PROCESSES FOR PREPARING DRONEDARONE AND ITS INTERMEDIATES

FIELD OF THE INVENTION

The invention relates to dronedarone or its pharmaceutically acceptable acid addition salts. More particularly, it relates to crystalline and amorphous forms of dronedarone or its pharmaceutically acceptable acid addition salts and processes for their preparation. The invention also relates to processes for the preparation of benzofuran derivative and intermediates thereof. The invention also relates to pharmaceutical compositions that includes dronedarone or its pharmaceutically acceptable acid addition salts thereof.

BACKGROUND OF THE INVENTION

The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated.

Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.

Dronedarone is a Class III anti-arrhythmia drug for the prevention of cardiac arrhythmias such as atrial fibrillation (AF). AF is a condition characterized by an irregular heart beat and occurs when the atria (the upper chambers of the heart) contract very rapidly. This causes the lower chambers of the heart, the ventricles, to contract chaotically so that blood is inefficiently pumped to the body, which can lead to tissue damage and even death.

Dronedarone, SR 33589, N-[2-Butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-

5-benzo- furanyl]methanesulfamide having the Formula (1), is a drug for the treatment of arrhythmia a the US '510).

(D

The US '510 discloses the method for preparing dronedarone (1), starting from 2-butyl-5-nitrobenzofuran according to the following scheme 1:

l

Methane sulfonyl chloride

The above chemical pathway has following drawbacks:

(a) friedel craft reaction of anisoyl chloride with 2-butyl-5-nitrobenzofuran in presence of tin tetrachloride involves use of class-I solvent ethylene dichloride. Also, tin tetrachloride is costly reagent and can be easily be replaced with suitable lewis acid.

(b) friedel craft reaction of anisoyl chloride with 2-butyl-5-nitrobenzofuran in presence of tin tetrachloride involves stirring for 24 hours i.e. longer duration of reaction.

(c) demethylation of methyl protecting group with aluminum chloride is also reported in ethylene dichloride, which is class 1 solvent.

(d) the reduction of 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy)benzoyl]-5-nitro benzofuran is disclosed with usage of platinum oxide in ethanol. It is very costly reagent for reduction.

(e) 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy)benzoyl]-5-nitro benzofuran is reported as oxalate salt with melting point 84°C (ether/isopropanol). There is no method for its preparation provided.

(f) the dronedarone free base was obtained by addition of methane sulfonyl chloride in presence of triethylamine. This results in formation of dimer impurity upto 30%. Therefore, the reaction is not advantageous for industrial scale. (g) the dronedarone hydrochloride was prepared by treating dronedarone freebase in anhydrous ethyl acetate using hydrogen chloride in ether. The process is not advantages as its requires dronedarone freebase of high purity to be converted to hydrochloride salt.

(h) further, the melting point of dronedarone hydrochloride is reported at 143°C (acetone). There is no method for its recrystallization provided.

The starting material 2-butyl-5-nitrobenzofuran can be prepared by the processes reported in the US '510 or in J. Methods in Enzymology, 1967, v. 1 1, 556 by H. R. Horton and D. E. oshland or as disclosed in International PCT Publications WO 2001/28974 A2 and WO 2001/29019 Al .

The US '510 discloses catalytic reduction of 2-butyl-5-nitrobenzofuran (3.4 atm H ₂ /Pt0 ₂ /EtOH) to obtain 2-butyl-5-benzofuranmine free base, which subsequent reaction with methanesulfonlylchloride in the presence of triethylamine as acid scavenger and carbon tetrachloride as a solvent to give N-(2-butyl-5-benzofuranyl)-N- (methylsulfonyl)- methanesulfonamide instead of N-(2-butyl-5- benzofuranyl)methartesulfonarnide.

Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x- ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid-state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. The polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. For a general review of polymorphs and the pharmaceutical applications of polymorphs, See G. M. Wall, Pharm Manuf. 3, 33 (1986); K. Haleblian and W. McCrone, J. Pharm. Sci., 58, 911 (1969); and J. K. Haleblian, J. Pharm. Sci., 64, 1269 (1975), all of which are incorporated herein by reference. EP 2354132 A2 patent application discloses three crystalline forms of dronedarone free base, viz. Form -A, Form-B and Form-C. International PCT publications WO 2010/040261 Al and WO 201 1/070380 Al discloses processes for the preparation of dronedarone hydrochloride and intrmediate thereof.

Several processes for the preparation of dronedarone hydrochloride and intermediates thereof is reported in of ivabradine hydrochloride and their processes for preparation have been disclosed, for example in U.S. Patent Nos 7,312,345 B2, 6,828,448 B2, 6,846,936 B2, 6,984,741 B2, 6,855,842 B l and U.S. Patent application No. 201 1/0009649 Al .

The European Medicies Agency assessment report for Multaq® (dronedarone hydrochloride) discloses it as a white to practically white, non-hygroscopic fine powder. It is practically insoluble in water, sligthly soluble in acetonitrile, soluble in ethanol and freely soluble in methanol, in methylene chloride as well as in dimethylsulfoxide. Only one crystalline form is known and its shows no isomerism. This active substance has no chiral center.

In view of the above, it is therefore, desirable to provide an efficeint more economical, less hazardous and eco-friendly process for the preparation of dronedarone or its pharmaceutically acceptable salts thereof in crystalline form or amorphous form. The crystalline forms disclosed herein is atleast stable under oridinary stability conditions with respect to purity, storage and is free flowing powder and substantailly free from amorphous form. The process is simple, cost-effective, eco-friendly and commercially viable.

SUMMARY OF THE INVENTION

The inventors have discovered novel pharmaceutically acceptable acid addition salts of dronedarone, particularly in crystalline and amorphous polymorphic forms thereof. The inventors have also discovered the crystalline form of dronedarone base and have developed an improved process for the preparation of dronedarone or its pharmaceutically acceptable acid addition salts.

In one general aspect, there are provided pharmaceutically acceptable acid additions salts of dronedarone. The pharmaceutically acceptable acid additions salts include hydrobromide, hydrogensulfate, phosphate, oxalate, tartrate, succinate, maleate, fumarate, besylate, mesylate, tosylate, and the like in crystalline or amorphous form thereof. In another general aspect there are provided crystalline Form-A and amorphous form of dronedarone hydrochloride.

In another general aspect there is provided a process for the preparation of pharmaceutically acceptable acid addition salts of dronedarone. The process includes providing a solution of dronedarone in one or more suitable solvents; adding a suitable acid; and isolating the pharmaceutically acceptable acid addition salts of dronedarone by removal of solvents.

In another general aspect, there is provided an improved process for the preparation of dronedarone of Formula (I) or its hydrochloride salt.

(I)

The process includes:

(a) reacting 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of Formula (V) with 1- chloro-3-di-n-butylamino propane in one or more suitable solvents in the presence of a suitable base to obtain 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy)-benzoyl]-5- nitro benzofuran of Formula (IV);

(IV)

(b) optionally, isolating 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy)-benzoyl]-5-nitro benzo- furan acid addition salt of Formula (IV A) by reacting with one or more suitable acids and liberating the compound of Formula (IV) by treating with a suitable base;

. Acid Addition Salt

(IVA) (c) hydrogenating the compound of Formula (IV) in presence of Raney Nickel or Palladium catalyst to obtain 5-amino 3-[4-(3-di-n-butyiamino-propoxy)benzoyl]-2- n-butyl benzofuran of Formula (III);

(III)

(d) optionally, preparing 5-amino 3-[4-(3-di-n-butylamino-propoxy)benzoyl]-2-n-butyl benzofuran acid addition salt of Formula (IIIA) by reacting with one or more of suitable acids and obtaining compound of Formula (III) by treating with suitable base;

. Acid Addition Salt

(IIIA)

(e) reacting compound of Formula (III) with methanesulfonyl chloride or methanesulfonic anhydride in absence of base in one or more of suitable solvents to obtain dronedarone; and

(f) optionally, converting dronedarone to its hydrochloride salt thereof by treating with a hydrochloric acid source.

In another general aspect, there is provided an improved process for the preparation of 2^n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of Formula (V), an intermediate of dronedarone

(V)

the process comprises:

(a) reacting 2-n-butyl-5-nitrobenzofuran with anisoyi chloride in the presence of a , Lewis acid in one or more of halogenated or non-halogenated hydrocarbon solvent to obtain 2-n-Butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran of Formula (VI); with proviso that Lewis acid is not tin tetrachloride and halogenated hydrocarbon is not dichloroethane,

(VI)

(b) demethylating 2-n-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran of Formula (VI) in presence of lewis acid catalyst in one or more of suitable solvents;

(c) extracting 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of Formula (V) in one or more mixture of suitable solvents followed by removal of suitable solvent;

(d) treating residue with one or more of suitable solvents; and

(e) isolating 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of Formula (V).

