The present invention provides a substantially pure and amorphous form of zuranolone or its salts, process for the preparation and composition thereof.

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

BACKGROUND OF THE INVENTION
Zuranolone having a chemical name; 1-[2-[(3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethyl-2,4,5,6,7,8,9,10,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl]pyrazole-4-carbonitrile is represented with structure as follows:

Formula I.

Zuranolone (SAGE-217) is being investigated for the potential treatment of Major depressive disorder. Zuranolone is also under clinical investigation for parkinson's disease, postpartum depression, essential tremor and insomnia.

US 9,512,165 (US’165) discloses zuranolone and process for the preparation thereof. US’165 also discloses process for purification of zuranolone using reverse phase preparative HPLC.

US 20190177359 (US’359) discloses crystalline Forms A, B, D, E, F, H, I, J, K, L, M, N, O, and P. US’359 also discloses crystalline anhydrate Form C of zuranolone.

As it is apparent from above disclosure(s), that there are several crystalline forms of zuranolone known from the prior published references. However, 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) in particular amorphous form can offer an opportunity to improve the performance profile of a pharmaceutical composition comprising the said API.

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 zuranolone or its salts that possess high solubility and can easily be formulated in a formulation having a desirable release profile.

OBJECT OF THE INVENTION
The main object of the present invention is to provide an amorphous form of zuranolone or its pharmaceutically acceptable salts.

Another object of the present invention is to provide a process for the preparation of amorphous form of zuranolone or its pharmaceutically acceptable salts, wherein said amorphous form is stable for atleast six months at 40oC and 75% RH and can be formulated easily for administering to patients.

Another object of the present invention is to provide an amorphous solid dispersion of zuranolone or its pharmaceutically acceptable salts, and process of preparation thereof.

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

SUMMARY OF THE INVENTION
In an aspect, the present invention provides amorphous form of zuranolone or its pharmaceutically acceptable salts.

In another aspect, the present invention provides a process for the preparation of amorphous form of zuranolone or pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a process for the preparation of amorphous form of zuranolone or its pharmaceutically acceptable salts, comprising the steps of:
a) providing a solution of zuranolone or its pharmaceutically acceptable salts in one or more suitable solvent; and
b) isolating the amorphous form of zuranolone or its pharmaceutically acceptable salts.

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

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

In another aspect, the present invention provides an amorphous solid dispersion of zuranolone or its pharmaceutically acceptable salt, with atleast one pharmaceutically acceptable carrier or polymer.

In another aspect, the present invention provides a process for the preparation of an amorphous solid dispersion of zuranolone or its pharmaceutically acceptable salt, comprising the steps of:
a) providing a solution of zuranolone or its pharmaceutically acceptable salt 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 zuranolone or its pharmaceutically acceptable salts.

In another aspect, the present invention provides a process for the preparation of a solid dispersion of zuranolone or its pharmaceutically acceptable salts comprising the steps of:
a) providing a solution of crystalline form of zuranolone or its pharmaceutically acceptable salts in a suitable solvent;
b) adding atleast one pharmaceutically acceptable carrier or polymer; and
c) removing the solvent and isolating to get solid dispersion of zuranolone or its pharmaceutically acceptable salts.

In another aspect, the present invention provides a process for the preparation of a premix of zuranolone or its pharmaceutically acceptable salt, comprising the steps of:
a) adding zuranolone 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 zuranolone or its pharmaceutically acceptable salts 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 zuranolone or its pharmaceutically acceptable salts, wherein said process comprises grinding of zuranolone or its pharmaceutically acceptable salts with atleast one pharmaceutically acceptable carrier.

DETAILED DESCRIPTION
Brief description of the drawings:
FIG. 1, represents the X-ray (powder) diffraction (XRPD) pattern of the amorphous form of zuranolone.
FIG. 2, represents the X-ray (powder) diffraction (XRPD) pattern of the amorphous form of zuranolone solid dispersion as per example 12.

