Login| Sign Up| Help| Contact|

Patent Searching and Data


Title:
IMPROVED PROCESS FOR THE PREPARATION OF DIROXIMEL FUMARATE AND SOLID FORMS THEREOF
Document Type and Number:
WIPO Patent Application WO/2021/074842
Kind Code:
A1
Abstract:
Aspects of the present application relate to crystalline and amorphous solid forms of Diroximel fumarate, pharmaceutical compositions and processes thereof. Further, aspects relate to improved processes for the preparation of Diroximel fumarate and intermediates thereof. Specific aspects of the present application provide amorphous solid dispersions of Diroximel fumarate and crystalline Form-DG and Form-DO with Gentisic acid and Oxalic acid, respectively.

Inventors:
SEN SAIKAT (IN)
ORUGANTI SRINIVAS (IN)
KOTTUR MOHAN KUMAR (IN)
KALLEM DIVYA JYOTHI (IN)
THIRUNAHARI SATYANARAYANA (IN)
MUKHERJEE ARIJIT (IN)
MAHAPATRA TRIDIP (IN)
RANGARAJU SUDHEER KUMAR (IN)
NEELAM UDAY KUMAR (IN)
MANNE NAGARAJU (IN)
Application Number:
PCT/IB2020/059703
Publication Date:
April 22, 2021
Filing Date:
October 15, 2020
Export Citation:
Click for automatic bibliography generation   Help
Assignee:
DR REDDY’S LABORATORIES LTD (IN)
International Classes:
C07C233/80
Download PDF:
Claims:
Claims

1. A crystalline Form-DG of Diroximel fumarate and Gentisic acid, characterized by a PXRD pattern comprising the peaks at 3.58 and 14.65° ± 0.2° 2Q.

2. The crystalline form-DG of claim 1, characterized by a PXRD pattern of figure 4.

3. A crystalline Form-DO of Diroximel fumarate and oxalic acid, characterized by a PXRD pattern comprising the peaks at 4.05 and 33.40° ± 0.2° 20.

4. The crystalline form-DG of claim 3, characterized by a PXRD pattern of figure 5.

5. An amorphous solid dispersion of Diroximel fumarate together with at least one pharmaceutically acceptable excipient.

6. The solid dispersion of claim 5, wherein the pharmaceutically acceptable excipient is selected from the group consisting of Copovidone, Soluplus, HPMC and mixtures thereof.

7. A pharmaceutical composition of Diroximel fumarate or its solid dispersion, wherein Diroximel fumarate is in amorphous state.

8. A process for the preparation of crystalline Form-DG of Diroximel fumarate of and Gentisic acid, comprising the step of contacting Diroximel fumarate with Gentisic acid.

9. A process for the preparation of crystalline Form-DO of Diroximel fumarate and oxalic acid, comprising the step of contacting Diroximel fumarate with oxalic acid.

10. A process for the preparation of crystalline Diroximel fumarate comprising the step of converting a crystalline form, selected from Form-DG and Form-DO, to other crystalline Diroximel fumarate.

11. A process for the preparation of an amorphous solid dispersion of Diroximel fumarate together with at least one pharmaceutically acceptable excipient, comprising the steps of: a) providing a solution of Diroximel fumarate and at least one pharmaceutically acceptable excipient in an inert solvent; b) removing the solvent from the solution obtained in step a), and c) isolating the amorphous solid dispersion of Diroximel fumarate.

12. A process for the preparation of Diroximel fumarate, comprising the step of esterification of monomethyl fumarate with (2,5-dioxopyrrolidin-l-yl)ethanol in the presence of an acid halide selected from the group consisting of acetyl chloride, Thionyl chloride and Oxalyl chloride.

13. A process for the preparation of Diroximel fumarate, comprising the step of esterification of (E)-4-(2-(2,5-dioxopyrrolidin-l-yl)ethoxy)-4-oxobut-2-enoic acid with methylation agent selected from the group consisting of 2,2- dimethoxypropane, trimethyl orthoformate and dimethyl carbonate.

14. A process for the isolation of (2,5-dioxopyrrolidin-l-yl)ethanol, comprising the steps of a) reacting succinimide with ethylene carbonate, optionally in the presence of a base; b) treating (2,5-dioxopyrrolidin-l-yl)ethanol obtained in step (a) with a suitable organic solvent selected from the group consisting of methyl /er/-butyl ether, diethyl ether, diisopropyl ether, ethyl acetate, hexane, heptane, toluene, xylene, 1,4-dioxane, chlorobenzene and mixtures thereof.

15. A process for the crystallization of Diroximel fumarate, comprising the steps of: a) providing a solution of Diroximel fumarate in an inert solvent or mixtures thereof, b) contacting the solution of step (a) with an anti-solvent, optionally in the presence of a seed crystal; wherein the inert solvent of step (a) is selected from the group consisting of methanol, ethanol, 2-propanol, dichloromethane, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide N,N-dimethylacetamide, N-methyl-2-pyrrolidone, ethylene glycol and mixtures thereof and the anti-solvent of step (b) is selected from the group consisting of diethyl ether, methyl tert. butyl ether, diisopropyl ether, water and mixtures thereof.

Description:
IMPROVED PROCESS FOR THE PREPARATION OF DIROXIMEL FUMARATE

AND SOLID FORMS THEREOF

INTRODUCTION

Aspects of the present application relate to amorphous and crystalline solid forms of Diroximel fumarate, pharmaceutical compositions and processes thereof. Aspects of the present application further relate to improved processes for the preparation of Diroximel fumarate.

The drug compound having the adopted name “Diroximel fumarate” has chemical name: 2-(2,5-Dioxopyrrolidin-l-yl)ethyl methyl fumarate as below.

Diroximel fumarate is an investigational, novel oral fumarate with a distinct chemical structure and developed by Alkermes pic, for the treatment of relapsing- remitting multiple sclerosis (RRMS) and is currently under review by U.S. Food and Drug Administration. Biogen, under an exclusive license from Alkermes, intends to market Diroximel fumarate under the brand name VUMERITY™.

US 8669281 B1 first disclosed Diroximel fumarate, its preparation, composition and use thereof for treating multiple sclerosis. US 10080733 B2 further discloses the crystalline solid form of Diroximel fumarate having an X-ray powder diffraction pattern comprising 2Q peaks at 11.6, 21.0, 24.3, 27.4, and 27.9 ±0.2 2Q.

WO 2017/108960 A1 also discloses various alternative synthetic approaches to make Diroximel fumarate and crystalline solid forms thereof, designated as Polymorphic forms A to D.

Hence, there remains a need for alternate solid forms of Diroximel fumarate and preparative processes thereof, exhibiting desired bioavailability and stability. Hence, it is desirable to provide a viable solid form of Diroximel fumarate. The known processes for the preparation of Diroximel fumarate are not viable at industrial scale due to the use of expensive reagents and catalyst such as coupling agents disclosed in US 8669281 Bl, with very low yields. Hence, there remains a need for the improved process to make Diroximel fumarate. SUMMARY

In an aspect, the present application provides a crystalline Form-DG of Diroximel fumarate and Gentisic acid, characterized by a PXRD pattern comprising the peaks at about 3.58 and 14.65° ± 0.2° 2Q.

