DESC:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

“PROCESS FOR PREPARATION OF VALBENAZINE AND SALTS”

Glenmark Life Sciences Limited
Glenmark Pharmaceuticals Limited
an Indian Company, registered under the Indian company’s Act 1957 and having its registered office at
Glenmark House,
HDO- Corporate Bldg, Wing-A,
B. D. Sawant Marg, Chakala,
Andheri (East), Mumbai- 400 099

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
[0001] The present invention relates to crystalline valbenazine tosylate and process for its preparation.

BACKGROUND OF THE INVENTION
[0002] Valbenazine, also known as L-valine (2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-yl ester, is represented by the structure of formula II.
II
[0003] Valbenazine tosylate, a compound of formula Ia, is a vesicular monoamine transporter 2 (VMAT2) inhibitor indicated for the treatment of adults with tardive dyskinesia.
Ia
[0004] The object of the present invention is to provide crystalline valbenazine tosylate.

SUMMARY OF THE INVENTION
[0005] The present invention provides a crystalline valbenazine tosylate.
[0006] In another embodiment, the present invention provides a process for the preparation of crystalline valbenazine tosylate, the process comprising:
(a) providing valbenazine in water, optionally in the presence of an organic solvent;
(b) adding p-toluene sulfonic acid, optionally in the presence of a solvent, to the mixture obtained in step (a);
(c) obtaining crystalline valbenazine tosylate from the mixture of step (b); and
(d) isolating the crystalline valbenazine tosylate.

BRIEF DESCRIPTION OF THE DRAWINGS
[0007] Figure 1 is a characteristic XRPD of valbenazine ditosylate as obtained in Example 1.
[0008] Figure 2 is a TGA thermogram of valbenazine ditosylate as obtained in Example 1.
[0009] Figure 3 is a DSC thermogram of valbenazine ditosylate as obtained in Example 1.

