DESC:The following specification particularly describes the invention and the manner in which it is to be performed:
AMORPHOUS SOLID DISPERSIONS OF ASUNDEXIAN

CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of Indian provisional patent application No. 202441007648 filed on 5 Feb 2024.

FIELD OF THE INVENTION
The present invention relates to amorphous solid dispersions of Asundexian, and pharmaceutical compositions thereof.

BACKGROUND OF THE INVENTION
The drug compound, having the International Non-Proprietary Name Asundexian has a chemical name 4-[[(2S)-2-[4-[5-chloro-2-[4-(trifluoromethyl)triazol-1-yl]phenyl]-5-methoxy-2-oxopyridin-1-yl]butanoyl]amino]-2-fluorobenzamide, and has the structure of Formula I

I
Asundexian is a small molecule factor XIa inhibitor developed by Bayer for the treatment of thrombotic disorders such as Thromboembolic events, Atrial Fibrillation, Acute Myocardial Infarction, and Non-cardioembolic Ischemic Stroke.
PCT publication WO 2017/005725 A1 describes substituted oxopyridine derivatives including Asundexian, their synthetic methods and their pharmaceutical compositions and their use as potent factor XIa inhibitors. Preparation of racemic Asundexian is exemplified in example-234 and separation of enantiomers using chiral HPLC is exemplified example-235.
PCT publication WO 2022/189278 A1 describes amorphous solid dispersions and solid pharmaceutical dosage forms of Asundexian for oral administration.
PCT publication WO 2022/189279 A1 describes crystalline modification I and crystalline modification II of Asundexian, process for their preparation and their use in pharmaceutical compositions.
PCT publication WO 2022/189280 A1 describes certain solvate forms of Asundexian, their preparative methods and pharmaceutical compositions.
PCT publication WO 2023/174399 A1 describes crystalline form A of Asundexian, process for their preparation and their use in pharmaceutical compositions.
The occurrences of different solid forms are possible for some compounds. A single compound may exist in different solid forms. Various solid forms of a drug substance can have different chemical and physical properties, including melting point, chemical reactivity, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can have a direct effect on the ability to process and/or manufacture the drug substance and the drug product, as well as on drug product stability, dissolution, and bioavailability. Thus, solid forms can affect the quality, safety, and efficacy of the drug product, regulatory authorities require that efforts shall be made to identify all solid forms, e.g., crystalline, amorphous, solvated, etc., of drug substance.
It has been "disclosed in the art that amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to crystalline forms [Konne T., Chem pharm Bull., 38, 2003(1990)]. Typically, the more crystalline the pharmaceutical agent, the lower is its bioavailability or vice versa, reducing the degree of crystallinity has a positive effect on bioavailability. Amorphous material generally offers interesting properties such as higher dissolution rate and solubility than crystalline forms, typically resulting in improved bioavailability.
New solid state forms and solid dispersions of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional solid dispersions of Asundexian.

SUMMARY OF THE INVENTION
The present invention generally relates to amorphous solid dispersions of Asundexian, their preparative methods and pharmaceutical compositions thereof.
In one aspect, the present invention provides process for preparation of amorphous solid dispersion comprising asundexian and one or more pharmaceutically acceptable polymer.
In another aspect, the present invention provides process for preparation of amorphous solid dispersion comprising asundexian and one or more pharmaceutically acceptable polymer, the process comprising:
(a) providing a solution of asundexian in a suitable solvent,
(b) adding a pharmaceutically acceptable polymer to the solution of step (a), and
(c) isolating the amorphous solid dispersion comprising asundexian.
In another aspect the present application provides solid pharmaceutical dosage forms of asundexian wherein asundexian exists in stable amorphous form.
In another aspect the present application provides process for preparation of amorphous form of Asundexian.
In another aspect the present application provides pharmaceutical compositions useful for oral administration comprising amorphous solid dispersion comprising Asundexian and one or more pharmaceutically acceptable polymer.

