DESC:The following specification describes particularly the invention and in the manner in which it is to be performed:

SOLID STATE FORMS OF RITLECITINIB AND ITS TOSYLATE SALT

FIELD OF THE INVENTION
The present application relates to amorphous solid dispersions of Ritlecitinib and its tosylate salt along with their preparative methods and pharmaceutical compositions thereof. The present application also relates to a novel crystalline form of Ritlecitinib and its tosylate salt along with their preparative methods and pharmaceutical compositions thereof.

BACKGROUND OF THE INVENTION
Ritlecitinib tosylate (I) is a dual inhibitor of the TEC family of tyrosine-protein kinases and of Janus kinase 3 (JAK3) being developed by Pfizer for the treatment of Alopecia Areata, Rheumatoid Arthritis, Ulcerative Colitis, Crohn's Disease, Vitiligo. Till date Ritlecitinib tosylate is only approved in US (June 2023). As per US label, it is indicated for the treatment of severe alopecia areata in adults and adolescents 12 years and older. Ritlecitinib tosylate is chemically known as 1-{(2S,5R)-2-Methyl-5-[(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}prop-2-en-1-one 4-methylbenzene-1-sulfonic acid..

WO2015083028A (herein after referred as WO’028) first discloses Ritlecitinib along with the process for preparation thereof. WO2020084435A1 (herein after referred as WO’435) discloses a process for preparation Ritlecitinib tosylate. Only one form i.e. crystalline Form 1 of Ritlecitinib tosylate is disclosed in WO’435. IPCOM000264449D discloses the preparation of amorphous form of Ritlecitinib tosylate. However, amorphous form of Ritlecitinib tosylate is associated with stability issues and crystal Form 1 of Ritlecitinib tosylate associated with manufacturing issues.
Hence it is important to find new polymorphic forms of Ritlecitinib tosylate to improve its stability and ease of manufacturing.
Further, new polymorphic forms, solvates 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 forms of Ritlecitinib tosylate.

SUMMARY OF THE INVENTION
First aspect of the present application relates to amorphous solid dispersions of Ritlecitinib tosylate, their preparative methods and pharmaceutical compositions thereof.

Second aspect of the present application provides amorphous solid dispersion comprising Ritlecitinib tosylate and one or more pharmaceutically acceptable excipient.

Third aspect of the present application provides a process for preparation of amorphous solid dispersion comprising Ritlecitinib tosylate and one or more pharmaceutically acceptable excipient; the process comprising;
a) providing a solution comprising Ritlecitinib tosylate and one or more pharmaceutically acceptable excipients by dissolving in a suitable solvent or mixture threreof,
b) removing solvent from the solution obtained in step (a), and
c) recovering the solid dispersion comprising Ritlecitinib tosylate and one or more pharmaceutically acceptable excipients.

Fourth aspect of the present application provides a pharmaceutical composition comprising amorphous solid dispersion of Ritlecitinib tosylate and at least one pharmaceutically acceptable carrier.

Fifth aspect of the present application relates to crystalline form D1 of Ritlecitinib tosylate characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 5.65, 15.47, 18.45, 18.75, 21.77 and 28.34 ± 0.2° 2?. In embodiments of the present application, crystalline form D1 of Ritlecitinib tosylate is further characterized by its PXRD pattern having additional peaks located at about 20.7, 21.44, 22.99, 25.2, 28.9 and 29.66 ± 0.2° 2?.

Sixth aspect of the present application relates to crystalline form D1 of Ritlecitinib characterized by a PXRD pattern substantially as illustrated in Figure 5.

Seventh aspect of the present application relates to a process for preparing crystalline form D1 of Ritlecitinib tosylate; the process comprising;
a) reacting Ritlecitinib with a p-Toluenesulfonic acid (PTSA) in a suitable solvent or mixture thereof;
b) isolating crystalline form D1 of Ritlecitinib tosylate;
c) optionally, drying the isolated product at suitable temperature.

Eighth aspect, the present application provides a pharmaceutical composition comprising crystalline form D1 of Ritlecitinib tosylate and at least one pharmaceutically acceptable carrier.

