WO2023105460A1

WO2023105460A1 - Co-crystals of upadacitinib

Info

Publication number: WO2023105460A1
Application number: PCT/IB2022/061932
Authority: WO
Inventors: Venkateswara Rao Nandepu; Hardev Nandepu; Narender Rao SOMISETTI; Venkata krishna Reddy BIJJULA
Original assignee: Metrochem Api Pvt Ltd.
Priority date: 2021-12-08
Filing date: 2022-12-08
Publication date: 2023-06-15

Abstract

The present invention relates to co-crystals of Upadacitinib, process for its preparation and pharmaceutical composition comprising the same.

Description

“CO-CRYSTALS OF UPADACITINIB”

Related applications:

This application claims the benefit under Indian Provisional Application No. 202141057042, filed on Dec 8, 2021 entitled “Co-crystals of Upadacitinib”, the content of which is incorporated by reference herein.

Field of the invention:

Background of the Invention:

Upadacitinib, sold under the brand name Rinvoq, is a Janus kinase (JAK) inhibitor medication for the treatment of moderately to severely active rheumatoid arthritis in adults. It was approved in its hemihydrate form for medical use in the United States and in the European Union in 2019, and was developed by the biotech company Abbvie. Upadacitinib is chemically known as (3S,4R)-3-Ethyl-4-(3H-imidazo[l,2-a]pyrrolo[2,3-e]pyrazin-8-yl)- N-(2,2,2-trifluoroethyl) pyrrolidine- 1 -carboxamide and structurally represented as shown in formula I: ‘

Formula I

Upadacitinib and process for its preparation was first disclosed in US8426411. The international publication WO2017066775 (the “WO’775 publication) discloses Form A, Form B, Form C (hemihydrate), Form D (anhydrous) and amorphous form for Upadacitinib free base.

Other than WO’775 publication different crystalline forms and solvated forms of Upadacitinib was disclosed in the patent publications such as W02020063939, W02020115212, W02020115213, WO2020177645 and WO2020224633.

INCORPORATED BY REFERENCE (RULE 20.6) Co-crystals are combinations of two or more distinct molecules arranged to create a unique crystal form. Co-crystals include two or more different components and often rely on hydrogen bonded assemblies between neutral molecules. Co-crystals with the same active pharmaceutical ingredient will have strikingly different pharmaceutical properties like melting point, solubility, dissolution, moisture uptake, chemical stability etc. depending on the nature of the second component.

A new crystalline form like co-crystal form of a compound may possess physical properties that differ from, and are advantageous over, those of other known crystalline or amorphous forms. These include, packing properties such as molar volume, density and hygroscopicity; thermodynamic properties such as melting temperature, vapor pressure and solubility; kinetic properties such as dissolution rate and stability under various storage conditions; surface properties such as surface area, wettability, interfacial tension and shape; mechanical properties such as hardness, tensile strength, compactibility, handling, flow and blend; and filtration properties. Variations in any one of these properties may affect the chemical and pharmaceutical processing of a compound as well as its bioavailability and may often render the new form advantageous for pharmaceutical and medical use.

Upadacitinib is one of the important pharmaceutical products available in the market useful for the treatment of rheumatoid arthritis. The discovery of new co-crystal form of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product such as Upadacitinib. Hence the main object of the present invention is to provide novel co-crystals of Upadacitinib.

Summary of the Invention:

Accordingly, the present invention provides novel co-crystals of Upadacitinib, process for its preparation and pharmaceutical compositions comprising the same. The novel cocrystals of Upadacitinib of the present invention have advantageous properties selected from at least one of: chemical purity, flowability, solubility, morphology or crystal habit, stability - such as storage stability. In one aspect, the present invention provides co-crystals of Upadacitinib and a suitable coformer.

In another aspect, the present invention provides co-crystal of Upadacitinib and adipic acid.

In another aspect, the present invention provides co-crystal of Upadacitinib and adipic acid characterized by a powder X-ray diffractogram that comprises one or more peaks at about 3.76, 7.00, 10.23, 10.45, 11.63, 14.98, 20.57 and 24.12 degrees 20±0.2 degrees 20, herein designated as crystalline Form MC2.

In another aspect, the present invention provides co-crystal of Upadacitinib and adipic acid further characterized by a powder X-ray diffractogram that comprises one or more additional peaks at about 7.69, 8.33, 8.69, 8.95, 13.04, 13.62, 21.36, and 22.09 degrees 20±0.2 degrees 20.

In another aspect, the present invention provides co-crystal of Upadacitinib and adipic acid characterized by a powder X-ray diffractogram substantially as shown in Figure 1 and/or Figure 2.

In another aspect, the present invention provides co-crystal of Upadacitinib and adipic acid characterized by a Differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 3.