BRIEF DESCRIPTION OF DRAWINGS
Figure-1 is powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion of Asundexian with HPMC AS according to example 1.
Figure-2 is powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion of Asundexian with Soluplus according to example 2.
Figure-3 is powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion of Asundexian with Eudragit L100-55 according to example 1.
Figure-4 is powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion of Asundexian with HPMC E5 according to example 1.
Figure-5 is powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion of Asundexian with PVAP according to example 1.
Figure-6 is overlay of powder X-ray diffraction (PXRD) pattern of solid dosage of Asundexian prepared according to example 6 and Placebo.
Figure-7 is overlay of powder X-ray diffraction (PXRD) pattern of solid dosage of Asundexian prepared according to example 7 and Placebo.
Figure-8 is overlay of powder X-ray diffraction (PXRD) pattern of solid dosage of Asundexian prepared according to example 8 and Placebo.
Figure-9 is overlay of powder X-ray diffraction (PXRD) pattern of solid dosage of Asundexian prepared according to example 9 and Placebo.
Figure-10 is overlay of powder X-ray diffraction (PXRD) pattern of solid dosage of Asundexian prepared according to example 10 and Placebo.
Figure-11 is overlay of powder X-ray diffraction (PXRD) pattern of solid dosage of Asundexian prepared according to example 11 and Placebo.
Figure-12 is overlay of powder X-ray diffraction (PXRD) pattern of solid dosage of Asundexian prepared according to example 12 and Placebo.
Figure-13 is overlay of powder X-ray diffraction (PXRD) pattern of solid dosage of Asundexian prepared according to example 13 and Placebo.
Figure-14 is powder X-ray diffraction (PXRD) pattern of amorphous Asundexian prepared according to example 14.

