TWI801421B - 結晶 - Google Patents
結晶 Download PDFInfo
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- TWI801421B TWI801421B TW107134006A TW107134006A TWI801421B TW I801421 B TWI801421 B TW I801421B TW 107134006 A TW107134006 A TW 107134006A TW 107134006 A TW107134006 A TW 107134006A TW I801421 B TWI801421 B TW I801421B
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Abstract
本發明之主要目的在於提供一種2-{4-[N-(5,6-二苯基吡𠯤-2-基)-N-異丙基胺基]丁氧基}乙酸(以下稱作「化合物B」)之新穎結晶。
本發明提供一種化合物B之I型結晶,其於使用Cu Kα放射線(λ=1.54Å)而得之粉末X射線繞射光譜中,於繞射角(2θ)為6.4度、8.1度、9.5度、10.9度、13.2度、15.7度、17.0度、19.5度、20.3度、21.0度及22.8度之繞射角顯示波峰。
本發明提供一種化合物B之II型結晶,其於使用Cu Kα放射線(λ=1.54 Å)而得之粉末X射線繞射光譜中,於繞射角(2θ)為9.6度、11.4度、11.7度、16.3度、17.5度、18.5度、18.7度、19.9度、20.1度、21.0度及24.6度之繞射角顯示波峰。
Description
醫藥品需要於各種流通或保管等條件下亦長時間地保持品質。因此,要求作為有效成分之化合物有較高物理化學穩定性。因此,醫藥品之有效成分一般採用可期待高穩定性之結晶。
於篩選醫藥品之有效成分之結晶之過程中,大多不僅難以找出用於獲得結晶之最佳條件,且即便獲得結晶之情形時,亦經常有存在多晶型之問題。該問題起因於物理化學穩定性因結晶形而異。
又,若作為醫藥品之有效成分所採用之結晶形之選擇錯誤,則根據保管時之外部環境,會發生純度下降、結晶形轉變等,難以將化合物維持於一定品質,因此根據不同結晶形,會導致藥效降低或副作用等難以預料之事態。因此,於成功取得作為醫藥品之有效成分之化合物之結晶之情形時,關於其多晶型,需要進行嚴密之物理化學穩定性之評價研究。
然而,不可能根據化合物之結構預測多晶型之有無或穩定之結晶形,進而亦有存在不能形成結晶之化合物之情形,需要對每種化合物形成結晶之條件進行各種研究。
另一方面,眾所周知化合物B具有優異之PGI2受體激動作用,顯示出血小板凝聚抑制作用、血管擴張作用、支氣管肌擴張作用、脂質沈積抑制作用、白血球活化抑制作用等多種藥效(例如,參照專利文獻1-6),但現狀為仍然不知多晶型是否存在,甚至不知究竟能否形成結晶,最佳之結晶之取得於開發作為醫藥品之方面成為重要課題。
[先前技術文獻]
[專利文獻]
[專利文獻1]國際公開第2002/088084號
[專利文獻2]國際公開第2009/157396號
[專利文獻3]國際公開第2009/107736號
[專利文獻4]國際公開第2009/154246號
[專利文獻5]國際公開第2009/157397號
[專利文獻6]國際公開第2009/157398號
[專利文獻7] US2014/0221397
[專利文獻8] US2011/0178103
[專利文獻9] US2011/0015211
[專利文獻10] US2011/0118254
[專利文獻11] US2011/0105518
[非專利文獻]
[非專利文獻1] Hepatology, 2007, Vol. 45, No. 1, p. 159 – 169.
[非專利文獻2] PubMed : Nihon Yakurigaku Zasshi, 2001, Feb, 117 (2), p. 123 - 130, Abstract.
[非專利文獻3] International Angiology, 29, Suppl. 1 to No. 2, p. 49 - 54, 2010.
[非專利文獻4] Japanese Journal of Clinical Immunology, Vol. 16, No. 5, p. 409 - 414, 1993.
[非專利文獻5] Japanese Journal of Thrombosis and Hemostasis, Vol. 1, No. 2, p. 94 - 105, 1990, Abstract.
