The present invention provides a substantially pure and a stable amorphous form of filgotinib, pharmaceutically acceptable salts, process for the preparation and composition thereof.

The present invention further provides an amorphous solid dispersion of filgotinib or pharmaceutically acceptable salts, and process for the preparation thereof, wherein said filgotinib or its pharmaceutically acceptable salt is either anhydrous, hydrate or solvate in nature. Moreover, there is provided a pharmaceutical composition comprising above said amorphous solid dispersion of filgotinib, or pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION
Filgotinib having a chemical name; N-[5-[4-[(1,1-Dioxo-1,4-thiazinan-4-yl)methyl]phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide is a Janus kinase inhibitor and is under analysis for the treatment of rheumatoid arthritis. Filgotinib is represented by the chemical structure according to Formula (I) below:
.

US 8,242,274 generically discloses filgotinib and its pharmaceutically acceptable salts; and US 8,088,764 specifically discloses filgotinib and process for the preparation thereof.

US 9,382,247 (US’247) discloses crystalline form of filgotinib hydrochloride trihydrate and filgotinib hydrochloride solvates. US’247 further provides certain filgotinib pharmaceutically acceptable salts, and process of preparation thereof.

WO 2017/012770 provides crystalline forms of filgotinib hydrochloride and process for the preparation thereof.

WO 2017/012771 provides crystalline forms of filgotinib sulfonic acid and process for the preparation thereof.

WO 2017/012773 provides crystalline forms of filgotinib free base and process for the preparation thereof.

As it is apparent from disclosure(s), there are few polymorphs of filgotinib known from the prior published references. It is also known that filgotinib has poor solubility and is required to be crystallized in a particular solvent to improve its purity and solubility in water and other solvents. It is known that the 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 stable amorphous form and/ or solid dispersions and/ or premix of filgotinib, pharmaceutically acceptable salts, hydrates and solvates thereof that possess high solubility and can easily be formulated in a formulation having a desirable release profile.

OBJECTIVE OF THE INVENTION
The main object of the present invention is to provide an amorphous solid dispersion of filgotinib, or pharmaceutically acceptable salt thereof, wherein said filgotinib or its pharmaceutically acceptable salt is either anhydrous, hydrates, or solvates in nature.

Another object of the present invention is to provide a stable amorphous form of filgotinib, or pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a process for the preparation of amorphous solid dispersion of filgotinib or pharmaceutically acceptable salt, with atleast one pharmaceutically acceptable carrier, wherein said filgotinib or its pharmaceutically acceptable salt is either anhydrous, hydrate or solvate in nature.

Another object of the present invention is to provide a process for the preparation of stable amorphous form of filgotinib 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 a pharmaceutical composition comprising solid forms of filgotinib, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein the physicochemical stability and the dissolution characteristics of the solid form is improved, and wherein said filgotinib is rendered more suitable for use in a pharmaceutical composition.

SUMMARY OF THE INVENTION
In an aspect, the present invention provides a stable amorphous form of filgotinib, or pharmaceutically acceptable salt thereof, wherein said amorphous form is stable for atleast six months at 40oC and 75% RH.

In another aspect, the present invention provides a process for the preparation of amorphous form of filgotinib, pharmaceutically acceptable salt thereof, comprising the steps of:
a) adding filgotinib or a pharmaceutically acceptable salt thereof to a suitable solvent;
b) optionally heating at a suitable temperature; and
c) lyophilizing and isolating to get the amorphous form of filgotinib, or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a process for the preparation of amorphous form of filgotinib, or pharmaceutically acceptable salts thereof, comprising the steps of:
a) adding filgotinib or pharmaceutically acceptable salt thereof, in one or more suitable solvent;
b) optionally heating at a suitable temperature; and
c) removing the solvent and isolating to get the amorphous form of filgotinib or pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides process for the preparation of an amorphous form of filgotinib or pharmaceutically acceptable salt thereof, wherein said process comprising the steps of:
a) treating 4-(4-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)benzyl)thiomorpholine 1,1-dioxide of Formula II or a pharmaceutically acceptable salt with a suitable solvent at a suitable temperature;
;
b) optionally adding anti-solvent to get precipitates;
c) isolating amorphous form of compound of Formula II or pharmaceutically acceptable salt;
d) converting amorphous form of compound of Formula II or pharmaceutically acceptable salt to filgotinib or its pharmaceutically acceptable salt; and
e) converting the filgotinib or its pharmaceutically acceptable salt to amorphous form by treating with a suitable solvent.