DETAILED DESCRIPTION OF THE INVENTION
[0010] The present invention provides a crystalline valbenazine tosylate.
[0011] In the present application, the term “room temperature” means a temperature of about 25°C to about 30°C.
[0012] In one embodiment, the present invention provides a crystalline valbenazine tosylate characterized by an X-ray powder diffraction (XRPD) spectrum as depicted in Figure 1.
[0013] In one embodiment, the present invention provides a crystalline valbenazine tosylate characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections as depicted in Table 1.
[0014] In one embodiment, the present invention provides a crystalline valbenazine tosylate characterized by TGA thermogram, showing a weight loss of about 1.1 weight% to 14 weight% up to 100°C determined over the temperature range of 0°C to 250°C and heating rate 10°C/min.
[0015] In one embodiment, the present invention provides a crystalline valbenazine tosylate characterized by TGA thermogram, showing a weight loss of about 3 weight% to 5 weight% up to 100°C determined over the temperature range of 0°C to 250°C and heating rate 10°C/min.
[0016] In one embodiment, the present invention provides a crystalline valbenazine tosylate characterized by TGA thermogram, showing a weight loss of about 3.5 weight% to 4.5 weight% up to 100°C determined over the temperature range of 0°C to 250°C and heating rate 10°C/min.
[0017] In one embodiment, the present invention provides a crystalline valbenazine tosylate characterized by TGA thermogram, showing a weight loss of about 3.9 weight% up to 100°C determined over the temperature range of 0°C to 250°C and heating rate 10°C/min which is substantially in accordance with Figure 2.
[0018] In one embodiment, the present invention provides a crystalline valbenazine tosylate characterized by DSC thermogram having two endothermic peaks with peak temperatures at about 140±5°C and 175±5°C.
[0019] In one embodiment, the present invention provides a crystalline valbenazine tosylate characterized by DSC thermogram having two endothermic peaks, the one endotherm with onset at about 130±5°C and the other onset was observed at about 166±5°C.
[0020] In one embodiment, the present invention provides a crystalline valbenazine tosylate characterized by DSC thermogram having two endothermic peaks, the one endotherm with onset at about 130±5°C with peak temperature at about 140±5°C, and the other onset was observed at about 166±5°C with peak temperature at about 175±5°C.
[0021] In one embodiment, the present invention provides a crystalline valbenazine tosylate characterized by DSC thermogram having endothermic peaks at about 140±4°C and about 175±4°C.
[0022] In one embodiment, the present invention provides a crystalline valbenazine tosylate characterized by DSC thermogram having endothermic peaks at about 140±4°C and about 175±4°C which is substantially in accordance with Figure 3.
[0023] In one embodiment, the present invention provides a crystalline valbenazine tosylate characterized by DSC thermogram having endothermic peaks at about 140±3°C and about 175±3°C.
[0024] In one embodiment, the present invention provides a crystalline valbenazine tosylate characterized by data selected from the group consisting of: an X-ray powder diffraction (XRPD) pattern as depicted in Figure 1, a TGA thermogram as depicted in Figure 2; a DSC thermogram as depicted in Figure 3; and any combination thereof.
[0025] In one embodiment, the present invention provides a crystalline valbenazine tosylate wherein the water content is in the range of 1.5-12.0% by Karl Fisher method.
[0026] In one embodiment, the present invention provides a crystalline valbenazine tosylate wherein the water content is in the range of 3.0-5.0% by Karl Fisher method.
[0027] In one embodiment, the crystalline valbenazine tosylate obtained is a hydrate.
[0028] In one embodiment, the present invention provides a crystalline valbenazine tosylate hydrate wherein the molar ratio of valbenazine and water is in the range of 1:0.5 to 1:6.
[0029] In one embodiment, the present invention provides a process for the preparation of crystalline valbenazine tosylate, the process comprising:
(a) providing valbenazine in water, optionally in the presence of an organic solvent;
(b) adding p-toluene sulfonic acid, optionally in the presence of a solvent, to the mixture obtained in step (a);
(c) obtaining crystalline valbenazine tosylate from the mixture of step (b); and
(d) isolating the crystalline valbenazine tosylate.
[0030] In (a) of the process for the preparation of crystalline valbenazine tosylate, valbenazine is mixed with water, optionally in the presence of an organic solvent.
[0031] The organic solvent includes but is not limited to haloalkanes such as dichloromethane, chloroform, ethylene dichloride and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, tert-butyl alcohol, n-pentyl alcohol, n-octyl alcohol and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dimethoxyethane, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; hydrocarbons such as heptane, hexane, pentane, cyclohexane, toluene, xylene, and the like; dimethyl sulfoxide; dimethylformamide; dimethyl acetamide; or mixtures thereof.
[0032] The mixture may be stirred for a period of about 10 minutes to about 20 hours, or longer. The temperature of the reaction mixture may range from about 20°C to about 100°C.
[0033] In (b) of the process for the preparation of crystalline valbenazine tosylate, p-toluene sulfonic acid is added, optionally in the presence of a solvent, to the mixture obtained in step (a).
[0034] The solvent includes but is not limited to haloalkanes such as dichloromethane, chloroform, ethylene dichloride and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, tert-butyl alcohol, n-pentyl alcohol, n-octyl alcohol and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dimethoxyethane, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; hydrocarbons such as heptane, hexane, pentane, cyclohexane, toluene, xylene, and the like; dimethyl sulfoxide; dimethylformamide; dimethyl acetamide; water; or mixtures thereof.
[0035] The reaction may be carried out at a temperature in the range from about 20°C to about 100°C. The stirring time may range from about 10 minutes to about 20 hours, or longer. The solution may be optionally treated with charcoal and filtered to get a particle-free solution.
[0036] In (c) of the process for the preparation of crystalline valbenazine tosylate, crystalline valbenazine tosylate is obtained from the mixture of step (b), the process comprising:
(i) optionally cooling and stirring the mixture obtained in step (b); or
(ii) removing the solvent from the mixture obtained in step (b); or
(iii) treating the mixture of step (b) with an anti-solvent and optionally, cooling and stirring the obtained mixture.
[0037] In (i) of the above process, crystalline valbenazine tosylate is obtained by optionally cooling and stirring the mixture obtained in step (b). The stirring time may range from about 1 hour to about 5 hours, or longer. The temperature may range from about 0°C to about 100°C.
[0038] In (ii) of the above process, crystalline valbenazine tosylate is obtained by removing the solvent from the mixture obtained in step (b). Removal of solvent may be accomplished by substantially complete evaporation of the solvent or concentrating the mixture, cooling the mixture if required and filtering the obtained solid. The mixture may be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720mm Hg. The mixture may also be completely evaporated as discussed supra, adding a second solvent, optionally cooling and stirring the obtained mixture and filtering the obtained solid.
[0039] The second solvent includes but is not limited to haloalkanes such as dichloromethane, chloroform, ethylene dichloride and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, tert-butyl alcohol, n-pentyl alcohol, n-octyl alcohol and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dimethoxyethane, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; hydrocarbons such as heptane, hexane, pentane, cyclohexane, toluene, xylene, and the like; dimethyl sulfoxide; dimethylformamide; dimethyl acetamide; water; or mixtures thereof.
[0040] In (iii) of the above process, crystalline valbenazine tosylate is obtained by adding an anti-solvent to the mixture obtained in step (b) and optionally, cooling and stirring the obtained mixture. The stirring time may range from about 2 hours to about 12 hours, or longer. The temperature may range from about 0°C to about 100°C.
[0041] The anti-solvent is selected such that crystalline valbenazine tosylate is precipitated out from the solution.
[0042] The anti-solvent includes but is not limited to haloalkanes such as dichloromethane, chloroform, ethylene dichloride and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, tert-butyl alcohol, n-pentyl alcohol, n-octyl alcohol and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dimethoxyethane, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; hydrocarbons such as heptane, hexane, pentane, cyclohexane, toluene, xylene, and the like; dimethyl sulfoxide; dimethylformamide; dimethyl acetamide; water; or mixtures thereof.
[0043] In (d) of the process for the preparation of crystalline valbenazine tosylate, the crystalline valbenazine tosylate is isolated by any method known in the art. The method, may involve any of techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like, complete evaporation in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum, or concentrating the mixture, cooling the mixture if required and filtering the obtained solid by gravity or by suction, centrifugation, and the like.
[0044] The present invention provides crystalline valbenazine tosylate, obtained by the above processes, as characterized and analyzed by following techniques:
A. X-ray powder diffraction profiles were obtained using an X-ray Diffractometer (Philips X’Pert Pro, PANalytical). The measurements were carried out with a Pre FIX module programmable divergence slit and anti-scatter Slit (Offset 0.00°) ; target, Cu; filter, Ni; detector, X’Celerator; Scanning Mode; Active length (2Theta) = 2.122°; generator 45KV; tube current 40mAmp. The samples were scanned in the full 2? range of 2-50° with a “time-per-step” optimized to 50 sec.
B. DSC (Mettler Toledo 822e): Temperature range is “30°C to 350°C” and heating rate is 10°C/minute.
C. Thermo Gravimetric Analyzer: TGA Q500 V6.5. Thermogram was recorded at 30-250°C at the rate of 10°C/min.
D. Karl Fischer: The water content was calculated by the following formula:
water content (%) = Burette reading × KF Factor × 100
Weight of sample in mg
[0045] In one embodiment, the present invention provides pharmaceutical compositions comprising valbenazine or salt thereof obtained by the processes herein described, having a D90 particle size of less than about 250 microns, preferably less than about 150 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns and most preferably less than about 10 microns.
[0046] In one embodiment, the present invention provides pharmaceutical compositions comprising valbenazine or salt thereof obtained by the processes herein described, having a D50 particle size of less than about 250 microns, preferably less than about 150 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns and most preferably less than about 10 microns.
[0047] The particle size disclosed here can be obtained by, for example, any milling, grinding, micronizing or other particle size reduction method known in the art to bring the solid state valbenazine or salt thereof into any of the foregoing desired particle size range.
[0048] The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.

