WO2022054096A1

WO2022054096A1 - Solid forms of substituted polycyclic pyridone compounds and prodrugs therof and process of preparation thereof

Info

Publication number: WO2022054096A1
Application number: PCT/IN2021/050894
Authority: WO
Inventors: Srinivas Laxminarayan Pathi; Ramanaiah CHENNURU; Anjaneya Raju INDUKURI; Prathap RENGARAJ; Ramesh DEVARAPALLI
Original assignee: Cipla Limited
Priority date: 2020-09-14
Filing date: 2021-09-11
Publication date: 2022-03-17

Abstract

Novel solid forms of substituted polycyclic pyridine compounds and prodrugs thereof, processes for their preparation, pharmaceutical compositions comprising the new solid forms, and use of the new solid forms for treating influenza A or B including strains resistant to current antiviral agents, are disclosed. These solid forms can be advantageously used to increase the chemical and polymorphic stability of substituted polycyclic pyridine compounds and prodrugs thereof.

Description

“SOLID FORMS OF SUBSTITUTED POLYCYCLIC PYRIDONE COMPOUNDS AND PRODRUGS THEROF AND PROCESS OF PREPARATION THEREOF”

Title

The present invention is related to the novel solid forms of substituted polycyclic pyridine compounds and prodrugs thereof and process of preparing said solid forms. More, particularly the invention provides novel polymorphs and novel amorphous solid dispersions of Baloxavir marboxil in combination with one or more pharmaceutically acceptable carrier, process for their preparation and pharmaceutical compositions comprising them.

Prior Art

Epidemic and pandemic influenza are major public health concerns and vaccination remains the primary method to prevent influenza. Influenza antiviral drugs are typically used to treat newly emerged or variant viruses due to their ability to target conserved parts of the virus. In some countries including the USA and Japan, such drugs are widely used to treat seasonal influenza in otherwise healthy patients. In spite of this, influenza spreads around the world in yearly outbreaks, resulting in about three to five million cases of severe illness and about 250,000 to 500,000 deaths. With growing concerns of resistance development to currently available influenza antivirals (i.e. adamantanes and neuraminidase inhibitors), new antiviral drugs with different mechanisms of action are currently undergoing clinical trials.

US 10,392,406 B2 describes that the substituted polycyclic pyridone compounds have a cap-dependent endonuclease inhibitory activity and are useful as a therapeutic and/or prophylactic agent for symptoms and/or diseases caused by infection of influenza virus.

Baloxavir marboxil (XofluzaTM; baloxavir) of Formula A

Formula A is a novel, cap-dependent endonuclease inhibitor that has been developed for the treatment of influenza A or B including strains resistant to current antiviral agents. Unlike neuraminidase inhibitors that impair viral release from infected host cells, Baloxavir blocks influenza virus proliferation by inhibiting the initiation of mRNA synthesis. On 23 February 2018, Baloxavir received its first global approval in Japan for the treatment of influenza A or B virus infections in pediatric and adult patients.

Polymorphism is the ability of a compound to exist in two or more different crystalline phases that differ in arrangement of the molecules in crystal lattice. Although polymorphs have the same chemical composition, they differ in packing and geometrical arrangement. and exhibit different physical properties such as melting point. X-ray diffraction patterns, density, stability, and solubility. Extensive study is carried out in the pharmaceutical industry for 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.

Prior art suggests that Baloxavir marboxil exist in different crystalline forms.

US 10,759,814 B2 which is hereby incorporated by reference discloses three different crystalline forms of Baloxavir marboxil namely Form I, II and III and process for the preparation thereof.

CN 111377944 A which is hereby incorporated by reference discloses three different crystalline forms of Baloxavir marboxil namely Form A and B and process for the preparation thereof.

Particular crystalline forms of Baloxavir marboxil can possess advantageous properties in terms of their solubility and/or stability and/or bioavailability and/or impurity profile and/or filtration characteristics and/or drying characteristics and/or their ability to be handled and/or micronized and/or preparation of solid oral forms.

The existence and possible numbers of polymorphic forms for a given compound cannot be predicted, and there are no "standard" procedures that can be used to prepare polymorphic forms of a substance.

It is also known that solid amorphous dispersions comprising a low-solubility drug in a polymer can increase the maximum concentration of drug that will dissolve in an aqueous solution in in vitro tests, or that will dissolve in body fluids such as those present in the gastrointestinal (GI) tract in in Vivo tests, and, in turn, enhance the bioavailability of the drug. Solid dispersions of a drug in a matrix such as a polymer-can be prepared, for example, by forming a homogeneous solution or melt of the drug in matrix material, followed by solidifying the mixture by cooling or removal of solvent. Such solid dispersions of crystalline drugs have been known for more than two decades, and often show enhanced bioavailability when administered orally relative to compositions comprising undispersed crystalline drug.

A major problem with solid dispersions of drugs is that while the dispersions may show enhanced bioavailability of the low-solubility drug if administered shortly after preparation, however, bioavailability typically decreases over a period of time upon storage due to changed environment in the solid dispersion. Such solid dispersions are often physically unstable in that the drug present in the dispersion reverts to the crystalline form upon storage-particularly at elevated temperature and humidity. Accordingly, the dispersion cannot be used to provide proper dosing of the drug because the bioavailability of the drug changes over time.

Further, amorphous dispersions of drugs tend to convert to crystalline forms over time, which can lead to improper dosing due to differences of the solubility of crystalline drug material compared to amorphous drug material.

Based on the situation, it is necessary to develop new solid forms which have good stability, low hygroscopicity, and are suitable for storage and industrial process. And the new forms should meet the requirements of further drug development.

What is therefore desired is a composition comprising a stable dispersion of Baloxavir marboxil in a polymer that provides superior bioavailability, together with improved stability of the dispersion in typical storage environments, particularly for dispersions where the drug is present in concentrations above its equilibrium value.

Objects of the invention

Accordingly, object of the present invention is to provide solid forms of Baloxavir marboxil.

Another object of the present invention is to provide a stable solid dispersion of Baloxavir marboxil.

Another object of the present invention is to provide polymorphs of Baloxavir marboxil.

Another object of the present invention is to provide a pharmaceutical composition comprising solid forms of Baloxavir marboxil.

Yet another object of the present invention to provide a process for preparing solid forms of Baloxavir marboxil.

It is still another object of the present invention to provide a process for preparing the pharmaceutical composition comprising solid forms of Baloxavir marboxil.

Summary of the invention

The present invention provides a novel pharmaceutical solid forms of Baloxavir marboxil and the process for the preparation thereof. According to a first aspect of the present invention, there is provided a novel pharmaceutical solid dispersion of Baloxavir marboxil and the process for its preparation whereby water insoluble drugs are combined with a carrier.

In some embodiments, the Baloxavir marboxil is complexed with a pharmaceutically acceptable carrier.

In an embodiment solid dispersion is in the amorphous form.

The solid dispersions of amorphous Baloxavir marboxil prepared according to the present invention are characterized by unique XRD and DSC patterns.

According to the second aspect, the present invention provides processes for the preparation of a stable solid dispersion of Baloxavir marboxil and one or more pharmaceutically acceptable carrier.

According to a third aspect the present invention provides novel crystalline forms of Baloxavir marboxil and preparation process, which are suitable for pharmaceutical development and industrial process.

The Baloxavir marboxil may be in anhydrous form or a pseudopolymorphic form. Accordingly, pseudopolymorphs provided include hydrates and/or solvates, more particularly, C1-C4 alcohol solvates, a benzyl alcohol solvate, a ketone solvates, a glycol solvate, a nitrile solvate, a DMSO (dimethylsulfoxide) solvate, a THF (tetrahydrofuran) solvate and/or hydrated solvates thereof.

Particularly preferred polymorphic form of the present invention is designated herein as “Form C2”. The novel polymorphic form of the present invention is characterized by unique XRD patterns.

The novel polymorphic form of the present invention possesses certain physical and chemical properties which render it particularly suitable for pharmaceutical development, such as good solubility, permeability and bioavailability. In addition, the novel form is suitable for bulk handling and formulation.