In another aspect, the present invention provides an amorphous solid dispersion of filgotinib or pharmaceutically acceptable salt thereof, with atleast one pharmaceutically acceptable carrier, wherein said filgotinib or its pharmaceutically acceptable salt is either anhydrous, hydrate or solvate in nature.

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

In another aspect, the present invention provides a process for the preparation of a premix of filgotinib or pharmaceutically acceptable salt thereof, comprising the steps of:
a) adding filgotinib 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 filgotinib 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 filgotinib or pharmaceutically acceptable salt thereof, wherein said process comprises grinding of filgotinib or its pharmaceutically salt with atleast one pharmaceutically acceptable carrier, wherein said filgotinib and its pharmaceutically acceptable salt is either anhydrous, hydrate or solvate in nature.

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

Definitions:
The terms “amorphous form of filgotinib or pharmaceutically acceptable salt thereof" indicate that the filgotinib or its pharmaceutically acceptable salt, 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 filgotinib or pharmaceutically acceptable salt thereof is amorphous. In other words, “substantially free from crystalline form” preferably means that the amorphous form does not contain detectable amounts of crystalline portions of filgotinib 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 "stable solid dispersion" as used in the context of the present invention, denotes a state where most of the filgotinib or pharmaceutically acceptable salt thereof, preferably 90%, 95% or all of the filgotinib 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 "excipient" or "pharmaceutically acceptable excipient" means a component of a pharmaceutical product that is not an active ingredient, and includes but not limited to filler, diluent, disintegrants, glidants, stabilizers, surface active agents etc. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and neither biologically nor otherwise undesirable, and are acceptable for veterinary use as well as human pharmaceutical use. One excipient can perform more than one function.

The terms “pharmaceutically acceptable salt” as used in the context of the present invention refers to inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid salt, carbonate salts; organic acids such as succinic acid, formic acids, acetic acid, diphenyl acetic acid, palmoic acid, triphenylacetic acid, caprylic acid, dichloroacetic acid, trifluoro acetic acid, propionic acid, butyric acid, lactic acid, citric acid, gluconic acid, mandelic acid, tartaric acid, malic acid, adipic acid, aspartic acid, fumaric acid, glutamic acid, maleic acid, malonic acid, benzoic acid, p-chlorobenzoic acid, dibenzoyl tartaric acid, oxalic acid, nicotinic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxy-naphthalene-2-carboxylic acid, hydroxynaphthalene-2-carboxylic acid, ethanesulfonic acid, ethane-1,2-disulfonic acid, 2-hydroxyethane sulfonic acid, methanesulfonic acid, (+)-camphor-10-sulfonic acid, benzenesulfonic acid, naphthalene-2-sulfonic acid, methyl benzene sulfonate, 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, pharmaceutically acceptable salts may further includes benethamine, benzathine, diethanolamine, ethanolamine, 4-(2-hydroxy-ethyl)morpholine, 1-(2-hydroxyethyl)pyrrolidine, N-methyl glucamine, piperazine, triethanol amine or tromethamine and the like.

'Solvate' refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, alcohols, hydrocarbons, halogenated solvents, sulfoxides, amides, formamides, ethers, ketones, esters, acids and mixture thereof. The salts of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. 'Solvate' encompasses both solution-phase and isolable solvates. Representative solvate includes ethanolates, methanolates, ethyl acetates etc.

