TWI377946B - Δ-crystalline form of ivabradine hydrochloride, a process for its preparation and pharmaceutical compositions containing it - Google Patents
Δ-crystalline form of ivabradine hydrochloride, a process for its preparation and pharmaceutical compositions containing it Download PDFInfo
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- 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
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- 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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Description
1377946 九、發明說明: 【發明所屬之技術領域】 本發明係關於式⑴之依伐布雷定(ivabradine)鹽酸鹽之δ 結晶型
.HC1
其製備方法及含其之醫藥組合物。 【先前技術】 依伐布雷定及其與醫藥學上可接受酸之加成鹽,且更尤 其為其鹽酸鹽具有極其重要醫藥及治療特性,尤其為減慢 心率藥特性,使得彼等化合物適用於治療或預防諸如心絞 痛、心肌梗塞及相關心律紊亂之心肌局部缺血之多種臨床 病況,亦及包括心律紊亂、尤其為室上性心律紊亂 (supraventricular rhythm disturbance)之多種病狀,及心臟 衰竭。 依伐布雷定及其與醫藥學上可接受酸之加成鹽,且更尤 其為其鹽酸鹽已於EP 0 534 859歐洲專利說明書中描述。 鑒於此化合物之醫藥價值,最重要的為獲得具有極好純 度之該化合物。亦重要的為,可藉助於可易於轉化成工業 規模、尤其呈允許快速過濾且乾燥之形式的方法來合成。 最後,彼形式必須完全可再現、易於調配且足夠穩定以允 許其在對溫度、光或氧含量無特定要求之情況下長期儲存。 114895.doc 1377946 ΕΡ Ο 534 859專利說明書描述依伐布雷定及其鹽酸鹽之 合成方法。然而,彼文獻並未說明用於獲得以可再現方式 展示彼等特徵之形式的依伐布雷定之條件。 【發明内容】 該申請案現已發現依伐布雷定之特定鹽,鹽酸鹽,可獲 得展示穩定性及可加工性之重要特徵之定義明確的結晶 型。 更特定言之,本發明係關於依伐布雷定鹽酸鹽之δ-結晶 型,其特徵為以下粉末X-光繞射圖,該圖使用PANalytical X'Pert Pro繞射儀連同X'Celerator偵測器量測且由線位置 (以度表示之布拉格角度(Bragg's angle)20)、線高(以計數表 示)、線面積(以計數X度表示)、半高處之線寬("FWHM”,以 度表示)及晶面間距d(以A表示)表示: 線編號 角度2Θ(度) 高度(計數) 面積(計數X度) FWHM (度) 晶面間距 (A) 1 4.1 1115 110 0.1004 21.753 2 6.8 183 145 0.8029 12.907 3 8.4 755 75 0.1004 10.531 4 10.9 1104 128 0.1171 8.087 5 12.2 195 19 0.1004 7.268 6 14.3 569 75 0.1338 6.214 7 14.7 1847 274 0.1506 6.013 8 15.3 1734 315 0.184 5.802 9 16.3 1164 154 0.1338 5.442 10 16.8 3420 734 0.2175 5.269 11 17.5 790 78 0.1004 5.069 12 17.9 3389 503 0.1506 4.960 13 19.2 2467 407 0.1673 4.635 114895.doc 線編號 角度2Θ(度) 高度(計數) 面積(計數X度) FWHM (度) 晶面間距 (Α) 14 19.8 145 29 0.2007 4.477 15 20.4 313 52 0.1673 4.362 16 21.2 928 169 0.184 4.198 17 21.7 2093 414 0.2007 4.099 18 22.2 3850 635 0.1673 4.007 19 22.5 576 76 0.1338 3.948 20 23.1 1588 236 0.1506 3.855 21 24.8 1665 247 0.1506 3.594 22 25.2 1212 120 0.1004 3.534 23 25.6 1507 249 0.1673 3.477 24 26.7 2042 303 0.1506 3.342 25 27.6 2281 414 0.184 3.229 26 28.4 485 96 0.2007 3.138 27 29.6 599 99 0.1673 3.014 本發明亦係關於一種製備依伐布雷定鹽酸鹽之δ-結晶型 之方法,該方法之特徵為:將乙腈或乙腈與水之混合物預 熱,添加依伐布雷定鹽酸鹽,使所得溶液冷卻至室溫,保 持於室溫下直至完全結晶,且收集所形成之晶體。 •在根據本發明之結晶方法中,可能使用以任何方法獲得 之依伐布雷定鹽酸鹽,例如藉由描述於ΕΡ 0 534 859專利 說明書中之製備方法獲得之依伐布雷定鹽酸鹽。 •該溶液可有利地在冷卻步驟中播晶種。 •較佳將乙腈或乙腈與水之混合物預熱至介於60°C與回流 之間的溫度,更佳介於65與75°C之間。 •稀釋液較佳大於15 mg/g,更佳介於50與100 ml/g之間。 本發明亦係關於包含作為活性成份之依伐布雷定鹽酸鹽 的δ-結晶型以及一或多種惰性且無毒之適合賦形劑的醫藥 組合物。在根據本發明之醫藥組合物中,更尤其可能提及 為彼等適於口服、非經腸(靜脈内或皮下)或經鼻投與之錠劑 114895.doc ⑸7946 或糖衣藥丸、舌下錠劑、膠囊、***劑、拴劑、乳霜、油 膏、皮膚凝膠、可注射製劑及可飲用之懸浮液。 適用劑量可根據病症之性質及嚴重程度、投藥途徑及患 者之年齡及體重而有所不同。該劑量每日自iiWO mg變 化’分一或多次投與。 【實施方式】 以下實例說明本發明。 在下列實驗條件下量測X-光粉末繞射光譜: • PANalyticalX'PertPro 繞射儀、X'Celerator偵測器、溫度 調節室, -電壓45 kV,強度40 mA, •安裝Θ-Θ, -鎳(Κβ)濾波器, -入射束及繞射束索勒狹縫(Soller slit) : 0.04雷得, -自動發散狹縫:輪射長度10 mm, •光罩:10 mm, -防散射狹缝:1/2°, -量測模式:以0.017。之增量自3。至30。連續量測, -每步驟量測時間:19.7 s, -總時間:4分32秒, -量測速度:〇.l〇8°/s, -量測溫度:周圍溫度。 實例1 :依伐布雷定鹽酸鹽之δ-結晶型 將160 ml乙腈預熱至70°C且隨後在攪拌下添加根據ΕΡ 0 114895.doc 1377946 534 859專利說明書中所述之方法獲得之2 g依伐布雷定鹽 酸鹽,直至完全溶解。將該溶液於室溫下儲存2天。在真空 下藉由過濾移出晶體且將其散佈於結晶盤上。 由電量法測定所得產物之水含量為2.8 %。 粉末X-光繞射圖: 依伐布雷定鹽酸鹽之δ-型之粉末X-光繞射圖概況(繞射 角)藉由於下表中整理之重要線給出:
線編號 角度2Θ(度) 高度(計數) 面積(計數X度) FWHM (度) 晶面間距 (Α) 1 4.1 1115 110 0.1004 21.753 2 6.8 183 145 0.8029 12.907 3 8.4 755 75 0.1004 10.531 4 10.9 1104 128 0.1171 8.087 5 12.2 195 19 0.1004 7.268 6 14.3 569 75 0.1338 6.214 7 14.7 1847 274 0.1506 6.013 8 15.3 1734 315 0.184 5.802 9 16.3 1164 154 0.1338 5.442 10 16.8 3420 734 0.2175 5.269 11 17.5 790 78 0.1004 5.069 12 17.9 3389 503 0.1506 4.960 13 19.2 2467 407 0.1673 4.635 14 19.8 145 29 0.2007 4.477 15 20.4 313 52 0.1673 4.362 16 21.2 928 169 0.184 4.198 17 21.7 2093 414 0.2007 4.099 18 22.2 3850 635 0.1673 4.007 19 22.5 576 76 0.1338 3.948 20 23.1 1588 236 0.1506 3.855 21 24.8 1665 247 0.1506 3.594 22 25.2 1212 120 0.1004 3.534 23 25.6 1507 249 0.1673 3.477 24 26.7 2042 303 0.1506 3.342 25 27.6 2281 414 0.184 3.229 26 28.4 485 96 0.2007 3.138 27 29.6 599 99 0.1673 3.014 114895.doc •10- 1377946 實例2 :醫藥組合物 製備1000個各含有5 mg依伐布雷定鹼之錠劑的配方: 實例1之化合物.........................................5.39 g 玉米澱粉....................................................20 g 無水膠狀二氧化矽......................................0.2 g 甘露醇....................................................63.91 g PVP.............................................................10 g 硬脂酸鎂....................................................0.5 g
114895.doc -11 -
Claims (1)
1377946 十、申請專利範圍: 1. 一種式(I)之依伐布雷定(ivabradine)鹽酸鹽的δ-結晶型,