Ninth aspect of the present application relates to crystalline form DB1 of Ritlecitinib characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about: 5.02, 15.07, 19.32, 21.20 ± 0.2° 2?. In embodiments of the present application, crystalline form DB1 of Ritlecitinib is further characterized by its PXRD pattern having additional peaks located at about 10.02, 18.21, 25.25 and 26.01 ± 0.2° 2?. In embodiments of the present application, crystalline form DB1 of Ritlecitinib is further characterized by its PXRD pattern having additional peaks located at about 26.7714, 28.54, 29.40, 29.91 and 30.41 ± 0.2° 2?.

Tenth aspect of the present application relates to crystalline form DB1 of Ritlecitinib characterized by a PXRD pattern substantially as illustrated in Figure 4.

Eleventh aspect of the present application relates to a process for preparing crystalline form DB1 of Ritlecitinib; the process comprising;
d) reacting Ritlecitinib tosylate with a suitable base in a suitable solvent or mixture thereof;
e) isolating crystalline form DB1 of Ritlecitinib;
f) optionally, drying the isolated product at suitable temperature.

Twelfth aspect of the present application provides a pharmaceutical composition comprising crystalline form DB1 of Ritlecitinib and at least one pharmaceutically acceptable carrier.

Thirteenth aspect of the present application provides amorphous solid dispersion comprising Ritlecitinib and one or more pharmaceutically acceptable excipient.

Fourteenth aspect of the present application provides a process for preparation of amorphous solid dispersion comprising Ritlecitinib and one or more pharmaceutically acceptable excipient; the process comprising;
d) providing a solution comprising Ritlecitinib and one or more pharmaceutically acceptable excipients by dissolving in a suitable solvent or mixture thereof,
e) removing solvent from the solution obtained in step (a), and
f) recovering the solid dispersion comprising Ritlecitinib and one or more pharmaceutically acceptable excipients.

Fifteenth aspect of the present application provides a pharmaceutical composition comprising amorphous solid dispersion of Ritlecitinib and at least one pharmaceutically acceptable carrier.

Sixteenth aspect of the present application provides a stable amorphous form of Ritlecitinib.

Seventeenth aspect of the present application provides a process for preparation of amorphous form of Ritlecitinib; the process comprising;
a) Reacting Ritlecitinib tosylate with a suitable base in a suitable solvent or mixture thereof;
b) isolating amorphous form of Ritlecitinib;
c) optionally, drying the isolated product at suitable temperature.

Eighteenth aspect of the present application provides a pharmaceutical composition comprising amorphous form of Ritlecitinib and at least one pharmaceutically acceptable carrier.

Nineteenth aspect of the present application relates a process for preparation of crystalline DB1 or amorphous form of Ritlectinib comprising converting pharmaceutically acceptable salt of ritlecitinib to retlicetinib in presence of a suitable base and a suitable solvent.

Twentieth aspect of the present application relates to the use of solid forms of Ritlecitinib disclosed herein for preparation of Ritlecitinib tosylate.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is powder X-ray diffraction ("PXRD") pattern of amorphous solid dispersion of Ritlecitinib tosylate prepared according to Example 1.
Figure 2 is powder X-ray diffraction pattern of amorphous solid dispersion of Ritlecitinib tosylate prepared according to Example 2.
Figure 3 is powder X-ray diffraction pattern of amorphous solid dispersion of Ritlecitinib tosylate prepared according to Example 3.
Figure 4 is powder X-ray diffraction ("PXRD") pattern of crystalline form DB1 of Ritlecitinib prepared according to Example 4.
Figure 5 is powder X-ray diffraction ("PXRD") pattern of crystalline form D1 of Ritlecitinib tosylate prepared according to Example 5.
Figure 6 is powder X-ray diffraction pattern of amorphous form of Ritlecitinib prepared according to Example 7.
Figure 7 is powder X-ray diffraction pattern of amorphous solid dispersion of Ritlecitinib prepared according to Example 8.
Figure 8 is powder X-ray diffraction pattern of amorphous solid dispersion of Ritlecitinib prepared according to Example 9.
Figure 9 is powder X-ray diffraction pattern of amorphous solid dispersion of Ritlecitinib prepared according to Example 10.
Figure 10 is powder X-ray diffraction pattern of amorphous solid dispersion of Ritlecitinib prepared according to Example 11.

