WO2012001673A1 - Amorphous form of dronedarone - Google Patents

Abstract

The present invention provides an amorphous form of dronedarone or salt thereof, particularly amorphous dronedarone HCl, pharmaceutical compositions comprising same, methods for its preparation and use thereof in treating cardiac arrhythmias. The amorphous dronedarone HCl has superior aqueous solubility and density characteristics as compared with crystalline dronedarone HCl.

Description

AMORPHOUS FORM OF DRONED ARONE

FIELD OF THE INVENTION

The present invention relates to an amorphous form of dronedarone hydrochloride, pharmaceutical compositions comprising same, and use thereof in treating cardiac arrhythmias.

BACKGROUND OF THE INVENTION

Dronedarone hydrochloride (also known as SR33589 or Multaq) is a drug used mainly for treating cardiac arrhythmias (irregular heartbeat). It was approved by the FDA on July 1, 2009 to help maintain normal heart rhythms in patients with a history of atrial fibrillation or atrial flutter (heart rhythm disorders). The drug is intended for use in patients whose hearts have returned to normal rhythm or in patients who take drug or undergo an electric-shock treatment to restore a normal heartbeat.

Dronedarone HCI is chemically named 2-butyl-3-[4-[3- (dibutylamino)propoxy]benzoyl]-5-(methylsulfonamido)benzofuran hydrochloride, and is represented by the following chemical structure:

o

Dronedarone and salts thereof and processes for their preparation are disclosed in US 5,223,510; US 7,323,493; EP 471609; WO 2007/140989; EP 1351907; EP 1343777; US 7,312,345; and WO 2009/044143.

A new form of a compound may possess physical properties that differ from, and are advantageous over, those of other crystalline or amorphous forms. These include, packing properties such as molar volume, density and hygroscopicity; thermodynamic properties such as melting temperature, vapor pressure and solubility; kinetic properties such as dissolution rate and stability under various storage conditions; surface properties such as surface area, wettability, interfacial tension and shape; mechanical properties such as hardness, tensile strength, compactibility, handling, flow and blend; and filtration properties. Variations in any one of these properties may affect the chemical and pharmaceutical processing of a compound as well as its bioavailability and may often render the new form advantageous for pharmaceutical and medical use.

There still remains an unmet need for solid state forms of dronedarone or salt thereof having good physicochemical properties, desirable bioavailability, and advantageous pharmaceutical parameters.

SUMMARY OF THE INVENTION

The present invention provides a new amorphous form of dronedarone hydrochloride, pharmaceutical compositions comprising this form, methods for its preparation and use thereof in treating cardiac arrhythmias.

The present invention is based in part on the unexpected finding that the new amorphous form disclosed herein possesses advantageous physicochemical properties which render its processing as a medicament beneficial. The amorphous form of the present invention has good bioavailability as well as desirable stability characteristics enabling its incorporation into a variety of different formulations particularly suitable for pharmaceutical utility. For example, the amorphous form of dronedarone HCl of the present invention is more soluble than the crystalline form in aqueous vehicles. Additionally, the amorphous form has lower bulk and tapped densities as compared to the crystalline form. Thus, the amorphous dronedarone HCl of the present invention may have an improved bioavailability and it can be easily formulated to a variety of solid dosage forms (e.g. tablets).

According to one aspect, the present invention provides an amorphous form of dronedarone or salt thereof. In one embodiment, the present invention provides an amorphous form of dronedarone HCl. In another embodiment, the present invention provides an amorphous form of dronedarone HCl characterized by an X-ray diffraction (XRD) profile substantially as shown in any of Figures 1A, IB, 6A, 11A, 11B, 11C, 11D, 12A, 12B or 12C. In yet another embodiment, the present invention provides an amorphous form of dronedarone HCl characterized by a DSC profile substantially as shown in any of Figures 2, 7, 13 or 17. In other embodiments, the amorphous form of dronedarone HCl has a glass transition temperature between about 7°C and about 50°C, for example between about 17°C and about 50°C, between about 30°C and about 50°C, or between about 45°C and about 49°C. In one embodiment, the glass transition temperature is about 35°C. In another embodiment, the glass transition temperature is about 47°C. In other embodiments, the amorphous form is characterized by an IR spectrum substantially as shown in any of Figures 3, 8 or 14. In some embodiments, the amorphous form of dronedarone HCl is characterized by an IR spectrum having characteristic peaks at about 774±4, 806±4, 843±4, 905±4, 972±4, 1053±4, 1150±4, 1249±4, 1331±4, 1372±4, 1422±4, 1461±4, 1502±4, 1572±4, 1598±4, 1637±4, 2513±4, 2620±4, 2871±4, 2958±4, and 3064±4 cm^"1. In certain embodiments, the amorphous form of dronedarone HCl is characterized by a Raman spectrum substantially as shown in any of Figures 4, 9 or 15. In particular embodiments, the Raman spectrum of the amorphous dronedarone HCl has characteristic peaks at about 292±4, 426±4, 528±4, 675±4, 860±4, 904±4, 1083±4, 1124±4, 1169±4, 1198±4, 1258±4, 1319±4, 1370±4, 1427±4, 1453±4, 1571±4, 1599±4, 1641±4, 2874±4, 2935±4, 2964±4, and 3069±4 crn In another embodiment, the amorphous form of dronedarone HCl is characterized by a TGA profile substantially as shown in any of Figures 5, 10, 16 or 18.

In one embodiment, the present invention provides a process for preparing amorphous dronedarone HCl, the process comprising the steps of:

(a) heating dronedarone HCl to melt; and

(b) cooling the melted dronedarone HCl obtained in step (a) under vacuum, so as to provide amorphous dronedarone HCl.

In one embodiment, the cooling in step (b) is selected from fast cooling and slow cooling. Each possibility represents a separate embodiment of the invention.

In another embodiment, the present invention provides a process for preparing amorphous dronedarone HCl, the process comprising the steps of: (a) dissolving dronedarone HCl in water; and

(b) evaporating the water by freeze drying so as to precipitate amorphous dronedarone HCl.

In yet another embodiment, the present invention provides a process for preparing amorphous dronedarone HCl, the process comprising the steps of:

(a) dissolving dronedarone HCl in at least one solvent; and

(b) evaporating the solvent so as to precipitate amorphous dronedarone HCl.