According to a fourth aspect, the present invention relates to process for preparing novel polymorphic form of Baloxavir marboxil.

The present invention also relates to pharmaceutical compositions containing novel solid dispersions of Baloxavir marboxil complexed with a pharmaceutically acceptable carrier and novel polymorphic form of Baloxavir marboxil or mixtures thereof, optionally comprising one or more pharmaceutically acceptable excipients.

The invention also provides methods of treatment of influenza virus wherein novel solid dispersions and novel polymorphic form of Baloxavir marboxil or mixtures thereof are useful.

In a further aspect of the present invention, there is provided method for the prevention or treatment of influenza virus which method comprises administering novel solid dispersions of Baloxavir marboxil and novel polymorphic form of Baloxavir marboxil or mixtures thereof to a patient in need thereof.

In a further aspect of the present invention, there is provided novel polymorphic form of Baloxavir marboxil and novel solid dispersions of Baloxavir marboxil or mixtures thereof for use in the prevention or treatment of influenza virus .

In another aspect, the present invention provides a process substantially as herein described with reference to the examples. Brief description of drawings

Figure 1 shows X-ray Powder Diffraction (XRPD) pattern of amorphous solid dispersion of Baloxavir marboxil with PVP K-30 prepared according to Examples 1 and 7.

Figure 2 shows modulated differential scanning calorimetry (DSC) of amorphous solid dispersion of Baloxavir marboxil with PVP K-30 prepared according to Examples 1 and 7

Figure 3 shows X-ray Powder Diffraction (XRPD) pattern of amorphous solid dispersion of Baloxavir marboxil with Kollidon VA64 prepared according to Examples 2, 8 and 12.

Figure 4 shows modulated differential scanning calorimetry (DSC) of amorphous solid dispersion of Baloxavir marboxil with Kollidon VA64 prepared according to Examples 2,8 and 12.

Figure 5 shows X-ray Powder Diffraction (XRPD) pattern of amorphous solid dispersion of Baloxavir marboxil with HPMC 6CPS prepared according to Examples 3 and 9.

Figure 6 shows modulated differential scanning calorimetry (DSC) of amorphous solid dispersion of Baloxavir marboxil with HPMC 6CPS prepared according to Examples 3 and 9.

Figure 7 shows X-ray Powder Diffraction (XRPD) pattern of amorphous solid dispersion of Baloxavir marboxil with HPMC AS prepared according to Examples 4 and 10. Figure 8 shows modulated differential scanning calorimetry (DSC) of amorphous solid dispersion of Baloxavir marboxil with HPMC AS prepared according to Examples 4 and 10.

Figure 9 shows X-ray Powder Diffraction (XRPD) pattern of amorphous solid dispersion of Baloxavir marboxil with HPMC phthalate prepared according to Examples 5 and 11.

Figure 10 shows modulated differential scanning calorimetry (DSC) of amorphous solid dispersion of Baloxavir marboxil with HPMC phthalate prepared according to Examples 5 and 11.

Figure 11 shows X-ray Powder Diffraction (XRPD) pattern of amorphous solid dispersion of Baloxavir marboxil with Eudragit prepared according to Example 6.

Figure 12 shows modulated differential scanning calorimetry (DSC) of amorphous solid dispersion of Baloxavir marboxil with Eudragit prepared according to Example 6.

Figure 13 shows the pH - dependent solubility of amorphous solid dispersion of Baloxavir marboxil with Kollidon VA64, amorphous solid dispersion of Baloxavir marboxil with Eudragit and Baloxavir marboxil Form I in buffer solutions at pH 1.2

Figure 14 shows the pH - dependent solubility of amorphous solid dispersion of Baloxavir marboxil with Kollidon VA64, amorphous solid dispersion of Baloxavir marboxil with Eudragit and Baloxavir marboxil Form I in buffer solutions at pH 4.5 Figure 15 shows the pH - dependent solubility of amorphous solid dispersion of Baloxavir marboxil with Kollidon VA64, amorphous solid dispersion of Baloxavir marboxil with Eudragit and Baloxavir marboxil Form I in buffer solutions at pH 6.8

Figure 16 shows X-ray Powder Diffraction (XRPD) pattern of Form-C2 of Baloxavir marboxil.

Figure 17 shows the pH - dependent solubility of Baloxavir marboxil Form C2 with Baloxavir marboxil Form I in buffer solutions at pH 1.2

Figure 18 shows the pH - dependent solubility of Baloxavir marboxil Form C2 with Baloxavir marboxil Form I in buffer solutions at pH 4.5

Figure 19 shows the pH - dependent solubility of Baloxavir marboxil Form C2 with Baloxavir marboxil Form I in buffer solutions at pH 6.8

Detailed description of the invention

Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, and are consistent with:

As used herein, the term "amorphous" refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically, such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically second order (glass transition).

As used herein, the term "crystalline" refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order (melting point).

As used herein, the term "polymer matrix" as used herein is defined to mean compositions comprising one or more polymers in which the active agent is dispersed or included within the matrix.

As used herein, the term "PXRD" refers to powder X-ray diffraction, the term "IR" refers to infrared, the term "NMR" refers to nuclear magnetic resonance, the term "TGA" refers to thermogravimetric analysis, the term "DSC" refers to differential scanning calorimetry and the term "DVC" refers to dynamic vapour sorption isotherm.

As used herein, the term "substantially the same X-ray powder diffraction pattern" is understood to mean that those X-ray powder diffraction patterns having diffraction peaks with 20 values within ± 0.2° of the diffraction pattern referred to herein are within the scope of the referred to diffraction pattern.

As used herein, the term “solvate" refers to an association or complex of one or more solvent molecules and a compound of the invention. Such solvents for the invention may not interfere with the biological activity of the solute. Typically, the solvent used is a pharmaceutically acceptable solvent. Examples of solvents that form solvates include, but are not limited to, C1-C4 alcohol solvents such as isopropanol, ethanol, methanol, 2-pentanol, dimethyl sulfoxide (DMSO), 1, 4-dioxane, tetrahydrofuran (THF), ethyl acetate and acetone, other than water at levels of more than 1%.

The solvate can be isolated either as an amorphous form or in a crystalline form, preferably in crystalline form.

The solvate can be further isolated either in anhydrous form or hydrated form.

As used herein, the term "hydrate" refers to the complex where the solvent molecule is water. The skilled person will appreciate that the water molecules are absorbed, adsorbed or contained within a crystal lattice of the solid compounds, usually in defined stoichiometric ratio. The notation for a hydrated compound may be. nFFO, where n is the number of water molecules per formula unit of the compound. For example, in a hemihydrate, n is 0.5; in a monohydrate n is one; in a sesquihydrate, n is 1.5; in a dihydrate, n is 2; and so on.

As used herein, the term "solid dispersion" refers to the dispersion of one or more active agents in a polymer matrix at solid state prepared by a variety of methods, including spray drying, the melting (fusion), solvent, or the meltingsolvent method.

As used herein, the term "amorphous solid dispersion", refers to stable solid dispersions comprising an amorphous active agent and a polymer matrix.

As used herein, the term “a substantially amorphous state may include at least about 80%, at least about 90%, or at least 95% of the drug substance in the dispersion is in an amorphous form.

As used herein, the term "pharmaceutically acceptable" indicates that the material does not have properties that would cause a reasonably prudent medical practitioner to avoid administration of the material to a patient, taking into consideration the disease or conditions to be treated and the respective route of administration. For example, it is commonly required that such a material be essentially sterile, e.g., for injectables.

As used herein, the term "carrier" refers to a glidant, diluent, adjuvant, excipient, or vehicle with which the compound is administered. Examples of carriers are described herein and also in "Remington's Pharmaceutical Sciences" by E.W. Martin.

As used herein, the term "polymer" refers to a chemical compound or mixture of compounds consisting of repeating structural units created through a process of polymerization. Suitable polymers useful in this invention are described throughout.