DETAILED DESCRITPION
First aspect of the present application relates to amorphous solid dispersions of Ritlecitinib tosylate, their preparative processes and pharmaceutical compositions thereof.

Second aspect of the present application also encompasses the use of solid dispersions of Ritlecitinib tosylate provided herein for the preparation of pharmaceutical dosage forms.

Third aspect of the present application provides a process for preparing amorphous solid dispersion comprising Ritlecitinib tosylate and one or more pharmaceutically acceptable excipient, the process comprising;
a) providing a solution comprising Ritlecitinib tosylate and one or more pharmaceutically acceptable excipients by dissolving in a suitable solvent or mixture thereof;
b) removing solvent from the solution obtained in step (a); and
c) recovering amorphous solid dispersion comprising Ritlecitinib tosylate and one or more pharmaceutically acceptable excipient.
Providing a solution in step (a) includes direct use of a reaction mixture containing Ritlecitinib tosylate that is obtained in the course of its synthesis or dissolving Ritlecitinib tosylate and pharmaceutically acceptable excipient in a solvent or a mixture of solvents.
Any physical form of Ritlecitinib tosylate may be utilized for providing the solution of step (a).
Suitable pharmaceutically acceptable excipients which can be used in step (a) include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, Polyethylene glycol, Copovidone, Soluplus, Silicified microcrystalline cellulose mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS). hydroxypropyl methylcellulose phthalate (HPMCP), HPMC-15 CPS; pregelatinized starches and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates such as Eudragit L and Eudragit S, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.
In a preferred embodiment, the pharmaceutically acceptable excipients are PVP-K 30, Copovidone and HPMC in various mole ratios.
Suitable solvent of step a) may include but not limited to, alcohols such as methanol, isopropanol and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as diethyl ether, tetrahydrofuran and the like; esters such as ethyl acetate, propyl acetate and the like; water; mixture thereof. Specifically, suitable solvent may be selected from alcohol solvent, preferably methanol.
After dissolution in step (a), optionally undissolved particles, if any, may be removed suitably by filtration, centrifugation, decantation, and any other known techniques. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
Step (b) involves removing solvent from the solution obtained in step (a). Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying such as drying using a rotavapor, spray drying, agitated thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze -drying, filtration or any other technique known in the art.
Step (c) involves recovering amorphous solid dispersion comprising Ritlecitinib tosylate and one or more pharmaceutically acceptable excipient. The said recovery can be achieved by using the processes known in the art.
The resulting compound obtained in step (c) may optionally be further dried. Drying can 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, or the like. The drying can be carried out at temperatures of less than about 75°C, less than about 50°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the Ritlecitinib tosylate is not degraded in its quality. The drying can be carried out for any desired time until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.
When the active ingredient is hygroscopic or the formulation contains a hygroscopic ingredient, and to increase the stability of the amorphous form or a solid dispersion comprising Ritlecitinib tosylate, addition of other carriers such as syloid, methyl cellulose, colloidal silicon dioxide, amorphous silica, micro crystalline cellulose, and the like, in the formulation has been found to be of particular value. Therefore, these ingredients may be combined during the preparation of solid dispersion or after the preparation of amorphous Ritlecitinib tosylate or solid dispersion to control hygroscopicity and to improve stability.

Fourth aspect of the present application provides a pharmaceutical composition comprising amorphous Ritlecitinib tosylate solid dispersion of the present invention and a pharmaceutically acceptable carrier.

Fifth aspect of the present application relates to crystalline form D1 of Ritlecitinib tosylate characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 5.65, 15.47, 18.45, 18.75, 21.77 and 28.34 ± 0.2° 2?. In embodiments of the present application, crystalline form D1 of Ritlecitinib tosylate is further characterized by its PXRD pattern having additional peaks located at about 20.7, 21.44, 22.99, 25.2, 28.9 and 29.66 ± 0.2° 2?.

