The present invention provides amorphous form of tozadenant or its pharmaceutically acceptable salts, their process for the preparation and composition thereof.

The present invention further provides amorphous solid dispersion of tozadenant or its pharmaceutically acceptable salts, and process for the preparation thereof. Moreover, there is provided a pharmaceutical composition comprising above said amorphous solid dispersion of tozadenant or pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION
Tozadenant having a chemical name; 4-hydroxy-4-methyl-piperidine-1-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide is represented with structure as follows:

Formula I

Tozadenant (SYN-115) a potent and selective adenosine A2A receptor antagonist, is under investigation for the treatment of Parkinson’s disease, as an adjunctive therapy with levodopa.

US 7,368,446 discloses tozadenant and process for the preparation thereof. US’446 further discloses the process for crystallizing tozadenant in ethanol.

WO 2018/059531 (A1) discloses the crystalline form CS1 of tozadenant and process for the preparation of said crystalline form CS1 of tozadenant by using different solvent like methanol, acetone, 1,4-dioxane or chloroform.

As it is apparent from the disclosure(s), there are few crystalline forms known from prior published references, however the known processes still suffers from drawbacks such as poor stability of solid forms of tozadenant. Also, it is known that bioavailability is the key determinant of a drug for its therapeutic effectiveness, which in turn depends upon the solubility of that drug in gastro intestinal fluid. The solubility of the drug in the vehicle determines its release rate and affects the absorption and therapeutic effectiveness.

The discovery of further solid forms of an active pharmaceutical ingredient (API) can offer an opportunity to improve the performance profile of a pharmaceutical composition comprising the said API i.e. tozadenant and its pharmaceutically acceptable salts.

Preparing a solid dispersion increases the solubility of drug in the vehicle and also said solid dispersions can easily be formulated. Based on above, the present invention is focussed on the preparation of amorphous form and/ or solid dispersions and/ or premix of tozadenant or its pharmaceutically acceptable salts that possess high stability as well as solubility, and can easily be formulated in a formulation having a desirable release profile.

OBJECTIVE OF THE INVENTION
The main object of the present invention is to provide amorphous form of tozadenant or pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a process for the preparation of amorphous form of tozadenant or pharmaceutically acceptable salt thereof, wherein the said amorphous form is stable for at least three months or more at 40oC±2oC and at relative humidity of 75%±5% RH and can easily be formulated for administering to patients.

Another object of the present invention is to provide amorphous solid dispersion of tozadenant or pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a process for the preparation of amorphous solid dispersion of tozadenant or pharmaceutically acceptable salt thereof with atleast one pharmaceutically acceptable carrier.

Another object of the present invention is to provide a pharmaceutical composition comprising solid form of tozadenant or its pharmaceutically acceptable salts, wherein the physicochemical stability and the dissolution characteristics of the solid form is improved, and wherein tozadenant or its pharmaceutically acceptable salts is rendered more suitable for use in a pharmaceutical composition.

SUMMARY OF THE INVENTION
In an aspect, the present invention provides amorphous form of tozadenant or pharmaceutical acceptable salt thereof.

In another aspect, the present invention provides a process for the preparation of amorphous form of tozadenant or pharmaceutically acceptable salt thereof, comprising the steps of:
a) providing a solution of tozadenant or pharmaceutically acceptable salt thereof in a polar solvent;
b) lyophilizing the solution obtained in step a); and
c) isolating the amorphous form of tozadenant or pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a process for the preparation of amorphous tozadenant or pharmaceutically acceptable salts, comprising the steps of:
a) milling/grinding tozadenant or its pharmaceutically acceptable salts under suitable milling conditions optionally with excipient; and
b) isolating the amorphous form of tozadenant or pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a process for the preparation of amorphous form of tozadenant or pharmaceutically acceptable salt thereof, comprising the steps of:
a) providing a solution of tozadenant or pharmaceutically acceptable salt thereof in one or more suitable solvent;
b) optionally heating the solution of step a); and
c) isolating the amorphous form of tozadenant or pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides amorphous solid dispersion of tozadenant or pharmaceutically acceptable salt thereof, with atleast one pharmaceutically acceptable carrier.

