CROSS REFERENCE

This application claims the benefit of priority to our Indian patent application numbers IN202241016761 filed on 24 Mar 2022; IN202241030322 filed on 26 May 2022 and IN202241042926 filed on 27 Jul 2022 which are incorporated herein by reference.

INTRODUCTION

Aspects of the present application relate to amorphous solid dispersions of Deucravacitinib and process for the preparation crystalline form of Deucravacitinib.

Deucravacitinib is the first and only new type of oral selective TYK2 inhibitor, clinically used to treat autoimmune and autoinflammatory diseases (such as psoriasis, psoriatic arthritis, lupus and inflammatory bowel disease, Crowe Grace, etc.). Deucravacitinib has been approved by USFDA for the treatment of moderate to severe plaque psoriasis. In addition, Deucravacitinib also shows good therapeutic effects in the treatment of systemic lupus erythematosus and Crohn's disease.

The chemical name of Deucravacitinib is 6-(cyclopropanecarboxamido)-4-[2- methoxy-3-(l-methyl-lH-l,2,4-triazol-3-yl)anilino]-N-(2H3)me thylpyridazine-3-carbox amide, the structural formula is shown below.

WO2018183656A1 discloses Deucravacitinib crystal form A and its process for the preparation. WO2021129467A1 discloses two crystalline forms of Deucravacitinib (CSI and CSII) and process for the preparation of crystalline Form of CSI. WO2021143498A1 discloses crystalline Form of Deucravacitinib (CSIII) and process for the preparation of crystalline Form of CSIII. WO2021055652A1 discloses Deucravacitinib dosage form comprising amorphous Deucravacitinib dispersed in a polymer matrix. However, there remains a need for stable alternate solid dispersions of Deucravacitinib and preparative processes thereof, exhibiting desired properties such as bioavailability and stability. Hence, it is desirable to provide a viable solid dispersion of Deucravacitinib.

SUMMARY

In an aspect, the present application provides a stable amorphous solid dispersion of Deucravacitinib comprising an amorphous Deucravacitinib and polymer matrix.

In an aspect, the present application provides a process for the preparation of stable amorphous solid dispersion of Deucravacitinib and polymer matrix, comprising

(a) providing a solution or suspension of Deucravacitinib and polymer matrix in a solvent;

(b) optionally heating the reaction mixture obtained in step (a); and

(c) isolating amorphous solid dispersion of Deucravacitinib.

In an aspect, the present application provides a process for the preparation of stable amorphous solid dispersion of Deucravacitinib and polymer matrix, comprising contacting Deucravacitinib with polymer matrix by grinding in ball mill or by subjecting to hot melt extrusion.

In specific aspect, the present application provides an amorphous solid dispersion of Deucravacitinib comprising an amorphous Deucravacitinib and cyclodextrin.

In specific aspect, the present application provides a process for the preparation of amorphous solid dispersion of Deucravacitinib and cyclodextrin, comprising contacting Deucravacitinib with cyclodextrin by grinding in ball mill or by subjecting to hot melt extrusion.

In another aspect, the present application provides stable premix of amorphous solid dispersion of Deucravacitinib together with at least one pharmaceutically acceptable polymer matrix and Syloid.

In another aspect, the present application provides process for the preparation of stable premix of amorphous solid dispersion of Deucravacitinib together with at least one pharmaceutically acceptable polymer matrix and Syloid, comprising the steps of

(a) providing a solution of Deucravacitinib and a pharmaceutically acceptable polymer matrix in a solvent;

(b) removing the solvent from reaction mass; and

(c) adding Syloid to the reaction mass.

In another aspect, the present application provides a process for the preparation of crystalline Deucravacitinib, comprising

(a) providing a solution or suspension of Deucravacitinib in a solvent;

(b) optionally adding seed crystal of crystalline Deucravacitinib;

(c) adding a second solvent for the solution or suspension obtained in step(a) or step (b);

(d) isolating crystalline Deucravacitinib crystalline.

BRIEF DESCRIPTION OF THE DRAWING

Figure 1 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Deucravacitinib and cyclodextrin prepared by the method of Example No 1.

Figure 2 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Deucravacitinib and eudragit prepared by the method of Example No 2.

Figure 3 is an illustrative X-ray powder diffraction pattern of crystalline form of Deucravacitinib prepared by the method of Example No 3.

Figure 4 is an illustrative powder X-ray diffraction pattern of amorphous solid dispersion of Deucravacitinib and Chitosan prepared by the method of Example No 5.

Figure 5 is an illustrative powder X-ray diffraction pattern of amorphous solid dispersion of Deucravacitinib and Polyvinyl alcohol prepared by the method of Example No 6.