DETAILED DESCRITPION OF THE INVENTION
The present invention provides amorphous solid dispersions and solid pharmaceutical dosage forms of Asundexian, their preparative methods and pharmaceutical compositions thereof.
In another aspect, the present invention provides process for preparation of amorphous solid dispersion comprising asundexian and one or more pharmaceutically acceptable polymer, the process comprising:
(a) providing a solution of asundexian in a suitable solvent,
(b) adding a pharmaceutically acceptable polymer to the solution of step (a), and
(c) isolating the amorphous solid dispersion comprising asundexian.
Providing a solution in step (a) includes direct use of a reaction mixture containing asundexian that is obtained in the course of its synthesis or dissolving asundexian in a suitable solvent. Any physical form of asundexian may be utilized for providing the solution of asundexian in step (a).
The solvent may be selected from the group consisting of alcohols, such as methanol, ethanol, 2-propanol, n- propanol, n-butanol, isoamyl alcohol, 1,2-propanediol, S-(+)-1,2-propanediol and ethylene glycol; ethers, such as diisopropyl ether, dibutyl ether, cyclopentyl methyl ether, methyl tert-butyl ether, diethyl ether, 1,4-dioxane, tetrahydrofuran (THF), and methyl THF; esters, such as methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate and t-butyl acetate; ketones, such as acetone, methyl ethyl ketone, cyclohexanone and methyl isobutyl ketone; halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; nitriles, such as acetonitrile; hydrocarbons include but not limited to such as toluene, xylene, pentane, hexane, heptane and cyclohexane; polar aprotic solvents, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl 2-pyrrolidone, dimethylsulfoxide, pyridine, phenol, DMA, acetic acid and the like; water; or mixtures thereof. Preferably the solvent is selected from THE group consisting of methanol, ethanol, isopropanol, acetone, dichloromethane and THF.
The step (b) involves addition of a pharmaceutically acceptable polymer to the solution obtained in step (a).
Suitable polymers for use in the subject solid dispersions include, but are not limited to Poloxamer, Gelucire, Tocopheryl polyethylene glycol succinate (TPGS), Polyvinyl acetate Phthalate (PVAP), Soluplus, Labrasol, Sucrose acetate Isobutyrate (SAIB), Polyvinylpyrrolidone (PVP), Hydroxypropyl methyl cellulose (HPMC), Hydroxypropyl methyl cellulose acetate succinate (HPMC-AS) and Eudragit. Preferably, the pharmaceutically acceptable polymer is selected from the group consisting of Poloxamer, Gelucire, Tocopheryl polyethylene glycol succinate (TPGS), Polyvinyl acetate Phthalate (PVAP).
Asundexian and the polymer are mixed in a ratio of 1 to 0.5 up to 1 to 10. Preferably in a ratio of asundexian to polymer of 1:0.5 to 1:4.
The polymer is added to the asundexian solution and is stirred for about 10 minutes to about 10 hours at a suitable temperature to get a clear solution.
Step (c) involves isolating the amorphous solid dispersion. The amorphous solid dispersion is isolated by removing the solvent.
The removal of solvent may be carried out by methods known in the art or any procedure disclosed in the present application. In preferred embodiments, removal of solvent may include, but not limited to: solvent evaporation or sublimation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Büchi® Rotavapor®, spray drying, freeze drying (Lyophilization), agitated thin film drying and the like.
The resulting asundexian solid dispersion may optionally be further dried. Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve a desired purity of the product, such as, for example, about 1 to about 15 hours, or longer.
In another aspect, the amorphous solid dispersion of asundexian of the present invention are stable under thermal, humid and stress conditions.
The amorphous solid dispersion of asundexian disclosed herein may be characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), modulated differential scanning calorimetry (mDSC), scanning electron microscopy (SEM), Karl Fischer water titration (KF), residual solvent, particle size, bulk density, tapped density, high pressure liquid chromatography (HPLC).
In another aspect, the amorphous solid dispersion of asundexian of the present invention or the pharmaceutical compositions thereof comprises asundexian with a chemical purity of at least 99% by HPLC or at least 99.5% by HPLC or at least 99.9% by HPLC.
In another aspect, the present application provides a solid pharmaceutical dosage form comprising amorphous solid dispersion of asundexian and one or more pharmaceutically acceptable excipients.
In another aspect, the present application provides a process for preparation of a solid pharmaceutical dosage form comprising amorphous solid dispersion of asundexian, comprising:
(a) providing a solution of asundexian and a suitable polymer in a suitable solvent,
(b) adding one or more pharmaceutically acceptable excipients to the solution of step (a), and
(c) removing the solvent from the mixture of step (b) to form the solid pharmaceutical dosage form comprising amorphous solid dispersion of asundexian.
Providing a solution in step (a) includes direct use of a reaction mixture containing asundexian that is obtained in the course of its synthesis or dissolving asundexian in a suitable solvent. Any physical form of asundexian may be utilized for providing the solution of asundexian in step (a).
The solvent may be selected from the group consisting of alcohols, such as methanol, ethanol, 2-propanol, n- propanol, n-butanol, isoamyl alcohol, 1,2-propanediol, S-(+)-1,2-propanediol and ethylene glycol; ketones, such as acetone, methyl ethyl ketone, cyclohexanone and methyl isobutyl ketone; halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; polar aprotic solvents, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl 2-pyrrolidone, dimethylsulfoxide, pyridine, phenol, DMA, acetic acid and the like; water; or mixtures thereof. Preferably the solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetone, dichloromethane and THF.
Adding a suitable polymer to the asundexian solution. Suitable polymers for use in the subject solid dispersions include, but are not limited to Poloxamer, Gelucire, Tocopheryl polyethylene glycol succinate (TPGS), Polyvinyl acetate Phthalate (PVAP), Soluplus, Labrasol, Sucrose acetate Isobutyrate (SAIB), Polyvinylpyrrolidone (PVP), Hydroxypropyl methyl cellulose (HPMC), Hydroxypropyl methyl cellulose acetate succinate (HPMC-AS) and Eudragit. Preferably, the pharmaceutically acceptable polymer is selected from the group consisting of Poloxamer, Gelucire, Tocopheryl polyethylene glycol succinate (TPGS), Polyvinyl acetate Phthalate (PVAP).
Asundexian and the polymer are mixed in a ratio of 1 to 0.5 up to 1 to 10. Preferably in a ratio of asundexian to polymer of 1:0.5 to 1:4.
The polymer is added to the asundexian solution and is stirred for about 10 minutes to about 10 hours at a suitable temperature to get a clear solution.
The step (b) involves addition of one or more pharmaceutically acceptable excipients to the solution obtained in step (a).
In the context of the present invention, “excipients” are fillers, lubricants, disintegration promoters, surfactants, sweeteners, flavoring agents, and colorants.
Fillers that can be used in the formulation according to the present invention are selected from the group consisting of cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, lactose (anhydrous or as a hydrate), dextrose, maltose, sucrose, glucose, fructose or maltodextrins. Preferably the filler is microcrystalline cellulose or lactose or a mixture thereof.
Lubricants that can be used in the formulation according to the present invention are those selected from the list consisting of talc, magnesium stearate, sodium stearylfumarate, stearic acid, glycerin monostearate, glycerin monobehenate, calcium behenate, hydogenated vegetable fat or oil, polyethylenglycol and talc. Preferred lubricants according to the present invention are those selected from the list consisting of magnesium stearate, stearic acid and talc.
Disintegration promoters suitable in the context of the present invention are those selected from the list consisting of alginic acid, maize starch, modified starch, and starch derivatives such as sodium carboxymethyl starch, cellulose derivatives such as carmellose calcium (carboxymethylcellulose calcium) and croscarmellose sodium (cross-linked polymer of carboxymethylcellulose sodium) or microcrystalline cellulose or a combination of croscarmellose sodium and microcrystalline cellulose. Preferred as a disintegration promoter is croscarmellose sodium or microcrystalline cellulose.
Surfactants according to the present invention are complexing agents such as cyclodextrins and sodium ethylene diamintetraacetic acid (EDTA), cosolvents such as ethanol, propylene glycol and dimethyl acetamide, tensides such as fatty alcohols (e.g. cetylalcohol), phospholipids (e.g. lecithine), bile acids, polyoxyethylene stearate fat esters (e.g. polyoxyethylene), polyoxyethylene sorbitan fat esters, polyoxypropylene- polyoxyethylene-block copolymers (e.g. Poloxamer), alkyl sulfates (e.g. sodium lauryl sulfate, sodium cetylstearyl sulfate), alkyl soaps (e.g. sodium palmitate, sodium stearate) and saccharose fatty acid esters. Preferred as surfactant is sodium lauryl sulfate.
Sweeteners suitable in the context of the present invention are those selected from the list consisting of sucralose, saccharin, sodium-, potassium- or calcium saccharin, potassium acesulfame, neotame, alitame, glycyrrhizin or thaumatin, or sugars such as glucose, mannitol, fructose, saccharose, maltose, maltitol, galactose, sorbitol or xylitol.
Flavoring agents suitable in the context of the present invention are those selected from the list consisting of synthetic/artificial flavoring agents such as amyl acetate (banana flavoring), benzaldehyde (cherry or almond flavor), ethyl butyrate (pineapple), methyl anthranilate (grape), natural flavoring agents such as essential oils and oleoresins, herbs and spices, and natural-identical flavoring agents which are flavoring substances that are obtained by synthesis or are isolated through chemical processes and whose chemical make-up is identical to their natural counterpart.
The pharmaceutical excipient is added to the solution of step (a) in a ratio of 1:1 to 1 to 50 to the weight of asundexian. Preferably in a ratio of 1:2 to 1:10.
Step (c) involves removal of solvent form the mixture obtained in step (b). Removal of solvent may be carried out by methods known in the art or any procedure disclosed in the present application. In preferred embodiments, removal of solvent may include, but not limited to: solvent evaporation or sublimation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Büchi® Rotavapor®, spray drying, freeze drying (Lyophilization) and the like.
The resulting solid pharmaceutical dosage from may optionally be further dried. Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve a desired purity of the product, such as, for example, about 1 to about 15 hours, or longer.
In another aspect, asundexian in the solid pharmaceutical dosage forms of the present invention exists in stable amorphous form.
In another aspect, the solid pharmaceutical dosage forms of asundexian of the present invention are stable under thermal, humid and stress conditions.
The solid pharmaceutical dosage forms of asundexian disclosed herein may be characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), modulated differential scanning calorimetry (mDSC), scanning electron microscopy (SEM), Karl Fischer water titration (KF), residual solvent, particle size, bulk density, tapped density, high pressure liquid chromatography (HPLC).
In another aspect, the solid pharmaceutical dosage forms of asundexian of the present invention comprises asundexian with a chemical purity of at least 99% by HPLC or at least 99.5% by HPLC or at least 99.9% by HPLC.
The solid pharmaceutical dosage forms of asundexian of the present invention may be isolated as granulate and the obtained granulate with or without further excipients is compressed into the pharmaceutical dosage form such as tablets and /or capsules.
The present invention further provides use of amorphous solid dispersion of asundexian and solid pharmaceutical dosage forms of asundexian for oral administration in accordance with the invention for treatment of disorders, particularly myocardial infarction, ischemic strokes including cardioembolic as well as non-cardioembolic strokes.

DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise.
The terms “amorphous” and “amorphous form” are used herein to describe a substance, component, or product that is not substantially crystalline as determined by X-ray diffraction. In certain embodiments, an amorphous form of a substance may be substantially free of crystal forms. In other embodiments, an amorphous form of a substance may contain less than about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% of one or more crystal forms on a weight basis. In other embodiments, an amorphous form of a substance may comprise additional components or ingredients (for example, an additive, a polymer, or an excipient that may serve to further stabilize the amorphous form).
Unless otherwise specified, the term “solid dispersion” refers to a solid state which comprises at least two constituents, wherein one constituent is homogenously dispersed significantly evenly throughout the other constituent or constituents. It includes solid or glassy solutions, i.e., the dispersion of the constituents is in such a way that the composition is chemically and physically homogenous in nature.
The term “polymer” refers to a compound comprising repeating structural units (monomers) connected by covalent chemical bonds. Polymers may be further derivatized, crosslinked, grafted or end- capped. Non-limiting examples of polymers include copolymers, terpolymers, quaternary polymers, and homologues. The term “copolymer” refers to a polymer consisting essentially of two or more different types of repeating structural units (monomers).
The term “pharmaceutically acceptable excipient” includes, without limitation, any adjuvant, carrier, excipient, binder, filler, disintegrant, lubricant, glidant, sweetening agent, diluent, preservative, dye, colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example, "about 10" should be construed as meaning within the range of 9 to 11, preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.
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, “comprising” means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended. 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.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present invention. While particular aspects of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

