200930379 九、發明說明： 【發明所屬之技術領域】 本發明係關於在室溫下穩定之非晶形玻璃狀阿斯匹靈且 關於其製備方法。 本申請案主張美國臨時專利申請案第60/999,445號、第 . 60/999,462號及第60/999,483號之權利，其全部於2007年10200930379 IX. DESCRIPTION OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to amorphous glassy aspirin which is stable at room temperature and relates to a process for the preparation thereof. The present application claims the rights of U.S. Provisional Patent Application No. 60/999,445, No. 60/999,462, and No. 60/999,48, all of which are incorporated herein by reference.
月17日提出申請且其全文皆以應用方式併入本文中。本申 請案亦與代理檔案號為1433 1/30004標題為PROCESS FOR © THE MODIFICATION OF THE SOLID STATE OF A COMPOUND AND C〇- AMORPHOUS COMPOSITIONS PRODUCED WITH SAME與本申請案同曰提出申請之美國 專利申請案第xx/xxx，xxx有關，該案件之全文亦併入本文 中0 【先前技術】 乙醯水楊酸（ASA)首先係由Charles Gerhardt於1 853年合 成。然而，Gerhardt沒有繼續他的發明。Bayer在1899年以 商標名阿斯匹靈（ASPIRIN)出售晶形乙酿水楊酸。關於晶 形乙醯水楊酸之美國專利第644,077號在1900年頒予Bayer 化學家Felix Hoffmann。直至近來，初始晶形（稱為I型）係 ' 阿斯匹靈之唯一習知晶形且係阿斯匹靈在室溫下唯一穩定 形式。如 C/iewica/ ά 五2005 年 11 月 21 日，Zaworotko等人，*/. Jw. Chem. Soc., 2005, 127, 16802 中所報導，其報導阿斯匹靈之第二種多晶形之合成。Π型 阿斯匹靈在100 K (-173°C)下動力學穩定，但在環境條件 135497.doc 200930379 下轉化恢復為i型。 業内亦已形成非晶態玻璃狀阿斯匹靈。然而，除對於一 些微小殘留物可能以外，非晶態阿斯匹靈僅在極低溫度下 產生。在高於約243開爾文（KelVin)(-3(TC )之玻璃化轉變溫 度下’非晶態阿斯匹靈迅速轉化為晶形I。因而，所有先 前技術形式的阿斯匹靈在室溫下皆轉化為。由於產生 且維持非晶態形式需要低溫，故業内基本上不存在非晶態 固態形式之實踐應用。The application is filed on the 17th of the month and the entire text is incorporated herein by reference. This application is also related to U.S. Patent Application Serial No. 1433 1/30004 entitled PROCESS FOR © THE MODIFICATION OF THE SOLID STATE OF A COMPOUND AND C〇- AMORPHOUS COMPOSITIONS PRODUCED WITH SAME Xx/xxx, xxx, the full text of the case is also incorporated herein. [Prior Art] Acetylsalicylic acid (ASA) was first synthesized by Charles Gerhardt in 1853. However, Gerhardt did not continue his invention. Bayer sold the crystalline form of salicylic acid in 1899 under the trade name Aspirin. U.S. Patent No. 644,077, on the form of crystalline acetyl salicylic acid, was awarded to Bayer chemist Felix Hoffmann