In another general aspect, there is provided an improved process for the preparation of 5-amino 3-[4-(3-di-n-butylamino-propoxy)benzoyl]-2-n-butyl benzofuran acid addition salt of Formula (IIIA),

. Acid Addition Salt

(IIIA)

the process comprises: ,

(a) reacting 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of Formula (V) with 1 - chloro-3-di-n-butylamino propane in one or more of suitable solvents in presence of suitable base to obtain 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy)-benzoyl]-5- nitro benzofuran of F

(IV)

(b) optionally, isolating 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy)-benzoyl]-5-nitro benzo- furan acid addition salt of Formula (IV A) by reacting with one or more of suitable acids and liberating compound of Formula (IV) by treating with suitable base;

. Acid Addition Salt

(IVA)

(c) hydrogenating the compound of Formula (IV) with Raney Nickel or 10% Palladium on carbon to obtain 5-amino 3-[4-(3-di-n-butylamino-propoxy)benzoyl]-2-n-butyl benzofuran of Formula (III); and

(HI)

(d) isolating 5-amino 3-[4-(3-di-n-butylamino-propoxy)benzoyl]-2-n-butyl benzofuran acid addition salt of Formula (IIIA) by reacting with one or more of suitable acids. In further general aspect, there is provided a process for the preparation of dronedarone of Formula (I) or its hydrochloride salt thereof;

(I)

the process comprises:

(a) reacting 5-amino 3-[4-(3-di-n-butylamino-propoxy)benzoyl]-2-n-butyl benzofuran of Formula (III)

(III)

with methane sulfonyl chloride or methane sulfonic anhydride in absence of one or more of suitable solvents to obtain dronedarone of Formula (I); (b) optionally converting dronedarone into one or more of its pharmaceutically acceptable acid addition salts thereof and obtaining dronedarone by treating with suitable base; and

(c) converting dronedarone to its hydrochloride salt thereof by treating with a hydrochloric acid source.

In another general aspect, there is provided a process for preparing dronedarone hydrochloride comprising:

(a) combining dronedarone and one or more of suitable solvent selected from the group consisting of water, a hydrocarbon, ester, C ₂ ^ ether, Ci _-8 alcohol, acetonitrile, ketone and the like;

(b) adding hydrochloric acid in an amount sufficient to dronedarone hydrochloride; and

(c) isolating dronedarone hydrochloride.

In further general aspect there is provided a process for the preparation of amorphous form pharmaceutically acceptable acid addition salts of dronedarone, the process comprising: providing a solution pharmaceutically acceptable acid addition salts of dronedarone in one or more suitable solvents; and isolating the amorphous form pharmaceutically acceptable acid addition salts of dronedarone.

According to one of the general aspect, there is provided dronedarone hydrochloride substantially free from disulfonamide impurity. Embodiments further include isolated disulfonamide impurity of the following Formula.

According to another general aspect, there are provided Crystalline 5-amino-3- [4-(3-di-n-butylamino-propoxy)benzoyl]-2-n-butyl benzofuran dioxalate Form-I characterized by X-ray powder diffraction as depicted in FIG.15 and differential scanning caiorimetry as depicted in FIG.16 as well as Crystalline 2-n-butyl-3-[4-(3-di- n-butylamino-propoxy)-benzoyl]-5-nitro benzofuran oxalate Form-I characterized by X-ray powder diffraction as depicted in FIG. 17 and differential scanning caiorimetry as depicted in FIG.18. In another general aspect, there is provided a process for preparing dronedarone hydrochloride or a pharmaceutical composition thereof having less than about 1% by HPLC of N-(2-butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)benzofuran- 5-yl)-N- (methylsulfonyl)- methane sulfonamide (disulfonamide impurity) comprising: measuring level of the dimer impurity in a batch of dronedarone free base, selected a batch having less than about 1% of dimer impurity; converting dronedarone of the said batch to dronedarone hydrochloride by treating with an hydrochloric acid source.

In another general aspect, there is provided a process for preparing .dronedarone hydrochloride or a pharmaceutical composition thereof having less than about 1% by HPLC of N-(2-butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)benzofuran- 5-yl)-N- (methylsulfonyl)- methane sulfonamide (disulfonamide impurity) comprising: measuring level of the dimer impurity in a batch of dronedarone free base, selected a batch having less than about 1 % of dimer impurity; converting dronedarone of the said batch to dronedarone hydrochloride by treating with an hydrochloric acid source

In another general aspect, there is provided crystalline dronedarone hydrochloride Form-A substantially free from disulfonamide impurity.

In another general aspect, there is provided a stable crystalline form of dronedarone hydrochloride thereof, which is stable during storage and drying.

In another general aspect, there is provided crystalline Form-A of dronedarone hydrochloride having particle size distributions wherein the 10th volume percentile particle size (D10) is less than about 20 μιη, the 50th volume percentile particle size (D50) is less than about 50 μηι, or the 90th volume percentile particle size (D90) is less than about 100 μηι, or any combination thereof.

In another general aspect, there is provided a pharmaceutical composition comprising crystalline Form-A of dronedarone hydrochloride substantially free from disulfonamide impurity.

In another general aspect, there is provided a pharmaceutical composition comprising crystalline Form-A of dronedarone hydrochloride and one or more pharmaceutically acceptable carriers, excipients or diluents.

The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description. BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS

FfG. l shows the X-ray diffractogram of crystalline Form-A dronedarone hydrochloride.

FIG.2 shows the DSC thermogram of crystalline Form-A dronedarone hydrochloride. FIG.3 shows the IR spectra of crystalline Form-A dronedarone hydrochloride.

FIG.4 shows the X-ray diffractogram (XRD) of crystalline dronedarone hydrobromide. FIG.5 shows the DSC thermogram of crystalline dronedarone hydrobromide.

FIG.6 shows the IR spectra of crystalline dronedarone hydrobromide.

FIG.7 shows the X-ray diffractogram (XRD) of amorphous dronedarone hydrobromide. FIG.8 shows the X-ray diffractogram (XRD) of crystalline dronedarone Hydrogensulfate.

FIG.9 shows the DSC thermogram of crystalline dronedarone hydrogensulfate.

FIG.10 shows the IR spectra of crystalline dronedarone hydrogensulfate.

FIG.1 1 shows the X-ray diffractogram (XRD) of amorphous dronedarone hydrogensulfate.

FIG.12 shows the X-ray diffractogram (XRD) of crystalline dronedarone free base.

FIG.13 shows the DSC thermogram of crystalline dronedarone free base.

FIG.14 shows the IR spectra of crystalline dronedarone free base.

FIG.15 shows the X-ray diffractogram of 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy)- benzoyl]-5-nitro benzofuran oxalate Form-I.

FIG.16 Shows the differential scanning calorimetry of 2-n-butyl-3-[4-(3-di-n- butylamino-propoxy)-benzoyl]-5-nitro benzofuran oxalate Form-I.

FIG.17 Shows the X-ray diffractogram of 5-amino-3-[4-(3-di-n-butylamino-propoXy) benzoyl]-2-n-butyI benzofuran dioxalate Form-I.

FIG.18 Shows the differential scanning calorimetry of 5-amino-3-[4-(3-di-n- butylamino-propoxy)benzoyl]-2-n-butyl benzofuran dioxalate Form-I.

FIG.19 Shows the X-ray diffractogram of amorphous dronedarone hydrochloride of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

As used herein the term "substantially free" means dronedarone or its pharmaceutically acceptable acid addition salts thereof having less than 1% of disulfonamide impurity, particularly less than about 0.5% of disulfonamide impurity and most particularly less than about 0.15% of disulfonamide impurity. The term "disulfonamide impurity" as used herein refers to the compound N-(2- butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)benzofuran-5-yl) -N- (methylsulfonyl)methane sulfonamide having the following structure.

All ranges recited herein include the endpoints, including those that recite a range "between" two values. Terms such as "about", "general", "substantially," and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.

"Suitable solvent" means a single or a combination of two or more solvents.

The term "isolation" used herein means to the process for removing the solvent comprises one or more of techniques like filtration, filtration under vacuum, decantation, centrifugation, distillation and distillation under vacuum and the like.

The term "acid addition salts" used herein means hydrobromide, hydrochloride, hydrogensulfate, phosphate, oxalate, tartrate, succinate, maleate, fumarate, besylate, mesylate, tosylate and the like.

In one aspect, the invention provides pharmaceutically acceptable acid additions salts of dronedarone selected from one or more hydrobromide, hydrogensulfate, phosphate, oxalate, tartrate, succinate, maleate, fumarate, besylate, mesylate, tosylate and the like in crystalline or amorphous form thereof.

In another general aspect, the invention provides crystalline Form-A of dronedarone hydrochloride. The crystalline Form-A is characterized by its X-ray powder diffraction pattern, infrared spectrum and differential scanning calorimetry thermogram as shown in Figures 1 , 2, and 3, respectively.

The inventors also have developed a process for the preparation of pharmaceutically acceptable acid addition salts of dronedarone, the process comprises: providing solution of dronedarone in one or more suitable solvents; addition of suitable acid; and isolating pharmaceutically acceptable acid addition salts of dronedarone by removal of solvents.

