WO2021044350A1

WO2021044350A1 - Solid forms of encequidar mesylate and processes thereof

Info

Publication number: WO2021044350A1
Application number: PCT/IB2020/058228
Authority: WO
Inventors: Arijit Mukherjee; Satyanarayana THIRUNAHARI
Original assignee: Dr. Reddy’S Laboratories Limited
Priority date: 2019-09-04
Filing date: 2020-09-04
Publication date: 2021-03-11

Abstract

Aspects of the present application relate to solid forms of Encequidar, its mesylate salt and pharmaceutical compositions thereof. Specific aspects relate to crystalline Form EM4, crystalline Form EM5, crystalline Form EM6 and crystalline Form EM-O of Encequidar mesylate. Further aspects relate to processes for the preparation of solid forms of Encequidar and its mesylate salt.

Description

SOLID FORMS OF ENCEQUIDAR MESYLATE AND PROCESSES THEREOF

INTRODUCTION

Aspects of the present application relate to solid forms of Encequidar, its mesylate salt and pharmaceutical compositions thereof. Specific aspects relate to the crystalline forms of Encequidar, mesylate salt thereof and processes for their preparation.

Encequidar is the adopted name of compound developed by Hanmi pharma having a chemical name: /V-[2-(2-{4-[2-(6,7-Dimethoxy-3,4-dihydro-2(lf/)isoquinolinyl)ethyl] phenyl }-2if-tetrazol-5-yl)-4,5-dimethoxyphenyl]-4-oxo-4if-chromene-2-carboxamide and the structure as below.

Encequidar is P-glycoprotein pump inhibitor, which can facilitate oral absorption of traditional cytotoxics such as Paclitaxel, Docetaxel, Topotecan, Irinotecan and Eribulin for improved patient tolerability and efficacy as compared to IV administration of the same cytotoxics.

US 7625926 B2 first discloses Encequidar, its mesylate salt, preparative process, pharmaceutical composition and their use for inhibiting activity of P-glycoprotein.

Further, US 9283218 B2 discloses a crystalline form of mesylate salt of Encequidar which is characterized through X-ray power diffraction pattern. However, US 9283218 B2 discloses neither the preparation nor the stability and viability of said polymorph in a pharmaceutical dosage form.

None of these arts disclose an amenable and / or scalable solid form of Encequidar mesylate that can be formulated as drug product. Hence, there remains a need for alternate solid forms of Encequidar mesylate which can overcome the disadvantages of the prior art and their preparation in a more cost effective and industrially viable manner. SUMMARY

In an aspect, the present application provides a crystalline Form EM4 of Encequidar mesylate, characterized by a PXRD pattern comprising the peaks at about 8.41, 19.09 and 24.07 ± 0.2° 20.

In another aspect, the present application provides a crystalline Form EM5 of Encequidar mesylate, characterized by a PXRD pattern comprising the peaks at about 4.04 and 17.50° ± 0.2° 20.

In another aspect, the present application provides a crystalline Form EM6 of Encequidar mesylate, characterized by a PXRD pattern comprising the peaks at about 3.3 and 9.0 ± 0.2° 2Q.

In another aspect, the present application provides a crystalline complex of Encequidar mesylate salt with Oxalic acid.

In another aspect, the present application provides a crystalline Form EM-0 of Encequidar mesylate with Oxalic acid, characterized by a PXRD pattern comprising the peaks at about 12.62, 24.47 and 26.05 ° ± 0.2° 20.

In another aspect, the present application provides a stable amorphous form of Encequidar mesylate.

In another aspect, the present application provides a process for the preparation of crystalline Form EM4 of Encequidar mesylate, comprising the steps of:

(i) treating Encequidar mesylate with formamide or a mixture thereof.

(ii) heating the solid form obtained from step (i) to obtain crystalline form EM4.

In another aspect, the present application provides a process for the preparation of crystalline Form EM5 of Encequidar mesylate, comprising the step of combining Encequidar mesylate with dimethyl acetamide.