As used herein, the term "pharmaceutically acceptable polymer" refers to a polymer that does not have properties that would cause a reasonably prudent medical practitioner to avoid administration of the material to a patient, taking into consideration the disease or conditions to be treated and the respective route of administration.

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

According to one aspect of the present invention, there is provided solid dispersions of Baloxavir marboxil.

A solid dispersion as such is not physically stable and the amorphous drug present in the dispersion tends to recrystallize over time. This is especially true where the concentration of the drug in the polymer is greater than its equilibrium value or supersaturated. Such dispersions may be considered a supersaturated solid solution. Such supersaturated solid solutions are not thermodynamically stable. Over time it is believed that such solid dispersions will separate into a mixture of two or more phases, one phase enriched in drug and the other phase enriched in polymer. The drug-rich phase generally contains crystalline or amorphous drug and the other phase generally contains a solid solution of the drug and polymer in which the drug is at a lower concentration (than the drugrich phase) and may be at or near equilibrium concentration in the polymer. Drug within the drug-rich phase may be crystalline or amorphous. Further, over time, the amorphous drug within the drug-rich phase that has separated from the polymer may also tend to crystallize. Separation of a drug-rich phase generally results in a decrease in bioavailability, because the bioavailability of the amorphous or crystalline form of a low-solubility drug is usually much less than its bioavailability in an amorphous drug dispersion in polymer. Thus, over time, the bioavailability of the drug in solid dispersions tends to decrease as increasing amounts of the drug separate as either amorphous or crystalline drug.

However, it has been determined by the present invention that the dispersions can be made physically stable over a relatively long period of time, i.e., up to several months or even years. Thus, by increasing the glass transition temperature (Tg) of the solid dispersion, the mobility of the drug may be decreased and hence its ability to form relatively pure domains, be they amorphous or crystalline, may be inhibited. In cases where amorphous drug-rich domains form, the drug present in such domains generally crystallizes rapidly relative to its rate of crystallization in the original dispersion. Further, by initially creating substantially homogenous dispersions, that is, dispersions wherein the drug is not present in drug-rich domains, the drug tends to be stabilized by the polymer and is not present in relatively pure drug domains that tend to be susceptible to crystallization. The solid dispersions of the present invention comprise a low-solubility drug Baloxavir marboxil and at least one polymer. At least a major portion of the drug in the dispersion is present in the amorphous, rather than the crystalline state. By “amorphous” is meant simply that the drug is in a non-crystalline state. As used herein, the term “a major portion” of the drug means that at least 80% of the drug once dispersed in the dispersion is in the amorphous form, rather than the crystalline form. Preferably, the drug in the dispersion is substantially amorphous. As used herein, substantially amorphous means that the amount of the drug in crystalline form does not exceed 10%. More preferably, the drug in the dispersion is "almost completely amorphous’ meaning that the amount of drug in the crystalline form does not exceed 5% as measured by using various techniques such as Hot Stage Microscopy (HSM), Differential Scanning Calorimetry (DSC), Scanning Electron Microscopy (SEM) optionally in combination with Energy Dispersive X-ray (EDX), and X-ray powder diffraction (XRD).

Another embodiment of the present disclosure is to provide a process for the preparation of amorphous solid dispersions of Baloxavir marboxil complexed with a pharmaceutically acceptable carrier polymer. Methods for preparing solid dispersions are known in the art and typically comprise the steps of dissolving the compound and the polymer in a common solvent and evaporating the solvent.

In general, the process for preparing solid dispersions according to the present invention comprises steps of: a) dissolving Baloxavir marboxil in a suitable solubilizing solvent or solvents mixture thereof to form a solution, b) contacting the solution with one or more pharmaceutically acceptable carrier capable of complexing with Baloxavir marboxil; c) removing the solvent; and d) isolating amorphous solid dispersion of Baloxavir marboxil.

Within the scope of the present invention is Baloxavir marboxil in any physical form (crystals, amorphous powder, any possible polymorphs, any possible solvates including the hydrate, anhydrate, complexes, semisolid thereof etc.). Included is also any analogue, derivative or active metabolite of Baloxavir marboxil, pharmaceutically acceptable salts, solvates, complexes and prodrugs thereof.

When referring to a solid dispersion we do not exclude the possibility that a proportion of the Baloxavir marboxil may be fully dissolved within the polymer used, the exact proportion, if any, will depend upon the physical properties of the Baloxavir marboxil and the polymer selected.

In an embodiment carrier is selected from copolymers, saccharides, oligosaccharides, polysaccharides, fats, waxes and urea, or a mixture thereof.

In one embodiment, the polymer used in the solid dispersion of Baloxavir marboxil is cellulosic polymer.

Polymers of cellulose derivatives which are suitable for use in the dispersions of the present invention are particularly selected to increase the glass transition temperature (Tg) of the solid dispersion thereby providing the stability to the solid dispersion. The polymer should have at least some solubility in aqueous solution at physiologically relevant pHs (e.g. pH 1-8). Virtually any such polymer which is inert should be suitable. By “inert” is merely meant not undesirably reactive or bioactive, yet still capable of positively affecting the drug's bioavailability. The polymer also should be biologically inert or non-toxic in the sense that it is acceptable for oral administration to a mammal such as a human. The amount of the polymer present in the dispersion may range from about 10 wt % to about 99 wt % of the dispersion. A preferred class of polymers of cellulose derivatives are cellulosic esters and ethers thereof, as well as mixed esters and ethers, including both so-called “enteric¹ and “non-enteric¹ polymers.

Preferred examples of cellulosic polymer useful in the solid dispersions of the subject invention include those that possess both a carboxylic acid functional aromatic substituent and an alkylate substituent. Exemplary polymers include but are not limited to: cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate succinate, hydroxypropyl methylcellulose acetate succinate, cellulose propionate phthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate trimellitate, methyl cellulose acetate trimelitate, ethyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate, trimelitate succinate, cellulose propionate trimellitate, cellulose butyrate trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetatepyridinedicarboxylate, salicylic acid cellulose acetate, hydroxypropyl salicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate, hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acid cellulose acetate, ethyl nicotinic acid cellulose acetate, and ethyl picolinic acid cellulose acetate.

Even more preferred are those cellulosics with both ester-linked phthalate or trimelitate groups and an alkylate group. Exemplary polymers of this class include: cellulose acetate phthalate, methyl cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxypropyl methylcellulose phthalate (HPMC phthalate), hydroxypropyl cellulose acetate phthalate succinate, cellulose propionate phthalate, hydroxypropyl cellulose butyrate phthalate, hydroxypropyl methyl cellulose trimellitate, cellulose acetate trimellitate, cellulose propionate trimellitate, cellulose butyrate trimellitate, cellulose acetate terephthalate, and cellulose acetate isophthalate.

Most preferred polymers are cellulose acetate phthalate, methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxypropyl methylcellulose phthalate (HPMC phthalate), HPMC (6CPS), cellulose acetate terephthalate, cellulose acetate isophthalate, and cellulose acetate trimellitate.

Suitable water soluble carriers include polymers such as polyethylene glycol, poloxamers, polyoxyethylene stearates, poly-s-caprolactone, l-ethenyl-2- pyrrolidinone homopolymer (e.g. povidone PVP K30), polyvinylpyrrolidone- polyvinylacetate copolymer PVP-PVA (Kollidon® VA64, Kollidon K640), polyvinyl caprolactam-polyvinyl acetate polyethylene glycol copolymers (e.g. Soluplus™), poly-methacrylic polymers (e.g. Eudragit, Eudragit SI 00, Eudragit LI 00, Eudragit® RS, Eudragit® RL, Eudragit® NE and polyvinylalcohol (PVA), methyl cellulose, and poly (ethylene oxide) (PEO), a-hydro-co- hydroxypoly (oxy-l,2-ethanediyl) (e.g. PEG 6000), ethyl ester of acetic acid with l-ethenyl-2-pyrrolidinone (e.g. Copovidone VA64), D-(+)-glucose, D-(+)- saccharose or urea, methylcellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, pectins, cyclodextrins, galactomannans, alginates, carragenates, Xanthan gums and mixtures thereof.

