DESC:RELATED PATENT APPLICATION(S)
This application claims the priority to and benefit of Indian Patent Application No. 201941002161 filed on January 18, 2019 and Indian Patent Application No. 201941017258 filed on April 30, 2019; the disclosures of which are incorporated herein by reference.

FIELD OF THE INVENTION
The present invention relates to premix or solid dispersion of Valbenazine or a salt thereof in combination with one or more pharmaceutically acceptable excipients and processes for preparation thereof. More particularly, the present invention relates to premix or solid dispersion of Valbenazine ditosylate in combination with one or more pharmaceutically acceptable excipients and a process for preparation thereof.

BACKGROUND OF THE INVENTION
Valbenazine ditosylate (INGREZZA®) is a vesicular monoamine transporter 2 (VMAT2) inhibitor indicated for the treatment of adults with tardive dyskinesia. Valbenazine ditosylate is chemically known as (2R,3R,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-2H-benzo(a)quinolizin-2-yl L-valinate bis(4-methylbenzenesulfonate). The chemical structure of Valbenazine ditosylate is represented as formula I

I
Valbenazine and a method for synthesizing thereof has been described in WO 2008/058261. Different solid-state forms of Valbenazine or salts thereof have been described in various patent publications including WO 2017/075340, WO 2018/001335, WO 2018/067945, WO 2018/130345 and WO 2018/153632.
Preparation of pharmaceutical dosage forms is often procedurally complex, particularly when combining the active ingredient with excipients. For example, workability or stability issues may arise when different components of the pharmaceutical dosage form come into close contact with one another. Pharmaceutical industries carry out extensive studies for the development of different polymorphs of various drug substances, to obtain suitable polymorphs that possess improved performance characteristics such as aqueous solubility, improved bioavailability, chemical stability, shelf life etc.
It may, thus, be advantageous to prepare solid dispersions or a pre-combined mixture (pre-mix) of excipients and active pharmaceutical ingredient to achieve good physiochemical properties, desirable bioavailability, and advantageous pharmaceutical parameters. Further, there remains a need for an efficient, simple and industrially viable process to prepare solid dispersion or a premix of Valbenazine ditosylate together with pharmaceutically acceptable excipients. Such solid dispersions and premixes facilitate and simplify the final processing of dosages forms.

OBJECTIVE OF THE INVENTION
One of the objects of the invention is to provide a solid premix or dispersion of Valbenazine or a salt thereof in combination with one or more pharmaceutically acceptable excipients.

Another object of the invention is to provide an industrially viable method for the preparation of solid premix or dispersion of Valbenazine or a salt thereof in combination with one or more pharmaceutically acceptable excipients.

SUMMARY OF THE INVENTION
The present invention aims to provide premix or solid dispersion of Valbenazine or a salt thereof in combination with one or more pharmaceutically acceptable excipients and methods for preparation thereof. Particularly, the present invention provides solid dispersion or a premix of Valbenazine ditosylate together with one or more pharmaceutically acceptable excipients or premix agents and an industrially viable process for preparation thereof.
In one aspect, the present invention provides a solid dispersion of Valbenazine ditosylate together with one or more pharmaceutically acceptable excipients.
In another aspect, the present invention provides a premix of Valbenazine ditosylate together with one or more pharmaceutically acceptable excipients or premix agents.
In yet another aspect, there is provided a process for preparing a premix or solid dispersion of Valbenazine of formula (Ia)

(Ia)
or a salt thereof, in combination with one or more pharmaceutically acceptable excipients, the process comprising:
a. treating a compound of formula (II) or a salt thereof with an acid in presence of suitable solvent,

b. adding one or more pharmaceutically acceptable excipients to the solution or suspension obtained in step (a);
c. removing the solvent from the solution or suspension obtained in step (b) or combining the solution or suspension obtained in step (b) with an anti-solvent; and
d. isolating the solid dispersion or premix comprising Valbenazine of formula (Ia) or a salt thereof in combination with one or more pharmaceutically acceptable excipients.

