The present invention provide solid forms of lanifibranor or pharmaceutically acceptable salt thereof, wherein said solid form is selected from amorphous form, crystalline hydrates, solvates; and process of preparation thereof.

The present invention further provides an amorphous solid dispersion of lanifibranor or its pharmaceutically acceptable salts, and process for the preparation thereof.

Moreover, there is provided a pharmaceutical composition comprising above said solid forms of lanifibranor or pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION
Lanifibranor having a chemical name; 4-[1-(1,3-benzothiazol-6-ylsulfonyl)-5-chloroindol-2-yl]butanoic acid is represented with structure as follows:

Formula I

Lanifibranor (IVA-337) is an orally-available small molecule that acts to induce antifibrotic, anti-inflammatory and beneficial metabolic changes in the body by activating all three peroxisome proliferator activated receptor (“PPAR”) isoforms, which are well characterized nuclear receptor proteins that regulate gene expression. Lanifibranor is a PPAR agonist that is designed to target all three PPAR isoforms in a moderately potent manner, with a well-balanced activation of PPARa and PPARd, and a partial activation of PPAR?. Lanifibranor is currently under investigation in a Phase II clinical trial for the treatment of non-alcoholic steatohepatitis (“NASH”), a common and progressive chronic liver disease.

US 7,795,297 discloses lanifibranor and process for the preparation thereof. However, it nowhere discloses the method of crystallization or any particular solid form of lanifibranor.

As it is apparent from above, there is no polymorphic form of lanifibranor known from the prior published references. It is known that bioavailability is the key determinant of a drug for its therapeutic effectiveness, which in turn depends upon the solubility of that drug in gastro intestinal fluid. The solubility of the drug in the vehicle determines its release rate and affects the absorption and therapeutic effectiveness.

The discovery of further solid forms of an active pharmaceutical ingredient (API) can offer an opportunity to improve the performance profile of a pharmaceutical composition comprising the said API.

Preparing a solid dispersion increases the solubility of drug in the vehicle and also said solid dispersions can easily be formulated. The present invention is focussed on the preparation of solid forms and/ or solid dispersions and/ or premix of lanifibranor its salts that possess high solubility and can easily be formulated in a formulation having a desirable release profile.

OBJECTIVE OF THE INVENTION
One object of the present invention is to provide an amorphous form of lanifibranor or its pharmaceutically acceptable salt and process of preparation thereof.

Another object of the present invention is to provide a process of preparing crystalline hydrates and solvates of lanifibranor or pharmaceutically acceptable salt thereof.

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

SUMMARY OF THE INVENTION
The main aspect of the present invention provides amorphous form of lanifibranor or pharmaceutically acceptable salt thereof.

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

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

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

In another aspect, the present invention provides crystalline form of lanifibranor wherein said crystalline form is either hydrate, solvate or anhydrous in nature.

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

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

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

In another aspect, the present invention provides a solid dispersion of lanifibranor pharmaceutically acceptable salt comprising lanifibranor 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 lanifibranor or pharmaceutically acceptable salt thereof, comprising the steps of:
a) adding lanifibranor or pharmaceutically acceptable salt thereof 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 lanifibranor or pharmaceutically acceptable salt thereof 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 lanifibranor or pharmaceutically acceptable salt thereof, wherein said process comprises grinding of lanifibranor or pharmaceutically acceptable salt thereof with atleast one pharmaceutically acceptable carrier.

DETAILED DESCRIPTION

Details of drawings:
Fig. 1 represents XRPD peaks of amorphous form of lanifibranor prepared as per Example 1.
Fig. 2 represents XRPD peaks of amorphous form of solid dispersion of lanifibranor prepared as per Example 5.

Definitions:
The terms “amorphous form of lanifibranor or pharmaceutically acceptable salt thereof" indicate that the lanifibranor 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 lanifibranor 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 lanifibranor free base or a 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. 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 "stable solid dispersion" as used in the context of the present invention, denotes a state where most of the lanifibranor or pharmaceutically acceptable salt thereof, preferably 90%, 95% or all of the lanifibranor 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 lanifibranor 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 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, 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, diethanolamine, ethanolamine, 4-(2-hydroxyethyl)morpholine, 1-(2-hydroxyethyl)pyrrolidine, N-methyl glucamine, piperazine, triethanol amine or tromethamine and the like.