In general, the solution of dronedarone may be obtained by dissolving any known forms of dronedarone free base or dronedarone free base in oil form in a suitable solvent. The solution may be obtained by heating the dronedarone in a solvent. The suitable acid is added to the resultant solution which may be clarified to remove foreign particulate matter or treated with charcoal to remove coloring and other related impurities. The solution so obtained may be concentrated to reduce the amount of solvent. The solution may be concentrated by removing the solvent completely to get a residue.

Alternatively, such a solution may be obtained directly from a reaction in which dronedarone or its pharmaceutically acceptable acid addition salts is formed. The solvent may be removed by a technique which includes, for example, filtration, filtration under vacuum, decantation, ce trifugation, distillation and distillation under vacuum. '

In another aspect, the invention provides an improved process for the preparation of dronedarone of Formula (I) or its hydrochloride salt thereof,

(I)

the process comprises:

(a) reacting 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of Formula (V) with 1- chloro-3-di-n-butylamino propane in one or more of suitable solvent in presence of suitable base to obtain 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy)-benzoyl]-5- nitro benzofuran of F (b) optionally, isolating 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy)-benzoyl]-5-nitro benzo- furan acid addition salt of Formula (IV A) by reacting with one or more of suitable acids and liberating compound of Formula (IV) by treating with suitable base;

. Acid Addition Salt

(IVA)

(c) hydrogenating the compound of Formula (IV) in presence of Raney Nickel or Palladium catalyst to obtain 5-amino 3-[4-(3-di-n-butylamino-propoxy)benzoyl]-2- n-butyl benzofuran of Formula (III);

(HI)

(d) optionally, preparing 5-amino 3-[4-(3-di-n-butylamino-propoxy)benzoyl]-2-n-butyl benzofuran acid addition salt of Formula (ΙΠΑ) by reacting with one or more of suitable acids and obtaining compound of Formula (III) by treating with suitable base;

. Acid Addition Salt

(HIA)

(e) reacting compound of Formula (III) with methanesulfonyl chloride or methanesulfonic anhydride in absence of base in one or more of suitable solvents to obtain dronedarone; and

(f) optionally, converting dronedarone to its hydrochloride salt thereof by treating with a hydrochloric acid source.

In general, the suitable solvents in step (a) comprises of acetone, methyl ethyl ketone, methyl isobutyl ketone, methanol, ethanol, propanol, isobutanol, ethyl acetate, n-butyl acetate, tert-butyl acetate, propyl acetate, toluene, xylene, cyclohexane, n- heptane, acetonitrile and the like. In particular, methyl ethyl ketone. Embodiments of the process includes the condensation of 2-n-butyl-3-(4- hydroxybenzoyI)-5-nitrobenzofuran of Formula (V) with l -chloro-3-di-n-butylamino propane is performed in methyl ethyl ketone at an elevated temperature, preferably at 75°C to 85°C in presence of suitable base.

The suitable base comprises of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium bicarbonate, sodium hydride, sodium methoxide, sodium ethoxide, potassium tert-butoxide triethylamine, diisopropylamine, n-butylamine, diisopropylethylamine, pyridine, piperidine, ammonia and the like. In particular, potassium carbonate.

In general, after the completion of the reaction the reaction mass may be diluted with water and the separated organic layer may be washed with sodium hydroxide solution to remove unreacted 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of Formula (V) in the form of sodium salt during filtration.

Further embodiments of the process optionally includes treating compound (IV) with suitable acids comprises of hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, benzenesulphonic acid and camphoric acid, or into a hydrate thereof. In particular, oxalic acid. The salt may be further treating with suitable base to obtain compound (IV).

In general, the acid addition salt of 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy)- benzoyl]-5-nitro benzofuran of Formula (IV A) may be prepared by treating with suitable acid for example oxalic acid in one or more of suitable solvent comprises of methanol, ethanol, isopropanol, Ν,Ν-dimethylformamide, N,N-dimethyl acetamide, acetone, acetonitrile, THF and water or mixtures thereof. In particular, methanol may be used to obtain 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy)-benzoyl]-5-nitro benzofuran oxalate salt. The reaction is carried out at an elevated temperature, particularly at about 60°C to 65°C followed by cooling to ambient temperature.

In general, the 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy)-benzoyl]-5-nitro benzofuran oxalate salt isolated is crystalline characterized by its X-ray powder diffraction pattern, and differential scanning calorimetry thermogram as shown in Figures 15 and 16 respectively. The crystalline 2-n-butyl-3-[4-(3-di-n-butylamino- propoxy)-benzoyl]-5-nitro benzofuran oxalate designated as "Form-I" is further characterized by X-ray powder diffraction having peaks at about 5.6, 6.9, 7.3, 13.1, 18.0, 20.5, 23.3, 24.4 and 25.7±0.2° 2Θ or differential scanning calorimetry having endothermic peak 87.85°C and 109.91°C.

The acid addition salts of Formula (IVA) of 2-n-butyl-3-[4-(3-di-n-butylamino- propoxy)-benzoyl]-5-nitro benzofuran is further treated with suitable base as disclosed herein above to obtain compound of Formula (IV). The reaction may be carried out in one or more of suitable solvent system comprises of toluene-water, toluene-methanol, ethyl acetate-water, butylacetate-methanol and the like. In particular, toluene-water followed by removal of organic solvent to obtain compound of Formula (IV).

Embodiments of the process further provides, hydrogenation of compound 2-n- butyl-3-[4-(3-di-n-butylamino-propoxy)-benzoyl]-5-nitro benzofuran of Formula (IV) in presence of catalyst like Raney Nickel or Palladium. In general, the said catalysts may be replaced by Platinum oxide, Fe-HCl, Sn-HCl, Na ₂ Sx and the like. The hydrogenation may be conducted in one or more of suitable solvents comprises methanol, ethanol, ethyl acetate, methanol with liquor ammonia, methanol with ammonia gas, ethyl acetate in methanol and the like at about 30 bar pressure in a hydrogenator to obtain 5-amino-3-[4-(3-di-n-butylamino-propoxy)- benzoyl]-2-n-butyl benzofuran of Formula (III).

Further embodiments of the process optionally includes treating compound (III) with suitable acids comprises of hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid, trifiuoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, benzenesulphonic acid and camphoric acid, or into a hydrate thereof. In particular, oxalic acid. The salt may be further treating with suitable base to obtain compound (IIIA).

In general, the acid addition salt of 5-amino-3-[4-(3-di-n-butylamino-propoxy)- benzoyl] -2-n-buty 1 benzofuran of Formula (IIIA) may be prepared by treating with suitable acid for example oxalic acid in one or more of suitable solvent comprises of methanol, ethanol, isopropanol, N,N-dimethylformamide, Ν,Ν-dimethyl acetamide, acetone, acetonitrile, THF and water or mixtures thereof. In particular, methanol may be used to obtain 5-amino-3-[4-(3-di-n-butylamino-propoxy)benzoyl]-2-n-butyl benzofuran dioxalate salt. The reaction is carried out at an elevated temperature, particularly at about 60°C to 65°C followed by cooling to ambient temperature. In general, the 5-amino-3-[4-(3-di-n-butylamino-propoxy)benzoyl]-2-n-butyl benzofuran dioxalate salt isolated is crystalline characterized by its X-ray powder diffraction pattern, and differential scanning calorimetry thermogram as shown in Figures 17 and 18 respectively. The crystalline 5-amino-3-[4-(3-di-n-butylamino- propoxy)benzoyl]-2-n-butyl benzofuran dioxalate Form-I characterized by X-ray powder diffraction having peaks at about 7.5, 10.0, 10.7, 15.3, 17.6, 20.1, 22.5, 24.6, 27.9 and 30.1±0.2° 2Θ or differential scanning calorimetry having endothermic peak at about 173.76°C.

The acid addition salts of Formula (IIIA) of 5-amino-3-[4-(3-di-n-butylamino- propoxy)- benzoyl] -2 -n-butyl benzofuran is further treated with suitable base as disclosed herein above to obtain .compound of Formula (III). The reaction may be carried out in one or more of suitable solvent system comprises of toluene-water, toluene-methanol, ethyl acetate-water, butylacetate-methanol and the like. In particular, toluene-water followed by removal of organic solvent to obtain compound of Formula (III).

In general, the compound 5-amino-3-[4-(3-di-n-butylamino-propoxy)benzoyl]- 2-n-butyl benzofuran of Formula (III) may be treated with methane sulfonyl chloride in absence of base.

The inventors of the present invention have found that sulfonation of 5-amino- 3-[4-(3-di-n-butylamino-propoxy)benzoyl]-2-n-butyl benzofuran of Formula (III) performed as per the process disclosed in U.S. Patent No. 5,223,510 in presence of triethylamine (base) provides about 25-30% of N-(2-butyl-3-(4-(3- (dibutylamino)propoxy)benzoyl)benzofuran-5-yl)-N-(methylsulf onyl)methane

The reaction proceeds very sluggishly and provides disulfonamide impurity alongwith dronedarone freebase. The said reaction is performed in presence of bases like triethylamine, pyridine, diisopropylamine, diisopropylethylamine, DBU or inorganic bases like potassium carbonate, potassium hydroxide, sodium hydroxide. In particular, triethylamine is exemplified.

