RS50661B - Beta kristalni oblik ivabradin hidrohlorida, postupak njegove izrade i farmaceutske smeše koje ga sadrže - Google Patents
Beta kristalni oblik ivabradin hidrohlorida, postupak njegove izrade i farmaceutske smeše koje ga sadržeInfo
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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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- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D81/00—Containers, packaging elements, or packages, for contents presenting particular transport or storage problems, or adapted to be used for non-packaging purposes after removal of contents
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
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- B65D85/00—Containers, packaging elements or packages, specially adapted for particular articles or materials
- B65D85/30—Containers, packaging elements or packages, specially adapted for particular articles or materials for articles particularly sensitive to damage by shock or pressure
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- D—TEXTILES; PAPER
- D21—PAPER-MAKING; PRODUCTION OF CELLULOSE
- D21H—PULP COMPOSITIONS; PREPARATION THEREOF NOT COVERED BY SUBCLASSES D21C OR D21D; IMPREGNATING OR COATING OF PAPER; TREATMENT OF FINISHED PAPER NOT COVERED BY CLASS B31 OR SUBCLASS D21G; PAPER NOT OTHERWISE PROVIDED FOR
- D21H21/00—Non-fibrous material added to the pulp, characterised by its function, form or properties; Paper-impregnating or coating material, characterised by its function, form or properties
- D21H21/14—Non-fibrous material added to the pulp, characterised by its function, form or properties; Paper-impregnating or coating material, characterised by its function, form or properties characterised by function or properties in or on the paper
- D21H21/16—Sizing or water-repelling agents
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- D21—PAPER-MAKING; PRODUCTION OF CELLULOSE
- D21H—PULP COMPOSITIONS; PREPARATION THEREOF NOT COVERED BY SUBCLASSES D21C OR D21D; IMPREGNATING OR COATING OF PAPER; TREATMENT OF FINISHED PAPER NOT COVERED BY CLASS B31 OR SUBCLASS D21G; PAPER NOT OTHERWISE PROVIDED FOR
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Abstract
β kristalni oblik ivabradin hidrohlorida formule (I):naznačen time što je dijagram difrakcije X zraka na prašku, u nastavku, izmeren na difraktometru PANalytical X'Pert Pro sa detektorom X'Celerator i, izražen je u vidu položaja linije (ugao Bragg 2 teta, izražen u stepenima), visinom linije (izražena u brojevima), površinom linije (izražena kao brojevi x stepeni), širinom linije u sredini visine ("FWHM", izražena u stepenima) i inter-retikularnom udaljenošću d (izražena u A):Linija n° Ugao 2 teta (stepeni) Visina (brojevi) Površina (brojevi x stepeni) FWHM (stepeni) Inter-retikularna udaljenost (A)1 6,8 130 86 0,6691 13,0192 9,2 6141 507 0,0836 9,6133 9,7 882 58 0,0669 9,0834 10,0 875 72 0,0836 8,8375 11,9 190 19 0,1004 7,4336 12,2 500 58 0,1171 7,2367 13,2 224 30 0,1338 6,69400 13,8 633 52 0,0836 6,4199 14,3 466 54 0,1171 6,20910 14,8 926 76 0,0836 5,97711 15,0 716 94 0,1338 5,88712 15,7 531 79 0,1506 5,63613 16,1 121 16 0,1338 5,50214 16,9 1354 223 0,1673 5,25415 18,4 5672 562 0,1004 4,82416 18,8 1328 131 0,1004 4,71617 19,7 1617 347 0,2175 4,50818 20,4 296 34 0,1171 4,34119 20,7 767 51 0,0669 4,28620 . 21,3 1419 211 0,1506 4,17821 21,6 2458 243 0,1004 4,11422 22,6 1737 258 0,1506 3,93723 23,0 1467 73 0,0502 3,86524 23,7 486 128 0,2676 3,75125 23,9 504 50 0,1004 3,71826 25,3 4606 304 0,0669 3,51327 25,7 791 91 0,1171 3,46428 26,2 458 91 0,2007 3,40629 26,6 221 44 0,2007 3,35230 27,4 706 151 0,2175 3,25131 27,7 208 27 0,1338 3,21532 28,1 483 40 0,0836 3,17633 28,8 242 24 0,1004 3,09634 29,3 450 74 0,1673 3,049Prijava sadrži još 5 patentnih zahteva.
