PROCESS FOR PREPARATION OF DRONEDARONE

PRIORITY

[0001] This application claims the benefit to Indian Provisional Applications 2048/MUM/2010, filed on July 16, 2010 and 2598/MUM/2010, filed on September 17, 2010 entitled "PROCESS FOR PREPARATION OF DRONEDARONE", which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Technical Field

[0002] The present invention relates to a process for the preparation of dronedarone, its pharmaceutically acceptable salts and pharmaceutical compositions thereof. The present invention relates to a novel amorphous form of dronedarone hydrochloride, and a process for its preparation.

Description of the Related Art

[0003] Dronedarone, also known as 2-n-butyl-3-[4-(3-di-n- butylaminopropoxy)benzoyl]-5-methylsulfonamidobenzofuran, is represented by the structure of formula I.

[0004] Dronedarone hydrochloride, compound of formula II, is an anti- arrhythmic agent used for the prevention and treatment of atrial fibrillation. Dronedarone hydrochloride is marketed under the brand name MULTAQ™ in the United States (approved in July 2009) and in Europe (approved in November 2009).

[0005] United States Patent No. 5223510 (the '510 patent) discloses dronedarone and its hydrochloride salt. The '510 patent discloses a process for the preparation of dronedarone hydrochloride as schematically represented by Scheme I.

MeS0 ₂ CI

Et ₃ N/ DCE

Ethyl acetate

HCI/ Ether

Scheme I

[0006] However, 5-amino-2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl] benzofuran disadvantageously reacts with methanesulfonyl chloride in the presence of triethylamine to give the undesired presence of 2-n-butyl-3-[4-(3-di-n- butylaminopropoxy)benzoyl]-5-bismethylsulfonamidobenzofuran, a compound of formula V along with dronedarone. Subsequently, the presence of which, requires the purification of dronedarone b column chromatography.

[0007] U.S. Patent No. 6828448 discloses a process for the preparation of dronedarone hydrochloride as schematically represented by Scheme II.

Scheme II

[0008] The starting material, 2-butyl-5-methylsulfonamidobenzofuran, was prepared by the reaction of 5-amino-2-butylbenzofuran with methanesulfonyl chloride or methanesulfonic anhydride in the presence of an acid acceptor, such as triethylamine or ammonia. 2-butyl-5-bismethylsulfonamidobenzofuran may be formed as an impurity which can be further carried in the preparation of dronedarone.

[0009] The processes known in the art for the preparation of dronedarone involve reaction of methanesulfonyl chloride or methanesulfonic anhydride with 5-amino substituted benzofuran which gives rise to 5-bismethylsulfonamido substituted benzofuran impurity and requires purification by column chromatography.

[0010] The use of chromatographic columns to isolate the desired final product can be avoided. As column chromatography always requires the use of high amounts of organic eluants, its avoidance clearly contributes to the industrial applicability of the process in terms of improved product quality, lower manufacturing costs and easier ecological disposal of process waste. There is a need in the art, therefore, for industrially applicable improved processes for the preparation of dronedarone and its pharmaceutically acceptable salts, which avoid tedious and time-consuming column chromatography.

SUMMARY OF THE INVENTION

[0011] The present invention provides a process for the preparation of dronedarone and pharmaceutically acceptable salts thereof, comprising:

a) hydrogenating 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-nitroben zofuran, compound of formula III

to 5-amino-2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]ben zofuran, compound of formula IV

in the presence of a suitable catalyst,

b) reacting the compound of formula IV with an acid to form a pharmaceutically acceptable salt form of formula IV,

c) neutralizing the salt form of formula IV with a base to a free form of formula IV, d) reacting the free form of formula IV obtained in (c) with methanesulfonyl chloride or methanesulfonic anhydride to form dronedarone, compound of formula I,

e) treating the resulting compound of formula I obtained in (d) with alcoholic alkali metal hydroxide to convert any amount of 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]- 5-bismethylsulfonamidobenzofuran, compound of formula V formed and present as an impurity to com ound of formula I,

f) optionally, treating the compound of formula I obtained in (e) with nonpolar solvent and converting to its pharmaceutically acceptable salt, with the proviso that the process is carried out without use of column chromatography purification.

[0012] In an embodiment, the present invention provides a process for the purification of dronedarone, compound of formula I

comprising treatin compound of formula I containing compound of formula V

ο ο a

with alcoholic alkali metal hydroxide to reduce the content of compound of formula V.

[0013] In another embodiment, the present invention provides dronedarone having less than 0.05% of compound of formula V. [0014] In another embodiment, the present invention provides an amorphous form of dronedarone hydrochloride, compound of formula II

having an X-ray powder diffraction (XRPD) pattern, which is substantially in accordance with Figure 1.

[0015] In another embodiment, the present invention provides a process for the preparation of dronedarone hydrochloride in amorphous form, comprising:

a) dissolving dronedarone hydrochloride in alcohol to form a solution,

b) removing alcohol from the solution obtained in (a).

