DESC:FIELD OF INVENTION
The present invention relates to solid state form of Valbenazine Ditosylate and pharmaceutical composition thereof. The present invention also relates to process for the preparation of Valbenazine Ditosylate.

BACKGROUND
Valbenazine, also known as (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester. It is also known as NBI-98854 and is represented by the chemical structure as depicted in Formula I:

Formula I
Valbenazine Ditosylate, also known as (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), which is represented by the chemical structure as depicted in Formula II.

Formula II

Valbenazine is an inhibitor of vesicular monoamine transporter 2 (VMAT2). Valbenazine is approved under the trademark “INGREZZA®” by US Food and Drug Administration for the treatment of adults with tardive dyskinesia.

US 8,039,627 discloses Valbenazine and method for synthesizing.

WO2017/112857 discloses preparation of Valbenazine Ditosylate by converting Valbenazine HCL to Valbenazine Ditosylate. The final step of the synthesis, described in example F on pages 58 discloses preparation of a Valbenazine free base solution from the dihydrochloride with aqueous sodium bicarbonate and the addition of p-Toluenesulfonic acid and crystallization of the Ditosylate.

WO2017/075340 discloses Valbenazine salts and polymorphs thereof. The document further discloses six crystalline forms (I, II, III, IV, V, and VI) of Valbenazine Ditosylate and two crystalline forms (I and II) of Valbenazine Dihydrochloride.

WO2018/067945 discloses polymorphs of Valbenazine, and Valbenazine salts. The document further discloses solid state forms of Valbenazine, Valbenazine tosylate, Valbenazine fumarate, Valbenazine stearate, Valbenazine palmitate, Valbenazine sulfate, Valbenazine mesylate,
WO2018153632 discloses two crystalline form (hydrate and anhydrate) of Valbenazine Ditosylate.

Many compounds can exist in different solid state forms such as amorphous, crystalline, and pseudo polymorph. These different solid state forms possess different physical properties but not every solid state form of a drug substance can be formulated into a suitable formulation. These different solid state forms provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, improving the dissolution profile, or improving stability and shelf-life. These different solid state forms may also provide improvements to the final dosage form such as improved bioavailability.

Consequently, there is still a need for an improved and reliable solid state form which would able to synthesis, by means of a process that can readily be converted to the industrial scale, especially in a form that allows rapid filtration and drying. Finally, that form had to be perfectly reproducible, easily formulated and sufficiently stable to allow its storage for long periods.

SUMMARY OF THE INVENTION
In one aspect, the present invention provides a process for the preparation of Valbenazine Ditosylate, a compound of Formula II

Formula II
comprising the steps of:
reacting a compound of formula I

Formula I
with 4-methylbenzene sulfonic acid to obtain a compound of formula II in a suitable solvent and mixture thereof under suitable conditions.

In another aspect, the present invention provides a process for the preparation of solid state form of Valbenazine Ditosylate, comprising the steps of:
i. dissolving the Valbenazine free base with solvent or mixture thereof;
ii. optionally cooling the reaction mixture;
iii. adding p-Toluenesulfonic acid to the above reaction mass and optionally stirring;
iv. optionally adding solvent or co-solvent or anti-solvent to above reaction mass; and
v. isolating the solid state form of Valbenazine Ditosylate.

In another aspect, the present invention provides a process for the preparation of solid state form of Valbenazine Ditosylate, comprising the steps of:
i. dissolving the Valbenazine free base with solvent or mixture thereof;
ii. optionally cooling the reaction mixture;
iii. adding p-Toluenesulfonic acid to the above reaction mass and optionally stirring;
iv optionally adding solvent or co-solvent or anti-solvent to above reaction mass;
v raising reaction mass temperature and optionally stirring;
vi. cooling the reaction mass and optionally stirring; and
vii. isolating the solid state form of Valbenazine Ditosylate.

In another aspect, the present invention provides a process for the preparation of solid state form of Valbenazine Ditosylate, comprising the steps of:
i. dissolving the Valbenazine free base with solvent or mixture thereof;
ii. optionally cooling the reaction mixture;
iii. adding p-Toluenesulfonic acid to the above reaction mass and optionally stirring;
iv. distil out reaction mass;
v. optionally adding solvent or co-solvent or anti-solvent to above reaction mass; and
vi. isolating the solid state form of Valbenazine Ditosylate.