Definitions:
The terms “amorphous form of zuranolone or its pharmaceutically acceptable salts" indicate that the zuranolone or its pharmaceutically acceptable salts 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 zuranolone or a 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 zuranolone or its pharmaceutically acceptable salts 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 polymer or carrier, where the active ingredients could exist in finely crystalline, solubilized or amorphous state. Solid dispersion consists of two or more components, generally a polymer or carrier and drug optionally along with stabilizing agent (and/or surfactant or other additives). The most important role of the added polymer 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 polymer or 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 polymer 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 zuranolone or its pharmaceutically acceptable salts, preferably 90%, 95% or all of the zuranolone or its pharmaceutically acceptable salts of the solid dispersion, is homogeneously molecularly dispersed in a solid polymer/ 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 polymer. 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 zuranolone or its pharmaceutically acceptable salts and at least one pharmaceutically acceptable carrier/polymer, 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 carrier 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, binder, lubricants, 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” or “salt” are used interchangeably in the context of the present invention. “Pharmaceutically acceptable salts” or “salts” 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. The inorganic salts may further includes alkali metal and alkaline earth metal salts such as sodium, potassium, barium, lithium, calcium, magnesium, rhodium, zinc, cesium, selenium, and the like or, benethamine, benzathine, dicyclohexyl amine, diethanolamine, ethanolamine, 4-(2-hydroxy-ethyl)morpholine, 1-(2-hydroxyethyl)pyrrolidine, N-methyl glucamine, piperazine, triethanol amine or tromethamine and the like.

The term “suitable solvent” used in context of the present invention, is selected from, but not limited to, alcohol 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, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol; halogenated solvent such as dichloromethane, chloroform, carbon tetrachloride, chlorobenzene; ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole; ketones such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone; esters solvents such as ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate; hydrocarbon such as toluene, xylene, hexane, n-heptane, n-pentane, anisole, ethyl benzene, cyclohexane and the like; nitriles such as acetonitrile, propionitrile, butanenitrile; water; and mixtures thereof.

In another embodiment, the present invention provides a stable amorphous form of zuranolone or its pharmaceutically acceptable salts, wherein said amorphous form is stable after exposure to 40°C °C/75% RH for a period of six months or 25°C /60% RH, for a period of at least 12 months contains less than about 0.5% (wt/wt) total impurities.

In another embodiment, the present invention provides a process for the preparation of a amorphous form of zuranolone or its pharmaceutically acceptable salts, comprising the steps of:
a) providing a solution of zuranolone or its pharmaceutically acceptable salts in one or more suitable solvent; and
b) isolating the amorphous form of zuranolone or its pharmaceutically acceptable salts.

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

In another embodiment, amorphous form is optionally 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), lyophilization 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 zuranolone or its pharmaceutically acceptable salts, comprising the steps of:
a) milling/grinding zuranolone or its pharmaceutically acceptable salts under suitable milling conditions; and
b) isolating the amorphous form of zuranolone or its pharmaceutically acceptable salts salt thereof.

In a preferred embodiment, any solid forms, either crystalline or amorphous form of zuranolone 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 an amorphous form of zuranolone or its pharmaceutically acceptable salts thereof, comprising the steps of:
a) providing a solution of zuranolone or its pharmaceutically acceptable salts in a solvent;
b) lyophilizing the solution obtained in step a); and
c) isolating the amorphous form of zuranolone or its pharmaceutically acceptable salts.

In another embodiment, the amorphous form of zuranolone or its pharmaceutically acceptable salt thereof, obtained after lyophilization, 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 zuranolone or its pharmaceutically acceptable salts and atleast one pharmaceutically acceptable excipient.

In one more embodiment, the present invention provides a substantially pure amorphous form of zuranolone or its pharmaceutically acceptable salts, 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 zuranolone or its pharmaceutically acceptable salts, wherein said process comprising of:
a) dissolving zuranolone in a suitable solvent and treating with suitable acid or base to form zuranolone salt;
b) neutralizing or desalting the zuranolone salt to give zuranolone free base;
c) optionally converting the zuranolone free base to its pharmaceutically acceptable salt;
d) providing a solution of zuranolone 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 e) to get amorphous form of zuranolone or its pharmaceutically acceptable salt.

The present invention provides a solid dispersion of zuranolone or its pharmaceutically acceptable salt thereof suitable for powder handling and downstream processes. The solid dispersion of zuranolone or its pharmaceutically acceptable salts 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 zuranolone or its pharmaceutically acceptable salts, with atleast one pharmaceutically acceptable carrier or polymer.

In the present invention, the solid dispersion technology is used for dispersing sparingly water soluble zuranolone 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 process either comprises dissolving a sparingly water-soluble zuranolone 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 zuranolone 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 zuranolone 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 zuranolone 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 zuranolone 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 zuranolone to an amorphous state and, hence, dispersion of the zuranolone in this amorphous state into the carrier.

