to the solution obtained in step (a); and
c) isolating the crystalline form SD1 of formic acid salt of Deutetrabenazine.
In embodiments of step a), Deutetrabenazine can be dissolved in formic acid to provide a solution.
In embodiment of step b), anti-solvent is added to solution obtained in step a). The anti-solvent can be a solvent in which Deutetrabenazine is insoluble or having very poor solubility. In embodiments the anti-solvent can be ether, alkanes, cycloalkanes or mixtures thereof. In embodiments the anti-solvent can be a mixture of Methyl Tert Butyl Ether and n-Heptane. In embodiments both anti-solvents can be added together or simultaneously. In embodiments Methyl Tert Butyl Ether was added first to the solution of step a) followed by addition of n-Heptane. In embodiments the ratio of solvent to anti-solvents can be in the range of 1:5 to 1:100 or preferably 1:5 to 1: 50 or any suitable combination. In embodiments the ratio of anti-solvents Methyl Tert Butyl Ether and n-Heptane can be in the range of 1:1 to1:10 or any suitable combination.
In an embodiment, the precipitation of crystalline form SD1 of formic acid salt of Deutetrabenazine can be obtained by cooling the solution or suspension obtained in step b). In embodiments, the solution or suspension obtained in step b) can be cooled to room temperature to -10°C. In embodiments, the slurry comprising precipitated crystalline form SD1 of formic acid salt of Deutetrabenazine can be maintained at any suitable temperatures, such as from about room temperature to about 0°C. In embodiments, the slurry comprising precipitated crystalline form SD1 of formic acid salt of Deutetrabenazine can be maintained for about 10 minutes to about 10 hours, or longer.
In embodiments, crystalline Form SD1 of formic acid salt of Deutetrabenazine can be isolated using any techniques, such as decantation, filtration by gravity or suction, centrifugation, or the solvent can be evaporated from the mass to obtain the desired product, and optionally the solid can be washed with a solvent, such as the solvent used for the crystallization to reduce the amount of entrained impurities in the product. In embodiments, crystalline form SD1 of formic acid salt of Deutetrabenazine can be isolated by filtration.
In another aspect, the application provides a crystalline form of formic acid salt of Deutetrabenazine, herein designated as Form SD2, characterized by a PXRD pattern having X-ray powder diffraction peaks selected from the following at about 7.83°, 11.32° and 24.24°± 0.2° 2?. The crystalline Form SD2 may be further characterized by X-ray powder diffraction peaks at about 15.82° and 24.91°± 0.2° 2?. PXRD pattern of crystalline form SD2 of formic acid salt of Deutetrabenazine is substantially depicted in FIG.2.
In another aspect, the present application provides a process for the preparation of crystalline form SD2 of formic acid salt of Deutetrabenazine, characterized by a PXRD pattern having peaks at about 7.83°, 11.32° and 24.24°± 0.2° 2?; by drying Form SD1. In embodiments, crystalline form SD1 of formic acid salt of Deutetrabenazine that is isolated can be dried at suitable temperatures such as room temperature to about 80°C under atmospheric or reduced pressures, for about 10 minutes to about 50 hours, or longer, using any types of drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. Preferably form SD2 of formic acid salt of Deutetrabenazine can be obtained by drying Form SD1 in vacuum tray dryer at 45°C for 1 h.
In another aspect, the application provides a crystalline form of formic acid salt of Deutetrabenazine, herein designated as Form SD3, characterized by a PXRD pattern having X-ray powder diffraction peaks selected from the following at about 10.38° and 19.20°± 0.2° 2?. The crystalline Form SD3 may be further characterized by X-ray powder diffraction peaks at about 22.90° and 25.90°± 0.2° 2?. PXRD pattern of crystalline form SD3 of formic acid salt of Deutetrabenazine is substantially depicted in FIG.3.
In another aspect, the present application provides a process for the preparation of crystalline form SD3 of formic acid salt of Deutetrabenazine, characterized by a PXRD pattern having peaks at about 10.38° and 19.20° ± 0.2° 2?; comprising,
a) providing the solution of Deutetrabenazine in mixture of formic acid and n-Heptane;
b) cooling the solution obtained in step (a); and
c) isolating the crystalline form SD3 of formic acid salt of Deutetrabenazine.
In embodiments of step a), Deutetrabenazine can be dissolved in mixture of formic acid and n-Heptane to provide a solution.
In embodiment of step b), the precipitation of crystalline form SD3 of formic acid salt of Deutetrabenazine can be obtained by cooling the solution or suspension obtained in step b). In embodiments, the solution or suspension obtained in step b) can be cooled to room temperature to 0°C. In embodiments, the slurry comprising precipitated crystalline form SD3 of formic acid salt of Deutetrabenazine can be maintained at any suitable temperatures, such as from about room temperature to about 0°C. In embodiments, the slurry comprising precipitated crystalline form SD3 of formic acid salt of Deutetrabenazine can be maintained for about 10 minutes to about 10 hours, or longer.