In general aspect, the present invention provides the process wherein reaction of

5-amino-3-[4-(3-di-n-butylamino-propoxy)benzoyl]-2-h-buty l benzofuran Formula (III) is treated with methane sulfonyl chloride or methane sulfonic anhydride in absence of base. The reaction may be carried out at an elevated temperature at about 75°C to

120°C, particularly at about 100°C to 1 10°C for atieast about 2 hours to selectively provide dronedarone substantially free from disulfonamide impurity.

In another general aspect, the compound 5-amino-3-[4-(3-di-n-butylamino- propoxy)benzoyl]-2-n-butyl benzofuran Formula (III) may be treated with methane sulfonyl chloride or methane sulfonic anhydride in absence of base at a temperature of about 50°C to 55°C for atieast about 15-20 hours to obtain dronedarone substantially free from disulfonamide impurity.

Embodiments of the process further provides converting dronedarone into its hydrochloride salt by treating with hydrochloride source which comprises of dry HC1

(g), isopropanolic HC1, Aqueous HC1, Cone. HC1, Ethyl Acetate-HCl and the like in one or more of suitable solvent.

In general, the suitable solvent comprises water, an aromatic hydrocarbon, C ester, C ₂ _4 ether, Ci _-8 alcohol, acetonitrile and a ketone. Particularly, the suitable solvent comprises methanol, ethanol, isopropanol, butanol, toluene, xylene, ethylbenzene, chlorobenzene, ethyl acetate, isopropyl acetate, n-butyl acetate, tert-butyl acetate, diethyl ether, diisopropyl ether, methyl tert-butyl ether, acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone and water or mixtures thereof. In particular, acetone or ethyl acetate or isopropanol may be used.

In general, the dronedarone hydrochloride salt may be isolated by addition of isopropanolic hydrochloride in an amount sufficient to provide a pH of about 1 to about

5 to obtain dronedarone hydrochloride.

In another general aspect, the invention provides an improved process for the preparation of 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of Formula (V), an intermediate of dronedarone (V)

the process comprises:

(a) reacting 2-n-butyl-5-nitrobenzofuran with anisoyi chloride in the presence of a lewis acid in one or more of halogenated or non-halogenated hydrocarbon solvent to obtain 2-n-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran of Formula (VI); with proviso that lewis acid is not tin tetrachloride and halogenated hydrocarbon is not dichloroethane,

(VI)

(b) demethylating 2-n-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran of Formula (VI) in presence of lewis acid catalyst in one or more of suitable solvents;

(c) extracting 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of Formula (V) in one or more mixture of suitable solvent followed by removal of suitable solvent;

(d) treating residue with one or more of suitable solvents; and

(e) isolating 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of Formula (V).

In general, the halogenated or non-halogenated solvent comprises wherein the halogenated or non-halogenated hydrocarbons comprises methylene dichloride, chlorobenzene, toluene, xylene, cyclohexane, heptane and the like, excluding dichloroethane.

The lewis acid comprises one or more of aluminum chloride, zinc chloride, boron trifluoride, stannic chloride, titanium tetrachloride, ferric chloride and mixtures thereof, excluding tin tetrachloride.

Embodiments of the process further includes, demethylating 2-n-butyl-3-(4- methoxybenzoyl) -5-nitrobenzofuran of Formula (VI) in one or, more of suitable solvent. The suitable solvent comprises of CMO alcohols, C _3-8 ketones, CM esters, halogenated and non-halogenated hydrocarbons, amides, nitriles and the like. In particular, the suitable solvent comprises of methanol, ethanol, isopropanol, butanol, pentanol, dodecanol, acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, tert-butyl acetate, n-butyl acetate, methylene dichloride, chlorobenzene, toluene, xylene, N,N-dimethylformamide, Ν,Ν-dimethyl- acetamide, acetonitrile, N- methylpyrrolidone, Ν,Ν-dimethylsulfoxide, sulfolane and the like. In general, the reaction may be done at an elevated temperature, particularly at about 65°C to 75°C. After the demethylation is completed, the reaction mixture may be treated with one or more of suitable solvent comprise of water, alcohols, amide, nitriles, ketones like methanol, ethanol, isopropanol, n-butanol, N,N- dimethylformamide, Ν,Ν-dimethylacetamide, acetonitrile, acetone, methylisobutyl ketone, methyl ethyl ketone or mixture thereof with water, In particular, water.

Further general aspect of the process provides extraction of 2-n-butyl-3-(4- hydroxybenzoyl)-5-nitrobenzofuran of Formula (V) in one or more mixture of suitable solvent. The suitable solvent comprises of methylene dichloride, chlorobenzene, toluene, xylene, cyclohexane, n-heptane, n-hexane, ethyl acetate, butyl acetate, diethyl ether, diisopropyl ether, methyl tert-butyl ether and the like. In particular, ethyl acetate.

Embodiments of the process provides, the reaction mixture obtained after demethylation may be partitioned between water and ethylacetate at an elevated temperature, particularly at 55°C to 65°C followed by removal of ethyl acetate. The residue may be treated with one or more of suitable solvent comprises of methylene dichloride, chlorobenzene, toluene, xylene, cyclohexane, n-heptane, n-hexane, ethyl acetate, butyl acetate, diethyl ether, diisopropyl ether, methyl tert-butyl ether and the like. In particular, toluene.

In general, the residue obtained is treated with toluene at an elevated temperature, particularly at about 65°C to 75°C for atleast about 60 minutes, particularly for about 30 minutes and may be cooled to ambient temperature. In particular at about 5°C to isolate 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of Formula (V).

In another general aspect, the invention provides an improved process for the preparation of 5-amino 3-[4-(3-di-n-butylamino-propoxy)benzoyl]-2-n-butyl benzofuran acid addition salt of Formula (IIIA),

. Acid Addition Salt

(IIIA)

the process comprises:

(a) reacting 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of Formula (V) with 1- chloro-3-di-n-butylamino propane in one or more of suitable solvents in presence of suitable base to obtain 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy)-benzoyl]-5- nitro benzofuran of Fo

(IV)

(b) optionally, isolating 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy)-benzoyl]-5-nitro benzo- furan acid addition salt of Formula (IVA) by reacting with one or more of suitable acids and liberating compound of Formula (IV) by treating with suitable base;

. Acid Addition Salt

(IVA)

(c) hydrogenating the compound of Formula (IV) with Raney Nickel or 10% Palladium on carbon to obtain 5-amino 3-[4-(3-di-n-butylamino-propoxy)benzoyl]-2-n-butyl benzofuran of Formula (III); and

(III)

(d) isolating 5-amino 3-[4-(3-di-n-butylamino-propoxy)benzoyl]-2-n-butyl benzofuran acid addition salt of Formula (IIIA) by reacting with one or more of suitable acids.

In general, the suitable acid addition salts comprises of hydrobromide, hydrochloride, hydrogensulfate, phosphate, oxalate, tartrate, succinate, maleate, fumarate, bes late, mesylate, tosylate and the like.

In further general aspect, the invention provides a process for the preparation of dronedarone of Formula (I) or its hydrochloride salt thereof;

(I)

the process comprises:

(a) reacting 5-amino 3-[4-(3-di-n-butylamino-propoxy)benzoyl]-2-n-butyl benzofuran of Formula (III)

with methane sulfonyl chloride or methane sulfonic anhydride in absence of base in one or more of suitable solvents to obtain dronedarone of Formula (I);

(b) optionally converting dronedarone into one or more of its pharmaceutically acceptable acid addition salts thereof and obtaining dronedarone by treating with suitable base; and

(c) converting dronedarone to its hydrochloride salt thereof by treating with a hydrochloric acid source.

In general, the suitable solvent comprises of methanol, ethanol, isopropanol, butanol, toluene, xylene, ethylbenzene, chlorobenzene, ethyl acetate, isopropyl acetate, n-butyl acetate, tert-butyl acetate, diethyl ether, diisopropyl ether, methyl tert-butyl ether, acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone and water or mixtures thereof. In particular, acetone or ethyl acetate or isopropanol.

In general, the pharmaceutically acceptable acid addition salts comprises salt with hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, . ascorbic acid, oxalic acid, methanesulphonic acid, benzenesulphonic acid, camphoric acid and the like.

Embodiments of the process further provides treating pharmaceutically acceptable acid additions salt of dronedarone with suitable base. The suitable base comprises of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium bicarbonate, sodium hydride, sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like. In particular, potassium carbonate or sodium hydroxide.

Embodiments of the process further provides converting dronedarone into its hydrochloride salt by treating with hydrochloride source which comprises of dry HC1 (g), isopropanolic HCl, Aqueous HCl, Cone. HCl, Ethyl Acetate-HCl and the like in one or more of suitable solvent.

