DESC:The following specification describes the invention.

INTRODUCTION
Aspects of the present application relate to amorphous Upadacitinib or a salt thereof, its amorphous solid dispersion and pharmaceutical compositions thereof. Aspects of the present application further relate to processes for the preparation of amorphous Upadacitinib or a salt thereof and its solid dispersion.
Upadacitinib is the adopted name of drug compound having a chemical name: (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and structure as below.

Upadacitinib, also known as ABT-494, is potent and selective JAK inhibitor under development for rheumatoid arthritis (RA). Upadacitinib is approximately 74 fold selective for Jak1 over Jak2 in cellular assays dependent on specific, relevant cytokines. Upadacitinib demonstrates efficacy in rat arthritis models. The safety and efficacy of Upadacitinib in 300 patients with moderate-to-severe RA and an inadequate response to methotrexate. The researchers found that the proportion of patients meeting the American College of Rheumatology 20 percent improvement criteria (ACR20) at week 12 was higher with Upadacitinib than placebo (62 to 80 percent versus 46 percent). Patients were randomized to receive immediate-release Upadacitinib at 3, 6, 12, or 18 mg twice daily or matching placebo. The researchers found that significantly more patients receiving Upadacitinib achieved an ACR20 response (53 to 71 percent) versus placebo (34 percent). Preliminary evidence suggests that compared to Tofacitinib, Upadacitinib may spare Jak2 and Jak3 dependent signaling. Further, the EMEA opinion (EMA/PDCO/672645/2015), discloses ABT-494 in the form of tartrate salt, "(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (2R,3R)-2,3-dihydroxybutanedioate, from AbbVie Ltd, for the treatment of chronic idiopathic arthritis (including rheumatoid arthritis, psoriatic arthritis, spondyloarthritis and juvenile idiopathic arthritis)”.
US 8426411 B2 discloses Upadacitinib, its composition and use for treating diseases (incl. Rheumatoid arthritis). Therein, the preparation of Upadacitinib or a salt thereof is specifically not described, however, a general route for the preparation of related compounds is disclosed at example-36 [e.g. (3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide]
PCT application, WO 2015061665 A1 discloses the method of treating Rheumatoid Arthritis and other autoimmune diseases using Upadacitinib (Compound 1) and also describes a similar approach for the preparation of Upadacitinib (as in US 8426411 B2) followed by extracting the aqueous reaction mass with ethyl acetate or DCM solvent and concentrating the organic layer under reduced pressure to give target product (Upadacitinib in free form) followed by its purification through Chiral preparative HPLC. Further, WO 2015061665 A1 discloses that, “Compound 1 (Upadactinib) was slowly absorbed from solution formulations, with peak concentrations noted 1 to 6 hours after dosing. Bioavailability in rats was moderate (30.5%), with higher values noted in both monkey (59.3%) and dog (76.8%)”, “Solutions of the tartrate salt provided Cmax and AUC values comparable to those obtained from solution formulations of the free base following oral dosing in dog (0.5-2 mg base/kg doses). In the rat, exposures from suspensions of the tartrate salt were also comparable to those obtained with the free base.” However, instant PCT application is silent about the nature of the Upadacitinib or a salt thereof.
Therefore, there remains a need for a solid form of Upadacitinib or a salt thereof and preparative processes thereof. Particularly, an amorphous form of a low soluble drug substance, may exhibit a higher bioavailability than its crystalline counterparts, which leads to the selection of the amorphous form as the final drug substance for pharmaceutical dosage form development. The solubility of crystalline form is lower than its amorphous counter parts, particularly aqueous solubility, which may result in the difference in their in-vivo bioavailability. Therefore, it is desirable to have an amorphous form of a drug substance to meet the needs of drug development which is stable and also a reproducible process for their preparation.

SUMMARY
In an aspect, the present application provides a stable amorphous form of Upadacitinib or a salt thereof.
In another aspect, the present application provides a process for the preparation of an amorphous form of Upadacitinib or a salt thereof, comprising the steps of:
a) providing a solution of Upadacitinib or a salt thereof in a suitable solvent or a mixture thereof;
b) removing the solvent from the solution obtained in step a); and
c) isolating the amorphous form of Upadacitinib or a salt thereof.
d) optionally, combining amorphous form of step c) with atleast one pharmaceutically acceptable excipient.
