NO338369B1 - ßd-krystalinsk form av ivabradin-hydroklorid, fremgangsmåte for dens fremstilling og farmasøytiske sammensetninger inneholdende den - Google Patents
ßd-krystalinsk form av ivabradin-hydroklorid, fremgangsmåte for dens fremstilling og farmasøytiske sammensetninger inneholdende den Download PDFInfo
- Publication number
- NO338369B1 NO338369B1 NO20060947A NO20060947A NO338369B1 NO 338369 B1 NO338369 B1 NO 338369B1 NO 20060947 A NO20060947 A NO 20060947A NO 20060947 A NO20060947 A NO 20060947A NO 338369 B1 NO338369 B1 NO 338369B1
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- Norway
- Prior art keywords
- ivabradine hydrochloride
- crystalline form
- expressed
- ivabradine
- preparation
- Prior art date
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- HLUKNZUABFFNQS-ZMBIFBSDSA-N ivabradine hydrochloride Chemical compound Cl.C1CC2=CC(OC)=C(OC)C=C2CC(=O)N1CCCN(C)C[C@H]1CC2=C1C=C(OC)C(OC)=C2 HLUKNZUABFFNQS-ZMBIFBSDSA-N 0.000 title claims description 26
- 229960000504 ivabradine hydrochloride Drugs 0.000 title claims description 20
- 238000000034 method Methods 0.000 title claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 206010003119 arrhythmia Diseases 0.000 claims description 4
- 230000006793 arrhythmia Effects 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 3
- 206010002383 Angina Pectoris Diseases 0.000 claims description 2
- 206010019280 Heart failures Diseases 0.000 claims description 2
- 206010042600 Supraventricular arrhythmias Diseases 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 230000000059 bradycardiac effect Effects 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 239000013078 crystal Substances 0.000 claims description 2
- 238000010586 diagram Methods 0.000 claims description 2
- 208000010125 myocardial infarction Diseases 0.000 claims description 2
- 208000031225 myocardial ischemia Diseases 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 0.000 claims description 2
- 230000007170 pathology Effects 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims 2
- 239000000969 carrier Substances 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 229960003825 ivabradine Drugs 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
Classifications
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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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- 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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- A61P9/00—Drugs for disorders of the cardiovascular system
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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- C10G45/00—Refining of hydrocarbon oils using hydrogen or hydrogen-generating compounds
- C10G45/32—Selective hydrogenation of the diolefin or acetylene compounds
- C10G45/34—Selective hydrogenation of the diolefin or acetylene compounds characterised by the catalyst used
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Description
Foreliggende oppfinnelse vedrører den nye pd-krystallinske form av ivabradin-hydroklorid med formel (I), en fremgangsmåte for dens fremstilling og farmasøytiske sammensetninger inneholdende den.
Ivabradin, og addisjonssalter derav med en farmasøytisk akseptabel syre, og mer spesielt dens hydroklorid, har svært verdifulle farmakologiske og terapeutiske egenskaper, spesielt bradykardiske egenskaper, som gjør disse forbindelser nyttige i behandlingen eller forebyggingen av forskjellige kliniske situasjoner av myokardiskemi slik som angina pectoris, myokardinfarkt og assosierte rytmeforstyrrelser, og også i forskjellige patologier som involverer rytmeforstyrrelser, spesielt supraventrikulære rytmeforstyrrelser, og i hjertesvikt.
Fremstillingen og terapeutisk bruk av ivabradin og addisjonssalter derav med en farmasøytisk akseptabel syre, og mer spesielt dens hydroklorid, har blitt beskrevet i den europeiske patentbeskrivelse EP 0 534 859.
I betraktning av denne forbindelsens farmasøytiske verdi, har det vært av stor viktighet å oppnå den med utmerket renhet. Det har også vært viktig å være i stand til å syntetisere den ved hjelp av en fremgangsmåte som lett kan konverteres til industriell skala, spesielt i en form som tillater rask filtrering og tørking. Til sist måtte denne form være fullstendig reproduserbar, lett formulert og tilstrekkelig stabil til å tillate dens lagring for lange perioder uten spesielle betingelser for temperatur, lys eller oksygennivå. Patentbeskrivelsen EP 0 534 859 beskriver en syntesefremgangsmåte for ivabradin og dens hydroklorid. Imidlertid spesifiserer ikke dette dokument betingelsene for å oppnå ivabradin i en form som foreviser disse karakteristika på en reproduserbar måte.
Søkeren har nå funnet at et spesielt salt av ivabradin, hydrokloridet, kan oppnås i en krystallinsk form som er godt definert og som foreviser verdifulle stabilitets- og prosesserbarhetskarakteristika.
