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WO2008125006A1 - Procédés de préparation du chlorhydrate d'ivabradine et de sa forme cristalline stable - Google Patents

Procédés de préparation du chlorhydrate d'ivabradine et de sa forme cristalline stable Download PDF

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Publication number
WO2008125006A1
WO2008125006A1 PCT/CN2008/000699 CN2008000699W WO2008125006A1 WO 2008125006 A1 WO2008125006 A1 WO 2008125006A1 CN 2008000699 W CN2008000699 W CN 2008000699W WO 2008125006 A1 WO2008125006 A1 WO 2008125006A1
Authority
WO
WIPO (PCT)
Prior art keywords
ivabradine
solvent
hydrochloride
stable
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2008/000699
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English (en)
Chinese (zh)
Inventor
Junzhi Luo
Yimin Yan
Yongrui Tu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Changzhou No4 Pharmaceutical Factory Co Ltd
UTOPHARM (SHANGHAI) CO Ltd
Original Assignee
Changzhou No4 Pharmaceutical Factory Co Ltd
UTOPHARM (SHANGHAI) CO Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from CN2007100394183A external-priority patent/CN101284813B/zh
Priority claimed from CN200710044290XA external-priority patent/CN101353325B/zh
Application filed by Changzhou No4 Pharmaceutical Factory Co Ltd, UTOPHARM (SHANGHAI) CO Ltd filed Critical Changzhou No4 Pharmaceutical Factory Co Ltd
Publication of WO2008125006A1 publication Critical patent/WO2008125006A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • 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
    • 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

