DESC:FIELD OF THE INVENTION
The present application relates to solid dispersions of Valbenazine ditosylate, their preparative methods and pharmaceutical compositions thereof.

BACKGROUND OF THE INVENTION
The drug compound having the adopted name Valbenazine, has a chemical name (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl-L-valinate, and is represented by the structure of formula I.

Valbenazine is a vesicular monoamine transporter 2 (VMAT2) inhibiter and is indicated for the treatment of tardive dyskinesia.
Valbenazine, its synthetic process and its pharmaceutical compositions are described in US patent No. 8,039,627 B2 (US ‘627). Valbenazine ditosylate and Valbenazine dihydrochloride salts, and its pharmaceutical compositions are described in US patent application No. 20170145008 A1 (US ‘008).
The US ‘008 also describes amorphous form and crystalline forms of Valbenazine ditosylate salt and their pharmaceutical compositions.
There remains a need to provide commercially viable and advantageous solid dispersions of Valbenazine ditosylate.

SUMMARY OF THE INVENTION
The present application generally relates to Valbenazine ditosylate solid dispersions and processes of preparation thereof.
In the first aspect, the present application provides amorphous solid dispersion comprising Valbenazine ditosylate and one or more pharmaceutically acceptable excipients.
In the second aspect, the present application provides a process for preparing amorphous solid dispersion comprising Valbenazine ditosylate and one or more pharmaceutically acceptable excipients, the process comprising;
a) providing a solution comprising Valbenazine ditosylate and one or more pharmaceutically acceptable excipients,
b) removing solvent from the solution obtained in step (a), and
c) recovering amorphous solid dispersion comprising Valbenazine ditosylate and one or more pharmaceutically acceptable excipient.
In the third aspect, the present application provides a pharmaceutical composition comprising any one of Valbenazine ditosylate solid dispersion of the present invention and a pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is powder X-ray diffraction pattern of amorphous solid dispersion comprising Valbenazine ditosylate and Povidone (1:1 w/w) prepared according to Example 1.
Figure 2 is powder X-ray diffraction pattern of amorphous solid dispersion comprising Valbenazine ditosylate and Copovidone (1:1 w/w) prepared according to Example 2.
Figure 3 is powder X-ray diffraction pattern of amorphous solid dispersion comprising Valbenazine ditosylate and HPMC AS (1:1 w/w) prepared according to Example 3.
Figure 4 is powder X-ray diffraction pattern of amorphous solid dispersion comprising Valbenazine ditosylate and HPMC-Phthalate (1:1 w/w) prepared according to Example 4.
Figure 5 is powder X-ray diffraction pattern of amorphous solid dispersion comprising Valbenazine ditosylate and HPMC (1:1 w/w) prepared according to Example 5.
Figure 6 is powder X-ray diffraction pattern of amorphous solid dispersion comprising Valbenazine ditosylate and HPC (1:1 w/w) prepared according to Example 6.
DETAILED DESCRITPION
In the first aspect, the present application provides amorphous solid dispersion comprising Valbenazine ditosylate and one or more pharmaceutically acceptable excipients.
In the second aspect, the present application provides a process for preparing amorphous solid dispersion comprising Valbenazine ditosylate and one or more pharmaceutically acceptable excipients, the process comprising;
a) providing a solution comprising Valbenazine ditosylate and one or more pharmaceutically acceptable excipients,
b) removing solvent from the solution obtained in step (a), and
c) recovering amorphous solid dispersion comprising Valbenazine ditosylate and one or more pharmaceutically acceptable excipient.
Providing a solution in step (a) includes direct use of a reaction mixture containing Valbenazine ditosylate that is obtained in the course of its synthesis or dissolving Valbenazine ditosylate and pharmaceutically acceptable excipient in a solvent or a mixture of solvents.
Any physical form of Valbenazine ditosylate may be utilized for providing the solution of step (a).
Suitable pharmaceutically acceptable excipient which can be used in step (a) include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, Polyethylene glycol, Copovidone, Soluplus, Silicified microcrystalline cellulose mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses such as HPMC-Phthalate, HPMC-AS, HPMC-15 CPS; pregelatinized starches and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.