In another aspect, the present application provides amorphous solid dispersion of Upadacitinib or a salt thereof together with atleast one pharmaceutically acceptable excipient.
In another aspect, the present application provides a process for the preparation of an amorphous solid dispersion of Upadacitinib or a salt thereof, comprising the steps of:
a) providing a solution of Upadacitinib or a salt thereof and atleast one pharmaceutically acceptable excipient in a suitable solvent or a mixture thereof;
b) removing the solvent from the solution obtained in step a), and
c) isolating the amorphous solid dispersion of Upadacitinib or a salt thereof.
d) optionally, combining amorphous solid dispersion of step c) with atleast one additional pharmaceutically acceptable excipient.
In another aspect, the present application provides a pharmaceutical composition comprising amorphous form of Upadacitinib or a salt thereof and an amorphous solid dispersion of Upadacitinib or a salt thereof together with atleast one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction pattern of amorphous form of Upadacitinib or a salt thereof prepared by the method of Example No 1.
Figure 2 is an illustrative X-ray powder diffraction pattern of amorphous form of Upadacitinib or a salt thereof prepared by the method of Example No 2.
Figure 3 is an illustrative X-ray powder diffraction pattern of amorphous form of Upadacitinib or a salt thereof prepared by the method of Example No 3.
Figure 4 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Upadacitinib or a salt thereof with povidone K-90 prepared by the method of Example No 4.

DETAILED DESCRIPTION
In an aspect, the present application provides an amorphous form of Upadacitinib or a salt thereof.
In an embodiment, the present aspect provides an amorphous form of Upadacitinib free form. In an embodiment, the present aspect provides an amorphous form of a salt of Upadacitinib. In an embodiment, the salt of Upadacitinib includes, but not limited to tartrate salt of Upadacitinib.
The present application provides a stable amorphous form of Upadacitinib or a salt thereof suitable for powder handling and downstream processes. Amorphous form of Upadacitinib or a salt thereof of the present application was surprisingly found to be highly stable under mechanical stress such as grinding and milling and stable under hygroscopic conditions such as higher relative humidity conditions of more than 60% RH.
In an embodiment, the present application provides a stable amorphous form of Upadacitinib or a salt thereof with less than 5% of crystallinity, preferably with less than 1% crystallinity and more preferably with less than 0.5% crystallinity as per X-ray diffraction analysis.
In an embodiment, the present application provides an amorphous form of Upadacitinib characterized by a powder X-ray diffraction (PXRD) pattern, substantially as illustrated by Figures 1, 2 or 3.

In another aspect, the present application provides a process for the preparation of an amorphous form of Upadacitinib or a salt thereof, comprising the steps of:
a) providing a solution of Upadacitinib or a salt thereof in a suitable solvent or a mixture thereof;
b) removing the solvent from the solution obtained in step a); and
c) isolating the amorphous form of Upadacitinib or a salt thereof.
d) optionally, combining amorphous form of step c) with atleast one pharmaceutically acceptable excipient.
In an embodiment, the present aspect provides a process for the preparation of an amorphous form of Upadacitinib free form. In an embodiment, the present aspect provides a process for the preparation of an amorphous form of a salt of Upadacitinib. In an embodiment, the salt of Upadacitinib includes, but not limited to tartrate salt of Upadacitinib.
In an embodiment, suitable solvent at step a) of this aspect may be selected from C1-C6 alcohols, C3-C6 ketones, C5-C8 aliphatic or aromatic hydrocarbons, C3-C6 esters, C2-C6 aliphatic or cyclic ethers, C2-C6 nitriles, halogenated hydrocarbons, water or mixtures thereof. In preferred embodiment, the suitable solvent may be selected from the group comprising of alcohol solvents such as methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol; dichloromethane; tetrahydrofuran; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; esters solvents such as methyl acetate, ethyl acetate, isopropyl acetate; water and mixtures thereof.