In another aspect, the present application provides a crystalline Form-DO of Diroximel fumarate and oxalic acid, characterized by a PXRD pattern comprising the peaks at about 14.05 and 33.40° ± 0.2° 20.

In another aspect, the present application provides amorphous Diroximel fumarate.

In another aspect, the present application provides amorphous solid dispersion of Diroximel fumarate together with at least one pharmaceutically acceptable excipient.

In another aspect, the present application provides a process for the preparation of crystalline Form-DG of Diroximel fumarate and Gentisic acid, comprising the step of contacting Diroximel fumarate with Gentisic acid.

In another aspect, the present application provides a process for the preparation of crystalline Form-DO of Diroximel fumarate and oxalic acid, comprising the step of contacting Diroximel fumarate with oxalic acid.

In another aspect, the present application provides a process for the preparation of an amorphous solid dispersion of Diroximel fumarate together with at least one pharmaceutically acceptable excipient, comprising the steps of: a) providing a solution of Diroximel fumarate and at least one pharmaceutically acceptable excipient in an inert solvent; b) removing the solvent from the solution obtained in step a), and c) isolating the amorphous solid dispersion of Diroximel fumarate.

In another aspect, the present application provides a process for the preparation of Diroximel fumarate, comprising the step of esterification of monomethyl fumarate with (2,5-dioxopyrrolidin-l-yl)ethanol in the presence of an acid halide. In another aspect, the present application provides a process for the preparation of Diroximel fumarate, comprising the step of esterification of (E)-4-(2-(2,5- dioxopyrrolidin-l-yl)ethoxy)-4-oxobut-2-enoic acid with methylation agent selected from the group consisting of 2,2-dimethoxypropane, trimethyl orthoformate and dimethyl carbonate.

In another aspect, the present application provides a process for the isolation of (2,5-dioxopyrrolidin-l-yl)ethanol, comprising the steps of a) reacting succinimide with ethylene carbonate, optionally in the presence of a base; b) treating (2,5-dioxopyrrolidin-l-yl)ethanol obtained in step (a) with a suitable organic solvent selected from the group consisting of methyl /er/-butyl ether, diethyl ether, diisopropyl ether, ethyl acetate, hexane, heptane, toluene, xylene, 1,4-dioxane, chlorobenzene and mixtures thereof.

In another aspect, the present application provides a process for the crystallization of Diroximel fumarate, comprising the steps of: a) providing a solution of Diroximel fumarate in an inert solvent or mixtures thereof b) contacting the solution of step (a) with an anti-solvent, optionally in the presence of a seed crystal.

In another aspect, the present application provides a process for the preparation of crystalline Diroximel fumarate, comprising the step of converting a crystalline form, selected from Form-DG and Form-DO, to other crystalline Diroximel fumarate.

BRIEF DESCRIPTION OF THE DRAWING

Figure 1 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Diroximel fumarate with Soluplus prepared by the method of Example No 1

Figure 2 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Diroximel fumarate with Co-povidone prepared by the method of Example No 2.

Figure 3 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Diroximel fumarate with HPMC prepared by the method of Example No 3.

Figure 4 is an illustrative X-ray powder diffraction pattern of crystalline Form-DG of Diroximel fumarate and Gentisic acid prepared by the method of Example No 4.

Figure 5 is an illustrative X-ray powder diffraction pattern of crystalline Form-DO of Diroximel fumarate and oxalic acid prepared by the method of Example No 5.

Figure 6 is an illustrative X-ray powder diffraction pattern of crystalline form of Diroximel fumarate prepared by the method of Example No 8.

DETAILED DESCRIPTION

In an aspect, the present application provides a crystalline Form-DG of Diroximel fumarate and Gentisic acid, characterized by a PXRD pattern comprising the peaks at about 3.58 and 14.65° ± 0.2° 2Q. In embodiments, the crystalline Form-DG of Diroximel fumarate and Gentisic acid may be characterized by one or more additional peaks at about 15.94, 19.44 and 21.62° ± 0.2° 2Q. In embodiments, the application provides crystalline Form-DG of Diroximel fumarate and Gentisic acid, characterized by a PXRD pattern of Figure 4. In embodiments, the crystalline Form-DG is a crystalline complex of Diroximel fumarate and Gentisic acid.

In another aspect, the present application provides a crystalline Form-DO of Diroximel fumarate and oxalic acid, characterized by a PXRD pattern comprising the peaks at about 14.05 and 33.40° ± 0.2° 20. In embodiments, the crystalline Form-DO of Diroximel fumarate and oxalic acid may be characterized by one or more additional peaks at about 15.07, 22.93 and 29.01° ± 0.2° 20. In embodiments, the application provides crystalline Form-DO of Diroximel fumarate and oxalic acid, characterized by a PXRD pattern of figure 5. In embodiments, the crystalline Form-DO is a crystalline complex of Diroximel fumarate and oxalic acid.

In an aspect, the present application provides an amorphous Diroximel fumarate.

In embodiments, the present application provides pharmaceutical composition of Diroximel fumarate, wherein Diroximel fumarate is in amorphous state. In embodiments, the solid dispersions of the Diroximel fumarate of the present application contain Diroximel fumarate in amorphous state.

In embodiments, the present application provides amorphous Diroximel fumarate with less than 5% of crystallinity, preferably with less than 1% crystallinity and more preferably with less than 0.5% crystallinity as per X-ray diffraction analysis. Diroximel fumarate in amorphous state exhibits higher bioavailability than its crystalline counterparts and preferred to formulate into pharmaceutical dosage form. The solubility of crystalline Diroximel fumarate is lower than its amorphous state, particularly aqueous solubility, which results in the difference in their in-vivo bioavailability.

In another aspect, the present application provides amorphous solid dispersion of Diroximel fumarate together with at least one pharmaceutically acceptable excipient.

In embodiments, the solid dispersion contains Diroximel fumarate in amorphous state. In an embodiment, the present application provides amorphous solid dispersion of Diroximel fumarate together with at least one pharmaceutically acceptable excipient characterized by a powder X-ray diffraction (PXRD) pattern, substantially as illustrated by Figures 1, 2, and 3.

In embodiments, the amorphous solid dispersions of the present application are stable for atleast one week under packed condition. In embodiments, the amorphous solid dispersions of the present application are stable for atleast two weeks under packed condition. In embodiments, the amorphous solid dispersions of the present application are stable for atleast one month under packed condition.

