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
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
  • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
  • C07D223/16—Benzazepines; Hydrogenated benzazepines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1682—Processes
  • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Definitions

• the present invention provides a compound of 7,8-dimethoxy-3-[3-[[(l S)-(4,5- dimethoxybenzocyclobutan- 1 -yl)methyl]methylamino]propy 1]- 1 ,3-de-hydro-7,8- dimethoxy-2H-3-benzazepin-2-one oxalate (de-hydro ivabradine oxalate salt) and process for its preparation.
• the present invention also provides a process for the purification of de- hydro ivabradine oxalate salt.
• the present invention further provides a novel process for the preparation of ivabradine using novel intermediate.
• the present invention further provides a novel amorphous solid dispersion of ivabradine hydrochloride in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it.
• Ivabradine hydrochloride is chemically, 7,8-dimethoxy-3-[3-[[(l S)-(4,5- dimethoxybenzocyclobutan-l -yl)methyl]methylamino]propyl]-l ,3,4,5-tetrahydro-7,8- dimethoxy-2H-3-benzazepin-2-one hydrochloride and has the structure formula I:
• Ivabradine hydrochloride is a novel medication used for the symptomatic management of stable angina pectoris. Ivabradine hydrochloride acts by reducing the heart rate in a mechanism different from beta blockers and calcium channel blockers, two commonly prescribed antianginal drugs. It is classified as a cardiotonic agent. It is marketed under the brand name Procoralan® by Abbott.
• ivabradine hydrochloride can be prepared by the condensation of (S)-N-[(4,5-dimethoxybenzocyclobut-lyl)methyl]-N-(methyl)amine with 7,8-dimethoxy-3-[3-iodopropyl]-l ,3-de-hydro -2H-3-benzazepin-2-one in acetone and potassium carbonate to obtain 7,8-dimethoxy-3-[3-[[(l S)-(4,5- dimethoxybenzocyclobutan-1 -yl)methyl]methylamino]propyl]-l ,3-de-hydro -7,8- dimethoxy-2H-3-benzazepin-2-one, and then reduced with palladium hydroxide in glacial acetic acid under the atmosphere of hydrogen gas to get ivabradine which is
• Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice.
• polymorphs are different crystalline structures of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules.
• Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph.
• Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).
• XRD X-ray diffraction
• DSC Differential Scanning Calorimetry
• IR Infrared spectrometry
• Solvent medium and mode of crystallization play very important role in obtaining one polymorphic Form over the other.
• Ivabradine and its hydrochloride salt can exist in different polymorphic Forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
• U.S. patent no. 7,867,994 disclosed a crystalline Form a of ivabradine hydrochloride.
• U.S. patent no. 7,361,649 disclosed a crystalline Form ⁇ of ivabradine hydrochloride.
• U.S. patent no. 7,358,240 disclosed a crystalline Form ⁇ of ivabradine hydrochloride.
• European patent no. 1695710 disclosed a crystalline Form pd of ivabradine hydrochloride.
• Crystalline Form Z, Form X and Form K of ivabradine hydrochloride were disclosed in PCT application publication no. WO 201 1/098582.
• a novel amorphous solid dispersion of ivabradine hydrochloride in combination with a pharmaceutically acceptable carrier is stable, reproducible and so, the amorphous solid dispersion of ivabradine hydrochloride is suitable for formulating ivabradine hydrochloride.
• Normally amorphous Forms are hygroscopic.
• Amorphous solid dispersion of ivabradine hydrochloride is found to be non-hygroscopic.
• one object of the present invention is to provide a compound of 7,8- dimethoxy-3-[3-[[(l S)-(4,5-dimethoxybenzocyclobutan-l -yl)methyl]methylamino]- propyl]-l ,3-de-hydro-7,8-dimethoxy-2H-3-benzazepin-2-one oxalate (de-hydro ivabradine oxalate salt) and process for its preparation.
• Another object of the present invention is to provide a process for the purification of 7,8-dimethoxy-3-[3-[[(l S)-(4,5-dimethoxybenzocyclobutan-l -yl)methyl]methylamino] propyl]- l ,3-de-hydro-7,8-dimethoxy-2H-3-benzazepin-2 -one oxalate (de-hydro ivabradine oxalate salt).
• Another object of the present invention is to provide a process for the preparation of ivabradine using novel intermediate.
• Another object of the present invention is to provide amorphous solid dispersion of ivabradine hydrochloride in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it.
