DESC:CROSS REFERENCE TO THE RELATED APPLICATIONS
This application claims the benefit of earlier Indian provisional patent application No. IN 202241007424, filed on Feb 11, 2022; the entire contents of each of which are incorporated by reference herein.

FIELD OF INVENTION
The present invention relates to Upadacitinib and its co-crystals.

BACKGROUND ART:
Upadacitinib, having a chemical name: (3S,4R)-3-ethyl-4-(3H-imidazo[l,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine- l-carboxamide and structure is as below.

Upadacitinib is a JAK1-selective inhibitor in development for the treatment of adult patients with moderate to severe rheumatoid arthritis and it is developed by AbbVie. Upadacitinib, also known as ABT-494.

Upadacitinib is known in US 8426411 B2, it also discloses the synthetic preparation of Upadacitinib in a general route as mentioned in Scheme-II.

OBJECT AND SUMMARY OF THE INVENTION.
The main object of the present invention is to provide Upadacitinib co-crystals and process for the preparation of the same.

In one object, the present invention provides Upadacitinib-fumaric acid co-crystal and Upadacitinib-succinic acid co-crystal.

In another object, the present invention provides a process for the preparation of Upadacitinib Fumaric acid co-crystal comprising the steps of:
a) taking upadacitinib and fumaric acid in a suitable organic solvent or mixtures thereof; and
b) removing the solvent to isolate Upadacitinib fumaric acid co-crystal.

In one more object, the present invention provides a process for the preparation of Upadacitinib succinic acid co-crystal comprising the steps of:
a) taking upadacitinib and succinic acid in a suitable organic solvent or mixtures thereof; and
b) removing the solvent to isolate Upadacitinib succinic acid co-crystal.

BRIEF DESCRIPTION OF THE DRAWINGS
Further aspects of the present disclosure together with additional features contributing thereto and advantages accruing therefrom will be apparent from the following description of embodiments of the disclosure which are shown in the accompanying figures wherein:
FIGURE 1: PXRD pattern of Upadacitinib fumaric acid co-crystal.
FIGURE 2: DSC of Upadacitinib fumaric acid co-crystal.
FIGURE 3: TGA pattern of Upadacitinib fumaric acid co-crystal.
FIGURE 4: NMR of Upadacitinib fumaric acid co-crystal.
FIGURE 5: PXRD pattern of Upadacitinib succinic acid co-crystal.
FIGURE 6: Overlay of FTIR spectra of upadacitinib (top), the novel 2:1 upadacitinib-fumaric acid co-crystal (middle) and fumaric acid (bottom).
FIGURE 7: 1H NMR spectrum of the novel 2:1 upadacitinib-fumaric acid co-crystal.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides co-crystals of Upadacitinib with fumaric and succinic acid.

Instrumentation Details:
PXRD Analysis:
The X-ray diffraction pattern of said polymorph of the invention was measured on a Bruker D8 ADVANCE powder diffractometer equipped with a goniometer of ?/2? configuration and LYNXEYE detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 2? range of 2.0°–50.0°, 0.033° step size and 0.4 seconds step time 62.s.
FT-IR spectroscopy:
The FT-IR data was recorded using Perkin Elmer spectrum one instrument in the range of 600-3800 cm-1 by using KBr pellets.
NMR spectroscopy:
The 1HNMR experiments were performed on Bruker 500 MHz Avance NMR spectrometer equipped with 5mm BBO probe in DMSO-d6. The data collected and processed by XWIN-NMR software.

In one aspect, the present invention provides a co-crystal of Upadacitinib-fumaric acid.
In one embodiment, the present invention provides a co-crystal of Upadacitinib-fumaric acid disclosed herein may be characterized by having an x-ray powder diffraction pattern comprising peaks with degrees two-theta positions of about 7.3, 8.6, 16.1, 18.4, 19.7 and 20.1 ± 0.2 degrees 2?.