In another aspect, the present application provides a process for the preparation of crystalline Form EM6 of Encequidar mesylate, comprising the step of exposing crystalline form EM5 to humid conditions.

In another aspect, the present application provides a process for the preparation of crystalline Form EM-0 of Encequidar mesylate with Oxalic acid, comprising the step of combining Encequidar mesylate with Oxalic acid in the presence of an inert organic solvent.

In another aspect, the present application provides a process for the preparation of amorphous form of Encequidar mesylate, comprising the steps of: a) providing a solution of Encequidar mesylate in a suitable solvent, b) removing the solvent of step a) and c) isolating amorphous form of Encequidar mesylate.

In another aspect, the present application provides pharmaceutical compositions comprising a crystalline form of Encequidar mesylate, selected from the group consisting of EM4, EM5, EM6 and mixtures thereof together with at least one pharmaceutically acceptable excipient.

In another aspect, the present application provides pharmaceutical compositions comprising a crystalline Form EM-0 of Encequidar mesylate together with at least one pharmaceutically acceptable excipient.

In another aspect, the present application provides pharmaceutical compositions comprising an amorphous form of Encequidar mesylate together with at least one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWING

Figure 1 is an illustrative X-ray powder diffraction pattern of crystalline Form EM4 of Encequidar, prepared by the method of Example No 1.

Figure 2 is an illustrative X-ray powder diffraction pattern of crystalline Form EM5 of Encequidar mesylate, prepared by the method of Example No 2. Figure 3 is an illustrative X-ray powder diffraction pattern of crystalline Form EM6 of Encequidar mesylate, prepared by the method of Example No 3.

Figure 4 is an illustrative X-ray powder diffraction pattern of crystalline Form EM-0 of Encequidar mesylate, prepared by the method of Example No 4.

Figure 5 is an illustrative X-ray powder diffraction pattern of amorphous form of Encequidar mesylate, prepared by the method of Example No 5.

Figure 6 is an illustrative X-ray powder diffraction pattern of stable crystalline form EM5 of Encequidar mesylate after 24 hours of heating in open condition.

DETAILED DESCRIPTION

In an aspect, the present application provides a crystalline Form EM4 of Encequidar mesylate, characterized by a PXRD pattern comprising the peaks at about 8.41, 19.09 and 24.07 ± 0.2° 20. In embodiments, the crystalline Form EM4 of Encequidar mesylate is characterized by one or more additional peaks at about 11.06 and 25.55 ° 20. In embodiments, the application provides crystalline Form EM4 of Encequidar mesylate, characterized by a PXRD pattern of figure 1. In embodiments, the crystalline Form EM4 of Encequidar mesylate may contain solvent content such as formamide content of about 0.1 % or less.

In another aspect, the present application provides a crystalline Form EM5 of Encequidar mesylate, characterized by a PXRD pattern comprising the peaks at about 4.04 and 17.50° ± 0.2° 20. In an embodiment, the crystalline Form EM5 is characterized by one or more additional peaks at about 10.27 and 18.07 ° ± 0.2° 20. In an embodiment, the application provides crystalline Form EM5, characterized by a PXRD pattern of figure 2. In embodiments, the crystalline Form EM5 of Encequidar mesylate may contain water content of about 0.5 % or less. In embodiments, crystalline Form EM5 is stable for atleast 24 hours at about 60 °C in open condition as illustrated by the XRPD pattern in figure 6.

In another aspect, the present application provides a crystalline Form EM6 of Encequidar mesylate, characterized by a PXRD pattern comprising the peaks at about 3.3 and 9.0 ± 0.2° 20. In embodiments, the crystalline Form EM6 of Encequidar mesylate is characterized by one or more additional peaks at about 8.2 and 11.2 ° 20. In embodiments, the application provides crystalline Form EM6 of Encequidar mesylate, characterized by a PXRD pattern of figure 3. In embodiments, the crystalline Form EM6 of Encequidar mesylate may contain water content of about 13 % or less.