In another aspect, the present invention provides a process for the preparation of amorphous solid dispersion of tozadenant or pharmaceutically acceptable salt thereof, comprising the steps of:
a) providing a solution of tozadenant or pharmaceutically acceptable salt thereof in a suitable solvent;
b) adding atleast one pharmaceutically acceptable carrier to the solution obtained in step a); and
c) isolating to get amorphous solid dispersion of tozadenant or pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides solid dispersion of tozadenant comprising tozadenant along with atleast one pharmaceutically acceptable carrier, wherein said solid dispersion is stable for at least three months at 40oC±2oC and at relative humidity of 75%±5% RH.

In another aspect, the present invention provides a solid dispersion of tozadenant pharmaceutically acceptable salt comprising tozadenant pharmaceutically acceptable salt along with at least one pharmaceutically acceptable carrier, wherein said solid dispersion is stable for at least three months at 40oC±2oC and at relative humidity of 75%±5% RH.

In another aspect, the present invention provides a process for the preparation of a premix of tozadenant or its pharmaceutically acceptable salt, comprising the steps of;
a) adding tozadenant or its pharmaceutically acceptable salt to atleast one pharmaceutically acceptable carrier to get a solid mass;
b) optionally adding solvent to get a solution; and
c) isolating the premix of tozadenant or its pharmaceutically acceptable salt either by removal of solvent from solution of step b) or by isolating the solid mass of step a).

In another aspect, the present invention provides a process for the preparation of a premix of tozadenant or pharmaceutically acceptable salt thereof, wherein said process comprises grinding of tozadenant or its pharmaceutically acceptable salts with atleast one pharmaceutically acceptable carrier.

DETAILED DESCRIPTION
Drawings:
Fig. 1 represents XRPD peaks of amorphous form of tozadenant
Fig. 2 represents XRPD peaks of solid dispersion of tozadenant prepared as per Example 8

Definitions:
The terms “amorphous form of tozadenant or pharmaceutically acceptable salt thereof" indicate that the tozadenant or pharmaceutically acceptable salt thereof is present in substantially amorphous state and is substantially free from crystalline form. It may be present in the form of solid dispersion, adsorbate or pharmaceutical composition. "Substantially pure amorphous” denotes that atleast 90%, preferably atleast 95%, more preferably atleast 99% of the tozadenant or pharmaceutically acceptable salt thereof is amorphous. In other words, “substantially free from crystalline form” preferably means that the amorphous form does not contain detectable amounts, of crystalline portions of tozadenant or pharmaceutically acceptable salt thereof e.g. measurable upon X-ray powder diffraction analysis and/or Differential scanning calorimetry, and preferably the crystalline form is less than about 5% w/w of the amorphous form.

“Solid dispersion” as used herein refers to the dispersion of one or more active ingredients in an inert carrier, where the active ingredients could exist in finely crystalline, solubilized or amorphous state. Solid dispersion consists of two or more components, generally a carrier and drug optionally along with stabilizing agent (and/or surfactant or other additives). The most important role of the added carrier in solid dispersion is to reduce the molecular mobility of the drug to avoid the phase separation and re-crystallization of drug during storage. The resulting solid dispersions may have increased solubility. The increase in solubility of the drug in solid dispersion is mainly because drug remains in amorphous form which is associated with a higher energy state as compared to crystalline counterpart and due to that it requires very less external energy to dissolve. A solid dispersion is a molecular dispersion of a compound, particularly a drug substance within a carrier. Formation of a molecular dispersion provides a means of reducing the particle size to nearly molecular levels (i.e. there are no particles). As the carrier dissolves, the drug is exposed to the dissolution media as fine particles that are amorphous, which can dissolve and be absorbed more rapidly than larger particles. Further, the term "solid dispersion" as used in the context of the present invention, denotes a state where most of the tozadenant or pharmaceutically acceptable salt thereof, preferably 90%, 95% or all of the tozadenant or pharmaceutically acceptable salt thereof of the solid dispersion, is homogeneously molecularly dispersed in a solid carrier matrix. In a preferred embodiment, in the solid dispersion according to the present invention no chemical bonds can be detected between the API and the carrier. In order to arrive at such a solid dispersion, preferably solid solution, it is required to have a substantial amount of API dissolved in a suitable solvent at least at one time point during preparation of said solid dispersion.