In particular embodiments, the at least one solvent is selected from the group consisting of acetone, methanol, CH₂CI₂, EtOAc, MEK, MTBE and mixtures thereof. Each possibility represents a separate embodiment of the invention.

In additional embodiments, the at least one solvent is selected from acetone, acetone:EtOAc (2: 1), acetone:MEK (2: 1), CH₂C1₂, CH₂C1₂:MEK (1 : 1), CH₂C1₂:MTBE (2: 1), and methanol. Each possibility represents a separate embodiment of the invention.

In further embodiments, the present invention provides a process for preparing amorphous dronedarone HCl, the process comprising the step of grinding crystalline dronedarone HCl so as to provide amorphous dronedarone HCl.

In certain embodiments, the present invention provides a pharmaceutical composition comprising an amorphous form of dronedarone or salt thereof, preferably amorphous dronedarone HCl as an active ingredient, and a pharmaceutically acceptable carrier.

In a particular embodiment, the pharmaceutical composition is in the form of a tablet.

In various embodiments, the present invention provides a pharmaceutical composition comprising an amorphous form of dronedarone or salt thereof, preferably amorphous dronedarone HCl as an active ingredient, and a pharmaceutically acceptable carrier for use in treating cardiac arrhythmias.

In some embodiments, the present invention provides a method of treating cardiac arrhythmias comprising administering to a subject in need thereof an effective amount of an amorphous form of dronedarone or salt thereof, preferably amorphous dronedarone HCl, or a pharmaceutical composition comprising an amorphous form of dronedarone or salt thereof.

In additional embodiments, the present invention provides the use of an amorphous form of dronedarone or salt thereof, preferably amorphous dronedarone HCl for the preparation of a medicament for treating cardiac arrhythmias.

In various embodiments, the subject is a mammal, such as a human.

Further embodiments and the full scope of applicability of the present invention will become apparent from the detailed description given hereinafter. However, it should be understood that the detailed description and examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 illustrates characteristic X-ray diffraction patterns of amorphous dronedarone HCl, obtained by fast or slow cooling (panels A and B, respectively) of a dronedarone HCl melt under vacuum. Also shown for comparison is the X-ray diffraction pattern of crystalline dronedarone HCl Form I (dronedarone API, panel C).

Figure 2 illustrates a characteristic Differential Scanning Calorimetry (DSC) profile of an amorphous form of dronedarone HCl, obtained by fast or slow cooling of a dronedarone HCl melt under vacuum.

Figure 3 illustrates a characteristic Fourier Transform Infrared (FTIR) spectrum of an amorphous form of dronedarone HCl obtained by fast or slow cooling of a dronedarone HCl melt under vacuum.

Figure 4 illustrates a characteristic Fourier Transform - Raman (FT-Raman) spectrum of an amorphous form of dronedarone HCl obtained by fast or slow cooling of a dronedarone HCl melt under vacuum. Figure 5 illustrates characteristic Thermogravimetric analysis (TGA) profiles of an amorphous form of dronedarone HCl, obtained by fast or slow cooling of a dronedarone HCl melt under vacuum.

Figure 6 illustrates a characteristic X-ray diffraction pattern of amorphous dronedarone HCl, obtained by dissolution of dronedarone API in water followed by water removal using freeze drying (panel A). Also shown for comparison is the X-ray diffraction pattern of crystalline dronedarone HCl (dronedarone API, panel B).

Figure 7 illustrates a characteristic Differential Scanning Calorimetry (DSC) profile of amorphous dronedarone HCl, obtained by dissolution of dronedarone API in water followed by water removal using freeze drying.

Figure 8 illustrates a characteristic Fourier Transform Infrared (FTIR) spectrum of amorphous dronedarone HCl, obtained by dissolution of dronedarone API in water followed by water removal using freeze drying.

Figure 9 illustrates a characteristic Fourier Transform - Raman (FT-Raman) spectrum of amorphous dronedarone HCl, obtained by dissolution of dronedarone API in water followed by water removal using freeze drying.

Figure 10 illustrates a characteristic Thermogravimetric analysis (TGA) profile of amorphous dronedarone HCl, obtained by dissolution of dronedarone API in water followed by water removal using freeze drying.

Figure 11 illustrates characteristic X-ray diffraction patterns of amorphous dronedarone HCl, obtained by dissolution of dronedarone API in C¾CI₂ (panel A), acetone:MEK 2:1 (panel B), acetone:EtOAc 2:1 (panel C) or in acetone (panel D), followed by removal of solvent using rotary evaporator below 50°C. Also shown for comparison is the X-ray diffraction pattern of crystalline dronedarone HCl (dronedarone API, panel E).

Figure 12 illustrates characteristic X-ray diffraction patterns of amorphous dronedarone HCl, obtained by dissolution of dronedarone API in MeOH (panel A), CH₂C1₂:MTBE 2:1 (panel B) or CH₂C1₂:MEK 1 :1 (panel C), followed by removal of solvent using rotary evaporator below 50°C. Also shown for comparison are the X-ray diffraction patterns of crystalline dronedarone HCl obtained by dissolution of dronedarone API in CH₂Cl₂:EtOAc 2:1 followed by removal of solvents using rotary evaporator below 50°C (panel D) and dronedarone API (panel E).

Figure 13 illustrates a characteristic Differential Scanning Calorimetry (DSC) profile of amorphous dronedarone HCl, obtained by dissolution of dronedarone API in acetone followed by removal of solvent using rotary evaporator below 50°C.

Figure 14 illustrates a characteristic Fourier Transform Infrared (FTIR) spectrum of amorphous dronedarone HCl, obtained by dissolution of dronedarone API in CH₂CI₂ followed by removal of solvent using rotary evaporator below 50°C.

Figure 15 illustrates a characteristic Fourier Transform - Raman (FT-Raman) spectrum of amorphous dronedarone HCl, obtained by dissolution of dronedarone API in CH₂C1₂ followed by removal of solvent using rotary evaporator below 50°C.

Figure 16 illustrates characteristic Thermogravimetric analysis (TGA) profiles of amorphous dronedarone HCl, obtained dissolution of dronedarone in acetone:MEK 2:1 (upper panel), acetone:EtOAc 2:1 (middle panel) and acetone (lower panel), followed by removal of solvent using rotary evaporator below 50°C.