In some embodiment, the said salt of Valbenazine in the above described process is selected from the group comprising of hydrochloride, oxalate, propionate, butyrate, lactate, citrate, acetate, benzoate, salicylate, succinate, malate, tartrate, fumarate, maleate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, or camphorsulfonate. In some other embodiment, the said salt of Valbenazine is selected from the group comprising of ditosylate or hydrochloride.
In some embodiment, in the above described process the amine protecting group “R” of formula (II) compound is selected from the group comprising of fluorenylmethoxycarbonyl (FMOC), tert-butoxycarbonyl (t-BOC), benzyloxycarbonyl (Z), formyl, benzoyl, trifluoroacetyl, p-tosyl, aryl, alkylphosphoryl, phenyl, benzylsulfonyl, o-nitrophenylsulfenyl, o-nitrophenoxyacetyl), tosyloxyalkyloxy, cyclopentyloxy, cyclohexyloxy or benzylthiocarbonyl. In some embodiment, the amine protecting group “R” of formula II compound is tert-butoxycarbonyl (t-BOC).
In some embodiment, the said suitable solvent in step (a) of the above described process is selected from the group comprising of water, alcohols, ether, esters, ketones, nitriles, amides, sulfoxides, aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons or mixture thereof.
In some embodiment, the said acid in step (a) of the above described process is selected from the group comprising of hydrochloric acid, oxalic acid, propionic acid, butyric acid, lactic acid, citric acid, acetic acid, benzoic acid, salicylic acid, succinic acid, malic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or camphorsulfonic acid.
In some embodiment, the said anti-solvent in step (b) of the above described process is selected from the group comprising of water, alcohols, ethers, esters, aliphatic hydrocarbon liquids, alicyclic hydrocarbon liquids, aromatic hydrocarbon liquids or mixture thereof.
In some embodiment, the said pharmaceutically acceptable excipient in the above described process is selected from the group comprising of mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, maltose, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose (MC), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMC-AS) or polyvinylpyrrolidones (PVP K-30).
In some embodiment, the premix or solid dispersion comprising Valbenazine or a salt thereof, in combination with one or more pharmaceutically acceptable excipients obtained is having powder X-ray diffraction pattern as shown in Figures 9 and 10.
In another aspect, the present invention provides a pharmaceutical composition comprising a premix of Valbenazine ditosylate described herein together with one or more pharmaceutically acceptable excipients, carriers or diluents.
In yet another aspect, the present invention provides a pharmaceutical composition comprising a solid dispersion of Valbenazine ditosylate described herein together with one or more pharmaceutically acceptable excipients, carriers or diluents.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an illustration of a powder X-ray diffractogram (PXRD) of Valbenazine ditosylate prepared according to Example 1.
Figure 2 is an illustration of a powder X-ray diffractogram (PXRD) of Valbenazine ditosylate prepared according to Example 2.
Figure 3 is an illustration of a powder X-ray diffractogram (PXRD) of Valbenazine ditosylate prepared according to Example 3.
Figure 4 is an illustration of a powder X-ray diffractogram (PXRD) of Valbenazine ditosylate prepared according to Example 4.
Figure 5 is an illustration of a powder X-ray diffractogram (PXRD) of Valbenazine ditosylate prepared according to Example 5.
Figure 6 is an illustration of a powder X-ray diffractogram (PXRD) of Valbenazine ditosylate prepared according to Example 6.
Figure 7 is an illustration of a powder X-ray diffractogram (PXRD) of Valbenazine ditosylate prepared according to Example 7.
Figure 8 is an illustration of a powder X-ray diffractogram (PXRD) of Valbenazine ditosylate prepared according to Example 8.
Figure 9 is an illustration of a powder X-ray diffractogram (PXRD) of Valbenazine ditosylate prepared according to Example 10.

Figure 10 is an illustration of a powder X-ray diffractogram (PXRD) of Valbenazine ditosylate prepared according to Example 11.

DETAILED DESCRIPTION OF THE INVENTION

DEFINITIONS
Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances.
As used herein, the term “premix” refers to combination of Valbenazine or a salt thereof and at least one pharmaceutical excipient or a premixing agent.
In general, the term “solid dispersion” refers to a system in a solid state comprising at least two components, wherein one component is dispersed throughout the other component or components. The term “solid dispersion” as used herein, refers to stable solid dispersions comprising Valbenazine or a salt thereof and one or more excipients, carriers, diluents, or polymers prepared by a variety of methods, including but not limited to spray drying, the melting (fusion), solvent, or the melting-solvent method.
Unless otherwise specified, the terms “premix” and “solid dispersion” may be used interchangeably. However, the invention is intended to include all such forms of expression.
As used herein, the term “salt” or “pharmaceutically acceptable salt” refers to those salts of the compounds formed by the process of the present invention which are safe and effective in human beings and that possess the desired biological activity. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free acid or base with a suitable base or acid. Examples of pharmaceutically acceptable salts include, but are not limited to: hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid, acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorsulfonate, citrate, formate, fumarate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts and the like.
The term “protecting group" refers to a group of atoms which purpose is to temporarily mask the functionality of the site to which it is attached on a molecule. Protecting group is generally a temporary group added during organic synthesis to prevent a portion of a molecule from reacting.
The term “excipient” or “pharmaceutically acceptable excipient” means a component of a pharmaceutical product that is not an active ingredient, and includes but not limited to filler, diluent, disintegrants, glidants, stabilizers, surface active agents etc. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and neither biologically nor otherwise undesirable, and are acceptable for veterinary use as well as human pharmaceutical use. One excipient can perform more than one function. The pharmaceutically acceptable excipients used in the process of preparing stable Valbenazine ditosylate premix may also be termed as "premixing agents".
The term “stability” as used in the description includes both physical and chemical stability. The term “physical stability” refers to maintaining the polymorphic form of Valbenazine ditosylate, such as crystalline, amorphous, or mixtures thereof, and “chemical stability” refers to maintaining acceptable concentrations of Valbenazine ditosylate-related impurities.
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, the terms "comprising" and "comprises" mean the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The term "including" is also to be construed as open ended. The terms "about," “substantially” and the like are to be construed as modifying a term or value such that it is not an absolute, but does not read on the prior art. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by one skilled in the art.
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.
The term "optionally" is taken to mean that the event or circumstance described in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.
Unless otherwise specified, the term "solvate(s)" as used herein, means compounds formed by solvation, for example as a combination of solvent molecules with molecules or ions of a solute. Well known solvent molecules include water, alcohols, nitriles, polar organic solvents etc.
As used herein, the term “anti-solvent” refers to a solvent that, when combined with a solution of compounds of formulae (I), (Ia) or (II), reduces solubility of the said compounds (I), (Ia) or (II) in the solution, causing crystallization or precipitation in some instances spontaneously, and in other instances with additional steps, such as seeding, cooling, scratching, and/or concentrating.
The premixes or solid dispersions of the present invention may provide multiple benefits in preparing formulations of Valbenazine or a salt thereof, for example, improved processability, increased stability of the pharmaceutical formulation or Active Pharmaceutical Ingredient (API), or improved pharmacokinetic properties of the pharmaceutical formulation.
In an aspect, the present invention provides a solid dispersion of Valbenazine or a salt thereof, together with one or more pharmaceutically acceptable excipients.
In an aspect, the present invention provides a premix of Valbenazine or a salt thereof, together with one or more one pharmaceutically acceptable excipients or premix agents.
In yet another aspect, there is provided a process for preparing a premix or solid dispersion of Valbenazine of formula (Ia)