In a preferred embodiment, suitable cyclodextrins according to the invention are selected from a-cyclodextrin, P-cyclodextrin, y-cyclodextrin, hydroxypropyl a- cyclodextrin and hydroxybutenyl cyclodextrin. In the most preferred embodiment, the carrier capable of complexing with Baloxavir marboxil is selected from Kollidon VA64, PVP K30, HPMC 6CPS, HPMC AS, HPMC Phthalate and Eudragit or a mixture thereof.

In certain embodiments, the weight ratio of Baloxavir marboxil to polymer is from about 10:1 to about 1 :10. In further embodiments, the weight ratio of Baloxavir marboxil to polymer is about 5:1 to about 1 :4, or from about 5:1 to about 1 :3, or from about 5: 1 to about 1 :2, or from about 2 : 1 to about 1 :2, or from about 2 : 1 to about 1 :1. In a specific embodiment, , the weight ratio of Baloxavir marboxil to polymer is about 1 : 1. In another embodiment, the weight ratio of Baloxavir marboxil to polymer is about 2: 1. In further embodiments, the weight ratio of Baloxavir marboxil to polymer is about 5: 1, 1 :4, 1 :3, or 1 :2. Increasing the fraction of polymer to a 1 : 1 ratio may, in some instances, result in an increased bioavailability.

As used herein, the term "solubilizing solvent," refers to a solvent capable of dissolving Baloxavir Marboxil and form a solution.

As used herein, the term "solubilizing solvent," unless otherwise indicated, refers to an alcohol solvent, an ester solvent, an ether solvent, ketone solvent, nitrile solvent, halogenated solvent, hydrocarbons, polar aprotic solvent, water, or a mixture thereof.

As used herein, alcohol solvents include, but are not limited to, methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, 2-butanol, t-butanol, pentanol, or mixtures thereof; ester solvents include, but are not limited to, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, t-butyl acetate or mixtures thereof; ether solvents include, but are not limited to, diethyl ether, dimethyl ether, di-isopropyl ether, methyl-t-butyl ether, 1,4-dioxane, THF, anisole or mixtures thereof; ketone solvents include, but are not limited to, acetone, methylethyl ketone, methyl isobutyl ketone, 2- butanone or mixtures thereof; nitrile solvents include, but are not limited to, acetonitrile, propionitrile or mixtures thereof, halogenated solvents include, but are not limited to, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, or mixtures thereof; hydrocarbons include, but are not limited to, toluene, xylene, cyclohexane, hexane, heptane; aprotic solvents include, but are not limited to Dimethyl sulfoxide, 1 -Methyl 2-pyrrolidone, N,N-Dimethyl formamide and N, N-dimethyl acetamide or mixtures thereof.

In the preferred embodiment a solubilizing solvent is selected from but not limited to methanol, ethanol, isopropyl alcohol, MDC, ethylene dichloride, acetone, methyl ethyl ketone, isobutyl methyl ketone, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, acetonitrile, propionitrile, THF, anisole, dimethyl sulfoxide, 1 -Methyl 2-pyrrolidone, N, N-dimethyl formamide and N, N-dimethyl acetamide or mixtures thereof.

According to the present embodiment, the solvent may be removed by known techniques which may include, but are not limited to, evaporation, distillation, spray drying, filtration, fluid granulation, electrospinning, solvent freeze-drying, lyophilization, thin film evaporation or agitated thin film drier (ATFD). Other techniques may be used such as solvent controlled precipitation, pH-controlled precipitation and supercritical fluid technology.

Spray drying is a well-known process wherein a liquid feedstock is dispersed into droplets into a drying chamber along with a heated process gas stream to aid in solvent removal and to produce a powder product. Suitable spray drying parameters are known in the art, and it is within the knowledge of a skilled artisan in the field to select appropriate parameters for spray drying. Spray-dried solutions and the resulting dispersions may also contain various additives which are miscible with the Baloxavir marboxil /pharmaceutical carrier melt mixture, that aid in the stability, dissolution, tabletting, or processing of the dispersion. Examples of such additives include surfactants, pH-controlling substances (e.g., acids, bases, buffers), fillers, disintegrators, or binders. Such additives may be added directly to the spray-drying solution such that the additive is dissolved or suspended in the solution as a slurry. Alternatively, such additives may be added following the spraying process to aid in forming the final dosage form.

In a specific aspect of the invention, the at least one of the one or more pharmaceutically acceptable additives is selected from the group consisting of silica acid or a derivative or salt thereof including silicates, silicon dioxide and polymers thereof, magnesium aluminosilicate and/or magnesium aluminometasilicate, bentonite, kaolin, magnesium trisilicate, montmorillonite and/or saponite.

The recovered product may optionally be further dried. Drying may be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer, rotatory dryer, and the like. Drying may be carried out at temperatures from about 25 °C to about 90°C with or without vacuum and in the presence or absence of an inert atmosphere like nitrogen, argon, neon, and helium. Drying may be carried out for a desired time period to achieve the desired product purity. Drying times from about 1 to about 15 hours, or longer, are frequently adequate.

Other options of preparation of stabilized amorphous substances are methods without the use of a solvent. In these processes the active pharmaceutical ingredient (Baloxavir marboxil) is mixed with a stabilizing substance (e.g. a polymer). This mixture is heated up and melted, producing a melt. A "melt" herein is a liquid or semi-solid (e.g., rubbery) state induced by elevated temperature wherein it is possible for a first component to become homogeneously distributed in a matrix comprising a second component. Typically, the second (matrix) component, for example a polymeric carrier, is in such a state and other components, for example including a compound of Formula A, dissolve in the melt, thus forming a solution. When the mixture is melted and has a suitable viscosity for its processing. The melt is subsequently cooled down, which produces an amorphous solid substance. As some examples of these processes hot melt extrusion, hot melt granulation, high shear mixer, fluid bed granulation without the use of a solvent etc. may be mentioned.

By "elevated temperature" herein is meant a temperature above a softening point of the polymeric carrier, as affected by other components if present, such as plasticizers or surfactants. The elevated temperature attained during this part of the process can suitably be about 70°C to about 250°C.

Preparation of the melt can take place in a variety of ways. Mixing of the components can take place before, during or after formation of the melt. For example, the components can be mixed first and then subjected to elevated temperature to form the melt; alternatively mixing and melting can take place simultaneously. In one embodiment the polymeric carrier is first melted, optionally with the surfactant component, and the API is then added to the resulting melt. Usually, the melt is thoroughly mixed while at elevated temperature in order to ensure homogeneous dispersion of the API.

To aid the process the melt may be extruded with any necessary additional excipient such as a plasticiser, including super critical fluids. The melting and mixing take place in an extruders or kneaders. Suitable extruders include single-screw extruders, intermeshing screw extruders and multiscrew extruders, for example twin-screw extruders, which can be corotating or counter-rotating and, optionally, equipped with kneading disks or other screw elements for mixing or dispersing the components of the melt.

Accordingly, in the first aspect the present application provides amorphous solid dispersion of Baloxavir marboxil with PVP K30.

The stable solid dispersion of Baloxavir marboxil with PVP K30 of the present invention may be prepared as follows, a. treating Baloxavir marboxil with PVP K30 in a halogenated solvent; b. removing the solvent; and c. drying to isolate the solid dispersion consisting of amorphous Baloxavir marboxil dispersed in the PVP K30.

In an embodiment, a solid dispersion of Baloxavir marboxil with PVP K30 is characterized by XRD as depicted in Figure 1.

In an embodiment, a solid dispersion of Baloxavir marboxil with PVP K30 is further characterized by a differential scanning calorimetry curve as depicted in Figure 2.

Accordingly, in the second aspect the present application provides amorphous solid dispersion of Baloxavir marboxil with Kollidon VA64.