EXAMPLES
Example-1: Preparation of amorphous solid dispersion of asundexian with HPMC AS
Asundexian (300 mg) and acetone (10 mL) were added to a beaker, clear solution was obtained. HPMC AS LG (600 mg) and 180 mL of acetone were added. The resultant clear solution was transferred into a 250 mL Buchi flask and concentrated under reduced pressure at 40 °C. The solid obtained was dried for 30 minutes at 40 °C, and further dried using vacuum tray dryer and analyzed by PXRD. The PXRD is shown in Figure 1.

Example-2: Preparation of amorphous solid dispersion of asundexian with Soluplus
Asundexian (300 mg) and acetone (10 mL) were added to a beaker, clear solution was obtained. Soluplus (600 mg) and 180 mL of acetone were added. The resultant clear solution was filtered and transferred into a 250 mL Buchi flask and concentrated under reduced pressure at 40 °C. The solid obtained was dried for 30 minutes at 40 °C, and further dried using vacuum tray dryer and analyzed by PXRD. The PXRD is shown in Figure 2.

Example-3: Preparation of amorphous solid dispersion of asundexian with Eudragit
Asundexian (50 mg) and acetone (5 mL) were added to a beaker, clear solution was obtained. Eudragit L100 55 (100 mg) and 35 mL of acetone were added. The resultant clear solution was filtered and transferred into a 100 mL Buchi flask and concentrated under reduced pressure at 50 °C. The solid obtained was dried for 30 minutes at 50 °C, and further dried using vacuum tray dryer and analyzed by PXRD. The PXRD is shown in Figure 3.

Example-4: Preparation of amorphous solid dispersion of asundexian with HPMC
Asundexian (50 mg) and methanol (5 mL) were added to a beaker, clear solution was obtained. HPMC E5 (100 mg) and 35 mL of acetone were added. The resultant clear solution was filtered and transferred into a 250 mL Buchi flask and concentrated under reduced pressure at 50 °C. The solid obtained was dried for 30 minutes at 50 °C, and further dried using vacuum tray dryer and analyzed by PXRD. The PXRD is shown in Figure 4.

Example-5: Preparation of amorphous solid dispersion of asundexian with PVAP
Asundexian (50 mg) and methanol (10 mL) were added to a beaker, clear solution was obtained. Polyvinyl acetate phthalate (PVAP) (100 mg) and 35 mL of acetone were added. The resultant clear solution was filtered and transferred into a 250 mL Buchi flask and concentrated under reduced pressure at 50 °C. The solid obtained was dried for 30 minutes at 50 °C, and further dried using vacuum tray dryer and analyzed by PXRD. The PXRD is shown in Figure 5.

Example-6: Preparation of solid dosage form of asundexian with Soluplus.
Asundexian (600 mg), Soluplus (1200 mg) and acetone (50 mL) were charged into glass vial and mixed well to get clear solution. Microcrystalline cellulose (Avicel PH101; 1800 mg) and Lactose monohydrate (1800 mg) were mixed well and the mixture was passed through a 30 ASTM sieve. The mixture of MCC and Lactose monohydrate was added to Petri dish and granulated by using Asundexian and Soluplus solution with Acetone.
The obtained wet solid was dried in a vacuum drier for 2 hours at 35 °C. Yield: 4.5 gm. The dried solid was passed through a 40 ASTM sieve. and analyzed by PXRD. The PXRD is shown in Figure 6.