Figure 6 is an illustrative powder X-ray diffraction pattern of amorphous solid dispersion of Deucravacitinib and Alginic acid prepared by the method of Example No 7.

Figure 7 is an illustrative powder X-ray diffraction pattern of amorphous solid dispersion of Deucravacitinib and soluplus prepared by the method of Example No 8. Figure 8 is an illustrative powder X-ray diffraction pattern of amorphous solid dispersion of Deucravacitinib and polyvinylpyrrolidone (PVP) K30 prepared by the method of Example No 9.

Figure 9 is an illustrative powder X-ray diffraction pattern of amorphous solid dispersion of Deucravacitinib and copovidone prepared by the method of Example No 12.

Figure 10 is an illustrative powder X-ray diffraction pattern of a premix of Syloid and amorphous solid dispersion of Deucravacitinb with HPMC prepared by the method of Example No 13.

Figure 11 is an illustrative powder X-ray diffraction pattern of amorphous Deucravacitinib with few crystalline peaks prepared by the method of Example No 14.

Figure 12 is an illustrative powder X-ray diffraction pattern of stable premix of amorphous Deucravacitinib and syloid prepared by the method of Example No 15.

Figure 13 is powder X-ray diffraction pattern illustrating the stability of the premix of amorphous Deucravacitinib with syloid after 12 days of storage in open container at ambient temperature conditions.

DETAILED DESCRIPTION

In an aspect, the present application provides a stable amorphous solid dispersion of Deucravacitinib comprising an amorphous Deucravacitinib and polymer matrix, wherin polymer matrix is selected from cyclodextrin, alginic acid, poly(N- hydroxyethyl acrylamide) (PHEAM), hydroxyethyl methacrylate, poly(vinyl alcohol), poly(acrylic acid), polyvinyl acetate, polyvinylchloride, polyethylene imine), poly(N-isopropyl acrylamide), poly(4-vinylphenol), polypropylene, poly(sodium 4-styrenesulfonate), polyethyleneglycol 6000, polyethyl ene-polypropylene glycol 188, poly(ethylene oxide), poly(chloromethylstyrene-co-styrene), alginate, poly(ethylene glycol)-block-poly(lactic acid), poly(ethylene oxide)-poly(propylene oxide) triblock, chitosan, polyvinyl alcohol, soluplus, syloid or mixture thereof.

In an aspect, the present application provides a process for the preparation of stable amorphous solid dispersion of Deucravacitinib and polymer matrix, comprising

(a) providing a solution or suspension of Deucravacitinib and polymer matrix in a solvent; (b) optionally heating the reaction mixture obtained in step (a); and

(c) isolating amorphous solid dispersion of Deucravacitinib.

Step (a) involves the providing a solution or suspension of Deucravacitinib and polymer matrix in a solvent;

Providing a solution or suspension of Deucravacitinib includes: i) direct use of a reaction mixture containing Deucravacitinib that is obtained in the course of its synthesis; or ii) dissolving or suspending Deucravacitinib in a solvent

Any physical form of Deucravacitinib including solvates, hydrates, anhydrous or amorphous may be utilized for providing solution or suspension of Deucravacitinib.

Suitable polymer matrix that may be used in step (a) is selected from cyclodextrin, alginic acid, poly(N-hydroxyethyl acrylamide) (PHEAM), hydroxyethyl methacrylate, poly(vinyl alcohol), poly(acrylic acid), polyvinyl acetate, polyvinylchloride, poly (ethylene imine), poly(N-isopropyl acrylamide), poly (4- vinylphenol), polypropylene, poly(sodium 4-styrenesulfonate), polyethyleneglycol 6000, polyethyl ene-polypropylene glycol 188, poly(ethylene oxide), poly(chloromethylstyrene-co-styrene), alginate, polyethylene glycol)-block-poly(lactic acid), poly(ethylene oxide)-poly(propylene oxide) triblock, chitosan, polyvinyl alcohol, soluplus, syloid, eudragit, polyvinylpyrrolidone (PVP) K30, copovidone or Hydroxypropyl methylcellulose (HPMC) or mixture thereof.

Suitable solvents that may be used in step (a) is selected from methanol, ethanol, 2-propanol, 1 -butanol, 2-butanol, 1 -pentanol, 2-pentanol, 3 -pentanol, di chloromethane, tetrahydrofuran, 1,4-di oxane, acetone, methyl ethyl ketone, methyl isobutyl ketone; methyl acetate, ethyl acetate, isopropyl acetate, water or mixtures thereof.