In another general aspect, there is provided a process for preparing dronedarone hydrochloride comprising:

(a) combining dronedarone and one or more of suitable solvent selected from the group consisting of water, a hydrocarbon, C ester, C2-4 ether, Ci _-8 alcohol, acetonitrile, ketone and the like;

(b) adding hydrochloric acid in an amount sufficient to form dronedarone hydrochloride; and

(c) isolating dronedarone hydrochloride.

In general, the suitable solvent comprises water, toluene, xylene, ethylbenzene, chlorobenzene, ethyl acetate, isopropyl acetate, n-butyl acetate, tert-butyl acetate, diethyl ether, diisopropyl ether, methyl tert-butyl ether, methanol, ethanol, isopropanol, butanol, dodecanol, acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone and water or mixtures thereof.

In another general aspect, the invention provides dronedarone of Formula (I) or its pharmaceutically acceptable acid addition salts substantially free from disulfonamide impurity. In particular, dronedarone hydrochloride substantially free from disulfonamide impurity. More particularly, crystalline Form-A of dronedarone hydrochloride substantially free from disulfonamide impurity.

In general, the crystalline Form-A of dronedarone hydrochloride may be characterized by

(a) X-ray powder diffraction having peaks at about 7.6, 8.0, 1 1.8, 13.7, 15.6, 19.9, 21.5, 23.4, 23.8, 26.0 and 26.8±0.2° 2Θ or X-ray powder diffraction substantially as depicted in FIG.1; or

(b) Fourier Transform Infrared spectra having peaks at about 3060, 2872, 2488, 1637, 1602, 1570, 1462, 1373, 1255, 1 155, 977, 810, 777, 667 and 505 cm ^"1 or Fourier Transfer Infrared spectra substantially as depicted in FIG.2; or

(c) Differential scanning calorimetry having endothermic peak at about 145.54°C or differential scanning calorimetry substantially as depicted in FIG.3.

In one general aspect, the invention provides an isolated N-(2-butyl-3-(4-(3- (dibutylamino)propoxy)benzoyl)benzofuran-5-yl)-N-(methylsulf onyl)methane sulfonamide "disulfonamide impurity" of following structure.

In another general aspect, the invention provides a process for preparing dronedarone hydrochloride or a pharmaceutical composition thereof having less than about 1% of N-(2-butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)benzofuran- 5-yl)-N- (methylsulfonyl)- methane sulfonamide (disulfonamide impurity) determined by HPLC; comprising: measuring level of the disulfonamide impurity in a batch of dronedarone free base, selected a batch having less than about 1% of disulfonamide impurity; converting dronedarone of the said batch to dronedarone hydrochloride by treating with an hydrochloric acid source.

Another aspect of the invention provides crystalline Form-A of dronedarone hydrochloride having particle size distributions wherein the 10th volume percentile particle size (D10) is less than about 20 μηι, the 50th volume percentile particle size (D50) is less than about 50 μπι, or the 90th volume percentile particle size (D90) is less than about 100 μηι, or any combination thereof.

In another general aspect, there is provided a pharmaceutical composition comprising crystalline Form-A of dronedarone hydrochloride substantially free from disulfonamide impurity.

In another general aspect, there is provided a pharmaceutical composition comprising crystalline Form-A of dronedarone hydrochloride and one or more pharmaceutically acceptable carriers, excipients or diluents.

In another general aspect, the invention provides a pharmaceutically acceptable acid addition salts of dronedarone selected from one or more of hydrobromide, hydrogensulfate, phosphate, oxalate, tartrate, succinate, maleate, fumarate, besylate, mesylate, tosylate and the like. Embodiments also include formation of crystalline and amorphous forms of pharmaceutically acceptable acid addition salts of dronedarone. In one general aspect, there is provided pharmaceutically acceptable acid addition salts of dronedarone characterized by:

(i) Crystalline dronedarone hydrobromide characterized by atleast one of the following: (a) X-ray powder diffraction having characteristic peaks at about 7.6°, 8.0°, 13.0, 13.5, 15.4, 16.1, 20.1, 20.6, 22.2, 22.9, 23.7 and 25.8±0.2° (2Θ) or X-ray powder diffraction substantially as depicted in FIG.4; or

(b) IR spectra having characteristic peaks at 3984, 2872, 2686, 2600, 1638, 1602, 1572, 1257, 1 157, 1048, 975, 777, 656, and 509 cm ^"1 or Fourier Transfer Infrared spectra substantially as depicted in FIG.5; or

(c) DSC having endothermic peak at about 134.97°C or differential scanning calorimetry substantially as depicted in FIG.6.

(ii) Crystalline dronedarone hydrogensuifate characterized by atleast one of the following:

(a) X-ray powder diffraction having characteristic peaks at about 4.7°, 10. , 18.0°, 20.0°, 22.0°, 23.6° and 25.5°±0.2° (2Θ) or X-ray powder diffraction substantially as depicted in FIG.8; or

(b) IR spectra having characteristic peaks at 2960, 2933, 2872, 1735, 161 1, 1598, 1571, 1508, 1465, 1371 , 1253, 1 157, 1 1 16, 1020, 929, 904 815, 777, and 522 cm ^'1 or

Fourier Transfer Infrared spectra substantially as depicted in FIG.9; or

(c) DSC having endothermic peak at about 1 14.97°C or differential scanning calorimetry substantially as depicted in FIG.10. According to another general aspect, the invention provides pharmaceutically acceptable acid additions salts of dronedarone in amorphous form. The amorphous form of may be characterized by:

(i) amorphous dronedarone hydrobromide characterized by X-ray powder diffraction substantially as depicted in FIG.7.

(ii) amorphous dronedarone hydrogensuifate characterized by X-ray powder diffraction substantially as depicted in FIG.11.

(iii) amorphous dronedarone hydrochloride characterized by X-ray powder diffraction substantially as depicted in FIG.19.

In general, the pharmaceutically acceptable acid addition salts like crystalline dronedarone hydrobromide or crystalline dronedarone hydrogensuifate may have particle size distributions the 10 ^th volume percentile particle size (D _{] 0} ) is less than about 50 μτη, the 50th volume percentile particle size (D ₅₀ ) is less than about 250 urn, or the 90 volume percentile particle size (D ₉₀ ) is less than about 500 μηι, or any combination thereof.

In another general aspect, the invention provides a process for the preparation of pharmaceutically acceptable acid addition salts of dronedarone, the process comprises: (a) providing solution of dronedarone in one or more suitable solvents;

(b) adding suitable acid; and

(c) isolating pharmaceutically acceptable acid addition salt of dronedarone by removal of solvents.

In general, the suitable solvent comprises one or more of C1-C4 alcohols, ketones, esters, aprotic solvents, water and the like or mixture thereof. In particular, the suitable solvent comprises of methanol, ethanol, isopropanol, n-butanol, heptanol, decanol, dodecanol, acetone, methyl ethyl ketone, methyl tert-butyl ketone, ethyl acetate, isopropyl acetate, butyl acetate, n-propyl acetate, dimethyl formamide, dimethyl acetamide, N-methylpyrrolidone, acetonitrile and water or mixture thereof.

In general, the suitable acid comprises of hydrobromic acid, sulfuric acid, hydrochloric acid, phosphoric acid, oxalic acid, tartartic acid, succinic acid, maleic acid, fumaric acid, benzenesulfonic acid, methanesulfonic acid, toluenesulfonic acid and the like.

Embodiments of the process further includes removal of the solvent comprises one or more of filtration, filtration under vacuum, decantation, centrifugation, distillation and distillation under vacuum.

In general, the process may further include optionally addition of one or more of suitable anti-solvent comprises of toluene, xylene, ethylbenzene, n-hexane, heptane, cyclohexane, and the like; ethers like diisopropylether, methyltert-butyl ether, tetrahydrofuran, and the like; In particular, hexane.

In another general aspect, there is provided a process for the preparation of amorphous form of dronedarone hydrochloride thereof without simultaneous formation of crystalline forms or which will enable the conversion of crystalline forms into the amorphous from.

In further general aspect, the invention provides a process for the preparation of amorphous form pharmaceutically acceptable acid addition salt of dronedarone, the process comprising: providing a solution pharmaceutically acceptable acid addition salts of dronedarone in one or more suitable solvent; and isolating the amorphous form pharmaceutically acceptable acid addition salt of dronedarone.

Embodiments of the process includes, providing a solution of pharmaceutically acceptable acid addition salts of dronedarone in one or more suitable solvent or mixture of solvent. The said solution may be obtained by: (i) direct use of a reaction mixture containing pharmaceutically acceptable acid addition salt of dronedarone that is obtained in the course of its synthesis; or

(ii) dissolving pharmaceutically acceptable acid addition salt of dronedarone in one or more of suitable solvent.

The suitable solvent comprises of water; alcohols such as methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol and the like; ketones such as acetone, butanone, 2- pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyi ketone, and the like; esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyi acetate, hydrocarbons like toluene, xylene, methylene dichloride, ethylene dichloride, chlorobenzene, and the like, nitriles like acetonitrile, and polar aprotic solvents like N,N-dimethyIformamide, N,N-dimethylacetamide, N- methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine and the like; and mixtures thereof.

