DESC:
RELATED PATENT APPLICATION(S)

This application claims the priority to and benefit of Indian Patent Application No. 202041016529 filed on April 16, 2020; the disclosures of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to solid forms of Baloxavir marboxil, processes for preparing the solid forms, and pharmaceutical compositions thereof.

BACKGROUND OF THE INVENTION

Baloxavir marboxil (XOFLUZA®) is a polymerase acidic (PA) endonuclease inhibitor indicated for the treatment Influenza A or B virus infection. The chemical name of Baloxavir marboxil is ({(12aR)-12-[(11S)-7,8-Difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl]-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate. The chemical structure of Baloxavir marboxil is represented as formula I.

I
Baloxavir marboxil is a prodrug that is converted by hydrolysis to Baloxavir (formula Ia), the active form that exerts anti-influenza virus activity.

Ia
The active form, Baloxavir inhibits the endonuclease activity of the polymerase acidic (PA) protein, an influenza virus-specific enzyme in the viral RNA polymerase complex required for viral gene transcription, resulting in inhibition of influenza virus replication.
Baloxavir marboxil as a compound exhibiting cap-dependent endonuclease inhibitory activity, having antiviral activity, particularly influenza virus growth inhibitory activity, synthesis thereof and pharmaceutical composition thereof is described in WO 2016/175224.

I-form, II-form and III-form crystals of Baloxavir marboxil are described in the patent publication WO 2018/030463.

In general, crystalline solids may have poor solubility and require a significant amount of energy for dissolution due to their highly organized, lattice like structures. For example, the energy required for a drug substance to escape from a crystal is more than from an amorphous or a non-crystalline form. (Konno T., Chem. Pharm. Bull. 38(7) 2003-2007 (1990)).

Preparation of pharmaceutical dosage forms is often procedurally complex, particularly when combining the active ingredient with excipients. For example, workability or stability issues may arise when different components of the pharmaceutical dosage form come into close contact with one another. Pharmaceutical industries carry out extensive studies for the development of different polymorphs of various drug substances, to obtain suitable polymorphs that possess improved performance characteristics such as aqueous solubility, improved bioavailability, chemical stability, shelf life etc.

It may, thus, be advantageous to prepare solid forms of an active ingredient to achieve good physiochemical properties, desirable bioavailability, and advantageous pharmaceutical parameters that meets the standards of various pharmaceutical regulatory agencies in a highly reproducible manner. Further, there remains a need for an efficient, simple and industrially viable process to prepare solid forms of Baloxavir marboxil.

OBJECTS OF THE INVENTION

One object of the invention is to provide an amorphous form of Baloxavir marboxil which is substantially pure.

Another object of the invention is to provide an efficient, simple and industrially viable process for preparing an amorphous form of Baloxavir marboxil.

A further object of the invention is to provide a solid dispersion comprising amorphous Baloxavir marboxil together with one or more pharmaceutically acceptable excipients, carriers, or diluents.

Yet another object of the invention is to provide a process for preparing a solid dispersion comprising amorphous Baloxavir marboxil in combination with one or more pharmaceutically acceptable excipients.

SUMMARY OF THE INVENTION

The present invention aims to provide solid forms of Baloxavir marboxil, processes for preparation thereof, and pharmaceutical compositions thereof.

One aspect of the present invention is to provide an amorphous form of Baloxavir marboxil.

The amorphous form of Baloxavir marboxil is substantially pure having purity above 98%.

The said amorphous form is substantially free from crystalline forms and residual solvents.

The said amorphous form of Baloxavir marboxil is characterized by a powder X-ray diffractogram (PXRD) substantially similar to the PXRD as illustrated in any one of Figures 2, 3, or 4.

Another aspect of the present invention is to provide a process for preparing an amorphous form of Baloxavir marboxil, comprising:
I. providing a solution or suspension of Baloxavir marboxil in a solvent; and
II. isolating the amorphous form of Baloxavir marboxil from the solution or suspension.

The solvent in step I of the present invention is selected from the group consisting of alcohols, ethers, esters, ketones, hydrocarbons, nitriles, amides, water, and mixtures of two or more thereof.

The step I of the present invention is carried out at a temperature ranging from about 0°C to about the reflux temperature of the solvent.

Another aspect of the present invention is to provide a solid dispersion comprising amorphous Baloxavir marboxil together with one or more pharmaceutically acceptable excipients, carriers, or diluents.