Description
BETA KRISTALNI OBLIK
IVABRADIN HIDROHLORIDA,
POSTUPAK NJEGOVE IZRADE I
FARMACEUTSKE SMEŠE KOJE GA
SADRŽE
Ovaj pronalazak se odnosi na novi kristalni oblik p" ivabradin hidrohlorida sa formulom (I), na njegov postupak izrade, kao i na farmaceutske smeše koje ga sadrže.
Ivabradin, kao i njegove adicione soli sa farmaceutski prihvatljivom kiselinom i, posebno, njegov hidrohlorid, poseduju veoma korisna farmakološka i terapeutska svojstva, između ostalih, bradikardijalna svojstva, koja omogućavaju ovim jedinjenjima da se upotrebljavaju za tečenje ili prevenciju različitih kliničkih situacija ishemije miokarda, kao što su angina pektoris, infarkt miokarda i udruženi poremećaji ritma, kao i u različitim patologijama ponašanja poremećaja ritma, između ostalog, supra-ventrikularnim i u srčanoj insuficijenciji.
Izrada i korišćenje u terapiji ivabradina i njegovih adicionih soli sa farmaceutski prihvatljivom kiselinom i, posebno, njegovog hidrohlorida, opisani su u evropskom patentu EP 0534 859.
Uzimajući u obzir farmaceutsku isplativost ovog jedinjenja, bilo je glavno da se ono dobije sa odličnom čistoćom. Isto tako, bilo je važno omogućiti sintezu u skladu sa postupkom koji je lako prevodiv na industrijski proces i, posebno, u jednom obliku koji će omogućiti filtraciju i brzo sušenje. Konačno, taj oblik derivata je bio savršeno reproducibilan, lako je formulisan i zadovoljavajuće stabilan kako bi se odobrilo njegovo produženo skladištenje bez posebnih uslova temperature, svetla ili protoka kiseonika.
Patent EP 0534 859 opisuje postupak sinteze ivabradina i njegovog hidrohlorida. Međutim, ovaj dokument ne precizira uslove dobijanja ivabradina u nekom obliku koji ispoljava svoje karakteristike na reproducibilan način.
Zahtevalac sada nalazi da se jedna posebna so ivabradina, hidrohlorid, može dobiti u jednom kristalnom obliku koji je dobro definisan i koji ispoljava korisne osobine stabilnosti i mogućnosti za postavljanje u postupak.
Preciznije, ovaj pronalazak se odnosi na 0 kristalni oblik ivabradin hidrohlorida, koji se karakteriše sledećim dijagramom difrakcije X zraka na prašku, koji je izmeren na difraktometru PANalvtical X'Pert Pro sa X'Celerator detektorom i izražen je u vidu položaja linija (ugao Bragga 2 teta, izražen u stepenima), visinom linije {izražene brojevima), površinom linije (izražene kao broj x stepeni), širinom linija po sredini visine ("FvVHM", izraženih u stepenima} i inter-retikularnom d udaljenošcu (izraženo u A):
Pronalazak se, isto tako, odnosi na jedan postupak izrade p kristalnog oblika ivabradin hidrohlorida, koji se karakteriše time da se zagreva smeša ivabradin hidrohlorida i vode ili smeša ivabradin hidrohlorida, izopropanola i vode do potpunog rastvara nj a zatim, progresivno hladi dok se ne završi kristalizacija i sakupe se tako obrazovani kristali. • U postupku kristalizacije, koji je u skladu sa pronalaskom, može se koristiti ivabradin hidrohlorid, koji je dobijen bilo kojim postupkom, na primer, ivabradin hidrohlorid dobijen postupkom izrade, koji je opisan u Patentu EP 0534 859.