In another aspect, the present invention provides co-crystal of Upadacitinib and adipic acid characterized by a Thermo gravimetric analysis (TGA) diagram substantially as shown in Figure 4.

In a further aspect, the present invention provides a process for the preparation of cocrystals of Upadacitinib, which comprises dissolving or suspending a co-former in a suitable solvent; mixing Upadacitinib with the obtained solution or suspension; or vice versa; stirring the suspension or solution for sufficient period of time and isolating the cocrystals of Upadacitinib. In a further aspect, the present invention provides a process for the preparation of cocrystal of Upadacitinib and adipic acid, which comprises a) dissolving Upadacitinib and adipic acid in a suitable solvent; b) adding Upadacitinib or Upadacitinib adipic acid cocrystal to the obtained solution; c) stirring the suspension for a sufficient period of time; and d) isolating the cocrystal of Upadacitinib and adipic acid.

In a further aspect, the present invention provides a pharmaceutical composition comprising co-crystal of Upadacitinib and adipic acid of the present invention and at least one pharmaceutically acceptable excipient.

Brief description of the drawings:

Figure- 1 shows an X-ray powder diffraction pattern of the Upadacitinib and adipic acid cocrystal Form MC2.

Figure-2 shows an X-ray powder diffraction pattern of the Upadacitinib and adipic acid cocrystal Form MC2.

Figure-3 shows a Differential scanning calorimetry (DSC) thermogram of the Upadacitinib and adipic acid cocrystal Form MC2.

Figure 4 shows a Thermo gravimetric analysis (TGA) diagram of the Upadacitinib and adipic acid cocrystal Form MC2.

The Powder X-ray diffraction (PXRD) pattern measured on an X-ray diffractometer (Instrument name Bruker D8 Advance) with measured using CuKa radiation of wavelength 1.54066A⁰ step size of 0.012°/min; scan range of 3-40° A.

Differential scanning calorimetry (DSC) data in the present disclosure were recorded on a Perkin Elmer (Model-DSC 4000) at a heating rate of 10.0°C/min in the temperature range of from 25°C to 350°C.

Thermo gravimetric analysis (TGA) data in the present disclosure were recorded on a Perkin Elmer (TGA-4000) at a heating rate of 20°C/min in the temperature range of from 30°C to 600°C. Detailed description of the Invention:

In one embodiment, the present invention provides co-crystals of Upadacitinib and a co-former. In a preferred embodiment, the co-former is adipic acid.

In another embodiment, the present invention provides co-crystal of Upadacitinib and adipic acid.

In another embodiment, the present invention provides co-crystal of Upadacitinib and adipic acid characterized by a powder X-ray diffractogram that comprises one or more peaks at about 3.76, 7.00, 10.23, 10.45, 11.63, 14.98, 20.57 and 24.12 degrees 20±0.2, herein designated as crystalline Form MC2.

In another embodiment, the present invention provides co-crystal of Upadacitinib and adipic acid further characterized by a powder X-ray diffractogram that comprises one or more additional peaks at about 7.69, 8.33, 8.69, 8.95, 13.04, 13.62, 21.36, and 22.09 degrees 20±0.2 degrees 20.

In another embodiment, the present invention provides co-crystal of Upadacitinib and adipic acid characterized by a powder X-ray diffractogram as shown in Figure 1 and/or Figure 2.

In another embodiment, the present invention provides co-crystal of Upadacitinib and adipic acid characterized by a Differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 3.

In another embodiment, the present invention provides co-crystal of Upadacitinib and adipic acid characterized by a Thermo gravimetric analysis (TGA) diagram substantially as shown in Figure 4.

In a further embodiment, the present invention provides a process for the preparation of cocrystal of Upadacitinib, which comprises dissolving or suspending a co-former in a suitable solvent; mixing Upadacitinib with the obtained solution or suspension; or vice versa; stirring the suspension or solution for sufficient period of time and isolating the cocrystal of Upadacitinib.

In the process for the preparation of cocrystal of Upadacitinib as described above, the coformer is adipic acid; and the suitable solvent is nitrile solvent and the reaction is carried out at a suitable temperature of about 20°C to about 35°C.

In a further embodiment, the present invention provides a process for the preparation of cocrystal of Upadacitinib and adipic acid, which comprises a) dissolving Upadacitinib and adipic acid in a suitable solvent; b) adding Upadacitinib or Upadacitinib adipic acid cocrystal to the obtained solution; c) stirring the suspension for a sufficient period of time; and d) isolating the cocrystal of Upadacitinib and adipic acid.

