[go: up one dir, main page]

WO2012001673A1 - Forme amorphe de la dronédarone - Google Patents

Forme amorphe de la dronédarone Download PDF

Info

Publication number
WO2012001673A1
WO2012001673A1 PCT/IL2010/000961 IL2010000961W WO2012001673A1 WO 2012001673 A1 WO2012001673 A1 WO 2012001673A1 IL 2010000961 W IL2010000961 W IL 2010000961W WO 2012001673 A1 WO2012001673 A1 WO 2012001673A1
Authority
WO
WIPO (PCT)
Prior art keywords
dronedarone
amorphous
hcl
dronedarone hcl
amorphous form
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IL2010/000961
Other languages
English (en)
Inventor
Ehud Marom
Shai Rubnov
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
MAPI PHARMA HOLDINGS (CYPRUS) Ltd
Original Assignee
MAPI PHARMA HOLDINGS (CYPRUS) Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by MAPI PHARMA HOLDINGS (CYPRUS) Ltd filed Critical MAPI PHARMA HOLDINGS (CYPRUS) Ltd
Publication of WO2012001673A1 publication Critical patent/WO2012001673A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms

Definitions

  • the present invention relates to an amorphous form of dronedarone hydrochloride, pharmaceutical compositions comprising same, and use thereof in treating cardiac arrhythmias.
  • Dronedarone hydrochloride also known as SR33589 or Multaq
  • Dronedarone hydrochloride 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:
  • 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.
  • 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.
  • the amorphous form of dronedarone HCl of the present invention is more soluble than the crystalline form in aqueous vehicles.
  • the amorphous form has lower bulk and tapped densities as compared to the crystalline form.
  • 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).
  • the present invention provides an amorphous form of dronedarone or salt thereof.
  • the present invention provides an amorphous form of dronedarone HCl.
  • 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.
  • XRD X-ray diffraction
  • 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.
  • 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.
  • 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 .
  • the amorphous form of dronedarone HCl is characterized by a Raman spectrum substantially as shown in any of Figures 4, 9 or 15.
  • 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
  • the amorphous form of dronedarone HCl is characterized by a TGA profile substantially as shown in any of Figures 5, 10, 16 or 18.
  • the present invention provides a process for preparing amorphous dronedarone HCl, the process comprising the steps of:
  • step (b) cooling the melted dronedarone HCl obtained in step (a) under vacuum, so as to provide amorphous dronedarone HCl.
  • the cooling in step (b) is selected from fast cooling and slow cooling.
  • fast cooling and slow cooling are selected from fast cooling and slow cooling.
  • the present invention provides a process for preparing amorphous dronedarone HCl, the process comprising the steps of: (a) dissolving dronedarone HCl in water; and
  • the present invention provides a process for preparing amorphous dronedarone HCl, the process comprising the steps of:
  • the at least one solvent is selected from the group consisting of acetone, methanol, CH 2 CI 2 , EtOAc, MEK, MTBE and mixtures thereof.
  • acetone methanol
  • CH 2 CI 2 CH 2 CI 2
  • EtOAc EtOAc
  • MEK MEK
  • MTBE MTBE
  • the at least one solvent is selected from acetone, acetone:EtOAc (2: 1), acetone:MEK (2: 1), CH 2 C1 2 , CH 2 C1 2 :MEK (1 : 1), CH 2 C1 2 :MTBE (2: 1), and methanol.
  • 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.
  • the present invention provides a pharmaceutical composition
  • 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.
  • the pharmaceutical composition is in the form of a tablet.
  • the present invention provides a pharmaceutical composition
  • 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.
  • 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.
  • 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.
  • the subject is a mammal, such as a human.
  • 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.
  • DSC Differential Scanning Calorimetry
  • 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.
  • FTIR Fourier Transform Infrared
  • 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.
  • TGA Thermogravimetric analysis
  • 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.
  • DSC Differential Scanning Calorimetry
  • 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.
  • FTIR Fourier Transform Infrared
  • 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.
  • FT-Raman Fourier Transform - Raman
  • FIG 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.
  • TGA Thermogravimetric analysis
  • Figure 11 illustrates characteristic X-ray diffraction patterns of amorphous dronedarone HCl, obtained by dissolution of dronedarone API in C3 ⁇ 4CI 2 (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), CH 2 C1 2 :MTBE 2:1 (panel B) or CH 2 C1 2 :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 CH 2 Cl 2 :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.
  • DSC Differential Scanning Calorimetry
  • Figure 14 illustrates a characteristic Fourier Transform Infrared (FTIR) spectrum of amorphous dronedarone HCl, obtained by dissolution of dronedarone API in CH 2 CI 2 followed by removal of solvent using rotary evaporator below 50°C.
  • FTIR Fourier Transform Infrared
  • Figure 15 illustrates a characteristic Fourier Transform - Raman (FT-Raman) spectrum of amorphous dronedarone HCl, obtained by dissolution of dronedarone API in CH 2 C1 2 followed by removal of solvent using rotary evaporator below 50°C.
  • FT-Raman Fourier Transform - Raman
  • FIG 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.
