WO2021044327A1

WO2021044327A1 - Solid forms of filgotinib maleate and processes thereof

Info

Publication number: WO2021044327A1
Application number: PCT/IB2020/058195
Authority: WO
Inventors: Vamsi Krishna Mudapaka; Satish Chowdary NEKKANTI; Satyanarayana THIRUNAHARI
Original assignee: Dr. Reddy's Laboratories Limited
Priority date: 2019-09-03
Filing date: 2020-09-03
Publication date: 2021-03-11

Abstract

Aspects of the present application relate to solid forms of Filgotinib maleate and pharmaceutical compositions thereof. Specific aspects of the present application relate to crystalline forms FM1, FM2 and FM3 of Filgotinib maleate characterized by X-ray diffraction patterns. Further aspect of the present application related to processes for the preparation of said crystalline forms of Filgotinib maleate.

Description

SOLID FORMS OF FILGOTINIB MALEATE AND PROCESSES THEREOF

INTRODUCTION

Aspects of the present application relate to solid forms of Filgotinib maleate and pharmaceutical compositions thereof. Specific aspects of the present application relate to crystalline forms of Filgotinib maleate and processes for their preparation.

The drug compound having the adopted name “Filgotinib” has chemical name: Cyclopropanecarboxylic acid {5-[4-(l,l-dioxo- thiomorpholin-4-ylmethyl)- phenyl]- [l,2,4]triazolo[l,5- a]pyridin-2-yl} -amide as below.

Filgotinib is a selective Jak-1 inhibitor developed by Galapagos NV and its maleate salt is under clinical studies as a oral treatment for various conditions such as Rheumatoid arthritis, Crohn’s disease; Ulcerative colitis and Psoriatic Arthritis.

US 8088764 B2 first discloses Filgotinib and its usefulness for the treatment of conditions such as Crohn's disease, rheumatoid arthritis, psoriasis, allergic airways disease (e.g. asthma, rhinitis), juvenile idiopathic arthritis, colitis, inflammatory bowel diseases and its pharmaceutical compositions. Further, it discloses preparative methods for the preparation of compounds disclosed therein including Filgotinib by reacting N-(5- bromo-[l,2,4]triazolo[l,5-a]pyridin-2-yl)cyclopropanecarboxamide with 4-(4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)thiomorpholine 1,1 -dioxide. The product was isolated by extracting into ethyl acetate followed by purification by flash chromatography. However, US 8088764 B2 does not disclose any salt form of Filgotinib.

US 2018007043 A1 describes a process for the preparation of maleate salt of Filgotinib by suspending a mixture of Filgotinib in 5% aqueous acetone and maleic acid in tetrahydrofuran overnight followed by filtration of the solids, which is characterized by XRPD as a crystalline Filgotinib maleate. Further, WO/2018/169875 A also discloses a similar procedure for the preparation of crystalline Filgotinib maleate, designated as Form I characterized by an XRPD pattern comprising peaks at 8.2, 11.9, 16.4, and 18.9 °2Q ± 0.2 °2Q as determined on a diffractometer using Cu-Ka radiation.

Hence, there remains a need for alternate solid forms of Filgotinib maleate and preparative processes thereof, exhibiting desired properties such as bioavailability and stability. Hence, it is desirable to provide a viable solid form of Filgotinib maleate.

SUMMARY

In an aspect, the present application provides a crystalline Form FM1 of Filgotinib maleate, characterized by a PXRD pattern comprising the peaks at about 8.68, 16.84, 17.27, 19.51, 21.62, 23.27, 25.14 and 27.16 ± 0.2° 2Q.

In another aspect, the present application provides a crystalline Form FM2 of Filgotinib maleate, characterized by a PXRD pattern comprising the peaks at about 9.31, 17.56, 26.33 ± 0.2° 2Q.

In another aspect, the present application provides a crystalline Form FM3 of Filgotinib maleate, characterized by a PXRD pattern comprising the peaks at about 8.60, 16.68, 17.00, 19.37, 21.50, 23.57, 25.04 and 27.18 ± 0.2° 20.

In another aspect, the present application provides a process for the preparation of crystalline Form FM1 of Filgotinib maleate, comprising the steps of combining Filgotinib with maleic acid in the presence of 1,4-dioxane and isolating crystalline Form FM1.

In another aspect, the present application provides a process for the preparation of crystalline Form FM2 of Filgotinib maleate, comprising the step of heating crystalline Form FM1 of Filgotinib maleate.

In another aspect, the present application provides a process for the preparation of crystalline Form FM3 of Filgotinib maleate, comprising the steps of combining Filgotinib maleate with anisole and isolating crystalline Form FM3.