In embodiments, Deucravacitinib can be dissolved or suspended in a solvent or mixture of one or more solvents. The dissolution or suspension temperatures may range from about 0°C to about the reflux temperature of the solvent, or less than about 100°C, less than about 70°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, or any other suitable temperatures without affecting its quality. In embodiments, a solution of Deucravacitinib and polymer matrix may be filtered to make it clear and free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.

Step (c) involves isolating amorphous solid dispersion of Deucravacitinib.

Isolating amorphous solid dispersion of Deucravacitinib in step (c) may involve removal of solvent by employing techniques like solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Biichi® Rotavapor®, spray drying, freeze drying, thin film drying, agitated thin film drying, rotary vacuum paddle dryer (RVPD) and the like.

The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, agitated nutsche filter & dryer or the like.

The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the Deucravacitinib is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved.

The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller and hammer milling, and jet milling.

In an aspect, the present application provides a process for the preparation of stable amorphous solid dispersion of Deucravacitinib and polymer matrix, comprising contacting Deucravacitinib with polymer matrix by grinding in ball mill or by subjecting to hot melt extrusion. In specific aspect, the present application provides an amorphous solid dispersion of Deucravacitinib comprising an amorphous Deucravacitinib and cyclodextrin.

In specific aspect, the present application provides a process for the preparation of amorphous solid dispersion of Deucravacitinib and cyclodextrin, comprising contacting Deucravacitinib with cyclodextrin by grinding in ball mill or by subjecting to hot melt extrusion.

In another aspect, the present application provides stable premix of amorphous solid dispersion of Deucravacitinib together with at least one pharmaceutically acceptable polymer matrix and Syloid.

In another aspect, the present application provides process for the preparation of stable premix of amorphous solid dispersion of Deucravacitinib together with at least one pharmaceutically acceptable polymer matrix and Syloid, comprising the steps of

(a) providing a solution of Deucravacitinib and a pharmaceutically acceptable polymer matrix in a solvent;

(b) removing the solvent from reaction mass; and

(c) adding syloid to the reaction mass.

Step (a) involves the providing a solution or suspension of Deucravacitinib and polymer matrix in a solvent;

Providing a solution or suspension of Deucravacitinib includes: i) direct use of a reaction mixture containing Deucravacitinib that is obtained in the course of its synthesis; or ii) dissolving or suspending Deucravacitinib in a solvent

Any physical form of Deucravacitinib including solvates, hydrates, anhydrous or amorphous may be utilized for providing solution or suspension of Deucravacitinib.

Suitable solvents that may be used in step (a) is selected from methanol, ethanol, 2-propanol, 1 -butanol, 2-butanol, 1 -pentanol, 2-pentanol, 3 -pentanol, di chloromethane, tetrahydrofuran, 1,4-di oxane, acetone, methyl ethyl ketone, methyl isobutyl ketone; methyl acetate, ethyl acetate, isopropyl acetate, water or mixtures thereof. Step (b) involves isolating amorphous solid dispersion of Deucravacitinib.

Isolating amorphous solid dispersion of Deucravacitinib in step (c) may involve removal of solvent by employing techniques like solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Biichi® Rotavapor®, spray drying, freeze drying, thin film drying, agitated thin film drying, rotary vacuum paddle dryer (RVPD) and the like.

In another aspect, the present application provides a process for the preparation of crystalline Deucravacitinib, comprising

(a) providing a solution or suspension of Deucravacitinib in a solvent;

(b) optionally adding seed crystal of crystalline Deucravacitinib;

(c) adding a second solvent for the solution or suspension obtained in step(a) or step (b);

(d) isolating crystalline Deucravacitinib crystalline.

Suitable solvents that may be used in step (a) is selected from methanol, di chloromethane, dimethyl sulfoxide (DMSO), ethanol, 2-propanol, 1 -butanol, 2- butanol, 1 -pentanol, 2-pentanol, 3 -pentanol, tetrahydrofuran, 1,4-di oxane, acetone, methyl ethyl ketone, methyl isobutyl ketone; methyl acetate, ethyl acetate, isopropyl acetate or mixtures thereof.

Suitable second solvent that may be used in step (c) is selected from water, hexane, heptane, cyclohexane, dioxane or mixtures thereof.

In embodiments, the solution of Deucravacitinib may be contacted with second solvent is added rapidly in single lot or gradually in multiple lots.

Isolation of crystalline form of Deucravacitinib may involve methods including cooling, concentrating the mass, adding seed crystals to induce crystallization, or the like. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation.

