DESC:INTRODUCTION
Aspects of the present application relate to a solid form of Upadacitinib and the pharmaceutical composition thereof. Specific aspects of present application relate to a crystalline form of Upadacitinib and the process for its preparation.
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 a second generation JAK inhibitor developed by AbbVie, which is highly selective for JAK1. RINVOQ® oral tablet containing Upadacitinib is authorized in many countries for the treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate.
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 (as 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 followed by its purification through Chiral preparative HPLC. However, instant PCT application is silent about the nature of the Upadacitinib.
Later on, another PCT application, WO 2017066775 A1 discloses Upadacitinib in amorphous and crystalline forms, namely Form A, Form B, Form C and Form D. Further, it discloses that, Form A and Form B have poor crystallinity and are unstable, as both the forms covert to amorphous Upadacitinib. This PCT application also states that, Form D is difficult to crystallize with poor reproducibility and can only be obtained at low water activity, otherwise Form D converts to Form C under humid conditions.
IN202041025283 discloses crystalline Form-US of Upadacitinib and succinic acid.
The existence and possible numbers of polymorphic forms for a given compound cannot be predicted, and there are no “standard” procedures that can be used to prepare polymorphic forms of a substance. This is well-known in the art, as reported, for example, by A. Goho, “Tricky Business,” Science News, Vol. 166(8), August 2004.
Therefore, there remains a need for a viable solid form of Upadacitinib and preparative processes thereof. Particularly, a crystalline form of Upadacitinib that is stable and can meet the requirements of drug development and the need for a reproducible process for its preparation.

SUMMARY
In an aspect, the present application provides a crystalline Form-UF of Upadacitinib and fumaric acid, characterized by a PXRD pattern comprising the peaks at about 4.5 and 7.4° ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline Form-UF of Upadacitinib, comprising the step of combining Upadacitinib with fumaric acid, optionally in the presence of an inert solvent.

In another aspect, the present application provides a pharmaceutical composition comprising crystalline Form-UF of Upadacitinib and fumaric acid together with atleast one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction pattern of crystalline Form-UF of Upadacitinib and fumaric acid, prepared by the method of Example No 1.

DETAILED DESCRIPTION
Aspects of the present application relates to solid form of Upadacitinib and the pharmaceutical composition thereof. Specific aspect of present application relates to Form-UF of Upadacitinib and fumaric acid. Further aspect relates to a process for the preparation of crystalline Form-UF.
In an aspect, the present application provides a crystalline Form-UF of Upadacitinib and fumaric acid, characterized by a PXRD pattern comprising the peaks at about 4.5 and 7.4°± 0.2° 2?. In an embodiment, the crystalline Form-UF is characterized by one or more additional peaks at about 5.2, 8.6 ° ± 0.2° 2?. In an embodiment, the present application provides crystalline Form-UF of Upadacitinib and fumaric acid, characterized by a powder X-ray diffraction pattern, as illustrated by Figures 1. In embodiments, the crystalline Form-UF is a complex of Upadacitinib and fumaric acid.
In another aspect, the present application provides a process for the preparation of crystalline Form-UF of Upadacitinib, comprising the step of combining Upadacitinib with fumaric acid, optionally in the presence of an inert solvent.
In embodiments, Upadacitinib used in this aspect may be obtained by any methods known in the art or a reaction mixture comprising Upadacitinib may be used directly.
In embodiments, combining Upadacitinib with fumaric acid, optionally in the presence of an inert solvent, may be carried out through the formation of a homogeneous solution or a heterogeneous mixture, under suitable temperature at about 0°C to reflux temperature the solvent or reaction mixture thereof.
Inert solvent may include, but not limited to Methyl Tertiary Butyl Ether (MTBE), tetrahydrofuran, water, acetone, methanol, dichloromethane and ethyl acetate.
In an embodiment, combining Upadacitinib with fumaric acid may be carried out by dissolving Upadacitinib and fumaric acid in an inert solvent, optionally by heating. In embodiments, the solution containing Upadacitinib and fumaric acid may be cooled to suitable temperature to crystallize Form-UF.
In an embodiment, the solvent from the solution containing Upadacitinib and fumaric acid may be removed by evaporation or filtration of the solvent, optionally under reduced pressure at about 0°C to reflux temperature.
In embodiments, Upadacitinib may be combined with fumaric acid by suspending Upadacitinib and fumaric acid in an inert solvent to form a slurry or suspension, optionally under heating.
In embodiments, Upadacitinib may be combined with fumaric acid for sufficient time to obtain crystalline Form-UF.
In embodiments, Upadacitinib may be combined with fumaric acid at suitable temperature to obtain crystalline Form-UF. In an embodiment, Upadacitinib may be combined with fumaric acid at suitable temperature of about 0°C to reflux temperature to obtain crystalline Form-UF.
In embodiments, the crystalline Form-UF may be isolated by separating the solids from the solvent through suitable techniques known in the art such as filtration, decantation and the like.
In embodiments, the isolated solid may be dried under suitable drying conditions such as aerial drying, drying under vacuum or inert gas at a suitable temperature of about 25°C or above.
In embodiments, the crystalline Form-UF obtained by the process of this aspect is characterized by a PXRD pattern comprising the peaks at about 4.5, 5.2, 7.4,8.6°± 0.2° 2?. In an embodiment, the crystalline Form-UF obtained by the process of this aspect is characterized by a PXRD pattern of figure 1.
In another aspect, the present application provides a complex of Upadacitinib and fumaric acid. In embodiments, the complex of Upadacitinib and fumaric acid is a crystalline complex. In embodiments, the complex contains Upadacitinib and fumaric acid in a ratio of about 1:0.5. In embodiments, the complex of Upadacitinib and fumaric acid is crystalline Form-UF, characterized by a PXRD pattern comprising the peaks at about 4.5, 5.2, 7.4,8.6°± 0.2° 2?.
In embodiments, the crystalline complex of Upadacitinib and fumaric acid stable under thermal, humid and stress conditions. Further, the crystalline complex of present application exhibits superior solubility in solvents such as Methyl Tertiary Butyl Ether, as compared to reported crystalline forms of Upadacitinib.
In another aspect, the present application provides a complex of Upadacitinib and fumaric acid, its crystalline Form-UF or the pharmaceutical compositions thereof, comprising Upadacitinib with 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.

Example
Example-1: Preparation of crystalline Form-UF of Upadacitinib and fumaric acid.
A mixture of Upadacitinib (380.4 mg), fumaric acid (60.4 mg) and MTBE (6 ml) was stirred for 21 hours at 25°C. The obtained reaction mass was filtered under reduced pressure to obtain title compound.
,CLAIMS:We claim:
1. A crystalline Form-UF of Upadacitinib and fumaric acid, characterized by a PXRD pattern comprising the peaks at about 4.5 and 7.4°± 0.2° 2?.
2. The crystalline Form-UF of Upadacitinib and fumaric acid of claim 1, further characterized by one or more additional peaks at about at about 5.2, 8.6 ° ± 0.2° 2?.
3. A process for the preparation of crystalline Form-UF of Upadacitinib and fumaric acid, comprising the step of combining Upadacitinib with fumaric acid.
4. A pharmaceutical composition comprising crystalline Form-UF of Upadacitinib and fumaric acid together with atleast one pharmaceutically acceptable excipient.