The term "premix" is used herein to describe combinations of tozadenant or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier, wherein individual particles of the components cannot be distinguished using techniques such as optical microscopy. In embodiments, the drug is considered as being uniformly or non-uniformly distributed over surfaces of excipient particles. In other embodiments, the premixes are considered to be in the nature of molecular dispersions, or solid solutions. Simple mixtures of powdered ingredients will not constitute premixes.

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 terms “pharmaceutically acceptable salt” as used in the context of the present invention refers to inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid salt, carbonate salts; organic acids such as succinic acid, formic acids, acetic acid, diphenyl acetic acid, palmoic acid, triphenylacetic acid, caprylic acid, dichloroacetic acid, trifluoro acetic acid, propionic acid, butyric acid, lactic acid, citric acid, gluconic acid, mandelic acid, tartaric acid, malic acid, adipic acid, aspartic acid, fumaric acid, glutamic acid, maleic acid, malonic acid, benzoic acid, p-chlorobenzoic acid, dibenzoyl tartaric acid, oxalic acid, nicotinic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxy-naphthalene-2-carboxylic acid, hydroxynaphthalene-2-carboxylic acid, ethanesulfonic acid, ethane-1,2-disulfonic acid, 2-hydroxyethane sulfonic acid, methanesulfonic acid, (+)-camphor-10-sulfonic acid, benzenesulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid and the like. It further includes inorganic salts selected from alkali metal and alkaline earth metal salts such as sodium, potassium, barium, lithium, calcium, magnesium, rhodium, zinc, cesium, selenium, and the like.

The term “suitable solvent” as used in the context of the present invention refers to polar or non-polar solvents selected from, but not limited to, the group comprising of alcohols, hydrocarbons, halogenated solvents, esters, ethers, ketones, sulfoxides, formamide, amides, nitriles, pyrrolidines, carbonates, water and the like. Specifically, the suitable solvent as used in the present invention is selected from, but not limited to, tetrahydrofuran, toluene, o/m/p-xylene, 1,4-dioxane, dichloromethane, carbon tetrachloride, dichloroethane, dichlorobenzene, chlorobenzene, methanol, ethanol, isopropyl alcohol, butanol, t-butanol, acetonitrile, ethyl acetate, acetone, methyl ethyl ketone, 2-methyl tetrahydrofuran, butyl acetate, isobutyl acetate, t-butyl acetate, propyl acetate, propylene acetate, methyl t-butyl ketone, dimethyl sulfoxide, N-methyl pyrrolidine, dimethyl acetamide, dimethyl formamide, N-methyl acetamide, acetamide, methyl isobutyl ketone, propionitrile, methyl ethyl ether, methyl tert-butyl ether, dimethyl ether, diethyl ether, cyclohexane, hexane, n-heptane, water and mixture thereof.

In one embodiment, the present invention provides amorphous form of tozadenant or pharmaceutical acceptable salt thereof.

Moreover, in a preferred embodiment, present invention provides amorphous form of tozadenant which is stable after exposure to 40°C±2°C/75%±5% RH for a period of six months or 25°C±2°C /60% ±5% RH, for a period of at least 6 months and contains less than about 0.5% (wt/wt) total impurities and doesn't change to any other solid forms.

In another embodiment, the amorphous form of tozadenant of the present invention remains stable and does not convert to any other solid form when stored at a temperature of up to about 40oC and at a relative humidity of about 25% to about 75% for about three months or more.

In another embodiment, the present invention provides a process for the preparation of amorphous form of tozadenant or pharmaceutically acceptable salt thereof, comprising the steps of:
a) providing a solution of tozadenant or pharmaceutically acceptable salt thereof in one or more suitable solvent;
b) optionally heating the solution obtained in step a); and
c) isolating the amorphous form of tozadenant or pharmaceutically acceptable salt thereof.

In another embodiment, solution of tozadenant or pharmaceutically acceptable salt thereof may be combined with the anti-solvent at suitable temperature and for sufficient time to obtain amorphous product.

In another embodiment, amorphous form is isolated by removal of solvent at step b) above, which may be carried out by methods known in the art or any procedure disclosed in the present invention wherein said method is selected from, but not limited to, solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Büchi® Rotavapor®, spray drying, freeze drying, thin film drying, agitated thin film drying, rotary vacuum paddle dryer (RVPD), lyophilisation and the like. In preferred embodiment, the solvent may be removed under reduced pressures and at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80°C, or any other suitable temperatures.