Figure 17 illustrates a characteristic Differential Scanning Calorimetry (DSC) profile of an amorphous form of dronedarone HCl, obtained by slow cooling of a dronedarone HCl melt under vacuum.

Figure 18 illustrates a characteristic Thermogravimetric analysis (TGA) profile of an amorphous form of dronedarone HCl, obtained by slow cooling of a dronedarone HCl melt under vacuum.

Figure 19 illustrates a characteristic dynamic vapor sorption (DVS) isotherm plot of an amorphous form of dronedarone HCl. Sorption (♦); Desorption (■).

Figure 20 illustrates a characteristic dynamic vapor sorption (DVS) isotherm plot of crystalline dronedarone HCl. Sorption (♦); Desorption (■).

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a novel amorphous form of 2-butyl-3-[4-[3- (dibutylamino)propoxy]benzoyl]-5-(methylsulfonamido)benzofuran hydrochloride. The present invention is further directed to pharmaceutical compositions comprising the amorphous form and a pharmaceutically acceptable carrier and their use in treating cardiac arrhythmias.

The present invention is further directed to methods of preparing the novel amorphous form of dronedarone HC1.

Polymorphs are two or more solid state phases of the same chemical compound that possess different arrangement and/or conformation of the molecules. Different polymorphs of an active pharmaceutical compound can exhibit different physical and chemical properties such as color, stability, processability, dissolution and even bioavailability.

One of the important physical properties of a compound used as an active ingredient of a medicament is its solubility in aqueous media, e.g. gastric and intestinal fluids. This may bear consequences on the absorption ability of the compound and hence on its bioavailability. The identification and characterization of various morphic or amorphic forms of a pharmaceutically active compound is therefore of great significance in obtaining medicaments with desired properties including a specific dissolution rate, milling property, bulk density, thermal stability or shelf-life. Surprisingly, an amorphous form of dronedarone, such as the amorphous dronedarone HC1 form disclosed herein possesses improved characteristics of bulk density and solubility in aqueous media. Furthermore, the amorphous dronedarone HC1 of the present invention has adequate chemical and solid state stability and it can therefore be stored over prolonged periods of time.

In one embodiment, the present invention provides an amorphous form of dronedarone or salt thereof such as the amorphous form of dronedarone HC1, which is characterized by an X-ray diffraction pattern having a single broad peak expressed between about 15 and about 35 degrees two theta [2Θ°] as is shown in any of Figures 1A, IB, 6A, 11 A, 11B, 11C, 11D, 12A, 12B or 12C. In some embodiments, the amorphous form is further characterized by its glass transition temperature and by using various techniques including infrared spectroscopy, Raman spectrometry, and thermal analysis (e.g. thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC)). g In one embodiment, the amorphous form of dronedarone HCl of the present invention is characterized by DSC profiles substantially as shown in any of Figures 2, 7, 13 or 17. In another embodiment, the amorphous form of dronedarone HCl of the present invention is further characterized by a TGA profile substantially as shown in any of Figures 5, 10, 16 or 18. In other embodiments, the amorphous form has a glass transition temperature between about 7°C and about 50°C, for example between about 17°C and about 50°C, between about 30°C and about 50°C, or between about 45 °C and about 49 °C. In another embodiment, the form is characterized by infrared spectrum substantially as shown in any of Figures 3, 8 or 14 with characteristic peaks at the following wavenumbers: about 774, about 806, about 843, about 905, about 972, about 1053, about 1150, about 1249, about 1331, about 1372, about 1422, about 1461, about 1502, about 1572, about 1598, about 1637, about 2513, about 2620, about 2871, about 2958, and about 3064 cm^"1. In other embodiments, the amorphous form of dronedarone HCl is characterized by Raman spectrum substantially as shown in any of Figures 4, 9 or 15 with characteristic peaks at the following wavenumbers: about 292, about 426, about 528, about 675, about 860, about 904, about 1083, about 1124, about 1169, about 1198, about 1258, about 1319, about 1370, about 1427, about 1453, about 1571, about 1599, about 1641, about 2874, about 2935, about 2964, and about 3069 cm^'1. Each possibility represents a separate embodiment of the present invention.

In other embodiments, the present invention further provides processes for the preparation of amorphous dronedarone HCl. The processes include thermal precipitations by fast or slow cooling, precipitations from saturated solutions and precipitations under high pressure. In one embodiment, these processes involve the use of dronedarone HCl, such as crystalline dronedarone API as the starting material or any other dronedarone HCl prepared by any methods known in the art, including, for example, the methods described in WO 2009/044143, EP 1351907, EP 1343777 or any other synthetic method. The contents of all of the aforementioned references are hereby incorporated by reference in their entirety. Alternatively, dronedarone free base made in accordance with any method known in the art and converted to its hydrochloride salt by conventional methods can be used as the starting material in the processes of the present invention. According to one embodiment, the dronedarone HCl starting material is heated until fully melted, preferably under vacuum followed by controlled precipitation by slow/fast cooling. According to another embodiment, the dronedarone HC1 starting material is dissolved in water. The water is then removed using freeze drying (lyophilization). According to an alternative embodiment, the dronedarone HC1 starting material is dissolved in a suitable solvent or a mixture of solvents, e.g., at room temperatures or at temperatures below the solvent boiling point. The solvent is then removed by evaporation. Suitable solvents include, but are not limited to acetone, methanol, methylene chloride (CH₂C1₂), ethyl acetate (EtOAc), methyl ethyl ketone (MEK), methyl t-butyl ether (MTBE) and mixtures thereof including, but not limited to, acetone:EtOAc (2:1), acetone:ME (2: 1), CH₂C1₂:MEK (1:1), and CH₂C1₂:MTBE (2:1). Each possibility represents a separate embodiment of the invention. In yet another embodiment, the dronedarone HC1 starting material is ground using e.g. mortar and pestle until transformation to the amorphous form occurs.

Additional methods for the preparation of amorphous dronedarone HC1 include, for example, precipitation from a suitable solvent, precipitation by cooling under vacuum, sublimation, growth from a melt, solid state transformation from another phase, precipitation from a supercritical fluid, and jet spraying. Techniques for precipitation from a solvent or solvent mixture include, for example, evaporation of the solvent, decreasing the temperature of the solvent mixture, freeze drying the solvent mixture, and addition of anti-solvents (counter-solvents) to the solvent mixture. The term "anti-solvent" as used herein refers to a solvent in which the compound has low solubility.