• the present invention provides 7,8-dimethoxy-3-[3-[[(l S)-(4,5- dimethoxybenzocyclobutan-l -yl)methyl]methylamino]propyl]-l ,3-de-hydro-7,8- dimethoxy-2H-3-benzazepin-2-one oxalate (de-hydro ivabradine oxalate salt) of formula
• the present invention provides a process for the preparation of de-hydro ivabradine oxalate salt of formula II, which comprises:
• step (b) dissolving residual solid obtained in step (b) in an ester solvent
• the present invention provides a process for the purification of de-hydro ivabradine oxalate salt of formula II, which comprises:
• step (a) heating the suspension obtained in step (a) at above 45°C;
• the present invention provides a novel process for the preparation of ivabradine using novel intermediate, which comprises:
• the present invention provides amorphous solid dispersion of ivabradine hydrochloride in combination with a pharmaceutically acceptable carrier.
• the present invention there is provided a process for the preparation of amorphous solid dispersion of ivabradine hydrochloride in combination with a pharmaceutically acceptable carrier, which comprises:
• pharmaceutically acceptable carriers selected form copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol or soluplus
• the present invention there is provided a process for the preparation of amorphous solid dispersion of ivabradine hydrochloride in combination with a pharmaceutically acceptable carrier, which comprises:
• step (b) adding one or more pharmaceutically acceptable carriers selected form copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol or soluplus to the solution obtained in step (b); and
• compositions comprising a therapeutically effective amount of amorphous solid dispersion of ivabradine hydrochloride along with a pharmaceutically acceptable carrier, and at least one pharmaceutically acceptable excipient.
• Figure 1 is a powder X-ray diffractogram patterns of crystalline 7,8-dimethoxy-3- [3-[[( 1 S)-(4,5-dimethoxybenzocyclobutan- 1 -yl)methyl]methylamino]propyl]- 1 ,3-de- hydro-7,8-dimethoxy-2H-3-benzazepin-2-one oxalate (De-hydro ivabradine oxalate salt) of formula II.
• Figure 2 is a powder X-ray diffractogram patterns of amorphous solid dispersion of ivabradine hydrochloride in combination with a pharmaceutically acceptable carrier.
• Powder X-ray diffraction spectrum was measured on a bruker AXS D8 advance powder X-ray diffractometer having a copper- ⁇ radiation. Approximately 500 mg of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two- theta, at 0.020 degrees two theta per step and a step time of 1 second. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 kV and current 35 mA.
• room temperature refers to temperature at about 25 to 35°C.
• a process for the preparation of de-hydro ivabradine oxalate salt of formula II which comprises: a) condensing the (S)-N-[(4,5-dimethoxybenzocyclobut- l-yl)methyl]-N- (methyl)amine hydrochloride with 7,8-dimethoxy-3-[3-iodopropyl]-l,3-de-hydro - 2H-3-benzazepin-2-one in the presence of potassium carbonate or sodium carbonate and dimethylformamide;
• step (b) dissolving residual solid obtained in step (b) in an ester solvent
• the reaction mass is concentrated in step (b) by distilling off the solvent.
• the distilling off the solvent may be carried out at atmospheric pressure or at reduced pressure.
• the distillation may preferably be carried out until the solvent is almost completely distilled off.
• the ester solvent used in step (c) may preferably be a solvent or a mixture of solvents selected from ethyl acetate, methyl acetate, isopropyi acetate, tert-butyl methyl acetate and ethyl formate, and more preferably the ester solvent is ethyl acetate.
• the ketonic solvent used in step (d) may be a solvent or mixture of solvents selected from acetone, methyl ethyl ketone, methyl isobutyl ketone and diethyl ketone, and more preferably the ketonic solvent is acetone.
• Isolation of de-hydro ivabradine oxalate salt in step (e) may preferably be performed by conventional techniques such as centrifugati n and filtration.
• a process for the purification of de-hydro ivabradine oxalate salt of formula ⁇ which comprises: a) suspending de-hydro ivabradine oxalate salt in a nitrile solvent and optionally adding water;
• step (a) heating the suspension obtained in step (a) at above 45°C;
• highly pure de-hydro ivabradine oxalate salt refers to de-hydro ivabradine oxalate salt having the purity greater than about 98% by weight, preferably greater than about 99% by weight, more preferably greater than about 99.5% by weight.
• the nitrile solvent used in step (a) may be a solvent or a mixture of solvents selected from acetonitrile, propionitrile, butyronitrile and benzonitrile. More preferably the nitrile solvent is acetonitrile.
• the reaction in step (b) may preferably be heated at about 50 to 65°C.
• Highly pure de-hydro ivabradine oxalate salt may be isolated in step (c) by the methods known such as filtration or centrifugation.
• de-hydro ivabradine oxalate salt The content of de-hydro ivabradine oxalate salt is determined by High performance liquid chromatography (HPLC).