In an embodiment, providing a solution at step a) may be carried out by dissolving Upadacitinib or a salt thereof in a suitable solvent or by taking the reaction mixture containing Upadacitinib or a salt thereof directly. In an embodiment, providing a solution at step a) may be carried out by dissolving Upadacitinib free form in a suitable solvent or by taking the reaction mixture containing Upadacitinib free form directly. In an embodiment, providing a solution at step a) may be carried out by dissolving a salt of Upadacitinib in a suitable solvent or by taking the reaction mixture containing Upadacitinib and an acid directly. In an embodiment, the acid includes, but not limited to tartaric acid.
In an embodiment, a solution of Upadacitinib or a salt thereof can be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
In an embodiment, a solution of Upadacitinib or a salt thereof may be filtered to make it clear, 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.
In an embodiment, removal of solvent at step b) may be carried out by methods known in the art or any procedure disclosed in the present application. In preferred embodiments, removal of solvent may include, but not limited to: solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Büchi® Rotavapor®, spray drying, freeze drying, thin film drying, agitated thin film drying, rotary vacuum paddle dryer (RVPD) and the like. In preferred embodiment, the solvent may be removed under reduced pressures and at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80°C, or any other suitable temperatures.
In an embodiment, the isolation of an amorphous form of Upadacitinib or a salt thereof at step c) involves recovering the solid obtained in step b). The solid obtained from step b) may be recovered using techniques such as by scraping, or by shaking the container, or adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used. In an embodiment, the amorphous form of Upadacitinib or a salt thereof obtained from step b) may be optionally dried before or after isolating it at step c).
Amorphous form of Upadacitinib or a salt thereof obtained at step c) may be optionally combined with atleast one pharmaceutically acceptable excipient at step d).
In an embodiment, amorphous form of Upadacitinib or a salt thereof may be combined with excipient using a technique known in art or by the procedures disclosed in the present application.
In preferred embodiment, amorphous form of Upadacitinib or a salt thereof may be combined with excipient either by physical blending of both the solid components or by suspending both the components in a suitable solvent and conditions, such that both the components remain unaffected. Blending may be carried out using techniques known in art such as rotatory cone dryer, fluidized bed dryer or the like optionally under reduced pressure / vacuum or inert atmosphere such nitrogen at suitable temperature and sufficient time to obtain uniform composition of amorphous form of Upadacitinib or a salt thereof and atleast one pharmaceutically acceptable excipient.
In an embodiment, amorphous form of Upadacitinib or a salt thereof may be combined with the excipient by evaporating the suspension or solution of amorphous form of Upadacitinib or a salt thereof and atleast one pharmaceutically acceptable excipient.
In an embodiment, pharmaceutically acceptable excipient may include, but not limited to an inorganic oxide such as SiO2, TiO2, ZnO2, ZnO, Al2O3 and zeolite; a water insoluble polymer is selected from the group consisting of cross-linked polyvinyl pyrrolidinone, cross-linked cellulose acetate phthalate, cross-linked hydroxypropyl methyl cellulose acetate succinate, microcrystalline cellulose, polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer, cross-linked carboxymethyl cellulose, sodium starch glycolat, and cross-linked styrene divinyl benzene or any other excipient at any aspect of present application.
In preferred embodiment, pharmaceutically acceptable excipient may be selected from the group consisting of silicon dioxide, e.g. colloidal or fumed silicon dioxide or porous silica or Syloid; copolymers, such as polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer; and cellulose, preferably microcrystalline cellulose.
Amorphous form of Upadacitinib or a salt thereof isolated at step c) or d) may be dried in suitable drying equipment such as vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.

In an aspect, the present application provides pharmaceutical composition comprising amorphous form of Upadacitinib or a salt thereof and atleast one pharmaceutically acceptable excipient. In an embodiment, the present aspect provides pharmaceutical composition comprising amorphous form of Upadacitinib and atleast one pharmaceutically acceptable excipient. In an aspect, the present aspect provides pharmaceutical composition comprising amorphous form of tartrate salt of Upadacitinib and atleast one pharmaceutically acceptable excipient.
