US20160289192A1 - Ivabradine hydrochloride form iv - Google Patents
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- US20160289192A1 US20160289192A1 US15/089,495 US201615089495A US2016289192A1 US 20160289192 A1 US20160289192 A1 US 20160289192A1 US 201615089495 A US201615089495 A US 201615089495A US 2016289192 A1 US2016289192 A1 US 2016289192A1
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- 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
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- 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
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- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
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- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
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- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
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- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2893—Tablet coating processes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the present invention relates to ivabradine hydrochloride Form IV, a process for its preparation, its use as therapeutically active ingredient, and pharmaceutical compositions containing it.
- Ivabradine, and addition salts thereof with a pharmaceutically acceptable acid, and more especially its hydrochloride have very valuable pharmacological and therapeutic properties, especially bradycardic properties, making those compounds useful in the treatment or prevention of various clinical situations of myocardial ischaemia such as angina pectoris, myocardial infarct and associated rhythm disturbances, and also in various pathologies involving rhythm disturbances, especially supraventricular rhythm disturbances, and in heart failure.
- Ivabradine is currently marketed with trade name Corlentor® and Procolaran® for treatment of chronic stable angina pectoris in coronary artery disease patients with normal sinus rhythm.
- EP0534859 describes a synthesis process for ivabradine and its hydrochloride salt. It is disclosed a product recrystallized in acetonitrile with its melting point Mp: 135-140° C.
- EP1589005 discloses the crystalline Form ⁇ of ivabradine hydrochloride, characterized by PXRD, and a process for its preparation.
- EP1695965 discloses the crystalline Form ⁇ , a tetrahydrate form of ivabradine hydrochloride, characterized by PXRD, and a process for its preparation.
- EP1695710 discloses the crystalline Form ⁇ d of ivabradine hydrochloride, characterized by PXRD, and a process for its preparation.
- EP1707562 discloses the crystalline Form ⁇ , a monohydrate form of ivabradine hydrochloride, characterized by PXRD, and a process for its preparation.
- EP1695709 discloses the crystalline Form ⁇ d of ivabradine hydrochloride, characterized by PXRD, and a process for its preparation.
- EP1775288 discloses the crystalline Form ⁇ , a hydrated form of ivabradine hydrochloride, characterized by PXRD, and a process for its preparation.
- EP1775287 discloses the crystalline Form ⁇ d of ivabradine hydrochloride, characterized by PXRD, and a process for its preparation.
- WO2008/125006 discloses a crystalline form of ivabradine hydrochloride, characterized by PXRD, and a process for its preparation.
- CN101768117 discloses a crystalline form of ivabradine hydrochloride, characterized by PXRD, and a process for its preparation.
- CN101805289 discloses the crystalline Form ⁇ of ivabradine hydrochloride, characterized by PXRD, and a process for its preparation.
- WO2011/098582 discloses three crystalline forms of ivabradine hydrochloride, characterized by PXRD, and a process for its preparation.
- WO2008/146308, CN101463008, CN101597261 and CN102050784 disclose amorphous form of ivabradine hydrochloride and a process for its preparation.
- polymorphic behaviour of drugs can be of crucial importance in pharmacy and pharmacology.
- Polymorphism is the ability of a substance to crystallize in different crystal modifications, each of them having the same chemical structure but different arrangements or conformations of the molecules in the crystal lattice.
- the differences in physical properties exhibited by polymorphs affect pharmaceutical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing), and dissolution rates (an important factor in determining bio-availability). Differences in stability can result from changes in chemical reactivity or mechanical changes or both. For example, a dosage form originating from one polymorph might discolor more rapidly when compound to another from a different polymorph.
- tablets might crumble on storage as a kinetically favoured polymorph spontaneously converts into a thermodynamically more stable polymorphic form.
- some polymorphic transitions may result in lack of potency or, at the other extreme, toxicity.
- the physical properties of the crystal may be important in processing: for example, one polymorph might be more likely to form solvates or might be difficult to filter and wash free of impurities.
- the most important solid state property of a pharmaceutical substance is its rate of dissolution in aqueous fluid.
- the rate of dissolution of an active ingredient in a patient's gastric fluid may have therapeutic consequences as it imposes an upper limit on the rate at which an orally-administered active ingredient reaches the blood stream.
- the solid state polymorphic form of a compound may also affect its behaviour on compaction and its storage stability.
- polymorphic form may give rise to thermal behaviour different form that of the amorphous material (or) another polymorphic form.
- any other polymorphs are metastable and may therefore transform to the more stable form. Overlooking the most stable polymorph may cause failure of a marketed product due to phase transformation during storage. A late-appearing stable polymorph can have a great impact on development timelines. Although metastable forms may survive years if a considerable activation energy barrier has to be overcome in moving from the metastable state to the stable state, this activation-energy barrier may be reduced by moisture, catalysts, impurities, excipients or temperature and the transformation into the stable form occurs spontaneously. Seeds of the stable form may also accelerate transformations.
- thermodynamically unstable modification in the production of tablets is sometimes the reason why unwanted changes take place in such formulations after a time of storage. Therefore, there is a need for a thermodynamically stable polymorphic form of ivabradine hydrochloride and methods of its preparation.
- a method described by Haleblian and McCrone can be used to determine the most stable polymorph at room temperature. This method utilizes the fact that the most stable polymorph will also be the less soluble at a given temperature and pressure. If crystals of both polymorphs are present in a saturated solution, the most stable form will grow at the expense of the less stable one. This method is called the solution phase transformation or solvent mediated transformation.
- ivabradine hydrochloride which would be suitable for use in the pharmaceutical industry and, in particular, allow easy production of ivabradine preparations in solid form meeting strict pharmaceutical standards, such as tablets, capsules, chewable tablets, powders, etc. for oral administration.
- ivabradine hydrochloride Form IV for administration to mammals in accordance with exacting health registration requirements of the U.S. and international health registration authorities, e.g. the FDA's Good Manufacturing Practices (“GMP”) requirements, there is a need to produce ivabradine hydrochloride Form IV in as pure a form as possible, especially a form having constant physical properties.
- GMP Good Manufacturing Practices
- ivabradine hydrochloride Form IV the drug substance ivabradine hydrochloride exists in a thermodynamically stable polymorphic form under certain experimental conditions of isolation or purification.
- This crystalline form is stable and easy to handle.
- the improved physical characteristics of said stable crystalline form compared with the ivabradine hydrochloride described in the art, involve enhanced manufacturing capabilities and the provision of a compound suitable for use in the preparation of pharmaceutical formulations.
- ivabradine hydrochloride exists as a less thermodynamically stable polymorph or a mixture of polymorphs. Such a mixture could lead to production of a ivabradine hydrochloride Form IV product which would exist as a variable mixture of variable composition (i.e., variable percent amounts of polymorphs) having variable physical properties, a situation unacceptable in view of stringent GMP requirements.
- ivabradine hydrochloride Form IV a novel thermodynamically stable and pure crystalline form of ivabradine hydrochloride (ivabradine hydrochloride Form IV), having constant physical properties.
- Ivabradine hydrochloride Form IV of the present invention is obtained with high yields and elevated richness. Furthermore, the drying conditions used do not affect in the stability of the process, its preparation process is consistently reproducible and robust, and, therefore, easily industrializable. In addition, solvents used during process of obtainment, such as toluene, can be removed without observing changes in the resulting crystalline form (Form IV) or other properties.
- ivabradine hydrochloride Form IV shows a suitable dissolution profile.
- the ivabradine hydrochloride Form IV is particularly suitable to obtain immediate release tablets.
- These tablets can be prepared by known and conventional processes, including direct compression, dry granulation and/or wet granulation.
- the wet granulation process is performed using organic solvents, acetone or alcohols (such as ethanol, methanol and isopropylalcohol), or the combination thereof.
- these tablets can be coated by different conventional excipients.