In an embodiment, at least one pharmaceutically acceptable excipient of this aspect may be selected from the group consisting of polyvinyl pyrrolidone, povidone K-30, povidone K-60, Povidone K-90, polyvinylpyrrolidone vinylacetate, co-povidone NF, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene-polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit or Eudragit- RLPO), hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), hydroxypropylmethyl cellulose, hydroxypropyl cellulose SSL(HPC-SSL), hydroxypropyl cellulose SL(HPC-SL), hydroxypropyl cellulose L (HPC- L), hydroxyethyl cellulose, Soluplus® (polyvinyl caprolactam-polyvinyl acetate- polyethylene glycol graft copolymer (PCL-P VAc-PEG)), gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxymethylethylcelluloseand the like. Solid dispersions of the present application also include the solid dispersions obtained by combining Diroximel fumarate with a suitable non- polymeric excipient by employing techniques known in the art or procedures described or exemplified in any aspect of the instant application.

In another aspect, the present application provides an amorphous solid dispersion of Diroximel fumarate with Soluplus. In embodiments, the amorphous solid dispersion is characterized by a powder X-ray diffraction (PXRD) pattern, substantially as illustrated by Figure 1.

In another aspect, the present application provides an amorphous solid dispersion of Diroximel fumarate with Copovidone. In embodiments, the amorphous solid dispersion is characterized by a powder X-ray diffraction (PXRD) pattern, substantially as illustrated by Figure 2.

In another aspect, the present application provides an amorphous solid dispersion of Diroximel fumarate with HPMC. In embodiments, the amorphous solid dispersion is characterized by a powder X-ray diffraction (PXRD) pattern, substantially as illustrated by Figure 3.

In another aspect, the present application provides a process for the preparation of crystalline Form-DG of Diroximel fumarate and Gentisic acid, comprising the step of contacting Diroximel fumarate with Gentisic acid.

In embodiments, Diroximel fumarate used in this aspect may be either in crystalline or in amorphous states. In embodiments, crystalline Diroximel fumarate may be in any of crystalline forms reported in the literature.

In embodiments, contacting Diroximel fumarate with Gentisic acid may be carried out, optionally in the presence of a suitable inert solvent. Suitable inert solvent may include, but not limited to water, methanol, chloroform, acetonitrile, dichloromethane and mixtures thereof.

In embodiments, contacting Diroximel fumarate with Gentisic acid may be carried out through the formation of solution or suspension containing Diroximel fumarate and Gentisic acid in a solvent.

In embodiments, contacting Diroximel fumarate with Gentisic acid may be carried out at a suitable temperature of about 0 °C or above. In embodiments, contacting Diroximel fumarate with Gentisic acid may be carried out for sufficient time to complete the formation of crystalline Form-DG. In an embodiment, the contacting Diroximel fumarate with Gentisic acid may be carried out for at least one hour or longer.

In an embodiment, contacting Diroximel fumarate with Gentisic acid may be carried out by suspending Diroximel fumarate and Gentisic acid in a solvent at a suitable temperature.

In another embodiment, crystalline Form-DG may be crystallized out from the solution containing Diroximel fumarate and Gentisic acid in a solvent by cooling the solution to a suitable temperature or by evaporating the solvent optionally under reduced pressure or by treating with a suitable anti-solvent. Anti-solvent is a solvent in which Diroximel fumarate and / or Gentisic acid are insoluble or less soluble.

In another embodiment, contacting Diroximel fumarate with Gentisic acid may be carried out by grinding the mixture of Diroximel fumarate and Gentisic acid, optionally in the presence of a suitable solvent. In embodiments, grinding the mixture may be carried out in a suitable grinding apparatus such as mortar - pestle or a milling apparatus such as ball mill.

In another embodiment, contacting Diroximel fumarate with Gentisic acid may be carried out by melting the mixture of Diroximel fumarate and Gentisic acid at a suitable temperature upto the melting points of the components. In embodiments, the melting of the mixture may be carried out either under atmospheric pressure or under reduced pressure, optionally under inert gas atmosphere such as Nitrogen.

In embodiments, crystalline Form-DG may be isolated from the solvent according to any suitable techniques know in the art such as filtration or centrifugation.

In embodiments, drying crystalline Form-DG may be carried out under suitable conditions such as aerial drying or drying under vacuum or inert gas atmosphere such as nitrogen. In embodiments, drying may be carried out in a suitable drying equipment, such as air or vacuum tray dryers.

The crystalline Form-DG of Diroximel fumarate and Gentisic acid obtained according to the process of this aspect may be characterized by a PXRD pattern comprising the peaks at about 3.58 and 14.65° ± 0.2° 2Q.

In another aspect, the present application provides a process for the preparation of crystalline Form-DO of Diroximel fumarate and Oxalic acid, comprising the step of contacting Diroximel fumarate with Oxalic acid.

In embodiments, Diroximel fumarate used in this aspect may be either in crystalline or in amorphous states. In embodiments, crystalline Diroximel fumarate may be in any of crystalline forms reported in the literature.

In embodiments, contacting Diroximel fumarate with Oxalic acid may be carried out, optionally in the presence of a suitable inert solvent. Suitable inert solvent may include, but not limited to water, chloroform, acetonitrile, dichloromethane and mixtures thereof.

In embodiments, contacting Diroximel fumarate with Oxalic acid may be carried out through the formation of solution or suspension containing Diroximel fumarate and Oxalic acid in a solvent.

In embodiments, contacting Diroximel fumarate with Oxalic acid may be carried out at a suitable temperature of about 0 °C or above. In embodiments, contacting Diroximel fumarate with Oxalic acid may be carried out for sufficient time to complete the formation of crystalline Form-DO. In an embodiment, the contacting Diroximel fumarate with Oxalic acid may be carried out for at least one hour or longer.

In an embodiment, contacting Diroximel fumarate with Oxalic acid may be carried out by suspending Diroximel fumarate and Oxalic acid in a solvent at a suitable temperature.

In another embodiment, crystalline Form-DO may be crystallized out from the solution containing Diroximel fumarate and Oxalic acid in a solvent by cooling the solution to a suitable temperature or by evaporating the solvent optionally under reduced pressure or by treating with a suitable anti-solvent. Anti-solvent is a solvent in which Diroximel fumarate and / or Oxalic acid are insoluble or less soluble.

In another embodiment, contacting Diroximel fumarate with Oxalic acid may be carried out by grinding the mixture of Diroximel fumarate and Oxalic acid, optionally in the presence of a suitable solvent. In embodiments, grinding the mixture may be carried out in a suitable grinding apparatus such as mortar - pestle or a milling apparatus such as ball mill.

In another embodiment, contacting Diroximel fumarate with Oxalic acid may be carried out by melting the mixture of Diroximel fumarate and Oxalic acid at a suitable temperature upto the melting points of the components. In embodiments, the melting of the mixture may be carried out either under atmospheric pressure or under reduced pressure, optionally under inert gas atmosphere such as Nitrogen.

In embodiments, crystalline Form-DO may be isolated from the solvent according to any suitable techniques know in the art such as filtration or centrifugation.

In embodiments, drying crystalline Form-DO may be carried out under suitable conditions such as aerial drying or drying under vacuum or inert gas atmosphere such as nitrogen. In embodiments, drying may be carried out in a suitable drying equipment, such as air or vacuum tray dryers.