In general, the isolation of an amorphous form of pharmaceutically acceptable acid addition salt of dronedarone from the said solution may be affected by removing solvent. Suitable techniques which may be used for the removal of solvent include using a rotational distillation device such as a Buchi Rotavapor, spray drying, agitated thin film dyring ("ATFD"), freeze drying (lyophilization), and the like or any other suitable technique.

In one general aspect, the invention provides spray drying a solution of pharmaceutically acceptable acid addition salt of dronedarone and that involves the spray drying of feed stock, which is prepared as hereinafter, wherein any crystalline form of pharmaceutically acceptable acid addition salt of dronedarone may be used. The feedstock is dozed into the spray-drying instrument JISL Mini Spray-drier LSD-48 and spray drying is carried out under the following parameters.

Sr. No Parameters Conditions 00614

dronedarone or the filtered cake that is obtained as an end result of the reaction or reaction mass comprising pharmaceutically acceptable acid addition salts of dronedarone or solution comprising pharmaceutically acceptable acid addition salts of dronedarone, can be used for the preparation of feed stock.

In one general aspect, the present invention provides compositions comprising dronedarone hydrochloride substantially free of one or more of its corresponding impurities as measured by HPLC.

An aspect of the present invention provides compositions comprising dronedarone hydrochloride substantially free residual solvents as measured by GC.

An aspect of the present invention provides compositions comprising dronedarone hydrochloride substantially free from crystalline forms.

Amorphous dronedarone hydrochloride is characterized as substantially depicted in XRD (FIG.19).

In another aspect, the invention provides a process for the preparation of crystalline dronedarone free base, the process comprising:

(a) providing suspension of dronedarone hydrochloride in one or more of suitable solvent;

(b) adding suitable base;

(c) extracting the aqueous layer with one or more of suitable solvents;

(d) removal of solvent to obtain residue;

(e) adding one or more suitable anti-solvent; and

(f) isolating crystalline dronedarone free base.

In general, the suitable solvent comprises of Q-C4 alcohols like methanol, ethanol, isopropanol, n-butanol, heptanol, decanol, dodecanol, ketones like acetone, methyl ethyl ketone, methyl tert-butyl ketone and the like, esters like ethyl acetate, isopropyl acetate, butyl acetate, n-propyl acetate and the like, aromatic hydrocarbons like toluene, xylene, ethylbenzene, and the like. In particular, toluene may be used as a solvent.

The suitable base comprises of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, or ammonia and the like. In particular, the base can be potassium carbonate. More particularly, the potassium carbonate may be added as solution in water or dry solid powder.

The suitable anti-solvent comprises of aliphatic hydrocarbons like n-heptane, n- hexane, cyclohexane and the like, ethers like diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran and the like. In particular, n-hexane.

Embodiments of the process includes, suspending dronedarone hydrochloride prepared by the process of the present invention in an aromatic hydrocarbon solvent to provide solution optionally by heating the suspension and aqueous potassium carbonate solution may be added and reaction mixture may be further heated. The reaction mixture may be heated from about 35°C to about 90°C. The organic layer may be separated followed by washing with water and may be subjected to distillation to remove organic solvent. The residue obtained may be treated with suitable antisolvent like hexane. In general, prior to the initiation of product crystallization or the slurry may be cooled prior to filtration to isolate dronedarone free base.

In general; the crystalline dronedarone free base may be characterized by X-ray powder diffraction having characteristic peaks at about 2.6°, 5.3°, 8.0°, 10.8°, 17.8°, 18.9°, 19.7°, 22.4° and 23.6°±0.2° (2Θ); IR spectra having characteristic peaks at 3182, 2954, 2927, 1625, 1600, 1556, 1508, 1469, 1373, 1328, 1253, 1 143, 979, 912, 846, 798, 783, 756, and 648 cm ^" ' ; and DSC thermogram having two endothermic peaks at about 55.68°C and 67.47°C.

The crystalline dronedarone free base may be characterized by a PXRD pattern substantially as depicted in FIG.12, IR spectra is substantially as depicted in FIG.13 and DSC thermogram is substantially as depicted in FIG.14.

In one another aspect, there is provided a stable crystalline form of dronedarone hydrochloride thereof, which is stable during storage and drying.

In an aspect, the present invention provides crystalline Form-A of dronedarone hydrochloride having an chemical purity of greater than about 95%, or greater than about 98%, or greater than about 99%, or greater than about 99.5%, or greater than about 99.8%, or greater than about 99.9%, as determined using high performance liquid chromatography (HPLC).

According to further embodiment, the scope of the present invention can be illustrated by scheme- 1 as shown below.

(i) Base

(ii) Reduction . Acid Addition Salt

(III)

(II)

(i) Base

(ii) Methane sulfoi

Dronedarone Hydrochloride

Scheme-1

Powder X-ray Diffraction of dronedarone hydrochloride form can be obtained under following conditions.

(i) Characterization by Powder X-ray Diffraction

The X-ray powder diffraction spectrum was measured under the following experimental conditions: Instrument : X-Ray Diffractometer, D/Max-2200/PC Make: Rigaku, Japan.

X- Ray : Cu/40kv/40mA

Diverging : 10

Scattering Slit : 10

Receiving Slit : 0.15 mm

Monochromator RS : 0.8 mm

Counter : Scintillation Counter

Scan Mode : Continuous

Scan Speed : 3.0000 / Min

Sampling Width : 0.020

Scan Axes : Two Theta / Theta

Scan Range : 2.0000 to 40.0000

Theta Offset : 0.0000

(ii) Characterization by Differential Scanning Calorimetry (DSC)

Analytical method: Differential scanning calorimetric analysis was performed using a Perkin Elmer Diamond DSC control unit and a DSC 300°C differential scanning calorimeter. 2-5 mg samples were placed in crimped aluminum pans and heated from 50°C to 250°C in a liquid nitrogen atmosphere at a heating rate of 10°C/minute. Zinc- Indium was used as the standard substance.

(iii) The IR spectrum was measured by the KBr method.

The invention also encompasses pharmaceutical compositions comprising dronedarone hydrochloride or salts thereof of the invention. As used herein, the term "pharmaceutical compositions" or "pharmaceutical Formulations" includes tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

Pharmaceutical compositions containing the dronedarone hydrochloride of the invention may be prepared by using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, and lubricants. Various modes of administration of the pharmaceutical compositions of the invention can be selected depending on the therapeutic purpose, for example tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations. 2011/000614

An embodiment of the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of crystalline dronedarone hydrochloride substantially free from amorphous form, and one or more pharmaceutically acceptable carriers, excipients or diluents.

Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification.

Example-1:

Preparation of 2-n-butyl 3-(4-methoxy benzoyl)-5-nitro benzofuran

Method-1:

44.5 g 2-n-butyl-5-nitro benzofuran and 44.3 g of anisoyl chloride in 310 ml of dichloromethane were taken in round bottom flask at 25°C. The reaction mixture was treated with 44.3 g of ferric chloride solution in 300 ml methylene dichloride. The reaction medium was heated under reflux for 2 hours, cooled and diluted with 40 ml of water. The organic phase was separated and washed with water, 5% sodium hydrogen carbonate solution. The organic phase was evaporated to dryness and the product thus obtained crystallizes rapidly. It was recrystallized from 250 ml of isopropanol and 90% of 2-n-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran.

M.P.: 94-96°C, Purity > 95% (HPLC).

Method-2:

45 g (0.2 mole) 2-ri-butyl 5-nitro benzofuran and 44 g of anisoyl chloride in 300 ml of chlorobenzene were taken in round bottom flask at 25°C. The reaction mixture was treated with 40 g of aluminum chloride solution in 300. ml chlorobenzene. The reaction medium was heated under reflux for 2 hours, cooled and diluted with 40 ml of water. The organic phase was separated and washed with water, 5% sodium hydrogen carbonate solution. The organic phase was evaporated to dryness and the product thus obtained crystallizes rapidly. It was recrystallized from 270 ml of isopropanol and 90% of 2-n-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran.

M.P.: 94-96°C, Purity > 96% (HPLC)

Example-2:

Preparation of 2-n-butyl 3-(4-hydroxy benzovD-5-nitro benzofuran

100 g 2-n-butyl-3-(4-methoxy benzoyl)-5-nitro benzofuran, 500 mL of chlorobenzene, and 143.40 g of aluminum chloride were heated at 75°C for 2 hours to obtain solution-A. 1 L water was cooled to 5°C and solution-A was added to it. The reaction mixture was heated to 65°C and stirred for 30 min. The organic layer was separated and washed with water at 65°C. The organic layer was distilled under vacuum at 80°C. The residue was treated with 400 mL ethyl acetate at 60°C and cooled to 10°C gradually. In another round bottom flask 500 mL water was cooled to 10°C and above reaction mixture was quenched in pre-cooled water. The reaction mixture was stirred for 30 min and settled at 25°C. The organic layer was separated and washed with 300 mL of water. The ethyl acetate layer was distilled under vacuum at 55°C. The residue was treated with 200 mL toluene and heated to 75°C for 30 min. The reaction mixture was allowed to cool. The precipitated product was filtered and washed with toluene. The product was dried in hot air oven for about 8 hours at 60°C to 65°C to obtain 92% 2-n-butyl-3-(4-hydroxy benzoyl)-5-nitro benzofuran.