Definitions

  • the invention relates to medicinal chemistry, in particular to a novel angina pectoris drug ivabradine (compound I) and a preparation method thereof, and to a stable ivabradine crystal of hydrochloric acid and a preparation method thereof.
  • Background technique :
  • Ivabradine approved by the European Medicines Accreditation Council (EMEA) on November 3, 2005, is available in 27 countries in Europe under the product name Procoralan for the treatment of normal sinus rhythm and beta receptors. Symptomatic treatment of chronic stable angina with contraindications or intolerance.
  • Procoralan is one of the most important advances in cardiovascular therapy over the past 20 years.
  • Procoralan is the first pure heart rate reduction drug that works by selectively suppressing the If channel, which controls the automatic depolarization of the sinus node and regulates heart rate.
  • Procoralan selectively acts on the sinus node and has no effect on intracardiac conduction, myocardial contractility or ventricular repolarization.
  • Procoralan does not cause sexual dysfunction, respiratory adverse reactions due to airway contraction and spasm, and bradycardia or recurrence.
  • the yield of the method is relatively low, especially in the catalytic hydrogenation step, the yield is only 40%, the total yield is 18%, and the product needs to be purified by column chromatography, which is not suitable for industrial production.
  • the method uses a scented aromatic substance as a solvent, which is highly toxic, has a high boiling point, is difficult to remove, and cannot meet the pharmacopoeia control limit of the drug residual solvent.
  • Patent CN200610058076. 5 and CN200610058074. 6 respectively describe the use of water or isopropanol plus water to obtain ⁇ -crystal form (tetrahydrate), respectively, and then dehydrated to obtain P d-crystal form; patents CN200610058078. 4 and CN200610058077.
  • X respectively describe 2-ethoxyethanol or 2-ethoxyethanol is crystallized with water or ethanol and water to obtain a Y-crystal form (monohydrate), which is then dehydrated to obtain a Y d-crystal form; patents CN 200610132229. 6 and CN200610132230.
  • the above patent describes the different crystal forms of ivabradine and its hydrochloride and the preparation method thereof, and the preparation process thereof is cumbersome, and the solvent used is not suitable for medicinal use, such as the patent CN200510051779.
  • 0 crystallized with N-methylpyrrolidone and toluene Obtaining ⁇ crystal form, the toxicity of toluene used is large, the boiling point of ⁇ -methylpyrrolidone is high, and it is difficult to remove, etc.; or the obtained crystal form is not stable enough, such as patent CN200610058074; 6 , CN200610058076. 5 , CN200610058077. X, CN200610058078.
  • the crystal form is water-containing.
  • the excessive water content of the raw material will affect its stability. It needs to be dried and dehydrated again, which is unfavorable to the integrity and stability of the obtained crystal form, and the preparation process is cumbersome.
  • DSC differential thermal analysis
  • thermogravimetric properties and physical and chemical properties of the crystal forms prepared.
  • the technical problem to be solved by the present invention is to overcome the deficiencies of the above preparation method, to study a method for preparing ivabradine and its salt suitable for industrial production, and to obtain stable ivabradine hydrochloride crystal by crystallization.
  • the invention provides a preparation method of ivabradine (compound I) and a salt thereof, which is 3-(3-substituted propyl)-7,8-dimethoxy-1,3-dihydrogen.
  • -2H-3-Benzazepine-2-one compound II as a starting material, catalyzed hydrogenation reaction at a suitable temperature, solvent and catalyst to give the compound 3-(3-substituted propyl)-7, 8-dimethoxy -1, 3, 4, 5-tetrahydro-2H-3-benzazepine-2-one compound III, then with (lS)-4,5-di at appropriate temperature, solvent and reaction promoter
  • the methoxy-1-(methylaminomethyl)-benzocyclobutane compound IV is subjected to a thiolation reaction to obtain an ivabradine compound I, which is represented by the reaction formula III.
  • the method is easier to carry out, and the reaction conditions are mild. High yield (about 80%).
  • R in the formula or III is a halogen atom such as Cl, Br, I or the like, or a similar leaving group such as a benzenesulfonyloxy group, a p-toluenesulfonyloxy group, a methanesulfonyloxy group or the like, preferably Cl, A halogen atom such as Br or I.
  • the pharmaceutically acceptable acid addition salt is then obtained by reacting with the corresponding hydrochloric acid as needed.
  • the catalyst used for the hydrogenation reaction of the compound of the formula ( ⁇ ) in the catalyst used for the hydrogenation reaction of the compound of the formula ( ⁇ ), it may be, but not limited to, palladium, platinum, nickel, rhodium, ruthenium and their compounds, particularly in the form of a load.
  • ruthenium carbon is preferred.
  • the catalyst used for the hydrogenation of the compound of formula (III) is 5% palladium on carbon or 10% ruthenium carbon, more preferably 5% ffi carbon.
  • the amount of the catalyst used for the catalytic hydrogenation of the compound of the formula (III) is from 1% to 30% w/w%, more preferably from 5 to 10% w/w%, based on the compound ( ⁇ ). 5: 1 ⁇ 1. 1: 1 ⁇
  • the molar ratio of the compound I II to the compound IV is from 1:1 to 1. 5: 1, more preferably 1. 05: 1 to 1. 1: 1.
  • the temperature for the hydrogenation reaction of the compound of the formula (III) is preferably room temperature to 120 ° C, more preferably 30 to 100 ° C, particularly preferably 40 to 80 ° C.
  • the hydrogen pressure for the hydrogenation reaction of the compound of the formula ( ⁇ ) is from 1 to 150 atm, preferably from 1 to 80 atm, particularly preferably from 1 to 40 atm.
  • the solvent used for the hydrogenation reaction of the compound of the formula ( ⁇ ) is an alcohol such as methanol or ethanol, a ketone such as acetone, butanone or pentanone N-methylpyrrolidone, a nitrile such as acetonitrile or propionitrile, ethyl acetate or acetic acid.
  • An ester such as propyl or butyl acetate; a halogenated hydrocarbon such as chloroform, chloroform, 1,2-dichloroethane or chlorobenzene; an ether such as isopropyl ether or tetrahydrofuran; DMF, DMSO, etc., preferably an alcohol
  • the ketones and the ketones are more preferably alcohols, and most preferably methanol, ethanol or the like.
  • reaction temperature described in the synthesis of the compound I is -10-100 ° C, preferably room temperature to 6 (TC,