In another aspect, the present application provides a process for the preparation of crystalline Form FM2 of Filgotinib maleate, comprising the step of heating crystalline Form FM3 of Filgotinib maleate.

In another aspect, the present application provides a pharmaceutical composition comprising crystalline Filgotinib maleate selected from the group consisting of crystalline form FM1, crystalline form FM2, crystalline form FM3 of Filgotinib maleate and mixtures thereof, and atleast one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWING

Figure 1 is an illustrative X-ray powder diffraction pattern of crystalline form FM1 of Filgotinib maleate prepared by the method of Example No 1.

Figure 2 is an illustrative X-ray powder diffraction pattern of crystalline form FM2 of Filgotinib maleate prepared by the method of Example No 3.

Figure 3 is an illustrative X-ray powder diffraction pattern of crystalline form FM3 of Filgotinib maleate prepared by the method of Example No 4.

Figure 4 is an illustrative X-ray powder diffraction pattern of crystalline form FM2 of Filgotinib maleate prepared by the method of Example No 5.

Figure 5 is an illustrative X-ray powder diffraction pattern of crystalline form FM1 of Filgotinib maleate prepared by the method of Example No 6.

Figure 6 is an illustrative X-ray powder diffraction pattern of crystalline form FM2 of Filgotinib maleate prepared by the method of Example No 7.

Figure 7 is an illustrative X-ray powder diffraction pattern of crystalline form FM1 of Filgotinib maleate for stability.

Figure 8 & 9 are illustrative X-ray powder diffraction patterns of crystalline form FM2 of Filgotinib maleate for stability.

X-ray powder diffraction analysis performed on Bruker D8 Advance diffractometer equipped with LYNXEYE XE detector in “Transmission” geometry from 3-45° 2Q and PANalytical Empyream instrument equipped with PiXcel Detector. Data was collected in reflection geometry from 3-45° 2Q.

DETAILED DESCRIPTION

In an aspect, the present application provides a crystalline Form FM1 of Filgotinib maleate, characterized by a PXRD pattern comprising the peaks at about 8.68, 16.84, 17.27, 19.51, 21.62, 23.27, 25.14 and 27.16 ± 0.2° 2Q. In embodiments, the crystalline Form FM1 of Filgotinib maleate is characterized by one or more additional peaks at about 17.82 and 18.77° 2Q. In embodiments, the application provides crystalline Form FM1 of Filgotinib maleate, characterized by a PXRD pattern of figure 1.

In embodiments, the present application provides a stable crystalline Form FM1 of Filgotinib maleate which is stable for atleast three months. In embodiments, crystalline Form FM1 of Filgotinib maleate is stable under packed storage conditions. In embodiments, the PXRD pattern of Form FM1 remained unchanged even after 3 months under packed condition at room temperature (RT) of about 25-30 °C as illustrated in figure 7.

In another aspect, the present application provides a crystalline Form FM2 of Filgotinib maleate, characterized by a PXRD pattern comprising the peaks at about 9.31, 17.56, 26.33 ± 0.2° 2Q. In embodiments, the crystalline Form FM2 of Filgotinib maleate is characterized by one or more additional peaks at about 3.90, 7.86, 16.27 and 17.97° 2Q. In embodiments, the application provides crystalline Form FM2 of Filgotinib maleate, characterized by a PXRD pattern of figure 2.

In embodiments, the present application provides a stable crystalline Form FM2 which is stable for atleast five weeks. In embodiments, crystalline Form FM2 of Filgotinib maleate is stable under packed storage conditions. In embodiments, the PXRD pattern of Form FM2 remained unchanged even after five weeks under packed condition at room temperature (RT) of about 25-30 °C as illustrated in figure 8. In embodiments, the PXRD pattern of Form FM2 remained unchanged even after three weeks under open condition at 25 °C and 70% relative humidity (RH), as illustrated in figure 9.

In another aspect, the present application provides a crystalline Form FM3 of Filgotinib maleate, characterized by a PXRD pattern comprising the peaks at about 8.60, 16.68, 17.00, 19.37, 21.50, 23.57, 25.04 and 27.18 ± 0.2° 20. In embodiments, the crystalline Form FM3 of Filgotinib maleate is characterized by one or more additional peaks at about 9.57, 17.86, 20.96 and 18.76° 20. In embodiments, the application provides crystalline Form FM3 of Filgotinib maleate, characterized by a PXRD pattern of figure 3.