The step a) of the forgoing process involves dissolution of Upadacitinib and adipic acid in a suitable solvent; for example nitrile solvent such as acetonitrile and can be carried out at a suitable temperature of about 10°C to about reflux temperature of the solvent used; preferably at about 15°C to about 40°C; addition of Upadacitinib or Upadacitinib adipic acid cocrystal to the obtained solution in step b) is carried out at a suitable temperature of about 15°C to about 40°C; and in step c) the obtained suspension was stirred for sufficient period of time till complete formation of crystalline material at a suitable temperature of about 15°C to about 40°C; preferably stirred for about 12-14 hours at about 25°C to about 35°C; then isolation of cocrystal of Upadacitinib and adipic acid in step d) is carried out by the methods known in the art; for example; filtration followed by drying at a suitable temperature.

In a preferred embodiment, the present invention provides a process for the preparation of cocrystal of Upadacitinib and adipic acid, which comprises a) dissolving Upadacitinib and adipic acid in acetonitrile at about 25°C to about 35°C; b) adding Upadacitinib or Upadacitinib adipic acid cocrystal to the obtained solution at about 25 °C to about 35 °C; c) stirring the obtained suspension at about 25°C to about 35°C; and d) isolating the cocrystals of Upadacitinib and adipic acid by filtration followed by drying. The drying can be suitably carried out in a tray dryer, vacuum oven, air oven and the like; the drying may be carried out at a suitable temperature, for example less than about 70°C, or any other suitable temperature. The drying may be carried out under reduced pressure, that is, less than standard atmospheric pressure or at atmospheric pressure or any other suitable pressure. The drying may take place over a period of about 30 minutes to about 12 hours, or any other suitable time period. Preferably, the crystalline Form MC2 dried at a temperature of about 40°C to about 45°C for 4-6 hours at the atmospheric pressure.

The starting Upadacitinib compound used herein in the present invention for the preparation of Upadacitinib adipic acid cocrystals may be any crystalline or other form of Upadacitinib, including various solvates and hydrates known in the art and same can be prepared by the methods known in the art; for example Upadacitinib hemihydrate prepared as per the method disclosed in WO 2017066775.

The Upadacitinib adipic acid co-crystalline form MC2 of the present invention has good stability and found to be stable for more than 6 months when kept under normal packing conditions at ambient temperature.

The present invention is based in part on the unexpected finding that the new co-crystal form of Upadacitinib-adipic acid disclosed herein possesses advantageous physicochemical properties which render their processing as medicaments beneficial. The new co-crystal form of the present invention has adequate stability characteristics enabling their incorporation into a variety of different formulations particularly suitable for pharmaceutical utility.

In another embodiment, the stoichiometry of each component in the co-crystal can vary. In some embodiments, the stoichiometry of the complex is 1: 1, i.e., one molecule of Upadacitinib co-crystallized with one molecule of adipic acid. In other embodiments, one molecule of Upadacitinib co-crystallizes with more than one molecule of adipic acid, such that the stoichiometry between the two molecules is, e.g., 1:2, 1:3, 1 :4 etc. Upadacitinib: adipic acid. In other embodiments, one molecule of Upadacitinib co-crystallizes with less than one molecule of adipic acid, such that the stoichiometry between the two molecules is, e.g., 4: 1, 3:1, 2:1, etc. Upadacitinib: adipic acid. The solvates and hydrates (e.g., monohydrate, dihydrate etc.) as well as anhydrous forms of Upadacitinib adipic acid cocrystals also included in the scope of the present invention.

The co-crystal of Upadacitinib and adipic acid of the present invention may readily be incorporate into pharmaceutical compositions for immediate or delayed or modified release for the treatment of rheumatoid arthritis. In a further embodiment, the present invention provides a pharmaceutical composition comprising co-crystal of Upadacitinib and adipic acid of the present invention and at least one pharmaceutically acceptable excipient.

The term “suitable solvents” used in the present invention until unless specified is selected from, but are not limited to “alcoholic solvents” such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; “ester solvents” such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like, “ether solvents” such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane and the like; “hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptane, n- pentane, petroleum ether and the like; “chloro solvents” such as dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform and the like; “polar aprotic solvents” such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methyl pyrrolidone and the like; “nitrile solvents” such as acetonitrile, propionitrile and the like; “ketone solvents” such as acetone, methyl isobutyl ketone, methyl ethylketone and the like; and water.

The term “co-crystal” means a crystalline material comprised of two or more unique solids at room temperature, each containing distinctive physical characteristics, such as structure, melting point and heats of fusion. In the context of the present invention, the term “cocrystal” means a crystalline material comprised of Upadacitinib and a second solid molecule (designated “co-crystal former or Co-former”).

