Stable co-amorphous form of upadacitinib along with a co-former and process for the preparation thereof

Abstract

The present invention relates to co-amorphous form of Upadacitinib along with a co-former. Yet another embodiment of the present invention relates to co-amorphous form of Upadacitinib along with Pamoic acid.

Description

[0001] STABLE CO-AMORPHOUS FORM OF UPADACITINIB ALONG WITH A CO-FORMER AND PROCESS FOR THE PREPARATION

[0002] THEREOF

[0003] FIELD OF THE INVENTION

[0004] The present invention relates to co-amorphous form of Upadacitinib along with a co-former.

[0005] The present invention relates to co-amorphous form of Upadacitinib along with Pamoic acid.

[0006] The present invention relates to a process for the preparation of co-amorphous form of Upadacitinib along with a co-former.

[0007] BACKGROUND OF THE INVENTION

[0008] Upadacitinib is a Janus kinase (JAK) inhibitor approved 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 and sold under the brand name Rinvoq. 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:

[0009] US 8,962,629 B2 claims Upadacitinib product and US RE47,221 El discloses process for the preparation of Upadacitinib.

[0010] US 9,951,080 B2 claims / disclose different Upadacitinib crystalline / amorphous forms of freebase. WO 2023 / 105460 Al discloses different co-crystals of Upadacitinib and adipic acid which is characterized by the specific XRD peaks.

[0011] IN 201741010259 disclose Amorphous Upadacitinib, its solid dispersion together with at least one pharmaceutically acceptable excipient. The excipient is selected from different polymers.

[0012] CN 117447481 A discloses amorphous substance of Upadacitinib-pyroglutamate as well as a preparation method and application of the amorphous substance.

[0013] However, none of the prior-art discloses co-amorphous form of Upadacitinib with pamoic acid.

[0014] The inventors of the present invention found that Upadacitinib forms a Co- amorphous product with an acid specifically pamoic acid, which is stable over shelf life and does not convert into any other solid-state forms.

[0015] OBJECTIVE OF THE INVENTION

[0016] The main objective of the present invention is to provide co-amorphous form of Upadacitinib along with a co-former.

[0017] Another objective of the present invention is to provide co-amorphous form of Upadacitinib along with a co-former free from other solid-state forms and stable over shelf life and does not convert into any other solid-state forms.

[0018] Yet another objective of the present invention is to provide a process for the preparation of Upadacitinib along with a co-former.

[0019] Still another objective of the present invention is to provide pharmaceutical compositions comprising the stable Upadacitinib along with a co-former. SUMMARY OF THE INVENTION

[0020] Accordingly, the present invention relates to co-amorphous form of Upadacitinib along with a co-former.

[0021] Yet another embodiment of the present invention relates to co-amorphous form of Upadacitinib along with pamoic acid.

[0022] The present invention also relates to a process for the preparation of co- amorphous form of Upadacitinib along with a co-former which comprises the steps: i) providing a solution of Upadacitinib and pamoic acid in a suitable solvent, ii) adding the above solution to water at a temperature of 0-5°C, wherein immediate precipitation is observed, iii) maintaining the reaction mass at 25-30°C, iv) filtering and drying the product to obtain co-amorphous form of Upadacitinib and pamoic acid.

[0023] The present invention also relates to another process for the preparation of co- amorphous form of Upadacitinib along with a co-former which comprises the steps: i) providing a solution of Upadacitinib and pamoic acid in a suitable solvent, ii) removing the solvent using a rotavapor at 80-100 tar vacuum for about 15-30 minutes at 60°C, iii) drying the material at 60°C in Rotavapor itself for 1 hour, and iv) recovering the material and drying the product to obtain co-amorphous form of Upadacitinib and pamoic acid. BRIEF DESCRIPTION OF DRAWINGS

[0024] Fig.l: Represents X-ray powder diffraction pattern of co-amorphous form of Upadacitinib along with Pamoic acid obtained by the process of Example 1 of the present invention.

[0025] Fig.2: Represents X-ray powder diffraction pattern of co-amorphous form of Upadacitinib along with Pamoic acid obtained by the process of Example 2 of the present invention.

[0026] Fig.3: Represents X-ray powder diffraction pattern of co-amorphous form of Upadacitinib along with Pamoic acid after thermal stability test.

[0027] DETAILED DESCRIPTION OF THE INVENTION

[0028] The present invention relates to stable co-amorphous form of Upadacitinib along with Pamoic acid.

[0029] In one aspect, the present invention provides co-amorphous form of Upadacitinib along with Pamoic acid characterized by XRD as shown in figure 1.

[0030] In one aspect, the present invention provides co-amorphous form of Upadacitinib along with Pamoic acid characterized by XRD as shown in figure 2.

[0031] In yet another embodiment, the starting material Upadacitinib used in the present invention can be prepared by any procedures disclosed in the prior-art.

[0032] In an embodiment of the present invention the solvent as used in the present invention are selected from or "esters solvents" such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, sec-butyl acetate, and the like, "ether solvents" such as di-tert-butyl ether, di methyl ether, diethyl ether, di isopropyl ether, 1,4- dioxane, methyl tert-butyl ether, ethyl tertbutyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 2-methoxyethanol and dimethoxy ethane, n-butanol, "hydrocarbon solvents" such as benzene, toluene, xylene, heptane, hexane and cyclohexane and the like or "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, isopropyl ketone; “Amide solvents” such as formamide, DMF, DMAC, N-methyl-2- pyrrolidone, N-methyl formamide, 2-pyrrolidone, l-ethenyl-2- pyrrolidone, haloalkanes such as dichloromethane, 1,2-dichloroethane and chloroform, “Amine solvents” selected from diethylenetriamine, ethylenediamine, morpholine, piperidine, pyridine, quinoline, tributylamine, di isopropyl amine, acids such as formic acid, acetic acid, propionic acid and / or mixtures thereof.