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

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

In another embodiment, the zuranolone 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 zuranolone or its pharmaceutically acceptable salts, 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 or polymer.

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 zuranolone 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 colour, insoluble materials, improve clarity of the solution, and/or remove impurities absorbable 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 zuranolone or its pharmaceutically acceptable salts, comprising the steps of:
a) heating zuranolone or its pharmaceutically acceptable salts in presence of atleast one pharmaceutically acceptable carrier or polymer to get a solution;
b) cooling the solution; and
c) isolating to get amorphous solid dispersion of zuranolone or its pharmaceutically acceptable salts.

In another embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of zuranolone or its pharmaceutically acceptable salts, wherein said zuranolone or its 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 zuranolone 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 zuranolone 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, zuranolone or its pharmaceutically acceptable salts as used for preparing amorphous solid dispersion, can be either crystalline, amorphous or mixture in nature.

In preferred embodiment, the solid dispersion is a substance obtained by dispersing zuranolone into a carrier in a mono-molecular state. In this dispersion, the zuranolone remains in a completely amorphous state. Generally, the amorphous form is in a higher energetic state compared to the crystalline form and is therefore expected to have a higher absorptivity.

In another embodiment, the present application provides a pharmaceutical composition comprising a solid dispersion of zuranolone or 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 and excipient.

In an embodiment, the present application provides a solid dispersion of zuranolone or its pharmaceutically acceptable salts, 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 zuranolone or its pharmaceutically acceptable salt with atleast one pharmaceutical acceptable polymer and/or carrier.

In one another embodiment, the present invention provides a process for the preparation of a premix of zuranolone or its pharmaceutically acceptable salts, comprising the steps of:
a) adding zuranolone or its pharmaceutically acceptable salts to atleast one pharmaceutically acceptable polymer to get a solid mass;
b) optionally adding solvent to get a solution; and
c) isolating the premix of zuranolone or its pharmaceutically acceptable salts 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 zuranolone or its pharmaceutically acceptable salts, together with atleast one pharmaceutically acceptable excipient.

In one more embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of zuranolone comprising the steps of:
a) providing a solution of amorphous form of zuranolone in a suitable solvent;
b) adding atleast one pharmaceutically acceptable carrier or polymer; and
c) removing the solvent and isolating to get amorphous solid dispersion of zuranolone.

In another embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of zuranolone pharmaceutically acceptable salt comprising the steps of:
a) providing a solution of amorphous form of zuranolone pharmaceutically acceptable salt in a suitable solvent;
b) adding atleast one pharmaceutically acceptable carrier or polymer; and
c) removing the solvent and isolating to get amorphous solid dispersion of zuranolone pharmaceutically acceptable salt.

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

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

In an embodiment, a solution of zuranolone or its pharmaceutically acceptable salts 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 zuranolone or its pharmaceutically acceptable salts 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 colour components, etc., before filtration.

In preferred embodiments, removal of solvent at any stage of preparation of amorphous form/ solid dispersion/ premix of zuranolone 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), lyophilization, 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 zuranolone or its pharmaceutically acceptable salts 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 zuranolone or pharmaceutically acceptable salt thereof and atleast one pharmaceutically acceptable carrier.

In another embodiment, amorphous form of zuranolone or its pharmaceutically acceptable salt may be combined with the carrier by evaporating the suspension or solution of amorphous form of zuranolone or a 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 polymer 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 glycolat, 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 zuranolone 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.

Amorphous form or ssolid dispersion or premix of zuranolone and its pharmaceutically acceptable salt, may be dried in suitable drying equipment such as vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.

In another embodiment, the present invention provides amorphous form of zuranolone or its pharmaceutically acceptable salts, as well as its solid dispersion comprising zuranolone or pharmaceutically acceptable salt thereof, wherein said zuranolone or its pharmaceutically acceptable salt 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 zuranolone or its pharmaceutically acceptable salt 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 zuranolone or its pharmaceutically acceptable salts, 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 zuranolone

Zuranolone (1.0 gm) was dissolved in methanol (20 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. The obtain product was re-dissolved in methanol (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 zuranolone with HPC (Hydroxypropyl cellulose)
A mixture of zuranolone (1.0 gm) 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-3: Preparation of amorphous form of zuranolone

Zuranolone (1.0gm) was dissolved in dichloromethane (50 mL) at 25°C and stirred at 60oC for 406h to get the reaction solution. Added n-heptane and filtered the precipitates to get zuranolone amorphous form.