In yet another aspect, the present invention provides solid state form of Valbenazine Ditosylate characterized by X-ray powder diffraction pattern comprising characteristic 2?° peaks at 6.3, and 12.5 ± 0.2 2?°. In particular aspect, the present invention provides solid state Form of Valbenazine Ditosylate characterized by X-ray powder diffraction pattern comprising characteristic 2?° peak at 6.3 ± 0.2 2?°.

In more particular aspect, the present invention provides solid state form of Valbenazine Ditosylate has an X-ray diffraction pattern substantially as shown in Figure 1. Solid state form of Valbenazine Ditosylate comprises crystalline and amorphous in a relative ratio of 20:80 to 40:60.

In another aspect, the present invention provides a pharmaceutical composition comprising Valbenazine Ditosylate prepared by the process of the invention and at least one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1: illustrates a representative of an X-ray powder diffraction (XRPD) pattern of Valbenazine Ditosylate solid state form.

DETAILED DESCRIPTION OF THE INVENTION
Definitions
Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

The term "Valbenazine" refers to the compound with the chemical name (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester, which is represented by the chemical structure as depicted in Formula I of the present invention. In the present invention "Valbenazine" indicates the free base form.

The term "Valbenazine Ditosylate" refers to the compound with the chemical name (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido [2,1-a]isoquinolin-2-yl-2-amino-3-methylbutanoate di(4-Methylbenzene- -sulfonate), also refers to the compound which is represented by the chemical structure as depicted in Formula II.

The term "solid state form" refers to any crystalline, amorphous form or a mixture thereof of a compound. Solid state form contains from about 20% to about 60%, about 30% to about 60%, about 40% to about 60%, about 50% to about 60%, preferably about 20% to about 40%, more preferably about 30% to about 40% crystalline Valbenazine Ditosylate. Accordingly, in some embodiments of the disclosure, the described solid state form of Valbenazine Ditosylate may contains from about 40% to about 80%, about 40% to about 70%, about 40% to about 60%, about 40% to about 50%, preferably about 60% to about 80%, more preferably about 60% to about 70% amorphous form of the Valbenazine Ditosylate as measured, for example, by XRPD.

The term "crystalline form" refers to any crystalline form of the compound.

The term "amorphous" refers to a solid form of a compound that is not crystalline. An amorphous compound possesses no long-range order and does not display a definitive X-ray diffraction pattern with reflections.
The term "about" or "approximately" means within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range. In certain embodiments, "about" or "approximately" with reference to X-ray powder diffraction two-theta peaks means within +0.2 degree.

The term "room temperature" refers to a temperature in the range of from about 20°C to about 30°C, about 22°C to about 27°C, or about 25°C.

Suitable solvents or co-solvent for use in preparing the solid state form of Valbenazine Ditosylate, include but are not limited to, 1,1-dichloroethene, 1,2-dichloroethane, 1,2-dichloroethene, butanol, propanol, 2-butanol, 2-methyl tetrahydrofuran, acetone, acetonitrile (ACN), cyclopentane, dichloromethane (DCM), dioxane, ethanol, ethers, including diethyl ether, isopropanol (IPA), methanol, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), N,N-dimethylacetamide, tetrahydrofuran (THF), toluene, xylene, hexane, heptane, cyclohexane, methyl cyclohexane, cyclopentane, Dimethylformamide, 1,4-butanole, 2-methoxyethanol, DMSO, ethyl acetate, isobutyl acetate, isopropyl acetate, water or a mixture thereof. Preferable solvent or co-solvent selected from acetone, dichloromethane, heptane, toluene, water or a mixture thereof.

The term "anti-solvent" refers to a liquid that is added to a solvent to reduce the solubility of a compound in that solvent, in some instances, resulting in precipitation of the compound. Anti-solvent selected from acetone, toluene, hexane(s), heptanes, diethyl ether, ethyl acetate, THF, isopropanol, water, and mixtures thereof.

In some embodiment, the present invention provides a process for the preparation of solid state form of Valbenazine Ditosylate, comprising the steps of:
i. dissolving the Valbenazine free base with solvent or mixture thereof;
ii. optionally cooling the reaction mixture;
iii. adding p-Toluenesulfonic acid to the above reaction mass and optionally stirring;
iv. optionally adding solvent or co-solvent or anti-solvent to above reaction mass; and
v. isolating the solid state form of Valbenazine Ditosylate.