The stable solid dispersion of Baloxavir marboxil with Kollidon VA64 of the present invention may be prepared as follows, a. treating Baloxavir marboxil with Kollidon VA64 in a polar solvent or a halogenated solvent; b. removing the solvent; and c. drying to isolate the solid dispersion consisting of amorphous Baloxavir marboxil dispersed in the Kollidon VA64.

In an embodiment, a solid dispersion of Baloxavir marboxil with Kollidon VA64 is characterized by XRD as depicted in Figure 3.

In an embodiment, a solid dispersion of Baloxavir marboxil with Kollidon VA64 is further characterized by a differential scanning calorimetry curve as depicted in Figure 4.

Accordingly, in the third aspect the present application provides amorphous solid dispersion of Baloxavir marboxil with HPMC 6CPS.

The stable solid dispersion of Baloxavir marboxil with HPMC 6CPS of the present invention may be prepared as follows, a. treating Baloxavir marboxil with HPMC 6CPS in a halogenated solvent; b. removing the solvent; and c. drying to isolate the solid dispersion consisting of amorphous Baloxavir marboxil dispersed in the HPMC 6CPS.

In an embodiment, a solid dispersion of Baloxavir marboxil with HPMC 6CPS is characterized by XRD as depicted in Figure 5.

In an embodiment, a solid dispersion of Baloxavir marboxil with HPMC 6CPS is further characterized by a differential scanning calorimetry curve as depicted in Figure 6. Accordingly, in the fourth aspect the present application provides amorphous solid dispersion of Baloxavir marboxil with HPMC AS.

The stable solid dispersion of Baloxavir marboxil with HPMC AS of the present invention may be prepared as follows, a. treating Baloxavir marboxil with HPMC AS in a halogenated solvent; b. removing the solvent; and c. drying to isolate the solid dispersion consisting of amorphous Baloxavir marboxil dispersed in the HPMC AS.

In an embodiment, a solid dispersion of Baloxavir marboxil with HPMC AS is characterized by XRD as depicted in Figure 7.

In an embodiment, a solid dispersion of Baloxavir marboxil with HPMC AS is further characterized by a differential scanning calorimetry curve as depicted in Figure 8.

Accordingly, in the fifth aspect the present application provides amorphous solid dispersion of Baloxavir marboxil with HPMC Phthalate.

The stable solid dispersion of Baloxavir marboxil with HPMC Phthalate of the present invention may be prepared as follows, a. treating Baloxavir marboxil with HPMC Phthalate in a halogenated or a polar aprotic solvent or a mixture thereof ; b. removing the solvent; and c. drying to isolate the solid dispersion consisting of amorphous Baloxavir marboxil dispersed in the HPMC Phthalate. In an embodiment, a solid dispersion of Baloxavir marboxil with HPMC Phthalate is characterized by XRD as depicted in Figure 9.

In an embodiment, a solid dispersion of Baloxavir marboxil with HPMC Phthalate is further characterized by a differential scanning calorimetry curve as depicted in Figure 10.

Accordingly, in the sixth aspect the present application provides amorphous solid dispersion of Baloxavir marboxil with Eudragit.

The stable solid dispersion of Baloxavir marboxil with Eudragit of the present invention may be prepared as follows, a. treating Baloxavir marboxil with Eudragit in a halogenated solvent; b. removing the solvent; and c. drying to isolate the solid dispersion consisting of amorphous Baloxavir marboxil dispersed in the Eudragit.

In an embodiment, a solid dispersion of Baloxavir marboxil with Eudragit is characterized by XRD as depicted in Figure 11.

In an embodiment, a solid dispersion of Baloxavir marboxil with Eudragit is further characterized by a differential scanning calorimetry curve as depicted in Figure 12.

The pure amorphous form of Baloxavir marboxil obtained by the present invention was found to have improved yield and of improved purity.

Normally amorphous forms are hygroscopic. Amorphous solid dispersion of Baloxavir marboxil is found to be non-hygroscopic. The pure amorphous form of Baloxavir marboxil obtained according to the present invention was found to be substantially free from crystalline forms of Baloxavir marboxil. “Substantially free” from other forms of Baloxavir marboxil shall be understood to mean that the polymorphs of Baloxavir marboxil contain less than 10%, preferably less than 5%, of any other forms of Baloxavir marboxil and less than 1% of other impurities, water or solvates. Thus, the amorphous form of Baloxavir marboxil prepared according to the present invention contains less than 10% total impurities, preferably less than 6% total impurities. In a particularly preferred embodiment, the amorphous form of Baloxavir marboxil prepared according to the present invention contains less than 1% total impurities.

The amorphous solid dispersion of Baloxavir marboxil in combination with a pharmaceutically acceptable carrier is stable and reproducible.

The amorphous solid dispersion of Baloxavir marboxil demonstrates increased bioavailability, a reduction or elimination of food-effect, a reduction in negative drug-drug interactions with acid suppressive therapies, a reduction in variability across patient populations, and an improvement in dose linearity at higher doses.

Thus, amorphous solid dispersion of Baloxavir marboxil of the present invention is suitable for formulating Baloxavir marboxil. The solid dispersions of the present invention may be formulated together with one or more pharmaceutically acceptable carrier, glidant, diluent, or excipient, as solid compositions for oral administration in the form of tablets, capsules, suspensions, dispersions, injectables, powders, granules or other pharmaceutical forms.

According to another aspect, the invention provides a method of treating or preventing influenza virus disease in a subject which method comprises administering therapeutically effective amounts of a pharmaceutical composition comprising solid dispersion of amorphous Baloxavir marboxil dispersed in a pharmaceutical carrier selected from the group comprising of PVP K30, Kollidon VA64, HPMC 6CPS, hydroxypropyl methylcellulose acetate succinate (HPMC AS), HPMC Phthalate, Eudragit and along with one or more suitable pharmaceutical carriers, in the form of tablets, capsules, suspensions, dispersions, injectables, powders, granules or other pharmaceutical forms.

An amorphous solid dispersion of Baloxavir marboxil, may be formulated in accordance with standard pharmaceutical practice for use in a therapeutic combination for therapeutic treatment (including prophylactic treatment) of influenza virus in mammals including humans.

According to yet another aspect of the present invention there is provided use of amorphous solid dispersion of Baloxavir marboxil as described above, in the preparation of a medicament useful in treating or preventing influenza virus.

Thus, in another aspect, the present invention provides the crystalline Baloxavir marboxil which is herein and in the claims designated as “Form-C2”, which has good flow characteristics.

The novel polymorphs of the present invention may be isolated in pseudo polymorphic form as a solvate optionally in hydrated form, or as a non-hydrated solvate.

As polymorphic forms are reliably characterized by peak positions in the X-ray diffractogram, the polymorphs of the present invention have been characterized by powder X-ray diffraction spectroscopy which produces a fingerprint of the crystalline form and is able to distinguish it from all other crystalline and amorphous forms of Baloxavir marboxil. Measurements of 20 values are accurate to within ± 0.2 degrees. All the powder diffraction patterns were measured on a PANalytical X’Pert³ X-ray powder diffractometer with a copper-

K-a radiation source.

In one embodiment, the crystalline Form-C2 is characterized by an X-ray powder diffraction pattern comprising the following 20 values measured using CuKa, radiation.

In an embodiment, the crystalline Form-C2 has an XRD pattern with characteristics peaks at 5.06, 8.65, 11.22, 12.31, 13.38, 15.12 and 19.48 ± O.2°20. The XRPD diffractogram may comprise further peaks at 16.56, 18.23 and 26.36 ± 0.2 °20. The XRPD diffractogram may be as depicted in Figure 16.

Those skilled in the art would recognize that Form-C2 may be further characterized by other methods including, but not limited to IR, solid state NMR, DSC, TGA, intrinsic dissolution and Raman spectroscopy.

Preferably the crystalline Form- C2 of Baloxavir marboxil, has a crystalline purity of at least 80%, more preferably at least 90%, more preferably at least 95%, most preferably at least 99% by weight.