The term “suitable solvent” as used in the context of the present invention comprises of polar and non-polar solvent selected from, but not limited to, the group comprising of alcohols such as methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, polyethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride; 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; ketone solvents 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; sulfoxides such as dimethyl sulfoxide; formamides such as N-methyl formamamide; carbonates; water; and mixtures thereof.

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

In another embodiment, the present invention provides a stable amorphous form of lanifibranor or pharmaceutically acceptable salt thereof, wherein said lanifibranor or pharmaceutically acceptable salt 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) of total impurities.

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

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

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

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

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

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

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

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

In another embodiment, the present application provides pharmaceutical composition comprising amorphous form of lanifibranor 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 lanifibranor and pharmaceutically acceptable salt thereof, wherein said amorphous form is substantially free from crystalline form.

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

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

In another embodiment, the present invention provides crystalline form of lanifibranor wherein said crystalline form is hydrate in nature.

In another embodiment, the present invention provides crystalline form of lanifibranor wherein said crystalline form is selected from monohydrate, dihydrate, hemihydrate and sesquihydrate of lanifibranor.

In another embodiment, the present invention provides crystalline form of lanifibranor wherein said crystalline form is anhydrous in nature.

In another embodiment, the present invention provides crystalline form of lanifibranor wherein said crystalline form is isolated in form of a solvate of lanifibranor, comprising the steps of;
a) dissolving lanifibranor in a suitable solvent to get a solution;
b) optionally, adding the solution of step a) to water;
c) optionally, cooling to a suitable temperature to get crystals; and
d) isolating the crystals to get crystalline solvate of lanifibranor.

In another embodiment, the solvent used for preparing crystalline solvate of lanifibranor is selected from, but not limited to, the group comprising of 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, polyethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride; 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; ketone solvents 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; and mixtures thereof.

In another embodiment, the present invention provides a process for the preparation of crystalline hydrate of lanifibranor, comprising the steps of;
a) dissolving lanifibranor in a suitable solvent;
b) optionally heating up to the temperature below reflux point of the solvent;
c) cooling to the temperature in the range of 0-25oC;
d) adding water to step c); and
e) isolating the crystalline hydrate of lanifibranor.

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

In the present invention, the solid dispersion technology is used for dispersing lanifibranor 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 lanifibranor and a water-soluble carrier, in an organic solvent capable of dissolving both and removing the solvent by evaporation or comprises dissolving the lanifibranor 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 lanifibranor 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 lanifibranor 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 the water insoluble lanifibranor 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 lanifibranor to an amorphous state and, hence, dispersion of the lanifibranor 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 lanifibranor or pharmaceutically acceptable salt thereof, comprising the steps of:
a) providing a solution of lanifibranor or 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 lanifibranor or a salt thereof.

In another embodiment, the lanifibranor 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 lanifibranor or its pharmaceutically acceptable salt, and the carrier present in weight ratios ranging from about 1:99 to about 99:1. Preferably, the ratio is about 50:50. In some embodiments, the solid dispersion described herein comprises one or more pharmaceutically acceptable carrier.

The dissolution temperatures may range from about 0°C to about the reflux temperature of the solvent, or less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, or any other suitable temperatures, as long as a clear solution of lanifibranor or its pharmaceutically acceptable salt is obtained without affecting its quality. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow.

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

In another embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of lanifibranor or pharmaceutically acceptable salt thereof, wherein said lanifibranor or 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 lanifibranor and a water-soluble carrier together under no more than the usual agitation force with heating within the temperature region not melting them, making the lanifibranor 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, lanifibranor 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 lanifibranor into a carrier in a mono-molecular state. In this dispersion, the lanifibranor remains in a completely amorphous state.

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

In an embodiment, the present application provides a solid dispersion of lanifibranor 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 lanifibranor or 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 lanifibranor or its pharmaceutically acceptable salt, comprising the steps of:
a) adding lanifibranor 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 lanifibranor 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 lanifibranor or pharmaceutically acceptable salt thereof, together with atleast one pharmaceutically acceptable excipient.

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

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

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

In preferred embodiment, the amorphous form of lanifibranor 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 lanifibranor or a salt thereof and atleast one pharmaceutically acceptable carrier.