- the commonly used coating agents are derivatives of cellulose such as hydroxypropylmethylcellulose (HPMC) and hydroxypropylcellulose (HPC), derivatives of Poly(methyl methacrylate) (PMMA) such as Eudragit®, Polyvinyl alcohol (PVA) and derivates of Polyvinyl alcohol.
- one aspect of the present invention relates to ivabradine hydrochloride Form IV.
- the invention relates to ivabradine hydrochloride Form IV as defined above, with a powder X-ray diffraction comprising the following 2 theta ( ⁇ 0.2) peaks: 8.74, 15.55, 17.17, 19.89, and 24.29, wherein the X-ray diffraction is measured using a CuK ⁇ radiation.
- the invention relates to ivabradine hydrochloride Form IV as defined above, with a powder X-ray diffraction comprising the following 2 theta ( ⁇ 0.2) peaks: 8.11, 8.74, 15.55, 17.17, 19.18, 19.89, 21.82, 22.49, 24.29 and 24.53, wherein the X-ray diffraction is measured using a CuK ⁇ radiation.
- the invention relates to ivabradine hydrochloride Form IV as defined above, with a powder X-ray diffraction essentially as depicted in FIG. 1 .
- the invention relates to ivabradine hydrochloride Form IV as defined above, having a Differential Scanning calorimetry thermogram which shows one endothermic peak from 153° C. to 157° C.
- the invention relates to ivabradine hydrochloride Form IV as defined above, having a Differential Scanning calorimetry thermogram essentially as depicted in FIG. 2 .
- the invention relates to ivabradine hydrochloride Form IV as defined above, with an average particle size from 0.1 to 600 ⁇ m, preferably from 10 to 100 ⁇ m, determined by laser diffraction using Malvern Mastersizer 2000 laser diffraction instrument.
- Another aspect of the present invention relates to ivabradine hydrochloric Form, which is essentially the crystalline form disclosed above.
- Another aspect of the present invention relates to a process for preparing ivabradine hydrochloride Form IV as defined above, which comprises the step of:
- the invention relates to the process as defined above, wherein the solvent system comprises at least two solvents.
- the invention relates to the process as defined above, wherein the solvent system comprises toluene and a second solvent selected from ethanol, acetone and ethyl acetate.
- the invention relates to the process as defined above, wherein the temperature of step (a) is lower than 60° C., preferably between 10° C. and 60° C., preferably is lower than 40° C., more preferably from 10° C. to 30° C. and even more preferably from 20° C. to 25° C.
- the invention relates to the process as defined above, wherein the reaction time for performing step (a) is less than 48 h, preferably is less than 24 h.
- the invention relates to the process as defined above, wherein the proportion in step (a) of liter of the solvent system versus kilogram of ivabradine hydrochloride Form IV is from 5 to 50, preferably from 8 to 12.
- the invention relates to the process as defined above, wherein the solvent system in step (a) is essentially toluene.
- the invention relates to the process as defined above, further comprising after performing step (a), the step of:
- the invention relates to the process as defined above, further comprising after performing step b, the step of:
- Another aspect of the present invention relates to a process for preparing ivabradine hydrochloride Form IV as defined above, comprising the steps of:
- Another aspect of the present invention relates to a process for preparing ivabradine hydrochloride Form IV as defined above, comprising the steps of:
- the invention relates to the process as defined above, wherein the solvent system of step (i), is toluene.
- the invention relates to the process as defined above, wherein the solution of chlorhydric acid of step (iii), is a hydrochloric acid solution in ethanol.
- Another aspect of the present invention relates to a process for preparing ivabradine hydrochloride Form IV as defined above, comprising the steps of:
- i′ stirring a solution of ivabradine free base in a solvent system, wherein the solvent system comprises toluene, ethanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate and mixtures thereof;
- ii′ maintaining the solution at a temperature lower than 60° C., preferably between 10° C. and 60° C., more preferably lower than 40° C.; and more preferably between 10° C. and 40° C.
- the invention relates to the process as defined above, wherein the solvent system of step (i′), is toluene.
- the invention relates to the process as defined above, wherein the solution of chlorhydric acid of step (iv′), is a hydrochloric acid solution in ethanol.
- Another aspect of the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising ivabradine hydrochloride Form IV as defined above, and at least a pharmaceutically acceptable excipient.
- the invention relates to the pharmaceutical composition as defined above, for oral administration.
- the invention relates to the pharmaceutical composition as defined above, in the form of tablets.
- the invention relates to the pharmaceutical composition as defined above, in the form of film-coated tablets.
- the invention relates to the coating agents, preferably these agents are derivatives of cellulose, more preferably hydroxypropylmethylcellulose (HPMC) and hydroxypropylcellulose (HPC), derivatives of Poly(methyl methacrylate) (PMMA), more preferably Eudragit®, Polyvinyl alcohol (PVA) and derivates of Polyvinyl alcohol.
- HPMC hydroxypropylmethylcellulose
- HPC hydroxypropylmethylcellulose
- HPC hydroxypropylcellulose
- HPC hydroxypropylcellulose
- HPC hydroxypropylcellulose
- HPC hydroxypropylcellulose
- PMMA Poly(methyl methacrylate)
- Eudragit® Poly(methyl methacrylate)
- PVA Polyvinyl alcohol
- the invention relates to the pharmaceutical composition as defined above that contains 5 to 9 mg of ivabradine hydrochloride Form IV.
- the invention in another embodiment, relates to a film-coated tablet contains about 5 mg ivabradine as free base (equivalent to 5.390 mg ivabradine hydrochloride Form IV).
- the invention in another embodiment, relates to a film-coated tablet contains about 7.5 mg ivabradine as free base (equivalent to 8.085 mg ivabradine hydrochloride Form IV).
- Another aspect of the present invention relates to a process for the manufacture of the pharmaceutical composition as defined above, characterized in that direct compression, dry granulation and/or wet granulation techniques are used.
- Another aspect of the present invention relates to a wet granulation process characterized in that said process comprises using organic solvents, preferably acetone or alcohols (such as ethanol, methanol and isopropylalcohol) or the combination thereof.
- organic solvents preferably acetone or alcohols (such as ethanol, methanol and isopropylalcohol) or the combination thereof.
- Another aspect of the present invention relates to ivabradine hydrochloride Form IV as defined above or the pharmaceutical composition as defined above, for use in therapy.
- Another aspect of the present invention relates to ivabradine hydrochloride Form IV as defined above or the pharmaceutical composition as defined above, for use in the treatment of bradycardics, myocardial ischaemia, supraventricular rhythm disturbances, chronic stable angina pectoris in coronary artery disease adults with normal sinus rhythm, myocardial infarct, heart failure and associated rhythm disturbances.
- under vacuum refers to conditions where the air (gas) pressure surrounding the substrate has been reduced below atmospheric pressure.
- under vacuum refers to a pressure from 25 mm Hg to 760 mm Hg (with the proviso that 760 mm Hg is not included), and more preferably from 50 mm Hg to 200 mm Hg.
- thermodynamically stable polymorphic form of ivabradine hydrochloride encompasses a thermodynamically stable polymorphic form of ivabradine hydrochloride.
- This Form may be characterized by X-ray diffraction diagram, measured with a Copper X-ray source, exhibiting characteristic peaks, degrees 2 theta, at about:
- the invention also encompasses a process for preparing the claimed crystalline form of ivabradine hydrochloride which comprises the step of slurrying ivabradine hydrochloride in a slurry solvent selected from toluene, ethanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate and mixtures thereof.
- a slurry solvent selected from toluene, ethanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate and mixtures thereof.
- Toluene is a preferred slurry solvent and can be used alone or with a second solvent selected from ethanol, acetone and ethyl acetate.
- the present invention also discloses a process for preparing the claimed crystalline form of ivabradine hydrochloride which further comprises the step of drying the isolated ivabradine hydrochloride after the slurrying step at a pressure less than 760 mm Hg and the temperature is about 65° C.
- Processes for preparing the claimed crystalline form of ivabradine hydrochloride disclosed in the present invention optionally can include the step of seeding with the novel crystalline form of ivabradine hydrochloride disclosed in the present invention.