In embodiments, Filgotinib used in this aspect may be obtained by any methods known in the art. In embodiments, Filgotinib free base may be used directly or it may be generated insitu from any other salt of Filgotinib according methods known in the art such as in the presence of a base. In embodiments, Filgotinib may be purified according to any suitable technique, before using in this aspect. In embodiments, Filgotinib may be crystalline or amorphous in nature.

In embodiments, combining Filgotinib with maleic acid may be carried out by combining the reaction mixture containing Filgotinib with maleic acid in the presence of

1.4-dioxane.

In embodiments, combining Filgotinib with maleic acid, may be carried out either through a homogeneous solution or a heterogeneous mixture containing Filgotinib and maleic acid in the presence of 1,4-dioxane, under suitable temperature at about 0 °C to reflux temperature of the mixture.

In embodiments, combining Filgotinib with maleic acid may be carried out by dissolving or suspending Filgotinib and maleic acid in the presence of 1,4-dioxane. In embodiments, combining Filgotinib with maleic acid may be carried out in the presence of

1.4-dioxane or a mixture of 1,4-dioxane with atleast one other solvent. Solvent may include, but not limited to water, ketone solvent, alcohol solvent, nitrile solvent, ether solvent, hydrocarbon solvent, halohydrocarbon solvent, polar aprotic solvents, ester solvents, and mixtures thereof. In embodiments, ketone solvent such as Acetone, Methyl ethyl ketone, Methyl isobutyl ketone; alcohol solvent such as methanol, ethanol, 1 -propanol, 2-propanol; nitrile solvent such as acetonitrile, propionitrile; ether solvents such as diethylether, diisopropyl ether, methyl tert. butyl ether, tetrahydrofuran, methyl tetrahydrofuran, 1,4- dioxane, 1,3-Dioxane, Dioxolane, glyme, diglyme; hydrocarbons solvents such as hexane, heptane, cyclohexane, petroleum ether; halohydrocarbon solvents such as dichloromethane, chloroform, carbon tetrachloride; ester solvents such as ethyl acetate, isopropyl acetate, methyl acetate; polar aprotic solvents such as dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide; water and mixtures thereof.

In embodiments, combining Filgotinib with maleic acid may be carried out by dissolving or suspending Filgotinib and maleic acid in the presence of mixture of 1,4- dioxane and water.

In embodiments, the mixture comprising Filgotinib, maleic acid and 1,4-dioxane may be a solution or suspension. In embodiments, the mixture comprising Filgotinib, maleic acid and 1,4-dioxane may be heated to a temperature of 25 °C or above. In preferred embodiments, the mixture may be heated to a temperature of 50 °C or above. In embodiments, the mixture may be heated for sufficient time for the formation of crystalline form FM1 of Filgotinib maleate. In preferred embodiments, the mixture may be heated for atleast one 1 hour or more.

In embodiments, the solvent of mixture containing Filgotinib maleate may be optionally removed, either completely or partially, using suitable methods known in the art or according to procedures described in the present application.

In embodiments, the mixture may be optionally cooled before the isolating crystalline form FM1 of Filgotinib maleate. In embodiments, the mixture may be cooled to a temperature of about 25 °C or below.

In embodiments, crystalline form FM1 of Filgotinib maleate may be isolated from the mixture according suitable method known in the art or by following the procedure described in the instant application.

In embodiments, the solvent from the mixture containing Filgotinib maleate may be removed through crystallization either by cooling the solution or by addition of anti solvent, followed by separation of the solids by filtration or decantation.

In embodiments, the solvent from mixture containing Filgotinib maleate may be removed by evaporating or sublimating the solvent, optionally under reduced pressure at about 0°C to reflux temperature.

The isolated crystalline form FM1 of Filgotinib maleate may be dried under suitable drying conditions such as aerial drying, drying under vacuum or under inert gas at a suitable temperature of about 25°C or above and for sufficient time to obtain the solids with constant weight.

In embodiments, the crystalline Form FM1 of Filgotinib maleate obtained by the process of this aspect may be characterized by a PXRD pattern comprising the peaks at about 8.68, 16.84, 17.27, 19.51, 21.62, 23.27, 25.14 and 27.16 ± 0.2° 2Q. In embodiments, crystalline Form FM1 may be characterized by a PXRD pattern of figure 1.

In embodiments, heating crystalline form FM1 may be carried out under suitable and controlled heating conditions. Heating may be carried out under vacuum or in the presence of inert gas.

In embodiments, the heating may be carried out at uniform rate with constant change in temperature per unit time. In embodiments heating may be carried out at a constant heating rate or ramp rate. In embodiments, heating may be carried out up to transition temperature, at which crystalline FM1 converts to Form FM2 of Filgotinib maleate. In embodiments, heating FM1 may be carried at about 100 °C or above.