The crystalline forms of Deucravacitinib may be recovered by methods including decantation, centrifugation, gravity filtration, suction filtration, agitated nutsche filter & dryer or any other technique for the recovery of solids under pressure or under reduced pressure. The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, agitated nutsche filter & dryer or the like.

The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the Deucravacitinib is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved.

Stability of the amorphous solid dispersion of Deucravacitinib is analyzed in different temperature at different humidity conditions and the results indicates that the amorphous form remained stable after 3 months in all the conditions. Stability studies details are provided in the below table. In embodiments, amorphous solid dispersion of Deucravacitinib and polymer, comprising the ratio of Deucravacitinib and polymer is 1 : 1 to 1 :5 w/w.

Inventors of present application have found that the premix of amorphous Deucravacitinib with Syloid remains stable after 12 days of being stored in open container at ambient temperature conditions. Figure 13 is a powder X-ray diffraction pattern illustrating the stability of the premix of amorphous Deucravacitinib with Syloid after 12 days of storage in open container at ambient temperature conditions.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

Examples

Example-1: Process for the preparation of amorphous solid dispersion of Deucravacitinib and cyclodextrin.

Deucravacitinib (lOOmg) and Beta cyclodextrin (lOOmg) were taken into ball milling capsule and milled for 90 minutes.

Example-2: Process for the preparation of amorphous solid dispersion of Deucravacitinib and eudragit.

Deucravacitinib (500 mg) and Eudragit L100 55 (500 mg) were dissolved in methanol (40 mL) at 66°C. The obtained clear solution was evaporated under reduced pressure at 65°C to obtain amorphous solid dispersion of Deucravacitinib and eudragit.

Example-3: Process for the preparation of crystalline form of Deucravacitinib.

Deucravacitinib (200 mg) was dissolved in methanol (90 mL) at 65°C. Water (50 mL) was added to the solution at 31 °C and stirred the mixture at the same temperature for 6 hours. The obtained solid was filtered and dried under vacuum to get the title compound.

Example-4: Process for the preparation of crystalline form of Deucravacitinib. Deucravacitinib (500 mg) was dissolved in dichloromethane (30 mL) at 40°C and the solution was filtered to make it particle free. Heptane (20 mL) was added to the solution at 24°C and stirred the mixture at the same temperature for 2 hours. The obtained solid was filtered and dried under vacuum to obtain the title compound.

Example-5: Process for the preparation of amorphous solid dispersion of Deucravacitinib and Chitosan.

Deucravacitinib (250mg) and Beta Chitosan (750mg) were taken into ball milling capsule and milled for 4 hours.

Example-6: Process for the preparation of amorphous solid dispersion of Deucravacitinib and Polyvinyl alcohol.

Deucravacitinib (2.5 g) dissolved in methanol (500 mL), Polyvinyl alcohol (2.5 g) dissolved in water (100 mL) at 70°C. Blended both the solutions and filtered to make it particle free. The obtained clear solution was spray dried to obtain amorphous solid dispersion of Deucravacitinib and Polyvinyl alcohol.

Example-7: Process for the preparation of amorphous solid dispersion of Deucravacitinib and Alginic acid.

Deucravacitinib (250mg) and Alginic acid (750mg) were taken into ball milling capsule and milled for 5 hours.

Example-8: Process for the preparation of amorphous solid dispersion of Deucravacitinib and Soluplus.

Deucravacitinib (500 mg) and Soluplus (1.5 g) were dissolved in methanol (150 mL) at 70 °C. The obtained clear solution was evaporated under reduced pressure at 70 °C to obtain amorphous solid dispersion of Deucravacitinib and Soluplus.

Example-9: Process for the preparation of amorphous solid dispersion of Deucravacitinib and polyvinylpyrrolidone (PVP) K30.

Deucravacitinib (50 mg) and polyvinylpyrrolidone (PVP) K30 (250 mg) were dissolved in 10% methanol in dichloromethane (15 mL). The solution was filtered to make it particle free. The obtained clear solution was concentrated under reduced pressure at 45 °C to obtain the title compound.

Example-10: Process for the preparation of amorphous solid dispersion of Deucravacitinib and polyvinylpyrrolidone (PVP) K30. Deucravacitinib (100 mg) and polyvinylpyrrolidone (PVP) K30 (200 mg) were dissolved in 10% methanol in di chloromethane (15 mL). The solution was filtered to make it particle free. The obtained clear solution was concentrated under reduced pressure at 45 °C to obtain the title compound.

Example-11: Process for the preparation of amorphous solid dispersion of Deucravacitinib and polyvinylpyrrolidone (PVP) K30.