in 1900. Until recently, the initial crystal form (referred to as type I) was the only known crystal form of aspirin and was the only stable form of aspirin at room temperature. As reported in C/iewica/ά 5, November 21, 2005, Zaworotko et al., */. Jw. Chem. Soc., 2005, 127, 16802, which reports the second polymorph of aspirin synthesis. Indole type Aspirin is kinetically stable at 100 K (-173 ° C), but is converted to i form under environmental conditions 135497.doc 200930379. Amorphous glassy aspirin has also been formed in the industry. However, amorphous aspirin is produced only at very low temperatures, except for some minor residues. At a temperature above about 243 Kelvin (KelVin) (-3 (TC), the amorphous state of aspirin is rapidly converted to Form I. Thus, all prior art forms of aspirin are at room temperature All are converted to. Since the production and maintenance of the amorphous form requires low temperatures, there is substantially no practical application of the amorphous solid form in the industry.
Johari等人 ’ 2000, 2，5479_5484報導阿斯匹靈之玻璃化，其係藉由熔融及冷 卻且藉由在環境溫度下球磨以形成在298K下數天内穩定抗 結晶之玻璃質或過冷黏性液體阿斯匹靈來達成。吾人發現 當該黏性液體在容器中傾斜時緩慢流動，但在298K下於4 至5天内不結晶。玻璃質阿斯匹靈樣品最終將完全結晶， 但當該等樣品保持在約340K時將加速結晶。Johari et al. 2000, 2, 5479_5484 report the vitrification of aspirin by melting and cooling and by ball milling at ambient temperature to form a stable anti-crystalline glassy or supercooled viscosity within 298 K for several days. The liquid liquid aspirin is reached. I have found that the viscous liquid flows slowly when tilted in the container, but does not crystallize within 4 to 5 days at 298K. The vitreous aspirin sample will eventually crystallize completely, but will accelerate crystallization as the samples remain at about 340K.