- DSC Differential scanning calorimetry
- TGA Thermal Gravimetric Analyses
- peaks at 2q can shift up to ⁇ 0.2 degrees (error). In one embodiment, all peaks in X-ray diffraction pattern shift up to +0.2 degrees, or up to ⁇ 0.2 degrees. An X-ray diffraction pattern or peaks within that error is considered the same or substantially similar.
- FT-IR-ATR Fourier Transform Infrared—Attenuated Total Reflectance
- MiBK when used in the context of the present invention refers to methyl isobutyl ketone.
- MEK when used in the context of the present invention refers to methyl ethyl ketone.
- any ranges given include both the lower and the upper end-points of the range.
- FIG. 1 shows a x-ray diffractogram for the novel crystalline form of ivabradine hydrochloride.
- FIG. 2 shows a DSC thermogram for the novel crystalline form of ivabradine hydrochloride.
- FIG. 3 shows an IR for the novel crystalline form of ivabradine hydrochloride.
- FIG. 4 shows a TGA analysis for the novel crystalline form of ivabradine hydrochloride.
- Crystalline ivabradine hydrochloride was obtained according to the process described in the patent EP0534859.
- Form ⁇ ivabradine hydrochloride was obtained according to the process described in the patent EP1589005.
- Form ⁇ was obtained according to the process described in the patent EP1956005.
- Ivabradine was obtained according to the process described in the patent EP0534859.
- Examples 2 to 7 were carried out according to the process described in Example 1. In all cases the obtention of Form IV was confirmed by PXRD.
- ivabradine hydrochloride 0.5 g were stirred with 25 ml of ethyl acetate at a temperature of 20-25° C. After seeding with the product obtained in the Example 1 the suspension was slurried for 4 days. The solid product was isolated and dried under vacuum at a temperature of 45° C. The crystalline product obtained was characterized by PXRD confirming its structure (Yield: 88%).
- Ivabradine HCl prepared according to its preparative example, was suspended in the solvent at room temperature. The suspension was slurried at a temperature of 20-25° C. The solid was filtered, dried under vacuum and analysed by PXRD.
- ivabradine HCl Form ⁇ and 10.0 mg of the Form IV prepared according to Example 1 were suspended in MiBK at room temperature. The suspension was slurried for 3 days at a temperature of 20-25° C. The solid was filtered, dried under vacuum. Analysis by PXRD confirmed that the crystalline ivabradine hydrochloride isolated was in its new crystalline form.
- Examples 22 to 24 were carried out according to the process described in Example 21. In all cases the obtention of the novel crystalline form was confirmed by PXRD.
- a solution which comprised 6.9 g of ivabradine in 90 mL of toluene was stirred maintaining the temperature below about 40° C. 16 ml of a chlorhydric acid solution in ethanol 1.75M were added. The solution was seeded with the product obtained in the Example 1. Crystal growth was promoted by stirring for 20 hours maintaining the temperature below about 40° C. The solid product obtained was isolated and dried under vacuum at a temperature of 65° C.
- Tablets of ivabradine hydrochloride Form IV were prepared using the ingredients listed in the following Table.
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Abstract
Ivabradine hydrochloride Form IV, its pharmaceutical composition, process for its preparation, and its use as therapeutically active ingredient and pharmaceutical compositions containing Ivabradine hydrochloride Form IV.
Description
- The present invention relates to ivabradine hydrochloride Form IV, a process for its preparation, its use as therapeutically active ingredient, and pharmaceutical compositions containing it.
- Ivabradine, (+)-3-[3-[N-[4,5-Dimethoxybenzocyclobutan-1(S)-ylmethyl]-N-methylamino]propyl]-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one, is represented by the structural formula (I):
- Ivabradine, and addition salts thereof with a pharmaceutically acceptable acid, and more especially its hydrochloride, have very valuable pharmacological and therapeutic properties, especially bradycardic properties, making those compounds useful in the treatment or prevention of various clinical situations of myocardial ischaemia such as angina pectoris, myocardial infarct and associated rhythm disturbances, and also in various pathologies involving rhythm disturbances, especially supraventricular rhythm disturbances, and in heart failure.
- Ivabradine is currently marketed with trade name Corlentor® and Procolaran® for treatment of chronic stable angina pectoris in coronary artery disease patients with normal sinus rhythm.
- The preparation and the therapeutic use of ivabradine and addition salts thereof with a pharmaceutically acceptable acid, and more especially its hydrochloride, have been described in the European patent specification EP0534859.
- EP0534859 describes a synthesis process for ivabradine and its hydrochloride salt. It is disclosed a product recrystallized in acetonitrile with its melting point Mp: 135-140° C.
- EP1589005 discloses the crystalline Form α of ivabradine hydrochloride, characterized by PXRD, and a process for its preparation.
- EP1695965 discloses the crystalline Form β, a tetrahydrate form of ivabradine hydrochloride, characterized by PXRD, and a process for its preparation.
- EP1695710 discloses the crystalline Form βd of ivabradine hydrochloride, characterized by PXRD, and a process for its preparation.
- EP1707562 discloses the crystalline Form γ, a monohydrate form of ivabradine hydrochloride, characterized by PXRD, and a process for its preparation.
- EP1695709 discloses the crystalline Form γd of ivabradine hydrochloride, characterized by PXRD, and a process for its preparation.
- EP1775288 discloses the crystalline Form δ, a hydrated form of ivabradine hydrochloride, characterized by PXRD, and a process for its preparation.
- EP1775287 discloses the crystalline Form δd of ivabradine hydrochloride, characterized by PXRD, and a process for its preparation.
- WO2008/125006 discloses a crystalline form of ivabradine hydrochloride, characterized by PXRD, and a process for its preparation.
- CN101768117 discloses a crystalline form of ivabradine hydrochloride, characterized by PXRD, and a process for its preparation.
- CN101805289 discloses the crystalline Form ω of ivabradine hydrochloride, characterized by PXRD, and a process for its preparation.
- WO2011/098582 discloses three crystalline forms of ivabradine hydrochloride, characterized by PXRD, and a process for its preparation.
- WO2008/146308, CN101463008, CN101597261 and CN102050784 disclose amorphous form of ivabradine hydrochloride and a process for its preparation.
- The polymorphic behaviour of drugs can be of crucial importance in pharmacy and pharmacology. Polymorphism is the ability of a substance to crystallize in different crystal modifications, each of them having the same chemical structure but different arrangements or conformations of the molecules in the crystal lattice. The differences in physical properties exhibited by polymorphs affect pharmaceutical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing), and dissolution rates (an important factor in determining bio-availability). Differences in stability can result from changes in chemical reactivity or mechanical changes or both. For example, a dosage form originating from one polymorph might discolor more rapidly when compound to another from a different polymorph. Or tablets might crumble on storage as a kinetically favoured polymorph spontaneously converts into a thermodynamically more stable polymorphic form. As a result of solubility/dissolution differences, in the extreme case, some polymorphic transitions may result in lack of potency or, at the other extreme, toxicity. In addition, the physical properties of the crystal may be important in processing: for example, one polymorph might be more likely to form solvates or might be difficult to filter and wash free of impurities.
- The most important solid state property of a pharmaceutical substance is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's gastric fluid may have therapeutic consequences as it imposes an upper limit on the rate at which an orally-administered active ingredient reaches the blood stream. The solid state polymorphic form of a compound may also affect its behaviour on compaction and its storage stability.
- These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic form of a substance. The polymorphic form may give rise to thermal behaviour different form that of the amorphous material (or) another polymorphic form.
- The discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.
