TWI314143B - Crystalline form of ivabradine hydrochloride, a process for its preparation and pharmaceutical compositions containing it - Google Patents

Crystalline form of ivabradine hydrochloride, a process for its preparation and pharmaceutical compositions containing it Download PDF

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TWI314143B
TWI314143B TW095105986A TW95105986A TWI314143B TW I314143 B TWI314143 B TW I314143B TW 095105986 A TW095105986 A TW 095105986A TW 95105986 A TW95105986 A TW 95105986A TW I314143 B TWI314143 B TW I314143B
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ivabradine hydrochloride
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Stephane Horvath
Marie-Noelle Auguste
Gerard Damien
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Servier Lab
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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
    • G—PHYSICS
    • G04—HOROLOGY
    • G04F—TIME-INTERVAL MEASURING
    • G04F1/00—Apparatus which can be set and started to measure-off predetermined or adjustably-fixed time intervals without driving mechanisms, e.g. egg timers
    • G04F1/04—Apparatus which can be set and started to measure-off predetermined or adjustably-fixed time intervals without driving mechanisms, e.g. egg timers by movement or acceleration due to gravity
    • G04F1/06—Apparatus which can be set and started to measure-off predetermined or adjustably-fixed time intervals without driving mechanisms, e.g. egg timers by movement or acceleration due to gravity by flowing-away of a prefixed quantity of fine-granular or liquid materials, e.g. sand-glass, water-clock
    • 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
    • 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
    • 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
    • H—ELECTRICITY
    • H04—ELECTRIC COMMUNICATION TECHNIQUE
    • H04L—TRANSMISSION OF DIGITAL INFORMATION, e.g. TELEGRAPHIC COMMUNICATION
    • H04L51/00—User-to-user messaging in packet-switching networks, transmitted according to store-and-forward or real-time protocols, e.g. e-mail
    • H04L51/21—Monitoring or handling of messages
    • H04L51/214—Monitoring or handling of messages using selective forwarding
    • H—ELECTRICITY
    • H04—ELECTRIC COMMUNICATION TECHNIQUE
    • H04L—TRANSMISSION OF DIGITAL INFORMATION, e.g. TELEGRAPHIC COMMUNICATION
    • H04L51/00—User-to-user messaging in packet-switching networks, transmitted according to store-and-forward or real-time protocols, e.g. e-mail
    • H04L51/21—Monitoring or handling of messages
    • H04L51/212—Monitoring or handling of messages using filtering or selective blocking

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  • Heart & Thoracic Surgery (AREA)
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  • Hospice & Palliative Care (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
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  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