M.P. 120°C, Purity (HPLC): 99.19%

Example-3:

Preparation of 2-n-butyl 3-f4-(3-di-n-burylamino-propoxy)benzoyll-5-nitro benzofuran

(A) 2-n-butyl 3-f4-(3-di-n-butylamino-propoxy)benzoyl1-5-nitro benzofuran oxalate salt

100 g 2-n-butyl-3-(4-hydroxy benzoyl)-5-nitro-benzofuran, 800 mL methyl ethyl ketone and 42.80 g of potassium carbonate were stirred at 25°C for 15 min. 63.70 g of l-chloro-3-di-n-butylamino propane was added to the reaction mixture and heated at 85°C for 20 hours. The reaction mixture was filtered and washed with 100 mL of methyl ethyl ketone. The filtrate was diluted with 500 mL water and stirred for 30 min.

The organic layer was separated, treated with 300 mL sodium hydroxide (5%) solution and allowed to settle. The separated organic layer was washed with water, distilled under vacuum and cooled 25°C to obtain 95% 2-n-butyl-3-[4-(3-di-n-butylamino- propoxy)benzoyl]-5-nitro benzofuran. Purity: > 95% (HPLC).

The residue was dissolved in methanol at 25°C and 52.20 g oxalic acid solution in methanol was added. The reaction mixture was heated to 65°C and stirred for 30 min at 50°C followed by cooling to 25°C. The product was filtered and washed with methanol and dried to obtain 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy)benzoyl]-5- nitro benzofuran oxalate salt. Purity > 99.5% (HPLC). The oxalate salt is characterized by XRD substantially as depicted in FIG.15 and DSC substantially as depicted in FIG.16.

(B) 2-n-butyl 3-f4-f3-di-n-butvIamino-propoxy)benzoyIl-5-nitro benzofuran

The oxalate salt obtained in step (A) was converted to 2-n-butyl-3-[4-(3-di-n- butylamino-propoxy)benzoyl]-5-nitro benzofuran free base by treatment with potassium carbonate in biphasic solvent system toluene and water. The residue was isolated by removal of solvent by distillation under vacuum. Purity > 99.5% (HPLC). Example-4: -

Preparation of 5-amino 3-f4-(3-di-n-butylamino-propoxy)benzoyll-2-n-butyl benzofuran

Method-l:

(A) 5-amino 3-f4-(3-di-n-butylamino-propoxy)benzoyll-2-n-butyl benzofuran dioxalate salt

100 g 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy)benzoyl]-5-nitro benzofuran, 700 mL methanol and 15 g of Raney Nickel were taken under nitrogen atmosphere at 25°C in 2.0 L autoclave. Hydrogen pressure of 0.5-1.0 Kg was flushed two times and released at 25°C. The hydrogen pressure upto 3.0 Kg/cm ² was applied and the reaction mixture was heated to 55°C. Further the pressure was increased to 5.0 Kg/cm ² and maintained for 8 hours at 55°C. After the completion of the reaction as monitored by TLC, the reaction mixture was cooled to 25°C. The reaction mixture was flushed with nitrogen pressure two times and filtered under nitrogen atmosphere at 25°C followed by washing with 50 mL methanol. The filtrate was distilled under vacuum at 65°C to obtain residue. The residue was dissolved in methanol at 25°C and 52.20 g oxalic acid solution in methanol was added. The reaction mixture was heated to 65°C and stirred for 30 min at 50°C followed by cooling to 25°C. The product was filtered and washed with methanol and dried to obtain 5-amino 3-[4-(3-di-n-butylamino-propoxy)benzoyl]- 2-n-butyl benzofuran dioxalate salt. Purity > 98% (HPLC)

The dioxalate salt is characterized by XRD substantially as depicted in FIG.17 and DSC substantially as depicted in FIG.18

(B) 5-amino 3-[4-(3-di-n-burylamino-propoxy)benzoyll-2-n-butyl benzofuran

100 g 5-amino 3-[4-(3-di-n-butylamino-propoxy)benzoyl]-2-n-butyl benzofuran dioxalate salt, 80 g of potassium carbonate, 500 mL toluene and 1 L of process water were stirred for 1 hour at 35°C. The reaction mixture was allowed at 50°C. The separated aqueous layer was extracted with 100 mL toluene at 50°C. The separated combined organic layer was washed with water and stirred for 30 min. The separated organic layer was distilled under vacuum to obtain 85% 5-amino 3-[4-(3-di-n- butylamino-propoxy)benzoyl]-2-n-butyl benzofuran. Purity > 99.9% (HPLC)

Method-2:

(A) 5-amino 3-[4-(3-di-n-butylamino-propoxy)benzoyll-2-n-butyl benzofuran dioxalate salt

100 g 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy)benzoyl]-5-nitro benzofuran, 700 mL (30%) methanolic ammonia and 25 g of Pd/C (10%) were taken under nitrogen atmosphere at 25°C in 2.0 L autoclave. Hydrogen pressure of 0.5-1.0 Kg was flushed two times and released at 25°C. The hydrogen pressure upto 3.0 Kg/cm ² was applied and the reaction mixture was heated to 55°C. Further the pressure was increased to 5.0 Kg/cm ² and maintained for 8 hours at 55°C. After the completion of the reaction as monitored by TLC, the reaction mixture was cooled to 25°C. The reaction mixture was flushed with nitrogen pressure two times and filtered under nitrogen atmosphere at 25°C followed by washing with 50 mL methanol. The filtrate was distilled under vacuum at 65°C to obtain residue. The residue was dissolved in methanol at 25°C and 52.20 g oxalic acid solution in methanol was added. The reaction mixture was heated to 65°C and stirred for 30 min at 50°C followed by cooling to 25°C. The product was filtered and washed with methanol and dried to obtain 5-amino 3-[4-(3-di-n- butylamino-propoxy)benzoyl]-2-n-butyl benzofuran dioxalate salt.

The dioxalate salt is characterized by XRD substantially as depicted in FIG.17 and DSC substantially as depicted in FIG.18

The process can also be conveniently completed by using dry methanolic ammonia solution prepared by using ammonia gas in methanol.

The dioxalate salt can be converted to free base as per the process described in method- 1.

Method-3:

(A) 5-amino 3-f4-(3-di-n-butylamino-propoxy)benzoyll-2-n-butyl benzofuran dioxalate salt

100 g 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy)benzoyl]-5-nitro benzofuran, 700 mL mixture of methanol and ethyl acetate (30%) and 25 g of Pd/C (10%) were taken under nitrogen atmosphere at 25°C in 2.0 L autoclave. Hydrogen pressure of 0.5- 1.0 Kg was flushed two times and released at 25°C. The hydrogen pressure upto 3.0 Kg/cm ² was applied and the reaction mixture was heated to 55°C. Further the pressure was increased to 5.0 Kg/cm ² and maintained for 8 hours at 55°C. After the completion of the reaction as monitored by TLC, the reaction mixture was cooled to 25°C. The reaction mixture was flushed with nitrogen pressure two times and filtered under nitrogen atmosphere at 25°C followed by washing with 50 mL methanol. The filtrate was distilled under vacuum at 65°C to obtain residue. The residue was dissolved in methanol at 25°C and 52.20 g oxalic acid solution in methanol was added. The reaction mixture was heated to 65°C and stirred for 30 min at 50°C followed by cooling to 25°C. The product was filtered and washed with methanol and dried to obtain 5-amino 3-[4- (3-di-n-butylamino-propoxy)benzoyl]-2-n-butyl benzofuran dioxalate salt. Purity > 98% (HPLC). The dioxalate salt is characterized by XRD substantially as depicted in FIG.17 and DSC substantially as depicted in FIG.18

The dioxalate salt can be converted to freebase as per the process described in method- 1.

Exam Ie-5:

Preparation of 2-n-butyl3-i4-(3-di-n-buty amino-propoxy)benzoyll5-methyIsulfon- amido benzofuran (Dronedarone)

100 g of 5-amino 3-[4-(3-di-n-butylamino-propoxy)benzoyl]-2-n-butyl benzofuran and 1 L toluene are heated to 105°C for 30 min. 100 mL solution of methane sulfonyl chloride in toluene was added within 30 min at 108°C and stirred for 3 hours. After the completion of the reaction as monitored by TLC, the reaction mixture was cooled to 25°C. The reaction mixture was quenched with 5% sodium bicarbonate solution 400 mL and heated to 60°C for 30 min. The organic layer was separated and washed with 250 mL of water at 60°C. The separated organic layer was charcoalized with 2.5 g activated charcoal at 60°C and filtered through hyflow bed and washed with 100 mL toluene at 60°C. The organic layer was distilled under vacuum to obtain 95% 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy)benzoyl]5-methyl-sulfonamido benzofuran (dronedarone) as an oil. Purity > 99.5% (HPLC).