In an aspect, the present application provides amorphous solid dispersion of Upadacitinib or a salt thereof together with atleast one pharmaceutically acceptable excipient. In an embodiment, the present aspect provides amorphous solid dispersion of Upadacitinib and atleast one pharmaceutically acceptable excipient. In an embodiment, the present aspect provides amorphous solid dispersion of a salt of Upadacitinib and atleast one pharmaceutically acceptable excipient. In an embodiment, the salt of Upadacitinib includes, but not limited to a tartrate salt.
In an embodiment, atleast one pharmaceutically acceptable excipient of this aspect may be selected from the group consisting of polyvinyl pyrrolidone, povidone K-30, povidone K-60, Povidone K-90, polyvinylpyrrolidone vinylacetate, co-povidone NF, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene–polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit or Eudragit-RLPO), hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), hydroxypropylmethyl cellulose, hydroxypropyl cellulose SSL(HPC-SSL), hydroxypropyl cellulose SL(HPC-SL), hydroxypropyl cellulose L (HPC-L), hydroxyethyl cellulose, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxymethylethylcelluloseand the like; cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, and the like; water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and the like; polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like; organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and guanidine or its derivatives, or any other excipient at any aspect of present application. The use of mixtures of more than one of the pharmaceutical excipients to provide desired release profiles or for the enhancement of stability is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, and mixtures are all within the scope of this invention without limitation. Solid dispersions of the present application also include the solid dispersions obtained by combining Upadacitinib or a salt thereof with a suitable non-polymeric excipient by employing techniques known in the art or procedures described or exemplified in any aspect of the instant application.
In an embodiment, the present application provides amorphous solid dispersion of Upadacitinib or a salt thereof together with atleast one pharmaceutically acceptable excipient characterized by a powder X-ray diffraction (PXRD) pattern, substantially as illustrated by Figures 4.
In another aspect, the present application provides a process for the preparation of an amorphous solid dispersion of Upadacitinib or a salt thereof, comprising the steps of:
a) providing a solution of Upadacitinib or a salt thereof and atleast one pharmaceutically acceptable excipient in a suitable solvent or a mixture thereof;
b) removing the solvent from the solution obtained in step a), and
c) isolating the amorphous solid dispersion of Upadacitinib or a salt thereof.
d) optionally combining amorphous solid dispersion of step c) with atleast one additional pharmaceutically acceptable excipient.
In an embodiment, the present aspect provides a process for the preparation of amorphous solid dispersion of Upadacitinib and atleast one pharmaceutically acceptable excipient. In an embodiment, the present aspect provides a process for the preparation of amorphous solid dispersion of salt of Upadacitinib and atleast one pharmaceutically acceptable excipient. In an embodiment, the salt of Upadacitinib includes, but not limited to a tartrate salt.
In an embodiment, suitable solvent at step a) of this aspect may be selected from C1-C6 alcohols, C3-C6 ketones, C5-C8 aliphatic or aromatic hydrocarbons, C3-C6 esters, C2-C6 aliphatic or cyclic ethers, C2-C6 nitriles, halogenated hydrocarbons, water or mixtures thereof.
In preferred embodiment, the suitable solvent may be selected from the group consisting of alcohol solvents such as methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol; dichloromethane, tetrahydrofuran; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; esters solvents such as methyl acetate, ethyl acetate, isopropyl acetate; water and mixtures thereof.
In an embodiment, atleast one pharmaceutically acceptable excipient of these aspects may be selected from the group consisting of polyvinyl pyrrolidone, povidone K-30, povidone K-60, Povidone K-90, polyvinylpyrrolidone vinylacetate, co-povidone NF, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene–polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit or Eudragit-RLPO), hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), hydroxypropylmethyl cellulose, hydroxypropyl cellulose SSL(HPC-SSL), hydroxypropyl cellulose SL(HPC-SL), hydroxypropyl cellulose L (HPC-L), hydroxyethyl cellulose, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxymethylethylcelluloseand the like; cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, and the like; water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and the like; polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like; organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and guanidine or its derivatives, or any other excipient at any aspect of present application. The use of mixtures of more than one of the pharmaceutical excipients to provide desired release profiles or for the enhancement of stability is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, and mixtures are all within the scope of this invention without limitation. Solid dispersions of the present application also include the solid dispersions obtained by combining Upadacitinib or a salt thereof with a suitable non-polymeric excipient by employing techniques known in the art or procedures described or exemplified in any aspect of the instant application.