Sixth aspect of the present application relates to crystalline form D1 of Ritlecitinib characterized by a PXRD pattern substantially as illustrated in Figure 5.

Seventh aspect of the present application relates to a process for preparing crystalline form D1 of Ritlecitinib tosylate; the process comprising;
a) reacting Ritlecitinib with p-Toluenesulfonic acid (PTSA) in a suitable solvent or mixture thereof;
b) isolating crystalline form D1 of Ritlecitinib tosylate;
c) optionally, drying the isolated product at suitable temperature.

In embodiments of step a) suitable solvent may include but not limited to ethers such as 1,4-dioxane, tetrahydrofuran and the like; alcohol solvents such as methanol, ethanol, isopropanol and the like; ester solvents such as ethyl acetate, propyl acetate and the like; ketone solvents such as acetone, methyl ethyl ketone, butanone and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane and the like. nitrile solvent such as acetonitrile, propionitrile, water and mixture thereof. preferably, the solvent may be a mixture of alcohol, ester and ketone solvents. More preferably, solvent is a mixture of methanol, ethylacetate and methyl ethyl ketone. The reaction may be carried out at a temperature of about 10 °C to about boiling point of the solvent.
In embodiments of step a), any physical form of ritlecitinib may be used as input material. More specifically crystalline form DB1 of ritlecitinib free base is used as input material in step a).
In embodiments of Step (b), further involves the removal of solvent from the solution obtained in step (a). Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying such as drying using a rotavapor, spray drying, agitated thin-film drying, freeze -drying or any other technique known in the art.
The resulting compound obtained in step (b) may optionally be further dried. Drying can 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, or the like. The drying can be carried out at temperatures of less than about 75°C, less than about 50°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the Ritlecitinib is not degraded in its quality. The drying can be carried out for any desired time until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.

Eighth aspect, the present application provides a pharmaceutical composition comprising crystalline form D1 of Ritlecitinib tosylate and at least one pharmaceutically acceptable carrier.

Ninth aspect of the present application relates to crystalline form DB1 of Ritlecitinib characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about: 5.02, 15.07, 19.32, 21.20 ± 0.2° 2?. In embodiments of the present application, crystalline form DB1 of Ritlecitinib is further characterized by its PXRD pattern having additional peaks located at about 10.02, 18.21, 25.25 and 26.01 ± 0.2° 2?. In embodiments of the present application, crystalline form DB1 of Ritlecitinib is further characterized by its PXRD pattern having additional peaks located at about 26.77, 28.54, 29.40, 29.91 and 30.41 ± 0.2° 2?.

Tenth aspect of the present application relates to crystalline form DB1 of Ritlecitinib characterized by a PXRD pattern substantially as illustrated in Figure 4.

Eleventh aspect of the present application relates to a process for preparing crystalline form DB1 of Ritlecitinib; the process comprising;
a) reacting Ritlecitinib tosylate with a suitable base in a suitable solvent or mixture thereof;
b) isolating crystalline form DB1 of Ritlecitinib;
c) optionally, drying the isolated product at suitable temperature.