  • the reaction solvent described in the synthesis of the compound I is an alcohol such as methanol or ethanol, a ketone such as acetone, butanone or pentanone, a nitrile such as acetonitrile or propionitrile, ethyl acetate, propyl acetate or butyl acetate.
  • the reaction accelerator described in the synthesis of the compound I is a basic compound such as an inorganic base such as NaOH or OH>K2C03 Na2C03, or an organic base such as diethylamine, triethylamine, pyridine, potassium t-butoxide or sodium methoxide. Preference is given to diethylamine and triethylamine. 5 ⁇ 1.
  • the molar ratio of the compound of the reaction promoter to the compound IV is from 1: 1 to 5: 1, preferably from 1: 1 to 2. 5: 1.
  • the ratio of the amount of the basic compound to the compound IV is from 1:1 to 5:1, preferably from 1:1 to 2. 5:1.
  • the present invention provides a stable ivabradine hydrochloride crystal.
  • - Stabilized ivabradine hydrochloride crystals of the invention having a DSC pattern having a single endothermic peak in the range of from 100 to 22 (TC range).
  • the present invention relates to a stable ivabradine hydrochloride crystal having a DSC pattern having a single endothermic peak in the range of 185 to 2 HTC.
  • the present invention relates to a stable ivabradine hydrochloride crystal having a melting point of 190-210 ° C and decomposition at 200 or 210 ° C or higher.
  • the invention relates to a stable ivabradine hydrochloride crystal, wherein the thermogravimetric map shows no crystal water or dissolution Agent.
  • Another object of the present invention is to provide a process for the preparation of stable ivabradine hydrochloride crystals comprising the step of heating and dissolving in a single solvent or a mixed solvent to obtain a pharmaceutically stable ivabradine hydrochloride crystal.
  • the present invention relates to a method for preparing stable ivabradine hydrochloride crystals, wherein a single solvent is a ketone or an ester solvent, and a mixed solvent is obtained by crystallizing N-methylpyrrolidone plus a ketone or an ester solvent.
  • the solvent is safer and easier to remove.
  • the invention relates to a preparation method of stable ivabradine hydrochloride crystal
  • the single solvent is methyl ethyl ketone, pentanone; ethyl formate, ethyl acetate, methyl acetate or propyl acetate, and the amount of ivabradine hydrochloride crystal 20 -100 times the amount of w/v, preferably 20-80 times the amount of solvent w/v; using a mixed solvent of N-methylpyrrolidone plus ethyl acetate or methyl ethyl ketone; or N-methylpyrrolidone plus butanone and acetic acid
  • the ethyl ester is used in an amount of from 1 to 10 times the amount of w/v of ivabradine hydrochloride, preferably from 1 to 3 times the amount of w/v.
  • the seed crystal of hydrochloric acid & Fabredine can be added during the cooling step.
  • the present inventors have found that the preparation of stable ivabradine hydrochloride crystals can also be obtained by simply heating ivabradine hydrochloride from a suitable solvent, which is particularly important in that the solvent is small, the treatment is simple, and it is easy to dry. .
  • Still another object of the present invention is to provide a further preparation method of stable ivabradine hydrochloride crystals, that is, a suspension of ibubradine hydrochloride and a single solvent or a mixed solvent, heated and cooked for a suitable period of time, and then gradually cooled until the crystal The precipitate was completely precipitated, and the formed crystals were collected by filtration to obtain a stable ivabradine hydrochloride crystal.
  • the solvent is preferably a solvent having a low thermal solubility to ifabrex hydrochloride, and is selected from the group consisting of ketones such as methyl ethyl ketone, 2-pentanone and the like, preferably butanone; or an ester solvent such as methyl acetate, acetic acid.
  • Ethyl acetate, propyl acetate or the like is preferably ethyl acetate; or a ketone ester-adding solvent such as methyl ethyl ketone or ethyl acetate.
  • a solvent of 1-100 times (w/v) of ivabradine hydrochloride is selected, preferably 1 times larger than ivabradine hydrochloride (W/
  • the solvent of V) is most preferably a solvent of 1-10 times (w/v).
  • the heating temperature is preferably from 0 ° C to 100 ° C, more preferably from 70 ° C to 100 ° C, and most preferably at a solvent reflux temperature.
  • the cooking time is preferably more than 1 minute, more preferably 1 to 60 minutes, and most preferably 1 to 30 minutes.
  • ivabradine hydrochloride obtained by any method can be used as a raw material. Since the stable ivabradine hydrochloride crystal prepared by the method of the present invention is extremely stable to temperature, light and humidity, it shows that it has high superiority in the processing and storage of the preparation.
  • the inventors measured the differential thermal analysis and thermogravimetric diagram of the stable ivabradine hydrochloride solution prepared by the method of the present invention under the following experimental conditions:
  • Test conditions 600/10/ 2 25.0-400.0' C (or 25.0-600.0 ⁇ C) 10* C/min N 2 50.0ml/min
  • the X-ray powder diffraction spectrum of ivabradine hydrochloride was measured under the following experimental conditions: (There may be a small displacement of the peak position in the figure ( ⁇ 0.2. 2 ⁇ )
  • Test instrument model RIGAKU D/raax 2550VB/PC diffractometer Test Conditions:
  • Test basis JY/T009-1996 target multi-crystal X-ray method general rule
  • Spectral description expressed as 2- Theta (the position of the ray), d (A) (the interplanar spacing d, denoted by A), Heigt (ray height), Area (radiation area) and FWHM (half height ray width) .
  • Fig. 1 Differential thermal analysis and thermogravimetric analysis of stable ivabradine hydrochloride crystals obtained by crystallization of methyl ethyl ketone.
  • Figure 2 Differential heat of stable ivabradine hydrochloride crystals obtained by heating with methyl ethyl ketone. Analysis and thermogravimetric diagram
  • Figure 4 Differential thermal analysis and thermogravimetric diagram of stable ivabradine hydrochloride crystals obtained by crystallization from N-methylpyrrole and ethyl acetate.
  • the method of the invention is simple, the raw materials are easy to obtain, and it is suitable for industrial production. Has a greater application value.
  • Embodiment 1 is a diagrammatic representation of Embodiment 1:
  • the sample for analysis was obtained by silica gel column chromatography, which was obtained as a pale yellow oil.