[非專利文獻6] The Journal of Rheumatology, Vol. 36, No. 10, p. 2244 - 2249, 2009.
[非專利文獻7] The Japanese Journal of Pharmacology, Vol. 43, No. 1, p. 81 - 90, 1987.
[非專利文獻8] British Heart Journal, Vol. 53, No. 2, p. 173 - 179, 1985.
[非專利文獻9] The Lancet, 1, 4880, pt 1, p. 569 - 572, 1981.
[非專利文獻10] European Journal of Pharmacology, 449, p. 167 - 176, 2002.
[非專利文獻11] The Journal of Clinical Investigation, 117, p. 464 - 72, 2007.
[非專利文獻12] American Journal of Physiology Lung Cellular and Molecular Physiology, 296 : L648 - L656, 2009.
[發明所欲解決之問題]
本發明之目的在於提供一種物理化學穩定性優異之化合物B之結晶以及提供含有該結晶作為有效成分之醫藥組合物。
[解決問題之技術手段]
化合物B之製造方法揭示於專利文獻1之實施例42中。然而,於專利文獻1之實施例42中,並未明示獲得了何種形態之化合物B。
因此,本發明人嘗試利用與專利文獻1之實施例42中所揭示之方法相同之順序製造化合物B,判明其形態為結晶(以下稱作「III型結晶」)(參照後述參考例1)。該III型結晶之粉末X射線繞射之測定、IR測定及DSC測定之結果分別示於圖1、圖2及圖3。
然而,如後述試驗例1所示,判明III型結晶之熱力學不穩定,故而本發明人為了解決上述課題而反覆進行了銳意研究,結果發現存在熱力學上更加穩定之I型結晶及II型結晶,從而完成本發明。
作為本發明,可列舉例如下述(1)~(7)。
(1)於使用Cu Kα放射線(λ=1.54Å)而得之粉末X射線繞射光譜中,於繞射角(2θ)為6.4度、8.1度、9.5度、10.9度、13.2度、15.7度、17.0度、19.5度、20.3度、21.0度及22.8度顯示繞射峰的化合物B之I型結晶(以下稱作「本發明I型結晶」)
(2)於紅外線吸收光譜中,於波數為2874 cm-1
、1736 cm-1
、1558 cm-1
、1375 cm-1
、1126 cm-1
及696 cm-1
顯示吸收峰之本發明I型結晶
(3)於示差掃描熱量測定中,具有127℃之吸熱峰之本發明I型結晶
(4)於使用Cu Kα放射線(λ=1.54Å)而得之粉末X射線繞射光譜中,於繞射角(2θ)為9.6度、11.4度、11.7度、16.3度、17.5度、18.5度、18.7度、19.9度、20.1度、21.0度及24.6度顯示繞射峰之化合物B之II型結晶(以下稱作「本發明II型結晶」)
(5)於紅外線吸收光譜中,於波數為2867 cm-1
、1749 cm-1
、1568 cm-1
、1382 cm-1
、1131 cm-1
及701 cm-1
顯示吸收峰之本發明II型結晶
(6)於示差掃描熱量測定中,具有147℃之吸熱峰之本發明II型結晶