The said solid dispersion comprising amorphous Baloxavir marboxil together with one or more pharmaceutically acceptable excipients, carriers, or diluents is characterized by a powder X-ray diffractogram (PXRD) substantially similar to the PXRD as illustrated in Figure 5.

Another aspect of the present invention is to provide a process for preparing a solid dispersion comprising amorphous Baloxavir marboxil, in combination with one or more pharmaceutically acceptable excipients, the process comprising:
i. providing, in a solvent, a solution or a suspension comprising Baloxavir marboxil and one or more pharmaceutically acceptable excipients; and
ii. isolating the solid dispersion comprising Baloxavir marboxil in combination with one or more pharmaceutically acceptable excipients.

The solvent in step i of the present invention is selected from the group consisting of alcohols, ethers, esters, ketones, hydrocarbons, nitriles, amides, water, and mixtures of two or more thereof.

The step i of the present invention is carried out at a temperature ranging from about 0°C to about the reflux temperature of the solvent.

Yet another aspect of the present invention is to provide a pharmaceutical composition comprising an amorphous Baloxavir marboxil or a solid dispersion of Baloxavir marboxil together with one or more pharmaceutically acceptable excipients, carriers, or diluents as described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is an illustration of a powder X-ray diffractogram (PXRD) of Baloxavir marboxil prepared according to Reference Example.

Figure 2 is an illustration of a powder X-ray diffractogram (PXRD) of Baloxavir marboxil prepared according to Example 1.

Figure 3 is an illustration of a powder X-ray diffractogram (PXRD) Baloxavir marboxil prepared according to Example 2.

Figure 4 is an illustration of a powder X-ray diffractogram (PXRD) of Baloxavir marboxil prepared according to Example 3.

Figure 5 is an illustration of a powder X-ray diffractogram (PXRD) of Baloxavir marboxil prepared according to Example 4.

DETAILED DESCRIPTION OF THE INVENTION

DEFINITIONS

Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances.

In general, the term “solid dispersion” refers to a system in a solid state comprising at least two components, wherein one component is dispersed throughout the other component or components. The term “solid dispersion” as used herein, refers to stable solid dispersions comprising Baloxavir marboxil and one or more excipients, carriers, diluents, or polymers prepared by a variety of methods, including but not limited to spray drying, the melting (fusion), solvent, or the melting-solvent method.

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 term “stability” as used in the description includes both physical and chemical stability. The term “physical stability” refers to maintaining the solid state form of Baloxavir marboxil, without converting to other forms, and “chemical stability” refers to maintaining acceptable concentrations of Baloxavir marboxil-related impurities.

All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated.

All temperatures are in degrees Celsius unless specified otherwise.

As used herein, the terms "comprising" and "comprises" mean the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The term "including" is also to be construed as open ended. The terms "about," “substantially” and the like are to be construed as modifying a term or value such that it is not an absolute, but does not read on the prior art. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by one skilled in the art.

All ranges recited herein include the endpoints, including those that recite a range between two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.

The term "optionally" is taken to mean that the event or circumstance described in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.

Unless otherwise specified, the term "solvate(s)" as used herein, means compounds formed by solvation, for example as a combination of solvent molecules with molecules or ions of a solute. Well known solvent molecules include water, alcohols, nitriles, polar organic solvents etc.

As used herein, the term “anti-solvent” refers to a solvent that, when combined with a solution of compound of formula I or Ia, reduces solubility of the said compounds I, or Ia in the solution, causing crystallization or precipitation in some instances spontaneously, and in other instances with additional steps, such as seeding, cooling, scratching, and/or concentrating.

Solid forms of the present invention are stable, reproducible and amicable for large scale preparation. The present invention offers unique solubility and dissolution characteristics, which may enhance bioavailability of Baloxavir marboxil, which is a low soluble drug. The solid forms of the present invention may provide multiple benefits in preparing formulations of Baloxavir marboxil, for example, improved processability, increased stability of the pharmaceutical formulation or Active Pharmaceutical Ingredient (API) or improved pharmacokinetic properties of the pharmaceutical formulation.

In an aspect, the present invention provides an amorphous form of Baloxavir marboxil. The amorphous form of Baloxavir marboxil may be substantially pure.

In an aspect, the present invention provides a process for preparing an amorphous form of Baloxavir marboxil, comprising:
I. providing a solution or suspension of Baloxavir marboxil in a solvent; and
II. isolating the amorphous form of Baloxavir marboxil from the solution or suspension.