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur un nouveau procédé de préparation de l'ivabradine qui est le médicament pour l'angine de poitrine. Dans ce procédé le composé III est obtenu à partir du composé II par hydrogénation catalytique, puis le composé III est alkylé par le composé IV pour obtenir le composé I. Ce procédé est simple et de faible coût car les matières premières ne sont pas chers. La forme cristalline du chlorhydrate d'ivabradine obtenu par le procédé de la présente invention est stable et appropriée pour un stockage de longue durée. Les solvants utilisés sont sans danger, faciles à éliminer et appropriés pour une production industrielle.
PCT/CN2008/000699 2007-04-12 2008-04-07 Procédés de préparation du chlorhydrate d'ivabradine et de sa forme cristalline stable Ceased WO2008125006A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN200710039418.3 2007-04-12
CN2007100394183A CN101284813B (zh) 2007-04-12 2007-04-12 伊伐布雷定的制备方法
CN200710044290.X 2007-07-27
CN200710044290XA CN101353325B (zh) 2007-07-27 2007-07-27 稳定型盐酸伊伐布雷定结晶及其制备方法

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WO2008125006A1 true WO2008125006A1 (fr) 2008-10-23

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2941695A1 (fr) * 2009-02-04 2010-08-06 Servier Lab Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable
WO2011098582A2 (fr) 2010-02-12 2011-08-18 Krka, D.D., Novo Mesto Nouvelles formes de chlorhydrate d'ivabradine
WO2012025940A1 (fr) 2010-08-25 2012-03-01 Cadila Healthcare Limited Forme polymorphe du chlorhydrate d'ivabradine et son procédé de préparation
US8212026B2 (en) 2007-05-30 2012-07-03 Ind-Swift Laboratories Limited Process for the preparation of ivabradine hydrochloride and polymorph thereof
EP2589594A1 (fr) * 2011-11-04 2013-05-08 Urquima S.A. Forme IV d'hydrochlorure d'ivabridine
WO2013102919A1 (fr) 2011-11-14 2013-07-11 Cadila Healthcare Limited Formes polymorphes de chlorhydrate d'ivabradine
ITMI20130684A1 (it) * 2013-04-24 2014-10-25 Chemo Res S L Nuovo polimorfo del cloridrato di ivabradina e metodo per la sua preparazione

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1683341A (zh) * 2004-04-13 2005-10-19 瑟维尔实验室 合成伊伐布雷定及其与药学上可接受的酸的加成盐的新方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1683341A (zh) * 2004-04-13 2005-10-19 瑟维尔实验室 合成伊伐布雷定及其与药学上可接受的酸的加成盐的新方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BOMHARD A. ET AL.: "Specific bradycardic agents. 2. Heteroaromatic modifications in the side chain of specific bradycardic benzazepinones: chemistry, pharmacology, and structure-activity relationships", JOURNAL OF MEDICINAL CHEMISTRY, vol. 34, no. 3, 1991, pages 942 - 947, XP002277379 *