其特徵為以下粉末X-光繞射圖,該圖使用PANalytical X'Pert Pro繞射儀連同X'Celerator偵測器量測且由線位置 (以度表示之布拉格角度(Bragg's angle)角2 Θ)、線高(以計 數表示)、線面積(以計數X度表示)、半高處之線寬 ("FWHM",以度表示)及晶面間距d(以A表示)表示: 線編號 角度Θ(度) 高度(計數) 面積(計數X度) FWHM (度) 晶面間距(人) 1 4.1 1115 110 0.1004 21.753 2 6.8 183 145 0.8029 12.907 3 8.4 755 75 0.1004 10.531 4 10.9 1104 128 0.1171 8.087 5 12.2 195 19 0.1004 7.268 6 14,3 569 75 0.1338 6.214 7 14.7 1847 274 0.1506 6.013 8 15.3 1734 315 0.184 5.802 9 16.3 1164 154 0.1338 5.442 10 16.8 3420 734 0.2175 5.269 11 17.5 790 78 0.1004 5.069 12 17.9 3389 503 0.1506 4.960 13 19.2 2467 407 0.1673 4.635 14 19.8 145 29 0.2007 4.477 15 20.4 313 52 0.1673 4.362 16 21.2 928 169 0.184 4.198 17 21.7 2093 414 0.2007 4.099 18 22.2 3850 635 0.1673 4.007 19 22.5 576 76 0.1338 3.948 20 23.1 1588 236 0.1506 3.855 21 24.8 1665 247 0.1506 3.594
114895.doc 1377946 , 翥 Λ 1編號 角度Θ(度) 高度(計數) 面積(計數X度) FWHM (度) 晶面間距(A) 22 25.2 1212 120 0.1004 3.534 23 25.6 1507 249 0.1673 3.477 24 26.7 2042 303 0.1506 3.342 25 27.6 2281 414 0.184 3.229 26 28.4 485 96 0.2007 3.138 27 29.6 599 99 0.1673 3.014 2. 一種製備如請求項1之依伐布雷定鹽酸鹽之δ-結晶型的方 法,其特徵為:將乙腈或乙腈與水之混合物預熱,添加 依伐布雷定鹽酸鹽,使所得溶液冷卻至室溫,保持於室 溫下直至完全結晶,且收集所形成之晶體。 3. 如請求項2之方法,其特徵為在冷卻步驟中於該依伐布雷 定鹽酸鹽溶液中播晶種。 4. 一種醫藥組合物,其包含與一或多種醫藥學上可接受之 惰性、無毒載劑相組合之作為活性成份的如請求項1之依 伐布雷定鹽酸鹽的δ-結晶型。 5. 一種如請求項1之依伐布雷定鹽酸鹽之δ-結晶型的用途, 其係用於製造用作減慢心率藥之藥物。 6. —種如請求項1之依伐布雷定鹽酸鹽之δ-結晶型的用途, 用於製造用作治療或預防諸如心絞痛、心肌梗塞及相關 心律紊亂之心肌局部缺血之多種臨床病況,亦及包括心 律紊亂、尤其為室上性心律紊亂(supraventricular rhythm disturbance)之多種病狀,及心臟衰竭的藥物。 114895.doc
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FR0510352A FR2891826B1 (fr) | 2005-10-11 | 2005-10-11 | Forme cristalline 6 du chlorhydrate de l'ivabradine, son procede de preparation et les compositions pharmaceutiques qui la contiennent |
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US (3) | US7358240B2 (zh) |
EP (2) | EP1956005A1 (zh) |
JP (1) | JP2007112796A (zh) |
KR (1) | KR20070040311A (zh) |
CN (1) | CN1948292A (zh) |
AP (1) | AP2303A (zh) |
AR (1) | AR056572A1 (zh) |
AU (1) | AU2006228027B2 (zh) |
BR (1) | BRPI0604250A (zh) |
CA (1) | CA2564367C (zh) |
CO (1) | CO5790166A1 (zh) |
CR (1) | CR8645A (zh) |
EA (1) | EA010296B1 (zh) |
EC (1) | ECSP066915A (zh) |
FR (1) | FR2891826B1 (zh) |
GE (1) | GEP20094653B (zh) |
GT (1) | GT200600450A (zh) |
IL (1) | IL178544A (zh) |
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MX (1) | MXPA06011766A (zh) |
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NO (1) | NO20064596L (zh) |
NZ (1) | NZ550435A (zh) |
PE (1) | PE20070492A1 (zh) |
SA (1) | SA06270370B1 (zh) |
SG (1) | SG131858A1 (zh) |
TW (1) | TWI377946B (zh) |
UA (1) | UA90265C2 (zh) |