In another embodiment, the present invention provides a co-crystal of Upadacitinib-fumaric acid disclosed herein may be characterized by having an x-ray powder diffraction pattern comprising further characteristic peaks with degrees two-theta positions of about 10.0, 10.6, 11.3, 11.8, 12.4, 23.8, 24.2, 24.8, 25.2 and 25.8 ± 0.2 degrees 2?.

In one more embodiment, the present invention provides a co-crystal of Upadacitinib-fumaric acid disclosed herein may be characterized by PXRD pattern substantially as depicted in FIG.1.

In one more embodiment, the present invention provides a co-crystal of Upadacitinib-fumaric acid disclosed herein may be characterized by having a differential scanning calorimetry thermogram as depicted in FIG.2.

In one more embodiment, the present invention provides a co-crystal of Upadacitinib-fumaric acid disclosed herein may be characterized by thermogravimetric analysis as depicted in FIG.3.

In one more embodiment, the present invention provides a co-crystal of Upadacitinib-fumaric acid disclosed herein may be characterized by NMR as depicted in FIG.4.

In another aspect, the present invention provides a co-crystal of Upadacitinib-succinic acid.
In another embodiment, the present invention provides a co-crystal of Upadacitinib-succinic acid disclosed herein may be characterized by having an x-ray powder diffraction pattern comprising peaks with degrees two-theta positions of about 7.3, 8.6, 16.1, 18.4, 19.7 and 20.1 ± 0.2 degrees 2?.

In another embodiment, the present invention provides a co-crystal of Upadacitinib-succinic acid disclosed herein may be characterized by having an x-ray powder diffraction pattern comprising further characteristic peaks with degrees two-theta positions of about 10.0, 10.6, 11.3, 11.8, 12.4, 23.8, 24.2, 24.8, 25.2 and 25.8 ± 0.2 degrees 2?.

In one more embodiment, the present invention provides a co-crystal of Upadacitinib-succinic acid disclosed herein may be characterized by PXRD pattern substantially as depicted in FIG.5.

In another aspect, the present invention provides a process for the preparation of Upadacitinib Fumaric acid co-crystal comprising the steps of:
a) taking upadacitinib and fumaric acid in a suitable organic solvent or mixtures thereof; and
b) removing the solvent to isolate Upadacitinib fumaric acid co-crystal.

According to the present invention, upadacitinib, fumaric acid and suitable organic solvent or mixtures thereof are stirred at ambient temperature and the solvent was removed to isolate Upadacitinib fumaric acid co-crystal.
The stirring of the above embodiment may carry out for 16 hrs to 5 days and removed solvent to isolate Upadacitinib fumaric acid co-crystal.
The suitable organic solvent or mixtures thereof for the above embodiment includes, but not limited to ether solvents such as diethyl ether, diisopropyl ether, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether; ester solvents such as isopropyl acetate, ethyl acetate, n-butyl acetate, tert- butyl acetate; preferably methyl tertiary butyl ether and mixture of methyl tert-butyl ether-isopropyl acetate.
Next, the solvent is removed from the above resulting upadacitinib-fumaric acid solution to isolate co-crystal of upadacitinib-fumaric acid and may further dried. The solvent removal of the above embodiment may carry out according to the methods well known in the art, for example, by filtration.

In another object, the present invention provides a process for the preparation of Upadacitinib succinic acid co-crystal comprising the steps of:
a) taking upadacitinib and succinic acid in a suitable organic solvent or mixtures thereof; and
b) removing the solvent to isolate Upadacitinib succinic acid co-crystal.

According to the present invention, upadacitinib, succinic acid and suitable organic solvent or mixtures thereof are stirred at ambient temperature for 45-55 hrs and the solvent was removed to isolate Upadacitinib succinic acid co-crystal.
The suitable organic solvent or mixtures thereof for the above embodiment includes, but not limited to ether solvents such as diethyl ether, diisopropyl ether, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether; ester solvents such as isopropyl acetate, ethyl acetate, n-butyl acetate, tert- butyl acetate. Preferably mixture of isopropyl acetate and methyl tert-butyl ether.
Next, the solvent is removed from the above resulting upadacitinib-succinic acid solution to isolate co-crystal of upadacitinib- succinic acid and may dried further. The solvent removal of the above embodiment may carry out according to the methods well known in the art, for example, by filtration.
In one embodiment, input Upadacitinib may be prepared by the processes known in the art such as US 8426411, WO2017066775 and WO2021176473.