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8212026B2 (en) 2007-05-30 2012-07-03 Ind-Swift Laboratories Limited Process for the preparation of ivabradine hydrochloride and polymorph thereof
EA019465B1 (ru) * 2009-02-04 2014-03-31 Ле Лаборатуар Сервье Способ синтеза ивабрадина и его солей присоединения с фармацевтически приемлемой кислотой
WO2010089475A1 (fr) * 2009-02-04 2010-08-12 Les Laboratoires Servier Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable
JP2012516880A (ja) * 2009-02-04 2012-07-26 レ ラボラトワール セルヴィエ イバブラジン及びその薬学的に許容しうる酸付加塩の新規の合成方法
US8415468B2 (en) 2009-02-04 2013-04-09 Les Laboratoires Servier Process for the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid
FR2941695A1 (fr) * 2009-02-04 2010-08-06 Servier Lab Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable
WO2011098582A2 (fr) 2010-02-12 2011-08-18 Krka, D.D., Novo Mesto Nouvelles formes de chlorhydrate d'ivabradine
EP2902384A1 (fr) 2010-02-12 2015-08-05 KRKA, D.D., Novo Mesto Formes de chlorhydrate d'ivabradine
WO2012025940A1 (fr) 2010-08-25 2012-03-01 Cadila Healthcare Limited Forme polymorphe du chlorhydrate d'ivabradine et son procédé de préparation
EP2589594A1 (fr) * 2011-11-04 2013-05-08 Urquima S.A. Forme IV d'hydrochlorure d'ivabridine
RU2619121C2 (ru) * 2011-11-04 2017-05-12 Уркуима, С.А. Форма iv ивабрадина гидрохлорида
KR20140101753A (ko) * 2011-11-04 2014-08-20 울퀴마, 에스. 에이. 이바브라딘 염산염 ｉｖ형
KR102050117B1 (ko) * 2011-11-04 2020-01-08 울퀴마, 에스. 에이. 이바브라딘 염산염 ｉｖ형
JP2014532673A (ja) * 2011-11-04 2014-12-08 ウルキマ，ソシエダッド アノニマ イバブラジン塩酸塩の形態ｉｖ
WO2013064307A1 (fr) 2011-11-04 2013-05-10 Urquima, S. A. Chlorhydrate d'ivabradine de forme iv
EP3263556A1 (fr) 2011-11-04 2018-01-03 Urquima, S.A. Forme iv d'hydrochlorure d'ivabridine
US9139531B2 (en) 2011-11-04 2015-09-22 Urquima, S.A. Ivabradine hydrochloride form IV
US9309201B2 (en) 2011-11-04 2016-04-12 Urquima, S.A. Process for preparating ivabradine hydrochloride form IV and methods of treatment of disease using ivabradine hydrochloride form IV
JP2017178965A (ja) * 2011-11-04 2017-10-05 ウルキマ，ソシエダッド アノニマ イバブラジン塩酸塩の形態ｉｖ
AU2012331395B2 (en) * 2011-11-04 2016-11-17 Urquima, S. A. Ivabradine hydrochloride form IV
EP2773620B1 (fr) 2011-11-04 2017-08-16 Urquima, S.A. Chlorhydrate d'ivabradine de forme iv
US9382209B2 (en) 2011-11-14 2016-07-05 Cadila Healthcare Limited Polymorphic forms of ivabradine hydrochloride
US9650344B2 (en) 2011-11-14 2017-05-16 Cadila Healthcare Limited Polymorphic forms of ivabradine hydrochloride
EP3156399A1 (fr) * 2011-11-14 2017-04-19 Cadila Healthcare Limited Formes polymorphes de chlorhydrate d'ivabradine
WO2013102919A1 (fr) 2011-11-14 2013-07-11 Cadila Healthcare Limited Formes polymorphes de chlorhydrate d'ivabradine
US9840469B2 (en) 2011-11-14 2017-12-12 Cadila Healthcare Limited Polymorphic forms of ivabradine hydrochloride
US9120755B2 (en) 2011-11-14 2015-09-01 Cadila Healthcare Limited Polymorphic forms of ivabradine hydrochloride
ITMI20130684A1 (it) * 2013-04-24 2014-10-25 Chemo Res S L Nuovo polimorfo del cloridrato di ivabradina e metodo per la sua preparazione

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