[0016] In another embodiment, the present invention provides dronedarone hydrochloride having 90% of particles with particle size less than 200 μπι and mean particle size less than 100 μπι.

[0017] In another embodiment, the present invention provides a pharmaceutical composition comprising dronedarone hydrochloride having 90% of particles with particle size less than 200 μιη and mean particle size less than 100 μπι and at least one pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 is a characteristic XRPD of dronedarone hydrochloride in amorphous form as obtained in Example 9.

[0019] Figure 2 is a scanning electron microscope (SEM) picture (magnification

1000 times) of particle size of dronedarone hydrochloride in amorphous form as obtained in Example 9. DETAILED DESCRIPTION OF THE INVENTION

[0020] The present invention relates to dronedarone, its pharmaceutical salts and compositions thereof. The present invention relates to amorphous form of dronedarone hydrochloride. [0021] The present invention provides a process for the preparation dronedarone, compound of formula I

and pharmaceutically acceptable salts thereof, comprising:

a) hydrogenating 2-n-butyl-3 - [4-(3 -di-n-butylaminopropoxy)benzoyl] -5-nitrobenzofuran, compound of formula III

to 5-amino-2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]ben zofuran, compound of formula IV

in the presence of a suitable catalyst,

b) reacting the compound of formula IV with an acid to form a pharmaceutically acceptable salt form of formula IV,

c) neutralizing the salt form of formula IV with a base to a free form of formula IV, d) reacting the free form of formula IV obtained in (c) with methanesulfonyl chloride or methanesulfonic anhydride to form dronedarone, compound of formula I,

e) treating the resulting compound of formula I obtained in (d) with alcoholic alkali metal hydroxide to convert any amount of 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]- 5-bismethylsulfonamidobenzofuran, compound of formula V formed and present as an impurity to com ound of formula I,

f) optionally, treating the compound of formula I obtained in (e) with nonpolar solvent and converting to its pharmaceutically acceptable salt, with the proviso that the process is carried out without use of column chromatography purification.

[0022] In (a) of the above process, 2-n-butyl-3-[4-(3-di-n- butylaminopropoxy)benzoyl]-5-nitrobenzofuran, compound of formula III is catalytically hydrogenated to 5-amino-2-n-butyl-3-[4-(3-di-n- butylaminopropoxy)benzoyl]benzofuran, compound of formula IV, in the presence of a suitable catalyst. The compound of formula III can be prepared by processes known in the art. Illustratively, the process is as disclosed in US 5223510, which is referenced herein in its entirety.

[0023] Herein, the term "room temperature" means a temperature of about 25 °C to about 30°C.

[0024] A suitable hydrogenation catalyst used in the process, includes, but is not limited to platinum oxide, palladium oxide, palladium on carbon. Preferably the hydrogenation catalyst selected is palladium on carbon.

[0025] The reaction is carried out in the presence of a suitable organic solvent.

The suitable organic solvent includes, but is not limited to alcohols such as ethanol, methanol, propanol, butanol and the like; esters such as methyl acetate, ethyl acetate, butyl acetate, isopropyl acetate and the like. Preferably the organic solvent selected is ethyl acetate.

[0026] The reaction may be carried out at a hydrogen pressure in the range of about 0.5 kg to 20 kg. Preferably the reaction is carried out at a hydrogen pressure of about 3 kg to about 5 kg. [0027] The reaction may be carried out at a temperature in the range of about 0°C to about 80°C. Preferably the reaction is carried out at a temperature of about 25°C to about 45°C.

[0028] The reaction is carried out for a period of about 2 hours to about 24 hours. Preferably the reaction is carried out for a period of about 8 hours to about 12 hours.

[0029] The completion of reaction may be monitored by thin layer chromatography (TLC) or high performance liquid chromatography (HPLC). After completion of reaction, the catalyst was filtered off carefully on a hyfio bed and was worked up by any standard procedure, known to one of ordinary skill in the art, to obtain the compound of formula IV.

[0030] In (b) of the above process, the compound of formula IV is reacted with an acid to form a pharmaceutically acceptable salt form of formula IV.

[0031] The acid may be inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid; organic acid such as oxalic acid, fumaric acid, succinic acid, citric acid, benzoic acid, methanesulfonic acid, p-toluenesulphonic acid. Preferably the acid is selected from organic acid and more preferably the acid is oxalic acid.

[0032] The molar equivalent of the acid employed is from about an equimolar amount to about 5 times the equimolar amount with respect to the compound of formula IV. Preferably the molar equivalent of the acid employed is about an equimolar amount to about 2.5 times the equimolar amount of the compound of formula IV.

[0033] The reaction is carried out in the presence of a suitable organic solvent.

The suitable organic solvent includes, but is not limited to alcohols such as ethanol, methanol, propanol, butanol and the like; ethers such as diethyl ether, ethyl methyl ether, methyl tertiary-butyl ether and the like. Preferably the organic solvent selected is ethanol.