In another aspect, the present application provides a crystalline complex of Encequidar mesylate salt with Oxalic acid. In embodiments, crystalline complex of Encequidar mesylate with Oxalic acid may be a molecular complex of Encequidar mesylate salt with Oxalic acid such as an inclusion complex, co-crystal or the like. In embodiments, the crystalline complex contains Encequidar mesylate and Oxalic acid in 1 : 1 ratio.

In another aspect, the present application provides a crystalline Form EM-0 of Encequidar mesylate with Oxalic acid, characterized by a PXRD pattern comprising the peaks at about 12.62, 24.47 and 26.05 ± 0.2° 2Q. . In an embodiment, the crystalline Form EM-0 is characterized by one or more additional peaks at about 7.67, 18.93 and 19.93° ± 0.2° 2Q. In an embodiment, the application provides crystalline Form EM-O, characterized by a PXRD pattern of figure 4. In embodiments, crystalline form EM-0 of Encequidar mesylate and Oxalic acid may be a molecular complex of Encequidar mesylate salt with Oxalic acid such as an inclusion complex, co-crystal or the like. In embodiments, crystalline form EM-0 contains Encequidar mesylate and Oxalic acid in 1 : 1 ratio.

In another aspect, the present application provides an amorphous form of Encequidar mesylate. In embodiments, the present application provides stable amorphous form. In embodiments, the present application provides an amorphous Encequidar mesylate 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. In embodiments, the application provides amorphous form of Encequidar mesylate, characterized by a PXRD pattern of figure 5.

In another aspect, the present application provides a stable amorphous form of Encequidar mesylate. In embodiments, the amorphous form of instant application is stable at all temperature and humidity conditions under all ICH packing and storage conditions.

The inventors of present application have surprisingly found that the amorphous form of Encequidar mesylate obtained according to the processes of instant application is physically and chemically stable under ambient storage conditions such as ambient temperature and relative humidity conditions. Further, the inventors of present application have found that the amorphous form of Encequidar mesylate it does not require any specific storage conditions and any stability enhancing agents such as excipients for physical stability or anti-oxidants for chemical stability.

(i) treating Encequidar mesylate with formamide or a mixture thereof.

In embodiments, Encequidar mesylate used in this aspect may be obtained by any methods known in the art or procedures described or exemplified in the present application, comprising the reaction of Encequidar with methane sulphonic acid under suitable conditions to form mesylate salt of Encequidar.

In embodiments, step (i) of treating Encequidar mesylate with formamide may be carried out by combining Encequidar mesylate with formamide to form a homogenous or heterogeneous mixture. In embodiments, the mixture may be in the form of a solution or suspension. In embodiments, when the mixture is a solution, the temperature of the mixture may be lowered to a suitable temperature or contacted with an anti-solvent, for the solid formation.

In embodiments, when the mixture is a suspension, the suspension may be stirred at suitable temperature, optionally through heating, for at least 1 hour or more. In embodiments, the mixture may be stirred at about 0 °C or above. In preferred embodiments, the mixture may be stirred at 30 °C or above.

In embodiments, the solid form obtained at step (i) may be separated according any suitable techniques such as filtration, centrifugation or the likes.

The step (ii) of this aspect may be carried out by heating the solid form of Encequidar mesylate obtained at step (i). In embodiments, the solid form obtained from step (i) may be heated at a suitable temperature of about 30 °C or above. In preferred embodiments, the solid form may be heated at about 50 °C or above.

In embodiments, heating at step (ii) may be carried out under suitable drying conditions such as aerial drying, drying under reduced pressure or drying under inert gas atmosphere such as nitrogen pressure. In embodiments, the drying may be carried out in a suitable drying equipment such as tray dryer, fluidized bed dryer, rotatory cone dryer or the likes.

In embodiments, the solid form of Encequidar mesylate obtained either at step (i) or step (ii) may be treated with an additional solvent. Additional solvent may be selected from the group consisting of n-hexane, n-heptane and a mixture thereof. In an embodiment, the solid form of Encequidar mesylate obtained at step (i) or step (ii) may be sonicated in the presence of additional solvent.

