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TW201008901A - New process for obtaining the crystalline form V of agomelatine - Google Patents

New process for obtaining the crystalline form V of agomelatine Download PDF

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TW201008901A
TW201008901A TW098126203A TW98126203A TW201008901A TW 201008901 A TW201008901 A TW 201008901A TW 098126203 A TW098126203 A TW 098126203A TW 98126203 A TW98126203 A TW 98126203A TW 201008901 A TW201008901 A TW 201008901A
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agomelatine
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Damien Martins
Gerard Coquerel
Julie Linol
Pascal Langlois
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Servier Lab
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Description

201008901 六、發明說明： 【發明所屬之技術領域】 本發明係關於一種獲得式⑴的阿戈美拉汀（或N-[2-(7-甲 氧基-1-萘基）乙基]乙醯胺）晶形V之新穎方法：
【先前技術】 阿戈美拉汀（或N-[2-(7-曱氧基-i_萘基）乙基]乙醯胺）具有 有價值的藥理學性質。 實際上，其具有一方面為褪黑素能系統受體的激動劑且 另一方面為5 -HTjc受體的拮抗劑之雙重特徵。此等性質使 其於中樞神經系統中具有活性，且尤其用於治療重度抑鬱 症、季節性情緒失調、睡眠障礙、心血管病症、消化系統 病症、因時差引起的失眠與疲勞、食慾失調與肥胖。 阿戈美拉>丁、其製備與其在治療中之用途已在歐洲專利 EP 0 447 285 中闡述。 鑒於該化合物的醫藥價值，最重要的在於要以優異純度 且尤其係以可完全再現的形式獲料，該彳再現形式具有 使其可長期儲存而對溫度、&、濕度或含氧量無特定需求 的有價值特徵。 ，專利申請案EP 1 752 443闡述一種阿戈美拉汀之明確晶 形(晶形V)’其特徵在於其之以下的χ射線粉末繞射圖， 其係利用Siemens D5005繞射儀（銅對陰極）測量且以晶面間 142205.doc 201008901 距4、布拉格（Bragg)角2Θ、及相對強度（以相對於最強線的 百分比表示）表示： 2-θ(°) 實驗值 d(A) 實驗值 強度 (%) 9.84 8.979 17 12.40 7.134 15 13.31 6.646 19 15.14 5.848 18 15.98 5.543 18 16.62 5.329 19 17.95 4.939 100 18.88 4.697 65 20.49 4.332 24 20.99 4.228 34 23.07 3.852 39 23.44 3.792 36 24.28 3.663 58 25.10 3.545 19 26.02 3.422 15 26.82 3.322 19 27.51 3.239 16 以可再現方式獲得的該明確晶形具有非常有價值的形態 性質’尤其其具有比其他所述形式大很多的比表面積。但 是’其隨時間經過的安定性相當短’且在所有情況中小於 6個月。 申請者如今已發展出一種以可完全再現之方式獲得阿戈 美拉汀晶形V之新穎方法，藉此增加其隨時間之安定性。 因此，該新穎方法可獲得具有適合其醫藥用途之性質的阿 戈美拉汀晶形V。過去僅可藉由所謂的「高能」研磨或藉 由利用由研磨獲得的該結構純淨形式播種得到晶形ν。迄 今申請者已驚人地發現可藉由喷霧乾燥獲得該形式。實際 上’喷霧乾燥為一種常用於獲得小尺寸固體顆粒的技術。 通常，所得物質為無定型的（Amorphous state. 142205.doc -4 - 201008901
Polymorphism in pharmaceutical industry, R. Hilfiker 編
輯，Wiley-VCH Weinheim 2006，第 X章，259-285 頁，S
Petit及G. Coquerel)。相對地，在本發明中，喷霧乾燥可獲 得明確晶形（形V)，且其隨時間具有更佳安定性。 【發明内容】 更明確而言，本發明係關於一種獲得式（1)阿戈美拉汀晶 心V之新顆方法’該方法特徵在於使溶於一種或可以任何 比例混合的兩種溶劑中且沸點小於！ 2〇°c之阿戈美拉汀溶 籲 液在喷霧乾燥器中霧化。 【實施方式】 喷霧乾燥為一種常用於農業、食品與醫藥部門以乾燥喷 霧通過熱氣體之溶液之技術。實際上，用於乾燥溶液的氣 體為空氣’但某些使用有機溶劑的醫藥製造方法需要惰性 氣體作爲乾燥氣體’進而避免某些分解過程。 較佳藉由嘴霧乾燥器進行根據本發明之結晶操作。根據 0 本發明之霧化甚至更佳係根據霧化原理利用具有平行流且 更佳具有並向流（即喷霧溶液與乾燥氣體係以相同方向流 動）之喷嘴進行。 所用氣趙最佳為壓縮空氣或惰性氣體，例如氮氣。 用於根據本發明之方法的較佳溶劑為乙醇、水、異丙 趟甲醇、乙酸乙醋或丙嗣。 所用的阿戈拉美汀溶液之最低濃度為5 g/1且使用1〇 g/1 溶液更佳。 根據本發明之方法的入口溫度最佳為70。(：至120°C。 142205.doc 201008901 在根據本發明之結晶方法令，可使用由任何方法獲得的 式（I)阿戈美拉汀。 以下實例闡述本發明，但不以任何方式作限制。 貧例ί : ν·[2-(7_甲氧基小萘基）乙基】乙醯胺之晶形v 將10 g/1的阿戈美拉汀之乙醇/異丙醚混合物（5〇/5〇:ν/ν) 溶液引入BUCHI 190迷你噴霧乾燥器型之霧化器中。乾燥 室之入口溫度為90。。，且出口溫度為66。。。將霧化粉末回 收在收集碗中且其特徵在於以下結晶數據： 1) 利用具有3。-30。之2Θ角度範圍、每步〇〇4。且每步4 3的 Siemens D5005繞射儀獲得的圖： •單位晶胞之晶體結構：單斜晶 -單位晶胞參數：a=11.967 A，b=17.902 A，c=15.423 A，β=124.50 -空間群：P2,/!! -單位晶胞内之分子數：8(Ζ·=2) -單位晶胞體積：V單ufSTSO.OA3 2) 以下的X·射線粉末繞射圖’其係利用Sieinens D5005繞 射儀（銅對陰極）測量且以晶面間距d、布拉格角2 Θ、與相對 強度（以相對於最強線的百分比表示）表示： 2-θ(°) 實驗值 d(A) 實驗值 強度 (%) 2-Θ (°) 計算值 9.84 8.979 17 9.85 12.40 7.134 15 12.46 13.31 6.646 19 13.33 15.14 5.848 18 15.16 15.98 5.543 18 15.91 16.62 5.329 19 16.66 17.95 4.939 100 17.96 142205.doc -6- 201008901 4.697 65 18.93 4.332 24 20.52 4.228 34 20.99 3.852 39 23.11 3.792 36 23.48 3.663 58 24.27 3.545 19 25.18 3.422 15 26.02 3.322 19 26.85 3.239 16 27.56 實例2 ·藉由赛化Ν·【2(7甲氧基p茶基）己基】己嫌坡得到 的县形V之致時間的安定性 18.88 20.49 20.99 23.07 23.44 24.28 25.10 26.02 26.82 27.51 將1 g實例1中獲得的化合物樣品置於慣用儲存條件下： 環境壓力與室温。2!個月後，所得樣品之繞射圖未變化且 保留所得晶形V之特徵。
142205.doc