Johari等人報導玻璃態具有較結晶態為高的能態且其聲 子模式之頻率較低且非諧和性較高，此使得直接自固態吸 收及同化更有效且高效。在其塊狀形式中，據報導玻璃質 阿斯匹靈溶解較相同質量的阿斯匹靈精細粉末狀晶體緩 慢°如業内所熟知，物質之塊狀樣品具有明顯較精細粉末 狀晶體小的表面積。此使得塊狀形式之溶解更加困難，此 係Johari等人所報導之塊狀玻璃質阿斯匹靈之溶解速率較 慢的原因。 【發明内容】 U5497.doc 200930379 本發明係關於非晶形阿斯匹靈。本發明非晶形阿斯匹靈 在約20°C至約30°C之溫度下於儲存期間至少約3〇天、較佳 地至少6個月且更佳地至少約丨年不結晶。本發明非晶形阿 斯匹靈可經微囊封。 本發明亦係關於製備非晶形阿斯匹靈之方法。該方法包 括將出自至少兩個不同雷射之雷射輻射施加至溶於溶劑中 • 之阿斯匹靈溶液，並蒸發該溶劑。較佳地，雷射輻射具有 ❹ 有效平均脈衝長度不超過約10_9秒之脈衝，且出自每個雷 射之雷射輻射具有不同的波長。較佳地，該等雷射中至少 一個會發射可見光。更佳地，一個雷射係發射近uv至藍 色範圍内之輻射，而一個雷射係發射紅色至近设範圍内之 輻射。採用來自以下雷射之雷射輻射已獲得良好結果：一 個發射波長在約400至約470奈米範圍内之輻射之雷射、及 一個發射波長在約620至約680奈米範圍内之輻射之雷射。 較佳地’該雷射輻射係經Strachan裝置（即由Strachan在 Φ 美國專利第6,〇64,500號及第6,81丨，564號中所揭示之類型裝 置）改良。更佳地’經改良雷射發射係經以以仏⑽裝置改良 之雷射的發射。較佳地，Strachan裝置能產生有效平均脈 衝長度低於約1〇·12秒，且較佳地不超過約1〇_!5秒之雷射脈 衝。然而’ Strachan裝置干擾圖案降低對短脈衝之需求。 可同時或以交替順序施加得自兩個雷射之雷射輻射的脈 衝。 較佳地’阿斯匹靈溶液中所使用溶劑係醇，且更佳地係 無水醇’例如無水乙醇。 135497.doc 200930379 較佳地，在本發明方法中，將溶於溶劑之阿斯匹靈溶液 置於有蓋容器中，將雷射輻射脈衝之脈衝施加至該阿斯匹 靈溶液’並在施加雷射脈衝的同時使至少一部分溶劑蒸發 掉，從而形成非晶形阿斯匹靈。較佳地，在施加雷射脈衝 期間加熱阿斯匹靈溶液。較佳地，將雷射輻射施加至阿斯 匹靈溶液直至溶劑之蒸發完成為止。當溶劑蒸發時可使阿 . 斯匹靈冷卻至室溫。 ❹ 較佳地，在開始施加雷射脈衝後一段時間内防止溶劑蒸 發。隨後使溶劑蒸發同時繼續施加雷射脈衝。 較佳地，本發明非晶形阿斯匹靈以包括下列之方法來製 備.使雷射輻射穿過Strachan裝置，其中該Strachan裝置包 括第一繞射光柵及第二繞射光栅及位於該第一及第二繞射 光栅之間之折射元件。此藉由相消干擾抵消一部分雷射輻 射，並藉由相長干擾產生雷射輻射之脈衝。隨後將穿過 Strachan裝置之雷射輕射施加至溶於溶劑中之阿斯匹靈溶 〇 液，並蒸發溶劑，產生本發明非晶形阿斯匹靈。較佳地， 在穿過strachan裝置後，雷射輻射之脈衝具有不超過約1〇_9 秒之有效平均脈衝長度。 【實施方式】 本文所用術語"非晶形阿斯匹靈"係指在粉末χ射線繞射 (PXRD)刀析時提供實質上不含任何峰之圖案 之任何形式的阿斯匹靈，該等pXRD峰係晶形阿斯匹靈 PXRD圖案之典型峰。 本發明係關於在室溫下穩定之非晶形乙酿水楊酸或阿斯 135497.doc 200930379 匹靈及關於用來製備該穩定之非晶形阿斯匹靈之方法。本 發明非晶形阿斯匹靈在約“它至”它之溫度下穩定至少約 24小時，較佳地至少約3〇天，更佳地至少3個月且最佳 地至〉'約6個月。本發明非晶形阿斯匹靈之樣品在約2〇。〇 至3 0 C之溫度下保持穩定至少約1年。 不欲党限於理論，據信化合物之非晶形在分子間晶格内 具有較該化合物之任何結晶形式高的自由能。此賦予非晶 φ 形在水中具有較咼的溶解度，該溶解度較晶形者溶解度高 約2至8倍，其中該等非晶形及晶形具有相似粒徑。此溶解 度的増加可轉變為更快地溶解、吸收及臨床作用以及明顯 較尚生物利用度。因而，本發明非晶形阿斯匹靈在經口攝 取或經黏膜遞送（例如經舌下）後之條件下可提供較晶形阿 斯匹靈更快的溶解速率，並提供較高的溶解度及生物利用 度。因此，本發明在約2(TC至約3(rc溫度下呈現穩定之非 晶形阿斯匹靈應具有優於晶形者之臨床及其他優點。 〇 晶形阿斯匹靈及本發明非晶形阿斯匹靈之粉末X -射線繞 射（PXRD)分析顯示出兩種形式中分子排列之差異。晶形 化合物之PXRD圖案在X-射線束之特定反射角（經量測為2θ 度）處具有典型的峰。通常，量測分辨率為約±〇2。2Θ。反 射係晶體中分子規則排列之結果。相反地，部分非晶形化 合物樣品之PXRD圓案具有實質上鈍頭峰或降低峰，而純 粹地非晶形化合物樣品之PXRD圖案通常並無任何典型的 峰。非晶形化合物中分子係隨機排列，且因而在pxRD圖 案中觀察不到反射峰。在一些非晶形化合物中可觀察到在 135497.doc -10- 200930379 寬範圍内出現之強度變化以及基線雜訊。 晶形阿斯匹靈之典型PXRD圊案繪示於圓1中。圖1之 PXRD圖案具有數個峰，其係晶形阿斯匹靈之特徵。 相比而言，圖2提供本發明非晶形阿斯匹靈之pxRD圖 案。非晶形阿斯匹靈之PXRD圖案與圖1中所示晶形阿斯匹 * 靈之咼度晶形圖案明顯相反。