The term “coformer” used in the present invention may selected from adipic acid, caffeine, citric acid, cinnamic acid, dimethyl sulfone, glutaric acid, glutamic acid, glycine, isoleucine, isonicotinamide, inosine, L-hydroxy proline, 4-hydroxy isoleucine, nicotinic acid, malic acid, L-proline, succinic acid, sorbic acid, 4- amino benzoic acid, oxalic acid, gallic acid, sorbitol, isonicotinic acid, melonic acid, piperine, pyroglutamic acid, fumaric acid, quinic acid, tartaric acid, trigonelline, urea, xylitol, resorcinol, luteolm, resveratrol, smapic acid, p-coumaric acid, caffiec acid, protocatechuic acid, ferulic acid, 4-hydroxy benzoic acid, quercetin, naringenin, nicotinamide, chlorogenic acid, theanine, epicatechin, ascorbic acid, bisdemethoxycurcumin, creatine and EGCG (Epigallocatechin gallate).

The following examples are set forth to aid the understanding of the invention, and are not intended and should not be construed to limit in any way the invention set forth in the claims which follow thereafter.

EXAMPLES:

Example 1:

Preparation of co-crystal of Upadacitinib and adipic acid (Form MC2):

Adipic acid (38.4 mg) and Upadacitinib (100 mg) was dissolved in acetonitrile (0.6 ml) at 25-30°C. To this solution, Upadacitinib (100 mg) was added at 25-30°C and the suspension was stirred for 40 hours at the same temperature. Acetonitrile was added to the obtained solid, filtered off and dried to get the title compound.

The PXRD of form MC2 obtained from this process is set forth in Figure 1.

Example 2:

Preparation of co-crystal of Upadacitinib and adipic acid (Form MC2):

The PXRD of form MC2 obtained from this process is set forth in Figure 2.

Example 3:

Preparation of co-crystal of Upadacitinib and adipic acid (Form MC2):

Upadacitinib (3 g) and adipic acid (576 mg) was dissolved in acetonitrile (9 ml) at 25-30°C. To this solution, Upadacitinib adipic acid cocrystal (100 mg) was added at 25-30°C and the obtained suspension was stirred for 14 hours at the same temperature. The solid obtained was filtered off, washed with acetonitrile and dried at 40-45 °C for 5 hrs to get the title compound.

Yield: 2.8 grams; Purity by HPLC: 99.35%.

The PXRD of form MC2 obtained from this process is set forth in Figure 2.

CO-CRYSTALS OF UPADACITINIB

Related applications:

Background of the Invention:

Upadacitinib, sold under the brand name Rinvoq, is a Janus kinase (JAK) inhibitor medication for the treatment of moderately to severely active rheumatoid arthritis in adults. It was approved in its hemihydrate form for medical use in the United States and in the European Union in 2019, and was developed by the biotech company Abbvie. Upadacitinib is chemically known as (3S,4R)-3-Ethyl-4-(3H-imidazo[l,2-a]pyrrolo[2,3-e]pyrazin-8-yl)- N-(2,2,2-trifluoroethyl) pyrrolidine-1 -carboxamide and structurally represented as shown in formula I:

Formula I

ERRONEOUSLY FILED (RULE 20.5bis)

Claims

We claim:

1. A co-crystal Form MC2 of Upadacitinib and adipic acid is characterized by powder X-ray diffractogram that comprises one or more peaks at about 3.76, 7.00, 10.23, 10.45, 11.63, 14.98, 20.57 and 24.12 degrees 20±0.2 degrees 20.

2. The co-crystal of Upadacitinib and adipic acid as claimed in claim 1, further characterized by one or more additional peaks at about 7.69, 8.33, 8.69, 8.95, 13.04, 13.62, 21.36, and 22.09 degrees 20±0.2 degrees 20.

3. A co-crystal Form MC2 of Upadacitinib and adipic acid is characterized by a powder X-ray diffractogram substantially as shown in Figure 1 and/or Figure 2.

4. The co-crystal of Upadacitinib and adipic acid as claimed in claim 1 is further characterized by a Differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 3.

5. The co-crystal of Upadacitinib and adipic acid as claimed in claim 1 is further characterized by a Thermo gravimetric analysis (TGA) diagram substantially as shown in Figure 4.

6. A process for the preparation of Upadacitinib and adipic acid cocrystal Form MC2, which comprises; dissolving or suspending a adipic acid in a suitable solvent; mixing Upadacitinib with the obtained solution or suspension; or vice versa; stirring the suspension or solution for sufficient period of time and isolating the cocrystal of Upadacitinib and adipic acid.

7. The process as claimed in claim 6, wherein the suitable solvent is selected from nitrile solvents.

8. The process as claimed in claim 6 is carried out at a suitable temperature of about 20°C to about 35°C. A process for the preparation of Upadacitinib and adipic acid cocrystal Form MC2, which comprises; a) dissolving Upadacitinib and adipic acid in acetonitrile; b) adding Upadacitinib or Upadacitinib adipic acid cocrystals to the obtained solution; c) stirring the obtained suspension; and d) isolating the Upadacitinib and adipic acid cocrystal form MC2. A pharmaceutical composition comprising Upadacitinib and adipic acid cocrystal as claimed in claim 1 and at least one pharmaceutically acceptable excipient.