(7)含有如(1)至(6)中任一項所記載之結晶作為有效成分之醫藥組合物(以下稱作「本發明醫藥組合物」)
於對本發明之實施例及申請專利範圍中之繞射峰之繞射角2θ進行特定時,應理解所得值設定為該值±0.2度之範圍內,較佳設定為該值±0.1度之範圍內。
又,於對本發明之實施例及申請專利範圍中之紅外線吸收光譜(以下稱作「IR光譜」)之吸收峰進行特定時,應理解所得值設定為該值±2 cm-1
之範圍內,較佳設定為該值±1 cm-1
之範圍內。
又,於對本發明之實施例及申請專利範圍中之示差掃描熱量測定(以下稱作「DSC」)之吸熱峰進行特定時,應理解所得值設定為該值±3℃之範圍內,較佳設定為該值±2℃之範圍內。
A. 本發明 I 型結晶
本發明I型結晶之特徵在於:於使用Cu Kα放射線(λ=1.54Å)而得之粉末X射線繞射光譜中,於繞射角(2θ)為6.4度、8.1度、9.5度、10.9度、13.2度、15.7度、17.0度、19.5度、20.3度、21.0度及22.8度顯示繞射峰。又,較佳為特徵在於除上述繞射峰以外,亦於15.8度、17.2度、21.9度、23.7度、24.5度、25.5度、25.8度、28.9度及32.0度顯示繞射峰。
又,本發明I型結晶之特徵在於:於IR光譜(KBr法)中,於波數為2874 cm-1
、1736 cm-1
、1558 cm-1
、1375 cm-1
、1126 cm-1
及696 cm-1
顯示吸收峰。
又,本發明I型結晶之特徵在於:於示差掃描熱量測定中,具有127℃之吸熱峰。
本發明I型結晶可利用例如後述之實施例1中所記載之方法獲得。
B. 本發明 II 型結晶
本發明II型結晶之特徵在於:於使用Cu Kα放射線(λ=1.54Å)而得之粉末X射線繞射光譜中,於繞射角(2θ)為9.6度、11.4度、11.7度、16.3度、17.5度、18.5度、18.7度、19.9度、20.1度、21.0度及24.6度顯示繞射峰。又,較佳為特徵在於除上述繞射峰以外,亦於19.4度、20.6度、21.1度、21.7度、22.7度、26.6度、26.7度、28.8度及30.8度顯示繞射峰。
又,本發明II型結晶之特徵在於:於IR光譜(KBr法)中,於波數為2867 cm-1
、1749 cm-1
、1568 cm-1
、1382 cm-1
、1131 cm-1
及701 cm-1
顯示吸收峰。
又,本發明II型結晶之特徵在於:於示差掃描熱量測定中,具有147℃之吸熱峰。
本發明II型結晶可利用例如後述之實施例2中所記載之方法獲得。
C. 醫藥用途、本發明醫藥組合物
本發明之化合物B具有優異之PGI2受體激動作用,顯示出血小板凝聚抑制作用、血管擴張作用、支氣管肌擴張作用、脂質沈積抑制作用、白血球活化抑制作用等各種藥效(例如參照專利文獻1)。
因此,本發明I型結晶、本發明II型結晶(以下總稱為「本發明結晶」)或本發明醫藥組合物有效用作短暫性腦缺血發作(TIA)、糖尿病性神經病變(例如參照非專利文獻1)、糖尿病性壞疽(例如參照非專利文獻1)、末梢循環障礙[例如慢性動脈阻塞症(例如參照非專利文獻2)、間歇性跛行(例如參照非專利文獻3)、末梢動脈栓塞症、振動病、雷諾氏病](例如參照非專利文獻4、非專利文獻5)、膠原病[例如全身性紅斑狼瘡、硬皮病(例如參照專利文獻7、非專利文獻6)、混合性結締組織病、血管炎症候群]、經皮腔內冠狀動脈成形術(PTCA)後之再阻塞/再狹窄、動脈硬化症、血栓症(例如急性期腦血栓症、肺栓塞症)(例如參照非