The “suitable solvent” or “solvent” as used in the context of the present invention represents protic and aprotic solvents and are 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; water; sulfoxides, formamides, carbonates and mixtures thereof.

According to one embodiment, the present invention provides a stable amorphous form of filgotinib or pharmaceutically acceptable salt thereof, wherein said amorphous form is stable for atleast six months at 40oC and 75% RH.

In another embodiment, the present invention provides a process for the preparation of an amorphous form of filgotinib or pharmaceutically acceptable salt thereof, comprising the steps of:
a) adding filgotinib or a pharmaceutically acceptable salt thereof to a suitable solvent;
b) optionally heating at a suitable temperature; and
c) lyophilizing and isolating to get the amorphous form of filgotinib or a pharmaceutically acceptable salt thereof.

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

In another embodiment, the present invention provides a process for the preparation of an amorphous form of filgotinib or pharmaceutically acceptable salts thereof, comprising the steps of:
a) adding filgotinib or pharmaceutically acceptable salt thereof, in one or more suitable solvent;
b) optionally heating at a suitable temperature; and
c) removing the solvent and isolating to get the amorphous form of filgotinib, or pharmaceutically acceptable salt thereof.

In one another embodiment, the present invention provides a process for preparing amorphous form of filgotinib or pharmaceutically acceptable salt thereof, wherein said process comprising of:
a) dissolving filgotinib in a suitable solvent and treating with suitable acid or base to form filgotinib salt at a suitable temperature;
b) neutralizing or desalting the filgotinib salt to give filgotinib free base;
c) optionally converting the filgotinib free base to its pharmaceutically acceptable salt;
d) providing a solution of filgotinib free base of step b) or its salt of step c) in a suitable solvent (s) at a suitable temperature; and
e) removing the solvent from the solution obtained in step d) to get amorphous form of filgotinib or its pharmaceutically acceptable salt.

In another embodiment, a solution/ suspension of filgotinib or pharmaceutically acceptable salt thereof is obtained after adding said filgotinib or its pharmaceutically acceptable salt to suitable solvent (s), which may be combined with the anti-solvent at suitable temperature and for sufficient time to obtain amorphous product.

In another embodiment, the amorphous form of filgotinib or pharmaceutically acceptable salt thereof, is prepared by heating the solution/ suspension of filgotinib or its pharmaceutically acceptable salt at suitable temperature ranging between 0oC to 250oC, preferably, at 20-150oC, most preferably at 30-100oC.

In another embodiment, amorphous form is isolated by the methods known in the art or any procedure disclosed in the present invention wherein said method is selected from, but not limited to, the solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Büchi® Rotavapor®, filtration, spray drying, freeze drying, thin film drying, agitated thin film drying, rotary vacuum paddle dryer (RVPD), lyophilization and the like. In another 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. 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 filgotinib or pharmaceutically acceptable salt thereof, along with atleast one pharmaceutically acceptable excipient.

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

In another embodiment, the present invention provides process for the preparation of an amorphous form of filgotinib or pharmaceutically acceptable salt thereof, wherein said process comprising the steps of:
a) treating 4-(4-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)benzyl)thiomorpholine 1,1-dioxide of Formula II or pharmaceutically acceptable salt with a suitable solvent at a suitable temperature;
;
b) optionally adding anti-solvent to get precipitates;
c) isolating amorphous form of compound of Formula II or pharmaceutically acceptable salt;
d) converting amorphous form of compound of Formula II or pharmaceutically acceptable salt to filgotinib and its pharmaceutically acceptable salt; and
e) converting the filgotinib and its pharmaceutically acceptable salt to amorphous form by treating with a suitable solvent.

In another embodiment, the present invention provides amorphous form of compound of Formula II or pharmaceutically acceptable salt, wherein said process comprising the steps of:
a) adding compound of Formula II in a suitable solvent at a suitable temperature;
b) treating with suitable acid to form a salt of compound of Formula II;
c) isolating the salt of compound of Formula II from step (b);
d) treating the salt of compound of Formula II obtained in step (c) with base to get free base of compound of Formula II; and
d) isolating the free base of compound of Formula II obtained in step d) to get amorphous form of compound of Formula II and optionally converting it to its pharmaceutically acceptable salt.