In embodiments, crystalline Form SD3 of formic acid salt of Deutetrabenazine can be isolated using any techniques, such as decantation, filtration by gravity or suction, centrifugation, or the solvent can be evaporated from the mass to obtain the desired product, and optionally the solid can be washed with a solvent, such as the solvent used for the crystallization to reduce the amount of entrained impurities in the product. In embodiments, crystalline form SD3 of formic acid salt of Deutetrabenazine can be isolated by filtration.
In embodiments, crystalline form SD3 of formic acid salt of Deutetrabenazine that is isolated can be dried at suitable temperatures such as room temperature to about 80°C under atmospheric or reduced pressures, for about 10 minutes to about 50 hours, or longer, using any types of drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
In embodiments, the solution of Deutetrabenazine used for preparing of Form SD1, Form SD2 and Form SD3 in the present application can be prepared at any suitable temperatures, such as from about room temperature to about the reflux temperature of the solvent used. Mixing may be used to reduce the time required for the dissolution process. In embodiments, a solution of Deutetrabenazine may be filtered to make it clear, free of undissolved particles. In embodiments, the obtained solution may be optionally treated with a decolorizing agent or an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
In embodiments, optionally the desired seed material can also be used for the preparation of the crystalline form SD1, Form SD2 and Form SD3 of formic acid salt of Deutetrabenazine.
In embodiments, crystalline forms SD1, SD2 and SD3 of formic acid salt of Deutetrabenazine obtained by a methods of the present application having a chemical purity greater than about 97%, greater than about 98%, greater than about 99%, greater than about 99.5%, or greater than about 99.9%, as determined using high performance liquid chromatography (HPLC). In embodiments, the process described in this application can also be useful to enhance the chemical purity of the Deutetrabenazine.
In embodiments, the crystalline forms SD1, SD2 and SD3 of formic acid salt of Deutetrabenazine according to the present application can be milled or micronized by any process known in the art, such as ball milling, jet milling, wet milling etc., to produce desired particle sizes and particle size distributions.
Any physical form of Deutetrabenazine may be utilized for providing the solution of Deutetrabenazine. Deutetrabenazine that may be used as the input for the process of the present invention may be obtained by the processes described in the art. For example Deutetrabenazine may be prepared by the processes described in US8524733B1, US9550780B2, WO2015084622A1, WO2011153157A2 and WO2017182916A1.
In another aspect, the present application provides a pharmaceutical composition comprising the crystalline forms SD1, SD2 and SD3 of formic acid salt of Deutetrabenazine together with at least one pharmaceutically acceptable excipient.
In another aspect of the present application provides pharmaceutical compositions containing a therapeutically effective amount of crystalline forms SD1, SD2 and SD3 of formic acid salt of Deutetrabenazine described herein, together with one or more pharmaceutically acceptable excipients. The pharmaceutical compositions comprising crystalline form SD1 of formic acid salt of Deutetrabenazine together with one or more pharmaceutically acceptable excipients may be formulated as: solid oral dosage forms, such as, but not limited to: powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze-dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate-controlling substances to form matrix or reservoir systems, or combinations of matrix and reservoir systems. The compositions may be prepared using any one or more of techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated powder coated, enteric coated, or modified release coated.
Pharmaceutically acceptable excipients that are useful in the present application include, but are not limited to, any one or more of: diluents such as starches, pregelatinized starches, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches, or the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, or the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, or the like; glidants such as colloidal silicon dioxide or the like; solubility or wetting enhancers such as anionic, cationic, and neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; and release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes, or the like. Other pharmaceutically acceptable excipients that are useful include, but are not limited to, film-formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, or the like.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.
The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example "about 10" should be construed as meaning within the range of 9 to 11, preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.