The invention encompasses a process for preparing the crystalline Form-C2 of Baloxavir marboxil comprising, a. treating Baloxavir marboxil in a suitable first solvent or mixture of solvents; b. treating with second solvent; c. isolating the precipitated solid; and d. drying the solid.

The Baloxavir marboxil used for the above process, as well as for the following processes, may be in any polymorphic form or in a mixture of any polymorphic forms such as hydrated, solvated, non-solvated or mixture of hydrated, solvated or non-solvated forms or amorphous form thereof.

In an embodiment, first solvent and second solvent are different. In an embodiment second solvent is an anti-solvent.

In one embodiment treating includes mixing, dissolving, slurring or suspending the Baloxavir marboxil in the first solvent.

Suitable first solvent includes polar solvent and non polar solvent. Polar solvents include but are not limited to C1-C4 alcohol such as methanol, ethanol, isopropanol, n-propanol, t-butanol, iso-butanol, trifluoro ethanol and the like; ketones such as acetone, butanone, and methyl isobutyl ketone, methyl isobutyl ketone, methyl vinyl ketone; nitriles such as acetonitrile, propionitrile; polar aprotic solvents such as dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, trioxane, N-methyl pyrrolidone and dimethyl acetamide; halogenated hydrocarbons such as MDC, EDC, chloroform, carbon tetrachloride; aliphatic hydrocarbons such as heptane, hexane;, aromatic hydrocarbons such as toluene, xylene, chlorobenzene and the like or mixture thereof.

Preferably, Baloxavir marboxil is treated with first solvent at about -20°C to about reflux temperature of the solvent used.

Preferably, the solution is maintained at about -20°C to about 30°C.

Suitable second solvent includes polar solvent and non-polar solvent. Polar solvents include but are not limited to water, ethers such as dimethyl ether, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1 ,4-dioxane; ketones such as isobutyl methyl ketone, ethyl methyl ketone, acetone, methyl t-butyl ketone, methyl isopropyl ketone, methyl amyl ketone, and diisobutyl ketone. Non-polar solvents include but are not limited to hexane, heptane, toluene, xylene, tetraline, chlorobezene and the like or mixture thereof.

Prior to the addition, preferably, second solvent is maintained at about -20°C to about 30°C, preferably at about -15°C to about 15°C.

Prior to the addition, optionally Form C2 seeds are charged to the second solvent solution to form the seed slurry.

In one embodiment, solution of first solvent is added to the either solution or slurry of second solvent while stirring.

In another embodiment, solution or slurry of second solvent is added to the solution of first solvent while stirring.

Typically, after the addition, a slurry is obtained. The obtained slurry is preferably maintained while stirring. Preferably, stirring is done for a period of about 15 minutes to about 10 hours, more preferably, for about 30 minutes to about 5 hours at about -20°C to about 30°C, preferably at about -15°C to about 15°C.

Typically a precipitate is formed in the solution. Preferably, removing the precipitate is done by filtration.

Preferably, the obtained precipitate is dried to obtain a solid form. The drying may be done in a vacuum oven at a temperature of about 30°C to about 60 °C, preferably at about 40°C to about 50 °C. Preferably, drying is performed for about 1 hour to about 10 hours, more preferably, for about 2 to about 5 hours. According to another aspect of the present invention, there is provided a pharmaceutical composition comprising polymorphic form of Baloxavir marboxil as described above, together with one or more pharmaceutically acceptable carrier, glidant, diluent, or excipient.

A polymorph form of Baloxavir marboxil, Formula A, may be formulated in accordance with standard pharmaceutical practice for use in a therapeutic combination for therapeutic treatment (including prophylactic treatment) of influenza virus in mammals including humans.

According to yet another aspect of the present invention there is provided use of polymorphic Form of Baloxavir marboxil as described above, in the preparation of a medicament useful in treating or preventing influenza virus.

The invention will now be further described by the following examples, which are illustrative rather than limiting.

Examples

Example 1

Preparation of Amorphous solid dispersion of Baloxavir marboxil with PVP K30

Baloxavir Marboxil (0.5 g) and PVP K30 (0.5 g) were dissolved in Dichloromethane (10 ml) at 20-25°C and stirred at 25-30°C for 10-15 minutes to get clear solution. The resultant clear solution was concentrated on a rotavapor under reduced pressure at 40°C to yield 0.8 g amorphous solid dispersion of Baloxavir marboxil with PVP K30.

The X-ray powder pattern and the glass transition temperature of 116.12°C of Amorphous solid dispersion of Baloxavir marboxil with PVP K30 are depicted in Figs 1 and 2 respectively. Example 2

Preparation of Amorphous solid dispersion of Baloxavir marboxil with Kollidon VA64

Baloxavir Marboxil (0.5 g) and Kollidon VA64 (0.5 g) were dissolved in Dichloromethane (10 ml) at 20-25°C and stirred at 25-30°C for 10-15 minutes to get clear solution. The resultant clear solution was concentrated on a rotavapor under reduced pressure at 40°C to yield 0.85 g amorphous solid dispersion of Baloxavir Marboxil with Kollidon VA64.

The X-ray powder pattern and the glass transition temperature of 115.55°C of Amorphous solid dispersion of Baloxavir marboxil with Kollidon VA64 are depicted in Figs 3 and 4 respectively.

Example 3

Preparation of Amorphous solid dispersion of Baloxavir marboxil with HPMC (6 CPS)

Baloxavir Marboxil (0.5 g) and HPMC 6CPS (0.5 g) were dissolved in Dichloromethane (10 ml) at 20-25°C and stirred at 25-30°C for 10-15 minutes to get clear solution. The resultant clear solution was concentrated on a rotavapor under reduced pressure at 40°C to yield 0.85 g amorphous solid dispersions of Baloxavir Marboxil with HPMC 6CPS.

The X-ray powder pattern and the glass transition temperature of 116.40°C of Amorphous solid dispersion of Baloxavir marboxil with HPMC 6CPS are depicted in Figs 5 and 6 respectively. Example 4

Preparation of Amorphous solid dispersion of Baloxavir marboxil with HPMC AS

Baloxavir Marboxil (0.5 g) and HPMC AS (0.5 g) were dissolved in mixture of Dichloromethane (10 ml) at 20-25°C and stirred at 25-30°C for 10-15 minutes to get clear solution. The resultant clear solution was concentrated on a rotavapor under reduced pressure at 40°C to yield 0.9 g amorphous solid dispersion of Baloxavir Marboxil with HPMC AS.

The X-ray powder pattern and the glass transition temperature of 117.28°C of Amorphous solid dispersion of Baloxavir marboxil with HPMC AS are depicted in Figs 7 and 8 respectively.

Example 5

Preparation of Amorphous solid dispersion of Baloxavir marboxil with HPMC Phthalate

Baloxavir Marboxil (0.5 g) and HPMC Phthalate (0.5 gm) were dissolved in Dichloromethane (20 ml) at 20-25°C and stirred at 25-30°C for 10-15 minutes to get clear solution. The resultant clear solution was concentrated on a rotavapor under reduced pressure at 40°C to yield 0.8 g amorphous solid dispersion of Baloxavir Marboxil with HPMC Phthalate.

The X-ray powder pattern and the glass transition temperature of 120.70°C of Amorphous solid dispersion of Baloxavir marboxil with HPMC Phthalate are depicted in Figs 9 and 10 respectively.

Example 6

Preparation of Amorphous solid dispersion of Baloxavir marboxil with

Eudragit Baloxavir Marboxil (0.5 g) and Eudragit (0.5 g) were dissolved in Dichloromethane (10 ml) at 20-25°C and stirred at 25-30°C for 10-15 minutes to get clear solution. The resultant clear solution was concentrated on a rotavapor under reduced pressure at 40°C to yield 0.85 g amorphous solid dispersion of Baloxavir Marboxil with Eudragit.

The X-ray powder pattern and the glass transition temperature of 119.30°C of Amorphous solid dispersion of Baloxavir marboxil with Eudragit are depicted in Figs 11 and 12 respectively.