In another aspect, the present invention provides process for the preparation of an amorphous form of 4-(4-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)benzyl)thiomorpholine 1,1-dioxide of Formula II or pharmaceutically acceptable salt thereof, wherein said process comprising the steps of:
a) treating 4-(4-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)benzyl)thiomorpholine 1,1-dioxide of Formula II or pharmaceutically acceptable salt with a suitable solvent at a suitable temperature;
;
b) optionally adding anti-solvent to get precipitates; and
c) isolating amorphous form of compound of Formula II or pharmaceutically acceptable salt.

In another embodiment, the amorphous form of 4-(4-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)benzyl)thiomorpholine 1,1-dioxide of Formula II or pharmaceutically acceptable salt thereof, is prepared by heating the solution/ suspension of said compound of Formula II or its salt at suitable temperature ranging between 0oC to 250oC, preferably, at 20-150oC, most preferably at 30-100oC.

The present invention further provides a solid dispersion of filgotinib or pharmaceutically acceptable salt thereof suitable for powder handling and downstream processes. A solid dispersion of filgotinib 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 the present invention, the solid dispersion technology is used for dispersing sparingly water soluble filgotinib monomolecularly in a solid state into an inert carrier. The technology specifically includes a solvent process, a fusion process, and a mixed-grinding process.

The solvent process either comprises dissolving a sparingly water-soluble filgotinib 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 filgotinib 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 filgotinib 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 filgotinib 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 sparingly water-soluble filgotinib 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 filgotinib to an amorphous state and, hence, dispersion of the filgotinib in this amorphous state into the carrier.

In another embodiment, the present invention provides an amorphous solid dispersion of filgotinib or pharmaceutically acceptable salt thereof, with atleast one pharmaceutically acceptable carrier, wherein said filgotinib or its pharmaceutically acceptable salt is either anhydrous, hydrate or solvate in nature.

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

In another embodiment, the filgotinib or pharmaceutically acceptable salt thereof, used for preparing solid dispersion is present as a solvate preferably, mono-, di-, or trisolvate. In a particular embodiment, the filgotinib pharmaceutically acceptable salt is a trisolvate. Alternatively, the salt of the invention is not a solvate.

In another embodiment, the filgotinib or pharmaceutically acceptable salt thereof, used for preparing solid dispersion is present as a hydrate, preferably as a pseudo, mono-, di-, or trihydrate. In a particular embodiment, the filgotinib pharmaceutically acceptable salt is a trihydrate. Alternatively, the salt of the invention is anhydrous that includes, but are not limited to, filgotinib hydrochloride, filgotinib maleate salt, filgotinib sulfonate, filgotinib oxalate, filgotinib tartarate and filgotinib palmoate salt. In the most preferred embodiment, the trihydrate includes, but are not limited to, filgotinib monohydrochloride trihydrate, filgotinib maleate trihydrate.

In another embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of filgotinib or its pharmaceutically acceptable salt comprising the steps of:
a) providing a solution of amorphous form of filgotinib or its pharmaceutically acceptable salt in a suitable solvent;
b) adding atleast one pharmaceutically acceptable carrier;
c) optionally adding therapeutically effective amount of compound of Formula II; and
d) removing the solvent and isolating to get amorphous solid dispersion of filgotinib salt, wherein said solid dispersion optionally comprises of therapeutically effective amount of compound of Formula II.

In another embodiment, the present invention provides a process for the preparation of a premix of filgotinib or pharmaceutically acceptable salt thereof, comprising the steps of:
a) adding filgotinib 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 filgotinib 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 embodiment, the present invention provides a process for the preparation of a premix of filgotinib or pharmaceutically acceptable salt thereof, wherein said process comprises grinding of filgotinib or its pharmaceutically salt with atleast one pharmaceutically acceptable carrier, wherein said filgotinib and its salt is either anhydrous, hydrate or solvate in nature.