Example-7: Preparation of solid dosage form of asundexian with Gelucire.
Asundexian (600 mg), Gelucire 48/16 (1200 mg) and acetone (50 mL) were charged into glass vial and mixed well to get clear solution. Microcrystalline cellulose (Avicel PH101; 3500 mg), Lactose monohydrate (1800 mg) and Talc (100 mg) were mixed well and the mixture was passed through a 30 ASTM sieve. The mixture of MCC, Lactose monohydrate and Talc was added on Petri dish and granulated using Asundexian and Gelucire solution with acetone. The obtained wet solid was dried in a vacuum drier for 3 hours at 35 °C. Yield: 7.2 gm. The dried solid was passed through a 40 ASTM sieve. and analyzed by PXRD. The PXRD is shown in Figure 7.

Example-8: Preparation of solid dosage form of asundexian with PVAP.
Asundexian (600 mg), Polyvinyl acetate phthalate (1200 mg) and methanol (50 mL) were charged into glass vial and mixed well to get clear solution. Microcrystalline cellulose (Avicel PH101; 3500 mg), Lactose monohydrate (1800 mg) and Talc (100 mg) were mixed well and the mixture was passed through a 30 ASTM sieve. The mixture of MCC, Lactose monohydrate and Talc was added to Petridis and granulated by using the Asundexian and Polyvinyl acetate phthalate solution with methanol. The obtained wet solid was dried in a vacuum drier for 3 hours at 35 °C. Yield: 7.2 gm. The dried solid was passed through a 40 ASTM sieve. and analyzed by PXRD. The PXRD is shown in Figure 8.

Example-9: Preparation of solid dosage form of asundexian with Labrasol.
Asundexian (600 mg), Labrasol ALF (1200 mg) and acetone (50 mL) were charged into glass vial and mixed well to get clear solution. Prosolv 730 (5400 mg) was passed through a 30 ASTM sieve and added to Petridis and granulated by using asundexian and Labrasol solution with Acetone. The obtained wet solid was dried in a vacuum drier for 3 hours at 35 °C. Yield: 7.2 gm. The dried solid was passed through a 40 ASTM sieve. and analyzed by PXRD. The PXRD is shown in Figure 9.

Example-10: Preparation of solid dosage form of asundexian with Labrasol.
Asundexian (600 mg), Labrasol ALF (1200 mg) and ethanol (10 gm) were charged into glass vial and mixed well to get clear solution. Microcrystalline cellulose (Avicel PH101; 900 mg) and Cross Carmellose sodium (AC-DI-SOL; 900 mg) were mixed well and mixture was passed through a 30 ASTM sieve. The mixture of MCC and Cross Carmellose sodium was added to Petridis and granulated by using asundexian and Labrasol solution with ethanol. The obtained wet solid was dried in a vacuum drier for 2 hours at 35 °C. Yield: 3.6 gm. The dried solid was passed through a 40 ASTM sieve. and analyzed by PXRD. The PXRD is shown in Figure 10.

Example-11: Preparation of solid dosage form of asundexian with TPGS.
Asundexian (600 mg), TPGS 1000 (600 mg) and acetone (10 gm) were charged into glass vial and mixed well to get clear solution. Prosolv 730 (6.0 gm) was passed through a 30 ASTM sieve and added to Petri dish and granulated by using the asundexian and TPGS solution with acetone. The obtained wet solid was dried in a vacuum drier for 3 hours at 35 °C. Yield: 7.2 gm. The dried solid was passed through a 40 ASTM sieve. and analyzed by PXRD. The PXRD is shown in Figure 11.

Example-12: Preparation of solid dosage form of asundexian with Polaxamer.
Asundexian (600 mg), Polaxamer 188 (600 mg) and acetone (10 gm) were charged into glass vial and mixed well to get clear solution. Prosolv 730 (6.0 gm) was passed through a 30 ASTM sieve and added to Petridis and granulated by using asundexian and Polaxamer solution with acetone. The obtained precipitation was granulated in a petri plate by hand and the material was dried in a vacuum drier for 3 hours at 35 °C. Yield: 7.2 gm. The dried solid was passed through a 40 ASTM sieve. and analyzed by PXRD. The PXRD is shown in Figure 12.