- Usually the most stable polymorphic form is preferred in a marketed formulation, because any other polymorphs are metastable and may therefore transform to the more stable form. Overlooking the most stable polymorph may cause failure of a marketed product due to phase transformation during storage. A late-appearing stable polymorph can have a great impact on development timelines. Although metastable forms may survive years if a considerable activation energy barrier has to be overcome in moving from the metastable state to the stable state, this activation-energy barrier may be reduced by moisture, catalysts, impurities, excipients or temperature and the transformation into the stable form occurs spontaneously. Seeds of the stable form may also accelerate transformations. Therefore using a thermodynamically unstable modification in the production of tablets is sometimes the reason why unwanted changes take place in such formulations after a time of storage. Therefore, there is a need for a thermodynamically stable polymorphic form of ivabradine hydrochloride and methods of its preparation.
- A method described by Haleblian and McCrone can be used to determine the most stable polymorph at room temperature. This method utilizes the fact that the most stable polymorph will also be the less soluble at a given temperature and pressure. If crystals of both polymorphs are present in a saturated solution, the most stable form will grow at the expense of the less stable one. This method is called the solution phase transformation or solvent mediated transformation.
- Therefore, there is a demand for alternative pure and crystalline forms of ivabradine hydrochloride which would be suitable for use in the pharmaceutical industry and, in particular, allow easy production of ivabradine preparations in solid form meeting strict pharmaceutical standards, such as tablets, capsules, chewable tablets, powders, etc. for oral administration.
- To prepare pharmaceutical compositions containing ivabradine hydrochloride Form IV for administration to mammals in accordance with exacting health registration requirements of the U.S. and international health registration authorities, e.g. the FDA's Good Manufacturing Practices (“GMP”) requirements, there is a need to produce ivabradine hydrochloride Form IV in as pure a form as possible, especially a form having constant physical properties.
- The applicants have now discovered that the drug substance ivabradine hydrochloride exists in a thermodynamically stable polymorphic form under certain experimental conditions of isolation or purification (ivabradine hydrochloride Form IV). This crystalline form is stable and easy to handle. The improved physical characteristics of said stable crystalline form compared with the ivabradine hydrochloride described in the art, involve enhanced manufacturing capabilities and the provision of a compound suitable for use in the preparation of pharmaceutical formulations.
- The applicants have discovered that ivabradine hydrochloride exists as a less thermodynamically stable polymorph or a mixture of polymorphs. Such a mixture could lead to production of a ivabradine hydrochloride Form IV product which would exist as a variable mixture of variable composition (i.e., variable percent amounts of polymorphs) having variable physical properties, a situation unacceptable in view of stringent GMP requirements.
- The applicants surprisingly and unexpectedly have obtained a novel thermodynamically stable and pure crystalline form of ivabradine hydrochloride (ivabradine hydrochloride Form IV), having constant physical properties.
- Ivabradine hydrochloride Form IV of the present invention is obtained with high yields and elevated richness. Furthermore, the drying conditions used do not affect in the stability of the process, its preparation process is consistently reproducible and robust, and, therefore, easily industrializable. In addition, solvents used during process of obtainment, such as toluene, can be removed without observing changes in the resulting crystalline form (Form IV) or other properties.
- Moreover, the applicants have discovered that ivabradine hydrochloride Form IV shows a suitable dissolution profile. The ivabradine hydrochloride Form IV is particularly suitable to obtain immediate release tablets. These tablets can be prepared by known and conventional processes, including direct compression, dry granulation and/or wet granulation. The wet granulation process is performed using organic solvents, acetone or alcohols (such as ethanol, methanol and isopropylalcohol), or the combination thereof.
- Furthermore, these tablets can be coated by different conventional excipients. The commonly used coating agents are derivatives of cellulose such as hydroxypropylmethylcellulose (HPMC) and hydroxypropylcellulose (HPC), derivatives of Poly(methyl methacrylate) (PMMA) such as Eudragit®, Polyvinyl alcohol (PVA) and derivates of Polyvinyl alcohol.
- Thus, one aspect of the present invention relates to ivabradine hydrochloride Form IV.
- In another embodiment, the invention relates to ivabradine hydrochloride Form IV as defined above, with a powder X-ray diffraction comprising the following 2 theta (±0.2) peaks: 8.74, 15.55, 17.17, 19.89, and 24.29, wherein the X-ray diffraction is measured using a CuKα radiation.
- In another embodiment, the invention relates to ivabradine hydrochloride Form IV as defined above, with a powder X-ray diffraction comprising the following 2 theta (±0.2) peaks: 8.11, 8.74, 15.55, 17.17, 19.18, 19.89, 21.82, 22.49, 24.29 and 24.53, wherein the X-ray diffraction is measured using a CuKα radiation.
- In another embodiment, the invention relates to ivabradine hydrochloride Form IV as defined above, with a powder X-ray diffraction essentially as depicted in
FIG. 1 . - In another embodiment, the invention relates to ivabradine hydrochloride Form IV as defined above, having a Differential Scanning calorimetry thermogram which shows one endothermic peak from 153° C. to 157° C.
- In another embodiment, the invention relates to ivabradine hydrochloride Form IV as defined above, having a Differential Scanning calorimetry thermogram essentially as depicted in
FIG. 2 . - In another embodiment, the invention relates to ivabradine hydrochloride Form IV as defined above, with an average particle size from 0.1 to 600 μm, preferably from 10 to 100 μm, determined by laser diffraction using
Malvern Mastersizer 2000 laser diffraction instrument. - Another aspect of the present invention relates to ivabradine hydrochloric Form, which is essentially the crystalline form disclosed above.
- Another aspect of the present invention relates to a process for preparing ivabradine hydrochloride Form IV as defined above, which comprises the step of:
- a) slurrying ivabradine hydrochloride in a solvent system, wherein the solvent system comprises toluene, ethanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate and mixtures thereof.
- In another embodiment, the invention relates to the process as defined above, wherein the solvent system comprises at least two solvents.
- In another embodiment, the invention relates to the process as defined above, wherein the solvent system comprises toluene and a second solvent selected from ethanol, acetone and ethyl acetate.
- In another embodiment, the invention relates to the process as defined above, wherein the temperature of step (a) is lower than 60° C., preferably between 10° C. and 60° C., preferably is lower than 40° C., more preferably from 10° C. to 30° C. and even more preferably from 20° C. to 25° C.
- In another embodiment, the invention relates to the process as defined above, wherein the reaction time for performing step (a) is less than 48 h, preferably is less than 24 h.
- In another embodiment, the invention relates to the process as defined above, wherein the proportion in step (a) of liter of the solvent system versus kilogram of ivabradine hydrochloride Form IV is from 5 to 50, preferably from 8 to 12.
- In another embodiment, the invention relates to the process as defined above, wherein the solvent system in step (a) is essentially toluene.
- In another embodiment, the invention relates to the process as defined above, further comprising after performing step (a), the step of:
- b) isolating the ivabradine hydrochloride Form IV.
- In another embodiment, the invention relates to the process as defined above, further comprising after performing step b, the step of:
- c) drying the isolated ivabradine hydrochloride Form IV under vacuum pressure, preferably at a pressure from 25 mm Hg to, but not including, 760 mm Hg, and more preferably from 50 mm Hg to 200 mm Hg, and at a temperature between 45° C. and 70° C.
- Another aspect of the present invention relates to a process for preparing ivabradine hydrochloride Form IV as defined above, comprising the steps of:
- a) slurrying ivabradine hydrochloride in a solvent system, wherein the solvent system comprises toluene, ethanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate and mixtures thereof;
- b) isolating the ivabradine hydrochloride Form IV, and
- c) drying the isolated ivabradine hydrochloride Form IV under vacuum pressure, preferably at a pressure from 25 mm Hg to, but not including, 760 mm Hg, and more preferably from 50 mm Hg to 200 mm Hg, and at a temperature between 45° C. and 70° C.
- Another aspect of the present invention relates to a process for preparing ivabradine hydrochloride Form IV as defined above, comprising the steps of:
- i) stirring a solution of ivabradine free base in a solvent system, wherein the solvent system comprises toluene, ethanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate and mixtures thereof;
- ii) maintaining the solution at a temperature lower than 60° C., preferably between 10° C. and 60° C., more preferably lower than 40° C.; and more preferably between 10° C. and 40° C.