Providing a solution or suspension of Baloxavir marboxil in step I may include:
1. direct use of a reaction mixture containing Baloxavir marboxil that is obtained during its synthesis which either comprises a suitable solvent, or may be combined with a suitable solvent; or
2. dissolving or suspending Baloxavir marboxil in a solvent.

Baloxavir marboxil may be prepared by methods described in WO 2016/175224 or by any other methods known from the literature, or using methods known to one skilled in the art.

In step I of the present invention, any physical form of Baloxavir marboxil may be utilized for providing the solution or suspension of Baloxavir marboxil.

The suitable solvent useful for providing a solution or suspension in step I of the present invention include, but are not limited to; water; alcohols, such as methanol, ethanol, 1 -propanol, 2- propanol, 1 -butanol, and 2-butanol; ethers, such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, cyclopropylmethyl ether, dioxane, and dimethoxyethane; esters, such as methyl acetate, ethyl formate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, and isobutyl acetate; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and diethyl ketone; nitriles, such as acetonitrile and propionitrile; amides, such as formamide, ?,?-dimethylformamide, and N,N- dimethylacetamide; sulfoxides, such as dimethylsulfoxide; aliphatic and aromatic hydrocarbons such as n-pentane, isopentane, neopentane, n-hexane, isohexane, n- heptane, cyclohexane, methylcyclohexane, cycloheptane, petroleum ethers, benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, indane, naphthalene, tetralin, trimethylbenzene; halogenated hydrocarbons such as dichloromethane, 1 ,2- dichloroethane, trichloroethylene, chloroform, carbon tetrachloride; or mixtures of two or more thereof.

In step I of the present invention, providing a solution or a suspension for the reaction, may be carried out at a suitable temperature, ranging from about 0° C to about the reflux temperature of the solvent, or less than about 100° C, less than about 80° C, less than about 60° C, less than about 40° C, less than about 10° C, or any other suitable temperatures.

The present invention provides substantially pure amorphous form of Baloxavir marboxil, which is substantially free from crystalline forms and residual solvents.

The present invention provides an amorphous form of Baloxavir marboxil which is stable under normal stability conditions.

Another aspect of the invention is to provide a solid dispersion comprising amorphous Baloxavir marboxil together with one or more pharmaceutically acceptable excipients, carriers, or diluents.

In an aspect, the present invention provide a process for preparing a solid dispersion comprising amorphous Baloxavir marboxil, in combination with one or more pharmaceutically acceptable excipients, the process comprising:
i. providing, in a solvent, a solution or a suspension comprising Baloxavir marboxil and one or more pharmaceutically acceptable excipients; and
ii. isolating the solid dispersion comprising Baloxavir marboxil in combination with one or more pharmaceutically acceptable excipients.

In embodiments of step i, suitable solvent useful for providing a solution or suspension include, but are not limited to; water; alcohols, such as methanol, ethanol, 1 -propanol, 2- propanol, 1 -butanol, and 2-butanol; ethers, such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, cyclopropylmethyl ether, dioxane, and dimethoxyethane; esters, such as methyl acetate, ethyl formate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, and isobutyl acetate; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and diethyl ketone; nitriles, such as acetonitrile and propionitrile; amides, such as formamide, ?,?-dimethylformamide, and N,N- dimethylacetamide; sulfoxides, such as dimethylsulfoxide; aliphatic and aromatic hydrocarbons such as n-pentane, isopentane, neopentane, n-hexane, isohexane, n- heptane, cyclohexane, methylcyclohexane, cycloheptane, petroleum ethers, benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, indane, naphthalene, tetralin, trimethylbenzene; halogenated hydrocarbons such as dichloromethane, 1 ,2- dichloroethane, trichloroethylene, chloroform, carbon tetrachloride; or mixtures of two or more thereof.

In embodiments of step i, providing a solution or a suspension for the reaction, may be carried out at a suitable temperature, ranging from about 0° C to about the reflux temperature of the solvent, or less than about 100° C, less than about 80° C, less than about 60° C, less than about 40° C, less than about 10° C, or any other suitable temperatures.