The crystalline Form -DO of Diroximel fumarate and oxalic acid obtained according to the process of this aspect may be characterized by a PXRD pattern comprising the peaks at about 14.05 and 33.40° ± 0.2° 20.

In another aspect, the present application provides a process for the preparation of crystalline Diroximel fumarate, comprising the step of converting a crystalline form, selected from Form-DG and Form -DO, to other crystalline Diroximel fumarate.

In another aspect, the present application provides a process for the preparation of an amorphous Diroximel fumarate, comprising the steps of: a) providing a solution comprising Diroximel fumarate in an inert solvent; b) removing the solvent from the solution obtained in step a); and c) isolating Diroximel fumarate in amorphous state.

In embodiments, the suitable solvent may be selected from the group consisting of methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol, di chi orom ethane; tetrahydrofuran, 1,4-dioxane, acetone, methyl ethyl ketone, methyl isobutyl ketone; methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide N,N-dimethylacetamide, N-methyl-2-pyrrolidone, ethylene glycol, water and mixtures thereof.

In embodiments, providing a solution at step a) may be carried out by dissolving Diroximel fumarate and optionally, an pharmaceutically acceptable excipient, in an inert solvent or by directly taking the reaction mixture containing Diroximel fumarate in an inert solvent. In embodiments, a solution of Diroximel fumarate can be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.

In embodiments, a solution of Diroximel fumarate may be filtered to make it clear and free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.

In an embodiment, removal of solvent at step b) may be carried out by methods known in the art or any procedure disclosed in the present application. In preferred embodiments, removal of solvent may include, but not limited to: solvent evaporation or sublimation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Biichi® Rotavapor®, spray drying, freeze drying (Lyophilization), thin film drying, agitated thin film drying, rotary vacuum paddle dryer (RVPD) and the like.

In preferred embodiment, the solvent may be removed under reduced pressures and at temperatures of less than about 100°C, less than about 80°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80°C, or any other suitable temperatures.

In embodiments, the isolation of an amorphous Diroximel fumarate at step c) involves recovering the solid obtained in step b). The solid obtained from step b) may be recovered using techniques such as by scraping, or by shaking the container, or triturating with a solvent to make slurry followed by filtration, or other techniques specific to the equipment used. In an embodiment, the amorphous form of Diroximel fumarate obtained from step b) may be optionally dried before or after isolating it at step c).

Diroximel fumarate in amorphous state, obtained at step c) may be optionally combined with at least one pharmaceutically acceptable excipient at step d).

In an embodiment, amorphous Diroximel fumarate obtained at step c) may be combined with excipient using a technique known in art or by the procedures disclosed in the present application.

In preferred embodiment, pharmaceutically acceptable excipient may be selected from the group consisting of silicon dioxide, e.g. colloidal or fumed silicon dioxide or porous silica or Syloid; copolymers, such as polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer; and cellulose, preferably microcrystalline cellulose.

The inventors of the present application have surprisingly found that flow ability of material is drastically improved when the amorphous Diroximel fumarate is admixed or blended with the excipient, such as Syloid, according to the methods described in the present application.

Amorphous Diroximel fumarate isolated at step c) or d) may be dried in suitable drying equipment such as vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.

In another aspect, the present application provides pharmaceutical composition comprising amorphous Diroximel fumarate and at least one pharmaceutically acceptable excipient.

In another aspect, the present application provides a process for the preparation of an amorphous solid dispersion of Diroximel fumarate together with at least one pharmaceutically acceptable excipient, comprising the steps of: a) providing a solution of Diroximel fumarate and at least one pharmaceutically acceptable excipient in an inert solvent; b) removing the solvent from the solution obtained in step a), and c) isolating the amorphous solid dispersion of Diroximel fumarate.

In embodiments, the inert solvent of this aspect may be selected from the solvents disclosed in the previous aspect of present application.

In embodiments, at least one pharmaceutically acceptable excipient of this aspect may be selected from the excipients disclosed at any aspect of present application.

In embodiments, providing a solution at step a) may be carried out by dissolving Diroximel fumarate and at least one pharmaceutically acceptable excipient simultaneously or separately in same or different solvents.

In embodiments, a solution of Diroximel fumarate and the excipient may be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.

In embodiments, a solution of Diroximel fumarate and the excipient may be filtered to make it clear and free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.

In embodiments, removal of solvent at step b) may be carried out by methods known in the art or any procedure disclosed in the present application. In preferred embodiments, removal of solvent may include, but not limited to: solvent evaporation or sublimation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Biichi® Rotavapor®, spray drying, freeze drying (Lyophilization), agitated thin film drying and the like.

In preferred embodiment, the solvent may be removed under reduced pressures, at temperatures of less than about 100°C, less than about 80°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80°C, or any other suitable temperatures.

In embodiments, the isolation of an amorphous solid dispersion of Diroximel fumarate with excipient at step c) involves recovering the solid obtained in step b). The solid obtained from step b) may be recovered using techniques such as by scraping, or by shaking the container, or triturating with a solvent to make slurry followed by filtration, or other techniques specific to the equipment used.

In embodiments, the amorphous solid dispersion of Diroximel fumarate and excipient obtained from step b) may be optionally dried before or after isolating at step c).

Amorphous solid dispersion of Diroximel fumarate obtained at step c) may be optionally combined with at least one additional pharmaceutically acceptable excipient to obtain an admixture of amorphous solid dispersion of Diroximel fumarate to enhance the flow properties of solid dispersion.

In an embodiment, amorphous solid dispersion of Diroximel fumarate may be combined with additional excipient using a technique known in art or according to the previous aspects of the present application.

Amorphous solid dispersion of Diroximel fumarate isolated at step c) or d) may be dried in a suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.

In an aspect, the present application provides pharmaceutical composition comprising amorphous solid dispersion of Diroximel fumarate with at least one pharmaceutically acceptable excipient and at least one additional pharmaceutically acceptable excipient.

In an aspect, the present application provides pharmaceutical compositions comprising amorphous Diroximel fumarate and at least one pharmaceutically acceptable excipient, in particular in the form of solid dispersions and adsorbates. In embodiments, the pharmaceutically acceptable excipient is selected from the excipients at any aspect of present application.

In embodiments, the present application provides adsorbates, wherein Diroximel fumarate is associated with a suitable substrate. Suitable substrate may be a particulate and/or porous substrate, wherein this substrate has an outer and/or inner surface onto which the API may be adsorbed. This means that if the substrate has pores, these pores are filled by the Diroximel fumarate and the substrate remains unaffected, it does not, at least not essentially, change during and / or after the adsorption. In embodiments, the suitable substrate is selected from the excipients at any aspect of present application.