• a novel process for the preparation of ivabradine using novel intermediate which comprises: a) dissolving de-hydro ivabradine oxalate salt in an alcoholic solvent; b) adding palladium on carbon to the solution;
• the alcoholic solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from methanol, ethanol, isopropanoi, n-butanol and n-pentanol, and more preferably the alcoholic solvent is methanol.
• Removal of the solvent may be carried out in step (d) at atmospheric pressure or at reduced pressure. Removal of the solvent may preferably be carried out until the solvent is almost completely distilled off.
• the base used in step (f) may preferably be an organic base or an inorganic base selected from ammonium, sodium hydroxide or potassium hydroxide, and more preferably the base is sodium hydroxide.
• the ester solvent used in step (g) may preferably be a solvent or a mixture of solvents selected from ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate and ethyl formate, and more preferably the ester solvent is ethyl acetate.
• reaction mass is concentrated in step (h) by distilling off the solvent.
• the distilling off the solvent may be carried out at atmospheric pressure or at reduced pressure.
• the distillation may preferably be carried out until the solvent is almost completely distilled off.
• amorphous solid dispersion of ivabradine hydrochloride in combination with a pharmaceutically acceptable carrier there is provided amorphous solid dispersion of ivabradine hydrochloride in combination with a pharmaceutically acceptable carrier.
• the powdered x-ray diffractogram (PXRD) of amorphous solid dispersion of ivabradine hydrochloride in combination with a pharmaceutically acceptable carrier is shown in figure 2.
• Amorphous solid dispersion of ivabradine hydrochloride in combination with a pharmaceutically acceptable carrier is found to be stable.
• the pharmaceutically acceptable carriers may be one or more of copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol or soluplus.
• a process for the preparation of amorphous solid dispersion of ivabradine hydrochloride in combination with a pharmaceutically acceptable carrier which comprises:
• pharmaceutically acceptable carriers selected form copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol or soluplus
• Ivabradine hydrochloride used in step (a) may preferably be ivabradine hydrochloride obtained by the known process.
• the solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from dimethyl sulfoxide, dimethylacetamide, methanol, ethanol, isopropanol, n- butanol and n-pentanol, and more preferably the solvents are dimethyl sulfoxide, dimethylformamide, methanol and n-butanol.
• the pharmaceutically acceptable carriers used in step (a) may be selected form copovidone or hydroxypropyl methylcellulose.
• the dissolution in step (a) may be performed, for example, by heating the mixture of ivabradine hydrochloride and one or more pharmaceutically acceptable carriers in the solvent.
• Drying in step (b) may preferably be carried out at about 70 to 90°C.
• a process for the preparation of amorphous solid dispersion of ivabradine hydrochloride in combination with a pharmaceutically acceptable carrier which comprises:
• step (b) adding one or more pharmaceutically acceptable carriers selected form copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol or soluplus to the solution obtained in step (b); and
• the solvent used in step (a) and step (b) may preferably be a solvent or a mixture of solvents selected from dimethyl sulfoxide, dimethylacetamide, methanol, ethanol, isopropanol, n-butanol and n-pentanol, and more preferably the solvents are dimethyl sulfoxide, dimethylformamide, methanol and n-butanol.
• the pharmaceutically acceptable carriers used in step (c) may be selected form copovidone or hydroxypropyl methylcellulose.
• Drying in step (d) may preferably be carried out at about 70 to 90°C.
• compositions comprising a therapeutically effective amount of amorphous solid dispersion of ivabradine hydrochloride along with a pharmaceutically acceptable carrier, and at least one pharmaceutically acceptable excipient.
• the amorphous solid dispersion of ivabradine hydrochloride may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.
• De-hydro ivabradine oxalate salt (100 gm; HPLC Purity: 96.5%) as obtained in example 1 was dissolved in acetonitrile (500 ml) and then heated to 50 to 55°C. The solution was stirred for 1 hour at 50 to 55°C and then cooled to room temperature. The contents were then stirred for 1 hour at room temperature and filtered. The solid obtained was dried to obtain 85 gm of de-hydro ivabradine oxalate salt.
• De-hydro ivabradine oxalate salt 100 gm was dissolved in a mixture of acetonitrile (400 ml) and water (100 ml), and then heated to 50 to 55°C. The solution was stirred for 1 hour at 50 to 55°C and then cooled to room temperature. The contents were then stirred for 1 hour at room temperature and filtered. The solid obtained was dried to obtain 80 gm of de-hydro ivabradine oxalate salt.
• De-hydro ivabradine oxalate salt (90 gm; HPLC Purity: 99.7%) as obtained in example 2 was dissolved in methanol (1510 ml) and then added palladium on carbon (45 gm). To the reaction mixture was applied hydrogen gas for 4 hours and filtered through hy-flow bed. The solvent was distilled off under vacuum at below 55°C and then added water (1000 ml). The pH of the reaction mass was adjusted to 9.0 to 9.5 with sodium hydroxide solution (20%) and then added ethyl acetate (1000 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate. Combined organic layers were dried with sodium sulfate and then concentrated to obtain 52 gm of ivabradine. Chromatographic purity of ivabradine: 99.7%.
