DESC:The following specification describes the invention.
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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-(1-methyl-1H-1,2,4-triazol-3-yl)anilino]-N-(2H3)methylpyridazine-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
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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
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(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
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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(Nhydroxyethyl
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, polyethylene-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
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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, polyethylene-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, 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, dichloromethane,
tetrahydrofuran, 1,4-dioxane, 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
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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.
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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, dichloromethane,
tetrahydrofuran, 1,4-dioxane, 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;
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(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,
dichloromethane, dimethyl sulfoxide (DMSO), ethanol, 2-propanol, 1-butanol, 2-
butanol, 1-pentanol, 2-pentanol, 3-pentanol, tetrahydrofuran, 1,4-dioxane, 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
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studies details are provided in the below table.
Storage condition Polymer matrix XRD
25°C ±2°C; 60% ± 5%RH (Initial) Eudragit Amorphous
25°C ±2°C; 60% ± 5%RH (1st month) Eudragit Amorphous
25°C ±2°C; 60% ± 5%RH (3rd month) Eudragit Amorphous
40°C ±2°C; 75% ± 5%RH (Initial) Eudragit Amorphous
40°C ±2°C; 75% ± 5%RH (1st month) Eudragit Amorphous
40°C ±2°C; 75% ± 5%RH (3rd month) Eudragit Amorphous
25°C ±2°C; 60% ± 5%RH (Initial) Betacyclodextrin 1:5 Amorphous
25°C ±2°C; 60% ± 5%RH (1st month) Betacyclodextrin 1:5 Amorphous
25°C ±2°C; 60% ± 5%RH (3rd month) Betacyclodextrin 1:5 Amorphous
40°C ±2°C; 75% ± 5%RH (Initial) Betacyclodextrin 1:5 Amorphous
40°C ±2°C; 75% ± 5%RH (1st month) Betacyclodextrin 1:5 Amorphous
40°C ±2°C; 75% ± 5%RH (3rd month) Betacyclodextrin 1:5 Amorphous
25°C ±2°C; 60% ± 5%RH (Initial) Alginic acid Amorphous
25°C ±2°C; 60% ± 5%RH (1st month) Alginic acid Amorphous
25°C ±2°C; 60% ± 5%RH (3rd month) Alginic acid Amorphous
40°C ±2°C; 75% ± 5%RH (Initial) Alginic acid Amorphous
40°C ±2°C; 75% ± 5%RH (1st month) Alginic acid Amorphous
40°C ±2°C; 75% ± 5%RH (3rd month) Alginic acid Amorphous
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
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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 (100mg) and Beta cyclodextrin (100mg) 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)
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dissolved in water (100 mL) at 70oC. 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 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-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 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-12: Process for the preparation of amorphous solid dispersion of
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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-dioxane (10 mL) and water
(15 mL) at 50 oC. 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.
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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 oC 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 oC. nbutanol
(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 oC 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 oC.
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 oC
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 dichloromethane (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.
,CLAIMS:Claims
1. A stable amorphous solid dispersion of Deucravacitinib comprising an
amorphous Deucravacitinib and polymer matrix.
2. The stable amorphous solid dispersion of claim 1, wherein the polymer
matrix is 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), polyet hyleneglycol 6000, polyethylenepolypropylene
glycol 188, poly(ethylene oxide), poly(chloromethylstyreneco-
styrene), alginate, poly(ethylene glycol)-block-poly(lactic acid),
poly(ethylene oxide)-poly(propylene oxide) triblock, chitosan, polyvinyl
alcohol, soluplus, syloid or mixture thereof.
3. The stable amorphous solid dispersion of claim 1, wherein the polymer
selected from cyclodextrin, alginic acid, chitosan, polyvinyl alcohol,
soluplus, syloid or mixture thereof.
4. 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.
5. The process of claim 4, where in the polymer matrix is 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-
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styrenesulfonate), polyethyleneglycol 6000, polyethylene-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, eudragit, polyvinylpyrrolidone (PVP) K30, copovidone or
Hydroxypropyl methylcellulose (HPMC) or mixture thereof.
6. The process of claim 4, wherein the solvent is selected from methanol,
ethanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-
pentanol, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetone, methyl
ethyl ketone, methyl isobutyl ketone; methyl acetate, ethyl acetate, isopropyl
acetate, water or mixtures thereof.
7. 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.
8. The process for the preparation of stable premix of amorphous solid
dispersion of Deucravacitinb 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.
9. The process of claim 8, wherein the solvent is selected from methanol,
ethanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-
pentanol, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetone, methyl
ethyl ketone, methyl isobutyl ketone; methyl acetate, ethyl acetate,
isopropyl acetate, water or mixtures thereof.
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10. 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.
11. The process of claim 10, wherein the solvent is selected from methanol, dichloromethane, dimethyl sulfoxide (DMSO), ethanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol, tetrahydrofuran, 1,4-dioxane, acetone, methyl ethyl ketone, methyl isobutyl ketone; methyl acetate, ethyl acetate, isopropyl acetate or mixtures thereof.
12. The process of claim 10, wherein the second solvent is selected from water, hexane, heptane, cyclohexane, dioxane or mixtures thereof.