Suitable solvents and anti-solvents for preparing the amorphous form include polar and nonpolar solvents. The choice of solvent or solvents is typically dependent upon one or more factors, including solubility of the compound in such solvent and vapor pressure of the solvent. Combinations of solvents may be employed; for example, the compound may be solubilized into a first solvent followed by the addition of an anti-solvent to decrease the solubility of the compound in the solution and to induce precipitation. Suitable solvents include, but are not limited to, polar aprotic solvents, polar protic solvents, and mixtures thereof. Particular examples of suitable polar protic solvents include, but are not limited to, alcohols such as methanol, ethanol, and isopropanol. Particular examples of suitable polar aprotic solvents include, but are not limited to, acetonitrile, tetrahydrofuran (THF), CH₂C1₂, acetone, dimethylformamide, dimethylsulfoxide, EtOAc, MEK and MTBE.

The amorphous form may be also obtained by distillation or solvent addition techniques such as those known to those skilled in the art. Suitable solvents for this purpose include any of those solvents described herein, including protic polar solvents, such as alcohols (including those listed above), aprotic polar solvents (including those listed above), and also ketones (for example, acetone, methyl ethyl ketone, and methyl isobutyl ketone).

Several non-limiting processes used to prepare amorphous dronedarone or amorphous dronedarone salt are provided herein.

Methods for "precipitation from solution" include, but are not limited to, evaporation of a solvent or solvent mixture, a concentration method, a slow cooling method, a fast cooling method, a reaction method (diffusion method, electrolysis method), a hydrothermal growth method, a fusing agent method, and so forth. The solution can be a saturated solution or supersaturated solution, optionally heated to temperatures below the solvent boiling point. The recovery of the forms can be done for example, by filtering the suspension and drying. Alternatively, the solvents may be removed by rotary evaporation at desired temperatures.

Within the scope of the present invention are high pressure techniques where the active ingredient is compressed using various forces (e.g. grinding) as is known in the art.

The novel dronedarone amorphous form, such as the amorphous dronedarone HC1 disclosed herein, is useful as a pharmaceutical for treating cardiac arrhythmias. The present invention thus provides pharmaceutical compositions comprising the amorphous form disclosed herein and a pharmaceutically acceptable carrier. The amorphous form can be safely administered orally or non-orally. Routes of administration include, but are not limited to, oral, topical, mucosal, nasal, parenteral, gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intracerebroventricular, intracerebral, subcutaneous, ophthalmic, transdermal, rectal, buccal, epidural and sublingual. Typically, amorphous dronedarone or salt thereof is administered orally. The pharmaceutical compositions can be formulated as tablets (including e.g. film-coated tablets), powders, granules, capsules (including soft capsules), orally disintegrating tablets, and sustained-release preparations as is well known in the art.

Pharmacologically acceptable carriers that may be used in the context of the present invention include various organic or inorganic carriers including, but not limited to, excipients, lubricants, binders, disintegrants, water-soluble polymers and basic inorganic salts. The pharmaceutical compositions of the present invention may further include additives such as, but not limited to, preservatives, antioxidants, coloring agents, sweetening agents, souring agents, bubbling agents and flavorings.

Suitable excipients include e.g. lactose, D-mannitol, starch, cornstarch, crystalline cellulose, light silicic anhydride and titanium oxide. Suitable lubricants include e.g. magnesium stearate, sucrose fatty acid esters, polyethylene glycol, talc and stearic acid. Suitable binders include e.g. hydroxypropyl cellulose, hydroxypropylmethyl cellulose, crystalline cellulose, a-starch, polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan and low-substitutional hydroxypropyl cellulose. Suitable disintegrants include e.g. crosslinked povidone (any crosslinked l-ethenyl-2- pyrrolidinone homopolymer including polyvinylpyrrolidone (PVPP) and l-vinyl-2- pyrrolidinone homopolymer), crosslinked carmellose sodium, carmellose calcium, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cornstarch and the like. Suitable water-soluble polymers include e.g. cellulose derivatives such as hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, methyl cellulose and carboxymethyl cellulose sodium, sodium polyacrylate, polyvinyl alcohol, sodium alginate, guar gum and the like. Suitable basic inorganic salts include e.g. basic inorganic salts of sodium, potassium, magnesium and/or calcium. Particular embodiments include the basic inorganic salts of magnesium and/or calcium. Basic inorganic salts of sodium include, for example, sodium carbonate, sodium hydrogen carbonate, disodiumhydrogenphosphate, etc. Basic inorganic salts of potassium include, for example, potassium carbonate, potassium hydrogen carbonate, etc. Basic inorganic salts of magnesium include, for example, heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium metasilicate aluminate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite, aluminahydroxidemagnesium and the like. Basic inorganic salts of calcium include, for example, precipitated calcium carbonate, calcium hydroxide, etc.

Suitable preservatives include e.g. sodium benzoate, benzoic acid, and sorbic acid. Suitable antioxidants include e.g. sulfites, ascorbic acid and a-tocopherol. Suitable coloring agents include e.g. food colors such as Food Color Yellow No. 5, Food Color Red No. 2 and Food Color Blue No. 2 and the like. Suitable sweetening agents include e.g. dipotassium glycyrrhetinate, aspartame, stevia and thaumatin. Suitable souring agents include e.g. citric acid (citric anhydride), tartaric acid and malic acid. Suitable bubbling agents include e.g. sodium bicarbonate. Suitable flavorings include synthetic substances or naturally occurring substances, including e.g. lemon, lime, orange, menthol and strawberry.

The amorphous dronedarone HC1 is particularly suitable for oral administration in the form of tablets, capsules, pills, dragees, powders, granules and the like. A tablet may be made by compression or molding, optionally with one or more excipients as is known in the art. For example, molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.