Example-13: Preparation of solid dosage form of asundexian with SAIB.
Asundexian (600 mg), Sucrose acetate Isobutyrate (SAIB NF) (600 mg) and acetone (10 gm) were charged into glass vial and mixed well to get clear solution. Prosolv 730 (6.0 gm) was passed through a 30 ASTM sieve and added to Petridis and granulated by using asundexian and SAIB solution with acetone. The obtained precipitation was granulated in a petripalte by hand and the material was dried in a vacuum drier for 3 hours at 35 °C. Yield: 7.2 gm. The dried solid was passed through a 40 ASTM sieve. and analyzed by PXRD. The PXRD is shown in Figure 13.

Example-14: Preparation of amorphous form of asundexian.
Asundexian (43 g) and ethyl acetate (50 mL) were mixed and the obtained solution was stirred for 2 hours at 35 C. The solution was diluted with ethyl acetate (400 mL) and stirred for 2 hours at 35 °C. The solution was filtered and the filtrate was concentrated at 45 °C under reduced pressure. To obtain 42 g of amorphous asundexian. Chemical Purity: 99.28%; Chiral Purity: 99.45% by HPLC. PXRD is shown in Figure 14.

Example-15: Preparation of amorphous solid dispersion of asundexian with Polyvinyl pyrrolidone (PVP)
Asundexian (50 mg), Polyvinyl pyrrolidone (PVP) (100 mg) and ethanol (10 mL) were charged into glass vial and mixed well to get clear solution. Microcrystalline cellulose (Avicel PH101; 300 mg) and Cross Carmellose sodium (AC-DI-SOL; 300 mg) were mixed well and mixture was passed through a 30 ASTM sieve and added to Petridis and granulated by using asundexian and PVP solution with ethanol. The obtained precipitation was granulated in a petri plate by hand and the material was dried in a vacuum drier for 3 hours at 35 °C. Yield: 680 mg. The dried solid was passed through a 40 ASTM sieve. and analyzed by PXRD. The solid dispersion is in amorphous form.

Example-16: Preparation of amorphous solid dispersions of asundexian
Sl. No. Asundexian Polymer API/Polymer ratio Solvent Adsorbent Preparation method
1 25 mg Gelucire (50 mg) 1:2 Acetone MCC (140 mg) + Lactose (75 mg) ASD prepared by hand granulation and dried in vacuum oven. With batch size 100 units prepared. ASD filled in HPMC capsule shell. Capsule in HDPE with silica gel loaded on stability study.
2 25 mg TPGS 1000 (25 mg) 1:1 Acetone Prosolv 730 (240 mg)
3 25 mg PVAP
(50 mg) 1:2 Methanol MCC (140 mg) + Lactose (75 mg)

Stability of the Solid Dispersions
Stability Condition / Interval API: Gelucire 48/16 :: 1:2
Example-7 API: TPGS :: 1:1
Example-11 API: PVAP :: 1:1
Example-8
Assay PXRD Assay PXRD Assay PXRD
3rd month
40 °C / 75% RH - Closed 99.3% Amorphous 103.0% Amorphous 98% Amorphous
6th month
25 °C / 60% RH - Closed 100.6% Amorphous 103.3% Amorphous 98% Amorphous
40 °C / 75% RH - Closed 100.1% Amorphous 102.2% Amorphous 97.8% Amorphous
All the 3 amorphous solid dispersions showed good stability over a period of 6 months.

Solubility of Amorphous Solid Dispersions in 0.1 N HCl
Example Polymer used & API polymer ratio PXRD Solubility (mg/mL), 0.1 N HCl
15 min 30 min 60 min 2 hrs 24 hrs
7 Gelucire
1:2 Amorphous 0.35 0.37 0.39 0.40 0.37
11 TPGS
1:1 Amorphous 0.13 0.18 0.19 0.21 0.20
8 PVAP
1:1 Amorphous 0.002 0.010 0.010 0.012 0.016

Solubility of Amorphous Solid Dispersions in 4.5 pH Acetate buffer
Example Polymer used & API polymer ratio PXRD Solubility (mg/mL), pH 4.5 Acetate buffer
15 min 30 min 60 min 2 hrs 24 hrs
7 Gelucire
1:2 Amorphous 0.37 0.42 0.46 0.46 0.48
11 TPGS
1:1 Amorphous 0.15 0.20 0.23 0.26 0.34
8 PVAP
1:1 Amorphous 0.10 0.25 0.25 0.30 0.36