[0034] The reaction may be carried out at a temperature in the range of about

20°C to about 40°C. The reaction is carried out for a period of about 0.5 hour to about 10 hours. Preferably the reaction is carried out at a temperature of about 20°C to about 30°C for a period of about 1 hour to about 4 hours.

[0035] In one preferred embodiment, the compound of formula IV is reacted with oxalic acid to form a dioxalate salt form of formula IV. [0036] The salt form of formula IV, obtained is purified and used in (c) of the above process.

[0037] The solvent used in the purification process includes, but is not limited to alcohols such as ethanol, methanol, propanol, butanol and the like. Preferably the organic solvent selected is methanol.

[0038] In (c) of the above process, the salt form of formula IV is neutralized with a base to a free form of formula IV.

[0039] The reaction is carried out in the presence of water and a suitable water immiscible organic solvent. The suitable water immiscible organic solvent includes, but is not limited to haloalkanes such as dichloromethane, chloroform and the like; ethers such as diethyl ether, dimethyl ether, ethyl methyl ether, diisopropyl ether, methyl tertiary-butyl ether and the like; aromatic hydrocarbons such as toluene and the like. Preferably the organic solvent is selected from dichloromethane, chloroform, toluene, diethyl ether; more preferably the solvent is dichloromethane.

[0040] The base includes, but is not limited to sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, aqueous ammonia. Preferably the base selected is aqueous ammonia and the pH is adjusted in the range of about 8-10.

[0041] The reaction may be carried out at a temperature in the range of about 10°C to about 30°C. Preferably the reaction is carried out at a temperature of about 15°C to about 25°C.

[0042] The reaction is carried out for a period of about 0.5 hour to about 10 hours, preferably for a period of about 1 hour to about 3 hours followed by the separation of the two layers. The organic layer containing free form of formula IV may be optionally treated with Norit™ charcoal. The solvent may be removed using any suitable method, known in the art, such as evaporation, atmospheric distillation, or distillation under vacuum. Preferably, the solvent is removed by distillation under vacuum.

[0043] In one preferred embodiment, the dioxalate salt form of formula IV is neutralized with aqueous ammonia to a free form of formula IV. [0044] In (d) of the above process, the compound of formula IV obtained in (c) is reacted with methanesulfonyl chloride or methanesulfonic anhydride in the presence of a suitable acid acceptor to form dronedarone.

[0045] The suitable acid acceptor includes, but is not limited to potassium carbonate, sodium bicarbonate, triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine. Preferably the acid acceptor selected is triethylamine.

[0046] The reaction is carried out in the presence of a suitable organic solvent.

The suitable organic solvent includes, but is not limited to haloalkanes such as dichloromethane, dichloroethane, chloroform and the like. Preferably the organic solvent selected is dichloromethane.

[0047] The reaction may be carried out at a temperature in the range of about 0°C to about 30°C. The reaction is carried out for a period of about 0.5 hour to about 10 hours.

Preferably the reaction is carried out at a temperature of about 20°C to about 30°C for a period of about 1 hour to about 4 hours.

[0048] In (e) of the above process, dronedarone obtained in (d) containing a compound of formula V, the presence of which is undesirable, and thus considered an impurity, is treated with alcoholic alkali metal hydroxide in a suitable organic solvent.

[0049] The alcohol used, includes, but is not limited to ethanol, methanol, propanol, butanol and the like. Preferably the alcohol selected is ethanol.

[0050] The alkali metal hydroxide used, includes, but is not limited to lithium hydroxide, sodium hydroxide, potassium hydroxide. Preferably the alkali metal hydroxide selected is sodium hydroxide.

[0051] The reaction is carried out in the presence of a suitable organic solvent.

The suitable organic solvent includes, but is not limited to alcohols such as ethanol, methanol, propanol, butanol and the like. Preferably the organic solvent selected is ethanol.

[0052] The molar equivalent of the alkali metal hydroxide employed is from about an equimolar amount to about 10 times the equimolar amount with respect to the compound of formula IV. Preferably the molar equivalent of the alkali metal hydroxide employed is about an equimolar amount to about 2.5 times the equimolar amount of the compound of formula IV. [0053] The reaction may be carried out at a temperature in the range of about

20°C to about 40°C. The reaction is carried out for a period of about 0.5 hour to about 10 hours. Preferably the reaction is carried out at a temperature of about 20°C to about 30°C for a period of about 1 hour to about 4 hours.

[0054] The completion of reaction may be monitored by thin layer chromatography (TLC) or high performance liquid chromatography (HPLC). After completion of reaction, the reaction mass is cooled to about 10°C to about 20°C and treated with water immiscible organic solvent and water.

[0055] The suitable water immiscible organic solvent includes, but is not limited to haloalkanes such as dichloromethane, chloroform and the like; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and the like; aromatic hydrocarbons such as toluene and the like. Preferably the water immiscible organic solvent is ethyl acetate.

[0056] The organic layer containing dronedarone may be optionally treated with Norit™ charcoal.