The pharmaceutically acceptable excipients useful in step i, include, but are not limited to mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol, inositol, trehalose, trehalose, maltose, raffinose, a, ß and ?-cyclodextrins, gum arabic, sodium alginate, propylene glycol alginate, agar, gelatin, tragacanth, xanthan gum, starch, lectins, urea, chitosan, chitosan glutamate, hydroxypropyl ß-cyclodextrin chitosan, hydroxypropyl methylcellulose (HPMC), Hydroxypropyl cellulose (HPC), methylcellulose (MC), cellulose acetate phthalate (CAP), Hydroxypropyl Methylcellulose Phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), carboxymethyl ethyl cellulose (CMEC), carboxymethyl cellulose, sodium carboxymethyl cellulose, cellulose acetate butyrate, hydroxyethyl cellulose, ethyl cellulose, co- (lactic/glycolic)copolymers, poly(orthoester), polyvinyl chloride, polyvinyl acetate, ethylene vinyl acetate, carbopols, silicon elastomers, polyacrylic polymers, polyvinylacetal diethylaminoacetate, amino alkyl methacrylate copolymers, methacrylic acid copolymers, and carboxyl vinyl polymer, polyvinylpyrrolidones (such as Polyvinylpyrrolidone K 30/PVP K-30), polyethylene glycols, polyethylene-/polypropylene-/polyethylene-oxide block copolymers, polymethacrylates, polyvinylalcohol (PVA) and co-polymers thereof with PVP or with other polymers, polyacrylates, polyhydric alcohols, polyoxyethylene derivatives, 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; diluents such as starches and derivative thereof, e.g. dextrin, pullulan, corn starch and potato starch pregelatinized starches; lactose, sucrose, glucose, reduced maltose, mannitol, sorbitol, xylitol, trehalose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, crystalline cellulose/carmellose sodium, hydroxypropyl cellulose, magnesium aluminometasilicate, silica excipients like silicon dioxide, syloid, light anhydrous silicic acid or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches or the like; disintegrants such as hydroxypropyl cellulose, low- substituted hydroxypropyl cellulose, croscarmellose sodium, a starch, methylcellulose, sodium alginate, sodium carboxymethyl starch, carmellose calcium, carmellose sodium, crystalline cellulose and crystalline cellulose/carmellose sodium, sodium starch glycolate, pregelatinized starches, crospovidones, colloidal silicon dioxide or the like; lubricants such as stearic acid, magnesium stearate, talc, light anhydrous silicic acid, calcium stearate, zinc stearate, magnesium oxide, sodium lauryl sulfate, sodium stearyl fumarate, magnesium aluminometasilicate or the like; flavoring agents such as sucrose, aspartame, mannitol, dextran, saccharin, menthol, citric acid, tartaric acid, malic acid, ascorbic acid, sweet hydrangea leaves, fennel, ethanol, fructose, xylitol, glycyrrhizinic acid, purified sucrose, L-glutamine, cyclodextrin, peppermint, methyl salicylate or the like; surfactants such as sodium lauryl sulfate, polysolvate 80, sucrose fatty acid ester, polyoxyl 40 stearate, polyoxyethylene 60 hydrogenated castor oil, sorbitan monostearate, sorbitan monopalmitate or the like; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes or the like. Other pharmaceutically acceptable carriers that can be used include, but are not limited to, film formers, plasticizers, colorants, viscosity enhancers, preservatives, antioxidants, or the like. The scope of the present invention without limitation includes, the use of mixtures of more than one of the pharmaceutical excipients to provide desired release profiles or for the enhancement of stability and also includes all viscosity grades, molecular weights, commercially available products, their copolymers and mixtures.

In embodiments of step i, any physical form of Baloxavir marboxil may be utilized for providing a solution or suspension of Baloxavir marboxil. Suitable forms for providing a solution or suspension in step i include for example amorphous Baloxavir marboxil, crystalline Baloxavir marboxil, solvates thereof or mixtures thereof.

In embodiments of step i, providing a solution or a suspension comprising Baloxavir marboxil and one or more pharmaceutically acceptable excipients, may be carried out at a suitable temperature, ranging from about 0° C to about the reflux temperature of the solvent, or less than about 100° C, less than about 80° C, less than about 60° C, less than about 40° C, less than about 10° C, or any other suitable temperatures.

In various embodiments, optionally, the solution obtained may be treated to remove any insoluble particles, before proceeding to the next step. 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 various embodiments of the present invention, isolation of amorphous Baloxavir marboxil or a solid dispersion comprising amorphous Baloxavir marboxil together with one or more pharmaceutically acceptable excipients, also include, removing the solvent from the solution or suspension obtained in the previous step, or combining the solution or suspension obtained in the previous step with a suitable anti-solvent.