- iii) adding a solution of hydrochloric acid to obtain ivabradine hydrochloride;
- iv) seeding with the ivabradine hydrochloride Form IV;
- v) isolating the ivabradine hydrochloride Form IV; and
- vi) drying the isolated ivabradine hydrochloride Form IV under vacuum pressure, preferably at a pressure from 25 mm Hg to, but not including, 760 mm Hg, and more preferably from 50 mm Hg to 200 mm Hg, and at a temperature between 45° C. and 70° C.
- In another embodiment, the invention relates to the process as defined above, wherein the solvent system of step (i), is toluene.
- In another embodiment, the invention relates to the process as defined above, wherein the solution of chlorhydric acid of step (iii), is a hydrochloric acid solution in ethanol.
- Another aspect of the present invention relates to a process for preparing ivabradine hydrochloride Form IV as defined above, comprising the steps of:
- i′) stirring a solution of ivabradine free base in a solvent system, wherein the solvent system comprises toluene, ethanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate and mixtures thereof;
- ii′) maintaining the solution at a temperature lower than 60° C., preferably between 10° C. and 60° C., more preferably lower than 40° C.; and more preferably between 10° C. and 40° C.
- iii′) seeding with the ivabradine hydrochloride Form IV;
- iv′) adding a solution of hydrochloric acid to obtain ivabradine hydrochloride;
- v′) isolating the ivabradine hydrochloride Form IV; and
- vi′) drying the isolated ivabradine hydrochloride Form IV under vacuum pressure, preferably at a pressure from 25 mm Hg to, but not including, 760 mm Hg, and more preferably from 50 mm Hg to 200 mm Hg, and at a temperature between 45° C. and 70° C.
- In another embodiment, the invention relates to the process as defined above, wherein the solvent system of step (i′), is toluene.
- In another embodiment, the invention relates to the process as defined above, wherein the solution of chlorhydric acid of step (iv′), is a hydrochloric acid solution in ethanol.
- Another aspect of the present invention relates to a pharmaceutical composition comprising ivabradine hydrochloride Form IV as defined above, and at least a pharmaceutically acceptable excipient.
- In another embodiment, the invention relates to the pharmaceutical composition as defined above, for oral administration.
- In another embodiment, the invention relates to the pharmaceutical composition as defined above, in the form of tablets.
- In another embodiment, the invention relates to the pharmaceutical composition as defined above, in the form of film-coated tablets.
- In another embodiment, the invention relates to the coating agents, preferably these agents are derivatives of cellulose, more preferably hydroxypropylmethylcellulose (HPMC) and hydroxypropylcellulose (HPC), derivatives of Poly(methyl methacrylate) (PMMA), more preferably Eudragit®, Polyvinyl alcohol (PVA) and derivates of Polyvinyl alcohol.
- In another embodiment, the invention relates to the pharmaceutical composition as defined above that contains 5 to 9 mg of ivabradine hydrochloride Form IV.
- In another embodiment, the invention relates to a film-coated tablet contains about 5 mg ivabradine as free base (equivalent to 5.390 mg ivabradine hydrochloride Form IV).
- In another embodiment, the invention relates to a film-coated tablet contains about 7.5 mg ivabradine as free base (equivalent to 8.085 mg ivabradine hydrochloride Form IV).
- Another aspect of the present invention relates to a process for the manufacture of the pharmaceutical composition as defined above, characterized in that direct compression, dry granulation and/or wet granulation techniques are used.
- Another aspect of the present invention relates to a wet granulation process characterized in that said process comprises using organic solvents, preferably acetone or alcohols (such as ethanol, methanol and isopropylalcohol) or the combination thereof.
- Another aspect of the present invention relates to ivabradine hydrochloride Form IV as defined above or the pharmaceutical composition as defined above, for use in therapy.
- Another aspect of the present invention relates to ivabradine hydrochloride Form IV as defined above or the pharmaceutical composition as defined above, for use in the treatment of bradycardics, myocardial ischaemia, supraventricular rhythm disturbances, chronic stable angina pectoris in coronary artery disease adults with normal sinus rhythm, myocardial infarct, heart failure and associated rhythm disturbances.
- In the above definitions, the term “under vacuum” refers to conditions where the air (gas) pressure surrounding the substrate has been reduced below atmospheric pressure. Preferably under vacuum refers to a pressure from 25 mm Hg to 760 mm Hg (with the proviso that 760 mm Hg is not included), and more preferably from 50 mm Hg to 200 mm Hg.
- One embodiment of the invention encompasses a thermodynamically stable polymorphic form of ivabradine hydrochloride. This Form may be characterized by X-ray diffraction diagram, measured with a Copper X-ray source, exhibiting characteristic peaks,
degrees 2 theta, at about: -
Angle Relative Intensity [°2theta] [%] 8.11 11.59 8.74 9.73 15.55 100.00 17.17 85.38 19.18 78.06 19.89 54.44 21.82 54.91 22.49 64.80 24.29 53.84 24.53 56.00
and additionally, by one endothermic peak about 155° C. as measured by differential scanning calorimetry (DSC). - The invention also encompasses a process for preparing the claimed crystalline form of ivabradine hydrochloride which comprises the step of slurrying ivabradine hydrochloride in a slurry solvent selected from toluene, ethanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate and mixtures thereof. Toluene is a preferred slurry solvent and can be used alone or with a second solvent selected from ethanol, acetone and ethyl acetate.
- The present invention also discloses a process for preparing the claimed crystalline form of ivabradine hydrochloride which further comprises the step of drying the isolated ivabradine hydrochloride after the slurrying step at a pressure less than 760 mm Hg and the temperature is about 65° C.
- Processes for preparing the claimed crystalline form of ivabradine hydrochloride disclosed in the present invention, optionally can include the step of seeding with the novel crystalline form of ivabradine hydrochloride disclosed in the present invention.
- Differential scanning calorimetry (DSC) analyses were carried out by means of a Mettler-Toledo DSC-822e calorimeter. Experimental conditions: aluminium crucibles of 40 μL volume, atmosphere of dry nitrogen with 50 mL/min flow rate, heating rate of 10° C./min. The calorimeter was calibrated with indium of 99.99% purity. Instrument could result in a different thermogram. The present invention is characterized by the thermogram values set forth herein obtained using this DSC Instrument as well as the equivalent thermogram values obtained using other types of DSC instruments.
- Thermal Gravimetric Analyses (TGA) were performed on a Mettler-Toledo TGA-851e thermobalance. Experimental conditions: alumina crucibles of 70 mL volume, atmosphere of dry nitrogen with 50 mL/min flow rate, heating rate of 10° C./min.
- Ivabradine hydrochloride Form IV PXRD analyses: The powder samples were sandwiched between polyester films of 20 micrometers of thickness and analysed in a PANalytical X'Pert PRO MPD θ/θ powder diffractometer of 240 millimetres of radius, in a configuration of convergent beam with a focalizing mirror and a flat sample transmission geometry, in the following experimental conditions: Cu K α radiation (I=1.5418 {tilde over (Å)}); Work power: 45 kV and 40 mA; Incident beam slits defining a beam height of 0.4 millimetres; Incident and diffracted beam 0.02 radians Soller slits; PIXcel detector: Active length=3.347 Å°: 2θ/θ scans from 2 to 40°2θ with a step size of 0.026°2θ and a measuring time of 75 seconds per step.
- The term “about” when used in the context of the present invention refers to ±10% of the specified amount. For the purpose of this invention, for X-ray diffraction patterns, depending on the calibration, sample or instrumentation, peaks at 2q can shift up to ±0.2 degrees (error). In one embodiment, all peaks in X-ray diffraction pattern shift up to +0.2 degrees, or up to −0.2 degrees. An X-ray diffraction pattern or peaks within that error is considered the same or substantially similar.