EXAMPLES
[0049] EXAMPLE 1
To a stirred suspension of valbenazine (10g) in water (40mL) at about 40°C, p-toluene sulfonic acid (8.22g) was added and the reaction mixture was stirred for about 30min. The reaction mixture was heated to about 80ºC to about 85ºC and was stirred for about 3h. The reaction mixture was cooled to about 25ºC and stirred for about 30min. The solid obtained was filtered, washed with water and dried at about 30°C to give valbenazine ditosylate. Yield: 13g
Table 1: XRD peaks of valbenazine ditosylate
Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]
5.38 16.40 37.24 19.88 4.46 13.47
6.07 14.55 0.99 20.20 4.39 12.33
6.75 13.08 100.00 20.37 4.35 8.80
7.93 11.14 87.35 20.65 4.30 14.51
8.35 10.58 8.08 20.91 4.24 11.59
8.99 9.83 2.16 21.46 4.13 37.81
10.72 8.25 37.50 21.80 4.07 9.49
12.15 7.28 2.03 22.76 3.90 7.98
12.83 6.89 15.63 23.21 3.82 4.07
13.09 6.76 27.89 23.80 3.73 27.07
13.47 6.57 13.35 23.98 3.70 15.79
14.08 6.28 5.80 24.18 3.67 17.94
14.33 6.17 5.43 24.46 3.63 5.98
14.72 6.01 3.56 24.73 3.59 5.17
15.42 5.74 3.40 25.10 3.54 5.78
15.83 5.59 40.63 25.77 3.45 3.78
16.07 5.51 35.54 26.28 3.38 6.84
17.00 5.21 39.63 26.57 3.35 8.27
17.11 5.18 34.87 26.90 3.31 4.92
17.54 5.05 3.41 27.35 3.25 5.98
17.81 4.97 3.99 27.54 3.23 11.45
18.38 4.82 20.14 28.32 3.14 4.26
18.78 4.72 2.28 28.81 3.09 1.95
19.50 4.55 22.44 29.50 3.02 5.41
19.67 4.51 8.92 29.86 2.98 13.61