In various embodiments of the present invention, the choice of solvents and anti-solvents for the process is customary to one skilled in the art. Suitable anti-solvents that may be used to combine a solution comprising compounds described herein above are selected from the group consisting of water, alcohols, ethers, esters, aliphatic hydrocarbon liquids, alicyclic hydrocarbon liquids, aromatic hydrocarbon liquids, and mixtures of at least two thereof.

In some embodiments of the present invention, removal of the solvent may be effected by using suitable techniques that include, but are not limited to, evaporation of the solvent, using a rotational distillation device such as a Buchi Rotavapor®, spray drying, thin film drying, freeze drying, lyophilisation, methods as mentioned herein, and the like, or any other suitable techniques. In some embodiments of the present invention, the removing of the solvent comprises evaporating the solvent, distilling, spray drying, thin film drying, agitated thin-film drying, freeze drying, lyophilisation, or a combination thereof.

The solvent may be removed, optionally under reduced pressures, at temperatures less than about 100° C., less than about 75° C., less than about 60° C., less than about 50° C., or any other suitable temperature.

In various embodiments of the present invention, isolation may be by removing the solvent by techniques mentioned herein above, or by any other precipitation technique. Suitable methods include, but are not limited to, concentration, removal of solvent by evaporation, distillation, crash cooling, flash evaporation, rotational drying, spray drying, thin film drying, freeze drying, and lyophilization.

In various embodiments of the present invention, the solid product obtained may be collected using techniques such as for example, scraping, shaking the container, or other techniques that are suited to the equipment used. Optionally, the isolated solid may be further dried.

In embodiments of the present invention, amorphous Baloxavir marboxil or a solid dispersion comprising amorphous Baloxavir marboxil together with one or more pharmaceutically acceptable excipients, after optional drying, may be optionally further subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of the product. Equipment that may be used for particle size reduction include, without limitation thereto, ball mills, roller mills, hammer mills, and jet mills.

Drying may be suitably carried out using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, at temperatures less than about 100° C., less than about 60° C., less than about 50° C., less than about 20° C., less than about 0° C., less than about -20° C., or any other suitable temperatures. The drying may be carried out for any time period suitable for obtaining a desired product quality, such as from about 15 minutes to 24 hours, or longer.

In an aspect of the invention the amorphous Baloxavir marboxil, obtained according to certain embodiments of the present invention has a particle size distribution wherein: mean particle size is less than about 200 µm or less than about 100 µm; d (0.5) is less than about 200 µm or less than about 25 µm or less than about 10 µm or less than about 5 µm; and d (0.9) is less than about 500 µm or less than about 50 µm or less than about 25 µm or less than about 10 µm.

In an aspect of the invention the solid dispersion comprising amorphous Baloxavir marboxil together with one or more pharmaceutically acceptable excipients, obtained according to certain embodiments of the present invention has a particle size distribution wherein: mean particle size is less than about 200 µm or less than about 100 µm; d (0.5) is less than about 200 µm or less than about 25 µm or less than about 10 µm or less than about 5 µm; and d (0.9) is less than about 500 µm or less than about 50 µm or less than about 25 µm or less than about 10 µm.

In aspects of the present invention, the amount of Baloxavir marboxil, preferably Baloxavir marboxil, relative to the amount of pharmaceutically acceptable excipients, carriers, polymers or diluents present in the solid dispersions or premixes depends on the pharmaceutically acceptable excipients, carriers or diluents. Preferably, the ratio of Baloxavir marboxil to the pharmaceutically acceptable excipients, carriers, polymers or diluents ranges from about 1:0.1 to about 1:10, preferably from about 1:0.5 to about 1:4.0.

Non-limiting examples of amorphous Baloxavir marboxil and solid dispersions of amorphous Baloxavir marboxil in combination with one or more pharmaceutically acceptable excipients prepared according to the processes described herein are characterized by a PXRD as illustrated in Figures 2 to 5.

In aspects of the present invention, the amorphous Baloxavir marboxil or the solid dispersion comprising amorphous Baloxavir marboxil together with one or more pharmaceutically acceptable excipients, prepared according to the processes described herein are substantially pure, with a purity greater than about 98%, or greater than about 99%, by weight, as determined using high performance liquid chromatography (HPLC).