Amorphous form of Diroximel fumarate or its solid dispersion may be obtained alternatively either by employing a melt-extrusion technique or by combining a solution of Diroximel fumarate as obtained any of the aspects of present application with a suitable anti-solvent. In embodiments, amorphous product may be obtained by employing suitable melt- extrusion conditions or any of the procedures known in the art for obtaining amorphous product by melt- extrusion technique. In embodiments, solution of Diroximel fumarate may be combined with the anti-solvent at suitable temperature and for sufficient time to obtain amorphous product. Suitable anti-solvent is a solvent, wherein Diroximel fumarate has low solubility.

In another aspect, the present application provides a pharmaceutical composition comprising amorphous solid dispersion of Diroximel fumarate together with atleast one pharmaceutically acceptable excipient and an additional pharmaceutically acceptable excipient. In embodiments, the pharmaceutical composition contains solid dispersion of Diroximel fumarate, wherein Diroximel fumarate is in amorphous state.

In another aspect, the present application provides a process for the preparation of Diroximel fumarate, comprising the step of esterification of monomethyl fumarate with (2,5-dioxopyrrolidin-l-yl)ethanol in the presence of an acid halide.

In embodiments, the starting materials used in this aspect, monomethyl fumarate and (2,5-dioxopyrrolidin-l-yl)ethanol, may be obtained according to any methods known in the art or according to the procedures described in the present application. Alternatively, both these starting materials may be procured from any commercially available sources. In embodiments, the starting materials may be purified according to suitable methods such as recrystallization, chromatography or the like, before using. In embodiments, monomethyl fumarate may be obtained from methylation of fumaric acid. In embodiments, monomethyl fumarate may be obtained through in situ isomerization of maleic acid to form fumaric acid followed by methylation.

In alternate embodiments, the monomethyl fumarate may be obtained by methylation maleic anhydride or its acid to obtain monomethyl maleate followed by its isomerization to monomethyl fumarate.

In embodiments, the other starting material, (2,5-dioxopyrrolidin-l-yl)ethanol may be obtained by treating succinic anhydride with ethanolamine under suitable reaction conditions. In alternate embodiments, the (2,5-dioxopyrrolidin-l-yl)ethanol may be obtained by treating succinimide with ethylene carbonate in the presence of a base.

In embodiments, the monomethyl fumarate is treated with (2,5-dioxopyrrolidin-l- yl)ethanol in the presence of an acid halide.

Acid halide is selected from the group consisting of acetyl chloride, Thionyl chloride and Oxalyl chloride. In embodiments, the monomethyl fumarate is treated with acid halide to obtain corresponding monomethyl fumaric acid halide followed by its reaction with (2,5-dioxopyrrolidin-l-yl)ethanol. In embodiments, the monomethyl fumaric acid halide is generated in situ and reacted with (2,5-dioxopyrrolidin-l- yl)ethanol.

In embodiments, the reaction is carried out in the presence of a base. Base is selected from the group consisting of tri ethyl amine, diisopropylethyl amine or the like.

In embodiments, the reaction may be carried out in the presence of a suitable inert solvent. Inert solvent may be selected from the group consisting of dichloromethane, tetrahydrofuron, acetonitrile and mixtures thereof

In embodiments, the reaction may be carried out at a suitable temperature of about 0 °C or above. In preferred embodiment, the reaction is carried out at 0 °C. In embodiments, the reaction may be carried out for sufficient time for the formation of Diroximel fumarate, for at least 5 minutes or more. In preferred embodiment, the reaction is carried out for at least 30 minutes or more at 0 °C.

In embodiments, the solid Diroximel fumarate obtained may be separated by filtration or centrifugation, optionally washing the wet solid with suitable solvents such as acetone, cyclohexane, diethyl ether and mixtures thereof. In embodiment, the solid Diroximel fumarate obtained may be dried under suitable drying conditions till constant weight is achieved. In another aspect, the present application provides a process for the preparation of Diroximel fumarate, comprising the step of esterification of (E)-4-(2-(2,5- dioxopyrrolidin-l-yl)ethoxy)-4-oxobut-2-enoic acid with methylation agent selected from the group consisting of 2,2-dimethoxypropane, trimethyl orthoformate and dimethyl carbonate.

Diroximel Fumarate

In embodiments, the starting material used in this aspect, (E)-4-(2-(2,5- dioxopyrrolidin-l-yl)ethoxy)-4-oxobut-2-enoic acid may be obtained according to any methods known in the art or according to the procedures described in the present application. Alternatively, both these starting materials may be procured from any commercially available sources. In embodiments, the starting materials may be purified according to suitable methods such as recrystallization, chromatography or the like, before using.

In embodiments, the (E)-4-(2-(2,5-dioxopyrrolidin-l-yl)ethoxy)-4-oxobut-2-enoic acid may be obtained by treating fumaric acid with (2,5-dioxopyrrolidin-l-yl)ethanol.

In alternate embodiments, the (E)-4-(2-(2,5-dioxopyrrolidin-l-yl)ethoxy)-4- oxobut-2-enoic acid may be obtained by treating maleic anhydride or its acid with (2,5- dioxopyrrolidin-l-yl)ethanol to obtain (Z)-4-(2-(2,5-dioxopyrrolidin-l-yl)ethoxy)-4- oxobut-2-enoic acid followed by its isomerization to (E)-4-(2-(2,5-dioxopyrrolidin-l- y 1 )ethoxy) -4 - oxobut-2 - enoi c aci d .

In embodiments, the esterification of (E)-4-(2-(2,5-dioxopyrrolidin-l-yl)ethoxy)- 4-oxobut-2-enoic acid may be carried out by methylation with 2,2-dimethoxypropane, trimethyl orthoformate and dimethyl carbonate. In embodiments, the methylation may be carried out with 2,2-dimethoxypropane . In embodiments, the methylation may be carried out in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, boron trifluoride, p-toluenesulfonic acid, methanesulfonic acid, camphorsulfonic acid and the likes thereof. In preferred embodiments, the methylation may be carried out in the presence of hydrochloric acid.

In embodiments, the methylation is carried out optionally in the presence of an additional solvent. In embodiments, the methylation agent such as 2,2-dimethoxypropane itself acts a solvent to facilitate the methylation. The inventors of present application has identified a greener methylation approach which avoids use of additional solvent and undesired methylating agents such as methyl chloroformate, methyl halides, methyl sulphates, diazomethane, trimethylsilyldiazomethane, 1 -methyl-3 -p-tolyltriazene or the likes, which are not preferred for the final step of a drug substance preparation, that needs further purification to get rid of the traces, if any.

In embodiments, methylation may be carried out at a temperature of about 0 °C or above. In embodiments, the methylation may be carried out at for sufficient time for the formation of Diroximel fumarate, for at least one hour or longer.

In embodiments, the solid Diroximel fumarate obtained may be separated by filtration or centrifugation, optionally washing or slurrying the solid in suitable solvents such as methyl tert-butyl ether, diethyl ether, diisopropyl ether, hexane, heptane, toluene, xylene and the likes thereof. In embodiments, the solid Diroximel fumarate obtained may be dried under suitable drying conditions till constant weight is achieved.