- Fourier Transform Infrared—Attenuated Total Reflectance (FT-IR-ATR) spectra were registered on a Perkin Elmer Spectrum One/100 FT-IR spectrometer with universal attenuated total reflectance (ATR) sampling accessory (SPECTRUM100 with UATR1BOUNCE). Sample is placed on the ATR plate and the measure is carried out in the 650-4000 cm-1 range. The term “IR or IR spectrum/ spectra” when used in the context refers to spectra registered in the conditions mentioned above.
- The term “MiBK” when used in the context of the present invention refers to methyl isobutyl ketone.
- The term “MEK” when used in the context of the present invention refers to methyl ethyl ketone.
- For the purposes of the invention, any ranges given include both the lower and the upper end-points of the range.
- The following drawings and examples illustrate the scope of the invention.
-
FIG. 1 : shows a x-ray diffractogram for the novel crystalline form of ivabradine hydrochloride. -
FIG. 2 : shows a DSC thermogram for the novel crystalline form of ivabradine hydrochloride. -
FIG. 3 : shows an IR for the novel crystalline form of ivabradine hydrochloride. -
FIG. 4 : shows a TGA analysis for the novel crystalline form of ivabradine hydrochloride. - Crystalline Ivabradine Hydrochloride.
- Crystalline ivabradine hydrochloride was obtained according to the process described in the patent EP0534859.
- Form α of Ivabradine Hydrochloride.
- Form α ivabradine hydrochloride was obtained according to the process described in the patent EP1589005.
- Form δ of Ivabradine Hydrochloride.
- Form δ was obtained according to the process described in the patent EP1956005.
- Form δd of Ivabradine Hydrochloride.
- Form δd was obtained according to the process described in the patent EP1775287.
- Ivabradine.
- Ivabradine was obtained according to the process described in the patent EP0534859.
- Form IV of Ivabradine Hydrochloride.
- 15.0 g of crystalline ivabradine hydrochloride of preparative Example 1 with a Karl Fisher value of 1.6% were slurried with 750 ml of toluene at a temperature of 20-25° C. for 4 days. The solid product was isolated and dried under vacuum at a temperature of 45° C. The crystalline product obtained was characterized by PXRD confirming its structure (HPLC Purity: 99.8%, Yield: 86%).
- Form IV of Ivabradine Hydrochloride.
- Examples 2 to 7 were carried out according to the process described in Example 1. In all cases the obtention of Form IV was confirmed by PXRD.
-
ivabradine HCl Solvent Yield Example (g) (mL) (%) 2 0.5 toluene/acetone(10:1) (25) 91 3 0.5 toluene/ethyl acetate (10:1) (25) 87 4 0.5 ethyl acetate/ethanol (9:1) (5) 70 5 0.5 isopropyl acetate (25) 96 6 0.5 toluene (5) 88 7 0.5 toluene/ethanol (9:1) (5) 64 - Form IV of Ivabradine Hydrochloride.
- 15.0 g of ivabradine hydrochloride were slurried with 750 ml of toluene at T: 20-25° C. for 1 day. The solid product was isolated and dried under vacuum at a temperature of 45° C. The crystalline product obtained was characterized by PXRD confirming its structure (Yield: 85%).
- Form IV of ivabradine hydrochloride.
- 0.5 g of ivabradine hydrochloride were stirred with 25 ml of ethyl acetate at a temperature of 20-25° C. After seeding with the product obtained in the Example 1 the suspension was slurried for 4 days. The solid product was isolated and dried under vacuum at a temperature of 45° C. The crystalline product obtained was characterized by PXRD confirming its structure (Yield: 88%).
- Form IV of Ivabradine Hydrochloride.
- Ivabradine HCl, prepared according to its preparative example, was suspended in the solvent at room temperature. The suspension was slurried at a temperature of 20-25° C. The solid was filtered, dried under vacuum and analysed by PXRD.
-
Weight Solvent Slurry Result Example Polymorph (mg) (mL) (days) PXRD 10 Form α 10.0 MiBK (1.5) 3 Form IV 11 Form α 10.5 MiBK (1.5) 2 Form IV 12 Form α 10.6 toluene (1.5) 2 Form IV 13 Form α + δd 10.5 MEK (1.5) 2 Form IV 14 Form δ 21.5 heptane (1.0) 4 Form IV 15 Form δ 20.6 MiBK (1.0) 4 Form IV 16 Form δ 20.0 toluene (1.0) 4 Form IV 17 Form δ 20.4 ethanol/ ethyl 4 Form IV acetate (1:9) (1.0) 18 Form δ 20.5 ethanol/n- 4 Form IV pentane (1:9) (1.0) 19 Form δd 20.1 toluene (1.0) 4 Form IV 20 Form δ + δd 20.2 toluene (1.0) 4 Form IV - Form IV of Ivabradine Hydrochloride
- 11.2 mg of ivabradine HCl Form α and 10.0 mg of the Form IV prepared according to Example 1 were suspended in MiBK at room temperature. The suspension was slurried for 3 days at a temperature of 20-25° C. The solid was filtered, dried under vacuum. Analysis by PXRD confirmed that the crystalline ivabradine hydrochloride isolated was in its new crystalline form.
- Form IV of Ivabradine Hydrochloride.
- Examples 22 to 24 were carried out according to the process described in Example 21. In all cases the obtention of the novel crystalline form was confirmed by PXRD.
-
Form α Form IV Solvent Slurry Result Example (mg) (mg) (mL) (days) PXRD 22 10.6 10.5 MiBK (1.5) 2 Form IV 23 10.0 10.6 toluene (1.5) 2 Form IV 24 11.0 10.5 MEK (1.5) 2 Form IV - Form IV of Ivabradine Hydrochloride.
- A solution which comprised 6.9 g of ivabradine in 90 mL of toluene was stirred maintaining the temperature below about 40° C. 16 ml of a chlorhydric acid solution in ethanol 1.75M were added. The solution was seeded with the product obtained in the Example 1. Crystal growth was promoted by stirring for 20 hours maintaining the temperature below about 40° C. The solid product obtained was isolated and dried under vacuum at a temperature of 65° C.
- The crystalline product obtained was characterized by PXRD confirming its structure (HPLC Purity: 99.17%, Yield: 68%).
- Tablets of Form IV of Ivabradine Hydrochloride.
- Tablets of ivabradine hydrochloride Form IV were prepared using the ingredients listed in the following Table.
-
Components % Ivabradine hydrochloride 5.39 Maize starch 15.00 Maltodextrin 5.00 Silica colloidal anhydrous 1.00 Monohydrate lactose 73.11 Magnesium stearate 0.50 - All the components, with the exception of magnesium stearate and silica colloidal anhydrous, were mixed. Finally, silica colloidal anhydrous and magnesium stearate were added and mixed. The blend was compressed in an excentric tabletting machine. The absence of any transformation of the crystalline Form IV of ivabradine hydrochloride was confirmed.
- Film-Coated Tablets of Form IV of Ivabradine Hydrochloride.
- Tablets were made with the indicated proportions of the ingredients mention in the following Table.
-
Components % Ivabradine hydrochloride 5.39 Maize starch 10.00 Maltodextrin 10.00 Silica colloidal anhydrous 1.00 Monohydrate lactose 72.61 Magnesium stearate 1.00 Ethanol anhydrous* — Coating excipient 3.00 *Ethanol evaporates during the drying process - All the components with the exception of magnesium stearate and silica colloidal anhydrous were mixed and granulated using ethanol as a granulating solvent. Then a wet calibration of the granules was performed. The obtained granules were dried followed by a dry calibration of the granules. Thereafter, silica colloidal anhydrous and magnesium stearate were added and mixed. The lubricated granulate was compressed in an eccentric tabletting machine.
- Finally, tablets were coated using conventional coating agents until a weight increase of approximately 3%.
- The absence of any transformation of the crystalline Form IV of ivabradine hydrochloride was confirmed.
Claims (21)
1. Ivabradine hydrochloride Form IV with a powder X-ray diffraction comprising the following degrees 2 theta (±0.2) peaks: 8.74, 15.55, 17.17, 19.89, and 24.29, wherein the X-ray diffraction is measured using a CuKα radiation.