In a preferred embodiment, the pharmaceutically acceptable excipients are Povidone, Copovidone, hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), HPMC-AS and HPMC-Phthalate.
Suitable solvent that can be used for dissolving the Valbenazine ditosylate include but are not limited to: alcohol solvents such as methanol, ethanol, isopropyl alcohol and the like; halogenated hydrocarbon solvents such as dichloromethane, dichloroethane, chlorobenzene and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; ethers such as diethyl ether, dimethyl ether, di-isopropyl ether, 1 ,4-dioxane and the like; and any mixtures of two or more thereof.
In a specific aspect the solvent used in step (a) is selected form the group comprising methanol, ethanol, acetone and dichloromethane.
After dissolution in step (a), optionally undissolved particles, if any, may be removed suitably by filtration, centrifugation, decantation, and any other known techniques. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
Step (b) involves removing solvent from the solution obtained in step (a);
Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying such as drying using a rotavapor, spray drying, agitated thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying, filtration or any other technique known in the art.
Step (c) involves recovering amorphous solid dispersion comprising Valbenazine ditosylate and one or more pharmaceutically acceptable excipients. The said recovery can be achieved by using the processes known in the art.
The resulting compound obtained in step (c) may optionally be further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 75°C, less than about 50°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the Valbenazine ditosylate is not degraded in its quality. The drying can be carried out for any desired time until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.
Alternatively the amorphous solid dispersion of Valbenazine ditosylate can be prepared by mixing Valbenazine ditosylate with a suitable pharmaceutically acceptable excipient such as Povidone, Copovidone, Hydroxypropyl cellulose (HPC), HPMC, HPMC-AS, HPMC-Phthalate, optionally in presence of a suitable solvent, followed by isolating and drying the amorphous solid dispersion of Valbenazine ditosylate.
When the active ingredient is hygroscopic or the formulation contains a hygroscopic ingredient, and to increase the stability of the amorphous form or a solid dispersion comprising Valbenazine ditosylate, addition of other carriers such as Syloid, methyl cellulose, colloidal silicon dioxide, Eudragit, amorphous silica, micro crystalline cellulose, and the like, in the formulation has been found to be of particular value. Therefore these ingredients may be combined during the preparation of solid dispersion or after the preparation of amorphous Valbenazine ditosylate or solid dispersion to control hygroscopicity and to improve stability.
In another aspect, the present application provides a pharmaceutical composition comprising any one of Valbenazine ditosylate solid dispersion of the present invention and a pharmaceutically acceptable carrier.
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.
DEFINITIONS
The following definitions are used in connection with the present invention unless the context indicates otherwise. The term “amorphous” refers to a solid lacking any long-range translational orientation symmetry that characterizes crystalline structures although; it may have short range molecular order similar to a crystalline solid.
Celite is flux-calcined diatomaceous earth. Hyflo is flux-calcined diatomaceous earth treated with sodium carbonate.
An “alcohol solvent” is an organic solvent containing a carbon bound to a hydroxyl group. “Alcoholic solvents” include, but are not limited to, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2- methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2- ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, or the like.
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.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, “comprising” means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range “between” two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
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. Reasonable variations of the described procedures are intended to be within the scope of the present invention. While particular aspects of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