In an embodiment, providing a solution at step a) may be carried out by dissolving Upadacitinib or a salt thereof and atleast one pharmaceutically acceptable excipient in a suitable solvent simultaneously or by dissolving components in a suitable solvent separately to form individual solutions and combining those solutions later.
In an embodiment, providing a solution at step a) may be carried out by dissolving Upadacitinib and atleast one pharmaceutically acceptable excipient. In an embodiment, providing a solution at step a) may be carried out by dissolving a salt of Upadacitinib and atleast one pharmaceutically acceptable excipient. In an embodiment, the salt of Upadacitinib includes, but not limited to a tartrate salt.
In an embodiment, a solution of Upadacitinib or a salt thereof and the excipient may be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
In an embodiment, a solution of Upadacitinib or a salt thereof and the excipient may be filtered to make it clear, 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.
In an embodiment, removal of solvent at step b) may be carried out by methods known in the art or any procedure disclosed in the present application. In preferred embodiments, removal of solvent may include, but not limited to: solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Büchi® Rotavapor®, spray drying, freeze drying, agitated thin film drying and the like.
In preferred embodiment, the solvent may be removed under reduced pressures, at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80°C, or any other suitable temperatures.
In an embodiment, the isolation of an amorphous solid dispersion of Upadacitinib or a salt thereof and excipient at step c) involves recovering the solid obtained in step b). The solid obtained from step b) may be recovered using techniques such as by scraping, or by shaking the container, or adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used.
In an embodiment, the amorphous solid dispersion of Upadacitinib or a salt thereof and excipient obtained from step b) may be optionally dried before or after isolating at step c).
Amorphous solid dispersion of Upadacitinib or a salt thereof obtained at step c) may be optionally combined with atleast one additional pharmaceutically acceptable excipient at step d). In an embodiment, the salt of Upadacitinib includes, but not limited to a tartrate salt.
In an embodiment, amorphous solid dispersion of Upadacitinib or a salt thereof may be combined with additional excipient using a technique known in art or by the procedures disclosed in the present application.
In preferred embodiment, amorphous solid dispersion of the present application may be combined with additional excipient either by physical blending of both the solid components or by suspending both the components in a suitable solvent and conditions, such that both the components remain unaffected. Blending may be carried out using techniques known in art such as rotatory cone dryer, fluidized bed dryer or the like optionally under reduced pressure / vacuum or inert atmosphere such nitrogen at suitable temperature and sufficient time to obtain uniform composition of amorphous solid dispersion of Upadacitinib or a salt thereof with pharmaceutically acceptable excipient and atleast one additional pharmaceutically acceptable excipient.
In an embodiment, amorphous solid dispersion of the present application may be combined with additional excipient by evaporating the suspension or solution of amorphous solid dispersion of Upadacitinib or a salt thereof and additional excipient.
In an embodiment, pharmaceutically acceptable additional excipient may be same or different from the excipient used in the preparation of amorphous solid dispersion of Upadacitinib or a salt thereof. Additional excipient may include, but not limited to an inorganic oxide such as SiO2, TiO2, ZnO2, ZnO, Al2O3 and zeolite; a water insoluble polymer is selected from the group consisting of cross-linked polyvinyl pyrrolidinone, cross-linked cellulose acetate phthalate, cross-linked hydroxypropyl methyl cellulose acetate succinate, microcrystalline cellulose, polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer, cross-linked carboxymethyl cellulose, sodium starch glycolat, and cross-linked styrene divinyl benzene or any other excipient at any aspect of present application.
In preferred embodiment, pharmaceutically acceptable additional excipient may be selected from the group consisting of silicon dioxide, e.g. colloidal or fumed silicon dioxide or porous silica or Syloid; copolymers, such as polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer; and cellulose, preferably microcrystalline cellulose.
Amorphous solid dispersion of Upadacitinib or a salt thereof isolated at step c) or d) may be dried in a suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
In an aspect, the present application provides pharmaceutical composition comprising amorphous solid dispersion of Upadacitinib or a salt thereof with atleast one pharmaceutically acceptable excipient and atleast one additional pharmaceutically acceptable excipient. In an embodiment, the salt of Upadacitinib includes, but not limited to a tartrate salt.