(Ia)
or a salt thereof, in combination with one or more pharmaceutically acceptable excipients, the process comprising:
a. treating a compound of formula (II) or a salt thereof with an acid in presence of suitable solvent,

b. adding one or more pharmaceutically acceptable excipients to the solution or suspension obtained in step (a);
c. removing the solvent from the solution or suspension obtained in step (b) or combining the solution or suspension obtained in step (b) with an anti-solvent; and
d. isolating the solid dispersion or premix comprising Valbenazine of formula (Ia) or a salt thereof in combination with one or more pharmaceutically acceptable excipients.

In embodiments of step (a), the amine protecting group “R” of formula (II) compound is selected from the group, fluorenylmethoxycarbonyl (FMOC), tert-butoxycarbonyl (t-BOC), benzyloxycarbonyl (Z), those of the acyl type (e.g., formyl, benzoyl, trifluoroacetyl, p-tosyl, aryl- and alkylphosphoryl, phenyl- and benzylsulfonyl, o-nitrophenylsulfenyl, o-nitrophenoxyacetyl), and of the urethane type (e.g. tosyloxyalkyloxy-, cyclopentyloxy, cyclohexyloxy- and benzylthiocarbonyl), and any other suitable amine protecting group known in the art.
The compound of formula (II) used in the reaction, some of which are known from the literature, may be obtained by methods known from the literature, or using methods known to one skilled in the art.
In preferred embodiments, the amine protecting group “R” of formula (II) compound is tert-butoxycarbonyl (t-BOC).
In embodiments of step (a), suitable solvent useful for providing a solution or suspension include, but are not limited to; water; alcohols such as methanol, ethanol, 1-propanol, 2- propanol, 1-butanol, and 2-butanol; ethers, such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopropylmethyl ether, dioxane, and dimethoxyethane; esters, such as methyl acetate, ethyl formate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, and isobutyl acetate; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and diethyl ketone; nitriles, such as acetonitrile and propionitrile; amides, such as formamide, ?,?-dimethylformamide, and N,N- dimethylacetamide; sulfoxides, such as dimethylsulfoxide; aliphatic and aromatic hydrocarbons such as n-pentane, isopentane, neopentane, n-hexane, isohexane, n- heptane, cyclohexane, methylcyclohexane, cycloheptane, petroleum ethers, benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, indane, naphthalene, tetralin, trimethylbenzene; halogenated hydrocarbons such as dichloromethane, 1, 2-dichloroethane, trichloroethylene, chloroform, carbon tetrachloride; or mixture thereof.
In embodiments of step (a), acid used for the reaction include, but are not limited to: inorganic acids such as hydrochloric, hydrobromic, hydroiodic, nitric, perchloric, sulfuric or phosphoric acid; organic acids, such as oxalic, propionic, butyric, glycolic, lactic, mandelic, citric, acetic, benzoic, 2- or 4-methoxybenzoic, 2- or 4-hydroxybenzoic, 2- or 4-chlorobenzoic, salicylic, succinic, malic, hydroxysuccinic, tartaric, fumaric, maleic, hippuric, hydroxymaleic, oleic, glutaric, D-gluconic, L-lactic, succinic, methanesulfonic, trifluoromethanesulfonic, ethanesulfonic, 2-hydroxyethanesulphonic, benzenesulfonic, p-toluenesulfonic, naphthalene-2-sulphonic or camphorsulfonic acids; lewis acids; or any other suitable acid.
In certain embodiments, the salt of formula (II) compound is selected from the group provided herein above.
In some embodiments, salt of Valbenazine formed is dependent on the acid used in reaction step (a). For example, using p-toluenesulfonic acid for the reaction results in ditosylate salt of Valbenazine.
In preferred embodiments, the salt of Valbenazine in solid dispersion or premix of the present invention is hydrochloride or ditosylate.
In more preferred embodiments, the salt of Valbenazine in solid dispersion or premix of the present invention is ditosylate.
In most preferred embodiments, the present invention relates to a process for preparing a premix or solid dispersion comprising Valbenazine ditosylate of formula (I) in combination with one or more pharmaceutically acceptable excipients.
In embodiment of the invention, step (a) is carried out at a suitable temperature, ranging from about 0°C to about the reflux temperature of the solvent, or less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 10°C, or any other suitable temperatures.
In preferred embodiments, the step (a) and step (b) reaction is carried out one-pot.