The tablets and other solid dosage forms of the pharmaceutical compositions described herein may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices and the like. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

The present invention provides a method of treating cardiac arrhythmias comprising administering to a subject in need thereof an effective amount of a composition comprising amorphous dronedarone, for example the amorphous dronedarone HC1 described herein, or any other amorphous form of dronedarone or salt thereof. "A therapeutically effective amount" as used herein refers to an amount of an agent which is effective, upon single or multiple dose administration to the subject in providing a therapeutic benefit to the subject. In one embodiment, the therapeutic benefit is prevention of cardiac arrhythmias. In another embodiment, the therapeutic benefit is a delayed conduction of the electrical impulse at the cardiac cell. In yet another embodiment, the therapeutic benefit is the prolongation of the refractory period (absolute period and efficacious period). In a further embodiment, the therapeutic benefit is an increase in the duration of the action potential of the cardiac cell. In additional embodiments, the amorphous form is used for the preparation of a medicament for treating cardiac arrhythmias.

The present invention further provides the administration of the amorphous dronedarone form in combination therapy with one or more other active ingredients. The combination therapy may include the two or more active ingredients within a single pharmaceutical composition as well as the two or more active ingredients in two separate pharmaceutical compositions administered to the same subject simultaneously or at a time interval determined by a skilled artisan.

The principles of the present invention are demonstrated by means of the following non-limiting examples.

EXAMPLES

Example 1: General Preparation and Assessment Methods of Dronedarone

Forms

1. Reagents

Acetonitrile, HPLC grade, Sigma, Lot No.07278PH; Merck, Lot No. IB01F60055

Dichloride methane, Alfa Aesar, HPLC grade, Lot No. C27S008

Methanol, AR, SCRC, Lot No. T20090912; HPLC grade, Merck, Lot No. SB0SF60097

Ethyl Acetate, AR, Yixing Secondary Chemical Company, Lot No. 090607 Acetone, AR, Sinopharm Chemical Reagent Co. Ltd, Lot No. 090104 tert-Butyl methyl ether, HPLC grade, Fluka, Lot No. 1359496

MEK, AR, SCRC, Lot No. T20090724

DMSO, HPLC grade, Sigma, Lot No. 27496kk

TFA, HPLC grade, Merck, Lot No. S6002262 009

Hydrochloric acid, AR, SCRC, Lot No. T20100302

Potassium chloride, AR, SCRC, Lot No. F20090409

Sodium dihydrogen phosphate, AR, SCRC, Lot No. F20100330

Acetic acid, AR, Jiangsu Qiangsheng chemical reagents, Lot No. 20100221

Sodium hydroxide, AR, Shanghai Lingfeng chemical reagents, Lot No. 081118

Potassium biphthalate, GR, Shanghai experimental reagents, Lot No. 070423

Monobasic potassium phosphate, AR, SCRC, Lot No. F20100413

Sodium lauryl sulfate, AR, SCRC, Lot No. F20080521

Lecithin, laboratory grade, Fisher chemical, Lot No. 091043

Sodium taurocholate, laboratory grade, Sigma, Lot No. 0001428479

Sodium chloride, AR, Jiangsu Qiangsheng chemical reagents, Lot No.12

2. Instruments

Sartorius CP 225D Balance

Mettler Toledo MX5 Balance

ELGA Water Purification Equipment

Waters 2695_2998

Mettler Toledo DSC

Mettler Toledo TGA Mettler Toledo TGA/DSC

Rigaku D/MAX 2200 X-ray powder diffractometer

Thermo Nicolet 380 FT-IR

Nikon LV100 Polarized Light Microscopy

Eyela FDU-1100 freeze dryer

Jobin Yvon LabRam-lB FT-Raman

SMS DVS

Mettler Toledo Seven Multi pH meter

Binder KBF115 Stability Chamber

GZX-9140MBE oven

ERWEKA SVM203 Tapped Density Tester

3. XRPD, DSC, TGA, and HPLC methods

3.1 XRPD method

Details of XRPD method used in the tests are mentioned below:

- X-ray Generator: Cu, ka, (λ=1.54056 )

- Tube Voltage: 40 kV, Tube Current: 40 mA

- DivSlit: 1 deg

- DivH.L.Slit: 10 mm

- SctSlit: 1 deg

- RecSlit: 0.15 mm

- Monochromator: Fixed Monochromator

- Scanning Scope: 2-40 deg

- Scanning Step: 10 deg/min 3.2 DSC and TGA methods

Details of DSC method used in the tests are mentioned below:

- Heat from 0 °C or 25 °C to 200 °C at 10 °C /min

Details of DSC (topem) method used in the tests are mentioned below:

- Heat from 0 °C to 150 °C at 2 °C /min

Details of TGA method used in the tests are mentioned below:

- Heat from 25 °C or 30 °C to 300 °C at 10 °C /min

3.3 FT-IR and FT-Raman method

Details of FT-IR method used in the tests are mentioned below:

- No. of scan: 32

- Time for collection: 38 s

- Scan Range: 400-4000 cm^"1

- Resolution: 4

Details of FT-Raman method used in the tests are mentioned below:

- Laser wave: 632.8 nm

- Power: 1 mW

- Resolution: 1 cm^"1

- Time for integration: 50 s

3.4 HPLC method

Details of chromatographic conditions used in the tests are mentioned in Table 1 below (The typical retention time of dronedarone main peak is 18.2 min): Table 1.

4. General Preparation Methods

4.1 Method I: Thermal heating/cooling experiments

Crystalline dronedarone HCl (Dronedarone API; Batch No. 081107) was heated to melt under vacuum followed by controlled precipitation of the melted compound by fast/slow cooling.

4.2 Method II: Precipitation from a water solution using freeze drying

Crystalline dronedarone HCl (Dronedarone API; Batch No. 081107) was dissolved in water. The water was then removed by freeze drying.

4.3. Method III: Fast precipitation from saturated solutions

Crystalline dronedarone HCl (Dronedarone API; Batch No. 081107) was dissolved in different solvents at room temperatures as follows: acetone, acetone:EtOAc=2:l, acetone:MEK=2:l, CH₂C1₂, CH₂C1₂:MEK=1 :1, CH₂C1₂:MTBE=2:1 and MeOH. Solvents were then removed using rotary evaporation below 50 °C. 4.4 Method IV: Grinding

Crystalline dronedarone HC1 (Dronedarone API; Batch No. 081107) was ground by using mortar and pestle for 10, 20 or 30 minutes.