[0057] The solvent may be removed using any suitable method, known in the art, such as evaporation, atmospheric distillation, or distillation under vacuum. Any temperature and vacuum conditions, generally, may be used provided these do not influence the nature of the product. The vacuum and the temperature used for the removal of the solvent depend on parameters like the boiling point range of the solvent, which are apparent to persons of ordinary skill in the art. Optionally, the organic layer containing dronedarone may be directly used in acid-addition salt formation of (f) in the process described.

[0058] The present invention provides dronedarone, which is obtained after alcoholic alkali metal hydroxide treatment of the process described above, having a content of compound of formula V below detection limit as measured by high performance liquid chromatography.

[0059] The dronedarone obtained in (e) of the process above is immediately used in acid-addition salt formation of (f).

[0060] In (f) of the above process, dronedarone obtained in (e) is optionally treated with nonpolar solvent and converted to its pharmaceutically acceptable salt. [0061] The nonpolar solvent used, includes, but is not limited to aliphatic hydrocarbons such as hexane, heptane, cyclohexane, pentane and the like; aromatic hydrocarbons such as toluene, xylene and the like. Preferably the nonpolar solvent selected is hexane.

[0062] The dronedarone acid-addition salts may be prepared by reacting dronedarone with a pharmaceutically acceptable acid, where the acid may be an aqueous acid or a solvent containing an acid or in gaseous form. The acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like; and organic acids such as oxalic acid, maleic acid, fumaric acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, and the like. Preferably the acid is hydrochloric acid. Preferably, a solvent containing an acid can be used.

[0063] The suitable solvent containing an acid, includes esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and the like; haloalkanes such as dichloromethane, chloroform and the like; ethers such as diethyl ether, dimethyl ether, ethyl methyl ether, diisopropyl ether, methyl tertiary-butyl ether and the like; alcohols such as ethanol, methanol, propanol, butanol and the like; ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone and the like. Preferably the solvent selected is acetone.

[0064] The dissolution of dronedarone is carried out by using suitable organic solvent which includes, but is not limited to, esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and the like; haloalkanes such as dichloromethane, chloroform and the like; ethers such as diethyl ether, dimethyl ether, ethyl methyl ether, diisopropyl ether, methyl tertiary-butyl ether and the like; alcohols such as ethanol, methanol, propanol, butanol and the like; ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone and the like. Preferably the solvent selected is acetone.

[0065] The dronedarone acid-addition salt formation may be carried out at a temperature in the range of about 0°C to about 30°C for a period of about 1 hour to about 10 hours. Preferably the reaction is carried out at a temperature of about 0°C to about 15°C for a period of about 1 hour to about 5 hours.

[0066] The dronedarone acid-addition salts may be purified by addition of solvent which includes, but is not limited to, esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and the like; alcohols such as ethanol, methanol, propanol, butanol and the like; ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone and the like; ethers such as diethyl ether, dimethyl ether, ethyl methyl ether, diisopropyl ether, methyl tertiary-butyl ether and the like; water and mixtures thereof. Preferably, the solvent is acetone, methanol, water and mixtures thereof.

[0067] Suitable temperatures for dissolution of dronedarone acid-addition salts in a solvent may range from about 10°C to about the reflux temperature of the solvent. Stirring may be continued for any desired time period to achieve complete dissolution of the compound. The stirring time may range from about 30 minutes to about 3 hours, or longer. The solution may be optionally treated with Norit™ charcoal and filtered to get a particle-free solution.

[0068] The product is isolated by conventional methods known in the art, preferably, filtration.

[0069] Drying may be carried out for any desired time until the required product quality is achieved. The drying time may vary from about 1 hour to about 20 hours, or longer.

[0070] The above purification process can optionally be repeated to get the desired purity.

[0071] The present invention provides a process for the purification of dronedarone,

comprising treatin compound of formula I containing compound of formula V

with alcoholic alkali metal hydroxide to reduce the content of compound of formula V. [0072] The alcohol that may be used, includes, but is not limited to ethanol, methanol, propanol, butanol and the like and the alkali metal hydroxide includes, but is not limited to lithium hydroxide, sodium hydroxide, potassium hydroxide. Preferably the alcohol is ethanol and the alkali metal hydroxide is sodium hydroxide.

[0073] The reaction is carried out in the presence of a suitable organic solvent.

The suitable organic solvent includes, but is not limited to alcohols such as ethanol, methanol, propanol, butanol and the like. Preferably the organic solvent is ethanol.

[0074] The molar equivalent of the alkali metal hydroxide employed is from about an equimolar amount to about 10 times the equimolar amount with respect to the compound of formula I. Preferably the molar equivalent of the alkali metal hydroxide employed is about an equimolar amount to about 2.5 times the equimolar amount of the compound of formula I.

[0075] The reaction may be carried out at a temperature in the range of about

20°C to about 40°C. The reaction is carried out for a period of about 0.5 hour to about 10 hours. Preferably the reaction is carried out at a temperature of about 20°C to about 30°C for a period of about 1 hour to about 4 hours.