Thus, the advantage of the present invention is that the process disclosed herein is simple, efficient and well suitable for the commercial production of premix or solid dispersion comprising Valbenazine or a salt thereof in combination with one or more pharmaceutically acceptable excipients. The premix or solid dispersion comprising Valbenazine or a salt thereof in combination with one or more pharmaceutically acceptable excipients, can be directly prepared from the formula (II) compound in a single pot, thereby avoiding multiple isolation, purification and other tedious work ups.
The pharmaceutically acceptable excipients useful in step (b), include but are not limited to mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol, inositol, trehalose, maltose, raffinose, a, ß and ?-cyclodextrins, gum arabic, sodium alginate, propylene glycol alginate, agar, gelatin, tragacanth, xanthan gum, starch, lectins, urea, chitosan, chitosan glutamate, hydroxypropyl ß-cyclodextrin chitosan, hydroxypropyl methylcellulose (HPMC), Hydroxypropyl cellulose (HPC), methylcellulose (MC), cellulose acetate phthalate (CAP), Hydroxypropyl Methylcellulose Phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), carboxymethyl ethyl cellulose (CMEC), carboxymethyl cellulose, sodium carboxymethyl cellulose, cellulose acetate butyrate, hydroxyethyl cellulose, ethyl cellulose, co- (lactic/glycolic)copolymers, poly(orthoester), polyvinyl chloride, polyvinyl acetate, ethylene vinyl acetate, carbopols, silicon elastomers, polyacrylic polymers, polyvinylacetal diethylaminoacetate, amino alkyl methacrylate copolymers, methacrylic acid copolymers, and carboxyl vinyl polymer, polyvinylpyrrolidones (such as Polyvinylpyrrolidone K 30/PVP K-30), polyethylene glycols, polyethylene-/polypropylene-/polyethylene-oxide block copolymers, polymethacrylates, polyvinylalcohol (PVA) and co-polymers thereof with PVP or with other polymers, polyacrylates, polyhydric alcohols, polyoxyethylene derivatives, organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and guanidine or its derivatives; diluents such as starches and derivative thereof, e.g. dextrin, pullulan, corn starch and potato starch pregelatinized starches; lactose, sucrose, glucose, reduced maltose, mannitol, sorbitol, xylitol, trehalose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, crystalline cellulose/carmellose sodium, hydroxypropyl cellulose, magnesium aluminometasilicate, silica excipients like silicon dioxide, syloid, light anhydrous silicic acid or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches or the like; disintegrants such as hydroxypropyl cellulose, low- substituted hydroxypropyl cellulose, croscarmellose sodium, a starch, methylcellulose, sodium alginate, sodium carboxymethyl starch, carmellose calcium, carmellose sodium, crystalline cellulose and crystalline cellulose/carmellose sodium, sodium starch glycolate, pregelatinized starches, crospovidones, colloidal silicon dioxide or the like; lubricants such as stearic acid, magnesium stearate, talc, light anhydrous silicic acid, calcium stearate, zinc stearate, magnesium oxide, sodium lauryl sulfate, sodium stearyl fumarate, magnesium aluminometasilicate or the like; flavoring agents such as sucrose, aspartame, mannitol, dextran, saccharin, menthol, citric acid, tartaric acid, malic acid, ascorbic acid, sweet hydrangea leaves, fennel, ethanol, fructose, xylitol, glycyrrhizinic acid, purified sucrose, L-glutamine, cyclodextrin, peppermint, methyl salicylate or the like; surfactants such as sodium lauryl sulfate, polysolvate 80, sucrose fatty acid ester, polyoxyl 40 stearate, polyoxyethylene 60 hydrogenated castor oil, sorbitan monostearate, sorbitan monopalmitate or the like; 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 or the like. Other pharmaceutically acceptable carriers that can be used include, but are not limited to, film formers, plasticizers, colorants, viscosity enhancers, preservatives, antioxidants, or the like. The scope of the present invention without limitation includes, the use of mixtures of more than one of the pharmaceutical excipients to provide desired release profiles or for the enhancement of stability and also includes all viscosity grades, molecular weights, commercially available products, their copolymers and mixtures.
In an aspect, the present invention provides a process for preparing a premix or solid dispersion comprising Valbenazine ditosylate in combination with one or more pharmaceutically acceptable excipients, the process comprising:
a. providing a solution or suspension of Valbenazine ditosylate and one or more pharmaceutically acceptable excipients in suitable solvent;
b. removing the solvent from the solution or suspension obtained in step (a) or combining the solution or suspension obtained in step (a) with an anti-solvent; and
c. isolating the solid dispersion or premix comprising Valbenazine or a salt thereof in combination with one or more pharmaceutically acceptable excipients.