In another aspect, the present application provides a process for the isolation of (2,5-dioxopyrrolidin-l-yl)ethanol, comprising the steps of a) reacting succinimide with ethylene carbonate, optionally in the presence of a base; b) treating (2,5-dioxopyrrolidin-l-yl)ethanol obtained in step (a) with a suitable organic solvent selected from the group consisting of methyl /er/-butyl ether, diethyl ether, diisopropyl ether, ethyl acetate, hexane, heptane, toluene, xylene, 1,4-dioxane, chlorobenzene and mixtures thereof.

In embodiments, step (a) of this aspect may be carried out in the presence of base selected from the group consisting of triethylamine, diisopropylethylamine, 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, 2, 6-dimethyl pyridine, N,N- dimethylaminopyridine or the like. In preferred embodiments, the reaction may be carried out in the presence of triethylamine.

In embodiments, the step (a) may be carried out at a suitable temperature of about 0 °C or above. In preferred embodiments, step (a) may be carried out at 90 °C or above.

In embodiments, the reaction mixture containing (2,5-dioxopyrrolidin-l-yl)ethanol obtained in step (a) may be optionally filtered to separate (2,5-dioxopyrrolidin-l- yl)ethanol from the reaction mixture. In alternate embodiments, the reaction mixture containing (2,5-dioxopyrrolidin-l-yl)ethanol obtained in step (a) may be directly combined with the organic solvents at step (b).

In embodiments, step (b) of this aspect may be carried out by treating (2,5- dioxopyrrolidin-l-yl)ethanol obtained in step (a) with organic solvents of step (b) at a suitable temperature of about 0 °C or above. In embodiments, (2,5-dioxopyrrolidin-l- yl)ethanol obtained in step (a) may be cooled to suitable temperature before treating with organic solvents of step (b).

In embodiments, the reaction mixture containing (2,5-dioxopyrrolidin-l-yl)ethanol obtained in step (a) may be homogeneous or heterogeneous.

In embodiments, at least one organic solvents of step (b) may be combined. In embodiments, step (b) may be carried out by combining the (2,5-dioxopyrrolidin-l- yl)ethanol obtained in step (a) with methyl /er/-butyl ether. In embodiments, step (b) may be carried out by combining the (2,5-dioxopyrrolidin-l-yl)ethanol obtained in step (a) with ethyl acetate.

In embodiments, the step (b) may be repeated with the same or different organic solvent. In embodiments, step (b) may be carried out by combining the (2,5- dioxopyrrolidin-l-yl)ethanol obtained in step (a) with methyl /er/-butyl ether followed by combining the separated solids with ethyl acetate.

In embodiments, step (b) of this aspect may be carried out for sufficient time to obtain the solid (2,5-dioxopyrrolidin-l-yl)ethanol of desired quality and quantity. In embodiments, the (2,5-dioxopyrrolidin-l-yl)ethanol obtained in step (b) is isolated as solid from the reaction mixture of step (b) according to any suitable methods known in the art such as filtration or centrifugation. In embodiments, the solid (2,5-dioxopyrrolidin- l-yl)ethanol isolated after step (b) may be optionally dried or used directly in the next step of preparing Diroximel fumarate.

In embodiments, (2,5-dioxopyrrolidin-l-yl)ethanol obtained according to the process of this aspect may be converted to Diroximel fumarate by following either the procedures described in the present application or any other methods known in the art.

In embodiments, the solid form of Diroximel fumarate obtained according to the processes of the present application is in amorphous or crystalline states. In embodiments, the solid form of Diroximel fumarate is a crystalline form reported in the literature.

In another aspect, the present application provides a process for the crystallization of Diroximel fumarate, comprising the steps of: a) providing a solution of Diroximel fumarate in an inert solvent or mixtures thereof b) contacting the solution of step (a) with an anti-solvent, optionally in the presence of a seed crystal. In embodiments, the Diroximel fumarate of step (a) may be obtained according to any of the processes disclosed in the instant application or procedures described in the literature.

In embodiments, providing the solution of Diroximel fumarate of step (a) may be carried out by dissolving Diroximel fumarate in an inert solvent, optionally under heating, or by directly taking the reaction mixture containing Diroximel fumarate in an inert solvent or mixtures thereof. In embodiments, the solution of step (a) may be filtered to make it particle free, optionally by treating with decolorizing agents like carbon or hydrose.

The inert solvent of step (a) may be selected from the group consisting of methanol, ethanol, 2-propanol, 1 -butanol, 2-butanol, dichloromethane, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide N,N-dimethylacetamide, N- methyl-2-pyrrolidone, ethylene glycol and mixtures thereof.

The anti-solvent of step (b) is a solvent in which Diroximel fumarate is less soluble or insoluble. In embodiments, anti-solvent may be selected from the group consisting of diethyl ether, methyl tert. butyl ether, diisopropyl ether, water or mixtures thereof.

In embodiments, step (b) of contacting the solution of step (b) with an anti-solvent may be carried out at suitable temperature of about 0 °C and above.

In embodiments, contacting with an anti-solvent may be carried out at in single or multiple lots. In embodiments, contacting with an anti-solvent may be carried out gradually for a time period sufficient to crystallize Diroximel fumarate. In embodiments, contacting with anti-solvent may be carried out for atleast 5 minutes and more.

In embodiments, step (b) of contacting the solution of step (a) with an anti-solvent may be carried out in the presence of a seed crystal of Diroximel fumarate.

In embodiments, the mixture of step (b) may be cooled to suitable temperature of about 30 °C and below.

In embodiments, the Diroximel fumarate obtained at step (b) may be isolated by any suitable techniques known in the art such as filtration, centrifugation or the like.

In embodiments, the Diroximel fumarate isolated after step (b) may be dried under suitable drying conditions known in the art such as aerial drying, drying under reduced pressure or inert gas atmosphere such as nitrogen.

In embodiments, or other procedures known in the art, may be subjected to a suitable particle size reduction operation such as milling, sifting, sieving or the like. In embodiments, milling may be include but not limited to drying milling such as air jet milling or wet milling.

In embodiments, the Diroximel fumarate obtained according to the process of present aspects may have a particle size of D50 of 100 microns and D90 of 150 microns. In embodiments, Diroximel fumarate may have particles size of D50 of 50 microns and D90 of 100 microns. In embodiments, Diroximel fumarate may have particle size of D10 of 10 microns, D50 of 30 microns and D90 of 80 microns.

In another aspect, the present application provides amorphous Diroximel fumarate, its solid dispersion with at least one pharmaceutically acceptable excipient, crystalline Form-DG, crystalline Form-DO or a pharmaceutical composition thereof; comprising Diroximel fumarate having a chemical purity of at least 99% by HPLC or at least 99.5% by HPLC or at least 99.9% by HPLC.