Example 7

Preparation of Amorphous solid dispersion of Baloxavir marboxil with PVP K30

Baloxavir Marboxil (1.0 g) and PVP K30 (1.0 g) were dissolved in Dichloromethane (20 ml) at 20-25 °C. Clear solution was subjected to spraydrying using Buchi mini spray dryer (Model: B-290) with set parameters Aspirator 100% , Inlet temperature 70°C, Nitrogen flow 40, Pump flow rate 20% and outlet observed temperature 40-45°C to yield amorphous solid dispersion of Baloxavir marboxil with PVP K30.

Example 8

Baloxavir Marboxil (1.0 g) and Kollidon VA64 (1.0 g) were dissolved in Dichloromethane (20 ml) at 20-25 °C. Clear solution was subjected to spraydrying using Buchi mini spray dryer (Model: B-290) with set parameters Aspirator 100% , Inlet temperature 70°C, Nitrogen flow 40, Pump flow rate 20% and outlet observed temperature 40-45°C to yield amorphous solid dispersion of Baloxavir Marboxil with Kollidon VA64. Example 9

Baloxavir Marboxil (1.0 g) and HPMC 6CPS (1.0 g) were dissolved in Dichloromethane (20 ml) and Methanol (20 ml) at 20-25 °C. Clear solution was subjected to spray-drying using Buchi mini spray dryer (Model: B-290) with set parameters Aspirator 100% , Inlet temperature 75°C, Nitrogen flow 40, Pump flow rate 20% and outlet observed temperature 40-45 °C to yield amorphous solid dispersions of Baloxavir Marboxil with HPMC 6CPS.

Example 10

Preparation of Amorphous solid dispersion of Baloxavir marboxil with HPMC AS

Baloxavir Marboxil (1.0 g) and HPMC AS (1.0 g) were dissolved in Dichloromethane (20 ml) at 20-25 °C. Clear solution was subjected to spraydrying using Buchi mini spray dryer (Model: B-290) with set parameters Aspirator 100% , Inlet temperature 75°C, Nitrogen flow 40, Pump flow rate 20% and outlet observed temperature 40-45°C to yield amorphous solid dispersion of Baloxavir Marboxil with HPMC AS

Example 11

Baloxavir Marboxil (1.0 g) and HPMC Phthalate (1.0 gm) were dissolved in Dichloromethane (20 ml) and Acetone (10 ml ) at 20-25 °C. Clear solution was subjected to spray-drying using Buchi mini spray dryer (Model: B-290) with set parameters Aspirator 100% , Inlet temperature 75°C, Nitrogen flow 40, Pump flow rate 20% and outlet observed temperature 40-45 °C to yield amorphous solid dispersion of Baloxavir Marboxil with HPMC Phthalate. Example 12

Baloxavir Marboxil (18.0 g) and Kollidon VA64 (18.0 g) were dissolved in Acetone (400 ml) at 40-45°C. The solution was clarified by filtration. The clear solution was subjected to spray-drying using Buchi mini spray dryer (Model: B- 290) with set parameters. The spray dried material was dried further at 40°C in VTD for 6-8 hours to yield amorphous solid dispersion of Baloxavir Marboxil with Kollidon VA64.

Parameters:

Aspirator: 100%

Nitrogen pressure: 40

Inlet temperature: 60°C

Feeding pump flow rate: 6-10% (~3.3 ml /min)

Outlet temperature: 44-48°C (Observed)

Chiller set temperature at inert loop B-295: -20°C Dry weight : 26 gm.

Example 13

Process for the preparation of Baloxavir marboxil Form-C2

Charged 3 ml of chlorobenzene into a clean RBF and chilled to below -15°C. Charged 1 g of Baloxavir marboxil amorphous form into the above chilled solvent and maintained it at same temperature for 20 min. Charged 8 ml of prechilled methyl tertiary butyl ether (MTBE) into the above solution and continued the stirring for 30 mins to 1 hour at -15°C. The solids were isolated by filtration and dried under vacuum at 40°C for 3 hours resulted the title compound.

The isolated solids were characterized by XRPD as depicted in Figure 16. Example 14

Process for the preparation of Baloxavir marboxil Form-C2

Dissolved Baloxavir marboxil amorphous form (4 g) in Trifluoro ethanol (4 ml) at 25°C. In another RBF was taken MTBE (80 ml) and chilled it to below -15°C. The chilled solution was seeded with Baloxavir marboxil Form-C2 (0.4 g). To the obtained seed slurry, clear solution of Baloxavir marboxil was added slowly and the reaction mass was maintained at -15°C for about 3 hours. The solids were isolated by filtration and dried under vacuum at 40°C for 3 hours resulted the title compound

The isolated solids were characterized by XRPD as depicted in Figure 16.

Example 15

Process for the preparation of Baloxavir marboxil Form-C2

Dissolved Baloxavir marboxil crystalline Form-I (4 g) in Trifluoro ethanol (6 ml) at 25°C. In another RBF was taken MTBE (80 ml) and chilled it to below - 15°C. The chilled solution was seeded with Baloxavir marboxil Form-C2 (0.4 g). To the obtained seed slurry, clear solution of Baloxavir marboxil was added slowly and the reaction mass was maintained at -15°C for about 4 hours. The solids were isolated by filtration and dried under vacuum at 40°C for 3 hours resulted the title compound

The isolated solids were characterized by XRPD as depicted in Figure 16.

Example 16

Determination of the solubility of Amorphous solid dispersions of Baloxavir marboxil in buffered solutions (Solubility as a Function of pH)

The aqueous solubility of Amorphous solid dispersions of Baloxavir marboxil with Kollidon VA64 and Baloxavir marboxil with Eudragit were compared with Baloxavir marboxil Form I. The solubility of solid dispersion of the invention was determined at pH 1.2 (Gastric Buffer), pH 4.5 (Acetate Buffer) and pH 6.8 (Intestinal Buffer), by suspending 0.3 g of Form I and 0.6 g of solid dispersions in 30 mL of corresponding aqueous solution. The samples were allowed to equilibrate at ambient temperature for at least 24 hours for pH 1.2, 4.5 and 6.8 Buffers. The supernatant was filtered and used for the solubility determination by UV-VIS spectroscopy. The solid residue was analyzed by XRPD.

The solubility data obtained are shown in Tables 1 to 3. The data and Figures 13-15 indicated that the solubility is pH and temperature dependent.

Table 1 H solubility data at pH 1.2

Table 2 H solubility data at pH 4.5

Table 3 H solubility data at pH 6.8

The above pH solubility data suggests that Amorphous solid dispersion of Baloxavir marboxil with Kollidon VA64 is having about 2 folds higher solubility in comparison to Baloxavir marboxil Form I in all the above studied pH buffers.

The above pH solubility data suggests that Amorphous solid dispersion of Baloxavir marboxil with Eudragit is having about 10 folds, 1.8 folds and 8 folds higher solubility in comparison to Baloxavir marboxil Form I at 1.2, 4.5 and 6.8 pH buffers respectively.

Example 17

Determination of the solubility of Baloxavir marboxil Form C2 in buffered solutions (Solubility as a Function of pH) The aqueous solubility of Baloxavir marboxil Form C2 was compared with Baloxavir marboxil Form I. The solubility of Form C2 of the invention was determined at pH 1.2 (Gastric Buffer), pH 4.5 (Acetate Buffer) and pH 6.8 (Intestinal Buffer), by suspending 0.3 g of Form C2 and Form I in 30 mL of corresponding aqueous solution. The samples were allowed to equilibrate at ambient temperature for at least 24 hours for pH 1.2, 4.5 and 6.8 Buffers. The supernatant was filtered and used for the solubility determination by UV-VIS spectroscopy. The solid residue was analyzed by XRPD.

The solubility data obtained are shown in Tables 4 to 6. The data and Figures 17-19 indicated that the solubility is pH and temperature dependent.

Table 4 H solubility data at pH 1.2

Table 5 H solubility data at pH 4.5

Table 6 H solubility data at pH 6.8

On the other side Baloxavir marboxil Form C2 is having comparable solubility with Baloxavir marboxil Form I in all the above studied pH buffers.