In an aspect, the present application provides pharmaceutical compositions comprising amorphous Upadacitinib or a salt thereof and atleast one pharmaceutically acceptable excipient, in particular in the form of solid dispersions and adsorbates, and a process for preparing the same. In embodiments, the pharmaceutically acceptable excipient is selected from the excipients at any aspect of present application.
In embodiments, the present application provides adsorbates, wherein Upadacitinib or a salt thereof is associated with a suitable substrate. Suitable substrate may be a particulate and/or porous substrate, wherein this substrate has an outer and/or inner surface onto which the API may be adsorbed. This means that if the substrate has pores, these pores are filled by the Upadacitinib or a salt thereof and the substrate remains unaffected, it does not, at least not essentially, change during and / or after the adsorption. In embodiments, the suitable substrate is selected from the excipients at any aspect of present application.
Amorphous form of Upadacitinib or a salt thereof or its solid dispersion may be obtained alternatively either by employing a melt-extrusion technique or by combining a solution of Upadacitinib or a salt thereof as obtained any of the aspects of present application with a suitable anti-solvent. In embodiment, amorphous product may be obtained by employing suitable melt-extrusion conditions or any of the procedures known in the art for obtaining amorphous product by melt-extrusion technique. In embodiment, solution of Upadacitinib or a salt thereof may be combined with the anti-solvent at suitable temperature and for sufficient time to obtain amorphous product.
In another aspect, the present application provides amorphous Upadacitinib or a salt thereof, its solid dispersion or pharmaceutical composition comprising Upadacitinib or a salt thereof having a chemical purity of atleast 99% by HPLC or atleast 99.5% by HPLC or atleast 99.9% by HPLC.
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 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.
The term “inert solvent” when used in the present application is a solvent that does not react with the reactants or reagent s under conditions that cause the chemical reaction indicated to take place.
The terms “amorphous form of Upadacitinib or a salt thereof" and “amorphous Upadacitinib or a salt thereof” indicate that the Upadacitinib or a salt thereof is present in substantially amorphous state in the composition (e.g. solid dispersion, adsorbate or pharmaceutical composition). "Substantially" amorphous denotes that 90 %, preferably 95 % or 99 %, more preferably all of the Upadacitinib or a salt thereof being present in the solid dispersion, on the adsorbate or in the pharmaceutical composition is amorphous. In other words, an "amorphous" Upadacitinib or a salt thereof composition denotes a Upadacitinib or a salt thereof-containing composition, which does not contain substantial amounts, preferably does not contain noticeable amounts, of crystalline portions of Upadacitinib or a salt thereof e.g. measurable upon X-ray powder diffraction analysis.
The term "solid dispersion" when used in the present application, denotes a state where most of the Upadacitinib or a salt thereof, preferably 90%, 95% or all of the Upadacitinib or a salt thereof of the solid dispersion, is homogeneously molecularly dispersed in a solid polymer matrix. Preferably solid dispersion, relates to a molecular dispersion where the API (active pharmaceutical ingredient) and polymer molecules are uniformly but irregularly dispersed in a non-ordered way. In other words, in a solid dispersion, the two components (polymer and API) form a homogeneous one-phase system, where the particle size of the API in the solid dispersion is reduced to its molecular size. In a preferred embodiment, in the solid dispersion according to the present invention no chemical bonds can be detected between the API and the polymer. In order to arrive at such a solid dispersion, preferably solid solution, it is required to have a substantial amount of API dissolved in a suitable solvent at least at one time point during preparation of said solid dispersion.
The term "adsorbate" when used in the present application, specifies that the Upadacitinib or a salt thereof is, preferably evenly, and preferably homogeneously, distributed on the inner and/or outer surface of the particulate substrate.
An “alcohol” is an organic compound containing a carbon bound to a hydroxyl group. “C1-C6 alcohols” include, but are not limited to, methanol, ethanol, 2-nitroethanol,2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, or the like.