In embodiments of step a) suitable base may be organic or inorganic base. Inorganic base include but not limited to metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like; metal alkoxide base such as sodium methoxide, sodium tert-butoxide and the like; metal carbonate bases such as potassium carbonate, sodium carbonate and the like; metal hydroxide bases such as lithium hydroxide, sodium hydroxide and the like; Organic base include but not limited to triethyl amine, diisopropyl ethyl amine (DIPEA), pyridine, dimethyl aminopyridine (DMAP), sodium methoxide, sodium tert-butoxide and the like; preferably, the base is selected from metal carbonate. More preferably, the base is sodium carbonate.
Suitable solvent of step a) may include but not limited to ethers such as 1,4-dioxane, tetrahydrofuran and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane and the like. nitrile solvent such as acetonitrile, propionitrile, water and mixture thereof. preferably, the solvent may be an ether solvent. More preferably, solvent is tetrahydrofuran (THF). The reaction may be carried out at a temperature of about 30 °C to about boiling point of the solvent.
In embodiments of Step (b), involves the use of a suitable additional solvent to isolate the Ritlecitinib free base. Suitable additional solvent of step b) may include but not limited to ester solvent such as ethyl acetate, butyl acetate and the like; ethers such as 1,4-dioxane, tetrahydrofuran and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane and the like. nitrile solvent such as acetonitrile, propionitrile, water and mixture thereof. preferably, the solvent may be an ester solvent. More preferably, solvent is ethyl acetate.
In embodiments of Step (b), further involves the removal of solvent from the solution obtained in step (a). Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying such as drying using a rotavapor, spray drying, agitated thin-film drying, freeze -drying or any other technique known in the art.
The resulting compound obtained in step (b) may optionally be further dried. Drying can 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, or the like. The drying can be carried out at temperatures of less than about 75°C, less than about 50°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the Ritlecitinib is not degraded in its quality. The drying can be carried out for any desired time until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.

Twelfth aspect, the present application provides a pharmaceutical composition comprising crystalline form DB1 of Ritlecitinib and at least one pharmaceutically acceptable carrier.

Thirteenth aspect of the present application provides amorphous solid dispersion comprising Ritlecitinib and one or more pharmaceutically acceptable excipient.

Fourteenth aspect of the present application provides a process for preparation of amorphous solid dispersion comprising Ritlecitinib and one or more pharmaceutically acceptable excipient; the process comprising;
g) providing a solution comprising Ritlecitinib and one or more pharmaceutically acceptable excipients by dissolving in a suitable solvent or mixture thereof,
h) removing solvent from the solution obtained in step (a), and
i) recovering the solid dispersion comprising Ritlecitinib and one or more pharmaceutically acceptable excipients.

Providing a solution in step (a) includes direct use of a reaction mixture containing Ritlecitinib that is obtained in the course of its synthesis or dissolving Ritlecitinib and pharmaceutically acceptable excipient in a solvent or a mixture of solvents.
Any physical form of Ritlecitinib may be utilized for providing the solution of step (a).
Suitable pharmaceutically acceptable excipients which can be used in step (a) include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, Polyethylene glycol, Copovidone, Soluplus, Silicified microcrystalline cellulose mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS). hydroxypropyl methylcellulose phthalate (HPMCP), HPMC-15 CPS; pregelatinized starches and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates such as Eudragit L and Eudragit S, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.
In a preferred embodiment, the pharmaceutically acceptable excipients are Copovidone, HPMC, HPMCAS and Eudragit in various mole ratios.
Suitable solvent of step a) may include but not limited to, alcohols such as methanol, isopropanol and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as diethyl ether, tetrahydrofuran and the like; esters such as ethyl acetate, propyl acetate and the like; water; mixture thereof. Specifically, suitable solvent may be selected from alcohol solvent, preferably methanol.
After dissolution in step (a), optionally undissolved particles, if any, may be removed suitably by filtration, centrifugation, decantation, and any other known techniques. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
Step (b) involves removing solvent from the solution obtained in step (a). Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying such as drying using a rotavapor, spray drying, agitated thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze -drying, filtration or any other technique known in the art.
Step (c) involves recovering amorphous solid dispersion comprising Ritlecitinib and one or more pharmaceutically acceptable excipient. The said recovery can be achieved by using the processes known in the art.
The resulting compound obtained in step (c) may optionally be further dried. Drying can 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, or the like. The drying can be carried out at temperatures of less than about 75°C, less than about 50°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the Ritlecitinib is not degraded in its quality. The drying can be carried out for any desired time until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.
When the active ingredient is hygroscopic or the formulation contains a hygroscopic ingredient, and to increase the stability of the amorphous form or a solid dispersion comprising Ritlecitinib, addition of other carriers such as syloid, methyl cellulose, colloidal silicon dioxide, amorphous silica, micro crystalline cellulose, and the like, in the formulation has been found to be of particular value. Therefore, these ingredients may be combined during the preparation of solid dispersion or after the preparation of amorphous Ritlecitinib or solid dispersion to control hygroscopicity and to improve stability.