  • TGA Thermogravimetric analysis
  • 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.
  • DSC Differential Scanning Calorimetry
  • 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.
  • TGA Thermogravimetric analysis
  • 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 ( ⁇ ).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 [2 ⁇ °] as is shown in any of Figures 1A, IB, 6A, 11 A, 11B, 11C, 11D, 12A, 12B or 12C.
  • 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)).
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • 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.
  • 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.
  • 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.
  • 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 .
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the dronedarone HCl starting material is heated until fully melted, preferably under vacuum followed by controlled precipitation by slow/fast cooling.
  • the dronedarone HC1 starting material is dissolved in water. The water is then removed using freeze drying (lyophilization).
  • 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 (CH 2 C1 2 ), 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), CH 2 C1 2 :MEK (1:1), and CH 2 C1 2 :MTBE (2:1).
  • EtOAc ethyl acetate
  • MEK methyl ethyl ketone
  • MTBE methyl t-butyl ether
  • 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.
  • anti-solvent 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.
  • Suitable polar aprotic solvents include, but are not limited to, acetonitrile, tetrahydrofuran (THF), CH 2 C1 2 , acetone, dimethylformamide, dimethylsulfoxide, EtOAc, MEK and MTBE.
  • 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).
  • 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.
  • 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.
  • 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
  • PVPP polyvinylpyrrolidone
  • 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.
  • 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 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.
  • the therapeutic benefit is prevention of cardiac arrhythmias.
  • the therapeutic benefit is a delayed conduction of the electrical impulse at the cardiac cell.
  • the therapeutic benefit is the prolongation of the refractory period (absolute period and efficacious period).
  • the therapeutic benefit is an increase in the duration of the action potential of the cardiac cell.
  • 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.
  • 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.
  • Crystalline dronedarone HCl (Dronedarone API; Batch No. 081107) was dissolved in water. The water was then removed by freeze drying.
  • Crystalline dronedarone HC1 (Dronedarone API; Batch No. 081107) was ground by using mortar and pestle for 10, 20 or 30 minutes.
  • Deliquescent Sufficient water is absorbed to form a liquid.
  • Hygroscopic Increase in mass is less than 15 % and equal to or greater than
  • Non-hygroscopic Increase in mass is less than 0.2 %.
  • 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 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 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 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 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 0.01 N HCl, 0.05 % sodium lauryl sulfate, 0.2 %
  • Fasted state simulated intestinal fluid 29 mM NaH 2 P0 4 , 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.
  • Testing media 0.1 N HCl, 50 mM pH 2, 4, 6, 8 phosphate buffers, 50 mM pH 2 phosphate buffers + 0.3 % H 2 0 2 , 50 mM pH 8 phosphate buffers + 0.3 % H 2 0 2.
  • Testing conditions 40 °C, 60 °C, 40 °C/RH 75 %, 60 °C/RH 75 %, light.
  • Testing conditions 40 °C, 60 °C, 40 °C/RH 75 %, 60 °C/RH 75 %, light.
  • 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:
  • 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 [2 ⁇ °] 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.
  • 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)
  • 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 [2 ⁇ °] 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.
  • 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 [2 ⁇ °] characteristic of an amorphous powder ( Figure 11, panels A-D and Figure 12, panels A-C).
  • Figure 13 bottom curve
  • Figure 13 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 CH 2 C1 2 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 CH 2 C1 2 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.
  • 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.
  • crystalline dronedarone HC1 was partially converted to amorphous dronedarone HC1 during the grinding process.
  • Amorphous dronedarone HC1 prepared according to method I 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% H 2 0 2 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 % H 2 0 2 have no significant change at 40 °C for 24 hours. Table 4.
  • 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.
  • Table 6 The results are summarized in Table 6.
  • 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 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une forme amorphe de la dronédarone ou un sel de celle-ci, plus précisément un chlorhydrate de dronédarone amorphe, des compositions pharmaceutiques la comprenant, ses procédés de préparation et son utilisation dans le traitement d'arythmies cardiaques. Le chlorhydrate de dronédarone amorphe présente des caractéristiques de solubilité aqueuse et de densité supérieures en comparaison du chlorhydrate de dronédarone cristallin.
PCT/IL2010/000961 2010-06-28 2010-11-17 Forme amorphe de la dronédarone Ceased WO2012001673A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US35895210P 2010-06-28 2010-06-28
US61/358,952 2010-06-28