Mer spesielt vedrører den foreliggende oppfinnelse den pd-krystallinske form av ivabradin-hydroklorid, som er kjennetegnet ved det følgende pulverrøntgendiffraksjons-diagram målt ved å anvende et PANalytical XTert Pro diffraktometer sammen med en X'Celerator detektor og uttrykket i form av stråleposisjon (Braggs vinkel 2 theta, uttrykket i grader), strålehøyde (uttrykket i tellinger), stråleareal (uttrykket i tellinger x grader), strålebredde ved halvhøyde ("FWHM", uttrykket i grader) og interplanær avstand d (uttrykket i A):
Oppfinnelsen vedrører også en fremgangsmåte for fremstillingen av den pd-krystallinske form av ivabradin-hydroklorid, hvilken fremgangsmåte erkarakterisert vedat en blanding av ivabradin-hydroklorid og vann eller en blanding av ivabradin-hydroklorid, isopropanol og vann varmes inntil oppløsning er fullstendig og deretter progressivt avkjøles inntil krystallisasjon er fullstendig, og de derved dannede krystaller samles og dehydratiseres.
I krystallisasjonsfremgangsmåten i henhold til oppfinnelsen er det mulig å anvende ivabradin-hydroklorid oppnådd ved enhver prosess, for eksempel ivabradin-hydroklorid oppnådd ved fremstillingsprosessen beskrevet i patentbeskrivelse EP 0 534 859.
Løsningen kan fordelaktig kimes under avkjølingstrinnet.
Oppfinnelsen vedrører også farmasøytiske sammensetninger omfattende som aktiv ingrediens den pd-krystallinske form av ivabradin-hydroklorid sammen med én eller flere passende, inerte, ikke-toksiske eksipienser. Blant de farmasøytiske sammensetninger i henhold til oppfinnelsen kan det nevnes mer spesielt de som er egnet for oral, parenteral (intravenøs eller subkutan) eller nasal administrasjon, tabletter eller drageer, sublingvale tabletter, gelatinkapsler, lozengere, suppositorier, kremer, salver, dermale geler, injiserbare preparater, drikkbare suspensjoner.
Den nyttige dosering kan varieres i henhold til lidelsens natur og alvorlighet, administrasjonsruten og pasientens alder og vekt. Denne dosering varierer fra 1 til 500 mg per dag i én eller flere administrasjoner.
De følgende eksempler illustrerer oppfinnelsen.
Pulverrøntgendiffraksjonsspektrumet ble målt under de følgende eksperimentelle betingelser: - PANalytical X'Pert Pro diffraktometer, X'Celerator detektor, temperaturregulert kammer,
- spenning 45 kV, intensitet 40 mA,
- montering 9-8,
- nikkel (Kp>filter,
- innfallende stråle og diffraktert stråle Soller-sHsse: 0,04 rad,
- fast vinkel av divergensslisser: 1/8°,
- maske: 10 mm,
- antispredningsslisse: 1/4°,
- målemodus: kontinuerlig fra 3° til 30°, i trinnvis økning på 0,017°,
- måletid per trinn: 19,7 s,
- total tid: 4 min 32 s,
- målehastighet: 0,1087s,
- måletemperatur: omgivelse.
EKSEMPEL 1: pd-krystallinsk form av ivabradin-hydroklorid
720 ml renset vann forvarmes til 50 °C, og deretter tilsettes 250 g ivabradin-hydroklorid oppnådd i henhold til prosessen beskrevet i patentbeskrivelsen EP 0 534 859 i porsjoner, med omrøring, og blandingen varmes ved 74 °C inntil oppløsning er fullstendig. Den resulterende klare løsning varmes i 2 timer til ved 74 °C og avkjøles deretter progressivt, først til 40 °C, og deretter til omgivelsestemperatur. Løsningen lagres deretter ved
omgivelsestemperatur i 2 dager, og deretter spres den faste suspensjon ut i et tynt sjikt på en krystallisasjonsplate. Overskuddsvannet drives av under en forsiktig strøm av nitrogen. Det derved oppnådde produkt dehydratiseres ved progressiv oppvarming ved en hastighet på 5 °C/min opp til en temperatur på 80 °C.