Fifteenth aspect of the present application provides a pharmaceutical composition comprising amorphous solid dispersion of Ritlecitinib and at least one pharmaceutically acceptable carrier.

Sixteenth aspect of the present application provides a stable amorphous form of Ritlecitinib.

Seventeenth aspect of the present application provides a process for preparation of amorphous form of Ritlecitinib; the process comprising;
d) Reacting Ritlecitinib tosylate with a suitable base in a suitable solvent or mixture thereof;
e) isolating amorphous form of Ritlecitinib;
f) optionally, drying the isolated product at suitable temperature.

In embodiments of step a) suitable base may be organic or inorganic base. Inorganic base include but not limited to metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like; metal alkoxide base such as sodium methoxide, sodium tert-butoxide and the like; metal carbonate bases such as potassium carbonate, sodium carbonate and the like; metal hydroxide bases such as lithium hydroxide, sodium hydroxide and the like; Organic base include but not limited to triethyl amine, diisopropyl ethyl amine (DIPEA), pyridine, dimethyl aminopyridine (DMAP), sodium methoxide, sodium tert-butoxide and the like; preferably, the base is selected from metal bicarbonate. More preferably, the base is sodium bicarbonate.

Suitable solvent of step a) may include but not limited to ethers such as 1,4-dioxane, tetrahydrofuran and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane and the like. nitrile solvent such as acetonitrile, propionitrile, water and mixture thereof. preferably, the solvent may be an ether solvent. More preferably, solvent is tetrahydrofuran (THF). The reaction may be carried out at a temperature of about 30 °C to about boiling point of the solvent.
In embodiments of Step (b), involves the use of a suitable additional solvent to isolate the Ritlecitinib free base. Suitable additional solvent of step b) may include but not limited to ester solvent such as ethyl acetate, butyl acetate and the like; ethers such as 1,4-dioxane, tetrahydrofuran and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane and the like. nitrile solvent such as acetonitrile, propionitrile, water and mixture thereof. preferably, the solvent may be an ester solvent. More preferably, solvent is ethyl acetate.
In embodiments of Step (b), further involves the removal of solvent from the solution obtained in step (a). Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying such as drying using a rotavapor, spray drying, agitated thin-film drying, freeze -drying or any other technique known in the art.
The resulting compound obtained in step (b) may optionally be further dried. Drying can 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, or the like. The drying can be carried out at temperatures of less than about 75°C, less than about 50°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the Ritlecitinib is not degraded in its quality. The drying can be carried out for any desired time until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.

Eighteenth aspect of the present application provides a pharmaceutical composition comprising amorphous form of Ritlecitinib and at least one pharmaceutically acceptable carrier.

Nineteenth aspect of the present application relates a process for preparation of crystalline DB1 or amorphous form of Ritlectinib comprising converting pharmaceutically acceptable salt of ritlecitinib to retlicetinib in presence of a suitable base and a suitable solvent.