In embodiments, the crystalline Form EM4 of Encequidar mesylate obtained by the process of this aspect may be characterized by a PXRD pattern comprising the peaks at about 8.41, 19.09 and 24.07 ± 0.2° 20. In embodiments, crystalline Form EM4 may be characterized by a PXRD pattern of figure 1.

In embodiments, Encequidar mesylate used in this aspect may be obtained by any methods known in the art or any process comprising the reaction of Encequidar with methane sulphonic acid under suitable conditions to form mesylate salt of Encequidar.

In embodiments, combining Encequidar mesylate with dimethylacetamide may be carried out through the formation of a homogeneous solution or a heterogeneous mixture, under suitable temperature at about 0°C to reflux temperature the solvent or reaction mixture thereof.

In an embodiment, combining Encequidar mesylate with dimethylacetamide may be carried out by dissolving Encequidar mesylate in dimethylacetamide, optionally by heating. In embodiments, the solution containing Encequidar mesylate in dimethylacetamide may be cooled to suitable temperature to crystallize form EM5.

In an embodiment, the solvent from the solution containing Encequidar mesylate in dimethylacetamide may be removed by evaporation or sublimation of the solvent, optionally under reduced pressure at about 0°C to reflux temperature of inert organic solvent or mixtures thereof.

In an embodiment, the solution containing Encequidar mesylate in dimethylacetamide may be contacted with a suitable anti-solvent, to crystallize form EM5. Anti-solvent is solvent in which the Encequidar mesylate is insoluble or low soluble.

In embodiments, Encequidar mesylate may be combined with dimethylacetamide by suspending Encequidar mesylate in dimethylacetamide to form a slurry or suspension, optionally under heating. In embodiments, amorphous Encequidar mesylate may be suspended in dimethylacetamide. In embodiments, suspending Encequidar mesylate may be carried out at about 50 °C or above.

In embodiments, Encequidar mesylate may be combined with dimethyl acetamide for sufficient time to obtain crystalline form EM5 of Encequidar mesylate.

In embodiments, Encequidar mesylate may be combined with dimethylacetamide at suitable temperature to obtain crystalline form EM5 of Encequidar mesylate. In preferred embodiments, Encequidar mesylate may be combined with dimethylacetamide at suitable temperature of about 0°C to reflux temperature to obtain crystalline form EM5.

In embodiments, the crystalline form EM5 of Encequidar mesylate may be isolated by separating the solids from the solvent through suitable techniques known in the art such as filtration, decantation and the like.

In embodiments, Encequidar mesylate may be combined through grinding or milling the Encequidar mesylate in the presence of dimethylacetamide. In embodiments, Encequidar mesylate may be ground in a suitable equipment such as mortar-pestle, milled in a ball mill or the like. In embodiments, Encequidar mesylate may be ground for sufficient time and at suitable temperature to obtain crystalline Form EM5.

In embodiments, the isolated solids may be dried under suitable drying conditions such as aerial drying, drying under vacuum or inert gas at a suitable temperature of about 25°C or above.

In embodiments, the crystalline Form EM5 of Encequidar mesylate obtained by the process of this aspect may be characterized by a PXRD pattern comprising the peaks at about 4.04 and 17.50° ± 0.2° 20. In an embodiment, the crystalline Form EM5 is characterized by one or more additional peaks at about 10.27 and 18.07 ° ± 0.2° 20. In an embodiment, the application provides crystalline Form EM5, characterized by a PXRD pattern of figure 2.

In embodiments, crystalline Form EM5 of Encequidar mesylate is characterized by a PXRD pattern comprising the peaks at about 4.04 and 17.50° ± 0.2° 20. In an embodiment, the crystalline Form EM5 is characterized by one or more additional peaks at about 10.27 and 18.07 ° ± 0.2° 20. In embodiments, crystalline Form EM5 of Encequidar mesylate may be optionally heated or dried under suitable temperature, before exposing to humid conditions.

