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

The present invention further provides an amorphous solid dispersion of Balovaptan 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 Balovaptan, or pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION
Balovaptan having a chemical name; 8-chloro-5-methyl-1-((1r,4R)-4-(pyridin-2-yloxy)cyclohexyl)-5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]-diazepine is represented with structure as follows:

.

Balovaptan is under study for the treatment of autism and is considered as an antagonist of vasopressin V1A receptor.

US 8,227,458 B2 disclose balovaptan and other related compounds, and process for the preparation thereof. US’458 further disclose the process for purifying balovaptan and other related compounds generically through flash chromatography.

WO 2015/082370 B2 discloses various crystalline forms of balovaptan free base and process of preparation thereof. WO’370 discloses crystalline forms A-H of balovapton and method of preparation thereof. It also discloses various solvates of balovaptan namely p-xylene hemi-solvate (crystalline form D), acetic acid hemi-solvate (crystalline form E), and butyronitrile solvate (crystalline form G). It also discloses the process for preparation of trihydrate of balovaptan (crystalline form H) and anhydrous form A of balovaptan.

As it is apparent from above disclosure(s), there are several crystalline polymorphs of balovaptan are known from the prior published references. Also, it is observed that balovaptan is sparingly water soluble. 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. As balovaptan is highly insoluble in water, hence, 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.

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 stable amorphous form and/ or solid dispersions and/ or premix of balovaptan, or its pharmaceutically acceptable salts that possess high solubility and can easily be formulated in a formulation having a desirable release profile.

Moreover, crystalline solids normally require a significant amount of energy for dissolution due to their highly organized lattice like structures. For example, the energy required for a drug molecule to escape from a crystal is more than from an amorphous or a non-crystalline form. It is known that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the crystalline form. Amorphous forms of some drugs exhibit much higher bioavailability than the crystalline forms, which leads to the selection of the amorphous form as the final drug substance for pharmaceutical dosage from development. Additionally, the aqueous solubility of crystalline form is lower than of amorphous form in some drugs, which may result in the difference in their in vivo bioavailability. Therefore, it is desirable to have amorphous forms of drugs with high purity to meet the needs of regulatory agencies and also highly reproducible process for their preparation.

In view of the above, it is also desirable to provide an efficient, economical and eco-friendly process for the preparation of highly pure balovaptan free base or pharmaceutically acceptable salt in amorphous form, solid dispersion and premix.

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

Another object of the present invention is to provide a process for the preparation of amorphous form of Balovaptan or pharmaceutically acceptable salt thereof, 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 Balovaptan or pharmaceutically acceptable salt thereof.

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

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

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

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

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

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

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

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

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

In another aspect, the present invention provides a solid dispersion of Balovaptan comprising Balovaptan along with atleast one pharmaceutically acceptable carrier.

In another aspect, the present invention provides a solid dispersion of Balovaptan pharmaceutically acceptable salt comprising Balovaptan pharmaceutically acceptable salt along with at least one pharmaceutically acceptable carrier.

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

DETAILED DESCRIPTION
Drawings:
Fig. 1 represents XRPD peaks of amorphous form of balovaptan free base prepared as per Example 3
Fig. 2 represents XRPD peaks of solid dispersion of balovaptan free base prepared as per Example 4

Definitions:
The terms “amorphous form of Balovaptan or pharmaceutically acceptable salt thereof" and “amorphous Balovaptan or pharmaceutically acceptable salt thereof” indicate that the Balovaptan 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 Balovaptan 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 Balovaptan 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 Balovaptan or pharmaceutically acceptable salt thereof, preferably 90%, 95% or all of the Balovaptan 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 Balovaptan 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 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” 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, hexanoic acid, hippuric acid, 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, methane sulfonic acid, naphthalene sulfonic acid, 1-hydroxy-naphthalene-2-carboxylic acid, palmitic acid, hydroxynaphthalene-2-carboxylic acid, ethanesulfonic acid, galactaric acid, gentisic acid, ethane-1,2-disulfonic acid, trans-cinnamic acid, saccharin, 2-hydroxyethane sulfonic acid, methanesulfonic acid, (+)-camphor-10-sulfonic acid, stearic acid, vanillic acid, vanillin, benzenesulfonic acid, naphthalene-2-sulfonic acid, 4-aminosalicylic 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, 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” as used for preparing amorphous form, and/or solid dispersion, and/or premix of Balovaptan or its pharmaceutically acceptable salts, are 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; dimethylformamide; dimethyl sulfoxide; carbonates; dimethyl acetamide; and mixtures thereof.