1314143 九、發明說明： 【發明所屬之技術領域】 本土明係關於化學式⑴之依伐布雷定鹽酸鹽之新型丫_結 晶型、其製備方法及含彼之醫藥組合物。
.HCI 【先前技術】
依伐布f定及其與醫㈣上可接受之酸之加成鹽（且更 尤其為其鹽酸鹽）’具有極富價值之藥理及治療特性(尤其 心動減緩特性|而使彼等化合物適用於治療或預防二 肌缺血之各種臨床表現，諸如心絞痛、錢梗塞及相關之 心律紊亂’且亦適用於治療或預防涉及心律聽，尤其室 上性心律紊亂之各種病狀及心臟衰竭。 依伐布雷定及其與醫藥學上可接受之酸之加成鹽（且更 尤其為其鹽酸鹽）的製備及治療用途已描述於歐洲專利說 明書 EP 〇 534 859 中。 鑒於此化合物之醫藥價值，獲得具有極高純度之該化合 物已為最重要的。亦為重要的是，能夠藉助可容易地轉化 為工業規模之方法合成（尤其）允許快速過濾及乾燥之形態 的該化合物。最後，該形態必須為極佳地可再現的，易於 調配且足夠穩定以使其不需要溫度、光線或氧含量之特殊 108741.doc 1314143 要求而長期儲存。 專利說明書EP 〇 534 859描述依伐布杂宕 八 ，田疋及其鹽酸鹽之 ° Μ法 '然而，該文獻並未缺用於獲得以再㈣H 展示該等特徵之形態之依伐布雷定的條件。 " 【發明内容】 本申請者現已發現，依伐布雷定之特定鹽（鹽酸鹽）可以 結晶型獲得，該結晶型係經良好界定且展示有價值之穩定 I*生及加工性能之特徵。
更具體s之，本發明係關於依伐布雷定鹽酸鹽之γ_結晶 型，其由如下之粉末X-射線繞射圖表徵，其中該粉末 線繞射圖係使用一PANalytical x，Pert Pro繞射儀與— X'Celerator偵測器一起量測且依據射線位置（布拉格 (Bragg)角2Θ，以度數表示）、射線高度（以計數表示广射 線面積（以計數X度數表示）、半高射線寬度（"FWhm'，，以 度數表示）及晶面間距d(以A表示）表示： 射線序號 角 2Θ (度數） 高度 (計數） 面積 (計數X 度數） FWHM (度數） 晶面間距 (A) 1 4.2 1456 144 0.1004 20.762 2 6.9 125 99 0.8029 12.880 3 8.4 182 18 0.1004 10.503 4 10.7 240 32 0.1338 8.249 5 11.3 74 15 0.2007 7.858 6 12.0 644 64 0.1004 7.392 108741.doc 1314143 射線序號 角 2Θ (度數） 高度 (計數） 面積 (計數X 度數） FWHM (度數） 晶面間距 (A) 7 12.5 1476 219 0.1506 7.060 8 13.4 2691 400 0.1506 6.612 9 14.5 541 80 0.1506 6.119 10 14.8 104 17 0.1673 5.981 11 15.9 815 67 0.0836 5.559 12 16.3 501 74 0.1506 5.419 13 17.0 1168 154 0.1338 5.210 14 17.9 430 43 0.1004 4.962 15 19.0 667 121 0.184 4.672 16 19.8 527 104 0.2007 4.483 17 20.2 726 144 0.2007 4.392 18 20.5 282 28 0.1004 4.323 19 21.1 2255 260 0.1171 4.208 20 21.4 694 68 0.1004 4.147 21 21.6 744 86 0.1171 4.111 22 22.3 175 35 0.2007 3.987 23 23.5 310 61 0.2007 3.784 24 24.2 1635 270 0.1673 3.683 25 24.5 1335 220 0.1673 3.625 26 24.9 523 95 0.184 3.568 27 25.5 657 130 0.2007 3.485 28 26.0 933 154 0.1673 3.431 10874】.doc 1314143 350 本發明亦係關於 高度 (計數) 面積 (計數X 度數） FWHM (度數） 晶面間距 (A) 230 0.1506 3.380 83 0.2007 3.323 69 0.2007 3.267 146 0.1338 3.186 19 0.1338 3.066 2 «亥方法之特徵在於將依伐布雷定鹽酸鹽與2_乙氧 基乙醇之混合物，佑我女 依伐布雷定鹽酸鹽、2·乙氧基乙醇盥水 之混合物或依伐布μ鹽酸鹽、乙醇與水之現合物加埶直 至完全溶解且接著將其冷卻直至完全結晶，且藉由過滤收 集產物η •在根據本發明之結晶方 * τ 」1史用以任何方法獲得之 依伐布雷定鹽酸鹽’例如藉由描述於專利說明書 ΕΡ 〇 534 859中之製備方法所獲得之依伐布雷定鹽酸鹽。 •可有利地於冷卻步驟期間接種該溶液。 本發明亦係關於包含作為活性成分之依伐布雷定鹽酸鹽 之γ-結晶型與一或多種適當、惰性、無毒 -呢形劑的醫藥 組合物。在根據本發明之醫藥組合物中， ' 灵尤其提及適用 於口服、非經腸(靜脈内或皮下)或鼻投藥、徒劑或糖衣華 丸、舌下鍵劑、明膠勝囊、口含劑、掩劑、乳膏、軟膏、 皮用凝膠（dermal gels)、可注射製劑、可私 坎用懸浮液之彼 等醫藥組合物。 & 108741.doc 1314143 適用劑量可根據病症之性質及嚴重性、投藥途徑及患者 之年齡及體重而加以變化。該劑量在每天一或多次投予i 至5 00 mg之間變化。 【實施方式】 下列實例說明本發明。 X-射線粉末繞射光譜係於下列實驗條件下量測： _ PANalytical XTert 巧〇繞射儀、x，Celerat〇r偵測器、溫 度調節腔室， -電壓45 kV，強度40 mA， -座架Θ-Θ， -鎳（Κβ)濾光片， -入射光束及繞射光束索勒狹縫（s〇Uer sUt) : 〇〇4拉德 (rad)， -發散狹缝之定角：1/8。， -遮罩：1 〇 mm， -反散射狹縫：1/4。， -量測模式：自3。至30。連續測量，增量為〇 〇17。， -每步驟之量測時間：19.7 s， -總時間：4 min 32 s， -量測速度：0.1 08Vs， -量測溫度：周圍溫度。 實例1 :依伐布雷定鹽酸鹽之結晶型 將40 ml 2-乙氧基乙醇預熱至8〇c，且接著伴隨攪拌將 8·4 g根據描述於專利說明書EP 〇 534 Μ9Φ夕古ία公 丁疋·万法所獲得 108741.doc -10- 1314143 • 之依伐布雷定鹽酸鹽以分成若干部分之方式加入，且於 80°C加熱該混合物直至完全溶解。在使該溶液返回周圍溫 度之後，將其儲存8日，且接著藉由過濾收集所形成之晶 體且用環己烷沖洗其。 所得晶體之水含量（藉由庫化分析法測定）為3.5 %，其對 應於單水合物。 X-射線粉末繞射圖’·
依伐布雷定鹽酸鹽之γ-型之X-射線粉末繞射分布（繞射 角）由整理於下表中之有效射線給出： 射線序號 角 2Θ (度數） 高度 (計數） 面積 (計數X 度數） FWHM (度數） 晶面間距 (Α) 1 4.2 1456 144 0.1004 20.762 2 6.9 125 99 0.8029 12.880 3 8.4 182 18 0.1004 10.503 4 10.7 240 32 0.1338 8.249 5 11.3 74 15 0.2007 7.858 6 12.0 644 64 0.1004 7.392 7 12.5 1476 219 0.1506 7.060 8 13.4 2691 400 0.1506 6.612 9 14.5 541 80 0.1506 6.119 10 14.8 104 17 0.1673 5.981 11 15.9 815 67 0.0836 5.559 12 16.3 501 74 0.1506 5.419 108741.doc -11 - 1314143 射線序號 角 2Θ (度數） 南度 (計數） 面積 (計數X 度數） FWHM (度數） 晶面間距 (A) 13 17.0 1168 154 0.1338 5.210 14 17.9 430 43 0.1004 4.962 15 19.0 667 121 0.184 4.672 16 19.8 527 104 0.2007 4.483 17 20.2 726 144 0.2007 4.392 18 20.5 282 28 0.1004 4.323 19 21.1 2255 260 0.1171 4.208 20 21.4 694 68 0.1004 4.147 21 21.6 744 86 0.1171 4.111 22 22.3 175 35 0.2007 3.987 23 23.5 310 61 0.2007 3.784 24 24.2 1635 270 0.1673 3.683 25 24.5 1335 220 0.1673 3.625 26 24.9 523 95 0.184 3.568 27 25.5 657 130 0.2007 3.485 28 26.0 933 154 0.1673 3.431 29 26.4 1549 230 0.1506 3.380 30 26.8 419 83 0.2007 3.323 31 27.3 350 69 0.2007 3.267 32 28.0 1108 146 0.1338 3.186 33 29.1 144 19 0.1338 3.066 實例2 :醫藥組合物 108741.doc -12· 1314143 用於製備1 〇〇〇錠各含5 mg依伐布雷定基礎物質之錠劑之 配方： 實例1之化合物...................................................5.39 g 玉米澱粉.......................................................... 20 g 無水矽膠...........................................................〇.2 g 甘露糖醇........................................................63.91 g PVP.................................................................... 10 g 硬脂酸鎂...........................................................0.5 g 108741.doc -13 -