In embodiments, exposing crystalline Form EM5 may be carried out under controlled humidification conditions. In embodiments, humidification may be carried out by exposing crystalline Form EM5 to constant relative humidity. In embodiments, humidification may be carried out at a relative humidity of atleast 40% or above.

In an embodiment, humidification of crystalline Form EM5 may be carried out by exposing Form EM5 to aerial humidity or to humid inert gas such as humid nitrogen. In embodiments, the humidification may be carried out in a suitable equipment such as desiccators, humidification chambers, fluidized bed dryer or the likes.

In embodiments, the crystalline Form EM6 of Encequidar mesylate obtained by the process of this aspect may be characterized by a PXRD pattern comprising the peaks at about 3.3 and 9.0 ± 0.2° 2Q. In embodiments, crystalline Form EM6 may be characterized by a PXRD pattern of figure 3.

In embodiments, combining Encequidar mesylate with oxalic acid may be carried out through the formation of a homogeneous solution or a heterogeneous mixture in the presence of an inert organic solvent, under suitable temperature at about 0°C to reflux temperature of the inert organic solvent or mixtures thereof.

In an embodiment, combining Encequidar mesylate with oxalic acid may be carried out by dissolving Encequidar mesylate and oxalic acid in an inert organic solvent. In embodiments, the solvent from solution containing Encequidar mesylate and oxalic acid may be optionally removed using suitable methods known in the art or according to procedures described in the present application. In embodiments, the solvent from solution containing Encequidar mesylate and oxalic acid may be removed completely or partially.

In an embodiment, the solvent from the solution containing combining Encequidar mesylate and oxalic acid 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 an embodiment, the solvent from solution containing Encequidar mesylate and oxalic acid may be removed by evaporating or sublimating the solvent, optionally under reduced pressure at about 0°C to reflux temperature of inert organic solvent or mixtures thereof.

In embodiments, Encequidar mesylate and Oxalic acid may be combined in the presence of inert organic solvent by suspending Encequidar mesylate and Oxalic acid in an inert organic solvent to form a slurry or suspension.

In embodiments, Encequidar mesylate and oxalic acid may be combined for sufficient time to obtain crystalline form EM-0 of Encequidar mesylate with Oxalic acid. In preferred embodiments, combining Encequidar mesylate and oxalic acid in the presence of an inert organic solvent may be carried out for atleast one hour or longer to obtain crystalline form EM-O.

In embodiments, Encequidar mesylate and oxalic acid may be combined at suitable temperature to obtain crystalline form EM-0 of Encequidar mesylate with oxalic acid. In preferred embodiments, Encequidar mesylate and oxalic acid may be combined at suitable temperature of about 0°C to reflux temperature to obtain crystalline form EM-O.

In embodiments, the crystalline form EM-0 of Encequidar mesylate with Oxalic acid may be isolated by separating the solids from the solvent through suitable techniques known in the art such as filtration, decantation and the like.

In embodiments, Encequidar mesylate and oxalic acid may be combined through grinding or milling the mixture in the presence of an inert organic solvent. In embodiments, Encequidar mesylate and oxalic acid may be ground in a suitable equipment such as mortar-pestle, milled in a ball mill or the like, in the presence of an inert organic solvent. In embodiments, Encequidar mesylate and oxalic acid may be ground for sufficient time and at suitable temperature to obtain crystalline Form EM-O.

In embodiments, inert organic solvent of this aspect may be selected from the group consisting of water, ketone solvent, alcohol solvent, nitrile solvent, ether solvent, halohydrocarbon solvent, halohydrocarbon solvent 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 diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4- dioxane; hydrocarbons solvents such as hexane, heptane, cyclohexane, pet-ether, nitromethane; halohydrocarbon solvents such as dichloromethane, chloroform, carbon tetrachloride and mixtures thereof. In preferred embodiments, the inert organic solvent may be selected from the group consisting of methanol, nitromethane and mixtures thereof.