專利文獻5、非專利文獻7)、高血壓、肺高血壓、缺血性疾病[例如腦梗塞、心肌梗塞(例如參照非專利文獻8)]、狹心症(例如穩定狹心症、不穩定狹心症)(例如參照非專利文獻9)、絲球體腎炎(例如參照非專利文獻10)、糖尿病性腎病(例如參照非專利文獻1)、慢性腎功能衰竭(例如參照專利文獻8)、過敏、支氣管哮喘(例如參照非專利文獻11)、潰瘍、褥瘡(bedsore)、動脈粥樣硬化切除術及支架置放術等冠狀動脈介入後之再狹窄、由透析引起之血小板減少、與器官或組織之纖維化相關之疾病[例如腎臟疾病{例如腎小管間質性腎炎(例如參照專利文獻9)}、呼吸道疾病{例如間質性肺炎(例如肺纖維化症)(例如參照專利文獻9)、慢性阻塞性肺病(例如參照非專利文獻12)}、消化器官疾病(例如肝硬化、病毒性肝炎、慢性胰臟炎、硬性胃癌)、心血管疾病(例如心肌纖維化症)、骨・關節疾病(例如骨髓纖維化症、類風濕性關節炎)、皮膚疾病(例如手術後之瘢痕、燙傷性瘢痕、蟹足腫、肥厚性瘢痕)、產科疾病(例如子宮肌瘤)、泌尿器官疾病(例如前列腺肥大症)、其他疾病(例如阿茲海默症、硬化症腹膜炎、I型糖尿病、手術後器官黏連)]、勃起功能障礙(例如糖尿病性勃起功能障礙、心因性勃起功能障礙、精神病性勃起功能障礙、由慢性腎功能衰竭引起之勃起功能障礙、用於摘除前列腺之骨盆內手術後之勃起功能障礙、伴隨年齡增長或動脈硬化之血管性勃起功能障礙)、炎症性腸病(例如潰瘍性大腸炎、克隆氏病、腸結核、缺血性大腸炎、伴隨貝西氏病之腸潰瘍)(例如參照專利文獻10)、胃炎、胃潰瘍、缺血性眼疾病(例如,視網膜動脈阻塞、視網膜靜脈阻塞、缺血性視神經症)、突發性失聰、無血管性骨壞死、伴隨投予非類固醇消炎藥(NSAIDs)(例如雙氯芬酸、美洛昔康、奧沙普秦、萘丁美酮、吲哚美辛、布洛芬、酮洛芬、萘普生、塞來昔布)之腸道損傷(例如,只要為於十二指腸、小腸、大腸上發病之損傷則無特別限制,例如,於十二指腸、小腸、大腸上所產生之糜爛等黏膜損傷或潰瘍)、伴隨脊柱管狹窄症(例如頸部脊柱管狹窄症、胸部脊柱管狹窄症、腰部脊柱管狹窄症、廣泛脊柱管狹窄症、腰椎骨狹窄症)之症狀(例如麻痹、感覺遲鈍、疼痛、麻木、步行能力降低)(參照專利文獻11)之預防劑或治療劑。
又,本發明結晶或本發明醫藥組合物亦有效用作基因治療或自己骨髓細胞移植等血管新生療法之促進劑、末梢血管再建術或血管新生療法中之血管形成促進劑。
本發明結晶於作為醫藥進行投予之情形時,直接或者於醫藥上允許之無毒性且惰性載體中,以例如0.1%~99.5%之範圍內,較佳為0.5%~90%之範圍內含有。
作為上述載體,可列舉固體、半固體或液狀之稀釋劑、填充劑、其他處方用助劑。可使用該等之一種或兩種以上。
本發明醫藥組合物以固體或液狀之用量單元,可採用粉末劑、膠囊劑、錠劑、糖衣錠、顆粒劑、散劑、懸浮劑、液劑、糖漿劑、酏劑、口含劑等經口投予製劑;注射劑、栓劑等非經口製劑之任何形態。亦可為緩釋性製劑。該等之中,特佳為錠劑等經口投予製劑。
粉末劑可藉由將本發明結晶粉碎至適當細度而製造。
散劑可藉由將本發明結晶粉碎至適當細度,繼而與同樣粉碎之醫藥用載體,例如澱粉、甘露醇般可食性碳水化合物進行混合而製造。可任意添加調味料、保存劑、分散劑、著色劑、香料等。