5. Methods of Assessment of Physical and Chemical Properties

5.1 Hygroscopicity

Details of hygroscopicity measurements are mentioned below: The amorphous form was tested for its sorption/desorption profiles at 25 °C under 0-90 % relative humidity. The following criteria were used for the classification:

Deliquescent: Sufficient water is absorbed to form a liquid.

Very hygroscopic: Increase in mass is equal to or greater than 15 %.

Hygroscopic: Increase in mass is less than 15 % and equal to or greater than

2 %.

Slightly hygroscopic: Increase in mass is less than 2 % and equal to or greater than 0.2 %.

Non-hygroscopic: Increase in mass is less than 0.2 %.

5.2 Aqueous solubility

Details of solubility measurements are mentioned below:

Testing media: water, pH 1.2, 4.5, 6.8, 7.4 USP buffers, 0.01 N HC1, 0.1 N HC1, SGF, FaSSIF, FeSSIF.

pH 1.2 (USP): 50 mL of 0.2 M potassium chloride solution was placed in a 200 mL volumetric flask followed by the addition of 85.0mL of 0.2M hydrochloric acid solution and water.

pH 4.5 (USP): 50 mL of 0.2 M potassium biphthalate solution was placed in a 200 mL volumetric flask followed by the addition of 8.8 mL of 0.2 M sodium hydroxide solution and water. pH 6.8 (USP): 50 mL of 0.2 M monobasic potassium phosphate solution was placed in a 200 mL volumetric flask followed by the addition of 22.4 mL of 0.2 M sodium hydroxide solution and water.

pH 7.4 (USP): 50 mL of 0.2 M monobasic potassium phosphate solution was placed in a 200 mL volumetric flask followed by the addition of 39.1 mL of 0.2 M sodium hydroxide solution and water.

Simulated gastric fluid (SGF): 0.01 N HCl, 0.05 % sodium lauryl sulfate, 0.2 %

NaCl.

Fasted state simulated intestinal fluid (FaSSIF): 29 mM NaH₂P0₄, 3 mM Na taurocholate, 0.75 mM lecithin, 103 mM NaCl, NaOH to pH 6.5.

Fed state simulated intestinal fluid (FeSSIF): 144 mM acetic acid, 15 mM Na taurocholate, 3.75 mM lecithin, 204 mM NaCl, NaOH to pH 5.0.

Testing procedure: Amorphous or crystalline dronedarone HCl (testing compound) were added into different media and were kept shaken for 24 hours at 25 °C. Then, the saturated solution was filtered and the concentration of the testing compound was determined in the filtrate by HPLC. The final pH was then tested.

5.3 Solution stability

Details of stability in solution measurements are mentioned below:

Testing media: 0.1 N HCl, 50 mM pH 2, 4, 6, 8 phosphate buffers, 50 mM pH 2 phosphate buffers + 0.3 % H₂0₂, 50 mM pH 8 phosphate buffers + 0.3 % H₂0_2.

5.3.1 Solution stability in 0.1 N HCl, 50 mM pH 2, 4 phosphate buffers

About 10 mg of compound were dissolved in methanol to obtain 1 mg/mL stock solution, which was diluted with different media (0.1 N HCl, 50 mM pH 2, 4 phosphate buffers) to about 100 μg/mL. The solution was then filtered through 0.22 μιη filter and the filtrate was stored at 40 °C for 24 hours. The concentration and total related substances were tested once per hour.

5.3.2 Solution stability in 50 mM pH 6 phosphate buffer

About 10 mg of compound were dissolved in DMSO to obtain 1 mg/mL stock solution, which was diluted with 50 mM pH 6 phosphate buffer to about 100 μg/mL. The solution was then filtered through 0.22 μιη filter and the filtrate was stored at 40 °C for 24 hours. The concentration and total related substances were tested once per hour.

5.3.3 Solution stability in 50 mM pH 8 phosphate buffer

About 10 mg of compound were dissolved in MeOH to obtain 1 mg/mL stock solution, which was diluted with 50 mM pH 8 phosphate buffer or 50 mM pH 8 phosphate buffer + 0.3 % H₂0₂.

5.4 Solid stability

Details of solid stability measurements are mentioned below:

Testing conditions: 40 °C, 60 °C, 40 °C/RH 75 %, 60 °C/RH 75 %, light.

Testing procedure: About 2 mg of compound were weighed in a glass vial and samples were stored under different conditions for 1 week or 2 weeks separately. The original compound was stored at -20 °C as control. The compounds were then checked for their physical appearances. The total assay and related substances were determined by HPLC at the end of the first and second week.

5.5 Physical stability

Details of physical stability measurements are mentioned below:

Testing conditions: 40 °C, 60 °C, 40 °C/RH 75 %, 60 °C/RH 75 %, light.

Testing procedure: About 50 mg of compound were weighed in a glass vial and samples were stored under different conditions for 1 week and 2 weeks separately. The original compound was stored at -20 °C as control. XRPD and DSC were measured at the end of the first and second week.

5.6 Bulk/Tapped density

Details of bulk/tapped density measurements are mentioned below:

Bulk density testing: A quantity of the compound sufficient to complete the test was passed through a 1.0 mm (No.18) screen to break up agglomerates that may have formed during storage. Then a quantity of the compound was weighed (M) and placed into 10 mL graduated cylinder. The powder was leveled without compacting, and the unsettled apparent volume was read (Vo). The bulk density was calculated in g per mL, according to the formula: Bulk Density=M Vo

Tapped density testing: A quantity of the compound sufficient to complete the test was passed through a 1.0 mm (No.18) screen to break up agglomerates that may have formed during storage. Then, a quantity of the compound was weighed (M) and placed into 10 mL graduated cylinder. The powder was leveled without compacting. The cylinder was tapped 500 times initially and the tapped volume, Va, was measured to the nearest graduated unit. The tapping was repeated for additional 750 times and the tapped volume, Vb, was measured to the nearest graduated unit. If the difference between the two volumes was less than 2%, Vb was the final tapped volume, Vf. The tapped density was calculated, in g per mL, according to the formula:

Tapped Density=M/Vf

Example 2: Amorphous Dronedarone HC1 (Method I)