Twentieth aspect of the present application relates to the use of solid forms disclosed herein for preparation of Ritlecitinib tosylate.
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.
DEFINITIONS
The following definitions are used in connection with the present invention unless the context indicates otherwise. The term “amorphous” refers to a solid lacking any long-range translational orientation symmetry that characterizes crystalline structures although; it may have short range molecular order similar to a crystalline solid.
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 Ritlecitinib tosylate and PVP K 30 L100 (1:9)
Ritlecitinib tosylate (0.2 g) and PVP K 30 (1.8 g), were dissolved in methanol (20 mL) at room temperature. The reaction mixture is filtered to remove the undissolved particle. The clear solution was distilled using rotary evaporator at 65°C to obtain the solid compound. The resulting solid was dried in VTD dryer at 50 °C for about 5 hours to obtain the title compound. PXRD pattern is shown in Figure 1.
Example-2: Preparation of amorphous solid dispersion of Ritlecitinib tosylate and Copovidone (1:9)
Ritlecitinib tosylate (0.2 g) and Co-povidone (1.8 g), were dissolved in methanol (20 mL) at room temperature. The reaction mixture is filtered to remove the undissolved particle. The clear solution was distilled using rotary evaporator at 65°C to obtain the solid compound. The resulting solid was dried in VTD dryer at 50 °C for about 5 hours to obtain the title compound. PXRD pattern is shown in Figure 2.
Example-3: Preparation of amorphous solid dispersion of Ritlecitinib tosylate and HPMC (1:9)
Ritlecitinib tosylate (0.2 g) and HPMC (1.8 g), were dissolved in methanol (100 mL) at room temperature. The reaction mixture is filtered to remove the undissolved particle. The clear solution was distilled using rotary evaporator at 65°C to obtain the solid compound. The resulting solid was dried in VTD dryer at 50 °C for about 5 hours to obtain the title compound. PXRD pattern is shown in Figure 3.
Example-4: Preparation of crystalline form DB1 of Ritlecitinib
To a solution of Ritlecitinib tosylate (5 g) in tetrahydrofuran (300 mL) was added an aqueous solution of sodium carbonate (2% solution, 100 mL) at 25 OC in a dropwise manner for about 1 hour. After addition, the reaction mixture was mixed with ethyl acetate (100 mL) at the same temperature. Organic and layers were separated. Aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were distilled and resulting solid was dried at 40 oC for 2 h. The resulting solid was further mixed with ethyl acetate (50 mL) and distilled again. The resulting solid was dried under vacuum at 30 ? for 2 h to obtain the title compound. PXRD pattern is shown in Figure 4.
Example-5: Preparation of crystalline form D1 of Ritlecitinib tosylate
A mixture of crystalline form DB1 of Ritlecitinib (100 mg) and p-Toluenesulfonic acid (50 mg) in methanol (0.25 mL), ethylacetate (0.25 mL) and methyl ethyl ketone (0.25 mL) was stirred at 25 OC for 6 hours. The resulting solid was filtered and dried under vacuum to obtain the title compound. PXRD pattern is shown in Figure 5.
Example-6: Preparation of Amorphous form of Ritlecitinib
To a solution of Ritlecitinib tosylate (5 g) in tetrahydrofuran (300 mL) was added an aqueous solution of sodium bicarbonate (2% solution, 100 mL) at 10 OC in a dropwise manner for about 30 minutes to adjust its pH to 7-8. After addition, the reaction mixture was heated to room temperature and mixed with ethyl acetate (100 mL). Organic and layers were separated. Aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were distilled and resulting solid was dried at room temperature for 24 h. to obtain the title compound. PXRD pattern is shown in Figure 7.
Example-7: Preparation of amorphous solid dispersion of Ritlecitinib and Copovidone (1:4)
Ritlecitinib (0.5 g) and Co-povidone (2 g), were dissolved in methanol (50 mL) at room temperature. The reaction mixture is filtered to remove the undissolved particle. The clear solution was distilled using rotary evaporator at 50 °C to obtain the solid compound. The resulting solid was dried in VTD dryer at 50 °C for about 3 hours to obtain the title compound. PXRD pattern is shown in Figure 8.
Example-8: Preparation of amorphous solid dispersion of Ritlecitinib and Eudragit L (1:4)
Ritlecitinib (0.5 g) and eudragit-L (2.0 g), were dissolved in methanol (50 mL) at room temperature. The reaction mixture is filtered to remove the undissolved particle. The clear solution was distilled using rotary evaporator at 50°C to obtain the solid compound. The resulting solid was dried in VTD dryer at 50 °C for about 3 hours to obtain the title compound. PXRD pattern is shown in Figure 9.
Example-9: Preparation of amorphous solid dispersion of Ritlecitinib and HPMC (1:4)
Ritlecitinib (0.5 g) and HPMC (2.0 g), were dissolved in dichloromethane (50 mL) at room temperature. The reaction mixture is filtered to remove the undissolved particle. The clear solution was distilled using rotary evaporator at 40°C to obtain the solid compound. The resulting solid was dried in VTD dryer at 50 °C for about 4 hours to obtain the title compound. PXRD pattern is shown in Figure 10.
Example-10: Preparation of amorphous solid dispersion of Ritlecitinib and HPMCAS-LG (1:4)
Ritlecitinib (0.5 g) and HPMCAS-LG (2.0 g), were dissolved in dichloromethane (50 mL) at room temperature. The reaction mixture is filtered to remove the undissolved particle. The clear solution was distilled using rotary evaporator at 40°C to obtain the solid compound. The resulting solid was dried in VTD dryer at 50 °C for about 4 hours to obtain the title compound. PXRD pattern is shown in Figure 11.
,CLAIMS:We Claim:
1. A process for preparation of amorphous solid dispersion comprising Ritlecitinib tosylate and one or more pharmaceutically acceptable excipient; the process comprising;
a) providing a solution comprising Ritlecitinib tosylate and one or more pharmaceutically acceptable excipients by dissolving in a suitable solvent or mixture threreof,
b) removing solvent from the solution obtained in step (a), and
c) recovering the solid dispersion comprising Ritlecitinib tosylate and one or more pharmaceutically acceptable excipients.