In another embodiment, the filgotinib 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 filgotinib or its pharmaceutically acceptable salt, wherein filgotinib is either anhydrous, hydrate or solvate in nature; 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 100°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 filgotinib 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 filgotinib or pharmaceutically acceptable salt thereof, comprising the steps of:
a) heating filgotinib 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 filgotinib or a pharmaceutically acceptable salt thereof.

In another embodiment, filgotinib or pharmaceutically acceptable salt thereof as used for preparing amorphous solid dispersion, can be either crystalline, amorphous or mixture in nature, and wherein said filgotinib is either anhydrous, hydrate or solvate in nature.

In preferred embodiment, the solid dispersion is a substance obtained by dispersing filgotinib into a carrier in a mono-molecular state. In this dispersion, the filgotinib 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 filgotinib 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 or premix, and any possible carrier and excipient.

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

In an embodiment, a solution of filgotinib 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 colored components, etc., before filtration.

In preferred embodiment, stable amorphous form of filgotinib or pharmaceutically acceptable salt thereof may be combined with excipient 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 filgotinib or pharmaceutically acceptable salt thereof and atleast one pharmaceutically acceptable excipient.

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 excipient 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, L-HPC, 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 filgotinib 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 another embodiment, the present invention provides stable amorphous form of filgotinib or pharmaceutically acceptable salt thereof, its solid dispersion comprising filgotinib or pharmaceutically acceptable salt thereof, wherein said filgotinib 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 filgotinib or pharmaceutically salt thereof, obtained by the process of the present invention is characterized by particle size distribution (D90) of less than about 300µm, preferably less than about 200µm and most preferably about 100µm.

In another embodiment, the amorphous form of filgotinib or pharmaceutically acceptable salt thereof, obtained by the process of the present invention is characterized by particle size distribution (D90) of less than about 50µm, preferably less than about 20µm and most preferably about 10µm.

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 Filgotinib
Filgotinib (0.4 g) was dissolved in ethanol (20 mL) at 40°C and filtered the solution to make it particle free. The solvent was evaporated in rotavapour under reduced pressure at 50°C. The obtained product was re-dissolved in ethanol (20 mL) at 40°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 Filgotinib
Charged Filgotinib (0.4 g) in water (20 mL) and heated at 50oC. Cooled the solution to room temperature and lyophilized to get the title compound.

Example-3: Preparation of Stable amorphous form of Filgotinib hydrochloride
Charged Filgotinib hydrochloride (0.4 g) in acetone (20 mL) at room temperature. Stirred for 1 h and evaporated the solvents under reduced pressure to get the title compound.

Example-4: Preparation of amorphous solid dispersion of Filgotinib with cross-povidone
A mixture of Filgotinib (0.5 g) and crosspovidone (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-5: Preparation of amorphous solid dispersion of Filgotinib with L-HPC
A mixture of filgotinib (1.0 g) and L-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-6: Preparation of amorphous solid dispersion of Filgotinib with co-povidone
A mixture of filgotinib (1.0 g) and co-povidone (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-7: Ball mill mixed-grinding process
Using a ball mill (SPEX Industries), a mixture of filgotinib (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 8: Preparation of solid dispersion of Filgotinib with more than one pharmaceutically acceptable carrier
To a mixture of hydroxypropylmethylcellulose (1g), low-substituted hydroxypropylcellulose (3 g) and lactose (5 g) is added a solution of filgotinib (1 g) in absolute ethanol and after stirring, the ethanol is evaporated in vacuo to provide a solid dispersion.

Example 9: Ball mill mixed-grinding method
Using a ball mill (SPEX Industries), a mixture of filgotinib (2 g), co-povidone (10 g) and crystalline cellulose (15 g) is mix-ground for 4 hours to provide a solid dispersion.