In another aspect, the present application provides crystalline or amorphous Diroximel fumarate, its solid dispersion with at least one pharmaceutically acceptable excipient, crystalline Form-DG, crystalline Form-DO or a pharmaceutical composition thereof, wherein the particle size of Diroximel fumarate is less than 250 microns. In embodiments, the particle size of Diroximel fumarate is less than 150 microns. . In embodiments, the particle size of Diroximel fumarate is less than 100 microns. In embodiments, the particle size of Diroximel fumarate is less than 50 microns. In embodiments, Diroximel fumarate particles have a D50 of 100 microns and D90 of 150 microns. In embodiments, Diroximel fumarate particles have a D50 of 50 microns and D90 of 100 microns. In embodiments, Diroximel fumarate particles have a D10 of 10 microns, D50 of 30 microns and D90 of 80 microns.

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 reagents under conditions that cause the chemical reaction indicated to take place.

The terms “amorphous form of Diroximel fumarate" and “amorphous Diroximel fumarate” indicate that the Diroximel fumarate is present in substantially amorphous state in the composition (e.g. solid dispersion, adsorbate or pharmaceutical composition). "Substantially" amorphous denotes that 90 %, preferably 95 % or 99 %, more preferably all of the Diroximel fumarate being present in the solid dispersion, on the adsorbate or in the pharmaceutical composition is amorphous. In other words, an "amorphous" Diroximel fumarate composition denotes a Diroximel fumarate-containing composition, which does not contain substantial amounts, preferably does not contain noticeable amounts, of crystalline portions of Diroximel fumarate e.g. measurable upon X-ray powder diffraction analysis.

The term "solid dispersion" when used in the present application, denotes a state where most of the Diroximel fumarate, preferably 90%, 95% or all of the Diroximel fumarate of the solid dispersion, is homogeneously molecularly dispersed in a solid polymer matrix. Preferably solid dispersion, relates to a molecular dispersion where the API (active pharmaceutical ingredient) and polymer molecules are uniformly but irregularly dispersed in a non-ordered way. In other words, in a solid dispersion, the two components (polymer and API) form a homogeneous one-phase system, where the particle size of the API in the solid dispersion is reduced to its molecular size. In a preferred embodiment, in the solid dispersion according to the present invention no chemical bonds can be detected between the API and the polymer. In order to arrive at such a solid dispersion, preferably solid solution, it is required to have a substantial amount of API dissolved in a suitable solvent at least at one time point during preparation of said solid dispersion.

The term "adsorbate" when used in the present application, specifies that the Diroximel fumarate is, preferably evenly, and preferably homogeneously, distributed on the inner and/or outer surface of the particulate substrate. EXAMPLES

Example-1: Preparation of Amorphous solid dispersion of Diroximel fumarate and Soluplus

Diroximel fumarate (50 mg) and Soluplus (500 mg) were dissolved in water (50 mL) at 27 °C. The clear solution was frozen at -78 °C and lyophilized for 16 hours. 50 mg of the obtained solid was combined with Syloid (50 mg) and ground for 30 minutes at 27 °C to obtain the admixture of the title compound. XRPD: Amorphous.

Example-2: Preparation of Amorphous solid dispersion of Diroximel fumarate with Copovidone

Diroximel fumarate (50 mg) and Copovidone (500 mg) were dissolved in water (30 mL) at 27 °C. The clear solution was frozen at -78 °C and lyophilized for 16 hours. 50 mg of the obtained solid was combined with Syloid (50 mg) and ground for 20 minutes to obtain the admixture of title compound. XRPD: Amorphous.

Example-3: Preparation of Amorphous solid dispersion of Diroximel fumarate and HPMC.

Diroximel fumarate (50 mg) and HPMC (500 mg) were dissolved in water (40 mL) at 27 °C. The clear solution was frozen at -78 °C and lyophilized for 16 hours. 50 mg of the obtained solid was combined with Syloid (50 mg) and ground for 45 minutes to obtain the admixture of title compound. XRPD: Amorphous.

Example-4: Preparation of crystalline Form-DG of Diroximel fumarate and Gentisic acid

A mixture of Diroximel fumarate (510 mg), Gentisic acid (308 mg), chloroform (0.2 mL) and methanol (0.1 mL) was milled for 120 minutes with 25 Hz frequency at 25 °C in a ball mill to obtain the title compound. XRPD: Crystalline Form-DG.

Example-5: Preparation of crystalline Form-DO of Diroximel fumarate and Oxalic acid

Diroximel fumarate (765 mg) and Oxalic acid (270 mg) were suspended in chloroform (1 mL) at 50 °C and stirred at the same temperature for 2 hours. Methyl tert. butyl ether (5 mL) was added to the mixture at 50 °C and stirred for 16 hours at 50 °C. The mixture was cooled to 25 °C and the solid was filtered to obtain the title compound. XRPD: Crystalline Form-DO.

Example-6: Preparation of crystalline Form-DO of Diroximel fumarate and Oxalic acid

A mixture of Diroximel fumarate (510 mg), Oxalic acid (180 mg) and chloroform (0.2 mL) was milled for 60 minutes with 25 Hz frequency at 25 °C in a ball mill to obtain the title compound. XRPD: Crystalline Form-DO.

Example-7: Preparation of l-(2-hydroxyethyl)pyrrolidine-2,5-dione

A mixture of succinimide (100 g), ethylene carbonate (70.6 mL) and triethylamine (14 mL) was heated to 90 °C and stirred at the same temperature for 24 hours. The reaction mixture was cooled to 0 °C; methyl /ert-butyl ether (300 mL) was added and the resulting mixture was stirred for 30 minutes at the same temperature. The solid was filtered and dried under vacuum for 5 minutes. The solid was combined with ethyl acetate (100 mL) at 0 °C and stirred at the same temperature for 30 minutes. The solid was filtered and dried in rotatory vacuum dryer at 40 °C for 30 minutes to obtain 142.5 g of the title compound as off-white solid with HPLC purity of 99.6%.

Example-8: Preparation of Diroximel fumarate

To a mixture of (E)-4-methoxy-4-oxobut-2-enoic acid (4.0 g) and dichloromethane (40 mL) at 5 °C, Oxalyl chloride (5.85 g) was added slowly in 10 minutes, then a drop of DMF was added at the same temperature and allowed the reaction mixture to warm up to 27 °C. After complete evolution of the gas, solvent was evaporated from the reaction mixture. To a mixture of l-(2-hydroxyethyl)pyrrolidine-2,5-dione (5.06 g) and dichloromethane (35 mL), diisopropylethylamine (DIPEA) (9.93 g) was added and cooled the reaction mixture to 5 °C. The former mixture of (E)-4-methoxy-4-oxobut-2-enoic acid chloride in dichloromethane was slowly added to this later mixture at 5 °C for 20 minutes and stirred at the same temperature for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution and the organic layer was separated. Organic layer was washed with 10% citric acid solution and then with brine solution. The solvent from the separated organic layer was evaporated completely at 30 °C and the resultant solid was combined with acetone (15 mL) at 27 °C and stirred for 8 hours at the same temperature. The solid was filtered and the cake was washed with chilled acetone (3 mL) and then with cyclohexane (4 mL). The wet solid was dried at 40 °C under vacuum to obtain 3.3 g of the title compound with HPLC purity of 99.95 %