晶形阿斯匹靈實質上不存在 • 高強度PXRD峰，此表明在本發明非晶形阿斯匹靈中至多 ❹ 僅存在極短範圍内排序。重要的是，應注意圖1之PXRD圖 案的分辨率比圓2中所繪示圖案之分辨率大7倍以上。因 此’在圖1中晶形阿斯匹靈之1>又111)圖案中所觀察到且可出 現在圖2中非晶形阿斯匹靈之PXRD圖案中的任何峰的強度 事實上不大於圖1中之基線雜訊。此明顯證明如圖2中所繪 示由PXRD所分析之阿斯匹靈實質上係純非晶形阿斯匹 靈。產生PXRD峰之樣品中實質上不存在阿斯匹靈分子之 排序。 φ 考慮到在室溫下阿斯匹靈結晶之強熱動力學趨勢，在圖 2中所繪示之樣品中可存在極短範圍内的微晶形成。然 而’在室溫下非晶形阿斯匹靈之pXRD圖案表明，至多具 有不多於數個阿斯匹靈分子之極短範圍内排序的微晶結構 可於整個樣品中隨機散射。實質上整個樣品係由實際玻璃 之完全隨機化典型連續相構成，該連續相可含有具有極短 範圍内排序之少數隨機微晶結構。據信本發明非晶形阿斯 匹靈之物理及化學性能實質上與彼等純玻璃所預計之性質 相同。分子之排列實質上係隨機的，此可能使得非晶形阿 135497.doc 200930379 斯匹靈較晶形更易溶解。 由於PXRD圖案之典型反射+消失，當樣品中非晶形化 合物之量增大時，傅立葉變換紅外（F〇urier Infrared (FTIR))光譜吸收帶變寬。此提供存在非晶形之額 外證據。晶形材料之紅外光譜通常呈現較非晶形為尖或更 • 好分辨之吸收帶。紅外光譜中某些帶亦可稍微位移，此乃 • 因同一化合物之晶形材料與非晶形之間之形式變化所致。 ❹ 晶形及非晶形阿斯匹靈之FTIR分析結果分別繪示於圖3 及4中。阿斯匹靈樣品係彼等在圖丨及2中由pxRD所分析 者。圖3中所繪示晶形阿斯匹靈之FTIR圊案的吸收峰相對 良好地得到界定。相比而言，圖4中所繪示非晶形阿斯匹 靈之FTIR圖案表1供相對較寬的吸收帶。晶形阿斯匹靈與本 發明非晶形阿斯匹靈之FTIR光譜的比較表明該兩種樣品係 相同的化學實體。然而，圖4中所分析樣品之ftir峰變寬 與化合物之非晶形一致。 ❿ 在晶形及非晶形之偏振光顯微鏡（PLM)顯微照片中亦可 觀察到先前技術晶形阿斯匹靈與本發明非晶形阿斯匹靈之 晶體結構的差異。在偏振光顯微鏡中，晶形阿斯匹靈產生 雙折射。雙折射出現在各向異性材料中，其中呈晶形之分 子排列成非晶形中不存在之高度有序圖案。因此，晶形阿 斯匹靈之偏振光顯微鏡顯微照片展示純非晶形阿斯匹靈中 未觀察到之高度雙折射，純非晶形阿斯匹靈沒有在晶形中 所發現之分子的有序排列。在晶形阿斯匹靈之偏振光顯微 鏡顯微照片中在整個高度晶形樣品中雙折射清晰可見，其 135497.doc -12- 200930379 展示高級白色干擾色。 相比而S ’在本發明純各向同性非晶形阿斯匹靈顆粒之 偏振光顯微鏡顯微照片中未觀察到雙折射。不存在雙折射 係證明本發明非晶形阿斯匹靈之證據。如上所述，雙折射 需要分子的有序排列’其發現於晶形中但非晶形中不存 在。 本發明非晶形阿斯匹靈係藉由在相對較高的脈衝重複速 率下將阿斯匹靈溶液暴露於得自至少兩個來源之不同波長 雷射光之超短脈衝下並蒸發溶劑而產生。可同時或以交替 順序施加雷射光之脈衝。 雷射脈衝之有效長度較佳地不大於皮秒（picosecond)範 圍（10至10秒），且可在飛秒（femtosecond)範圍（1〇·丨5至 10秒）内或亞飛秒（sub-femtosecond)範圍（<10-丨5秒）内。一 個雷射較佳具有集中在可見光譜之下半部分中之發射，即 介於約400與約550奈米之間，較佳地在近紫外線（uv)至藍 色範圍内’更佳地在約400至約470奈米之波長下。另一雷 射較佳具有集中在可見光谱之上半部分中之發射，即介於 約550與約700奈米之間，較佳地在紅色至近紅外線（IR) 内，更佳地在約620至約680奈米之波長下。使用兩個具有 集中在類似波長下之發射之雷射（即兩個短波雷射、兩個 長波雷射或兩個發射集中在接近550奈米之雷射）可用於某 些應用中。然而，使用一個中心波長為約4〇〇至約47〇奈米 之雷射及中心波長為約400至約470奈米之第二雷射已得到 良好結果。 135497.doc 13 200930379 不欲受限於理論，據信雷射之輸出帶寬係藉由有效短脈 衝長度來加宽。此遵循測不准原理（Uncertainty Principle)。因此，據信雷射光之短脈衝提供與阿斯匹靈之 多個振動態及/或電子態相互作用之光子以提供非晶形。 因此’無需具有對應於阿斯匹靈特定吸收帶之發射的雷 • 射。 較佳地，超短雷射脈衝係藉由改良雷射之輸出以產生電 ❹ 磁（EM)波之相長干擾的稀疏節點而產生’如頒予Strachan 之美國專利第6,064,500號及第6,811，564號中所揭示，其揭 示内容其全文以引用方式併入本文中。