TGA analysis of valbenazine ditosylate shows a weight loss of about 3.99 weight% up to 100°C determined over the temperature range of 0°C to 250°C and heating rate 10°C/min.
DSC analysis of valbenazine ditosylate shows endothermic peaks, the one endotherm with onset at about 128.71°C with peak temperature at about 142.19°C, and the other onset was observed at about 170.56°C with peak temperature at about 179.44°C.
Water content by KF method: 4.99%

[0050] EXAMPLE 2
p-Toluene sulfonic acid (1.64g) was added to the solution of valbenazine (2g) in water (20mL). The solution was then heated to about 80ºC to about 85ºC and was maintained for about 18h. The reaction mixture was cooled to about room temperature. Water (20mL) was added to the reaction mixture. The solid obtained was filtered, washed with water and dried at about 50°C to give valbenazine ditosylate. Yield: 3.4g
XRD peaks of valbenazine ditosylate: The XRD peaks are similar as depicted in Table 1 and Figure 1.
TGA analysis of valbenazine ditosylate shows a weight loss of about 3.72 weight% up to 100°C determined over the temperature range of 0°C to 250°C and heating rate 10°C/min.
DSC analysis of valbenazine ditosylate shows endothermic peaks, the one endotherm with onset at about 131.78°C with peak temperature at about 142.8°C, and the other onset was observed at about 162.15°C with peak temperature at about 170.49°C.
Water content by KF method: 5.21%

[0051] EXAMPLE 3
To a stirred solution of valbenazine (2g) in methanol (10mL), water (2mL) was added and the reaction mixture was stirred for about 30min. The temperature of the reaction mixture was raised to about 40°C to about 45°C. p-Toluene sulfonic acid (1.64g) was added to the reaction mixture which stirred for about 40min. The reaction mixture was cooled to about 25ºC and seeded with valbenazine ditosylate. The solid obtained was filtered, washed with water and dried at about 41°C to give valbenazine ditosylate. Yield: 1.5g
XRD peaks of valbenazine ditosylate: The XRD peaks are similar as depicted in Table 1 and Figure 1.
TGA analysis of valbenazine ditosylate shows a weight loss of about 3.83 weight% up to 100°C determined over the temperature range of 0°C to 250°C and heating rate 10°C/min.
DSC analysis of valbenazine ditosylate shows endothermic peaks, the one endotherm with peak temperature at about 136.08°C, and the other onset was observed at about 163.48°C with peak temperature at about 173.9°C.
Water content by KF method: 5.04%