The starting material Valbenazine free base can be prepared by the methods known in the art. The another starting material 4-methylbenzene sulfonic acid is commercially available.

Dissolving the Valbenazine free base with solvent preferable solvent is Dichloromethane for dissolving the Valbenazine free base. The dissolution temperature at which Valbenazine free base dissolved in the range of 20-30°C preferably 25-28°C more preferably 25°C. The reaction mixture may be stirred at room temperature till clear solution is obtained. Optionally, the reaction mass can be cooled to about 0-10°C preferably 0±2°C.
Adding p-Toluenesulfonic acid to the obtained solution in lot wise within about 10-40minutes preferably about 30minutes more preferably about 10-15minutes at about to about 0-30°C preferably 0-10°C more preferably 0±2°C and may be stirred for sufficient period of time, for about 1-2hour preferably 30-60minutes more preferably 15-20minutes. Optionally, the reaction mass can be cooled to about 0-15°C preferably 0-10°C more preferably 0-5°C.
In one embodiment, present invention provides adding of p-Toluenesulfonic acid to the obtained solution in lot wise within about 10-40minutes preferably about 30minutes more preferably about 10-15minutes at about 0-30°C preferably 0-10°C more preferably 0±2°C and subjected to stirred for about 3-4hour. Optionally, the reaction mass can be cooled to about 0-15°C preferably 0-10°C more preferably 0-5°C.
Optionally adding solvent or co-solvent and the reaction mass may be stirred for sufficient period of time, preferably for about 10-90minutes, more preferably for about 10-60minutes.
The product may be isolated from the reaction mass by conventional process including filtering, optional washing with solvent or co-solvent and drying.

In yet another embodiment, the present invention provides a process for the preparation of solid state form of Valbenazine Ditosylate, comprising the steps of:
i. dissolving the Valbenazine free base with solvent or mixture thereof;
ii. optionally cooling the reaction mixture;
iii. adding p-Toluenesulfonic acid to the above reaction mass and optionally stirring;
iv. optionally adding solvent or co-solvent or anti-solvent to above reaction mass;
v. raising reaction mass temperature and optionally stirring;
vi. cooling the reaction mass and optionally stirring; and
vii. isolating the solid state form of Valbenazine Ditosylate.

The starting material Valbenazine free base can be prepared by the methods known in the art. The another starting material 4-methylbenzene sulfonic acid is commercially available.

Dissolving the Valbenazine free base with solvent preferable solvent is Dichloromethane for dissolving the Valbenazine free base. The dissolution temperature at which Valbenazine free base dissolved in the range of 20-30°C preferably 25-28°C more preferably 25°C. The reaction mixture may be stirred at room temperature till clear solution is obtained. Optionally, the reaction mass can be cooled to about 0-10°C preferably 0±2°C.
Adding p-Toluenesulfonic acid to the obtained solution in lot wise within about 10-40minutes preferably about 30minutes more preferably about 10-15minutes at about to about 0-30°C preferably 0-10°C more preferably 0±2°C and may be stirred for sufficient period of time, for about 1-2hour preferably 30-60minutes more preferably 15-20minutes. Optionally, the reaction mass can be cooled to about 0-15°C preferably 0-10°C more preferably 0-5°C.
Adding solvent or co-solvent to the reaction mixture and raising temperature up to about 10-30°C preferably 20-30°C more preferably 20-25°C and subjected to stir for about 10-60minutes preferably about 10-30minutes more preferably about 10-15minutes. The reaction mass can be cooled to about 0-15°C preferably 0-10°C more preferably 0-5°C and subjected to stir for about 10-60minutes preferably about 10-30minutes.
The product may be isolated from the reaction mass by conventional process including filtering, optional washing with solvent or co-solvent and drying.

In yet another embodiment, the present invention provides a process for the preparation of Valbenazine Ditosylate, comprising the steps of:
i. dissolving the Valbenazine free base with solvent or mixture thereof;
ii. optionally cooling the reaction mixture;
iii. adding p-Toluenesulfonic acid to the above reaction mass and optionally stirring;
iv. distil out reaction mixture;
v. optionally adding solvent or co-solvent or anti-solvent to above reaction mass; and
vi. isolating the solid state form of Valbenazine Ditosylate.