[0033] The stable co-amorphous form of Upadacitinib along with Pamoic acid of the present invention is stable over the shelf life under different stability conditions, consistently reproducible and have good flow properties, and which is particularly suitable for bulk preparation and handling. The stable co-amorphous form of Upadacitinib along with pamoic acid of the present invention is also suitable for formulating into different dosage forms.

[0034] The stability data of the co-amorphous form of Upadacitinib along with Pamoic acid is carried out by heating under nitrogen till 220 °C and cooled it back to CRT. The heat cool sample subjected for PXRD. Lack of crystallization of Upadacitinib or pamoic acid from co-amorphous warrants high temperature stability of co-amorphous form.

[0035] In pharmaceutical products both thermal stability and polymorphic stability is very important. Otherwise one solid state form converts into other solid-state form. Further there is no control on the conversion rate at different time intervals and in different storage conditions. This means at different time points during shelf life the product might have mixture of two different solid states in different ratios. It is clearly reported in the literature that this has impact on the solubility and bioavailability of the product. This has direct impact on the efficacy of the product. Hence, it is very important to have polymorphic stability. In a preferred embodiment, the present invention provides a pharmaceutical composition of co-amorphous form of Upadacitinib along with pamoic acid along with the pharmaceutically acceptable excipients such as diluents, chelating agents, disintegrate, glidant, lubricants and or anti- adherents.

[0036] The term "pharmaceutical composition" is intended to encompass a drug product including the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients. Accordingly, the pharmaceutical compositions encompass any composition made by admixing the active ingredient, active ingredient dispersion or composite, additional active ingredient(s), and pharmaceutically acceptable excipients.

[0037] The pharmaceutical compositions comprising co-amorphous form of Upadacitinib along with pamoic acid may be further formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze-dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using procedures such as direct blending, dry granulation, wet granulation, or extrusion and spherization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. Compositions of the present application may further comprise one or more pharmaceutically acceptable excipients. The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

[0038] EXAMPLES

[0039] Example 1: Process for the preparation of co-amorphous form of Upadacitinib and pamoic acid

[0040] Upadacitinib (1 gm) and Pamoic acid (0.5 gm) were dissolved in DMSO ( ~5 ml) at 25-30°C. In a separate vessel Water (25 ml) was kept at 0-5°C. Above DMSO solution of Upadacitinib and Pamoic acid was dumped to the water at 0-5°C. Immediate precipitation was observed. The reaction mass was maintained at 25-30°C for about 1 hour. The obtained product was filtered and dried the solid under VTD for about 6-8 hours at 45-50 °C to get the title compound.

[0041] Example 2: Process for the preparation of co-amorphous form of Upadacitinib and pamoic acid

[0042] Upadacitinib (1 gm) and Pamoic acid (0.5 gm) were dissolved in THF (75 ml) at 50°C. The solvent was removed using Rotavapor at 80-100 tar vacuum for about 15- 30 minutes at 60°C. The obtained material was dried at 60°C in Rotavapor itself for 1 hour. The material was recovered and dried under VTD at 45°C for about 8 hours to get title compound. Yield: 80%; Purity by HPLC: 99.95%.

[0043] Example 3: Process for the preparation of co-amorphous form of Upadacitinib and pamoic acid

[0044] Upadacitinib (1 gm) was dissolved in dimethyl sulfoxide (DMSO) (~5 ml) at 25-30°C, then Pamoic acid (0.5 gm) was added. The reaction mass temperature was raised to 50°C to get a clear solution and make it particle free. Water (25 ml) was kept at 0-5°C, then above particle free solution was added to the water at 0-5°C.. The reaction mass was maintained at 0-5°C for about 1 hour to about 2 hours. The obtained product was filtered and dried, then suspended in water (25 vol) and stirred at room temperature for about 1 hour to about 2 hours. The obtained product was filtered, suck dried and dried under VTD for about 12-18 hours at 30-35 °C to get the title compound. Yield: 80%; Purity by HPLC: 99.95%

Claims

WE CLAIM:

1. A co-amorphous form of Upadacitinib and pamoic acid.

2. A process for the preparation of a co-amorphous form of Upadacitinib and Pamoic acid, comprising: a) preparing a solution of Upadacitinib in a suitable solvent; b) adding pamoic acid to the solution obtained in step (a); c) adding the solution obtained in step (b) to water; and d) isolating the co-amorphous form of Upadacitinib and pamoic acid.

3. The process as claimed in claim 2, wherein the solvent used in step (a) is selected from “polar- aprotic solvents” such as dimethylacetamide (DM Ac), dimethylformamide (DMF), di methyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP), “polar solvents” such as water and mixtures thereof.

4. A process for the preparation of a co-amorphous form of Upadacitinib and Pamoic acid, comprising: a) preparing a solution of Upadacitinib in dimethyl sulfoxide (DMSO); and b) adding pamoic acid to the solution obtained in step (a); c) adding the solution obtained in step (b) to water; and d) isolating the co-amorphous form of Upadacitinib and pamoic acid.

5. A process for the preparation of co-amorphous form of Upadacitinib along and pamoic acid, comprising: a) preparing a solution of Upadacitinib in tetrahydrofuran (THF); b) adding pamoic acid to the solution obtained in step (a); c) removing the solvent to obtain co-amorphous form of Upadacitinib and pamoic acid.

6. The process as claimed in claim 5, wherein the co-amorphous form of Upadacitinib and pamoic acid is characterized by a powder X-ray diffraction (PXRD) pattern as illustrated in Figure 1 and 2.

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