[0076] The completion of reaction may be monitored by thin layer chromatography (TLC) or high performance liquid chromatography (HPLC). After completion of reaction, the reaction mass is cooled to about 10°C to about 20°C and treated with water immiscible organic solvent and water.

[0077] The suitable water immiscible organic solvent includes, but is not limited to haloalkanes such as dichloromethane, chloroform and the like; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and the like; aromatic hydrocarbons such as toluene and the like. Preferably the water immiscible organic solvent is ethyl acetate.

[0078] The organic layer containing dronedarone may be optionally treated with

Norit™ charcoal. The solvent may be removed using any suitable method, known in the art, such as evaporation, atmospheric distillation, or distillation under vacuum. Optionally, the organic layer containing dronedarone may be directly used in acid- addition salt formation. [0079] The present invention provides dronedarone having less than 0.1 % of compound of formula V as measured by high performance liquid chromatography.

[0080] The present invention provides dronedarone having less than 0.05% of compound of formula V as measured by high performance liquid chromatography.

[0081] The present invention provides dronedarone having compound of formula

V below detection limit as measured by high performance liquid chromatography.

[0082] The present invention provides dronedarone, obtained by the above process, having chemical purity, as described, analyzed by using high performance liquid chromatography (HPLC) with the conditions described below:

Column: Inertsil ODS 3V, 250 x 4.6mm, 5μ; Column Temperature: 30°C

Mobile phase: Mobile Phase A = Buffer; Buffer: 0.2% Triethylamine in water. Adjust pH to 3.5 with acetic acid; Mobile Phase B = Acetonitrile

Diluent: Water: Acetonitrile (1 : 1 , v/v); Flow Rate: 1.OmL/minute; Detection: UV 290nm; Injection Volume: 20 μΐ.

[0083] The present invention provides amorphous form of dronedarone hydrochloride having an X-ray powder diffraction (XRPD) pattern substantially in accordance with Figure 1.

[0084] The X-Ray powder diffraction can be measured by an X-ray powder diffractometer equipped with a Cu-anode (λ=1.54 Angstrom), X-ray source operated at 45 kV, 40 mA and a Ni filter is used to strip K-beta radiation. Two-theta calibration is performed using an NIST SRM 640c Si standard. The sample was analyzed using the following instrument parameters: measuring range=2-50° 2Θ; step width=0.017°; and measuring time per step=5 sec.

[0085] The present invention provides a process for the preparation of dronedarone hydrochloride in amorphous form, comprising the steps of:

a) dissolving dronedarone hydrochloride in alcohol to form a solution, b) removing alcohol from the solution obtained in (a).

[0086] The alcohol used, includes, but is not limited to ethanol, methanol, propanol, butanol and the like. Preferably the alcohol selected is methanol.

[0087] In one preferred embodiment, dronedarone hydrochloride is dissolved in methanol at room temperature to form a solution.

[0088] Removal of alcohol may be accomplished by substantially complete evaporation of the solvent or concentrating the solution, cooling the solution if required and filtering the obtained solid. The solution may also be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720mm Hg, or evaporated by spray drying to obtain a dry amorphous powder. Preferably alcohol was removed under vacuum to give amorphous dronedarone hydrochloride.

[0089] The present invention provides dronedarone hydrochloride having 90% of particles with particle size less than 400 μπι.

[0090] The present invention provides dronedarone hydrochloride having 90% of particles with particle size less than 200 μπι and mean particle size less than 100 μπι.

Preferably, 90% of particles have particle size less than 100 μπι, more preferably less than 50 μηι. Preferably, the mean particle size is less than 50 μπι, more preferably less than 30 μπι and greater than 15 μιη.

[0091] "Particle size distribution" means the cumulative volume size distribution of equivalent spherical diameters. "Mean particle size" refers to the mean of said particle size distribution. D ₉₀ refers to at least 90% of the particles have a size smaller than the stated value.

[0092] The methodology and protocols for particle size distribution of dronedarone hydrochloride by laser diffraction are described below:

Instrument: Malvern Mastersizer 2000

Sample Handling Unit: Hydro2000S (A)

Range: 0.02μπι to 2000μιη

Pump/Stirrer Speed: 2800 RPM

Ultrasound: 10%

Dispersant: Silicon oil Backgroud: With Dispersant

Sample Preparation: About 150mg of sample in beaker. Add 3-4 drops of silicon oil. Make a paste. Add 25 mL of silicon oil and stir to mix well. Sonicate for 60 seconds. Obscuration: Between 10-20%

[0093] The present invention provides dronedarone hydrochloride wherein the particles are needle-shaped, which is substantially in accordance with Figure 2.

[0094] The scanning electron microscopic picture of dronedarone hydrochloride can be obtained as described below:

Instrument: Jeol-400

Method of Analysis: Sample is taken into the stub and coated with gold. The photographs are observed at different magnifications.