Moreover, drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller or hammer milling; or jet milling; or bead milling.

In another embodiment, the present invention provides a process for the preparation of amorphous tozadenant or its pharmaceutically acceptable salts, comprising the steps of:
a) milling/grinding tozadenant or its pharmaceutically acceptable salts under suitable milling conditions; and
b) isolating the amorphous form of tozadenant or pharmaceutically acceptable salt thereof.

In a preferred embodiment, any solid forms, either crystalline or amorphous form of tozadenant or its pharmaceutically acceptable salts can be used to mill it with one or more pharmaceutically acceptable carriers.

In another embodiment, the present invention provides a process for the preparation of amorphous form of tozadenant or pharmaceutically acceptable salt thereof, comprising the steps of:
a) providing a solution of tozadenant or pharmaceutically acceptable salt thereof in a polar solvent;
b) lyophilizing the solution obtained in step a); and
c) isolating the amorphous form of tozadenant or pharmaceutically acceptable salt thereof.

In another embodiment, the polar solvent used for preparing amorphous form of tozadenant is selected from, but not limited to, the group comprising of alcohols such as methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, polyethylene glycol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol; esters such as ethyl acetate, butyl acetate, t-butyl acetate, n-propyl acetate, iso-propyl acetate, isobutyl acetate; ethers such as tetrahydrofuran, methyl tetrahydrofuran, diethyl ether, dioxane; nitriles such as acetonitrile, propionitrile; ketones such as methyl ethyl ketone, acetone, methyl t-butyl ketone, methyl iso-butyl ketone; water; and mixture thereof.

In another embodiment, the amorphous form of tozadenant or pharmaceutically acceptable salt thereof, obtained after lyophilisation, is isolated by a process such as drying at room temperature, drying under vacuum, or by any known conventional method. Moreover, drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller or hammer milling; or jet milling; or bead milling.

In another embodiment, the present application provides pharmaceutical composition comprising amorphous form of tozadenant or pharmaceutically acceptable salt thereof and atleast one pharmaceutically acceptable excipient.

In one more embodiment, the present invention provides a substantially pure amorphous form of tozadenant and pharmaceutically acceptable salts thereof, wherein said amorphous form is substantially free from crystalline form.

In one another embodiment, the present invention provides a process for preparing amorphous form of tozadenant or pharmaceutically acceptable salt thereof, wherein said process comprising of:
a) dissolving tozadenant in a suitable solvent and treating with suitable acid or base to form tozadenant salt;
b) neutralizing or desalting the tozadenant salt to give tozadenant free base;
c) optionally converting the tozadenant free base to its pharmaceutically acceptable salt;
d) providing a solution of tozadenant free base of step b) or its salt of step c) in a suitable solvent (s); and
e) removing the solvent from the solution obtained in step d) to get amorphous form of tozadenant or its pharmaceutically acceptable salt.
The present invention provides a solid dispersion of tozadenant or pharmaceutically acceptable salt thereof suitable for powder handling and downstream processes. A solid dispersion of tozadenant or pharmaceutically acceptable salt thereof of the present application was surprisingly found to be highly stable under mechanical stress such as grinding and milling and stable under hygroscopic conditions such as higher relative humidity conditions of more than 60% RH.
In another embodiment, the present invention provides amorphous solid dispersion of tozadenant or pharmaceutically acceptable salt thereof, with atleast one pharmaceutically acceptable carrier.

In the present invention, the solid dispersion technology is used for dispersing sparingly water soluble tozadenant monomolecularly in a solid state into an inert carrier. The technology specifically includes a solvent process, a fusion process, and a mixed-grinding process.

The solvent process either comprises dissolving a sparingly water-soluble tozadenant and a water-soluble polymer, i.e. the carrier, in an organic solvent capable of dissolving both and removing the solvent by evaporation or comprises dissolving the tozadenant in an organic solvent, dispersing the solution in the carrier and removing the solvent by evaporation to provide the desired solid dispersion.

The fusion process either comprises heating the tozadenant and the water-soluble polymer together by utilizing the phenomenon of melting point depression, cooling the melt to solidify and pulverizing the resulting solid to provide the desired solid dispersion, or comprises dissolving the tozadenant in a comparatively low-melting water-soluble polymer under heating, cooling the resulting solution to solidify and pulverizing the solid to provide the desired solid dispersion.