EXAMPLES
Example-1: Preparation of amorphous solid dispersion of Valbenazine ditosylate and Povidone (1:1 w/w).
Povidone (PVP-K30) (500 mg), methanol (20 mL) and Valbenazine ditosylate (500 mg) were charged into a conical flask and the mixture was sonicated for 10 minutes. The mixture was passed through a filter paper and the clear solution was charged into a Buchi flask. The reaction mass was completely evaporated under reduced pressure at 45 °C. The solid was collected from the Buchi flask. PXRD pattern: Fig. 1.

Example 2: Preparation of amorphous solid dispersion of Valbenazine ditosylate and Copovidone (1:1 w/w).
Copovidone (500 mg), methanol (20 mL) and Valbenazine ditosylate (500 mg) were charged into a conical flask and the mixture was sonicated for 10 minutes. The mixture was passed through a filter paper and the clear solution was charged into a Buchi flask. The reaction mass was completely evaporated under reduced pressure at 45 °C. The solid was collected from the Buchi flask. PXRD pattern: Fig. 2.

Example 3: Preparation of amorphous solid dispersion of Valbenazine ditosylate and Hydroxy Propyl Methyl Cellulose-Acetate Succinate (1:1 w/w).
Hydroxy Propyl Methyl Cellulose-Acetate Succinate (HPMC-AS) (500 mg), methanol (20 mL) and Valbenazine ditosylate (500 mg) were charged into a conical flask and the mixture was sonicated for 10 minutes. The mixture was passed through a filter paper and the clear solution was charged into a Buchi flask. The reaction mass was completely evaporated under reduced pressure at 45 °C. The solid was collected from the Buchi flask. PXRD pattern: Fig. 3.

Example 4: Preparation of amorphous solid dispersion of Valbenazine ditosylate and Hydroxy Propyl Methyl Cellulose-Phthalate (1:1 w/w).
Hydroxy Propyl Methyl Cellulose-Phthalate (HPMC-Phthalate) (500 mg), methanol (20 mL), methylene chloride (DCM) (15 mL) and Valbenazine ditosylate (500 mg) were charged into a conical flask and the mixture was sonicated for 10 minutes. The mixture was passed through a filter paper and the clear solution was charged into a Buchi flask. The reaction mass was completely evaporated under reduced pressure at 30 °C. The solid was collected from the Buchi flask. PXRD pattern: Fig. 4.

Example 5: Preparation of amorphous solid dispersion of Valbenazine ditosylate and Hydroxy Propyl Methyl Cellulose (1:1 w/w).
Hydroxy Propyl Methyl Cellulose (HPMC) (500 mg), methanol (20 mL) and Valbenazine ditosylate (500 mg) were charged into a conical flask and the mixture was sonicated for 10 minutes. The mixture was passed through a filter paper and the clear solution was charged into a Buchi flask. The reaction mass was completely evaporated under reduced pressure at 45 °C. The solid was collected from the Buchi flask. PXRD pattern: Fig. 5.

Example 6: Preparation of amorphous solid dispersion of Valbenazine ditosylate and Hydroxy Propyl Cellulose (HPC) (1:1 w/w).
Hydroxy propyl cellulose (HPC) (500 mg), methanol (20 mL), and Valbenazine ditosylate (500 mg) were charged into a conical flask and the mixture was sonicated for 10 minutes. The mixture was passed through a filter paper and the clear solution was charged into a Buchi flask. The reaction mass was completely evaporated under reduced pressure at 45 °C. The solid was collected from the Buchi flask. PXRD pattern: Fig. 6.
,CLAIMS:CLAIMS
We claim:
1. Amorphous solid dispersion comprising Valbenazine ditosylate and one or more pharmaceutically acceptable excipients.
2. The amorphous solid dispersion as claimed in claim 1, wherein the pharmaceutically acceptable excipient is selected form the group comprising povidone, copovidone, hydroxy propyl methyl cellulose (HPMC), and hydroxy propyl cellulose (HPC).
3. The amorphous solid dispersion as claimed in claim 1, wherein the pharmaceutically acceptable excipient is povidone.
4. The amorphous solid dispersion as claimed in claim 1, wherein the pharmaceutically acceptable excipient is copovidone.
5. The amorphous solid dispersion as claimed in claim 1, wherein the pharmaceutically acceptable excipient is hydroxy propyl cellulose (HPC).
6. The amorphous solid dispersion as claimed in claim 1, wherein the pharmaceutically acceptable excipients is hydroxy propyl methyl cellulose (HPMC).
7. The amorphous solid dispersion as claimed in claim 6, wherein the HPMC is HPMC-Phthalate.
8. The amorphous solid dispersion as claimed in claim 6, wherein the HPMC is HPMC-Acetate succinate.
9. A process for preparing amorphous solid dispersion comprising Valbenazine ditosylate and one or more pharmaceutically acceptable excipients, the process comprising;
(a) providing a solution comprising Valbenazine ditosylate and one or more pharmaceutically acceptable excipients,
(b) removing solvent from the solution obtained in step (a), and
(c) recovering amorphous solid dispersion comprising Valbenazine ditosylate and one or more pharmaceutically acceptable excipient.
10. A pharmaceutical composition comprising amorphous solid dispersion as claimed claims 1 to 8, and a pharmaceutically acceptable carrier.