Example-6:

Preparation of Dronedarone Hydrochloride

100 g dronedarone free base as oil and 175 mL ethyl acetate was taken in round bottom flask at 25°C and stirred for 15 min. 2.5 g activated carbon was added and stirred for 30 min. The reaction mixture was filtered through hyflow bed and washed with 100 mL ethyl acetate. The organic layer was cooled to 0°C and 52.50 g isopronolic hydrochloride solution was added at 0°C. The reaction mixture was stirred at 0°C and heated to 70°C for 30 min. The reaction mixture was gradually cooled to 0°C and stirred for 1 hour. The precipitated product was filtered and washed with 100 mL chilled ethyl acetate and further dried to obtain dronedarone hydrochloride.

Exam le-7:

Preparation of Dronedarone Hydrochloride

100 g dronedarone free base as oil and 175 mL isopropanol was taken in round bottom flask at 25°C and stirred for 15 min. 2.5 g activated carbon was added and stirred for 30 min. The reaction mixture was filtered through hyflow bed and washed with 100 mL isopropanol. The organic layer was cooled to 0°C and 52.50 g isopronolic hydrochloride solution was added at 0°C. The reaction mixture was stirred at 0°C and heated to 70°C for 30 min. The reaction mixture was gradually cooled to 0°C and stirred for 1 hour. The precipitated product was filtered and washed with 100 mL chilled isopropanol and further dried to obtain dronedarone hydrochloride.

Example-8:

Preparation of Dronedarone Hydrochloride

100 g dronedarone freebase as oil and 175 mL acetone was taken in round bottom flask at 25°C and stirred for 15 min. 2.5 g activated carbon was added and stirred for 30 min. The reaction mixture was filtered through hyflow bed and washed with 100 mL acetone. The organic layer was cooled to 0°C and 52.50 g isopronolic hydrochloride solution was added at 0°C. The reaction mixture was stirred at 0°C and heated to 70°C for 30 min. The reaction mixture was gradually cooled to 0°C and stirred for 1 hour. The precipitated product was filtered and washed with 100 mL chilled acetone and further dried to obtain dronedarone hydrochloride.

Example-9:

Preparation of Dronedarone Hydrochloride

100 g dronedarone freebase as oil and 175 mL acetone was taken in round bottom flask at 25°C and stirred for 15 min. 2.5 g activated carbon was added and stirred for 30 min. The reaction mixture was filtered through hyflow bed and washed with 100 mL acetone. The organic layer was cooled to 0°C and 52.50 g isopronolic hydrochloride solution was added at 0°C. The reaction mixture was stirred at 0°C and heated to 70°C for 30 min. The reaction mixture was gradually cooled to 0°C and stirred for 1 hour. The precipitated product was filtered and washed with 100 mL chilled acetone and further dried to obtain dronedarone hydrochloride.

Example-10:

Preparation of Dronedarone Hydrochloride Form A

100 g dronedarone hydrochloride and 400 mL acetone were taken in round bottom flask at and heated at 60°C for 30 min. The reaction mixture was cooled to 0°C and stirred for 1 hour to precipitate crystalline dronedarone hydrochloride. The product was filtered and washed with chilled 200 mL chilled acetone and further dried in hot air oven for about 8 hours at 60°C to 65°C to obtain crystalline dronedarone hydrochloride Form-A in 80% yield. The crystalline Form A is characterized by XRD substantially as depicted in FIG.l, Infrared spectrum substantially as depicted in FIG.2 and DSC substantially as depicted in FIG.3.

Example-11:

Preparation of Amorphous dronedarone hydrochloride

25.0 g of crystalline dronedarone hydrochloride is dissolved in 250.0 mL of acetone at 25°C to 30°C. The content is stirred for 30 minutes at 25°C to 30°C. To this, 1.0 g charcoal was added and stirred for 30 minutes at 25°C to 30°C. The content is filtered through Hyflosupercel, and the Hyflosupercel pad is washed with 50.0 mL acetone. The filtrate is concentrated under vacuum below 45°C till 100 mL acetone remains. 50 mL acetone was added and stirred to get clear solution. The reaction mixture followed by spray drying in JISL Mini spray drier LSD-48 under the below conditions. The product is collected from cyclone and is further dried at 40°C±5°C under vacuum for 16 hours to get 19.0 g of stable amorphous dronedarone hydrochloride.

The spray-dried Dronedarone hydrochloride is amorphous in nature. The obtained product contains residual solvent well within ICH limit.

Example-12:

Preparation of crystalline dronedarone hvdrobromide

15 g dronedarone freebase as solid and 30 mL ethyl acetate was taken in round bottom flask at 25°C and heated to 65°C for 1 hour. 7.4 g of cone. Hydrobromic acid (48%) solution was added and stirred for 30 min. 90 mL hexane was added to the reaction mixture and cooled to 25°C.The reaction mixture was stirred for 30 mins and filtered. The wet-cake was washed with hexane and dried to obtain 15 g (87%) of crystalline dronedarone hydrobromide. The crystalline form is characterized by XRD substantially as depicted in FIG.4, Infrared spectrum substantially as depicted in FIG.5 and DSC substantially as depicted in FIG.6.

Example-13:

Preparation of Amorphous dronedarone hvdrobromide

10.0 g of crystalline dronedarone hydrobromide is dissolved in 250.0 mL of acetone at 25°C to 30°C. The content is stirred for 30 minutes at 25°C to 30°C. To this, 1.0 g charcoal was added and stirred for 30 minutes at 25°C to 30°C. The content is filtered through Hyflosupercel, and the Hyflosupercel pad is washed with 50.0 mL acetone. The filtrate is concentrated under vacuum below 45°C till 100 mL acetone remains. 50 mL acetone was added and stirred to get clear solution. The solution was spray dried in JISL Mini spray drier LSD-48 under the below conditions. The product is collected from cyclone and is further dried at 40°C ± 5°C under vacuum for 16 hours to get 7.5.0 g of amorphous dronedarone hydrobromide.

The spray-dried dronedarone hydrobromide is amorphous in nature. The obtained product contains residual solvent well within ICH limit. The amorphous form is characterized by XRD substantially as depicted in FIG.7.

Example-14:

Preparation of crystalline dronedarone hydrogensulfate

10 g dronedarone freebase as solid and 50 mL ethyl acetate was taken in round bottom flask at 25°C and stirred to get clear solution. Cone. Sulfuric acid solution (1 gm in 10 ml ethyl acetate) was added and stirred for 30 min. The reaction mixture was heated to 65°C to 70°C and stirred for 30 tnins. The reaction mixture was cooled to 25°C and filtered. The wet-cake was washed with ethyl acetate and dried to obtain 9.6 g (75%) of crystalline dronedarone hydrogensulfate. The crystalline form is characterized by XRD substantially as depicted in FIG.8, Infrared spectrum substantially as depicted in FIG.9 and DSC substantially as depicted in FIG.10.

Example-15:

Preparation of Amorphous dronedarone hydrogensulfate

10.0 g of crystalline dronedarone hydrogensulfate is dissolved in 250.0 mL of ethyl acetate at 25°C to 30°C. The content is stirred for 30 minutes at 25°C to 30°C. To this, 1.0 g charcoal was added and stirred for 30 minutes at 25°C to 30°C. The content is filtered through Hyflosupercel, and the Hyflosupercel pad is washed with 50.0 mL ethyl acetate. The filtrate is concentrated under vacuum below 45°C till 100 mL acetone remains. 50 mL ethyl acetate was added and stirred to get clear solution. The solution was spray dried in JISL Mini spray drier LSD-48 under the below conditions. The product is collected from cyclone and is further dried at 40°C±5°C under vacuum for 16 hours to get 7.5 g of amorphous dronedarone hydrogensulfate.

,The spray-dried Dronedarone hydrobromide is amorphous in nature. The obtained product contains residual solvent well within ICH limit. The amorphous form is characterized by XRD substantially as depicted in FIG. l 1.

Example-16:

Preparation of crystalline dronedarone free base

185 g dronedarone hydrochloride Form-A and 925 mL toluene was taken in round bottom flask at 25°C and stirred for 15 minutes. 52 g potassium carbonate aqueous solution was added to the reaction mixture and stirred for 30 mins. The aqueous layer was separated and extracted with 185 mL toluene. The combined toluene layer was washed with water and distilled under vacuum to remove toluene. The residue was treated with 925 mL hexane and cooled to 0°C. The reaction mixture was cooled overnight and precipitated solid was filtered and washed with chilled hexane. The product was dried to obtain 145 g of dronedarone free base solid. The crystalline form is characterized by XRD substantially as depicted in FIG.12, Infrared spectrum substantially as depicted in FIG.13 and DSC substantially as depicted in FIG.14.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

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