本文所用術語 "Strachan裝置"係指strachan在彼等專利中所揭示類型之裝 置。第’500號及第’564號專利中所定義及本文所使用之 Strachan裝置包括第一繞射光栅及第二繞射光柵及位於該 第一及第二繞射光柵之間之折射元件。當連續或脈衝雷射 束穿過第一繞射光柵、折射元件及第二繞射光栅時，該束 ❹ 之至少一部分實質上由相消干擾抵消。當穿過Strachan裝 置之光束離開Strachan裝置時，其相互作用產生實質上抵 消該等束之相消干擾。折射元件使得在雷射源之較小百分 數内而非在單個關鍵波長處出現抵消。 相長干擾之相對稀疏區出現在抵消元件在選定方向上自 開孔之高頻與低頻通道之間。僅在其中以^仏⑽裝置之輸 出在距該裝置一定距離處產生相長干擾的情況下出現相長 干擾之稀疏節點。相長干擾僅在超短時間内出現，且因而 產生光之超短脈衝。據信.，脈衝之有效脈衝長度不超過約 135497.doc 14 200930379 ίο·9 秒。 採用Strachan裝置，雷射波長或雷射波長之相對幅值的 微小變化導致該等節點之位置迅速移動，如同（例如）雷射 二極體中電流的微小變化及接面溫度波動導致雷射中心頻 率變化一樣。結果，連續雷射束藉由相對較小的低頻調幅 • 之簡單方法而轉換為一串持續時間極短的脈衝。在大於」 MHz之頻率下二極體雷射之調幅在彼等熟習此項技術者所 熟知技術範圍内。因而，可容易地獲得持續時間在皮秒範 ❹ 圍内之脈衝長度，且用適當製備之Strachan裝置及調幅二 極體雷射可獲得飛秒或亞飛秒脈衝。 舉例而言，採用連續二極體雷射，極短持續時間的脈衝 串之脈衝重複頻率由直接雷射二極體驅動或聲_光或電-光 調製裝置之調幅頻率來界定。直接雷射驅動方法之固有電 流調變將導致雷射中心帛率之較大波動且縮多豆重合脈衝之 時間，同時若經調製束之開孔大於晶體最佳調製開孔之直 φ 徑，則聲_光調製提供類似作用，此乃因外徑將比内徑之 調製程度低，此造成有效開孔在功能上有所變化。 在本發明產生非晶形阿斯匹靈之方法_，將出自至少兩 不同雷射之快速、父替順列的超短雷射脈衝施加至阿斯 匹靈如上所論述，據信雷射之輸出帶寬係藉由短脈衝長 度來加寬。此係遵摘不確定度原理。因而，據信雷射光之 短脈衝可提供與阿斯匹靈之多個振動態及/或電子態相互 作用之光子，以產生非晶形。因此，對應於阿斯匹靈之特 定吸收帶之發射雷射是不需要的，且因而雷射之選擇並不 •35497.do, 200930379 是關鍵。使用在藍色-紫色帶（較佳約400至約470奈米）發射 之雷射及在紅色至近紅外線波長帶（較佳約620至約680奈 米）發射之雷射業已獲得良好結果。 較佳地，較佳的交替順序包括在使用一或多個Strachan 裝置而產生之兩個波長區域中的超短持續時間之相長性干 擾的稀疏知點。不欲受限於理論，據信交替順序的超短雷 射脈衝與阿斯匹靈之電子態及/或振動態會相互作用，此 會破壞分子間相互作用，且因而阻止晶體形成及/或破壞 ^ 曰曰a體結構。 本發明室溫下穩定之非晶形阿斯匹靈較佳地係以交替施 加出自至少兩個不同雷射之調幅稀疏相長節點所產生的， 該等雷射穿過Strachan裝置並施加至溶於溶劑中之阿斯匹 靈溶液。較佳地，該交替施加係以重複性的方式頻繁施 加。 有用的溶劑通常係有機溶劑，於其中阿斯匹靈至少可以 〇 適度溶解’且在約室溫至約13(TC下會蒸發且係無毒的。 較佳地’該阿斯匹靈係溶於醇類，且更佳地乙醇中。溶劑 較佳是無水的，且最佳之溶劑係無水乙醇。 較佳地，將雷射輻射施加至阿斯匹靈溶液直至溶劑實質 上蒸發為止。更佳地，在施加雷射輻射及蒸發溶劑期間加 熱阿斯匹靈溶液。最佳地，首先將雷射輻射施加至阿斯匹 靈溶液，其中該溶液用實質上防止溶劑蒸發之透明蓋覆 蓋。隨後去除該透明蓋，並當溶劑蒸發時繼續施加雷射輻 射。 135497.doc 16- 200930379 較佳地，雷射包括在藍色_紫色波長内發射之雷射及在 紅色-橙色波長帶内發射之雷射。更佳地，該等雷射較佳 地分別在約400至約470奈米範圍内及在約62〇至約68〇奈米 範圍内發射。本發明可使用兩個以上在不同波長下發射之 雷射。採用Strachan裝置及在408奈米及674奈米下發射之 • 二極體雷射已得到良好的結果。 . 儘管已展示本發明方法在標準大氣存在下提供非晶形阿 ❹ 冑匹靈’但該方法亦可在惰性氣氛中實施。惰性氣氛可使 用氮氣、氦氣、氬氣或其他惰性氣體來提供。出於成本原 因，氮氣較佳。惰性氣體之使用將消除在處理期間阿斯匹 靈氧化之任何趨勢。 以下非限制性實例僅出於闡釋本發明較佳實施例之目 的，且不應視為限制本發明，本發明範圍由隨附申請專利 範圍來界定。 如上所論述，非晶形阿斯匹靈在室溫下遠達不到熱動力 _ 學平衡，且以前發現其在高於玻璃化轉變溫度（其遠低於 室溫）直至高達熔融溫度之溫度下始終呈晶形或結晶。