Example-4: Preparation of amorphous form of zuranolone

Zuranolone (30 gm) was dissolved in water (350 ml), stirred for 15 minutes at room temperature. The solution was filtered on hyflo bed and the bed washed with water (25 ml). The resulting solution was subjected to freeze drying at -180 deg C for 13 hours to obtain zuranolone amorphous form.

Example-5: Preparation of amorphous form of zuranolone

Zuranolone (2.5gm) was dissolved in 24.5 ml of methanol, concentrated to 10 ml on a rotary evaporator and to this solution were added 50 ml of ether. The formed precipitate was filtered and dried on a rotary evaporator (50°C, 100 mbar, 24 h) to obtain amorphous form of zuranolone.

Example-6: Preparation of amorphous form of zuranolone

Zuranolone (9 gm), was dissolved in methyl isobutyl ketone (60 ml), stirred for 1 hr at RT, then the solvent was evaporated under reduced pressure to obtained the title compound.

Example-7: Preparation of amorphous form of zuranolone

Zuranolone (9 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 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 zuranolone.
Example-8: Preparation of solid dispersion of zuranolone with PVP K-90

A mixture of zuranolone (0.4 gm) and PVP K-90 (0.6 gm) 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-9: Preparation of solid dispersion of zuranolone with HPC (Hydroxypropyl cellulose)

A mixture of zuranolone (1.5gm) and HPC (1.4g) 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 10: Preparation of solid dispersion of zuranolone with more than one pharmaceutically acceptable carrier

A universal mixer was charged with zuranolone (25 gm), hydroxypropylmethylcellulose (135 gm), low-substituted hydroxypropylcellulose (85 gm) and crystalline cellulose (340gm) and the charge is mixed at 150° C. for 4 hours to provide a solid dispersion.

Example-11: Preparation of solid dispersion of zuranolone with PEG 8000

The samples was prepared by dissolving zuranolone in a small volume of 180 ml of methanol in a 250 ml round bottom flask. The flask was vortexed and then placed in a water bath maintained at 75° C. The 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 methanol. 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 zuranolone.

Example 12 Preparation of solid dispersion of zuranolone with HPMC

Zuranolone (1.0g) was dissolved in methanol and 1.0g of HPMC is dissolved in water. Solutions are then mixed by sonication to produce a clear solution, which is then spray dried using spray dryer.

CLAIMS:We claim:
1. An amorphous form of zuranolone or pharmaceutically acceptable salt thereof.

2. A process for preparing amorphous form of zuranolone or pharmaceutically acceptable salt thereof, comprising the steps of:
a) providing a solution of zuranolone or pharmaceutically acceptable salt thereof in a solvent;
b) lyophilizing the solution obtained in step a); and
c) isolating the amorphous form of zuranolone or pharmaceutically acceptable salt thereof.

3. A process for preparing amorphous form of zuranolone or pharmaceutically acceptable salt thereof, comprising the steps of:
a) providing a solution of zuranolone or pharmaceutically acceptable salt thereof, in one or more suitable solvent; and
b) isolating the amorphous form of zuranolone free base, isomer, or a salt thereof.

4. An amorphous solid dispersion of zuranolone or pharmaceutically acceptable salt thereof, with atleast one pharmaceutically acceptable carrier or polymer.

5. A process for the preparation of an amorphous solid dispersion of zuranolone or pharmaceutically acceptable salt thereof, comprising the steps of:
a) providing a solution of zuranolone 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 zuranolone or pharmaceutically acceptable salt thereof.

6. A stable amorphous form of zuranolone or its pharmaceutically acceptable salt, wherein the amorphous zuranolone or its pharmaceutically acceptable salt is stable when stored at a temperature of up to about 40oC and at a relative humidity of about 25% to about 75% for about six months and more.

7. The process as claimed in claim 5, wherein said process comprising the steps of:
a) providing a solution of zuranolone or pharmaceutically acceptable salt thereof in a suitable solvent;
b) adding hydroxypropyl methyl cellulose to the solution obtained in step a); and
c) isolating to get amorphous solid dispersion of zuranolone or pharmaceutically acceptable salt thereof.

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

9. A method for preparation of composition as claimed in claim 8, wherein said said composition is prepared by combining either amorphous form of zuranolone or amorphous solid dispersion of zuranolone with atleast one pharmaceutically acceptable excipients.

10. Amorphous form of zuranolone, wherein said zuranolone having a chemical purity of atleast 99%.