In embodiments, the crystalline Form EM-0 of Encequidar mesylate with Oxalic acid obtained by the process of this aspect may be characterized by a PXRD pattern comprising the peaks at about 12.62, 24.47, 26.05 ± 0.2° 2Q. In an embodiment, the crystalline Form EM-0 is characterized by one or more additional peaks at about 7.67, 18.93 and 19.93° ± 0.2° 2Q. In an embodiment, crystalline Form EM-0 may be characterized by a PXRD pattern of figure 4. In embodiments, crystalline form EM-0 contains Encequidar mesylate and Oxalic acid in 1 : 1 ratio.

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, dichloromethane; 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 Encequidar mesylate in solvent or by directly taking the reaction mixture containing Encequidar mesylate in the solvent. In embodiments, a solution of Encequidar mesylate 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 Encequidar mesylate 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 Encequidar mesylate 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 Encequidar mesylate obtained from step b) may be optionally dried before or after isolating it at step c).

Encequidar mesylate in amorphous state, obtained at step c) may be optionally combined with at least one pharmaceutically acceptable excipient. In an embodiment, amorphous Encequidar mesylate 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, amorphous Encequidar mesylate may be combined with excipient either by physical blending of both the solid components or by suspending both the components in a suitable solvent and conditions, such that both the components remain unaffected. Blending may be carried out using techniques known in art such as grinding in mortar and pestle, drying in rotatory cone dryer, fluidized bed dryer or the like optionally under reduced pressure / vacuum or inert atmosphere such nitrogen at suitable temperature and sufficient time to obtain uniform composition of amorphous Encequidar mesylate and at least one pharmaceutically acceptable excipient.

In an embodiment, pharmaceutically acceptable excipient may include, but not limited to an inorganic oxide such as SiCh, TiC , ZnCE, ZnO, AI2O3 and zeolite; a water insoluble polymer is selected from the group consisting of cross-linked polyvinyl pyrrolidinone, cross-linked cellulose acetate phthalate, cross-linked hydroxypropyl methyl cellulose acetate succinate, microcrystalline cellulose, polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer, cross-linked carboxymethyl cellulose, sodium starch glycolate, and cross-linked styrene divinyl benzene or any other excipient at any aspect of present application.

Amorphous Encequidar mesylate isolated at step c) 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 Encequidar mesylate, selected from the group consisting of crystalline forms EM4, EM5, EM6, EMO and amorphous form, according to instant application and pharmaceutical compositions thereof, wherein the chemical purity of Encequidar mesylate may be more than 99% by HPLC or more than 99.5% by HPLC or more than 99.9% by HPLC.

In another aspect, the present application provides pharmaceutical compositions comprising an amorphous form of Encequidar mesylate together with at least one pharmaceutically acceptable excipient. 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 organic solvent” when used in the present application is a solvent that does not react with the reactants or reagent s under conditions that cause the chemical reaction indicated to take place.

EXAMPLES

Example-1: Preparation of crystalline form EM4 of Encequidar Mesylate

Encequidar mesylate (600 mg) was suspended in formamide (6 mL) at 70 °C for 22 hours and the solid was filtered. The wet solid was dried under reduced pressure at 80 °C for 4 hours. The dried solid was combined with n-hexane (3 mL) and sonicated for 15 minutes at 25 °C. The solid was filtered and dried under reduced pressure to obtain the title compound. XRPD: Crystalline form EM4 as depicted in Figure- 1.

Example-2: Preparation of crystalline form EM5 of Encequidar mesylate

Encequidar mesylate (100 mg) was dissolved in dimethylacetamide (3 mL) and the solution was heated to 70 °C. The mixture was stirred at the same temperature for 64 hours and the solid was separated to obtain the title compound. XRPD: Crystalline form EM5. Example-3: Preparation of crystalline form EM6 of Encequidar Mesylate

Encequidar mesylate (100 mg) was dried at 80 °C for 30 minutes in a vacuum oven and then placed in a desiccator under 85% relative humidity (produced by placing saturated potassium chloride solution inside a desiccator) for a day to obtain the title compound. XRPD: Crystalline form EM6.