General description of the PXRD equipment
X-ray diffraction was measured using PANalytical X-ray diffractometer, Model: X'Pert PRO. System description: CuK-Alpha 1 wavelength= 1 .54060, voltage 45kV, current 40 mA, divergence slit=0.5°; Sample stage=Reflection-Transmission Spinner. Scan type: Continuous; Detector - X'Celerator; Measurement parameters: Start Position [°2Th.]: 3; End Position [°2Th.]: 40; Step Size [°2Th.]:0.0167; Scan Step Time [s]: 64.770.

EXAMPLES
Example-1: Preparation of crystalline form SD1 of Deutetrabenazine
Deutetrabenazine (5 g) was charged into easymax reactor at room temperature. Formic acid (3 mL) was added slowly to the easymax reactor at room temperature. The mixture was stirred for 1 h at room temperature and further heated to 70°C. Deutetrabenazine (500 mg) was further added to easymax reactor at 70°C stirred for 2 h to get clear solution. The clear solution was cooled to room temperature from 70°C in 30 minutes and stirring maintained for 23 h at 25°C. The crystallized material was filtered.
Yield: 3.56 g
The PXRD pattern of the isolated material is represented as Figure-1.

Example-2: Preparation of crystalline form SD1 of Deutetrabenazine
Deutetrabenazine (5 g) was charged into easymax reactor at room temperature. Formic acid (5 mL) was added slowly to the easymax reactor at room temperature. The mixture was stirred for 5 minutes at room temperature and further heated to 70°C to get clear solution. The clear solution was cooled to 25°C and Methyl Tert Butyl Ether (20 mL) was slowly added in 10 minutes and n-Heptane (80 mL) was added to the solution and stirred for 35 minutes at 25°C. The product was obtained by filtration of the precipitated material.
Yield: 3.92 g
The PXRD pattern of the isolated material is represented as Figure-1.

Example-3: Preparation of crystalline form SD2 of Deutetrabenazine
Deutetrabenazine (5 g) was charged into easymax reactor at room temperature. Formic acid (3 mL) was added slowly to the easymax reactor at room temperature. The mixture was stirred for 10 minutes at room temperature and further heated to 70°C. Deutetrabenazine (500 mg) was added to easymax reactor at 70°C stirred for 45 minutes to get clear solution. The clear solution was cooled to room temperature and stirring continued for 90 min at 25°C. The product was obtained by filtration of the precipitated material. The obtained material was dried in VTD at 45°C for 1 h.
Yield: 4.32 g
The PXRD pattern of the isolated material is represented as Figure-2.

Example-4: Preparation of crystalline form SD3 of Deutetrabenazine
n-Heptane (80 mL) and Formic acid (1 mL) were added to the easymax reactor at room temperature and stirred for 10 minutes. Deutetrabenazine (0.750 g) was charged into easymax reactor containing the solvent at room temperature. The solution was heated to 40°C and maintained for 1 h under stirring. The clear solution was cooled to room temperature and stirring continued for 40 minutes at 25°C. The product was obtained by filtration of the precipitated material.
The PXRD pattern of the isolated material is represented as Figure-3.
,CLAIMS:We Claim:

1. Crystalline formic acid salt of Deutetrabenazine.
2. Crystalline Form SD1 of formic acid salt of Deutetrabenazine characterized by an X-ray powder diffraction pattern comprising the peak at about 7.93°, 11.44° and 24.33°± 0.2° 2?.
3. Crystalline Form SD1 of formic acid salt of Deutetrabenazine as claimed in 2 further characterized by PXRD pattern having additional peaks at about 17.41°, 18.22°, and 25.01°± 0.2° 2?.
4. A process for preparing crystalline Form SD1 of formic acid salt of Deutetrabenazine comprising the steps of;
a) providing the solution of Deutetrabenazine in formic acid;
b) cooling the solution obtained in step (a); and
c) isolating the crystalline form SD1 of formic acid salt of Deutetrabenazine.
5. Crystalline Form SD2 of formic acid salt of Deutetrabenazine characterized by an X-ray powder diffraction pattern comprising the peak at about 7.83°, 11.32° and 24.24°± 0.2° 2?.
6. A process for preparing crystalline Form SD2 of formic acid salt of Deutetrabenazine by drying Form SD1.
7. Crystalline Form SD3 of formic acid salt of Deutetrabenazine characterized by an X-ray powder diffraction pattern comprising the peak at about 10.38° and 19.20°± 0.2° 2?.
8. A process for preparing crystalline Form SD3 of formic acid salt of Deutetrabenazine comprising the steps of;
a) providing the solution of Deutetrabenazine in mixture of formic acid and n-Heptane;
b) cooling the solution obtained in step (a); and
c) isolating the crystalline form SD3 of formic acid salt of Deutetrabenazine.
9. A pharmaceutical composition comprising the crystalline Forms of formic acid salt of Deutetrabenazine selected from Form SD1, Form SD2 and Form SD3 and pharmaceutically acceptable excipients.