The mixed-grinding technology, in which the sparingly water-soluble tozadenant and the water-soluble polymer are mix-ground or roll-mixed without heating. It is considered that here various factors arising from mechanical manipulation, such as lattice defect or lattice modulation, increases in specific surface area and surface energy and so on, enhances the activity of the solid phase to encourage transition of the tozadenant to amorphous state and, hence, dispersion of the tozadenant in this amorphous state into the carrier.

Accordingly, in an embodiment, the present invention provides a process for the preparation of amorphous solid dispersion of tozadenant or pharmaceutically acceptable salt thereof, comprising the steps of:
a) providing a solution of tozadenant or pharmaceutically acceptable salt thereof in a suitable solvent;
b) adding atleast one pharmaceutically acceptable carrier to the solution obtained in step a); and
c) isolating to get amorphous solid dispersion of tozadenant or pharmaceutically acceptable salt thereof.

In another embodiment, the solid dispersion of tozadenant or its pharmaceutically acceptable salt is stable for at least three months at 40oC±2oC and at relative humidity of 75%±5% RH.

In another embodiment, the tozadenant and the pharmaceutically acceptable carriers may be dissolved either in the same solvent or they may be dissolved in different solvents and then combined to form a mixture. In embodiments, the solid dispersion described herein comprises amorphous or crystalline tozadenant or its pharmaceutically acceptable salt, and the carrier present in weight ratios ranging from about 1:99 to about 99:1. Preferably, the ratio is about 50:50. In some embodiments, the solid dispersion described herein comprises one or more pharmaceutically acceptable carrier.

The dissolution temperatures may range from about 0°C to about the reflux temperature of the solvent, or less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, or any other suitable temperatures, as long as a clear solution of tozadenant or its pharmaceutically acceptable salt is obtained without affecting its quality. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered 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.

In another embodiment, the present invention provides a process for the preparation of amorphous solid dispersion of tozadenant or pharmaceutically acceptable salt thereof, comprising the steps of:
a) heating tozadenant or pharmaceutically acceptable salt thereof in presence of atleast one pharmaceutically acceptable carrier to get a solution;
b) cooling the solution; and
c) isolating to get amorphous solid dispersion of tozadenant or pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a process for the preparation of amorphous solid dispersion of tozadenant or pharmaceutically acceptable salt thereof, wherein said tozadenant or its pharmaceutically acceptable salt is mixed with pharmaceutically acceptable water soluble polymer at ambient temperature.

In preferred embodiment, the present invention provides a simple process which comprises mixing a sparingly water-soluble tozadenant and a water-soluble polymer together under no more than the usual agitation force with heating within the temperature region not melting them, making the sparingly water-soluble tozadenant as amorphous in nature to thereby yield a solid dispersion insuring very high solubility and bioavailability which have never been achieved by any dry process heretofore known.

In another embodiment, tozadenant or pharmaceutically acceptable salt thereof as used for preparing amorphous solid dispersion, can be either crystalline, amorphous or mixture in nature.

In another embodiment, the present invention further provides a pharmaceutical composition comprising solid dispersion of tozadenant or pharmaceutically acceptable salt thereof together with atleast one pharmaceutically acceptable excipient.

The pharmaceutical composition of the present invention may be formulated in accordance with conventional methods, and may be prepared in the form of oral formulations such as tablets, pills, powders, capsules, syrups, emulsions, micro emulsions, and others, or formulation for parenteral injection, e.g., intramuscular, intravenous, or subcutaneous administration. The pharmaceutical composition of the present invention may comprise the inventive solid dispersion, and any possible carrier.

In an embodiment, the present application provides amorphous solid dispersion of tozadenant, or pharmaceutically acceptable salt thereof, with less than 5% of crystallinity, preferably with less than 1% crystallinity and more preferably with less than 0.5% crystallinity as per X-ray diffraction analysis.

In one another embodiment, the present invention provides a premix of tozadenant or its pharmaceutically acceptable salt with atleast one pharmaceutical acceptable carrier.