General method I was performed. Thus, Dronedarone API was heated to melt and then cooled down fast (quenching) or slow. This new amorphous form showed a broad X-ray diffraction peak between about 15 and about 35 [2Θ°] characteristic of an amorphous powder (Figure 1, panels A and B). Figure 2 (bottom curve) illustrates a characteristic DSC profile. The glass transition temperature of the different batches is between 45 °C and 49 °C. Figure 3 illustrates a characteristic IR spectrum with peaks at about 774, 806, 843, 905, 972, 1053, 1150, 1249, 1331, 1372, 1422, 1461, 1502, 1572, 1598, 1637, 2513, 2620, 2871, 2958, and 3064 cm^"1. Figure 4 illustrates a characteristic Raman spectrum with peaks at about 292, 426, 528, 675, 860, 904, 1083, 1124, 1169, 1198, 1258, 1319, 1370, 1427, 1453, 1571, 1599, 1641, 2874, 2935, 2964, and 3069 cm^"1. Figure 5 illustrates characteristic TGA profiles with about 1.5% weight loss from room temperatures to 135°C. When performing a scale up using general method I with controlled slow cooling of the melt, the glass transition temperature of the amorphous form is about 35.56 °C (Figure 17). Figure 18 illustrates a characteristic TGA profile of the scale up of the amorphous form. Example 3: Amorphous Dronedarone HC1 (Method II)

General method II was performed. Thus, Dronedarone API was dissolved in water followed by their removal with lyophilization (freeze-drying). The amorphous form showed a broad X-ray diffraction peak between about 15 and about 35 [2Θ°] characteristic of an amorphous powder (Figure 6, panel A). Figure 7 (bottom curve) illustrates a characteristic DSC profile. The amorphous form prepared by this method was relatively less stable as is evident from the DSC peak at about 140°C and relatively low glass transition temperature between about 30 °C and about 35 °C. Figure 8 illustrates a characteristic IR spectrum with peaks at about 774, 813, 843, 905, 972, 1053, 1150, 1250, 1331, 1372, 1422, 1461, 1573, 1598, 1637, 2509, 2616, 2871, 2958, and 3057 cm^"1. This IR spectrum is substantially similar to the spectrum obtained by using Method I (Example 2) and could be used as an alternative for the identification of the amorphous form of the present invention. Figure 9 illustrates a characteristic Raman spectrum with peaks at about 292, 369, 429, 528, 649, 716, 751, 821, 850, 911, 978, 1067, 1127, 1166, 1198, 1264, 1315, 1370, 1427, 1459, 1510, 1577, 1603, 1637, 2878, 2916, 2932, 2967, and 3075 cm^"1. This Raman spectrum is substantially similar to the spectrum obtained by using Method I (Example 2) and could be used as an alternative for the identification of the amorphous form of the present invention. Figure 10 illustrates a characteristic TGA profile with about 1.2% weight loss from room temperatures to 96°C and about 1.4% weight loss from 96°C to 175°C. Without being bound by any theory or mechanism of action, the second weight loss might correspond to the peak at about 140°C in the DSC profile.

Example 4: Amorphous Dronedarone HC1 (Method III)

General method III was performed. Thus, Dronedarone API was dissolved in acetone, acetone:EtOAc=2:l, acetone:MEK=2:l, CH₂C1₂, CH₂C1₂:MEK=1 :1, CH₂C1₂:MTBE=2:1 or MeOH at room temperatures. The solvent was then evaporated using rotary evaporation below 50 °C. This amorphous form showed a broad X-ray diffraction peak between about 15 and about 30 [2Θ°] characteristic of an amorphous powder (Figure 11, panels A-D and Figure 12, panels A-C). Figure 13 (bottom curve) illustrates a characteristic DSC profile of the amorphous form prepared from an acetone solution. The amorphous form prepared by this method has a glass transition temperature of up to about 22°C. Figure 14 illustrates a characteristic IR spectrum of the amorphous form prepared from a CH₂C1₂ solution. Characteristic peaks appear at about 774, 810, 843, 901, 973, 1053, 1150, 1249, 1331, 1372, 1461, 1505, 1573, 1598, 1637, 2509, 2620, 2871, 2959, and 3061 cm^"1. This IR spectrum is substantially similar to the spectrum obtained by using Method I (Example 2) and could be used as an alternative for the identification of the amorphous form of the present invention. Figure 15 illustrates a characteristic Raman spectrum of the amorphous form prepared from a CH₂C1₂ solution. Characteristic peaks appear at about 292, 362, 423, 525, 643, 713, 821, 847, 907, 968, 1070, 1118, 1166, 1191, 1261, 1312, 1366, 1424, 1459, 1513, 1571, 1599, 1637, 2878, 2913, 2935, 2967, 3008 and 3075 cm^"1. This Raman spectrum is substantially similar to the spectrum obtained by using Method I (Example 2) and could be used as an alternative for the identification of the amorphous form of the present invention. Figure 16 illustrates characteristic TGA profiles: upper curve shows a TGA profile of the amorphous form prepared from an acetone :MEK 2:1 solution, middle curve shows a TGA profile of the amorphous form prepared from an acetone :EtO Ac 2:1 solution, and lower curve shows a TGA profile of the amorphous form prepared from an acetone solution. The profiles are characterized by a weight loss of about 2.8% from room temperatures to 181°C.

Example 5: Amorphous Dronedarone HC1 (Method IV)

General method IV was performed. Thus, Dronedarone API was ground using mortar and pestle for 10, 20 or 30 minutes. A mixture of amorphous dronedarone HC1 and crystalline dronedarone HC1 was obtained. Hence, crystalline dronedarone HC1 was partially converted to amorphous dronedarone HC1 during the grinding process.

Example 6: Physical and Chemical Properties of Amorphous Dronedarone HC1

Amorphous dronedarone HC1 prepared according to method I (scale up) was characterized for assessing its physical and chemical properties. The DVS isotherm plots of the amorphous and crystalline forms are shown in Figures 19 and 20, respectively. The results are summarized in Table 2. Table 2.

The amorphous dronedarone HC1 of the present invention is classified as being slightly hygroscopic.

The amorphous dronedarone HC1 of the present invention shows good solubility in water, 0.01N HC1, FaSSIF and FeSSIF (Table 3; aqueous solubility). The amorphous form is more soluble than the crystalline form in all vehicles except FeSSIF. Without being bound by any theory or mechanism of action, increased solubility usually indicates better bioavailability of the amorphous form in comparison to the crystalline form. Table 3.