膠囊劑可藉由將首先如上述般成為粉末狀之粉末劑或散劑或者如錠劑之項目中所述般進行顆粒化而得者,填充至例如明膠膠囊般之膠囊外皮之中而製造。又,可藉由將潤滑劑或塑化劑,例如膠體狀之二氧化矽、滑石、硬脂酸鎂、硬脂酸鈣、固體之聚乙二醇與粉末狀之粉末劑或散劑進行混合,此後,進行填充操作而製造。若添加崩解劑或助溶劑,例如羧甲基纖維素、羧甲基纖維素鈣、低取代羥丙纖維素、交聯羧甲基纖維素鈉、羧甲基澱粉鈉、碳酸鈣、碳酸鈉,則能夠改善膠囊劑被攝取時之醫藥之有效性。
又,可將本發明結晶之微粉末懸浮分散於植物油、聚乙二醇、甘油、界面活性劑中,將其以明膠薄片包裹而製成軟膠囊劑。
錠劑可藉由於經粉末化之本發明結晶中添加賦形劑製作粉末混合物,進行顆粒化或渣化,繼而加入崩解劑或潤滑劑後,進行打錠而製造。
粉末混合物可藉由將適當經粉末化之本發明結晶與稀釋劑或基劑混合而製造。根據需要可添加結合劑(例如羧甲基纖維素鈉、甲基纖維素、羥丙基甲基纖維素、明膠、聚乙烯吡咯啶酮、聚乙烯醇)、溶解延遲劑(例如石蠟)、再吸收劑(例如四級鹽)、吸附劑(例如膨潤土、高嶺土)等。
顆粒可藉由首先將粉末混合物以結合劑例如糖漿、澱粉糊、阿拉伯膠、纖維素溶液或高分子物質溶液浸濕,攪拌混合,使其乾燥、進行粉碎而製造。亦可代替如此將粉末顆粒化,而首先放入打錠機後,將所得之不完全形態之渣進行粉碎並顆粒化。藉由於如此製作之顆粒中添加硬脂酸、硬脂酸鹽、滑石、礦物油等作為潤滑劑,可防止互相附著。
又,錠劑亦可不經由如上述般顆粒化或渣化之步驟,而藉由將本發明結晶與流動性之惰性載體混合之後直接打錠而製造。
可對如此製造之錠劑施加膜衣或糖衣。亦可使用由蟲膠之密閉覆膜構成之透明或半透明之保護覆膜、由糖或高分子材料之覆膜及蠟構成之拋光覆膜。
其他經口投予製劑例如液劑、糖漿劑、口含劑、酏劑亦可製成使其一定量含有本發明結晶之一定量的用量單元形態。
糖漿劑可將本發明結晶溶解於適當之香味水溶液中而製造。酏劑可藉由使用非毒性之醇性載體而製造。
懸浮劑可藉由將本發明結晶分散於非毒性載體中而製造。根據需要,可添加助溶劑或乳化劑(例如乙氧化之異硬脂醇類、聚氧乙烯山梨醇酯類)、保存劑、調味賦予劑(例如胡椒薄荷油、糖精)等。
若有需要,可將用於經口投予之用量單元處方進行微膠囊化。該處方亦可藉由進行覆膜、嵌入高分子、蠟等中而帶來作用時間延長或持續釋放。
非經口投予製劑可採取作為皮下、肌肉或靜脈內注射之液狀用量單元形態,例如溶液或懸浮液之形態。該非經口投予製劑可藉由使一定量之本發明結晶懸浮或溶解於適合注射目的之非毒性之液狀載體中,例如水性或油性介質,繼而對該懸浮液或溶液進行滅菌而製造。又,可添加穩定劑、保存劑、乳化劑等。
栓劑可使本發明結晶溶解或懸浮於可溶或不溶於低熔點之水中之固體,例如聚乙二醇、可可脂、半合成之油脂[例如Witepsol(註冊商標)]、高級酯類(例如棕櫚酸肉豆蔻酯)或該等之混合物而製造。
投予量因體重、年齡等患者之狀態、投予路徑、疾病之性質與程度等而異,但一般而言,對成人而言,作為本發明結晶之量,1天0.001 mg~100 mg之範圍內較為適當,較佳為0.01 mg~10 mg之範圍內。
根據不同情形,有時此以下用量即足夠,或者反之,需要此以上之使用量。又,可1天1次至數次投予或間隔1天至數天投予。
[實施例]
以下,揭示實施例、試驗例對本發明進行進一步詳細說明,但本發明並不限定於該等任一者。
粉末X射線繞射光譜利用SmartLab((股)Rigaku製造)(光學系統:集中法,電壓:45 kV,電流:200 mA,波長:Cu Kα,索勒狹縫:5.0度,掃描範圍:4~40度,掃描速度:47.3度/分鐘,試樣旋轉:60度/分鐘)進行測定。