In one another embodiment, the present invention provides a process for the preparation of a premix of tozadenant or its pharmaceutically acceptable salt, comprising the steps of:
a) adding tozadenant or its pharmaceutically acceptable salt to atleast one pharmaceutically acceptable carrier to get a solid mass;
b) optionally adding solvent to get a solution; and
c) isolating the premix of tozadenant or its pharmaceutically acceptable salt either by removal of solvent from solution of step b) or by isolating the solid mass of step a).

In another embodiment, the present application provides a pharmaceutical composition comprising a premix of tozadenant or pharmaceutically acceptable salt thereof, together with atleast one pharmaceutically acceptable excipient.

In another embodiment, a solution of tozadenant or pharmaceutically acceptable salt thereof used to prepare amorphous solid dispersion/ premix/ amorphous form of tozadenant or its pharmaceutically acceptable salt, may be prepared by dissolving tozadenant or pharmaceutically acceptable salt thereof in a suitable solvent or by taking the reaction mixture containing tozadenant or pharmaceutically acceptable salt thereof directly.

In an embodiment, providing a solution of tozadenant or pharmaceutically acceptable salt thereof to prepare amorphous solid dispersion/ premix/ amorphous form of tozadenant or its pharmaceutically acceptable salt, may be prepared by dissolving a salt of tozadenant in a suitable solvent or by taking the reaction mixture containing tozadenant and an acid directly.

In an embodiment, a solution of tozadenant or pharmaceutically acceptable salt thereof in a suitable solvent can be prepared at any suitable temperature, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.

In an embodiment, a solution of tozadenant or pharmaceutically acceptable salt thereof in a suitable solvent may be filtered to make it clear, free of unwanted particles. In an embodiment, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove coloured components, etc., before filtration.

In preferred embodiments, removal of solvent at any stage of preparation of amorphous form/ solid dispersion/ premix of tozadenant or its pharmaceutically acceptable salt may include, but not limited to, solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Büchi® Rotavapor®, flash evaporation, rotational dying, agitated nutsche filter drying, spray drying, freeze drying, thin film drying, agitated thin film drying, rotary vacuum paddle dryer (RVPD), lyophilisation, and the like. In preferred embodiment, the solvent may be removed under reduced pressures and at a temperature of less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80°C, or any other suitable temperatures.

In preferred embodiment, amorphous form of tozadenant or pharmaceutically acceptable salt thereof may be combined with carrier either by physical blending of both the solid components or by suspending both the components in a suitable solvent and conditions, such that both the components remain unaffected. Blending may be carried out using techniques known in art such as rotatory cone dryer, fluidized bed dryer or the like optionally under reduced pressure / vacuum or inert atmosphere such nitrogen at suitable temperature and sufficient time to obtain uniform composition of amorphous form of tozadenant or pharmaceutically acceptable salt thereof and atleast one pharmaceutically acceptable excipient.

In another embodiment, the amorphous form of tozadenant or pharmaceutically acceptable salt thereof may be combined with the carrier by evaporating the suspension or solution of amorphous form of tozadenant or pharmaceutically acceptable salt thereof and atleast one pharmaceutically acceptable carrier.

In another embodiment, pharmaceutically acceptable carrier used for preparing solid dispersion may include, but not limited to, an inorganic oxide such as SiO2, TiO2, ZnO2, ZnO, Al2O3 and zeolite; a water insoluble carrier is selected from the group consisting of cross-linked polyvinyl pyrrolidinone, cross-linked cellulose acetate phthalate, cross-linked hydroxypropyl methyl cellulose acetate succinate, microcrystalline cellulose, polyethylene glycol, polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer, cross-linked carboxymethyl cellulose, sodium starch glycolate, and cross-linked styrene divinyl benzene or any other carrier at any aspect of present application. In an embodiment, atleast one pharmaceutically acceptable carrier may be selected from the group consisting of polyvinyl pyrrolidone, povidone K-30, povidone K-60, Povidone K-90, polyvinylpyrrolidone vinylacetate, co-povidone NF, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene–polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit or Eudragit-RLPO), hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), hydroxypropylmethyl cellulose, hydroxypropyl cellulose SSL(HPC-SSL), hydroxypropyl cellulose SL(HPC-SL), hydroxypropyl cellulose L (HPC-L), hydroxyethyl cellulose, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxy methyl ethyl cellulose and the like; cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, and the like; water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and the like; polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like; 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, or any other carrier at any aspect of present application. The use of mixtures of more than one of the pharmaceutical carrier to provide desired release profiles or for the enhancement of stability is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, and mixtures are all within the scope of this invention without limitation. Solid dispersions of the present application also include the solid dispersions obtained by combining tozadenant or pharmaceutically acceptable salt thereof with a suitable non-polymeric carrier by employing techniques known in the art or procedures described or exemplified in any aspect of the instant application.