An “aliphatic hydrocarbon” is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds. A liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called“aromatic.” Examples of “C5-C8aliphatic or aromatic hydrocarbons” include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, or any mixtures thereof.
An “ester” is an organic compound containing a carboxyl group -(C=O)-O- bonded to two other carbon atoms. “C3-C6esters” include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like.
An “ether” is an organic compound containing an oxygen atom –O- bonded to two other carbon atoms. “C2-C6 ethers” include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like.
A “halogenated hydrocarbon” is an organic compound containing a carbon bound to a halogen. Halogenated hydrocarbons include, but are not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the like.
A “ketone” is an organic compound containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “C3-C6 ketones” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, or the like.
A “nitrile” is an organic compound containing a cyano -(C=N) bonded to another carbon atom. “C2-C6Nitriles” include, but are not limited to, acetonitrile, propionitrile, butanenitrile, or the like.

EXAMPLES
Example-1: Preparation of Upadacitinib

(3S,4S)-3-ethyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (11. 2 g) was dissolved in 1,4-dioxane (168 mL) at 27°C and 1N sodium hydroxide solution ( 2.52 g of NaOH dissolved in 63 mL of water) was added drop wise to the reaction mixture at 27°C. The reaction mixture was heated to 55°C and stirred at the same temperature for 1 hour. The reaction mixture was cooled to 27°C and water (200 mL) was added. The reaction mixture was extracted with ethyl acetate (4 x 140 mL) and the combined organic layer was washed with brine solution (140 mL). The separated organic solution was washed with sodium sulfate and concentrated the organic solution under reduced pressure at 42°C. The crude compound obtained was purified by column chromatography using silica gel (60-120 mesh) and 6 – 8% methanol – dichloromethane as eluent. The fractions containing the compound were concentrated under reduced pressure at 42°C to obtain solid. The solid was suspended in heptane (25 mL) and acetone (50 mL) at 27°C for 30 minutes and the solid was filtered. The solid was dried under reduced pressure at for 30 minutes to obtain the title compound as pale brown solid. Yield: 5.52 g, Purity by HPLC: 99.69% and XRPD: Amorphous.

Example-2: Preparation of Amorphous form of Upadacitinib.
Upadacitinib (0.4 g) was dissolved in methanol (20 mL) at 25°C and filtered the solution to make it particle free. The solvent was evaporated in rotavapour under reduced pressure at 50°C. The obtain product was re-dissolved in methanol (20 mL) at 25°C and the solvent was evaporated in rotavapour under reduced pressure at 50°C for 20 minutes to obtain title compound. XRPD: Amorphous.

Example-3: Preparation of Amorphous form of Upadacitinib
Upadacitinib (1.5 g) was dissolved in methanol (75 mL) at 30°C and filtered the solution to make it particle free. The clear solution was spray dried using ProCeptTM spray dryer using following parameters to obtain the title compound.
• Feed pump speed: 60 rpm
• Inlet temperature: 120 °C
• Nozzle diameter: 0.8 mm
• Inlet gas flow rate: 0.25 m3/min
• Nozzle pressure : 2 bar
XRPD: Amorphous.

Example-4: Preparation of Amorphous solid dispersion of Upadacitinib or a salt thereof with PVP K-90
A mixture of Upadacitinib (0.5 g) and PVP K-90 (0.5 g) was dissolved in methanol (25 mL) at 25°C and filtered the solution to make it particle free. The solvent was evaporated in rotavapour under reduced pressure at 50°C to obtain title compound. XRPD: Amorphous.

We Claim:
1. An amorphous solid dispersion of Upadacitinib or a salt thereof together with atleast one pharmaceutically acceptable excipient.
2. A process for the preparation of an amorphous solid dispersion of Upadacitinib or a salt thereof, comprising the steps of:
a) providing a solution of Upadacitinib or a salt thereof and atleast one pharmaceutically acceptable excipient in a suitable solvent or a mixture thereof;
b) removing the solvent from the solution obtained in step a);
c) isolating the amorphous solid dispersion of Upadacitinib or a salt thereof;
d) optionally, combining amorphous solid dispersion of step c) with atleast one additional pharmaceutically acceptable excipient.