In another embodiment, the amorphous form of lanifibranor or pharmaceutically acceptable salt thereof may be combined with the carrier by evaporating the suspension or solution of amorphous form of lanifibranor 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 carriers 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 lanifibranor or a 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 lanifibranor 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 stable amorphous form of lanifibranor or pharmaceutically acceptable salt thereof, and stable solid dispersion comprising lanifibranor or pharmaceutically acceptable salt thereof, wherein said lanifibranor 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 lanifibranor 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 lanifibranor 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 amorphous form of lanifibranor:
1.0g lanifibranor was dissolved in acetone (45mL) at 25°C, then the resultant suspension was stirred at 50-60oC for 4-6 h. Lyophilized the solution to obtained lanifibranor amorphous form.

Example-2: Preparation of amorphous form of lanifibranor:
8.7g lanifibranor of was dissolved in 120 mL methylene dichloride and heated to obtain clear solution at 35-40oC. The reaction mixture was distilled atmospherically at 40-45°C. 100 mL isopropanol was added to the residue and stirred for 15 minutes. The reaction mixture was distilled partially and filtered. The wet-cake was dissolved in 125 mL of methylene dichloride. Then the solvent was evaporated under reduced pressure and the residue so obtained was triturated with 70 mL methyl tert-butyl ether. The precipitated product was filtered and washed with methyl tert-butyl ether. The product was dried under vacuum at 60°C for 6 hours to obtain amorphous lanifibranor.

Example-3: Preparation of amorphous form of lanifibranor:
3.0g of crystalline lanifibranor was dissolved in 30 ml acetone at RT and then the clear solution obtained was subjected to spray drying in a mini spray dryer with an inlet temperature of 74–77°C and an outlet temperature of 52–58°C. The fine powder of lanifibranor in an amorphous form was collected. It was further dried under vacuum at 30–35°C to yield lanifibranor amorphous form.

Example-4: Preparation of amorphous form of lanifibranor:
Lanifibranor (1.2 g) was dissolved in acetonitrile (50 mL) at 25°C and stirred at 60oC to get the reaction mixture for 4-6h. Lyophilized the solution so obtained to get amorphous compound.

Example-5: Preparation of solid dispersion of lanifibranor with PEG 8000:
The sample was prepared by dissolving lanifibranor in a small volume of 180 ml of ethanol in a 180 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 ethanol. After the majority of ethanol had evaporated, the flask was immersed in an ice bath for 15 minutes. The contents of the flask were then vacuum dried at room temperature for 6 hours. The solid was transferred to a crystallization dish and was placed under vacuum overnight to remove residual ethanol and to obtain solid dispersion of lanifibranor.

CLAIMS:We Claim

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

2. A process for the preparation of amorphous form of lanifibranor or pharmaceutically acceptable salt thereof, comprising the steps of:
a) providing lanifibranor or pharmaceutically acceptable salt thereof in one or more suitable solvent; and
b) isolating the amorphous form of lanifibranor or pharmaceutically acceptable salt thereof.

3. Crystalline form of lanifibranor wherein said crystalline form is either hydrate, solvate or anhydrous in nature.

4. Crystalline solvate of lanifibranor wherein said crystalline solvate is prepared by a process comprising the steps of:
a) dissolving lanifibranor in a suitable solvent to get a solution;
b) optionally, adding the solution of step a) to water;
c) optionally, cooling to a suitable temperature to get crystals; and
d) isolating the crystals to get crystalline solvate of lanifibranor.

5. Amorphous form of lanifibranor wherein said amorphous form is stable for atleast six months at 25oC to 40oC and 60% to 75% RH, and/or possess purity of 99.0% and more.

6. Amorphous solid dispersion of lanifibranor or pharmaceutically acceptable salt thereof, with atleast one pharmaceutically acceptable carrier.

7. A process for the preparation of amorphous solid dispersion of lanifibranor or pharmaceutically acceptable salt thereof as claimed in claim 6, wherein said process comprising the steps of:
a) providing a solution of lanifibranor 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 lanifibranor or pharmaceutically acceptable salt thereof.

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

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

10. A method for preparation of composition comprising lanifibranor or pharmaceutically acceptable salt thereof, wherein said composition is prepared by combining either crystalline hydrate, or crystalline solvate, or amorphous form of lanifibranor.