In embodiments, heating may be carried out by heating the crystalline FM1 in a suitable heating instrument such as thermogravimetric analyzer, calorimeter or in a suitable heating equipment such as a dryer under vacuum or inert gas, up to the transition temperature to obtain crystalline form FM 2 of Filgotinib maleate. In embodiments, the crystalline form FM2 may be recovered after cooling the heating equipment or instrument.

In embodiments, the crystalline Form FM2 of Filgotinib maleate obtained by the process of this aspect may be characterized by a PXRD pattern comprising the peaks at about 9.31, 17.56, 26.33 ± 0.2° 2Q. In embodiments, crystalline Form FM2 may be characterized by a PXRD pattern of figure 2.

In embodiments, combining Filgotinib maleate with anisole may be carried out at a suitable temperature of about 0 °C to reflux temperature of the mixture.

In embodiments, combining Filgotinib maleate with anisole through the formation of heterogeneous mixture.

In embodiments, combining Filgotinib maleate with anisole by suspending Filgotinib maleate in anisole or a mixture thereof.

In embodiments, the mixture comprising Filgotinib maleate and anisole may be heated to a temperature of 50 °C or above. In embodiments, the mixture may be heated for sufficient time for the formation of crystalline form FM3 of Filgotinib maleate. In preferred embodiments, the mixture may be heated for atleast one 1 hour or more.

In embodiments, the mixture may be optionally cooled to a temperature of about 25 °C or below, before the isolating crystalline form FM3 of Filgotinib maleate. In embodiments, the crystalline FM3 of Filgotinib maleate may be isolated either by filtration or centrifugation.

The isolated crystalline form FM3 of Filgotinib maleate may be dried under suitable drying conditions such as aerial drying, drying under vacuum or under inert gas at a suitable temperature of about 25°C or above and for sufficient time to obtain the solids with constant weight.

In embodiments, the crystalline Form FM3 of Filgotinib maleate obtained by the process of this aspect may be characterized by a PXRD pattern comprising the peaks at about 8.60, 16.68, 17.00, 19.37, 21.50, 23.57, 25.04 and 27.18 ± 0.2° 20. In embodiments, crystalline Form FM3 may be characterized by a PXRD pattern of figure 3.

In embodiments, heating crystalline form FM3 may be carried out under suitable and controlled heating conditions. Heating may be carried out under vacuum or in the presence of inert gas.

In embodiments, the heating may be carried out at uniform rate with constant change in temperature per unit time. In embodiments heating may be carried out at a constant heating rate or ramp rate. In embodiments, heating may be carried out up to transition temperature, at which crystalline FM3 converts to Form FM2 of Filgotinib maleate. In embodiments, heating FM3 may be carried at about 100 °C or above.

In embodiments, heating may be carried out by heating the crystalline FM3 in a suitable heating instrument such as thermal gravimetric analyzer (TGA), calorimeter or in a suitable heating equipment such as a dryer under vacuum or inert gas, up to the transition temperature to obtain crystalline form FM 2 of Filgotinib maleate. In embodiments, the crystalline form FM2 may be recovered after cooling the heating equipment or instrument.

In embodiments, the crystalline Form FM2 of Filgotinib maleate obtained by the process of this aspect may be characterized by a PXRD pattern comprising the peaks at about 9.31, 17.56, 26.33 ± 0.2° 2Q. In embodiments, crystalline Form FM2 may be characterized by a PXRD pattern of figure 4.

In another aspect, the present application provides crystalline forms FM1, FM2 and FM3 of Filgotinib maleate or a pharmaceutical composition thereof; comprising Filgotinib maleate 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 gas” when used in the present application is a gas that does not react with the reactants or reagents under conditions that cause the chemical reaction indicated to take place such nitrogen, argon or the like.

EXAMPLES

Example-1: Preparation of crystalline form FM1 of Filgotinib maleate

Filgotinib (1 g) was combined with maleic acid (0.6 g) and a mixture of 1,4-dioxane (15 mL) and water (5 mL) at 65 °C. The resulting mixture was stirred at the same temperature for 4 hours and cooled to 10 °C. The precipitated solid was filtered to obtain the title compound. XRPD pattern: FM1.