IR光譜利用IR Affinity-1((股)島津製作所製造)(測定模式:%Transmittance,累計次數:16次,分解:2.0,波數範圍:400~4000 cm-1
)進行測定。
DSC利用DSC-50((股)島津製作所製造)(單元:氧化鋁(開路),氣體:氮氣(20.0 mL/分鐘),加熱速度:10.0℃/分鐘,保持溫度:250℃,保持時間:0分鐘)進行測定。
參考例 1 III 型結晶之製造
將2-{4-[N-(5,6-二苯基吡𠯤-2-基)-N-異丙基胺基]丁氧基}乙酸第三丁酯(例如,參照專利文獻1)(13.15 g)溶解於甲醇(179.7 mL)後,添加1N氫氧化鈉水溶液(41.47 mL)。將該混合物加熱還流1小時後,於減壓下蒸餾去除溶劑,於殘留物中加水使其溶解。以二乙醚洗淨之後,對所得之水層以1N鹽酸(44 mL)進行中和,利用乙酸乙酯進行提取。對所得之乙酸乙酯層以無水硫酸鎂進行乾燥,於減壓下蒸餾去除溶劑後,於殘留物中添加二異丙基醚使其結晶化,過濾該結晶,利用適量之二異丙基醚洗淨。以40℃於減壓下乾燥,得到III型結晶(9.88 g)。
將III型結晶之粉末X射線繞射之測定、IR測定及DSC測定之結果分別示於圖1、圖2及3。
繞射角2θ:8.4度、12.6度、13.4度、14.3度、14.6度、15.9度、16.9度、18.0度、18.8度、19.4度、20.3度、20.6度、21.6度、21.7度、22.3度、22.5度、23.3度、23.7度、23.9度、27.0度、29.6度及30.8度
IR吸收峰:2867 cm-1
、1747 cm-1
、1558 cm-1
、1380 cm-1
、1131 cm-1
及701 cm-1
DSC吸熱峰:118℃
參考例 2 化合物 B 之製造
於2-{4-[N-(5,6-二苯基吡𠯤-2-基)-N-異丙基胺基]丁氧基}-N-(甲磺醯基)乙醯胺(例如,參照專利文獻1)(300 g)之異丙醇(1425 mL)懸浮液中,添加氫氧化鈉水溶液(將氫氧化鈉(120.8 g)溶解於水(570 mL)中而得者)。於100℃下攪拌11小時後,冷卻至10℃以下。滴加濃鹽酸後,於10℃以下攪拌1小時後,過濾生成之析出物,利用適量之50%異丙醇水溶液、水及乙腈洗淨析出物。將該析出物於65℃下於減壓下乾燥,獲得目標化合物(208.3 g)。
實施例 1 本發明 I 型結晶之製造
將參考例2中所製造之化合物B(63 g)於90℃下溶解於乙腈(315 mL),以相同溫度攪拌30分鐘。過濾溶液,以乙腈5 mL洗淨,再次加溫攪拌。添加參考例2中所製造之少量之化合物B作為刺激之後,緩慢冷卻,於10℃以下攪拌1小時後,過濾結晶,利用適量之乙腈洗淨。於65℃下於減壓下乾燥,獲得本發明I型結晶59.5 g。
將本發明I型結晶之粉末X射線繞射之測定、IR測定及DSC測定之結果分別示於圖4、圖6及圖8。
繞射角2θ:6.4度、8.1度、9.5度、10.9度、13.2度、15.7度、15.8度、17.0度、17.2度、19.5度、20.3度、21.0度、21.9度、22.8度、23.7度、24.5度、25.5度、25.8度、28.9度及32.0度
IR吸收峰:2874 cm-1
、1736 cm-1
、1558 cm-1
、1375 cm-1
、1126 cm-1
及696 cm-1
DSC吸熱峰:127℃
實施例 2 本發明 II 型結晶之製造