The starting material Valbenazine free base can be prepared by the methods known in the art. The another starting material 4-methylbenzene sulfonic acid is commercially available.

Dissolving the Valbenazine free base with solvent preferable solvent is Dichloromethane for dissolving the Valbenazine free base. The dissolution temperature at which Valbenazine free base dissolved in the range of 20-30°C preferably 25-28°C more preferably 25°C. The reaction mixture may be stirred at room temperature till clear solution is obtained. Optionally, the reaction mass can be cooled to about 0-10°C preferably 0±2°C.
Adding p-Toluenesulfonic acid to the obtained solution in lot wise within about 10-40minutes preferably about 30minutes more preferably about 10-15minutes at about to about 0 - 30°C preferably 0-10°C more preferably 0±2°C and may be stirred for sufficient period of time, for about 1-2hour preferably 30-60minutes more preferably 15-20minutes. Optionally, the reaction mass can be cooled to about 0-15°C preferably 0-10°C more preferably 0-5°C.
The reaction mixture is subjected to distill out at about 20-35°C preferably 25-35°C more preferably 30±2°C. Adding solvent to the residue; preferable solvent is dichloromethane followed by addition of RO water to get the clear solution. Optionally, the reaction mass can be cooled to about 0-10°C preferably 0±2°C.
Optionally adding solvent or co-solvent and the reaction mass may be stirred for sufficient period of time, preferably for about 30-120minutes, more preferably for about 30-60minutes.
The product may be isolated from the reaction mass by conventional process including filtering, optional washing with solvent or co-solvent and drying.

In yet another embodiment, the present invention provides solid state form of Valbenazine Ditosylate characterized by X-ray powder diffraction pattern comprising characteristic 2?° peak at 6.3, and 12.5 ± 0.2 2?°. In particular embodiment, the present invention provides solid state form of Valbenazine Ditosylate characterized by X-ray powder diffraction pattern comprising characteristic 2?° peak at 6.3 ± 0.2 2?°.

In particular embodiment, the present invention provides solid state form of Valbenazine Ditosylate has an X-ray diffraction pattern substantially as shown in Figure 1.

In yet another embodiment, the present invention provides solid state form contains from about 20% to about 60%, about 30% to about 60%, about 40% to about 60%, about 50% to about 60%, preferably about 20% to about 40%, more preferably about 30% to about 40% crystalline Valbenazine Ditosylate. Accordingly, in some embodiments of the disclosure, the described solid state form of Valbenazine Ditosylate may contains from about 40% to about 80%, about 40% to about 70%, about 40% to about 60%, about 40% to about 50%, preferably about 60% to about 80%, more preferably about 60% to about 70% amorphous form of the Valbenazine Ditosylate as measured, for example, by XRPD.

In another embodiment, the present invention provides the solid state form of Valbenazine Ditosylate comprises crystalline and amorphous form in a relative ratio of 20:80 to 40:60.

In another embodiment, the present invention provides a pharmaceutical composition comprising Valbenazine Ditosylate prepared by the process of the invention and at least one pharmaceutically acceptable excipient.
Pharmaceutical composition containing Valbenazine Ditosylate of the present invention may be prepared by using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, and lubricants. Various modes of administration of the pharmaceutical composition of the invention can be selected depending on the therapeutic purpose, for example tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

The following examples are provided for illustration purpose only and are not intended to limit the scope of the invention.

EXAMPLES
Preparation of solid state form of Valbenazine Ditosylate (XRPD: as per Figure-1)

Example 1: Dichloromethane (225mL) was charged in Round Bottom flask (RBF), Valbenazine free base (5g) was added at room temperature, and stirred the reaction mass for 5-10minutes, clear solution was observed. Reaction mass was cooled down to 0±2°C. p-Toluenesulfonic acid (4.5g) was slowly added within 30minutes at 0±2°C. The reaction mixture was stirred for 1hour to 2hour at 0±2°C (after 10-15minutes formation of thick solid mass was observed, which was slowly converted into free slurry in next 20-30minutes) and the solid was filtered and washed with chilled Dichloromethane (25mL). The solid was suck dried for 15-30minutes under vacuum and suck dried solid was dried in vacuum tray dryer at 30-32°C for 6-8hour.
Yield: Dry solid weight - 3.8g.