Claims

43 We Claims

1. An amorphous solid dispersion of Baloxavir marboxil, comprising Baloxavir marboxil complexed with a pharmaceutically acceptable carrier.

2. The amorphous solid dispersion of claim 1, wherein Baloxavir marboxil to a pharmaceutically acceptable carrier is in the weight ratio of about 10:1 to about 1 : 10.

3. The amorphous solid dispersion of claim 1 or 2, wherein the pharmaceutically acceptable carriers may be one or more of copolymers, saccharides, oligosaccharides, polysaccharides, fats, waxes and urea, or a mixture thereof.

4. The amorphous solid dispersion of claim 3, wherein the pharmaceutically acceptable carriers may be one or more of Kollidon VA64, PVP K30, HPMC 6CPS, HPMC AS, HPMC Phthalate and Eudragit or a mixture thereof.

5. A process for the preparation of amorphous solid dispersion of Baloxavir marboxil, as claimed in any preceding claims which comprises: a. dissolving Baloxavir marboxil in a suitable solubilizing solvent or solvents mixture thereof to form a solution; b. contacting the solution with one or more pharmaceutically acceptable carrier capable of complexing with Baloxavir marboxil; c. removing the solvent; and d. isolating amorphous solid dispersion of Baloxavir marboxil 44 . The process of claim 5, wherein solubilizing solvent is selected from alcohol solvent, an ester solvent, an ether solvent, ketone solvent, nitrile solvent, halogenated solvent, hydrocarbons, polar aprotic solvent, water, or a mixture thereof . The amorphous solid dispersion of claim 4, wherein the pharmaceutically acceptable carrier is Kollidon VA64. . The amorphous solid dispersion of claim 7, having powdered X-ray diffractogram as depicted in Figure 3. . The amorphous solid dispersion of claim 7, having a differential scanning calorimetry curve as depicted in Figure 4. 0. A process for the preparation of amorphous solid dispersion of Baloxavir marboxil with Kollidon VA64 which comprises: a. treating Baloxavir marboxil with Kollidon VA64 in a polar solvent or halogenated solvent; b. removing the solvent; and c. drying to isolate the solid dispersion consisting of amorphous Baloxavir marboxil dispersed in the Kollidon VA64. 1. The amorphous solid dispersion of claim 4, wherein the pharmaceutically acceptable carrier is PVP K30. 2. The amorphous solid dispersion of claim 11, having powdered X-ray diffractogram as depicted in Figure 1. 45 3. The amorphous solid dispersion of claim 11, having a differential scanning calorimetry curve as depicted in Figure 2. 4. A process for the preparation of amorphous solid dispersion of Baloxavir marboxil with PVP K30 which comprises: a. treating Baloxavir marboxil with PVP K30 in a halogenated solvent; b. removing the solvent; and c. drying to isolate the solid dispersion consisting of amorphous Baloxavir marboxil dispersed in the PVP K30. 5. The amorphous solid dispersion of claim 4, wherein the pharmaceutically acceptable carrier is HPMC 6CPS.

6. The amorphous solid dispersion of claim 15, having powdered X-ray diffractogram as depicted in Figure 5.

7. The amorphous solid dispersion of claim 15, having a differential scanning calorimetry curve as depicted in Figure 6.

8. A process for the preparation of amorphous solid dispersion of Baloxavir marboxil with HPMC 6CPS which comprises: a. treating Baloxavir marboxil with HPMC 6CPS in a halogenated solvent; b. removing the solvent; and c. drying to isolate the solid dispersion consisting of amorphous Baloxavir marboxil dispersed in the HPMC 6CPS.

9. The amorphous solid dispersion of claim 4, wherein the pharmaceutically acceptable carrier is HPMC AS. 0. The amorphous solid dispersion of claim 19, having powdered X-ray diffractogram as depicted in Figure 7. 1. The amorphous solid dispersion of claim 19, having a differential scanning calorimetry curve as depicted in Figure 8. 2. A process for the preparation of amorphous solid dispersion of Baloxavir marboxil with HPMC AS which comprises: a. treating Baloxavir marboxil with HPMC AS in a halogenated solvent; b. removing the solvent; and c. drying to isolate the solid dispersion consisting of amorphous Baloxavir marboxil dispersed in the HPMC AS. 3. The amorphous solid dispersion of claim 4, wherein the pharmaceutically acceptable carrier is HPMC Phthalate. 4. The amorphous solid dispersion of claim 23, having powdered X-ray diffractogram as depicted in Figure 9. 5. The amorphous solid dispersion of claim 23, having a differential scanning calorimetry curve as depicted in Figure 10. 6. A process for the preparation of amorphous solid dispersion of Baloxavir marboxil with HPMC Phthalate which comprises: a. treating Baloxavir marboxil with HPMC Phthalate in a halogenated solvent or a polar aprotic solvent or a mixture thereof; b. removing the solvent; and c. drying to isolate the solid dispersion consisting of amorphous Baloxavir marboxil dispersed in the HPMC Phthalate. 7. The amorphous solid dispersion of claim 4, wherein the pharmaceutically acceptable carrier is Eudragit. 8. The amorphous solid dispersion of claim 27, having powdered X-ray diffractogram as depicted in Figure 11. 9. The amorphous solid dispersion of claim 27, having a differential scanning calorimetry curve as depicted in Figure 12. 0. A process for the preparation of amorphous solid dispersion of Baloxavir marboxil with Eudragit which comprises: a. treating Baloxavir marboxil with Eudragit in a halogenated solvent; b. removing the solvent; and c. drying to isolate the solid dispersion consisting of amorphous Baloxavir marboxil dispersed in the Eudragit. 1. A crystalline Baloxavir marboxil Form C2. 2. The crystalline Baloxavir marboxil Form C2 of claim 31 characterized by having an XRPD diffractogram comprising peaks at 5.06, 8.65, 11.22, 12.31, 13.38, 15.12 and 19.48 ± O.2°20. 3. The crystalline Baloxavir marboxil Form C2 of claim 32 wherein the XRPD diffractogram comprising further peaks at 16.56, 18.23 and 26.36 ± O.2°20. 4. The crystalline Baloxavir marboxil Form C2 as claimed in any one of claims 31 to 33 characterized by the XRPD diffractogram as depicted in Figure 16. 48 The crystalline Baloxavir marboxil Form C2 as claimed in any one of claims 31 to 33, wherein the crystalline form is an anhydrous form. A process for the preparation of crystalline Baloxavir marboxil Form

C2 which comprises: a. treating Baloxavir marboxil in a suitable first solvent or mixture of solvents; b. treating with second solvent; c. isolating the precipitated solid; and d. drying the solid. The process of claim 34, further comprises: (bl) optionally seeding the solution from step (b) with appropriate seed and allowing the solution to stir until a slurry forms. A pharmaceutical composition comprising solid dispersions of Baloxavir marboxil, complexed with a pharmaceutically acceptable carrier of any one of the claims 1 to 30, optionally comprising one or more pharmaceutically acceptable excipients. A method for the prevention or treatment of influenza virus which method comprises administering solid dispersions of Baloxavir marboxil complexed with a pharmaceutically acceptable carrier of any one of the claims 1 to 30 to a patient in need thereof. Use of solid dispersions of Baloxavir marboxil complexed with a pharmaceutically acceptable carrier of any one of the claims 1 to 30, in the preparation of a medicament useful in treating or preventing influenza virus. 49 A pharmaceutical composition comprising crystalline Baloxavir marboxil Form C2 of any one of the claims 31 to 37, optionally comprising one or more pharmaceutically acceptable excipients. A method for the prevention or treatment of influenza virus which method comprises administering crystalline Baloxavir marboxil Form C2 of any one of the claims 31 to 37 to a patient in need thereof. Use of crystalline Baloxavir marboxil Form C2 of any one of the claims 31 to 37, in the preparation of a medicament useful in treating or preventing influenza virus.