[0052] EXAMPLE 4
Valbenazine (1g) was added to a mixture of ethyl acetate (20mL) and water (1mL).The reaction mixture was stirred for about 15min. p-Toluene sulfonic acid (0.86g) was added to the reaction mixture which was stirred for about 3h. The solid obtained was filtered, washed with water and dried at about room temperature to give valbenazine ditosylate. Yield: 1.45g
XRD peaks of valbenazine ditosylate: The XRD peaks are similar as depicted in Table 1 and Figure 1.
TGA analysis of valbenazine ditosylate shows a weight loss of about 3.76 weight% up to 100°C determined over the temperature range of 0°C to 250°C and heating rate 10°C/min.
DSC analysis of valbenazine ditosylate shows endothermic peaks, the one endotherm with onset at about 131.42°C with peak temperature at about 140.41°C, and the other onset was observed at about 169.47°C with peak temperature at about 177.6°C.
Water content by KF method: 11.19

WE CLAIM
1. Crystalline valbenazine tosylate.
2. Crystalline valbenazine tosylate as claimed in claim 1, characterized by an X-ray powder diffraction (XRPD) peaks at 5.3, 6.7, 7.9, 15.8, 17.1±0.2 2?.
3. Crystalline valbenazine tosylate as claimed in claim 1, characterized by TGA thermogram, showing a weight loss of about 1.1 weight% to about 14 weight% up to 100°C determined over the temperature range of 0°C to 250°C and heating rate 10°C/min.
4. Crystalline valbenazine tosylate as claimed in claim 1, characterized by DSC thermogram having two endothermic peaks, the one endotherm with peak temperature at about 140±5°C and the other with peak temperature at about 175±5°C.
5. Crystalline valbenazine tosylate as claimed in claim 1, in hydrate form wherein the molar ratio of valbenazine and water is in the range of 1:0.5 to 1:6.
6. A Process for the preparation of crystalline valbenazine tosylate, the process comprising:
(a) providing valbenazine in water, optionally in the presence of an organic solvent;
(b) adding p-toluene sulfonic acid, optionally in the presence of a solvent, to the mixture obtained in step (a);
(c) obtaining crystalline valbenazine tosylate from the mixture of step (b); and
(d) isolating the crystalline valbenazine tosylate.
7. The process as claimed in claim 6, wherein the organic solvent is selected from the group consisting of haloalkanes, ketones, alcohols, ethers, esters, hydrocarbons, and mixtures thereof.
Dated this 22nd day of August, 2019

(Signed)____________________
DR. MADHAVI KARNIK
SENIOR GENERAL MANAGER-IPM
GLENMARK LIFE SCIENCES LIMITED
,CLAIMS:WE CLAIM
1. Crystalline valbenazine tosylate.
2. Crystalline valbenazine tosylate as claimed in claim 1, characterized by an X-ray powder diffraction (XRPD) peaks at 5.3, 6.7, 7.9, 15.8, 17.1±0.2 2?.
3. Crystalline valbenazine tosylate as claimed in claim 1, characterized by TGA thermogram, showing a weight loss of about 1.1 weight% to about 14 weight% up to 100°C determined over the temperature range of 0°C to 250°C and heating rate 10°C/min.
4. Crystalline valbenazine tosylate as claimed in claim 1, characterized by DSC thermogram having two endothermic peaks, the one endotherm with peak temperature at about 140±5°C and the other with peak temperature at about 175±5°C.
5. Crystalline valbenazine tosylate as claimed in claim 1, in hydrate form wherein the molar ratio of valbenazine and water is in the range of 1:0.5 to 1:6.
6. A Process for the preparation of crystalline valbenazine tosylate, the process comprising:
(a) providing valbenazine in water, optionally in the presence of an organic solvent;
(b) adding p-toluene sulfonic acid, optionally in the presence of a solvent, to the mixture obtained in step (a);
(c) obtaining crystalline valbenazine tosylate from the mixture of step (b); and
(d) isolating the crystalline valbenazine tosylate.
7. The process as claimed in claim 6, wherein the organic solvent is selected from the group consisting of haloalkanes, ketones, alcohols, ethers, esters, hydrocarbons, and mixtures thereof.
Dated this 22nd day of August, 2019

(Signed)____________________
DR. MADHAVI KARNIK
SENIOR GENERAL MANAGER-IPM
GLENMARK LIFE SCIENCES LIMITED