2. Ivabradine hydrochloride Form IV according to claim 1 , with a powder X-ray diffraction comprising the following degrees 2 theta (±0.2)peaks: 8.11, 8.74, 15.55, 17.17, 19.18, 19.89, 21.82, 22.49, 24.29 and 24.53, where in the X-ray diffraction is measured using a CuKα radiation.
3. Ivabradine hydrochloride Form IV according to claim 1 , with a powder X-ray diffraction essentially as depicted in FIG. 1 .
4. Ivabradine hydrochloride Form IV according to claim 1 , having a Differential Scanning calorimetry thermogram which shows one endothermic peak from 153° C. to 157° C.
5. Ivabradine hydrochloride Form IV according to claim 1 , having a Differential Scanning calorimetry thermogram essentially as depicted in FIG. 2 .
6. A process for preparing ivabradine hydrochloride Form IV according to claim 1 , which comprises the step of:
a) slurrying ivabradine hydrochloride in a solvent system, wherein the solvent system comprises toluene, ethanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate and mixtures thereof.
7. The process according to claim 6 , wherein the temperature of step (a) is lower than 60° C.
8. The process according to claim 6 , wherein the reaction time for performing step (a) is less than 48 h.
9. The process according to claim 6 , wherein the proportion in step (a) of liter of the solvent system versus kilogram of ivabradine hydrochloride Form IV is from 5 to 50.
10. The process according to claim 6 , further comprising the step of:
b) isolation of ivabradine hydrochloride Form IV, and
c) drying the isolated ivabradine hydrochloride Form IV under vacuum pressure and at a temperature between 45° C. and 70° C.
11. A process for preparing ivabradine hydrochloride Form IV according to claim 6 comprising the steps of:
i) stirring a solution of ivabradine free base in a solvent system, wherein the solvent system comprises toluene, ethanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate and mixtures thereof;
ii) maintaining the solution at a temperature lower than 60° C.;
iii) adding a solution of hydrochloric acid to obtain ivabradine hydrochloride;
iv) seeding with the ivabradine hydrochloride Form IV;
v) isolating the ivabradine hydrochloride Form IV and
vi) drying the isolated ivabradine hydrochloride Form IV under vacuum pressure and at a temperature between 45° C. and 70° C.
12. A pharmaceutical composition comprising ivabradine hydrochloride Form IV according to claim 1 , and at least a pharmaceutically acceptable excipient.
13. The pharmaceutical composition according to claim 12 wherein the said composition is in the form of a tablet for oral administration.
14. The pharmaceutical composition according to claim 12 , wherein the coating agent is selected from derivatives of cellulose, derivatives of Poly(methylmethacrylate), Polyvinyl alcohol and derivates of Polyvinyl alcohol.
15. The pharmaceutical composition according to claim 12 , wherein said composition contains from about 5 mg to about 9 mg of ivabradine hydrochloride Form IV.
16. A process for the manufacture of the composition according to claim 12 , characterized in that said process comprises using direct compression, dry granulation and/or wet granulation techniques.
17. The process, according to claim 16 , characterized in that the wet granulation process comprises using organic solvents.
18. A method for the treatment of a disease in a subject in need comprising administering to said subject in need an effective amount of ivabradine hydrochloride Form IV according to claim 1 .
19. A method for the treatment of a disease in a subject in need comprising administering to said subject in need an effective amount of a pharmaceutical composition according to claim 12 .
20. A method for the treatment of bradycardics, myocardial ischaemia, supraventricular rhythm disturbances, chronic stable angina pectoris in coronary artery disease adults with normal sinus rhythm, myocardial infarct, heart failure and associated rhythm disturbances in a subject in need comprising administering to said subject an effective amount of ivabradine hydrochloride Form IV according to claim 1 .
21. A method for the treatment of bradycardics, myocardial ischaemia, supraventricular rhythm disturbances, chronic stable angina pectoris in coronary artery disease adults with normal sinus rhythm, myocardial infarct, heart failure and associated rhythm disturbances in a subject in need comprising administering to said subject an effective amount of a pharmaceutical composition according to claim 12 .
Priority Applications (1)
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US15/089,495 US20160289192A1 (en) | 2011-11-04 | 2016-04-02 | Ivabradine hydrochloride form iv |
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EP11382339.7A EP2589594A1 (en) | 2011-11-04 | 2011-11-04 | Ivabradine hydrochloride Form IV |
EP11382339.7 | 2011-11-04 | ||
PCT/EP2012/068615 WO2013064307A1 (en) | 2011-11-04 | 2012-09-21 | Ivabradine hydrochloride form iv |
US201414356240A | 2014-05-05 | 2014-05-05 | |
US14/806,224 US9309201B2 (en) | 2011-11-04 | 2015-07-22 | Process for preparating ivabradine hydrochloride form IV and methods of treatment of disease using ivabradine hydrochloride form IV |
US15/089,495 US20160289192A1 (en) | 2011-11-04 | 2016-04-02 | Ivabradine hydrochloride form iv |
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US14/806,224 Continuation US9309201B2 (en) | 2011-11-04 | 2015-07-22 | Process for preparating ivabradine hydrochloride form IV and methods of treatment of disease using ivabradine hydrochloride form IV |
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US20160289192A1 true US20160289192A1 (en) | 2016-10-06 |
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US14/356,240 Active US9139531B2 (en) | 2011-11-04 | 2012-09-21 | Ivabradine hydrochloride form IV |
US14/806,224 Active US9309201B2 (en) | 2011-11-04 | 2015-07-22 | Process for preparating ivabradine hydrochloride form IV and methods of treatment of disease using ivabradine hydrochloride form IV |
US15/089,495 Abandoned US20160289192A1 (en) | 2011-11-04 | 2016-04-02 | Ivabradine hydrochloride form iv |
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US14/356,240 Active US9139531B2 (en) | 2011-11-04 | 2012-09-21 | Ivabradine hydrochloride form IV |
US14/806,224 Active US9309201B2 (en) | 2011-11-04 | 2015-07-22 | Process for preparating ivabradine hydrochloride form IV and methods of treatment of disease using ivabradine hydrochloride form IV |
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US (3) | US9139531B2 (en) |
EP (3) | EP2589594A1 (en) |
JP (3) | JP6359971B2 (en) |
KR (1) | KR102050117B1 (en) |
AU (1) | AU2012331395B2 (en) |
BR (1) | BR112014010767B1 (en) |
CA (1) | CA2854549C (en) |
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DK (1) | DK2773620T3 (en) |
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SI (1) | SI2773620T1 (en) |
WO (1) | WO2013064307A1 (en) |
ZA (1) | ZA201403073B (en) |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2589594A1 (en) * | 2011-11-04 | 2013-05-08 | Urquima S.A. | Ivabradine hydrochloride Form IV |
US9120755B2 (en) | 2011-11-14 | 2015-09-01 | Cadila Healthcare Limited | Polymorphic forms of ivabradine hydrochloride |