Publications (1)

Publication Number Publication Date
WO2012001673A1 true WO2012001673A1 (fr) 2012-01-05

Family

ID=45401478

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IL2010/000961 Ceased WO2012001673A1 (fr) 2010-06-28 2010-11-17 Forme amorphe de la dronédarone

Country Status (1)

Country Link
WO (1) WO2012001673A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103694206A (zh) * 2013-12-05 2014-04-02 福建广生堂药业股份有限公司 一种盐酸决奈达隆新晶型及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070243257A1 (en) * 2004-09-17 2007-10-18 Sanofi-Aventis Pharmaceutical composition comprising a solid dispersion with a polymer matrix containing a continuous polydextrose phase and a continuous phase of a polymer other than polydextrose
US20090111997A1 (en) * 2005-11-23 2009-04-30 Aaron Cote Method of Generating Amorphous Solid for Water-Insoluble Pharmaceuticals
US20100048694A1 (en) * 2008-04-17 2010-02-25 Sanofi-Aventis Use of dronedarone for the preparation of a medicament for use in the prevention of cardiovascular hospitalization or of mortality

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070243257A1 (en) * 2004-09-17 2007-10-18 Sanofi-Aventis Pharmaceutical composition comprising a solid dispersion with a polymer matrix containing a continuous polydextrose phase and a continuous phase of a polymer other than polydextrose
US20090111997A1 (en) * 2005-11-23 2009-04-30 Aaron Cote Method of Generating Amorphous Solid for Water-Insoluble Pharmaceuticals
US20100048694A1 (en) * 2008-04-17 2010-02-25 Sanofi-Aventis Use of dronedarone for the preparation of a medicament for use in the prevention of cardiovascular hospitalization or of mortality

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SAVOLAINEN: "New Insights into the Amorphous State and Related Solid-State Transformations", 2008, UNIVERSITY OF HELSINKI, pages 1 - 49, Retrieved from the Internet <URL:https://helda.helsinki.fi/bitstream/handle/10138/19106/newinsig.pdf?sequence=1> [retrieved on 20110315] *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103694206A (zh) * 2013-12-05 2014-04-02 福建广生堂药业股份有限公司 一种盐酸决奈达隆新晶型及其制备方法
CN103694206B (zh) * 2013-12-05 2015-09-16 福建广生堂药业股份有限公司 一种盐酸决奈达隆新晶型及其制备方法

Similar Documents

Publication Publication Date Title
US9206197B2 (en) Amorphous form of dolutegravir
EP2991999B1 (fr) Co-cristal de dapagliflozine et de lactose
WO2012063246A1 (fr) Forme amorphe du chlorhydrate de lurasidone
US20120035142A1 (en) Polymorphs of darunavir
US9096574B2 (en) Polymorphs of perampanel
US9453024B2 (en) Polymorphs of darunavir
US20220002297A1 (en) Polymorphs of x842
US9994522B2 (en) Amorphous form of apremilast
WO2012114325A1 (fr) Polymorphes d&#39;de maléate d&#39;asénapine
WO2017109772A1 (fr) Forme amorphe du sélexipag
US20130225830A1 (en) Polymorphs of febuxostat
US20200216422A1 (en) Odm-201 crystalline form, preparation method therefor, and pharmaceutical composition thereof
US20130059872A1 (en) Polymorphs of alogliptin benzoate
WO2012001673A1 (fr) Forme amorphe de la dronédarone
AU2010353051A1 (en) Polymorphs of alogliptin benzoate
EP4649078A1 (fr) Polymorphes de sel d&#39;acide maléique de linaprazan glurate
CN116171277A (zh) Pn6047盐酸盐的多晶型物
WO2013024474A1 (fr) Polymorphes de préladénant

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10854023

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10854023

Country of ref document: EP

Kind code of ref document: A1