然 而，根據本發明重複施加雷射輻射將阿斯 ㈣晶形玻璃狀形式，已發現該形式在室溫下 少長達約1年。 實例1 將得自strachan裝置之長波長（紅色）674奈米隨後短波 長（紫色）408奈米的調幅及結構化雷射光（每種光^分鐘） 的單序列施加至阿斯匹靈於無水乙醇中之溶液。使每個約 135497.doc •17· 200930379 3公分經擴展束在距Strachan裝置25公分處的樣品上方緩慢 旋轉。經處理阿斯匹靈採用平面偏振光顯微鏡之分析表明 偶爾產生小部分微小各向同性阿斯匹靈小滴（其尺寸通常 小於1毫米（1 mm))，該等小滴在溶劑蒸發後於室溫下穩 定。大部分小滴具有雙折射晶形材料的核心及各向同性阿 • 斯匹靈之暈圈，但少數小滴係純各向同性》當各向同性材 • 料鄰接結晶材料前沿形成時其抵抗結晶之能力表明經由該 ❿ 方法所產生之本發明非晶形阿斯匹靈在實施去溶劑化後穩 實例2 為產生穩定之非晶形玻璃狀阿斯匹靈，頻繁、重複定序 • 施加雷射輻射使得產生高達約80至約90。/。或更多的透明玻 璃狀非晶形阿斯匹靈。已發現約2至3毫米或更大之純玻璃 状材料小滴及幾十個毫米寬的玻璃狀阿斯匹靈湖（lake)在 室溫下穩定長達約1年。 Ο 如上所論述，參照標準晶形阿斯匹靈係藉由PXRD來分 析。參照標冑晶形阿斯匹靈之反射峰的典$圖案繪示於圖 中晶形阿斯匹靈亦使用傅立葉變換紅外光譜進行分 析如圖3中所繪示。由於呈非晶形態之化合物的pxRD圖 案使得典型反射峰消失，因而FTIR光譜確定化合物身份， 並與阳態相比展示在非晶形中出現之吸收帶變寬進一步證 明為非晶形態。 阿斯匹靈之两度非晶形玻璃態係藉由重複施加經 trachan裝置調製及結構化之長波長隨後短波長雷射光之 135497.doc -18· 200930379 序列的數個循環而產生。藉由在9麵轉/分鐘㈣叫下用磁 力搜拌器授拌而將10毫克晶形阿斯匹靈參照標準品之樣品 冷於450毫克無水乙醇中，同時在塞住的Μ。細"Μ燒瓶中 加熱至14G°C持續Ι2·5分鐘。將溶液轉移至⑼毫米⑴毫米 玻璃Petri培養皿中，用玻璃蓋蓋住。將petH培養皿在熱板 • 上加熱至100°C。 用’里Strachan裝置改良之雷射輻射的重複循環處理阿斯 E靈溶液。第-個循環係施加得自中心波長為674奈米之 二極體雷射之調幅二極體雷射光。第二個循環係施加得自 中心波長為408奈米之二極體雷射之調幅二極體雷射光。 使樣品在距Strachan裝置25公分處旋轉緩慢穿過約3公分經 擴展束中的每一個。 674奈米雷射二極體束之峰值功率在沒有光學器件之情 況下為4.80 在穿過Thorlabs 5倍束擴展器及⑽ 裝置後，峰值功率降低約5〇%。使用Strachan裝置將 ❿ 奈米束調節至80%相位抵消程度以得到約0,48 mW之3公分 直徑束。 刀 408奈米束之峰值功率在無附加光學元件的情況下為約 4.8 mW。在穿過Thorlabs 5倍束擴展器及Strachan裝置後， 峰值功率降低約50%。使用Strachan裝置，將4〇8奈米束調 節至80%相位抵消程度以得到約〇 48 mW23公分直徑束。 在6.25赫茲（MHz)下對兩種束以電子方式進行調幅。如 上所論述，不欲受限於理論，據信雷射之輸出帶寬係藉由 由Straehan裝置所產生之短脈衝長度來加寬，其遵循不確 135497.doc •19- 200930379 定度原理。此提供雷射光中光子與阿斯匹靈分子之多個電 子及/或振動模式之相互作用。 在經覆蓋玻璃Petri培養皿中同時在熱板上用674奈米組 態處理阿斯匹靈溶液1分鐘，隨後用4〇8奈米組態處理！分 鐘，如上文所述。此後實施調幅及結構化674奈米組態、 ' 隨後4〇8奈米雷射組態的另一循環，每個雷射系統實施i分 • 鐘。674奈米雷射隨後408奈米雷射處理之第三序列利用每 個雷射系統實施2分鐘。 φ 於此循環後，自Petri培養皿去除玻璃蓋以使乙醇蒸發。 關於雷射處理之持續時間，在5個以上的循環内，將阿斯 匹靈於乙醇中之溶液保持在熱板上。674奈米隨後4〇8奈米 雷射處理之下一循環利用每個雷射系統實施2分鐘。隨後 施加4個674奈米隨後408奈米雷射處理之循環，每個循環 為2分鐘，其中每個雷射系統每個循環施加丨分鐘。在完成 最後一個雷射處理循環後，自熱板移除經雷射處理之阿斯 ❹ 匹靈樣品以在約18°C至2〇°C之室溫及35%濕度下繼續溶劑 蒸發之製程。 在雷射處理結束時，大部分溶劑已蒸發掉，產生約3公 分寬的清澈透明玻璃狀阿斯匹靈"湖、環繞該湖之外邊緣 窄結晶邊沿已形成相當於圓周周長的約3〇%之帶。儘管形 成活性結晶前沿，但在完成定序雷射處理之各循環後該前 沿之擴展可忽略。 在雷射處理之後蒸發去溶劑製程的！