In an aspect, the present invention provides a pharmaceutical composition comprising amorphous Baloxavir marboxil or solid dispersion of Baloxavir marboxil described herein together with one or more pharmaceutically acceptable excipients, carriers, or diluents.

In certain embodiments, solid dispersions or premixes of Baloxavir marboxil together with one or more pharmaceutically acceptable excipients, carriers, or diluents described herein may be formulated using the methods known in the art. The solid dispersions or premixes of Baloxavir marboxil together with one or more pharmaceutically acceptable excipients, carriers, or diluents described herein may be formulated as oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, or capsules. Formulations may be in the forms of immediate release, delayed release, or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, or modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using techniques such as direct mixing, dry granulation, wet granulation, or extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, or modified release coated. Compositions of the present application may further comprise one or more pharmaceutically acceptable excipients.

The choice of the excipients, carriers or diluents may be customary to one skilled in the art. However, non-limiting examples of pharmaceutically acceptable excipients that are useful include: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methyl celluloses, pregelatinized starches, or the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, or the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, or the like; glidants such as colloidal silicon dioxide or the like; stabilizers such as salts of sodium, potassium, magnesium, calcium and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins or resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes, or the like. Other pharmaceutically acceptable excipients that are of use include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, or the like.

The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. Thus, for example, in each instance herein any of the terms “comprising” and “consisting of” may be replaced with either of the terms. In addition, the solvents, temperatures, reaction durations, etc. delineated herein are for purposes of illustration only and one of ordinary skill in the art will recognize that variation of the reaction conditions can produce the desired products accordingly.

Certain specific aspects and embodiments of the present invention will be better understood in connection with 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.

EXAMPLES

Reference Example: Preparation of Baloxavir marboxil

(Intermediate – I compound is prepared according to the procedure described in WO 2016/175224. Alternatively, the Intermediate – I and/or Baloxavir marboxil can also be synthesized by other methods known in the art or by the methods known to one skilled in the art)

Dimethyl acetamide (39 mL) was charged into a round bottom flask followed by Intermediate-I (13.0 g) and Lithium chloride (4.8 g) at 25-30°C and stirred at 80°C for 3-4 hours. After completion of the reaction, the reaction mixture was cooled to 5-10 °C and diluted with acetone (13 mL), 0.5 M hydrochloric acid (65 mL) and water (26 mL). The resulting mixture was stirred for 2 hours at 5-10°C and the solid precipitated out was filtered, washed with water and suck dried. The resultant solid was purified by recrystallisation with chloroform/isopropyl ether. The obtained solid was filtered and dried under suction for 30 minutes. The resultant solid was dried in oven under vacuum at 60°C for 5 hours to obtain compound Ia as a pale pink solid. Yield: 10.0 g

Dimethyl acetamide (7.5 mL) was charged in to a round bottom flask followed by Ia compound (1.5 g) in chloromethyl methyl carbonate (0.77 g), potassium carbonate (1.07 g) and potassium iodide (1.5 g) were added at 25-30°C and reaction mixture was heated to 50°C for 4 hours. After completion of the reaction, reaction mixture was cooled to room temperature and diluted with dimethyl acetamide (9.0 mL), the solid was filtered and again washed with dimethyl acetamide (7.5 mL). The combined filtrate was quenched with 1.0 M hydrochloric acid (20.0 mL) further diluted with water (8.0 mL) and stirred at room temperature for 1 hour. The obtained solid was filtered, washed with water (9.0 mL) and dried under suction for 20 minutes. The resultant solid was dried in oven under vacuum at 50°C for 15-16 hours to obtain the title compound (Formula I). Yield: 1.2 g

The powder X-ray diffractogram (PXRD) of the obtained Baloxavir marboxil is as illustrated in Figure 1.

Example 1: Preparation of amorphous Baloxavir marboxil

Baloxavir marboxil (1.0 g) was charged into a round bottom flask followed by dichloromethane (10 mL) at 25-30°C to provide a clear solution. The solvent was evaporated under vacuum at 45-50°C and to the resultant solid, dichloromethane (10 mL) was added and solvent was evaporated under vacuum at 45-50°C. The resultant solid was dried under vacuum at 45-50°C for 15-16 hours to obtain the title compound as an amorphous solid. Yield: 0.93 g

The powder X-ray diffractogram (PXRD) of the obtained amorphous solid is as illustrated in Figure 2.