Pulverrøntgendiffraksjonsdiagram:
Pulverrøntgendiffraksjonsprofilen (diffraksjonsvinkler) av pd-formen av ivabradin-hydroklorid er gitt ved de signifikante stråler sammenholde i den følgende tabell:
EKSEMPEL 2: Farmasøytisk sammensetning
Formulering for fremstillingen av 1000 tabletter hver inneholdende S mg ivabradin-base:
Claims (6)
1. pd-krystallinsk form av ivabradin-hydroklorid med formel (I):
karakterisert veddet følgende pulverrøntgendiffraksjonsdiagram målt ved å anvende et PANalytical X'Pert Pro diffraktometer sammen med en X'Celerator detektor og uttrykket i form av stråleposisjon (Braggs vinkel 2 theta, uttrykket i grader), strålehøyde (uttrykket i tellinger), stråleareal (uttrykket i tellinger x grader), strålebredde ved halvhøyde ("FWHM", uttrykket i grader) og interplanær avstand d (uttrykket i Å):
2. Fremgangsmåte for fremstillingen av den pd-krystallinske form av ivabradin-hydroklorid ifølge krav 1,karakterisert vedat en blanding av ivabradin-hydroklorid og vann eller en blanding av ivabradin-hydroklorid, isopropanol og vann varmes inntil oppløsning er fullstendig og deretter progressivt avkjøles inntil krystallisasjon er fullstendig, og de derved dannede krystaller samles og dehydratiseres deretter.
3. Fremgangsmåte ifølge krav 2,karakterisert vedat løsningen av ivabradin-hydroklorid kimes under avkjølingstrinnet.
4. Farmasøytisk sammensetning omfattende som aktiv ingrediens den pd-krystallinske form av ivabradin-hydroklorid ifølge krav 1, i kombinasjon med én eller flere farmasøytisk akseptable, inerte, ikke-toksiske bærere.
5. Anvendelse av den pd-krystallinske form av ivabradin-hydroklorid ifølge krav 1 i fremstillingen av medikamenter som er nyttige som bradykardika.
6. Anvendelse av den pd-krystallinske form av ivabradin-hydroklorid ifølge krav 1 i fremstillingen av medikamenter som er nyttige i behandlingen eller forebyggingen av forskjellige kliniske situasjoner av myokardiskemi slik som angina pectoris, myokardinfarkt og assosiert rytmeforstyrrelser, og også i forskjellige patologier som involverer rytmeforstyrrelser, spesielt supraventrikulære rytmeforstyrrelser, og i hjertesvikt.
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FR0501987A FR2882554B1 (fr) | 2005-02-28 | 2005-02-28 | Forme critalline beta d du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
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KR100870174B1 (ko) * | 2003-12-04 | 2008-11-24 | 바이엘 크롭사이언스 아게 | 살충 및 살비성을 가지는 활성 물질 배합물 |
FR2868777B1 (fr) * | 2004-04-13 | 2006-05-26 | Servier Lab | Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
FR2882554B1 (fr) * | 2005-02-28 | 2007-05-04 | Servier Lab | Forme critalline beta d du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
FR2882556B1 (fr) * | 2005-02-28 | 2007-05-04 | Servier Lab | Forme cristalline gamma d du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
FR2882553B1 (fr) * | 2005-02-28 | 2007-05-04 | Servier Lab | Forme cristalline beta du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
FR2882555B1 (fr) * | 2005-02-28 | 2007-05-04 | Servier Lab | Forme cristalline gamma du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
FR2891827B1 (fr) * | 2005-10-11 | 2007-12-28 | Servier Lab | Forme cristalline deltad du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
FR2891826B1 (fr) * | 2005-10-11 | 2007-12-28 | Servier Lab | Forme cristalline 6 du chlorhydrate de l'ivabradine, son procede de preparation et les compositions pharmaceutiques qui la contiennent |
FR2894825B1 (fr) * | 2005-12-21 | 2010-12-03 | Servier Lab | Nouvelle association d'un inhibiteur du courant if sinusal et d'un inhibiteur de l'enzyme de conversion et les compositions pharmaceutiques qui la contiennent |
WO2008065681A2 (en) | 2006-11-30 | 2008-06-05 | Cadila Healthcare Limited | Process for preparation of ivabradine hydrochloride |
CN101353325B (zh) * | 2007-07-27 | 2011-11-09 | 上海优拓医药科技有限公司 | 稳定型盐酸伊伐布雷定结晶及其制备方法 |
JP5632279B2 (ja) | 2007-05-30 | 2014-11-26 | アイエヌディー−スイフト ラボラトリーズ リミテッド | 塩酸イバブラジンの調製方法及びポリモルフ |
FR2920773B1 (fr) * | 2007-09-11 | 2009-10-23 | Servier Lab | Derives de 1,2,4,5-tetrahydro-3h-benzazepines, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