In an embodiment, the present invention provides amorphous form of balovaptan free base, or pharmaceutical acceptable salt thereof, wherein said amorphous form comprises of less than about 5% w/w of crystalline form.

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

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

In another embodiment, solution of Balovaptan 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, solution of Balovaptan or pharmaceutically acceptable salt thereof may be heated 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), 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 form of Balovaptan or its pharmaceutically acceptable salts, comprising the steps of:
a) milling/grinding Balovaptan or its pharmaceutically acceptable salts under suitable milling conditions; and
b) isolating the amorphous form of Balovaptan or pharmaceutically acceptable salt thereof.

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

In another embodiment, the amorphous form of Balovaptan or 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 Balovaptan 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 Balovaptan and pharmaceutically acceptable salts thereof, wherein said amorphous form is substantially free from crystalline form.

In another embodiment, the present invention provides a substantially pure amorphous form of Balovaptan wherein about 90%, preferably 95% or 99%, more preferably all of the Balovaptan or pharmaceutically acceptable salt thereof is in amorphous form.

In one another embodiment, the present invention provides a process for preparing amorphous form of Balovaptan or pharmaceutically acceptable salt thereof, wherein said process comprising the steps of:
a) dissolving Balovaptan in a suitable solvent and treating with suitable acid or base to form Balovaptan salt;
b) neutralizing or desalting the Balovaptan salt to give Balovaptan free base;
c) optionally converting the Balovaptan free base to its pharmaceutically acceptable salt;
d) providing a solution of Balovaptan 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 Balovaptan or its pharmaceutically acceptable salt.

The present invention provides a solid dispersion of Balovaptan or pharmaceutically acceptable salt thereof suitable for powder handling and downstream processes. A solid dispersion of Balovaptan 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 an amorphous solid dispersion of Balovaptan or pharmaceutically acceptable salt thereof, with atleast one pharmaceutically acceptable carrier.

In the present invention, the solid dispersion technology is used for dispersing Balovaptan 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 Balovaptan and a water-soluble carrier, in an organic solvent capable of dissolving both and removing the solvent by evaporation or comprises dissolving the Balovaptan 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 Balovaptan and the water-soluble carrier 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 Balovaptan in a comparatively low-melting water-soluble carrier under heating, cooling the resulting solution to solidify and pulverizing the solid to provide the desired solid dispersion.

The mixed-grinding technology, in which Balovaptan and the water-soluble carrier 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 Balovaptan to an amorphous state and, hence, dispersion of the Balovaptan in this amorphous state into the carrier.

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

In another embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of Balovaptan or pharmaceutically acceptable salt thereof, comprising the steps of:
a) providing a solution of Balovaptan 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 Balovaptan or a salt thereof.

In another embodiment, the Balovaptan 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 Balovaptan or 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 Balovaptan or pharmaceutically acceptable 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 an amorphous solid dispersion of Balovaptan or pharmaceutically acceptable salt thereof, comprising the steps of:
a) heating Balovaptan 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 Balovaptan or pharmaceutically acceptable salt thereof.

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

In preferred embodiment, the present invention provides a simple process which comprises mixing Balovaptan and a water-soluble carrier together under no more than the usual agitation force with heating within the temperature region not melting them, making Balovaptan as amorphous in nature 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, Balovaptan or pharmaceutically acceptable salt thereof 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 Balovaptan into a carrier in a mono-molecular state. In this dispersion, the Balovaptan 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 Balovaptan 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 excipient.

In an embodiment, the present application provides a solid dispersion of Balovaptan 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 Balovaptan 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 Balovaptan or its pharmaceutically acceptable salt, comprising the steps of:
a) adding Balovaptan 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 Balovaptan 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 Balovaptan or pharmaceutically acceptable salt thereof, 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 Balovaptan comprising the steps of:
a) providing a solution of amorphous form of Balovaptan in a suitable solvent;
b) adding atleast one pharmaceutically acceptable carrier; and
c) removing the solvent and isolating to get amorphous solid dispersion of Balovaptan.