In preferred embodiment, pharmaceutically acceptable carrier may be selected from the group consisting of silicon dioxide, e.g. colloidal or fumed silicon dioxide or porous silica or Syloid; copolymers, such as polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer; and cellulose, preferably microcrystalline cellulose.

In another embodiment, the present invention provides amorphous form of tozadenant or pharmaceutically acceptable salt thereof, solid dispersion comprising tozadenant or pharmaceutically acceptable salt thereof, wherein said tozadenant or pharmaceutically acceptable salt thereof is having a chemical purity of atleast 99% by HPLC or atleast 99.5% by HPLC or atleast 99.9% by HPLC.

In another embodiment, the amorphous solid dispersion of tozadenant or pharmaceutically acceptable salt thereof, obtained by the process of the present invention is characterized by particle size distribution of less than about 300µm, preferably less than about 200µm and most preferably about 100µm.

In another embodiment, the amorphous form of tozadenant or pharmaceutically acceptable salt thereof, obtained by the process of the present invention is characterized by particle size distribution of less than about 300µm, preferably less than about 200µm and most preferably about 100µm.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

EXAMPLES
Example-1: Preparation of amorphous form of tozadenant
To a stirred solution of Tozadenant (0.5 g) in acetonitrile (20 mL) at 25°C, then heated to 50oC to get cleared solution, then filtered and the filtrate was evaporated in rotavapour under reduced pressure at 50°C. The obtained product was re-dissolved in acetonitrile (20 mL) at 25°C and the solvent was evaporated in rotavapour under reduced pressure at 50°C for 20 minutes to obtain title compound.

Example-2: Preparation of solid dispersion of tozadenant with PVP K-90
A mixture of Tozadenant free base (0.5 g) and PVP K-90 (0.5 g) was dissolved in ethanol (25 mL) at 25°C and filtered the solution to make it particle free. The solvent was evaporated in rotavapour under reduced pressure at 50°C to obtain title compound.

Example-3: Preparation of amorphous form of tozadenant
Tozadenant (1.0g) was dissolved in ethyl acetate (50 mL) at 25°C and stirred at 60oC to get the reaction mixture for 4-6h. Lyophilized the solution so obtained to get title compound.

Example-4: Preparation of solid dispersion of tozadenant HPC (Hydroxypropyl cellulose)
A mixture of tozadenant (1.0 g) and HPC (1.0 g) was dissolved in methanol (25 mL) at 25°C and filtered the solution to make it particle free. The solvent was evaporated in rotavapour under reduced pressure at 50°C to obtain title compound.

Example-5- Ball mill mixed-grinding process for preparing solid dispersion of tozadenant
Using a ball mill (SPEX Industries), a mixture of tozadenant (1 g), hydroxypropylmethylcellulose (5 g), low-substituted hydroxypropylcellulose (3 g) and crystalline cellulose (12 g) is mix-ground for 4 hours to provide a solid dispersion.

Example-6: Preparation of amorphous form of tozadenant
Tozadenant (8 gm), was dissolved in methyl isobutyl ketone (55ml), stirred for 1 hr at RT, then the solvent was evaporated under reduced pressure to obtain the title compound.

Example-7: Preparation of amorphous form of tozadenant
Tozadenant (8 gm) of was dissolved in 125 mL methylene dichloride and heated to obtain clear solution at 50°C. The reaction mixture was distilled atmospherically at 40-45°C. 100 mL isopropanol was added to the residue and stirred for 15 minutes. The reaction mixture was distilled partially and filtered. The wet-cake was dissolved in 125 mL of methylene dichloride. The solution was distilled to remove methylene dichloride and the residue was triturated with 75 ml methyltert-butyl ether at 0°C. The precipitated product was filtered and washed with methyltert-butyl ether. The product was dried under vacuum at 60°C for 6 hours to obtain amorphous tozadenant.