3. The solvent according to claim 2 is selected from C1-C6 alcohols, C3-C6 ketones, C5-C8 aliphatic or aromatic hydrocarbons, C3-C6 esters, C2-C6 aliphatic or cyclic ethers, C2-C6 nitriles, halogenated hydrocarbons, water or mixtures thereof.
4. A process for the preparation of an amorphous form of Upadacitinib or a salt thereof, comprising the steps of:
a) providing a solution of Upadacitinib or a salt thereof in a suitable solvent or a mixture thereof;
b) removing the solvent from the solution obtained in step a);
c) isolating the amorphous form of Upadacitinib or a salt thereof,
d) optionally, combining amorphous form of step c) with atleast one pharmaceutically acceptable excipient.
5. The solvent according to claim 4 is selected from C1-C6 alcohols, C3-C6 ketones, C5-C8 aliphatic or aromatic hydrocarbons, C3-C6 esters, C2-C6 aliphatic or cyclic ethers, C2-C6 nitriles, halogenated hydrocarbons, water or mixtures thereof.
6. A pharmaceutical composition comprising an amorphous solid dispersion of Upadacitinib or a salt thereof together with atleast one pharmaceutically acceptable excipient.
7. Pharmaceutical excipients according to claim is selected from from the group comprising of polyvinyl pyrrolidine, povidone K-30, povidone K-60, Povidone K-90,polyvinylpyrrolidone vinylacetate, co-povidone NF, polyvinylacetaldiethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80,polyoxyethylene–polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit), hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethyl cellulose phthalate (HPMC phthalate), hydroxypropylmethyl cellulose acetate succinate (HPMC AS), hydroxypropyl cellulose SL (HPC), hydroxy ethyl cellulose (HEC) and ethyl cellulose (EC).
,CLAIMS:We Claim:
1. An amorphous solid dispersion of Upadacitinib or a salt thereof together with atleast one pharmaceutically acceptable excipient.
2. A process for the preparation of an amorphous solid dispersion of Upadacitinib or a salt thereof, comprising the steps of:
a) providing a solution of Upadacitinib or a salt thereof and atleast one pharmaceutically acceptable excipient in a suitable solvent or a mixture thereof;
b) removing the solvent from the solution obtained in step a);
c) isolating the amorphous solid dispersion of Upadacitinib or a salt thereof;
d) optionally, combining amorphous solid dispersion of step c) with atleast one additional pharmaceutically acceptable excipient.
3. The solvent according to claim 2 is selected from C1-C6 alcohols, C3-C6 ketones, C5-C8 aliphatic or aromatic hydrocarbons, C3-C6 esters, C2-C6 aliphatic or cyclic ethers, C2-C6 nitriles, halogenated hydrocarbons, water or mixtures thereof.
4. A process for the preparation of an amorphous form of Upadacitinib or a salt thereof, comprising the steps of:
a) providing a solution of Upadacitinib or a salt thereof in a suitable solvent or a mixture thereof;
b) removing the solvent from the solution obtained in step a);
c) isolating the amorphous form of Upadacitinib or a salt thereof,
d) optionally, combining amorphous form of step c) with atleast one pharmaceutically acceptable excipient.
5. The solvent according to claim 4 is selected from C1-C6 alcohols, C3-C6 ketones, C5-C8 aliphatic or aromatic hydrocarbons, C3-C6 esters, C2-C6 aliphatic or cyclic ethers, C2-C6 nitriles, halogenated hydrocarbons, water or mixtures thereof.
6. A pharmaceutical composition comprising an amorphous solid dispersion of Upadacitinib or a salt thereof together with atleast one pharmaceutically acceptable excipient.
7. Pharmaceutical excipients according to claim is selected from from the group comprising of polyvinyl pyrrolidine, povidone K-30, povidone K-60, Povidone K-90,polyvinylpyrrolidone vinylacetate, co-povidone NF, polyvinylacetaldiethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80,polyoxyethylene–polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit), hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethyl cellulose phthalate (HPMC phthalate), hydroxypropylmethyl cellulose acetate succinate (HPMC AS), hydroxypropyl cellulose SL (HPC), hydroxy ethyl cellulose (HEC) and ethyl cellulose (EC).