Deucravacitinib (150 mg) and polyvinylpyrrolidone (PVP) K30 (150 mg) were dissolved in 10% methanol in di chloromethane (15 mL). The solution was filtered to make it particle free. The obtained clear solution was concentrated under reduced pressure at 45 °C to obtain the title compound.

Example-12: Process for the preparation of amorphous solid dispersion of Deucravacitinib and copovidone.

Deucravacitinib (150 mg) and copovidone (150 mg) were dissolved in 10% methanol in dichloromethane (15 mL). The solution was filtered to make it particle free. The obtained clear solution was concentrated under reduced pressure at 45 °C to obtain the title compound.

Example-13: Process for the preparation of premix of amorphous solid dispersion of Deucravacitinib with HPMC and Syloid.

Deucravacitinib (150 mg) and HPMC (150 mg) were dissolved in 10% methanol in dichloromethane (15 mL). The solution was filtered to make it particle free. The obtained clear solution was concentrated under reduced pressure at 45 °C to obtain solid dispersion of Deucravacitinib and HPMC as a sticky solid. Syloid 244 FP (150 mg) was added to the sticky solid and the mixture obtained was ground for 1 hour to obtain the title compound.

Example-14: Process for the preparation of amorphous Deucravacitinib with few crystalline peaks.

Deucravacitinib (250 mg) was dissolved in 10% methanol in dichloromethane (15 mL). The solution was filtered to make it particle free. The obtained clear solution was concentrated rapidly under reduced pressure at 45 °C to obtain the title compound.

Example-15: Process for the preparation of stable premix of amorphous Deucravacitinib and Syloid. Deucravacitinib (150 mg) was dissolved in 10% methanol in dichloromethane (20 mL). The solution was filtered to make it particle free. Syloid 244 FP (150 mg) was added to the clear solution. The obtained mixture was concentrated rapidly to dryness under reduced pressure at 45 °C to obtain the title compound.

Example-16: Process for the preparation of stable premix of amorphous Deucravacitinib and Syloid.

Deucravacitinib (200 mg) was dissolved in a mixture of 1,4-di oxane (10 mL) and water (15 mL) at 50 °C. The solution was filtered to make it particle free. The obtained solution was frozen and then lyophilized for 18 hours to obtain dry material. Syloid (150 mg) was added to the obtained dry material and the mixture was ground for 15 minutes to obtain the title compound.

Example-17: Process for the preparation of crystalline form of Deucravacitinib.

Deucravacitinib (200 mg) was dissolved in dimethyl sulfoxide (5 mL) at 50 °C. The obtained solution was slowly added to water (100 mL) at 0 °C. The resultant mixture was stirred at 25 °C for 3 hours. The obtained solid was filtered and dried under vacuum to obtain the title compound.

Example-18: Process for the preparation of crystalline form of Deucravacitinib.

Deucravacitinib (300 mg) was dissolved in 10% methanol in dichloromethane (15 mL). The solution was filtered to make it particle free. n-Hexane (45 mL) was added to the solution at 27 °C and the resultant mixture was stirred at the same temperature for 3 hours. The obtained solid was filtered and dried under vacuum to obtain the title compound.

Example-19: Process for the preparation of crystalline form of Deucravacitinib.

Deucravacitinib (300 mg) was dissolved in N-Methyl-2 -Pyrrolidone (2 mL) at 70 °C. n- butanol (5 mL) was added to the solution at 27 °C and the resultant mixture was stirred at the same temperature for 2 hours. The obtained suspension was cooled to 0 °C and stirred at the same temperature for 15-20 min. The resultant suspension was filtered and dried under vacuum to obtain the title compound.

Example-20: Process for the preparation of crystalline form of Deucravacitinib. Deucravacitinib (250 mg) was dissolved in N-Methyl-2 -Pyrrolidone (2 mL) at 65 °C. Methanol (4 mL) was added to the solution at 27 °C and the resultant mixture was stirred at the same temperature for 2 hours. The obtained suspension was cooled to 0 °C and stirred at the same temperature for 15-20 min. The resultant suspension was filtered and dried under vacuum to obtain the title compound.

Example-21: Process for the preparation of crystalline form of Deucravacitinib.

Deucravacitinib (250 mg) was dissolved in 10% methanol in di chloromethane (15 mL). The solution was filtered to make it particle free and then concentrated to dryness under reduced pressure at 40 °C. Ethyl acetate (500 mL) was added to the residue obtained and the mixture was stirred at 27 °C for 2 hours. The solution obtained was filtered to make it particle free and then concentrated under reduced pressure at 40 °C to obtain the title compound.