Example-8: Preparation of solid dispersion of tozadenant with PEG 8000
The sample was prepared by dissolving tozadenant in a small volume of 180 ml proof ethanol in a 250 ml round bottom flask. The flask was vortexed and then placed in a water bath maintained at 75°C. PEG 8000 was added to the hot alcohol solution with continual swirling until the PEG melted. The flask was then attached to a rotary evaporator, immersed in the water bath (75°C) under vacuum for 15 minutes to remove the ethanol. After the majority of ethanol had evaporated, the flask was immersed in an ice bath for 15 minutes. The contents of the flask were then vacuum dried at room temperature for 6 hours. The solid was transferred to a crystallization dish and was placed under vacuum overnight to remove residual ethanol to obtain solid dispersion of tozadenant.

Example 9: Preparation of a pre-mix of amorphous tozadenant with 10 w/w microcrystalline cellulose
Tozadenant (5 g) was dissolved in dimethyl sulfoxide (12.5 ml) at 25°C - 30°C. The solution was filtered to remove undissolved particulate and washed with dimethyl sulfoxide (2.5 ml). The clear solution of tozadenant was added into water (150ml) maintained at 25°C-30°C for 30minutes. The reaction mass was further stirred for 30minutes. Microcrystalline cellulose (0.556 g, Grade: AVICEL PH 101) was then added into the reaction mass and which was then stirred for 1 hour. The solid obtained was filtered out, washed with water (20 ml), and dried at 30°C under vacuum for 16 hours. It was then further dried at 40°C under vacuum for 24 hours.

WE CLAIM

1. Amorphous form of tozadenant or pharmaceutically acceptable salt thereof.

2. A process for preparing amorphous form of tozadenant or pharmaceutically acceptable salt thereof, wherein said process comprising the steps of:
a) providing a solution of tozadenant or pharmaceutically acceptable salt thereof, in one or more suitable solvent;
b) optionally heating the solution of step a); and
c) isolating the amorphous form of tozadenant or pharmaceutically acceptable salt thereof.

3. The amorphous form as claimed in claim 1, wherein said amorphous form is stable at a temperature of about 40oC and at a relative humidity of about 25% to about 75% for about six months and more.

4. Amorphous solid dispersion of tozadenant or pharmaceutically acceptable salt thereof, with atleast one pharmaceutically acceptable carrier.

5. A process for the preparation of amorphous solid dispersion of tozadenant or pharmaceutically acceptable salt thereof as claimed in claim 4, wherein said process comprising the steps of:
a) providing a solution of tozadenant or pharmaceutically acceptable salt thereof in a suitable solvent;
b) adding atleast one pharmaceutically acceptable carrier to the solution obtained in step a); and
c) isolating to get amorphous solid dispersion of tozadenant or pharmaceutically acceptable salt thereof.

6. The process as claimed in claim 5, wherein said process further comprising the steps of:
a) providing a solution of tozadenant or pharmaceutically acceptable salt thereof in a suitable solvent;
b) optionally heating the solution obtained in step a);
c) adding PEG 8000 to the solution obtained in step a); and
d) isolating to get amorphous solid dispersion of tozadenant or pharmaceutically acceptable salt thereof.

7. The process as claimed in claims 5 or 6, wherein said solution of tozadenant or pharmaceutically acceptable salt thereof may be obtained by dissolving tozadenant or pharmaceutically acceptable salt thereof in a suitable solvent or by directly taking the reaction mixture containing tozadenant or its pharmaceutically acceptable salt.

8. The amorphous solid dispersion as claimed in claim 4, wherein said solid dispersion is stable at a temperature of about 40oC and at a relative humidity of about 25% to about 75% for about six months and more.

9. Composition comprising tozadenant or pharmaceutically acceptable salt thereof, and atleast one pharmaceutically acceptable excipient, wherein said tozadenant or pharmaceutically acceptable salt thereof is selected from amorphous form or solid dispersion of tozadenant.

10. A method for preparation of composition comprising tozadenant or pharmaceutically acceptable salt thereof as claimed in claim 9, wherein said composition is prepared by combining either amorphous form of tozadenant or its salt, or amorphous solid dispersion of tozadenant or its salt, along with atleast one pharmaceutically acceptable excipients.