• Rastvor, korisno, može biti zasejan tokom etape hlađenja.
Pronalazak se, takođe, odnosi na farmaceutske smeše koje, kao aktivni princip, sadrže p kristalni oblik ivabradin hidrohlorida sa jednim ili više inertnih ekscipijenata, koji su odgovarajući i nisu otrovni. Među farmaceutskim smešama koje su u skladu sa pronalaskom mogu se navesti naročito one koje su pogodne za oralnu, parenteralnu (intravensku ili subkutanu) ili nazalnu primenu, jednostavne pilule ili dražeje, sublingvalne pilule, želatinske kapsule, tablete, supozitorije, kremovi, masti, dermo-gelovi, injektabilni preparati, suspenzije koje se piju.
Doziranje koje se koristi, prilagodi se prema prirodi i ozbiljnosti bolesti, načinu primenjivanja, kao i starosti i težini pacijenta. Takvo doziranje varira od 1 do 500 mg dnevno, jednom ili više puta.
Primeri koji slede ilustruju pronalazak.
Spektar difrakcije X zrakova na prašku izmeren je pod sledećim eksperimentalnim uslovima: - Difraktometar PANalvtical X'Pert Pro, detektor X'Celerator, odeljak regulisane temperature,
- Pritisak 45 KV, intenzitet 40 mA,
- Sklapanje 6-9,
- Niklovani filter (K0),
- Sollerov prorez na umetnutom zračenju i na prelomljenom zračenju : 0,04 rad,
- Prorezi fiksne divergencije: ugao 1/8°,
- Zaklon : 10 mm,
- Anti-difuzioni prorez : 1/4° ,
- Način merenja : neprekidno od 3° do 30°, sa jednim porastom od 0,017°,
- Vreme merenja po koraku . 19,7 s,
- Ukupno vreme : 4 min 32 s,
- Brzina merenja : 0,108°/s,
- Temperatura merenja : temperatura sredine.
PR1MER 1: pkristalni oblik ivabradin hidrohlorida
720 ml prečišćene vode je prethodno zagrejano na 50°C, a zatim je, deo po deo, uz mešanje, dodato 250 g ivabradin hidrohlorida, koji je dobijen u skladu sa postupkom, koji je opisan u Patentu EP 0534 859 i, reakciona sredina je grejana na 74°C do potpunog rastvaranja. Dobijeni bistar rastvor je grejan dodatnih 2h na 74°C, zatim je progresivno ohlađen do 40°C, a zatim, na temperaturu sredine. Rastvor je onda čuvan na temperaturi sredine tokom 2 dana, a zatim je čvrsta suspenzija izložena kao fini sloj na ploči za kristalizaciju. Višak vode je istisnut pod slabim prilivom azota.
Sadržaj vode dobijenog proizvoda, koji je određen kulometrijski, iznosi 12,4%, što odgovara tetrahidratu.
Dijagram difrakcije X zraka na prašku:
Profil difrakcije X zraka na prašku (difrakcioni uglovi) p oblika ivabradin hidrohlorida je prikazan značajnim linijama, koje su zajedno date u sledećoj tabeli:
PR1MER 2 :Farmaceutska smeša
Formula za izradu 1000 pilula doze od 5 mg ivabradin baze:
Claims (6)
1. pkristalni oblik ivabradin hidrohlorida formule (I):
naznačen time štoje dijagram difrakcije X zraka na prašku, u nastavku, izmeren na difraktometru PANalvtical X'Pert Pro sa detektorom X'Celerator i, izražen je u vidu položaja linije (ugao Bragg 2 teta, izražen u stepenima), visinom linije (izražena u brojevima), površinom linije (izražena kao brojevi x stepeni), širinom linije u sredini visine ("FWHM", izražena u stepenima) i inter-retikularnom udaljenošću d (izražena u A):
2. Postupak izrade p kristalnog oblika ivabradin hidrohloridanaznačentimeštose zagreva smeša ivabradin hidrohlorida i vode ili smeša ivabradin hidrohlorida, izopropanola i vode do potpunog rastvaranja i zatim, progresivno hladi dok se ne završi kristalizacija te se sakupljaju tako obrazovani kristali.