EP2367782B1 (en) | 2008-12-22 | 2013-02-13 | KRKA, D.D., Novo Mesto | Process for preparation of ivabradine |
CN101774969B (zh) | 2009-01-13 | 2012-07-04 | 江苏恒瑞医药股份有限公司 | 硫酸伊伐布雷定及其i型结晶的制备方法 |
PL2902384T3 (pl) | 2010-02-12 | 2018-04-30 | Krka, D.D., Novo Mesto | Postać chlorowodorku iwabradyny |
HUP1000245A2 (en) | 2010-05-07 | 2011-11-28 | Richter Gedeon Nyrt | Industrial process for the production ivabradin salts |
CA2800444C (en) | 2010-06-14 | 2018-03-20 | Ratiopharm Gmbh | Ivabradine-containing pharmaceutical composition |
WO2012025940A1 (en) | 2010-08-25 | 2012-03-01 | Cadila Healthcare Limited | Polymorphic form of ivabradine hydrochloride and process for preparation thereof |
WO2013017582A1 (en) | 2011-08-02 | 2013-02-07 | Sandoz Ag | Acetone solvate of ivabradine hydrochloride |
EP2773621B1 (en) | 2011-11-04 | 2015-12-30 | Synthon BV | A process for making crystalline delta-form of ivabradine hydrochloride |
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 |
EP2948432B1 (en) | 2013-01-24 | 2018-09-19 | Synthon BV | Process for making ivabradine |
CZ305096B6 (cs) | 2013-10-02 | 2015-04-29 | Zentiva, K.S. | Pevná forma Ivabradin hydrochloridu a (S)-mandlové kyseliny a její farmaceutická kompozice |
MX363389B (es) | 2013-12-12 | 2019-03-20 | Synthon Bv | Composicion farmaceutica que comprende ivabradina amorfa. |
SI2774606T1 (sl) | 2014-02-14 | 2019-05-31 | Synthon B.V. | Farmacevtski sestavek, ki obsega polimorf IV ivabradin hidroklorida |
CZ305436B6 (cs) | 2014-07-10 | 2015-09-16 | Zentiva, K.S. | Pevná forma Ivabradin hydrochloridu a (R)-mandlové kyseliny a její farmaceutická kompozice |
CN107056706B (zh) * | 2015-12-21 | 2020-05-05 | 江苏恒瑞医药股份有限公司 | 一种用于制备盐酸伊伐布雷定α晶型的方法 |
TR201703066A2 (tr) | 2017-02-28 | 2018-09-21 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | İvabradi̇ni̇n kati oral farmasöti̇k kompozi̇syonlari |
EP3366282A1 (en) | 2017-02-28 | 2018-08-29 | Sanovel Ilac Sanayi ve Ticaret A.S. | Solid oral pharmaceutical compositions of ivabradine |
JP7132757B2 (ja) | 2018-06-12 | 2022-09-07 | プレス工業株式会社 | スライド窓保持装置 |
IT202000025312A1 (it) | 2020-10-26 | 2022-04-26 | Cambrex Profarmaco Milano S R L | Processi per la preparazione di polimorfi di ivabradina hcl |
IT202100019988A1 (it) | 2021-07-27 | 2023-01-27 | Campagnolo Srl | Dispositivo manuale di comando per bicicletta |
IT202100019967A1 (it) | 2021-07-27 | 2023-01-27 | Campagnolo Srl | Dispositivo manuale di comando per bicicletta |
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DE3119874A1 (de) * | 1981-05-19 | 1982-12-09 | Dr. Karl Thomae Gmbh, 7950 Biberach | "benzazepinderivate, ihre herstellung und ihre verwendung als arzneimittel" |
DE3418270A1 (de) * | 1984-05-17 | 1985-11-21 | Dr. Karl Thomae Gmbh, 7950 Biberach | Neue aminotetralinderivate, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung |
FR2868777B1 (fr) * | 2004-04-13 | 2006-05-26 | Servier Lab | Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
FR2882556B1 (fr) * | 2005-02-28 | 2007-05-04 | Servier Lab | Forme cristalline gamma d du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
FR2882555B1 (fr) * | 2005-02-28 | 2007-05-04 | Servier Lab | Forme cristalline gamma du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
FR2882553B1 (fr) * | 2005-02-28 | 2007-05-04 | Servier Lab | Forme cristalline beta du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
FR2882554B1 (fr) * | 2005-02-28 | 2007-05-04 | Servier Lab | Forme critalline beta d du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
FR2891826B1 (fr) * | 2005-10-11 | 2007-12-28 | Servier Lab | Forme cristalline 6 du chlorhydrate de l'ivabradine, son procede de preparation et les compositions pharmaceutiques qui la contiennent |
FR2891827B1 (fr) * | 2005-10-11 | 2007-12-28 | Servier Lab | Forme cristalline deltad du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
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EP0534859A1 (fr) * | 1991-09-27 | 1993-03-31 | Adir Et Compagnie | 3-Benzazépin-zones substituées par un groupe benzocyclobutyl- ou indanyl-alkyl-amino-alkyle, utiles dans le traitement des affections cardiovasculaires |
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