In embodiments of step (a), any physical form of Valbenazine ditosylate may be utilized for providing a solution or suspension of Valbenazine ditosylate. Valbenazine ditosylate may be obtained by methods known from the literature. Suitable forms for providing a solution or suspension in step (a) include for example amorphous Valbenazine ditosylate, crystalline Valbenazine ditosylate or mixture thereof.
In embodiments of step (a), suitable solvent useful for providing a solution or suspension of Valbenazine ditosylate or solvate thereof, include, but are not limited to; water; alcohols, ethers, esters, ketones, amides, sulfoxides, aliphatic and aromatic hydrocarbons, halogenated hydrocarbons or mixtures of two or more thereof.
In embodiments of step (a), providing a solution or a suspension comprising Valbenazine ditosylate or a solvate thereof and one or more pharmaceutically acceptable excipients, may be carried out at a suitable temperature, ranging from about 0°C to about the reflux temperature of the solvent, or less than about 100° C, less than about 80° C, less than about 60° C, less than about 40° C, less than about 10° C, or any other suitable temperatures.
The pharmaceutically acceptable excipients useful in step (a), are selected from the list provided in the previous embodiments.
In certain embodiments, optionally, the solution obtained may be treated to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques, under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the concentration and temperature of the solution and the equipment used, the filtration apparatus may optionally be preheated to avoid premature crystallization.
In various embodiments, the choice of solvents and anti-solvents for the process is customary to one skilled in the art. Suitable anti-solvents that may be used to combine a solution comprising compounds described herein above are selected from the group consisting of water, alcohols, ethers, esters, aliphatic hydrocarbon liquids, alicyclic hydrocarbon liquids, aromatic hydrocarbon liquids, and mixtures of at least two thereof.
In some embodiments, the solvent may be removed, optionally under reduced pressures, at temperatures less than about 100°C, less than about 75°C, less than about 60°C, less than about 50°C, or any other suitable temperatures.
In some embodiments, removal of the solvent may be effected by using suitable techniques that include, but are not limited to, evaporation of the solvent, using a rotational distillation device such as a Buchi Rotavapor®, spray drying, thin film drying, freeze drying, lyophilisation, methods as mentioned herein, and the like, or any other suitable techniques. In some embodiments, the removing the solvent comprises evaporating the solvent, distilling, spray drying, thin film drying, agitated thin-film drying, freeze drying, lyophilisation, or a combination thereof. The solvent may be removed, optionally under reduced pressures, at temperatures less than about 100°C, less than about 75°C, less than about 60°C, less than about 50°C, or any other suitable temperature.
In various embodiments, isolation may be affected by removing the solvent by techniques mentioned herein above, or by any other precipitation technique. Suitable methods include, but are not limited to, concentration, removal of solvent by evaporation, distillation, crash cooling, flash evaporation, rotational drying, spray drying, thin film drying, freeze drying, and lyophilization.
In various embodiments, the solid product obtained may be collected using techniques such as for example, scraping, shaking the container, or other techniques that are suited to the equipment used. Optionally, the isolated solid may be further dried.
In embodiments of the present invention, the solid dispersions or premixes of Valbenazine or salt thereof, preferably Valbenazine ditosylate, after optional drying, may be optionally further subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of the product. Equipment that may be used for particle size reduction include, without limitation thereto, ball mills, roller mills, hammer mills, and jet mills.
Drying may be suitably carried out using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, at temperatures less than about 100°C, less than about 60°C, less than about 50°C, less than about 20°C, less than about 0°C, less than about -20°C, or any other suitable temperatures. The drying may be carried out for any time period suitable for obtaining a desired product quality, such as from about 15 minutes to 24 hours, or longer.
In an aspect of the invention premix or solid dispersion comprising Valbenazine or a salt thereof, preferably Valbenazine ditosylate, obtained according to certain embodiments of the present invention has a particle size distribution wherein: mean particle size is less than about 200 urn or less than about 100 µm; d (0.5) is less than about 200 µm or less than about 25 µm or less than about 10 µm or less than about 5 µm; and d (0.9) is less than about 500 µm or less than about 50 µm or less than about 25 µm or less than about 10 µm.
In aspects of the present invention, the amount of Valbenazine or a salt thereof, preferably Valbenazine ditosylate, relative to the amount of pharmaceutically acceptable excipients, carriers, polymers or diluents present in the solid dispersions or premixes depends on the pharmaceutically acceptable excipients, carriers or diluents. Preferably, the ratio of Valbenazine ditosylate to the pharmaceutically acceptable excipients, carriers, polymers or diluents ranges from about 1:0.1 to about 1:10, preferably from about 1:0.5 to about 1:4.0.
In certain embodiments, the solid dispersions or premixes of the present invention encompass all physical forms of Valbenazine or a salt thereof. The solid dispersion or premix comprise Valbenazine or a salt thereof, preferably Valbenazine ditosylate, in amorphous, crystalline form or mixtures thereof, with one or more pharmaceutically acceptable excipients.
Non-limiting examples of solid dispersions or premixes of Valbenazine ditosylate in combination with one or more pharmaceutically acceptable excipients prepared according the processes described herein are characterized by a PXRD as illustrated in Figures 1 to 10. In some embodiment, the premix or solid dispersion comprising Valbenazine or a salt thereof, in combination with one or more pharmaceutically acceptable excipients obtained is having powder X-ray diffraction pattern as shown in Figures 9 and 10.
In aspects of the present invention, solid dispersions or premixes of Valbenazine or a salt thereof, preferably Valbenazine ditosylate, prepared according to the processes described herein are substantially pure, with a chemical purity greater than about 98%, or greater than about 99% by weight, as determined using high performance liquid chromatography (HPLC).
In an aspect, the present invention provides a pharmaceutical composition comprising a premix of Valbenazine ditosylate described herein together with one or more pharmaceutically acceptable excipients, carriers, or diluents.
In an aspect, the present invention provides a pharmaceutical composition comprising a solid dispersion of Valbenazine ditosylate described herein together with one or more pharmaceutically acceptable excipients, carriers, or diluents.
In certain embodiments, solid dispersions or premixes of Valbenazine ditosylate together with one or more pharmaceutically acceptable excipients, carriers, or diluents described herein may be formulated using the methods known in the art. The solid dispersions or premixes of Valbenazine ditosylate together with one or more pharmaceutically acceptable excipients, carriers, or diluents described herein may be formulated as oral dosage forms such as, but not limited to powders, granules, pellets, tablets or capsules. Formulations may be in the forms of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving or flash melt preparations, or modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using techniques such as direct mixing, dry granulation, wet granulation, or extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, or modified release coated. Compositions of the present application may further comprise one or more pharmaceutically acceptable excipients.
The choice of the excipients, carriers or diluents may be customary to one skilled in the art. However, non-limiting examples of pharmaceutically acceptable excipients that are useful include: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methyl celluloses, 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; stabilizers such as salts of sodium, potassium, magnesium, calcium and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins or resins; 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 of use include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, or the like.
The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. Thus, for example, in each instance herein any of the terms “comprising” and “consisting of” may be replaced with either of the terms. In addition, the solvents, temperatures, reaction durations, etc. delineated herein are for purposes of illustration only and one of ordinary skill in the art will recognize that variation of the reaction conditions can produce the desired products accordingly.
Certain specific aspects and embodiments of the present invention will be better understood in connection with 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.