[0095] The present invention provides a pharmaceutical composition comprising dronedarone hydrochloride having 90% of particles with particle size less than 200 μηι and mean particle size less than 100 μηι and at least one pharmaceutically acceptable carrier.

[0096] The pharmaceutically acceptable carrier may comprise diluents, adjuvants, disintegrating agents, binders, excipients, lubricants, solubility enhancing agents and the like. In one preferred embodiment, the pharmaceutically acceptable carrier comprises a solubility enhancing agent.

[0097] The following solubility enhancing agent may be used: co-solvents such as polyethylene glycol (PEG) 300, propylene glycol, ionic surfactants, such as sodium lauryl sulfate or non-ionic surfactants such as different poloxamers (polyoxyethylene and polyoxypropylene copolymers), natural or synthesized lecithins, esters of sorbitan and fatty acids (such as Span®), esters of polyoxyethylenesorbitan and fatty acids (such as Tween®), polyoxyethylated hydrogenated castor oil (such as Cremophor®), polyoxyethylene stearates (such as Brij®), dimethylpolysiloxane, or any combination of the above mentioned surfactants. In one preferred embodiment, the surface active agent is selected from co-solvents, fatty acids and esters, oil, ionic surfactants.

[0098] The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention in any manner. EXAMPLES

EXAMPLE 1

[0099] Preparation of 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5- nitrobenzofuran, compound of formula III

To a solution of lOOg of 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran in l OOOmL of methyl ethyl ketone was added 48.8g of potassium carbonate at about room temperature. The reaction mass was stirred for about 30min and 69.7g of l -chloro-3-di-n- butylaminopropane was added to it. The reaction mass was heated to reflux (about 78°C to about 82°C) and stirred at about the same temperature for about 12h. The reaction mass was then cooled to about room temperature and the insoluble solid was filtered and washed with lOOmL of methyl ethyl ketone. The filtrate and washings were collected together and concentrated under vacuum at about temperature below 50°C to obtain pale brown thick oil which was degassed under vacuum at about temperature below 50°C for about 30min. The oil was then dissolved in 700mL of ethyl acetate at about room temperature and 200mL of water was added to it under stirring. The two layers were separated and the organic layer was washed twice, each with 200mL of water. The organic layer was dried over sodium sulphate and concentrated under vacuum at about temperature below 50°C to give pale brown thick oil which was degassed under vacuum at about temperature below 50°C for about 30min. Yield: 160g

Purity (HPLC): 98.71%

EXAMPLE 2

[0100] Preparation of 5-amino-2-n-butyl-3-[4-(3-di-n- butylaminopropoxy)benzoyl]benzofuran, compound of formula IV

a) To a solution of 145g of 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5- nitrobenzofuran, compound of formula III (prepared as in Example 1) in 1450mL of ethyl acetate, flushed twice with nitrogen, was added 7.25g of 10% palladium on carbon (50% wet) at about 25°C to about 30°C. The reaction mass was stirred under hydrogen pressure of about 3kg to about 5kg at about 25°C to about 35°C, till no pressure drop was observed. After completion of reaction, as monitored by high performance liquid chromatography (HPLC), the catalyst was filtered off carefully on a hyflo bed and the hyflo bed was washed with 290mL of ethyl acetate under nitrogen atmosphere. The filtrate and the washings were collected together and concentrated under vacuum to give 130g of pale brown thick oil.

Purity (HPLC): 96.76%

b) 75.5g of oxalic acid was slowly added at about 25°C to about 30°C to a stirred solution of the oil obtained in (a) in 650mL of ethanol. The reaction mass was stirred for about lh and filtered to give pale yellow solid which was washed with 130mL of ethanol.

Yield: 170g

170g of the above crude oxalate salt in 1785mL of methanol was stirred under reflux (about 60°C to about 65 °C) to get a clear solution. The reaction mass was stirred at reflux temperature for about 15min and then cooled to about 25°C to about 30°C. The solid obtained was filtered and washed with lOOmL of methanol. Yield: 135 g

c) To a stirred mixture of 135g of oxalate salt obtained in (b), lOOOmL of water and 400mL of dichloromethane, was added l lOmL of 1 :1 aqueous ammonia solution drop wise at about 25°C to about 30°C to adjust pH between 8 and 9. The reaction mass was stirred at about 25°C to about 30°C for about 30min. The two layers were separated and the aqueous layer was extracted twice with 400mL of dichloromethane. The organic layers were combined, then washed with water and dried over sodium sulphate. The organic layer was further treated with Norit™ charcoal, stirred for about 30min at about 25°C to about 30°C and filtered over hyflo bed. The hyflo bed was washed with 250mL of dichloromethane. The combined filtrate and washings were collected together and concentrated under vacuum to give 75g of pale brown thick oil.