Example 2: Preparation of amorphous Baloxavir marboxil

Baloxavir marboxil (1.0 g) was charged into a lyophilizer flask followed by acetonitrile (10 mL) and water (4 mL) at 25-30°C and resulting solution was freezed in dry ice-methanol bath at -70°C and lyophilized for 4 hours. The resultant fluffy solid was dried under vacuum at 45-50°C for 3 hours to obtain the title compound as an amorphous solid. Yield: 0.912 g

The powder X-ray diffractogram (PXRD) of the obtained amorphous solid is as illustrated in Figure 3.

Example 3: Preparation of amorphous Baloxavir marboxil

Baloxavir marboxil (1.0 g) was charged into a lyophilizer flask followed by tetrahydrofuran (12 mL) and water (15 mL) at 25-30°C and resulting solution was freezed in dry ice-methanol bath at -70°C and lyophilized for 4 hours. The fluffy solid thus obtained further dried under vacuum at 45-50°C for 3 hours to obtain the title compound as an amorphous solid. Yield: 0.91 g

The powder X-ray diffractogram (PXRD) of the obtained amorphous solid is as illustrated in Figure 4.

Example 4: Preparation of solid dispersion of amorphous Baloxavir marboxil with PVPK-30

Baloxavir marboxil (0.5 g) was charged into a round bottom flask followed by dichloromethane (5 mL) and PVPK-30 (0.5 g) at 25-30°C and the reaction mixture was stirred at the same temperature for 60-90 minutes. The solvent was evaporated from the reaction mixture under vacuum at 45-50°C. The resultant solid was dried under vacuum at 45-50°C for 16 hours to obtain the title compound as an amorphous solid. Yield:0.95 g

The powder X-ray diffractogram (PXRD) of the obtained amorphous solid is as illustrated in Figure 5.

Solid dispersions of amorphous Baloxavir marboxil with other excipients may be prepared in a similar manner as described in the example given above.
,CLAIMS:1) An amorphous form of Baloxavir marboxil.

2) The amorphous form of Baloxavir marboxil as claimed in claim 1, wherein the said amorphous form is substantially pure.

3) The amorphous form of Baloxavir marboxil as claimed in claim 1 or 2, wherein the amorphous form is substantially free from crystalline forms and residual solvents.

4) The amorphous form of Baloxavir marboxil as claimed in claim 1, characterized by a powder X-ray diffractogram (PXRD) substantially similar to the PXRD as illustrated in any one of Figures 2, 3, or 4.

5) A process for preparing an amorphous form of Baloxavir marboxil, comprising:
I. providing a solution or suspension of Baloxavir marboxil in a solvent; and
II. isolating the amorphous form of Baloxavir marboxil from the solution or suspension.

6) The process as claimed in claim 5, wherein the solvent is selected from the group consisting of alcohols, ethers, esters, ketones, hydrocarbons, nitriles, amides, water, and mixtures of two or more thereof.

7) The process as claimed in claim 5, wherein step I is carried out at a temperature ranging from about 0°C to about the reflux temperature of the solvent.

8) A solid dispersion comprising amorphous Baloxavir marboxil together with one or more pharmaceutically acceptable excipients, carriers, or diluents.

9) The solid dispersion comprising amorphous Baloxavir marboxil together with one or more pharmaceutically acceptable excipients, carriers, or diluents as claimed in claim 8, characterized by a powder X-ray diffractogram (PXRD) substantially similar to the PXRD as illustrated in Figure 5.

10) A process for preparing a solid dispersion comprising amorphous Baloxavir marboxil, in combination with one or more pharmaceutically acceptable excipients, the process comprising:
i. providing, in a solvent, a solution or a suspension comprising Baloxavir marboxil and one or more pharmaceutically acceptable excipients; and
ii. isolating the solid dispersion comprising Baloxavir marboxil in combination with one or more pharmaceutically acceptable excipients.

11) The process as claimed in claim 10, wherein the solvent is selected from the group consisting of alcohols, ethers, esters, ketones, hydrocarbons, nitriles, amides, water, and mixtures of two or more thereof.

12) The process as claimed in claim 10, wherein step i is carried out at a temperature ranging from about 0°C to about the reflux temperature of the solvent.

13) A pharmaceutical composition comprising amorphous Baloxavir marboxil or a solid dispersion of Baloxavir marboxil together with one or more pharmaceutically acceptable excipients, carriers, or diluents, prepared according to the process as claimed in any of the preceding claims.