3. Postupak, kao u Patentnom zahtevu 2, naznačen timeštose rastvor ivabradin hidrohlorida zasejava u toku etape hlađenja.
4. Farmaceutska smeša kao aktivni princip sadrži 3 kristalni oblik ivabradin hidrohlorida, kao u Patentnom zahtevu 1, zajedno sa jednim ili više inertnih vehikuluma, koji nisu otrovni i farmaceutski su prihvatljivi.
5. Korišćenje p kristalnog oblika ivabradin hidrohlorida, kao u Patentnom zahtevu 1, za proizvodnju tekova, koji se koriste kao bradikardiačni lekovi.
6. Korišćenje p kristalnog oblika ivabradin hidrohlorida, kao u Patentnom zahtevu 1, za proizvodnju tekova, koji se koriste u lečenju ili prevenciji različitih kliničkih situacija ishemije miokarda, kao što su angina pektoris, infarkt miokarda i udruženi poremećaji ritma, kao i u različitim patologijama ponašanja poremećaja ritma, između ostalog, supra-ventrikularnim i u srčanoj insuficijenciji.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0501985A FR2882553B1 (fr) | 2005-02-28 | 2005-02-28 | Forme cristalline beta du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
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| Publication Number | Publication Date |
|---|---|
| RS50661B true RS50661B (sr) | 2010-06-30 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| RSP-2008/0551A RS50661B (sr) | 2005-02-28 | 2006-02-28 | Beta kristalni oblik ivabradin hidrohlorida, postupak njegove izrade i farmaceutske smeše koje ga sadrže |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| EP2460797A3 (en) | 2006-11-30 | 2012-12-05 | Cadila Healthcare Limited | Process for preparation of ivabradine hydrochloride |
| FR2911279B1 (fr) * | 2007-01-11 | 2009-03-06 | Servier Lab | Utilisation de l'ivabradine pour l'obtention de medicaments destines au traitement de la dysfonction endotheliale |
| 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 |
| PT2471780E (pt) | 2007-05-30 | 2015-02-24 | Ind Swift Lab Ltd | Sais oxalato de ivabradina cristalinos e seus polimorfos |
| FR2938194B1 (fr) * | 2008-11-07 | 2012-08-31 | Servier Lab | Utilisation de l'ivabradine comme agent de diagnostic dans la methode d'angiographie coronaire par tomodensitometrie multicoupe |
| ES2402765T3 (es) | 2008-12-22 | 2013-05-08 | Krka, D.D., Novo Mesto | Procedimiento de preparación de ivabradina |
| 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 |
| EP2534135A2 (en) | 2010-02-12 | 2012-12-19 | KRKA, D.D., Novo Mesto | Novel forms of ivabradine hydrochloride |
| HUP1000245A2 (en) | 2010-05-07 | 2011-11-28 | Richter Gedeon Nyrt | Industrial process for the production ivabradin salts |
| TWI499587B (zh) * | 2010-06-03 | 2015-09-11 | Jiangsu Hengrui Medicine Co | 硫酸伊伐佈雷定及其ｉ型結晶的製備方法 |
| PL2579859T3 (pl) | 2010-06-14 | 2015-12-31 | Ratiopharm Gmbh | Kompozycja stała zawierająca iwabradynę |
| WO2012025940A1 (en) | 2010-08-25 | 2012-03-01 | Cadila Healthcare Limited | Polymorphic form of ivabradine hydrochloride and process for preparation thereof |
| CN102304088B (zh) * | 2011-07-07 | 2013-06-19 | 石药集团欧意药业有限公司 | 一种伊伐布雷定化合物、制备方法及其药物组合物 |
| WO2013017582A1 (en) | 2011-08-02 | 2013-02-07 | Sandoz Ag | Acetone solvate of ivabradine hydrochloride |
| EP2589594A1 (en) * | 2011-11-04 | 2013-05-08 | Urquima S.A. | Ivabradine hydrochloride Form IV |
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| EP3156399A1 (en) | 2011-11-14 | 2017-04-19 | Cadila Healthcare Limited | Polymorphic forms of ivabradine hydrochloride |