ITMI20130684A1 (en) * | 2013-04-24 | 2014-10-25 | Chemo Res S L | NEW POLIMORFO OF IVABRADINA CHLORIDRATE AND METHOD FOR ITS PREPARATION |
HUE047705T2 (en) | 2013-03-19 | 2020-05-28 | Chemo Res S L | New polymorph of ivabradine hydrochloride and method for its preparation |
CZ2013767A3 (en) | 2013-10-02 | 2015-04-29 | Zentiva, K.S. | Solid form of ivabradine hydrochloride and (S)-mandelic acid as well as pharmaceutical composition thereof |
MX363389B (en) | 2013-12-12 | 2019-03-20 | Synthon Bv | Pharmaceutical composition comprising amorphous ivabradine. |
PT2774606T (en) | 2014-02-14 | 2019-05-06 | Synthon Bv | Pharmaceutical composition comprising ivabradine hydrochloride polymorph iv |
CZ2014478A3 (en) | 2014-07-10 | 2015-09-16 | Zentiva, K.S. | Ivabradine hydrochloride and (R)-mandelic acid solid form and pharmaceutical composition thereof |
GR1008821B (en) | 2015-06-11 | 2016-08-01 | Φαρματεν Ανωνυμος Βιομηχανικη Και Εμπορικη Εταιρεια Φαρμακευτικων Ιατρικων Και Καλλυντικων Προϊοντων | Pharmaceutical composition comprising ivabradine hydrochloride and method for preparation thereof |
TR201703066A2 (en) | 2017-02-28 | 2018-09-21 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Solid oral pharmaceutical compositions of ivabradine |
EP3366282A1 (en) | 2017-02-28 | 2018-08-29 | Sanovel Ilac Sanayi ve Ticaret A.S. | Solid oral pharmaceutical compositions of ivabradine |
TWI791621B (en) | 2017-09-19 | 2023-02-11 | 日商三井化學股份有限公司 | Eyewear |
WO2020092288A1 (en) * | 2018-10-30 | 2020-05-07 | Amgen Inc. | Process of making ivabradine hydrochloride drug product |
IT202000025312A1 (en) | 2020-10-26 | 2022-04-26 | Cambrex Profarmaco Milano S R L | PROCESSES FOR THE PREPARATION OF IVABRADINE HCL POLYMORPHS |
Family Cites Families (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2681862B1 (en) | 1991-09-27 | 1993-11-12 | Adir Cie | NOVELS (BENZOCYCLOALKYL) ALKYLAMINES, THEIR PREPARATION PROCESS, AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
FR2868777B1 (en) | 2004-04-13 | 2006-05-26 | Servier Lab | NOVEL PROCESS FOR THE SYNTHESIS OF IVABRADINE AND ITS SALTS OF ADDITION TO A PHARMACEUTICALLY ACCEPTABLE ACID |
FR2882554B1 (en) | 2005-02-28 | 2007-05-04 | Servier Lab | IVABRADINE HYDROCHLORIDE BETA D-CRYSTALLINE FORM, PROCESS FOR PREPARING THE SAME, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
FR2882556B1 (en) | 2005-02-28 | 2007-05-04 | Servier Lab | CRYSTALLINE GAMMA D FORM OF IVABRADINE HYDROCHLORIDE, PROCESS FOR PREPARING THE SAME, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
FR2882555B1 (en) * | 2005-02-28 | 2007-05-04 | Servier Lab | CRYSTALLINE GAMMA FORM OF IVABRADINE HYDROCHLORIDE, PROCESS FOR PREPARING THE SAME, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
FR2882553B1 (en) | 2005-02-28 | 2007-05-04 | Servier Lab | CRYSTALLINE BETA FORM OF IVABRADINE HYDROCHLORIDE, PROCESS FOR PREPARING THE SAME, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
FR2891827B1 (en) | 2005-10-11 | 2007-12-28 | Servier Lab | CRYSTALLINE DELTAD FORM OF IVABRADINE HYDROCHLORIDE, PROCESS FOR PREPARING THE SAME, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
FR2891826B1 (en) * | 2005-10-11 | 2007-12-28 | Servier Lab | CRYSTALLINE FORM 6 OF IVABRADINE HYDROCHLORIDE, PROCESS FOR PREPARING THE SAME, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
WO2008065681A2 (en) | 2006-11-30 | 2008-06-05 | Cadila Healthcare Limited | Process for preparation of ivabradine hydrochloride |
WO2008125006A1 (en) * | 2007-04-12 | 2008-10-23 | Utopharm (Shanghai) Co., Ltd | Preparation processes for ivabradine hydrochloride and its stable crystalline form |
EP2162438A4 (en) * | 2007-05-30 | 2011-07-06 | Ind Swift Lab Ltd | Process for the preparation of ivabradine hydrochloride and polymorph thereof |
CN101597261A (en) | 2008-06-06 | 2009-12-09 | 北京深蓝海生物医药科技有限公司 | Amorphous ivabradine hydrochloride |
US20100323471A1 (en) | 2008-08-21 | 2010-12-23 | Applied Materials, Inc. | Selective Etch of Laser Scribed Solar Cell Substrate |
CN101768117B (en) | 2008-12-29 | 2014-05-07 | 北京德众万全药物技术开发有限公司 | New crystalline form of hydrochloric acid Ivabradine and preparation method thereof |
CN101463008A (en) | 2009-01-11 | 2009-06-24 | 山东鲁抗辰欣药业有限公司 | Ivabradine amorphous article and preparation thereof |
CN101805289A (en) | 2009-02-17 | 2010-08-18 | 成都威克药业有限责任公司 | Omega-crystal form, preparation method and medicine composite of ivabradine hydrochloride |
CN102050784B (en) | 2009-11-04 | 2014-07-09 | 扬子江药业集团北京海燕药业有限公司 | Novel method for preparing amorphous Ivabradine hydrochloride |
EA201290772A1 (en) | 2010-02-12 | 2013-02-28 | КРКА, д.д., НОВО МЕСТО | NEW FORMS OF IVABRADIN HYDROCHLORIDE |
WO2012025940A1 (en) | 2010-08-25 | 2012-03-01 | Cadila Healthcare Limited | Polymorphic form of ivabradine hydrochloride and process for preparation thereof |
EP2589594A1 (en) * | 2011-11-04 | 2013-05-08 | Urquima S.A. | Ivabradine hydrochloride Form IV |
US9120755B2 (en) * | 2011-11-14 | 2015-09-01 | Cadila Healthcare Limited | Polymorphic forms of ivabradine hydrochloride |
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2011
- 2011-11-04 EP EP11382339.7A patent/EP2589594A1/en not_active Withdrawn
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2012
- 2012-09-21 RU RU2014122261A patent/RU2619121C2/en active
- 2012-09-21 SI SI201231092T patent/SI2773620T1/en unknown
- 2012-09-21 BR BR112014010767-0A patent/BR112014010767B1/en active IP Right Grant
- 2012-09-21 WO PCT/EP2012/068615 patent/WO2013064307A1/en active Application Filing
- 2012-09-21 HU HUE12766056A patent/HUE034996T2/en unknown
- 2012-09-21 KR KR1020147015092A patent/KR102050117B1/en active IP Right Grant
- 2012-09-21 AU AU2012331395A patent/AU2012331395B2/en active Active
- 2012-09-21 JP JP2014539268A patent/JP6359971B2/en active Active
- 2012-09-21 CA CA2854549A patent/CA2854549C/en active Active
- 2012-09-21 RS RS20171010A patent/RS56464B1/en unknown
- 2012-09-21 US US14/356,240 patent/US9139531B2/en active Active
- 2012-09-21 DK DK12766056.1T patent/DK2773620T3/en active
- 2012-09-21 PL PL12766056T patent/PL2773620T3/en unknown
- 2012-09-21 EP EP17184888.0A patent/EP3263556A1/en not_active Withdrawn
- 2012-09-21 EP EP12766056.1A patent/EP2773620B1/en active Active
- 2012-09-21 MX MX2014005362A patent/MX359288B/en active IP Right Grant
- 2012-09-21 ES ES12766056.1T patent/ES2562843T3/en active Active
- 2012-09-21 LT LTEP12766056.1T patent/LT2773620T/en unknown
- 2012-09-21 PT PT127660561T patent/PT2773620T/en unknown
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2014
- 2014-04-25 ZA ZA2014/03073A patent/ZA201403073B/en unknown
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2015
- 2015-07-22 US US14/806,224 patent/US9309201B2/en active Active
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2016
- 2016-04-02 US US15/089,495 patent/US20160289192A1/en not_active Abandoned
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2017
- 2017-05-30 JP JP2017106708A patent/JP2017178965A/en not_active Withdrawn
- 2017-10-09 HR HRP20171511TT patent/HRP20171511T1/en unknown
- 2017-10-12 CY CY20171101069T patent/CY1119798T1/en unknown
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2018
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