EXAMPLES

Following examples demonstrate the premix or solid dispersion of Valbenazine ditosylate with one or more pharmaceutically acceptable excipients and process for preparation thereof.

Example 1: Preparation of premix of Valbenazine ditosylate and HPMC:
Methanol (2.5 mL) was charged in to a four-neck flask at 20-25°C and to this Valbenazine ditosylate (0.250 g) was charged, followed by HPMC-5 at 20-25°C. Water (1.0 mL) was added to the reaction mixture at 20-25°C and stirred for 10-15 minutes at 20-25°C. The resultant reaction mixture was distilled in rotary evaporator at 70-80°C. Methanol (2.0 mL × 2) was charged to the above obtained residue and was again distilled at 70-80°C. Obtained solid was dried in an oven under vacuum at 40-42°C for 12-16 hours to afford the titled product as off-white solid.
Yield: 0.388 g
The powder X-ray diffractogram (PXRD) of the resultant product is illustrated in Figure 1.

Example 2: Preparation of premix of Valbenazine ditosylate and HPMC:
Methanol (2.6 mL) was charged in to a four-neck flask at 20-25°C and to this Valbenazine ditosylate (0.250 g) was added, followed by HPMC-15 (0.250 g) at 20-25°C. Water (1.0 mL) was added to the reaction mixture at 20-25°C and was stirred for 10-15 minutes at 20-25°C. The reaction mass was distilled in rotary evaporator at 70-80°C. Methanol (2.0 mL × 2) was charged to the above obtained residue and was again distilled at 70-80°C. Obtained solid was dried in an oven under vacuum at 40-42°C for 12-16 hours to afford the titled product as white solid.
Yield: 0.411 g
The powder X-ray diffractogram (PXRD) of the resultant product is illustrated in Figure 2.

Example 3: Preparation of premix of Valbenazine ditosylate and Mannitol:
Methanol (5.0 mL) was charged in to a four-neck flask at 20-25°C and to this Valbenazine ditosylate (0.500 g) was added, followed by Mannitol 200 SD (0.508 g) at 20-25°C. To the reaction mixture, water (6.0 mL) was added at 20-25°C and was stirred for 10-20 minutes at 20-25°C. The reaction mass was distilled in rotary evaporator at 70-80°C. Methanol (2.0 mL × 2) was charged to the above obtained residue and was again distilled at 70-80°C. Obtained solid was dried in an oven under vacuum at 40-42°C for 12-16 hours to afford the titled product as white solid.
Yield: 0.740 g
The powder X-ray diffractogram (PXRD) of the resultant product is illustrated in Figure 3.