| US9409913B2 (en) * | 2012-11-21 | 2016-08-09 | Enaltec Labs Private Limited | Polymorphic forms of alcaftadine |
| EP2948432B1 (en) | 2013-01-24 | 2018-09-19 | Synthon BV | Process for making ivabradine |
| HRP20200300T4 (hr) | 2013-03-19 | 2023-09-15 | Chemo Research, S.L. | Novi polimorf ivabradin hidroklorida i metoda za njegovu pripremu |
| CZ2013767A3 (cs) | 2013-10-02 | 2015-04-29 | Zentiva, K.S. | Pevná forma Ivabradin hydrochloridu a (S)-mandlové kyseliny a její farmaceutická kompozice |
| WO2015001133A1 (en) | 2013-12-12 | 2015-01-08 | Synthon B.V. | Pharmaceutical composition comprising amorphous ivabradine |
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| GR1008821B (el) | 2015-06-11 | 2016-08-01 | Φαρματεν Ανωνυμος Βιομηχανικη Και Εμπορικη Εταιρεια Φαρμακευτικων Ιατρικων Και Καλλυντικων Προϊοντων | Φαρμακευτικο σκευασμα που περιλαμβανει υδροχλωρικη ιβαμπραδινη και μεθοδος παρασκευης αυτου |
| 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 |
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| EP3366282B1 (en) | 2017-02-28 | 2025-10-01 | Sanovel Ilac Sanayi ve Ticaret A.S. | Solid oral pharmaceutical compositions of ivabradine |
| TR201703066A2 (tr) | 2017-02-28 | 2018-09-21 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | İvabradi̇ni̇n kati oral farmasöti̇k kompozi̇syonlari |
| WO2020092288A1 (en) | 2018-10-30 | 2020-05-07 | Amgen Inc. | Process of making ivabradine hydrochloride drug product |
| US11969424B2 (en) | 2019-12-16 | 2024-04-30 | Tenax Therapeutics, Inc. | Levosimendan for treating pulmonary hypertension with heart failure with preserved ejection fraction (PH-HFpEF) |
| IT202000025312A1 (it) | 2020-10-26 | 2022-04-26 | Cambrex Profarmaco Milano S R L | Processi per la preparazione di polimorfi di ivabradina hcl |
| US20250064799A1 (en) | 2021-12-31 | 2025-02-27 | Tenax Therapeutics, Inc. | Oral formulations of levosimendan for treating pulmonary hypertension with heart failure with preserved ejection fraction |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3119874A1 (de) * | 1981-05-19 | 1982-12-09 | Dr. Karl Thomae Gmbh, 7950 Biberach | "benzazepinderivate, ihre herstellung und ihre verwendung als arzneimittel" |
| US4490369A (en) * | 1981-05-19 | 1984-12-25 | Dr. Karl Thomae Gesellschaft Mit Beschrankter Haftung | Benzazepine derivatives, their pharmaceutical compositions and method of use |
| AU647528B2 (en) | 1990-08-29 | 1994-03-24 | Humanetics Corporation | Treatment process for promoting weight loss employing a substituted delta5-androstene |
| FR2681862B1 (fr) * | 1991-09-27 | 1993-11-12 | Adir Cie | Nouvelles (benzocycloalkyl)alkylamines, leur procede de preparation, et les compositions pharmaceutiques qui les contiennent. |
| FR2818552B1 (fr) | 2000-12-26 | 2003-02-07 | Servier Lab | Compositions pharmaceutique solide thermoformable pour la liberation controlee d'ivabradine |
| FR2834896B1 (fr) * | 2002-01-23 | 2004-02-27 | Servier Lab | Composition pharmaceutique orodispersible d'ivabradine |
| 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 |
| 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 |
| 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 |
| 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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