FTIR analysis
An overlay of the FTIR spectra of pure upadacitinib, the novel 2:1 co-crystal of upadacitinib and fumaric acid, and pure fumaric acid are shown in Fig. 6. Table 1 lists the absorptions indicative of co-crystal formation. No significant change is observed in the absorption corresponding to the amide >C=O group of upadacitinib after co-crystalation (1645.85 cm-1 in the co-crystal, as opposed to 1644.54 cm-1 in pure upadacitinib), indicating that the amide group does not participate in any interaction in the co-crystal. However, the >C=O vibration corresponding to the carboxylic group of fumaric acid is blue-shifted to 1701.53 cm-1 in the co-crystal, from 1673.94 cm-1 in pure fumaric acid, suggesting that the carboxylic acid groups of fumaric acid are participating in interaction with the heterocyclic moiety of upadacitinib. We can also conclude from this wavenumber (1701.53 cm-1) that the carboxylic acid groups are in the neutral state, confirming the formation of a co-crystal, and not a salt.
Table 1
Functional group Upadacitinib Fumaric acid Co-crystal
>C=O (Amide) 1644.54 - 1645.85
>C=O (Acid) - 1673.94 1701.53

Indicative stability:
The physical stability of the novel 2:1 co-crystal of upadacitinib and fumaric acid was determined by storing the samples at 25°C and 60% RH, 40°C and 75% RH conditions for two months, followed by analysis of the samples by P XRD. The results of the study are summarized in Table 2. The novel 2:1 co-crystal of upadacitinib and fumaric acid was found to be physically stable under all conditions studied.

Table 2
Conditions/Polymorph Co-crystal of upadacitinib-fumaric acid (2:1)
PXRD
at 25°C/60% RH
Initial Co-crystal
1 month Stable
2 months Stable
at 40°C/75% RH
Initial Co-crystal
1 month Stable
2 months Stable

1H NMR spectrum:
Fig. 7 shows the 1H NMR spectrum of the novel 2:1 co-crystal of upadacitinib and fumaric acid. The NMR spectra of co-crystal shows the two olefinic protons of fumaric acid are seen as a singlet at 6.62 ppm and the two hydroxy protons of the carboxylic group are seen as a singlet at 13.12 ppm whereas the pyrrole NH and pyrazine CH of the upadacitinib moiety are shown as singlet at 12.27 ppm and 8.57 ppm respectively further confirming the stoichiometry of the co-crystal of upadacitinib and fumaric acid as 2:1.

In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.

Examples:
Example-1: Upadacitinib-Fumaric acid Co-crystal.
In an RBF, 50 mg of Upadacitinib, 7.5 mg of fumaric acid, 1 mL of methyl tert-butyl ether were charged at 25±3°C. The reaction mass was stirred for 16h at 25±5°C.The product obtained was filtered and suck dried for 10 min at 25±3°C. Further, dried the material under vacuum at 40 °C for 16 h. The solid obtained was identified by PXRD as 1:0.5 co-crystal of Upadacitinib Fumaric acid. Yield: 45 mg.

Example-2: Upadacitinib-Fumaric acid Co-crystal.
In an RBF, 100 mg of Upadacitinib, 31 mg of fumaric acid, 2.2 mL mixture of isopropyl acetate and methyl tert-butyl ether (1:1, v/v) were charged at 25±3°C. The reaction mass was stirred for 5 days at 25±5°C. The product obtained was filtered and suck dried for 10min at 25±3°C. Further dried the material under vacuum at 40 °C for 16h. The solid obtained was identified by PXRD as 2:1 co-crystal of Upadacitinib Fumaric acid. Yield: 90 mg.