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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 |
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 |
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 |
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 |
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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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 |
WO2011098582A2 (en) | 2010-02-12 | 2011-08-18 | 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 |
FR2961105B1 (fr) * | 2010-06-15 | 2013-02-08 | Servier Lab | Utilisation de l'association d'un inhibiteur du courant if sinusal et d'un inhibiteur de l'enzyme de conversion de l'angiotensine pour le traitement de l'insuffisance cardiaque |
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EP2726462B1 (en) | 2011-08-02 | 2017-03-22 | Sandoz AG | Acetone solvate of ivabradine hydrochloride |
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CZ305096B6 (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 |
EP2774606B1 (en) | 2014-02-14 | 2019-01-30 | Synthon B.V. | Pharmaceutical composition comprising ivabradine hydrochloride polymorph IV |
CZ305436B6 (cs) | 2014-07-10 | 2015-09-16 | Zentiva, K.S. | Pevná forma Ivabradin hydrochloridu a (R)-mandlové kyseliny a její farmaceutická kompozice |
WO2016102423A1 (en) | 2014-12-22 | 2016-06-30 | Ratiopharm Gmbh | Composition comprising ivabradine in a dissolved form |
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 |
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EP3366282A1 (en) | 2017-02-28 | 2018-08-29 | 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 |
IT202000025312A1 (it) | 2020-10-26 | 2022-04-26 | Cambrex Profarmaco Milano S R L | Processi per la preparazione di polimorfi di ivabradina hcl |
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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 |
GB9017453D0 (en) | 1990-08-09 | 1990-09-26 | Mcivor Robert C | Fluid additive regulating apparatus |
FR2681862B1 (fr) * | 1991-09-27 | 1993-11-12 | Adir Cie | Nouvelles (benzocycloalkyl)alkylamines, leur procede de preparation, et les compositions pharmaceutiques qui les contiennent. |
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 |
CA2504863A1 (en) * | 2005-04-21 | 2006-10-21 | Larry J. Chernoff | Integrated valve system |
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