The stability of the amorphous form in various solutions was tested. The amorphous dronedarone HCl of the present invention was examined for its stability in each one of the following media 0.1 N HCl, pH 2, pH 4, pH 6, and pH 2 + 0.3% H₂0₂ and the percentage of remaining amorphous form exceeded 98% under all conditions. The TRS results are summarized in Table 4. The assay and TRS of the amorphous form of dronedarone HCl in 0.1 N HCl, 50 mM pH 2, 4, 6 phosphate buffers and 50 mM pH 2 phosphate buffers + 0.3 % H₂0₂ have no significant change at 40 °C for 24 hours. Table 4.

At pH 8 phosphate buffer with or without 0.3% H₂0₂ turbidness phenomenon occurred immediately even upon changing the solvent and increasing the media ratios to 100 μg/ml solutions. The results are summarized in Table 5.

Table 5.

The solid stability of the amorphous form was examined in various conditions. The assay and TRS showed no significant change under different conditions (40 °C, 60 °C, 40 °C/75 %RH, 60 °C/75 %RH) at the end of the first and second week. The percentage of remaining amorphous form under light at the end of the first and second weeks was 78.84 % and 74.29 %, respectively. The results are summarized in Table 6.

Table 6.

— Samples were used for standard curve

X-ray powder diffraction and differential scanning calonmetry of the amorphous dronedarone HCl were performed after storing the samples in a glass vial under different conditions for 1 and 2 weeks. The amorphous dronedarone HCl was stable under light and 40 °C at end of the first and second weeks and was converted to crystalline at 60 °C, 40 °C/ 75 %RH, 60 °C/75 %RH at the end of the first week.

The bulk and tapped density of amorphous dronedarone HCl were measured and compared to crystalline dronedarone and the results are summarized in Table 7.

Table 7.

The amorphous dronedarone HCl of the present invention has lower bulk density and tapped density as compared with the crystalline form. Thus, the amorphous dronedarone HCl can be more easily formulated as tablets.

While the present invention has been particularly described, persons skilled in the art will appreciate that many variations and modifications can be made. Therefore, the invention is not to be construed as restricted to the particularly described embodiments, and the scope and concept of the invention will be more readily understood by reference to the claims, which follow.

Claims

1. An amorphous form of dronedarone HCl.

2. The amorphous dronedarone HCl according to claim 1, characterized by an X- ray diffraction profile substantially as shown in any of Figures 1A, IB, 6 A, 1 1 A, 1 IB, 11C, 1 ID, 12A, 12B or 12C.

3. The amorphous dronedarone HCl according to claim 1, characterized by a DSC profile substantially as shown in any of Figures 2, 1, 13 or 17.

4. The amorphous dronedarone HCl according to claim 1, characterized by an IR spectrum substantially as shown in any of Figures 3, 8 or 14.

5. The amorphous dronedarone HCl according to claim 1, characterized by an IR spectrum having characteristic peaks at about 774±4, 806±4, 843±4, 905±4, 972±4, 1053±4, 1150±4, 1249±4, 1331±4, 1372±4, 1422±4, 1461±4, 1502±4, 1572±4, 1598±4, 1637±4, 2513±4, 2620±4, 2871±4, 2958±4, and 3064±4 crn

1

6. The amorphous dronedarone HCl according to claim 1, characterized by a Raman spectrum substantially as shown in any of Figures 4, 9 or 15.

7. The amorphous dronedarone HCl according to claim 1, characterized by a Raman spectrum having characteristic peaks at about 292±4, 426±4, 528±4, 675±4, 860±4, 904±4, 1083±4, 1124±4, 1169±4, 1198±4, 1258±4, 1319±4, 1370±4, 1427±4, 1453±4, 1571±4, 1599±4, 1641±4, 2874±4, 2935±4, 2964±4, and 3069±4 cm^"1.

8. The amorphous dronedarone HCl according to claim 1 characterized by a TGA profile substantially as shown in any of Figures 5, 10, 16 or 18.

9. A pharmaceutical composition comprising as an active ingredient the amorphous form of dronedarone HCl according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier.

10. The pharmaceutical composition according to claim 9 in the form of a tablet.

11. The pharmaceutical composition according to claim 9 for use in treating cardiac arrhythmias.

12. A method of treating cardiac arrhythmias comprising administering to a subject in need thereof an effective amount of a composition comprising the amorphous form of dronedarone HCl according to any one of claims 1 to 8.

13. The method according to claim 12, wherein the subject is a human.

14. Use of the amorphous form of dronedarone HCl according to any one of claims 1 to 8 for the preparation of a medicament for treating cardiac arrhythmias.

15. An amorphous form of dronedarone HCl according to any one of claims 1 to 8 for use in the treatment of cardiac arrhythmias.

16. A process for preparing amorphous dronedarone HCl according to any one of claims 1 to 8, comprising the steps of:

(a) heating dronedarone HCl to melt; and

(b) cooling the melted dronedarone HCl obtained in step (a), so as to provide amorphous dronedarone HCl.

17. The process according to claim 16, wherein the cooling step comprises fast cooling or slow cooling.

18. A process for preparing amorphous dronedarone HCl according to any one of claims 1 to 8, comprising the steps of:

(a) dissolving dronedarone HCl in water; and

(b) evaporating the water by freeze drying so as to precipitate amorphous dronedarone HCl.

19. A process for preparing amorphous dronedarone HCl according to any one of claims 1 to 8, comprising the steps of:

(a) dissolving dronedarone HCl in at least one solvent; and

(b) evaporating the solvent so as to precipitate amorphous dronedarone HCl.

20. The process according to claim 19, wherein the at least one solvent is selected from the group consisting of acetone, methanol, CH₂C1₂, EtOAc, MEK, MTBE and mixtures thereof.

21. The process according to claim 19, wherein the solvent is selected from acetone, acetone:EtOAc (2:1), acetone:MEK (2:1), CH₂C1₂, CH₂C1₂:MEK (1 :1), CH₂C1₂:MTBE (2:1), and methanol.

22. A process for preparing amorphous dronedarone HCl according to any one of claims 1 to 8 comprising the step of grinding crystalline dronedarone HCl so as to provide amorphous dronedarone HCl.