Example-2: Preparation of crystalline form FM1 of Filgotinib maleate

Filgotinib (2 g) was combined with maleic acid (1.2 g) and a mixture of 1,4-dioxane (30 mL) and water (10 mL) at 62.5 °C. The resulting mixture was stirred at the same temperature for 2 hours and cooled to 25 °C. The precipitated solid was filtered and dried at 40 °C under reduced pressure to obtain the title compound. XRPD pattern: FM1.

Example-3: Preparation of crystalline form FM2 of Filgotinib maleate

Crystalline form FM1 of Filgotinib maleate (29.82 mg) obtained according previous example was heated to 160.00 °C in a Themogravimetric analyser (TGA Q500) at ramp rate of 20.00 °C/minute and Isothermal for 5 minutes. The TGA analyzed sample was cooled to obtain the title compound. XRPD pattern: FM2.

Example-4: Preparation of crystalline form FM3 of Filgotinib maleate

Crystalline form FM1 of Filgotinib maleate (3 g) was suspended in anisole (9 mL) at 30°C and the resulting mixture was heated at 100 °C for 4 hours. The mixture was cooled to 30 °C and the solid was filtered obtain the title compound. XRPD pattern: FM3.

Example-5: Preparation of crystalline form FM2 of Filgotinib maleate

Crystalline form FM3 of Filgotinib maleate (30 mg) obtained according previous procedures was heated to 130 °C in a Themal gravimetric analyser (TGA Q500) at ramp rate of 20.00 °C/minute and Isothermal for 5 minutes. The TGA analyzed sample was cooled to obtain the title compound. XRPD pattern: FM2.

Example-6: Preparation of crystalline form FM1 of Filgotinib maleate

Filgotinib maleate (30 grams) was dissolved in a mixture of 1,4-Dioxane (500 mL) and water (100 mL) at 70 °C and the clear solution was filtered to make it particle free. The solution was cooled to 28 °C and stirred at the same temperature for 18 hours. The solid was filtered under nitrogen atmosphere to obtain title compound. XRPD pattern: FM1.

Example-7: Preparation of crystalline form FM2 of Filgotinib maleate

Crystalline Filgotinib maleate form FM1 prepared according to previous example was dried in vacuum tray dryer at 120 °C for about 15 hours to obtain the title compound. XRPD pattern: FM2.

Dated: 3^rd of September 2020.

Claims

1. A crystalline Form FM1 of Filgotinib maleate, characterized by X-ray powder diffraction pattern comprising the peaks at 8.68, 16.84, 17.27, 19.51, 21.62, 23.27, 25.14 and 27.16 ± 0.2° 2Q.

2. The crystalline Form FM1 of Filgotinib maleate of claim 1, characterized by additional peaks at 17.82 and 18.77° 2Q.

3. The crystalline Form FM1 of claim 1, characterized by X-ray powder diffraction pattern as depicted in Figure 1.

4. A crystalline Form FM2 of Filgotinib maleate, characterized by X-ray powder diffraction pattern comprising the peaks at 9.31, 17.56, 26.33 ± 0.2° 2Q.

5. The crystalline Form FM2 of claim 4, characterized by additional peaks at 3.90, 7.86, 16.27 and 17.97° 2Q.

6. The crystalline Form FM2 of claim 4, characterized by X-ray powder diffraction pattern as depicted in Figure 2 or 4 or 6.

7. A crystalline Form FM3 of Filgotinib maleate, characterized by X-ray powder diffraction pattern comprising the peaks at 8.60, 16.68, 17.00, 19.37, 21.50, 23.57, 25.04 and 27.18 ± 0.2° 20.

8. The crystalline Form FM3 of claim 7, characterized by additional peaks at about 9.57, 17.86, 20.96 and 18.76° 20.

9. The crystalline Form FM3 of claim 7, characterized by X-ray powder diffraction pattern as depicted in Figure 3.

10. A process for the preparation of crystalline Form FM1 of Filgotinib maleate of claim 1, comprising the steps of combining Filgotinib with maleic acid in the presence of 1,4-dioxane and isolating crystalline Form FM1.

11. A process for the preparation of crystalline Form FM2 of Filgotinib maleate of claim 4, comprising the step of heating crystalline Form FM1 of Filgotinib maleate.

12. A process for the preparation of crystalline Form FM3 of Filgotinib maleate of claim 7, comprising the steps of combining Filgotinib maleate with anisole and isolating crystalline Form FM3.

13. A process for the preparation of crystalline Form FM2 of Filgotinib maleate of claim 4, comprising the step of heating crystalline Form FM3 of Filgotinib maleate.

14. A process for the preparation of pharmaceutical compositions comprising the step of using crystalline Filgotinib maleate selected from the group consisting of FM1, FM2, FM3 and mixtures thereof.