2. Crystalline form D1 of Ritlecitinib tosylate characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 5.65, 15.47, 18.45, 18.75, 21.77 and 28.34 ± 0.2° 2?. In embodiments of the present application, crystalline form D1 of Ritlecitinib tosylate is further characterized by its PXRD pattern having additional peaks located at about 20.7, 21.44, 22.99, 25.2, 28.9 and 29.66 ± 0.2° 2?.

3. A process for preparing crystalline form D1 of Ritlecitinib tosylate; the process comprising;
a) reacting Ritlecitinib with a p-Toluenesulfonic acid (PTSA) in a suitable solvent or mixture thereof;
b) isolating crystalline form D1 of Ritlecitinib tosylate;
c) optionally, drying the isolated product at suitable temperature.

4. Crystalline form DB1 of Ritlecitinib characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about: 5.02, 15.07, 19.32, 21.20 ± 0.2° 2?. In embodiments of the present application, crystalline form DB1 of Ritlecitinib is further characterized by its PXRD pattern having additional peaks located at about 10.02, 18.21, 25.25 and 26.01 ± 0.2° 2?. In embodiments of the present application, crystalline form DB1 of Ritlecitinib is further characterized by its PXRD pattern having additional peaks located at about 26.7714, 28.54, 29.40, 29.91 and 30.41 ± 0.2° 2?.

5. A process for preparing crystalline form DB1 of Ritlecitinib; the process comprising;
a) reacting Ritlecitinib tosylate with a suitable base in a suitable solvent or mixture thereof;
b) isolating crystalline form DB1 of Ritlecitinib;
c) optionally, drying the isolated product at suitable temperature.

6. A process for preparation of amorphous solid dispersion comprising Ritlecitinib and one or more pharmaceutically acceptable excipient; the process comprising;
a) providing a solution comprising Ritlecitinib and one or more pharmaceutically acceptable excipients by dissolving in a suitable solvent or mixture thereof,
b) removing solvent from the solution obtained in step (a), and
c) recovering the solid dispersion comprising Ritlecitinib and one or more pharmaceutically acceptable excipients.

7. A process for preparation of amorphous form of Ritlecitinib; the process comprising;
a) Reacting Ritlecitinib tosylate with a suitable base in a suitable solvent or mixture thereof;
b) isolating amorphous form of Ritlecitinib;
c) optionally, drying the isolated product at suitable temperature.

8. The process as claimed in claims 1 & 6, where in polymer is selected from group comprising PVP, HPMC, Co-povidone, HPMCAS, Eudragit or a mixture thereof.

9. The process as claimed in claims 1, 3, 5-7, where in suitable solvent is selected from group comprising methanol, tetrahydrofuran, ethyl acetate, dichloromethane, water or a mixture thereof.