Claims (1)

  1. 201008901 、 七、申請專利範圍： 1. 一種獲得式（I)之阿戈美拉汀晶形V之方法：
    其特徵在於使已溶於一種或可以任意比例混合的兩種溶 劑中且沸點小於120°c的阿戈美拉汀溶液在喷霧乾燥器 中霧化。 ❹ 2.如請求項1之獲得式（I)之阿戈美拉汀晶形V之方法，其特 徵在於所得晶形V具有以下的X-射線粉末繞射圖，其係 利用Siemens D5005繞射儀（銅反陰極）測量且以晶面間距 d、布拉格（Bragg)角2Θ、及相對強度（以相對於最強線的 百分比表示）表示： 2-θ(°) 實驗值 d(A) 實驗值 強度 (%) 2-Θ (。） 計算值 9.84 8.979 17 9.85 12.40 7.134 15 12.46 13.31 6.646 19 13.33 15.14 5.848 18 15.16 .15.98 5.543 18 15.91 16.62 5.329 19 16.66 17.95 4.939 100 17.96 18.88 4.697 65 18.93 20.49 4.332 24 20.52 20.99 4.228 34 20.99 23.07 3.852 39 23.11 23.44 3.792 36 23.48 24.28 3.663 58 24.27 25.10 3.545 19 25.18 26.02 3.422 15 26.02 26.82 3.322 19 26.85 27.51 3.239 16 27.56 142205.doc 201008901 其特 其特 其特 3_如請求項1之獲得式（I)之阿戈美拉汀晶形v之方法 徵在於所用溶劑為乙醇與異丙醚。 4. 如請求項1之獲得式（I)之阿戈美拉汀晶形v之方法 徵在於所用氣體為氮氣。 5. 如請求項1之獲得式（I)之阿戈美拉汀晶形v之方& 徵在於所用阿戈美拉汀溶液之最小濃度為5 g/l ^ 142205.doc 201008901 四、指定代表圈： (一) 本案指定代表圖為：（無） (二) 本代表圖之元件符號簡單說明： 五、本案若有化學式時，請揭示最能顯示發明特徵的化學式：
    NHCOMe MeO
    (I) 142205.doc
TW098126203A 2008-08-05 2009-08-04 New process for obtaining the crystalline form V of agomelatine TW201008901A (en)

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FR0804466A FR2934856B1 (fr) 2008-08-05 2008-08-05 Nouveau procede d'obtention de la forme cristalline v de l'agomelatine

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EP2705023A4 (en) * 2011-01-04 2014-11-19 Symed Labs Ltd PROCESSES FOR THE PREPARATION OF N- [2- (7-METHOXY-1-NAPHTHYLLELYHYL) ACETAMIDE
WO2012130837A1 (en) 2011-03-28 2012-10-04 Ratiopharm Gmbh Solid agomelatine in non-crystalline form
EP2872129B1 (en) 2012-07-16 2017-03-08 ratiopharm GmbH Complex of agomelatine and cyclodextrin
WO2015124496A1 (en) 2014-02-19 2015-08-27 Synthon B.V. Pharmaceutical composition comprising amorphous agomelatine

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FR2866335B1 (fr) * 2004-02-13 2006-05-26 Servier Lab Nouveau procede de synthese de l'agomelatine
FR2889522B1 (fr) * 2005-08-03 2007-12-28 Servier Lab Nouvelle forme cristalline iv de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent
FR2889523B1 (fr) * 2005-08-03 2007-12-28 Servier Lab Nouvelle forme cristalline v de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent
FR2889521B1 (fr) * 2005-08-03 2007-12-28 Servier Lab Nouvelle forme cristalline iii de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent
WO2008141033A1 (en) * 2007-05-08 2008-11-20 Auspex Pharmaceuticals Inc. Substituted naphthalenes
FR2923482B1 (fr) * 2007-11-09 2010-01-29 Servier Lab Nouvelle forme cristalline vi de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent

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