Example-4: Preparation of crystalline form EM-O of Encequidar mesylate with oxalic acid

A mixture of Encequidar mesylate (300 mg), oxalic acid (34.4 mg) and methanol (0.5 mL) were ground in a ball mill (Retsch MM 400) at a shaking frequency of 25 per second for 1 hour to obtain the title compound as solid. XRPD: Crystalline form EM-O.

Alternate method: Encequidar mesylate (300 mg) and oxalic acid (34.4 mg) in nitromethane (2 mL) were stirred at 25 °C for 3 days and the solid was filtered to obtain the title compound. XRPD: Crystalline form EM-O.

Example-5: Preparation of amorphous form of Encequidar mesylate

Encequidar mesylate was dissolved in dichloromethane (200 mL) at 35°C and the solution was filtered on hyflo bed. The solvent from the clear solution was evaporated through spray drying at inlet temperature of 60 °C and outlet temperature of 46 °C to obtain the title compound. XRPD: Amorphous.

Example-6: Preparation of crystalline form EM5 of Encequidar mesylate

(a) A suspension of amorphous Encequidar mesylate in dimethylacetamide (100 mg / 3 m L) was stirred at 70 °C overnight and the solid was separated and dried at 70 °C to obtain the title compound. XRPD pattern: Crystalline form EM5.

(b) A suspension of amorphous Encequidar mesylate in dimethylacetamide (100 mg / m L) was stirred at 70 °C overnight and the solid was separated and dried at 70 °C to obtain the title compound. XRPD pattern: Crystalline form EM5.

Claims

1. A crystalline Form EM4 of Encequidar mesylate, characterized by a X-ray diffraction pattern comprising the peaks at 8.41, 19.09 and 24.07 ± 0.2° 20.

2. The crystalline Form EM4 of claim 1, characterized by additional peaks at 11.06 and 25.55 ° 20.

3. A crystalline Form EM5 of Encequidar mesylate, characterized by a X-ray diffraction pattern comprising the peaks at 4.04 and 17.50° ± 0.2° 20.

4. The crystalline Form EM5 of claim 3, characterized by additional peaks at 10.27 and 18.07 ° 20.

5. A crystalline Form EM6 of Encequidar mesylate, characterized by a X-ray diffraction pattern comprising the peaks at 3.3 and 9.0 ± 0.2° 20.

6. The crystalline Form EM6 of claim 5, characterized by additional peaks at 8.2 and 11.2 ° 20.

7. A crystalline complex of Encequidar mesylate salt with Oxalic acid.

8. A crystalline Form EM-0 of Encequidar mesylate with Oxalic acid, characterized by a X-ray diffraction pattern comprising the peaks at 12.62, 24.47 and 26.05 ° ± 0.2° 20.

9. A stable amorphous form of Encequidar mesylate.

10. A process for the preparation of crystalline Form EM4 of Encequidar mesylate, comprising the steps of: a. treating Encequidar mesylate with formamide or a mixture thereof. b. heating the solid form obtained from step (i) to obtain crystalline form EM4.

11. A process for the preparation of crystalline Form EM5 of Encequidar mesylate, comprising the step of combining Encequidar mesylate with dimethyl acetamide.

12. The process of claim 11, where in amorphous Encequidar mesylate is suspended in dimethylacetamide.

13. A process for the preparation of crystalline Form EM6 of Encequidar mesylate, comprising the step of exposing crystalline form EM5 to humid conditions.

14. A process for the preparation of crystalline Form EM-0 of Encequidar mesylate with Oxalic acid, comprising the step of combining Encequidar mesylate with Oxalic acid in the presence of an inert organic solvent.

15. A process for the preparation of amorphous form of Encequidar mesylate, comprising the steps of: a. providing a solution of Encequidar mesylate in a suitable solvent, b. removing the solvent of step a), and c. isolating amorphous form of Encequidar mesylate.