將參考例2中所製造之化合物B(0.5 g)於80℃下溶解於異丙醇(2.5 mL)及8%氫氧化鈉水溶液(1.5 mL)中,以相同溫度攪拌30分鐘。緩慢地室溫冷卻,於室溫下利用4N鹽酸水溶液調整至pH5~6後,於10℃以下攪拌1小時後,過濾結晶,利用適量之水洗淨。於65℃下於減壓下乾燥,獲得本發明II型結晶(0.45 g)。
將本發明II型結晶之粉末X射線繞射之測定、IR測定及DSC測定之結果分別示於圖5、圖7及圖9。
繞射角2θ:9.6度、11.4度、11.7度、16.3度、17.5度、18.5度、18.7度、19.4度、19.9度、20.1度、20.6度、21.0度、21.1度、21.7度、22.7度、24.6度、26.6度、26.7度、28.8度及30.8度
IR吸收峰:2867 cm-1
、1749 cm-1
、1568 cm-1
、1382 cm-1
、1131 cm-1
及701 cm-1
DSC吸熱峰:147℃
試驗例 1 穩定性試驗
將化合物B之各種結晶形分別置於玻璃瓶中,栓緊並保存於90℃。於1天、5天及14天後取出試樣,以1 mg/mL之濃度溶解於甲醇中並利用HPLC(高效液相層析法,High Performance Liquid Chromatography)進行類似物質測定,並且對14天後之結晶確認結晶形。其結果示於表1。
試驗例 2 本發明 I 型結晶之於各種溶劑中之溶劑懸浮試驗
將本發明I型結晶與各種溶劑混合,於室溫下攪拌30分鐘。過濾所形成之結晶,確認結晶形。其結果示於表2。
圖1係表示III型結晶之粉末X射線繞射光譜圖。縱軸表示峰強度(cps),橫軸表示繞射角(2θ[°])。
圖2係表示III型結晶之IR光譜圖。縱軸表示透過率(%),橫軸表示波數(cm-1
)。
圖3係表示將III型結晶於1分鐘內溫度每上升10℃之情形時之DSC測定圖。圖之縱軸表示發熱量(mW)(負情形時為吸熱量),橫軸表示溫度(℃)。
圖4係表示本發明I型結晶之粉末X射線繞射光譜圖。縱軸表示峰強度(cps),橫軸表示繞射角(2θ[°])。
圖5係表示本發明II型結晶之粉末X射線繞射光譜圖。縱軸表示峰強度(cps),橫軸表示繞射角(2θ[°])。
圖6係表示本發明I型結晶之IR光譜圖。縱軸表示透過率(%),橫軸表示波數(cm-1
)。
圖7係表示本發明II型結晶之IR光譜圖。縱軸表示透過率(%),橫軸表示波數(cm-1
)。
圖8係表示將本發明I型結晶於1分鐘內溫度每上升10℃之情形時之DSC測定圖。縱軸表示每秒之發熱量(mW)(負情形時為吸熱量),橫軸表示溫度(℃)。
圖9係表示將本發明II型結晶於1分鐘溫度每上升10℃之情形時之DSC測定圖。圖之縱軸表示發熱量(mW)(負情形時為吸熱量),橫軸表示溫度(℃)。
Claims (6)
- 一種醫藥組合物,其含有如請求項1至3中任一項之結晶作為有效成分。
- 一種PGI2受體激動劑,其含有如請求項1至3中任一項之結晶作為有效成分。
- 一種伴隨糖尿病性神經病變、糖尿病性壞疽、末梢循環障礙、慢性動脈阻塞症、間歇性跛行、硬皮病、血栓症、肺高血壓、心肌梗塞、狹心症、絲球體腎炎、糖尿病性腎病、慢性腎功能衰竭、支氣管哮喘、間質性 肺炎(肺纖維化症)、慢性阻塞性肺病、腎小管間質性腎炎、炎症性腸病、或脊柱管狹窄症之症狀之治療劑,其含有如請求項1至3中任一項之結晶作為有效成分。
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