Example-9: Preparation of Diroximel fumarate

To a mixture of (E)-4-methoxy-4-oxobut-2-enoic acid (100.0 g) and dichloromethane (1000 mL) at 5 °C, Oxalyl chloride (117 g) was added slowly in 15 minutes, then catalytic DMF (1 mL) was added slowly at the same temperature and allowed the reaction mixture to warm up to 27 °C. After complete evolution of the gas, solvent was evaporated from the reaction mixture. To a mixture of l-(2-hydroxyethyl)pyrrolidine-2,5-dione (110 g) and dichloromethane (900 mL), diisopropylethylamine (DIPEA) (139 g) was added and cooled the reaction mixture to -5 °C. The former mixture of (E)-4-methoxy-4-oxobut-2- enoic acid chloride in dichloromethane (100 mL) was slowly added to this later mixture at - 5 °C for 60 minutes and stirred at the same temperature for 1 hour. The reaction mixture was quenched with water and the organic layer was separated. Organic layer was washed with 10% citric acid solution, 10% NaHC0 3 solution and then with brine solution. The solvent from the separated organic layer was evaporated completely at 30 °C and the resultant solid was combined with acetone (400 mL) at 27 °C. The reaction mixture was heated to 45 °C and stirred at the same temperature for 1 hour. The mixture was cooled to 27 °C and stirred for 8 hours at the same temperature. The solid was filtered and the cake was washed with methanol (200 mL). The wet solid was dried at 45 °C under vacuum to obtain 120 g of the title compound with HPLC purity of 99.97 %

Example-10: Preparation of (E)-4-(2-(2,5-dioxopyrrolidin-l-yl)ethoxy)-4-oxobut-2- enoic acid

A mixture of succinimide (100 g), ethylene carbonate (70.6 mL) and triethylamine (14 mL) was heated to 90 °C and stirred at the same temperature for 24 hours. The reaction mixture was cooled to 50 °C and triethylamine was removed by evaporation under vacuum. The reaction mixture was heated to 90 °C to distill out the traces of triethylamine under vacuum. The reaction mixture was cooled to 40 °C. Acetone (300 mL), maleic anhydride (106.2 g) and triethylamine (6.31 mL) were added. The resulting mixture was stirred at 40 °C for 6 hours. The mixture was cooled to 20 °C and acetyl chloride (12 mL) was added slowly over a period of 30 minutes. The mixture was slowly heated to 50 °C and stirred for 20 hours at the same temperature followed 2 hours at 0 °C. The solid was filtered and washed with cold acetone (2 x 120 mL).The wet solid was dried at 40 °C for 2 hours to obtain 194.2 g of the title compound as white solid with HPLC purity of 99.55%

Example-11: Preparation of Diroximel fumarate

Diroximel Fumarate

To a mixture of (E)-4-(2-(2,5-dioxopyrrolidin-l-yl)ethoxy)-4-oxobut-2-enoic acid (5 g) and 2,2-dimethoxypropane (50 mL) at 29 °C, concentrated hydrochloric acid (1 mL) and water (5 mL) were added and stirred at the same temperature for 17 hours at the same temperature. The pH of the reaction mixture was adjusted to 7 with a saturated aqueous solution of NaHCCh and the solvent was evaporated completely at 40 °C. To the resultant solid, water (50 mL) was added at 29 °C and stirred for 15 minutes. The solid was filtered and dried under vacuum at 29 °C for 5 hours. The resultant solid was combined with methyl /er/-butyl ether (50 mL) at 29 °C and stirred for 20 hours at the same temperature. The solid obtained was filtered and washed with diethyl ether (20 mL). The wet solid was dried under vacuum for 3 hours at 29 °C to obtain 3.3 g of the title compound as white solid with HPLC purity of 98.11%

Example-12: Preparation of Amorphous solid dispersion of Diroximel fumarate with Copovidone

Diroximel fumarate (100 mg) and Copovidone (500 mg) were dissolved in acetone (30 mL) at 30 °C. The clear solution was filtered to make it particle free and the solvent was evaporated in a rotavapor at 45 °C under reduced pressure to obtain the title amorphous solid dispersion. The solid dispersion (100 mg) obtained was combined with Syloid (500 mg) and ground for 20 minutes to obtain the admixture of title compound. XRPD: Amorphous.

Example-13: Crystallization of Diroximel fumarate

Diroximel fumarate (20 g) was dissolved in acetone (80 mL) at 43 °C and methyl tert. butyl ether (30 mL) was added to the clear solution. A suspension of crystalline Diroximel fumarate seed (0.25 g) in methyl tert. butyl ether (10 m) was added at 40 °C and stirred the mixture at the same temperature for 30 minutes. Methyl tert. butyl ether (280 mL) was added slowly for 2 hours at 41 °C. The mixture was cooled to 25 °C in 3 hours and then to 0 °C in 1 hour. The mixture was stirred at 0 °C for 1 hour and the solid was filtered. The wet solid was washed with methyl tert. butyl ether (40 mL) and dried at 42 °C for 6 hours to obtain the title compound.

PXRD: Crystalline; Malvern particle size: D v (10) 7.776 pm, D v (50) 31.292 pm & D v (90) 133.437 pm

Example-14: Crystallization of Diroximel fumarate

Diroximel fumarate (20 g) was dissolved in acetone (80 mL) at 43 °C and DM water (100 mL) was added to the clear solution. A crystalline Diroximel fumarate seed (0.20 g) was added at 42 °C and stirred the mixture at the same temperature for 10 minutes. DM water (100 mL) was added slowly at 41 °C. The mixture was cooled to 28 °C in 1 hour. The mixture was stirred at 28 °C for 2 hour and the solid was filtered to obtain the title compound.

PXRD: Crystalline; Malvern particle size: Dv (10) 8.59 pm, Dv (50) 61.08 pm & Dv (90) 187.07 pm

Example-15: Crystallization of Diroximel fumarate

Diroximel fumarate (20 g) was dissolved in acetone (80 mL) at 45 °C and DM water (400 mL) was added to the clear solution. The mixture was cooled to 30 °C in 1 hour and the solid was filtered to obtain the title compound.

PXRD: Crystalline; Malvern particle size: Dv (10) 7.22 pm, Dv (50) 45.5 pm &

Dv (90) 136.7 pm

Example-16: Crystallization of Diroximel fumarate

Diroximel fumarate (20 g) was dissolved in Isopropyl acetate (360 mL) at 55 °C and cooled to 28 °C. A crystalline Diroximel fumarate seed (0.25 g) was added at 28 °C and cool to 5 °C. The mixture was stirred for 1 hour at the same temperature and the solid was filtered to obtain the title compound.

PXRD: Crystalline; Malvern particle size: Dv (10) 7.3 pm, Dv (50) 43.18 pm & Dv (90) 133.56 pm