Example 10: Preparation of filgotinib from 4-(4-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)benzyl)thiomorpholine 1,1-dioxide of Formula II
To a solution of 4-(4-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)benzyl)thiomorpholine 1,1-dioxide of Formula II in dry MeCN (150 mL) at 15°C-25oC is added triethyl amine followed by cyclopropanecarbonyl chloride. The reaction mixture is then allowed to warm to ambient temperature and stirred until all starting material is consumed. After completion of reaction, evaporated the solvents under vacuum and the resultant residue is treated with ethanolic ammonia solution and stirred at ambient temperature to hydrolyse any bis-acylated product. Product isolation is made by removal of volatiles in vacuum followed by trituration with tetrahydrofuran. The solids are collected by filtration, washed with water, acetone and tetrahydrofuran, then dried in vacuum to give the desired compound.

Example 11: Preparation of amorphous form of 4-(4-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)benzyl)thiomorpholine 1,1-dioxide of Formula II
Charged 4-(4-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)benzyl)thiomorpholine 1,1-dioxide of Formula II (1.0 g) in water (50 mL) and stirred at 10oC-20oC. The mixture is filtered to remove undissolved mass and frozen the filtrate in a -78 °C bath. The solvent is removed using a freeze drier to yield the title compound.

Dated this, ¬¬¬¬14th Day of Jan, 2020 For Mankind Pharma Ltd.

WE CLAIM

1. A stable amorphous form of filgotinib, or pharmaceutically acceptable salt thereof, wherein said amorphous form is stable for atleast six months at 40oC and 75% RH.

2. A process for the preparation of amorphous form of filgotinib, or pharmaceutically acceptable salts thereof, comprising the steps of:
a) adding filgotinib or pharmaceutically acceptable salt thereof, in one or more suitable solvent;
b) optionally heating at a suitable temperature; and
c) removing the solvent and isolating to get the amorphous form of filgotinib or pharmaceutically acceptable salt thereof.

3. A process for the preparation of amorphous form of filgotinib, or pharmaceutically acceptable salts thereof, comprising the steps of:
a) treating 4-(4-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)benzyl)thiomorpholine 1,1-dioxide of Formula II or a pharmaceutically acceptable salt with a suitable solvent at a suitable temperature;
;
b) optionally adding anti-solvent to get precipitates;
c) isolating amorphous form of compound of Formula II or pharmaceutically acceptable salt;
d) converting amorphous form of compound of Formula II or pharmaceutically acceptable salt to filgotinib or its pharmaceutically acceptable salt; and
e) converting the filgotinib or its pharmaceutically acceptable salt to amorphous form by treating with a suitable solvent.

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

5. A process for preparing the amorphous solid dispersion as claimed in claim 4, wherein said process comprising the steps of:
a) adding filgotinib 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 filgotinib or pharmaceutically acceptable salt thereof.

6. The process as claimed in claim 5, wherein said filgotinib or pharmaceutically acceptable salt thereof, is either anhydrous, hydrate or solvate in nature.

7. A process for the preparation of an amorphous solid dispersion of filgotinib or its pharmaceutically acceptable salt comprising the steps of:
a) providing a solution of amorphous form of filgotinib or its pharmaceutically acceptable salt in a suitable solvent;
b) adding atleast one pharmaceutically acceptable carrier;
c) optionally adding therapeutically effective amount of compound of Formula II; and
d) removing the solvent and isolating to get amorphous solid dispersion of filgotinib salt, wherein said solid dispersion optionally comprises of therapeutically effective amount of compound of Formula II.

8. The amorphous form as claimed in claim 1, wherein said amorphous form is substantially free from crystalline form.

9. Composition comprising filgotinib or its pharmaceutically acceptable salt along with atleast one pharmaceutically acceptable excipient, wherein said filgotinib or its pharmaceutically acceptable salt is present either as an amorphous form or as a solid dispersion with pharmaceutically acceptable carrier.

10. A method of preparation of composition as claimed in claim 9, wherein said amorphous form or solid dispersion of filgotinib or its pharmaceutically acceptable salt is substantially free from crystalline form.