Purity (HPLC): 98.34%

EXAMPLE 3

[0101] Preparation of 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5- methylsulfonamidobenzofuran (dronedarone)

a) A solution of 8g of methanesulfonyl chloride in 150mL of dichloromethane was added dropwise to a stirred solution of 30g of 5-amino-2-n-butyl-3-[4-(3-di-n- butylaminopropoxy)benzoyl]benzofuran and 10.6mL of triethylamine in 150mL of dichloromethane at about 25°C to about 30°C over about lh. The reaction mixture was stirred at about 25°C to about 30°C. After completion of reaction, as monitored by HPLC, the reaction mixture was cooled to about 10°C to about 15°C followed by addition of 150mL of water. The reaction mixture was stirred for about 15min and the two layers were separated. The organic layer was washed twice with 150mL of water, dried over sodium sulphate and concentrated under vacuum to give 35g of pale brown thick oil.

Purity (HPLC): 93.39%

Impurity compound of formula V: 4.57%

b) To a stirred solution of 35g of crude product obtained in (a) in 90mL of ethanol was added dropwise a solution of 2.5g of sodium hydroxide in 150mL of ethanol at about 20°C to about 25°C over about lh. The reaction mixture was stirred at about 25°C to about 30°C for about 30minutes. 300mL of ethyl acetate and 750mL of water were then slowly added to the reaction mixture at about 10°C to about 25°C and stirred for about 15min. The two layers were separated and the aqueous layer was extracted twice with 300mL of ethyl acetate. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to give 34g of pale brown thick oil.

Purity (HPLC): 97.67%

Impurity compound of formula V: below detection limit

c) 34g of oil obtained in (b) in 60mL of hexane was stirred at about 40°C to about 45°C to get a clear solution. The solution was further stirred for about 2h at about 25°C to about 30°C. The solution was then cooled to about 15°C to about 20°C and 30mL of hexane was added to it and further stirred for about 30minutes. The solid obtained was filtered, washed with 50mL of hexane and dried under vacuum at about 30°C to about 35°C till constant weight. Yield: 25g

Purity (HPLC): 98.15%

EXAMPLE 4

[0102] Preparation of dronedarone hydrochloride

lOg of dronedarone (prepared as in Example 3) in 30mL of acetone was stirred at about 25°C to about 30°C for about 10-15min to get a clear solution. The solution was cooled to about 5°C to about 10°C. A solution of aqueous hydrogen chloride in 5mL of acetone was added dropwise to adjust the pH to about 2.5-3. The reaction mixture was stirred at about 5°C to about 10°C for about 3.5h. The solid obtained was filtered, washed with 5mL of cold acetone and dried under vacuum at about 40°C to about 45°C till constant weight. Yield: 7g

Purity (HPLC): > 99% EXAMPLE 5

[0103] Preparation of 5-amino-2-n-butyl-3-[4-(3-di-n- butylaminopropoxy)benzoyl]benzofuran, compound of formula IV

a) To a solution of 80g of 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5- nitrobenzofuran, compound of formula III (prepared as in Example 1 ) in 700mL of ethyl acetate, flushed twice with nitrogen, was added a slurry of 4.8g of 10% palladium on carbon (50% wet) in ethyl acetate at about room temperature. The reaction mass was stirred under hydrogen pressure of about 3kg to about 4kg at about 25 to about 35°C. After completion of reaction, as monitored by high performance liquid chromatography (HPLC), the catalyst was filtered off on a hyflo bed and the hyflo bed was washed with ethyl acetate under nitrogen atmosphere. The filtrate and the washings were collected together and concentrated under vacuum to give 75g of pale brown thick oil.

b) 42g of oxalic acid was slowly added at about room temperature to a stirred solution of the oil obtained in (a) in 240mL of ethanol (industrial solvent). The reaction mass was cooled to about 20°C to about 25 °C. The reaction mass was stirred at about the same temperature for about 3h and filtered to give pale yellow solid which was washed with 40mL of ethanol (industrial solvent). The solid was dried under vacuum at about 40°C to about 45°C for about lOh to 12h. Yield: 90g

90g of above crude oxalate salt in 450mL of methanol was stirred under reflux (about 63 °C to about 67°C) to get a clear solution. The reaction mass was stirred at about reflux temperature for about 30min and then cooled to about room temperature. The reaction mass was further cooled to about 10°C to about 15°C and stirred at about the same temperature for about 2h. The solid obtained was filtered and washed with 45mL of cold (about 0°C to about 5°C) methanol. . The solid was dried under vacuum at about 40°C to about 45°C for about 8h to 1 Oh. Yield: 76g

c) To a stirred mixture of 60g of oxalate salt obtained in (b), 600mL of water and 180mL of dichloromethane, was added 90mL of 1 : 1 aqueous ammonia solution drop wise over about 30-45min to adjust the pH to between about 8 to 10. The reaction mass was stirred at about 15°C to about 20°C for about 30min. The two layers were separated and the aqueous layer was extracted twice, each with 180mL of dichloromethane. The organic layer was washed with 180mL of 10% sodium chloride solution. The organic layer was further treated with Norit™ charcoal, stirred for about 30min at about 25°C to about 30°C and filtered over hyflo bed. The hyflo bed was washed with 60mL of dichloromethane. The combined filtrate and washings were collected together and concentrated under vacuum to give pale brown thick oil which was degassed under vacuum at about temperature below 40°C for about 30min. Yield: 43g