Example-3: Upadacitinib-Fumaric acid Co-crystal.
In an RBF, 500 mg of Upadacitinib, 76 mg of fumaric acid, 10 mL mixture of isopropyl acetate and methyl tert-butyl ether (1:1, v/v) were charged at 25±3 °C. The reaction mass was stirred for 42h at 25±3 °C. The product obtained was filtered, washed with mixture of isopropyl acetate (0.5mL) and methyl tert-butyl ether (0.5 mL) and suck dried for 20min at 25±3°C. Further dried the material under vacuum at 40 °C for 12h. The solid obtained was identified by PXRD as 2:1 co-crystal of Upadacitinib Fumaric acid. Yield: 500 mg.

Example-4: Upadacitinib-Fumaric acid Co-crystal.
Suspended 2 g of Upadacitinib and 0.45 g of fumaric acid in 60 mL of methyl tertiary butyl ether at 25±2°C. Maintained the reaction mass under stirring for 16 hours at 25±2°C. Filtered the resulting reaction mass, washed it with methyl tertiary butyl ether (2 mL) and suck-dried for 30 minutes under vacuum. The solid obtained was dried under vacuum at 70°C for 15 hours. The product obtained was identified by PXRD as the novel 2:1 co-crystal of Upadacitinib and fumaric acid. Yield: 2.15 g.

Example-5: Upadacitinib-Succinic acid Co-crystal.
In an RBF, 50 mg of upadacitinib, 16 mg of succinic acid, mixture of isopropyl acetate and methyl tert-butyl ether (1.1 mL, 1:1, v/v) were charged at 25±3°C. The reaction mass was stirred for 48h at 25±5 °C. The product obtained was filtered and suck dried for 10 mins at 25±3 °C. The solid obtained was identified by PXRD as 2:1 co-crystal of Upadacitinib Succinic acid. Yield: 50 mg.
,CLAIMS:We claim:
1. A co-crystal of Upadacitinib selected from:
a) Upadacitinib-fumaric acid co-crystal;
b) Upadacitinib-succinic acid co-crystal.

2. A crystalline form of co-crystal of Upadacitinib-fumaric acid has at least one characteristic or combination selected from the group:
a) an x-ray powder diffraction pattern comprising peaks about 7.3, 8.6, 16.1, 18.4, 19.7 and 20.1 ± 0.2 degrees 2?.
b) a PXRD pattern substantially as depicted in FIG.1.

3. A crystalline form of co-crystal of Upadacitinib-succinic acid has at least one characteristic or combination selected from the group:
a) an x-ray powder diffraction pattern comprising peaks about 7.3, 8.6, 16.1, 18.4, 19.7 and 20.1 ± 0.2 degrees 2?.
b) a PXRD pattern substantially as depicted in FIG.5.

4. A process for the preparation of Upadacitinib Fumaric acid co-crystal comprising the steps of:
a) taking upadacitinib and fumaric acid in a suitable organic solvent or mixtures thereof; and
b) removing the solvent to isolate Upadacitinib fumaric acid co-crystal.

5. The process as claimed in claim 4, wherein the suitable organic solvent is selected from ether solvents and ester solvents.

6. The process as claimed in claim 5, wherein the ether solvent includes diethyl ether, diisopropyl ether, dimethyl ether, diisopropyl ether, and methyl tertiary butyl ether; ester solvent includes isopropyl acetate, ethyl acetate, n-butyl acetate, and tert-butyl acetate.

7. A process for the preparation of Upadacitinib succinic acid co-crystal comprising the steps of:
a) taking upadacitinib and succinic acid in a suitable organic solvent or mixtures thereof; and
b) removing the solvent to isolate Upadacitinib succinic acid co-crystal.

8. The process as claimed in claim 7, wherein the suitable organic solvent is selected from ether solvents and ester solvents.

9. The process as claimed in claim 8, wherein the ether solvent includes diethyl ether, diisopropyl ether, dimethyl ether, diisopropyl ether, and methyl tertiary butyl ether; ester solvent includes isopropyl acetate, ethyl acetate, n-butyl acetate, and tert-butyl acetate.