Example 4: Preparation of premix of Valbenazine ditosylate and PVPK-30:
Methanol (5.0 mL) was charged in to a four-neck flask at 20-25°C and to this, Valbenazine ditosylate (0.500 g) was added, followed by PVPK-30 (0.504 g) at 20-25°C. The reaction mixture was stirred for 10-20 minutes at 20-25°C. The reaction mass was distilled in rotary evaporator at 70-80°C. Methanol (2.0 mL × 2) was charged to the above obtained residue and was again distilled at 70-80°C. Obtained solid was dried in an oven under vacuum at 40-42°C for 12-16 hours to afford the titled product as white solid.
Yield: 0.810 g
The powder X-ray diffractogram (PXRD) of the resultant product is illustrated in Figure 4.

Example 5: Preparation of premix of Valbenazine ditosylate, HPMC and Mannitol:
Methanol (5.0 mL) was charged in to a four-neck flask at 20-25°C and to this, Valbenazine ditosylate (0.510 g) was added, followed by HPMC-5 (0.250 g) and Mannitol 200 SD (0.258 g) at 20-25° C. To the above reaction mixture, water (4.0 mL) was added at 20-25°C and the reaction mass was stirred for 15-20 minutes at 20-25°C. The reaction mass was distilled in rotary evaporator at 60-70°C. Methanol (2.0 mL × 2) was charged to the above obtained residue and was again distilled at 60-70°C. Obtained solid was dried in rotary evaporator under vacuum at 60-70°C for 3-4 hours to afford the titled product as white solid.
Yield: 0.888 g
The powder X-ray diffractogram (PXRD) of the resultant product is illustrated in Figure 5.

Example 6: Preparation of premix of Valbenazine ditosylate, HPMC and Mannitol:
Methanol (5.0 mL) was charged in to a four-neck flask at 20-25°C and to this, Valbenazine ditosylate (0.518 g) was added, followed by HPMC-15 (0.257 g) and Mannitol 200 SD (0.256 g) at 20-25°C. To the above reaction mixture, water (4.0 mL) was added at 20-25°C and the reaction mass was stirred for 10-20 minutes at 20-25°C. The reaction mass was distilled in rotary evaporator at 60-70° C. Methanol (2.0 mL × 2) was charged to the above obtained residue and was again distilled at 60-70°C. Obtained solid was dried in rotary evaporator under vacuum at 60-65°C for 3-4 hours to afford the titled product as white solid.
Yield: 0.830 g.
The powder X-ray diffractogram (PXRD) of the resultant product is illustrated in Figure 6.

Example 7: Preparation of premix of Valbenazine ditosylate, HPMC and PVPK-30:
Methanol (5.0 mL) was charged in to a four-neck flask at 20-25°C and to this, Valbenazine ditosylate (0.514 g) was added, followed by HPMC-5 (0.255 g) and PVPK-30 (0.252 g) at 20-25°C. To the reaction mixture, water (1.0 mL) was added at 20-25°C and the reaction mass was stirred for 15-20 minutes at 20-25°C. The reaction mass was distilled in rotary evaporator at 60-70°C. Methanol (2.0 mL × 2) was charged to the above obtained residue and was again distilled at 60-70°C. Obtained solid was dried in rotary evaporator under vacuum at 60-65°C for 3-4 hours to afford the titled product as white solid.
Yield: 0.825 g
The powder X-ray diffractogram (PXRD) of the resultant product is illustrated in Figure 7.

Example 8: Preparation of premix of Valbenazine ditosylate, HPMC and PVPK-30:
Methanol (5.0 mL) was charged in to a four-neck flask at 20-25°C. and to this, Valbenazine ditosylate (0.514 g) was added, followed by HPMC-15 (0.251 g) and PVPK-30 (0.253 g) at 20-25°C. To the reaction mixture, water (1.0 mL) was added at 20-25°C and the reaction mass was stirred for 15-20 minutes at 20-25°C. The reaction mass was distilled out on rota evaporator at 60-70°C. Methanol was (2.0 mL) charged in residue and distilled out. Methanol addition and distillation was done for one more time at 60-70 C. Obtained solid was dried in rota evaporator under vacuum at 60-65°C for 3-4 hours to afford the titled product as white solid.
Yield: 0.850 g
The powder X-ray diffractogram (PXRD) of the resultant product is illustrated in Figure 8.

Example 9: Preparation of (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-((tert-butoxycarbonyl) amino)-3-methylbutanoate (formula II, R is t-BOC):
Water (60 mL) and (S)-(+)-camphorsulfonic acid salt of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (50 g) was charged in four neck flask at 20-25°C. Reaction mass was stirred for 10-15 min at 20-25°C and aqueous solution of sodium hydroxide (10 %) was added in the reaction mass at 20-25°C and the pH was adjusted to 10-11. The reaction slurry was filtered, and suck dried at 20-25°C. The obtained solid was dried in oven under vacuum for 12-16 hours at 60°C to afford (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol. Yield: 29.4 g
In a four neck flask, DMF (30 mL), (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (10 g), N-Boc-L-valine (8.2 g) and 4-dimethylaminopyridine (1.16 g) were charged at 20-25°C. The reaction mass was cooled to -5 to 0°C and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (10 g) was added in portions at -5 to 0°C. The reaction mass was gradually heated to 20-25°C and stirred for 12-16 hours at 20-25°C. After completion of reaction, the reaction mixture was added dropwise in water (100 mL) at 20 to 25°C. The solid thus obtained was collected by filtration and washed with 5% isopropanol in water (30.0 mL × 3 times) and suck dried. The resultant solid was dried in oven under vacuum at 60°C for 12-16 hrs to afford (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-((tert-butoxycarbonyl) amino)-3-methylbutanoate (formula II, R is t-BOC). Yield: 14.1 g.