Purity (HPLC): 99.08%

EXAMPLE 6

[0104] Preparation of 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5- methylsulfonamidobenzofuran (dronedarone)

a) A solution of 13.75g of methanesulfonyl chloride in 250mL of dichloromethane was added dropwise to a stirred solution of 50g of 5-amino-2-n-butyl-3-[4-(3-di-n- butylaminopropoxy)benzoyl]benzofuran and 17.6mL of triethylamine in dichloromethane at about room temperature. The reaction mass was stirred at about room temperature for about 30min. After completion of reaction, as monitored by HPLC, the reaction mass was cooled to about 15°C to about 20°C followed by slow addition of 250mL of water. The reaction mass was stirred for about 15min and the two layers were separated. To the organic layer at about 15°C to about 20°C, was added 150mL of water and the pH was adjusted with sodium hydroxide solution to about above 8. The organic layer was washed with water and sodium chloride solution and concentrated under vacuum to give pale brown thick oil which was degassed under vacuum at about temperature below 40°C for about 30min. Yield: 60g

Purity (HPLC): 91.04%

Impurity compound of formula V: 6.3%

b) To a stirred solution of 60g of crude product obtained in (a) in 240mL of ethanol (industrial solvent) was added drop wise a solution of 7.6g of sodium hydroxide in 240mL of ethanol (industrial solvent) at about room temperature over about lh. The reaction mass was stirred at the same temperature for about 30min. The reaction mass was then cooled to about 15°C to about 20°C. 600mL of ethyl acetate and 2400mL of water were then slowly added to the reaction mass at about 15°C to about 25°C over about 30min. The reaction mass was stirred at about room temperature for about 15min. The two layers were separated and the aqueous layer was extracted twice, each with 300mL of ethyl acetate. The combined organic layer was washed with 300mL of 10% sodium chloride solution. The organic layer was treated with 3g of Norit™ charcoal and stirred for about 30min at about room temperature. The reaction mass was filtered over hyflo bed and washed with 60mL of ethyl acetate. The filtrate and the washings were collected together and concentrated under vacuum to give pale brown thick oil which was degassed under vacuum at about temperature below 40°C for about 30min. Yield: 57g Purity (HPLC): 96.64%

Impurity compound of formula V: 0.04%

EXAMPLE 7

[0105] Preparation of dronedarone hydrochloride

To a stirred solution of 57g of dronedarone in acetone at about 0°C to about 5°C was added drop wise a solution of 13mL of aqueous hydrogen chloride in acetone to adjust pH to about 2 to about 3 and stirred for 30min at about the same temperature to get off- white slurry. The reaction mass was then stirred at about 5°C to about 10°C. The solid obtained was filtered, washed with cold acetone and dried under vacuum at about 40°C to about 45°C for about lOh to 12h. Yield: 43g

A solution of 43 g of above solid and 129mL of methanol was stirred at about room temperature for about 30min to get a clear solution and 645mL of water was then added to it. The reaction mass was cooled to about 10°C to about 15°C and stirred for about 2h. The solid obtained was filtered, washed with 129mL of water and dried under vacuum at about 45°C to about 50°C for about 12h to 14h. Yield: 40g

Purity (HPLC): 99.43%

EXAMPLE 8

[0106] Purification of Dronedarone hydrochloride

a) 50g of dronedarone hydrochloride in 1500mL of acetone was stirred under reflux for about 30min, then cooled and filtered over hyflo bed. The hyflo bed was washed with 25mL of hot (about 45°C to about 50°C) acetone. The filtrate and washings were collected together and concentrated up to 500mL of acetone under vacuum. The concentrated solution was allowed to cool to about 20°C to about 25 °C and stirred at about the same temperature for about 3h. The solid obtained was filtered and washed with 25mL of cold acetone and dried under vacuum at about 40°C to about 45°C for about lOh to 12h.

Purity (HPLC): 99.81%

EXAMPLE 9

[0107] Preparation of amorphous dronedarone hydrochloride

4g of dronedarone hydrochloride (prepared as either by Example 7 or Example 8) in 50mL methanol was stirred at about 25°C to about 30°C to get a clear solution. The solvent was removed under vacuum to obtain the title compound.

Yield: 4g EXAMPLE 10

[0108] Preparation of dronedarone hydrochloride tablets

The preparation of dronedarone hydrochloride tablet formulation below comprising dronedarone hydrochloride having 90% of particles with particle size less than 200 μπι:

the process comprising:

blending dronedarone hydrochloride, microcrystalline cellulose, lactose and HPMC; granulating said blend with solution of sodium lauryl sulfate in water; mixing the resulting granules with anhydrous colloidal silica and stearic acid; compressing the final mixture into tablets.