Claims (1)

1314143 . 十、申請專利範圍： 曰曰 1. 一種化學式（I)之依伐布雷定（ivabradine)鹽酸鹽之γ-結 型：
och3 och3 .HC1
射 格 射 以 其係由如下之粉末X-射線繞射圖表徵，其中該粉末X· 線繞射圖係使用一 PANalytical X'Pert Pro繞射儀與 X’Celerator彳貞測器一起量測且依據射線位置（布拉 (Bragg)角2Θ，以度數表示）、射線高度（以計數表示）、 線面積（以計數X度數表示）、半高射線寬度（"FWHM"， 度數表示）及晶面間距d(以A表示）表示： 射線序號 角 2Θ (度數） 高度 (計數） 面積 (計數X 度數） FWHM (度數） 晶面間距 (A) 1 4.2 1456 144 0.1004 20.762 2 6.9 125 99 0.8029 12.880 3 8.4 182 18 0.1004 10.503 4 10.7 240 32 0.1338 8.249 5 11.3 74 15 0.2007 7.858 6 12.0 644 64 0.1004 7.392 7 12.5 1476 219 0.1506 7.060 8 13.4 2691 400 0.1506 6.612 108741.doc 1314143 射線序號 角 2Θ (度數） 焉度 (計數） 面積 (計數x 度數） FWHM (度數） 晶面間距 (A) 9 14.5 541 80 0.1506 6.119 10 14.8 104 17 0.1673 5.981 11 15.9 815 67 0.0836 5.559 12 16.3 501 74 0.1506 5.419 13 17.0 1168 154 0.1338 5.210 14 17.9 430 43 0.1004 4.962 15 19.0 667 121 0.184 4.672 16 19.8 527 104 0.2007 4.483 17 20.2 726 144 0.2007 4.392 18 20.5 282 28 0.1004 4.323 19 21.1 2255 260 0.1171 4.208 20 21.4 694 68 0.1004 4.147 21 21.6 744 86 0.1171 4.111 22 22.3 175 35 0.2007 3.987 23 23.5 310 61 0.2007 3.784 24 24.2 1635 270 0.1673 3.683 25 24.5 1335 220 0.1673 3.625 26 24.9 523 95 0.184 3.568 27 25.5 657 130 0.2007 3.485 28 26.0 933 154 0.1673 3.431 29 26.4 1549 230 0.1506 3.380 30 26.8 419 83 0.2007 3.323 108741.doc 1314143
3. 士叫求項2之方法，其特徵在於於該冷卻 該依伐布雷定鹽酸鹽之溶液。 步驟期間接種 4. 一種醫藥組合物，其包含你成、M +八 匕3作為活性成分之如請求項i之 依伐布雷定鹽酸鹽的紝曰 ..._ 、 J γ、，D日日型組合一或多種醫藥學上可 接受、惰性、無毒之載劑。 5. 一種如請求項1之依伐布雷定鹽酸鹽之γ_結晶型於製造醫 藥品的用途，該等醫藥品係用作心動減緩劑。 6. 一種如請求項1之依伐布雷定鹽酸鹽之γ_結晶型於製造醫 藥品的用途，該等醫藥品係用於治療或預防心肌缺血之 各種臨床表現，諸如心絞痛、心肌梗塞及相關之心律紊 亂，且亦係用於治療或預防涉及心律紊亂，尤其室上性 心律紊亂之各種病狀及心臟衰竭。 108741.doc
TW095105986A 2005-02-28 2006-02-22 Crystalline form of ivabradine hydrochloride, a process for its preparation and pharmaceutical compositions containing it TWI314143B (en)

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FR0501989A FR2882555B1 (fr) 2005-02-28 2005-02-28 Forme cristalline gamma du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutiques qui la contiennent

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