Example 2: Dichloromethane (67.5mL) was charged in Round Bottom flask (RBF), Valbenazine free base (1.5g) was added at room temperature, and stirred the reaction mass for 5-10minutes, clear solution was observed. Reaction mass was cooled down to 0±2°C. p-Toluenesulfonic acid (1.35g) was slowly added within 10minutes at 0±2°C. The reaction mixture was stirred for 30minutes at 0±2°C (after 10-15minutes formation of thick solid mass was observed, then after 15minutes it became free slurry), pre cooled (0-5°C) n-heptane (15mL) was slowly added, temperature raised to 20-25°C and reaction mass was stirred for 10-15minutes at 20-25°C. The reaction mass was cooled to 0-5°C and stirred for 30minutes. The solid was filtered under vacuum. The solid was suck dried for 15-30minutes under vacuum and suck dried solid was dried in vacuum tray dryer at 30-32°C for 6-8hour.
Yield: Dry solid weight - 2.3g.

Example 3: Dichloromethane (1125mL) was charged in Round Bottom flask (RBF), Valbenazine free base (25g) was added at room temperature, and stirred the reaction mass for 5minutes, clear solution was observed. Reaction mass was cooled down to 0-5°C. p-Toluenesulfonic acid (22.5g) was slowly added within 10minutes at 0-5°C. The reaction mixture was stirred for 30minutes at 0-5°C (after 5minutes formation of thick solid mass was observed), pre cooled (3°C) n-heptane (250mL) was slowly added in 10minutes and stirred the reaction mass for 10minutes at 0 to 5°C. The solid was filtered and suck dried under vacuum. Suck dried solid was dried in vacuum tray dryer at 40-42°C for 18-20hour.
Yield: Dry solid weight - 38.5g.

Example 4: Dichloromethane (67.5mL) was charged in Round Bottom flask (RBF), Valbenazine free base (1.5g) was added at room temperature, and stirred the reaction mass for 5-10minutes, clear solution was observed. Reaction mass was cooled down to 0±2°C. p-Toluenesulfonic acid (1.35g) was slowly added within 10minutes at 0±2°C. The reaction mixture was stirred for 60minutes. The reaction mixture was distilled out under vacuum at 30±2°C, a residual foamy solid was obtained. Dichloromethane (100mL) at 25-28°C was added to get the clear solution, a drop of RO water was added at 15-20°C. Reaction mass was cooled down to 0±2°C, n-heptane (25mL) was added and stirred for 30minutes. The solid was filtered under vacuum. The solid was suck dried for 15-30minutes under vacuum and suck dried solid was dried in vacuum tray dryer at 30-32°C for 6-8hour.
Yield: Dry solid weight – 1.9g. ,CLAIMS:1. A process for the preparation of solid state form of Valbenazine Ditosylate comprising:
i. dissolving the Valbenazine free base in a solvent or mixture of solvent;
ii. adding p-Toluenesulfonic acid to the reaction mixture obtained in the step i;
iii. optionally adding solvent or co-solvent or anti-solvent to the reaction mixture obtained in step ii.
iv. filtering the product.

2. The solvent or co-solvent according to claim 1, selected from acetone, dichloromethane, heptane, toluene water or mixtures thereof.

3. The anti-solvent according to claim 1, selected from acetone, toluene, hexane(s), heptanes, diethyl ether, ethyl acetate, THF, isopropanol, water or mixtures thereof.

4. A process for the preparation of solid state form of Valbenazine Ditosylate comprising:
i. dissolving the Valbenazine free base with solvent or mixture of solvent;
ii. adding p-Toluenesulfonic acid to the reaction mixture obtained in the step i;
iii. distilling out reaction mixture obtained in the step ii;
iv. optionally adding solvent or co-solvent or anti-solvent to the reaction mixture obtained in the step iii.
v. filtering the product.

5. The solvent or co-solvent according to claim 4, selected from acetone, dichloromethane, heptane, toluene water or mixtures thereof.

6. The anti-solvent according to claim 4, selected from acetone, toluene, hexane(s), heptanes, diethyl ether, ethyl acetate, THF, isopropanol, water or mixtures thereof

7. Solid state form of Valbenazine ditosylate, characterized by data selected from one or more of the following:
i. a XRPD pattern consisting essentially of a peak at 6.3, and 12.5 ± 0.2 2?°
ii. an XRPD pattern substantially as depicted in Figure 1; and
iii. combinations of these data.