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

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

In an embodiment, a solution of Balovaptan 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 Balovaptan 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 embodiment, amorphous form of Balovaptan 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 Balovaptan or pharmaceutically acceptable salt thereof and atleast one pharmaceutically acceptable carrier.

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

Amorphous form or solid dispersion or premix of Balovaptan or 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 Balovaptan or pharmaceutically acceptable salt thereof, its solid dispersion comprising Balovaptan or pharmaceutically acceptable salt thereof, wherein said Balovaptan 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 Balovaptan or pharmaceutically acceptable salt thereof, 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 Balovaptan or pharmaceutically acceptable salt thereof, is characterized by particle size distribution wherein, d90 is between 0.1µm to 200 µm, specifically d90 is between 2.0 µm to 150µm.

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 stable amorphous form of Balovaptan Free base

Balovaptan free base (0.4 g) 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 stable amorphous form of Balovaptan Free base using dimethyl sulfoxide as solvent

Balovaptan free base (0.2 g) was dissolved in dimethyl sulfoxide (15 mL) at 25°C with stirring. Added 10 ml of water dropwise to initiate precipitation. Filtered the precipitates and dried to obtain title compound.

Example-3: Preparation of stable amorphous form of Balovaptan Free base in water

Balovaptan free base (0.4 g) was suspended in water (20 mL) at 40°C. Cooled the reaction to 25oC and lyophilized to obtain the title compound.

Example-4: Preparation of stable solid dispersion of Balovaptan free base with HPMC

A mixture of Balovaptan free base (0.5 g) and HPMC (0.5 g) was dissolved in ethanol (25 mL) and water (25ml) 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: Preparation of solid dispersion of Balovaptan free base with HPC

A mixture of balovaptan free base (1.0 g) in ethylacetate was added to HPC (1.0 g) 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-6: Ball mill mixed-grinding process

Using a ball mill (SPEX Industries), a mixture of balovaptan (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-7: Preparation of stable solid dispersion of R-balovaptan with PVP K-90

A mixture of R-balovaptan (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-8: Preparation of balovaptan free base premix with Polyvinylpyrrolidone (PVP)

Charge methanol (75 ml), balovaptan free base (10g) and Polyvinylpyrrolidone (3.7 g) at 25-30°C to the flask under stirring, stirred for 1 h, then distilled out methanol under vacuum up to 55 °C. Cool the reaction mixture to 25-30°C, added acetone (200 ml) to reaction mass in l h at 25-35°C, stirred the reaction mixture for 1-3 h at 25-30°C and distilled out the solvent dry to get title compound.

Example-9: Preparation of 1:1 admixture of balovaptan free base with Polyvinylpyrrolidone (PVP)

Charge methanol (75 ml), balovaptan free base (10g) and Polyvinylpyrrolidone (10.0 g) at 25-30°C to the flask under stirring, stirred for 1 h, then distilled out methanol under vacuum up to 55°C. Cool the reaction mixture to 25-30°C, added methanol (100 ml) to reaction mass at 25-35°C, stirred the reaction mixture for 1-3 h at 25-30°C and distilled out the solvent dry to get title compound.

We claim:

1.An amorphous form of Balovaptan or pharmaceutically acceptable salt thereof.

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

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

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

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

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

7. A stable amorphous form of Balovaptan or pharmaceutically acceptable salt thereof, wherein said amorphous form is stable 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.

8. Composition comprising Balovaptan or pharmaceutically acceptable salt thereof as claimed in claims 1 or 4, along with atleast one pharmaceutically acceptable excipient.

9. A method for preparation of composition comprising Balovaptan or pharmaceutically acceptable salt thereof, wherein said composition is prepared by combining either amorphous form of Balovaptan or amorphous solid dispersion of Balovaptan, with atleast one pharmaceutically acceptable excipient.

10. Amorphous form of Balovaptan, wherein said Balovaptan comprises less than about 5% w/w of crystalline form.