個小時内，經8〇% 或更高質量的樣品穩定之系統固化成清澈非晶形玻璃狀而 135497.doc -20· 200930379 非晶形。繼續在約18°C至22°C之室溫下及約30至40%濕度 下儲存6個月以上之時間’樣品外觀沒有變化，且即使批 鄰結晶邊沿仍維持透明玻璃狀阿斯匹靈之寬擴張。 儲存6個月之後’藉由PXRD研究經雷射處理之阿斯匹 靈。示於圖2中之此圖案表明該材料為高度χ_射線非晶 - 形’此與圖1中所示對照晶形阿斯匹靈之高度晶形圖案明 、 顯相反。與晶形阿斯匹靈所看見之高強度反射峰相比較， ❹ 對於經雷射處理之阿斯匹靈而言該等峰基本上完全消除， 此表明在所產生之非晶形玻璃形式中至多僅存在極短範圍 的排序。再儲存6個月之後亦未觀察到結晶。該等觀察表 明用本發明方法所產生非晶形阿斯匹靈的穩定性。 隨後使用傅立葉變換紅外（FTIR)光譜儀掃描又_射線非晶 形阿斯匹靈樣品，如圖4中所示。與圖3中所示阿斯匹靈參 照晶形材料之FTIR光譜相比較，與晶形阿斯匹靈參照樣品 之較多限定帶相比，阿斯匹靈χ·射線非晶形樣品中相對較 ❷ 寬吸收帶明顯。晶形材料之紅外光譜通常呈現較非晶形尖 或更好分辨的吸收帶，此乃因晶格中分子移動之自由度降 低所致紅外光譜中某些帶亦可稍微位移，此乃因相同化 合物之晶形材料與非晶形之間之形式變化所致。比較晶形 阿斯匹靈與經雷射處理之阿斯匹靈之FTIR光譜，該等化合 物月顯係相同的化學實體。經雷射處理之阿斯匹靈中光譜 峰的變寬係與非晶形阿斯匹靈一致的另一特徵。 實例3 隨後以長波長及短波長之反向順序（即短波長隨後長波 135497.doc 21 - 200930379 一致之測試。此方 晶形玻璃狀阿斯匹 將含有此非晶形阿 長循環定序雷射處理）重複與實例2方案 案亦產生高達90%產率的室溫穩定之非 靈’其在室溫下保持穩定23個月以上。 。未觀察到 斯匹靈樣品之Petri培養皿側立放置約6周時間 樣品流動。 比較實例Johari et al. reported that the glassy state has a higher crystalline state and its phonon mode has a lower frequency and higher inharmonicity, which makes direct self-solids absorption and assimilation more efficient and efficient. In its block form, it has been reported that vitreous aspirin dissolves as fine as fine powder crystals of the same quality as aspirin. As is well known in the art, bulk samples of matter have significantly finer powdery crystals. Surface area. This makes the dissolution of the bulk form more difficult, which is why the dissolution rate of the massive vitreous aspirin reported by Johari et al. is slow. SUMMARY OF THE INVENTION U5497.doc 200930379 The present invention relates to amorphous aspirin. The amorphous aspirin of the present invention does not crystallize at a temperature of from about 20 ° C to about 30 ° C for at least about 3 days, preferably at least 6 months, and more preferably at least about ten years. The amorphous aspirin of the present invention can be microencapsulated. The invention is also directed to a method of preparing amorphous aspirin. The method includes applying a laser radiation from at least two different lasers to a