• Ivabradine (5 gm) as obtained in example 4 was dissolved in methanol (50 ml) and then pH was adjusted to 2.0 with a solution of hydrochloric acid in methanol (1 N). The solution was stirred for 10 minutes at room temperature and then added copovidone (5 gm). The solvent was distilled off under vacuum at below 65°C and then dried under vacuum at 70°C for 2 hours to obtain 9 gm of amorphous ivabradine hydrochloride solid dispersion with copovidone.
• Ivabradine (5 gm) was dissolved in methanol (50 ml) and then pH was adjusted to
• Example 5 was repeated using ethanol solvent instead of methanol solvent to obtain amorphous ivabradine hydrochloride solid dispersion with copovidone.
• ivabradine hydrochloride 5 gm
• copovidone 6 gm
• n-butanol 100 ml
• the solution was stirred for 15 minutes at room temperature and the solvent was distilled off under vacuum at below 75°C.
• the resulting solid was subjected to drying at 70°C for 4 hours to obtain 10 gm of amorphous ivabradine hydrochloride solid dispersion with copovidone.
• ivabradine hydrochloride (20 gm) and copovidone (4 gm) was dissolved in methanol (240 ml) at room temperature. The solution was stirred for 15 minutes at room temperature and the solvent was distilled off under vacuum at below 75°C. The resulting solid was subjected to drying at 70°C for 2 hours to obtain 22 gm of amorphous ivabradine hydrochloride solid dispersion with copovidone.
• Example 8 was repeated using dimethyl sulfoxide solvent instead of n-butanol solvent to obtain amorphous ivabradine hydrochloride solid dispersion with copovidone.
• Example 1 1
• Example 8 was repeated using ethanol solvent instead of n-butanol solvent to obtain amorphous ivabradine hydrochloride solid dispersion with copovidone.
• Example 8 was repeated using dimethylacetamide solvent instead of n-butanol solvent to obtain amorphous ivabradine hydrochloride solid dispersion with copovidone.
• ivabradine hydrochloride (10 gm) and hydroxypropyl methylcellulose (10 gm) was dissolved in n-butanol (200 ml) at room temperature. The solution was stirred for 15 minutes at room temperature and the solvent was distilled off under vacuum at below 75°C. The resulting solid was subjected to drying at 70°C for 3 hours to obtain 19 gm of amorphous ivabradine hydrochloride solid dispersion with hydroxypropyl methylcellulose.
• Example 13 was repeated using dimethyl sulfoxide solvent instead of n-butanol solvent to obtain amorphous ivabradine hydrochloride solid dispersion with hydroxypropyl methylcellulose.
• Example 15 was repeated using dimethyl sulfoxide solvent instead of n-butanol solvent to obtain amorphous ivabradine hydrochloride solid dispersion with hydroxypropyl methylcellulose.
• Example 13 was repeated using dimethylacetamide solvent instead of n-butanol solvent to obtain amorphous ivabradine hydrochloride solid dispersion with hydroxypropyl methylcellulose.
• Example 13 was repeated using methanol solvent instead of n-butanol solvent to obtain amorphous ivabradine hydrochloride solid dispersion with hydroxypropyl methylcellulose.
• Example 17 was repeated using methanol solvent instead of n-butanol solvent to obtain amorphous ivabradine hydrochloride solid dispersion with hydroxypropyl methylcellulose.
• Example 13 was repeated using ethanol solvent instead of n-butanol solvent to obtain amorphous ivabradine hydrochloride solid dispersion with hydroxypropyl methylcellulose.
• ivabradine hydrochloride (10 gm) and soluplus (8 gm) was dissolved in n-butanol (150 ml) at room temperature. The solution was stirred for 15 minutes at room temperature and the solvent was distilled off under vacuum at below 75°C. The resulting solid was subjected to drying at 70°C for 3 hours to obtain 17 gm of amorphous ivabradine hydrochloride solid dispersion with soluplus.
• De-hydro ivabradine oxalate salt (90 gm; HPLC Purity: 99.7%) as obtained in example 2 was dissolved in methanol (1510 ml) and then added palladium on carbon (45 gm). To the reaction mixture was applied hydrogen gas for 4 hours and filtered through hy-flow bed. The solvent was distilled off under vacuum at below 55°C and then added water (1000 ml). The pH of the reaction mass was adjusted to 9.0 to 9.5 with sodium hydroxide solution (20%) and then added ethyl acetate (1000 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate.

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