Example 10: Preparation of premix of Valbenazine ditosylate and PVPK-30:
Methanol (10 mL) was charged in four neck flask at 20-25°C and to this (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-((tert-butoxycarbonyl)amino)-3-methylbutanoate (formula II, R is t-BOC) (1 g) and p-toluene sulfonic acid (0.81 g) were charged at 20-25°C. The reaction mass stirred at 50-55°C for 40-43 hrs. After completion of the reaction, PVPK-30 (1.48 g) was added in reaction mass at 50-55°C. The reaction was stirred for 2-3 hours at 50-55°C. The reaction mass was distilled out on rota evaporator at 50-55°C. The obtained solid was dried on rota evaporator at 50-55? to afford a premix comprising Valbenazine ditosylate and PVPK-30. Yield: 2.8 g
The powder X-ray diffractogram (PXRD) of the resultant premix is illustrated in Figure 9.

Example 11: Preparation of premix of Valbenazine ditosylate and PVPK-30:
Acetonitrile (10 mL) was charged in four neck flask at 20-25°C and to this (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-((tert-butoxycarbonyl)amino)-3-methylbutanoate (formula II, R is t-BOC) (1 g) and p-toluene sulfonic acid (0.807 g) were charged at 20-25°C. The reaction mass stirred at 50-55°C for 12-16 hrs. After completion of reaction, PVPK-30 (1.47 g) was added in the reaction mass at 50-55°C. The reaction was stirred for 4-5 hours at 50-55°C. The reaction was cooled to 25-30°C and stirred for 12-16 hours at 25-30°C. The reaction slurry was distilled out on rota evaporator at 45-50°C to afford a premix comprising Valbenazine ditosylate and PVPK-30. Yield: 2.8 g
The powder X-ray diffractogram (PXRD) of the resultant premix is illustrated in Figure 10.
,CLAIMS:1. A process for preparing a premix or solid dispersion of Valbenazine of formula (Ia)

(Ia)
or a salt thereof, in combination with one or more pharmaceutically acceptable excipients, the process comprising:
a. treating a compound of formula (II) or a salt thereof with an acid in presence of suitable solvent,

b. adding one or more pharmaceutically acceptable excipients to the solution or suspension obtained in step (a);
c. removing the solvent from the solution or suspension obtained in step (b) or combining the solution or suspension obtained in step (b) with an anti-solvent; and
d. isolating the solid dispersion or premix comprising Valbenazine of formula (Ia) or a salt thereof in combination with one or more pharmaceutically acceptable excipients.
2. The process as claimed in claim 1, wherein said salt of Valbenazine is selected from the group comprising of hydrochloride, oxalate, propionate, butyrate, lactate, citrate, acetate, benzoate, salicylate, succinate, malate, tartrate, fumarate, maleate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, or camphorsulfonate.

3. The process as claimed in claim 1, wherein said salt of Valbenazine is selected from the group comprising of ditosylate or hydrochloride.

4. The process as claimed in claim 1, wherein said amine protecting group “R” of formula (II) compound is selected from the group comprising of fluorenylmethoxycarbonyl (FMOC), tert-butoxycarbonyl (t-BOC), benzyloxycarbonyl (Z), formyl, benzoyl, trifluoroacetyl, p-tosyl, aryl, alkylphosphoryl, phenyl, benzylsulfonyl, o-nitrophenylsulfenyl, o-nitrophenoxyacetyl), tosyloxyalkyloxy, cyclopentyloxy, cyclohexyloxy or benzylthiocarbonyl.

5. The process as claimed in claim 1, wherein said amine protecting group “R” of compound of formula (II) is tert-butoxycarbonyl (t-BOC).

6. The process as claimed in claim 1, wherein said suitable solvent for providing a solution or suspension is selected from the group comprising of water, alcohols, ether, esters, ketones, nitriles, amides, sulfoxides, aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons or mixture thereof.

7. The process as claimed in claim 1, wherein said acid is selected from the group comprising of hydrochloric acid, oxalic acid, propionic acid, butyric acid, lactic acid, citric acid, acetic acid, benzoic acid, salicylic acid, succinic acid, malic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or camphorsulfonic acid.

8. The process as claimed in claim 1, wherein said anti-solvent is selected from the group comprising of water, alcohols, ethers, esters, aliphatic hydrocarbon liquids, alicyclic hydrocarbon liquids, aromatic hydrocarbon liquids or mixture thereof.

9. The process as claimed in claim 1, wherein said pharmaceutically acceptable excipient is selected from the group comprising of mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, maltose, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose (MC), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMC-AS) or polyvinylpyrrolidones (PVP K-30).

10. The process as claimed in any of the preceding claims, wherein the premix or solid dispersion comprising Valbenazine or a salt thereof, in combination with one or more pharmaceutically acceptable excipients obtained is having powder X-ray diffraction pattern as shown in Figures 9 and 10.