Solubility of Amorphous Solid Dispersions in 6.8 pH Phosphate buffer
Example Polymer used & API polymer ratio PXRD Solubility (mg/mL), pH 6.8 Phosphate buffer
15 min 30 min 60 min 2 hrs 24 hrs
7 Gelucire
1:2 Amorphous 0.39 0.41 0.46 0.48 0.44
11 TPGS
1:1 Amorphous 0.12 0.21 0.29 0.37 0.38
8 PVAP
1:1 Amorphous 0.08 0.07 0.01 0.03 0.07
15 PVP
1:2 Amorphous
0.01 0.02 0.02 0.03 0.04
Considering above solubility data it is observed that amorphous solid dispersions with Gelucire, TPGS and PVAP having higher solubility as compared to the amorphous solid dispersions with PVP.
,CLAIMS:CLAIMS
We claim
1. An amorphous solid dispersion of Asundexian with one or more pharmaceutically acceptable polymers, wherein the polymer is selected from a group consisting of Gelucire, Tocopheryl Polyethylene Glycol Succinate (TPGS), Poloxamer, Soluplus, Labrasol, Polyvinyl Acetate Phthalate (PVAP), Sucrose Acetate Isobutyrate (SAIB) and mixture thereof.
2. The amorphous solid dispersion of Asundexian of claim 1, wherein pharmaceutically acceptable polymer is Gelucire.
3. The amorphous solid dispersion of Asundexian of claim 1, wherein pharmaceutically acceptable polymer is TPGS.
4. The amorphous solid dispersion of Asundexian of claim 1, wherein pharmaceutically acceptable polymer is PVAP.
5. An amorphous solid dispersion of asundexian claimed in any of claims 1 to 4, and one or more pharmaceutically acceptable excipients, wherein one or more pharmaceutically acceptable excipient is selected from the group comprising of Microcrystalline cellulose, Lactose monohydrate, Cross Carmellose sodium, Prosolv, Talc and mixture thereof.
6. An amorphous solid dispersion consisting of Asundexian, Gelucire, Microcrystalline cellulose and Lactose monohydrate.
7. An amorphous solid dispersion consisting of Asundexian, TPGS, and Prosolv.
8. An amorphous solid dispersion consisting of Asundexian, PVAP, Microcrystalline cellulose and Lactose monohydrate.
9. A solid pharmaceutical dosage form comprising, amorphous solid dispersion of asundexian with Gelucire, Microcrystalline cellulose and Lactose monohydrate, and one or more pharmaceutically acceptable excipients.
10. A solid pharmaceutical dosage form comprising, amorphous solid dispersion of asundexian with TPGS, and Prosolv, and one or more pharmaceutically acceptable excipients.
11. A solid pharmaceutical dosage form comprising, amorphous solid dispersion of asundexian with PVAP, Microcrystalline cellulose, Lactose monohydrate, and one or more pharmaceutically acceptable excipients.
12. A process for preparation of amorphous solid dispersion of asundexian of claim 6, the process comprising:
(a) providing a solution of asundexian in a suitable solvent,
(b) adding Gelucire to the solution of step (a),
(c) adsorbing the mixture of step (b) on Microcrystalline cellulose or Lactose monohydrate or a mixture thereof, and
(d) optionally, mixing the amorphous solid dispersion with one or more pharmaceutically acceptable excipients.
13. A process for preparation of amorphous solid dispersion of asundexian of claim 7, the process comprising:
(a) providing a solution of asundexian in a suitable solvent,
(b) adding TPGS to the solution of step (a),
(c) adsorbing the mixture of step (b) on Prosolv, and
(d) optionally, mixing the amorphous solid dispersion of step (c) with one or more pharmaceutically acceptable excipients.
14. A process for preparation of amorphous solid dispersion of asundexian of claim 8, the process comprising:
(a) providing a solution of asundexian in a suitable solvent,
(b) adding PVAP to the solution of step (a),
(c) adsorbing the mixture of step (b) on Microcrystalline cellulose or Lactose monohydrate or a mixture thereof, and
(d) optionally, mixing the amorphous solid dispersion of step (c) with one or more pharmaceutically acceptable excipients.