solution of aspirin dissolved in a solvent and evaporating the solvent. Preferably, the laser radiation has a pulse having an effective average pulse length of no more than about 10-9 seconds, and the laser radiation from each of the lasers has a different wavelength. Preferably, at least one of the lasers emits visible light. More preferably, a laser system emits radiation in the near uv to blue range, while a laser system emits red to near range radiation. Good results have been obtained with laser radiation from the following lasers: a laser that emits radiation in the range of about 400 to about 470 nanometers, and a radiation with an emission wavelength in the range of about 620 to about 680 nanometers. Laser. Preferably, the laser radiation is modified by a Strachan device (i.e., a device of the type disclosed in Tr. US Patent No. 6, pp. 64,500 and No. 6,81, 564). More preferably, the modified laser beam is transmitted by a laser modified by a helium (10) device. Preferably, the Strachan device is capable of producing a laser pulse having an effective average pulse length of less than about 1 〇 12 seconds, and preferably no more than about 1 〇 5 minutes. However, the Strachan device interference pattern reduces the need for short pulses. The pulses from the laser radiation of the two lasers can be applied simultaneously or in an alternating sequence. Preferably, the solvent used in the aspirin solution is an alcohol, and more preferably an anhydrous alcohol such as absolute ethanol. 135497.doc 200930379 Preferably, in the method of the invention, the solution of the aspirin dissolved in a solvent is placed in a covered container, and a pulse of a laser pulse is applied to the aspirin solution' and a thunder is applied. At least a portion of the solvent is evaporated while the pulse is being injected to form an amorphous aspirin. Preferably, the aspirin solution is heated during the application of the laser pulse. Preferably, laser radiation is applied to the aspirin solution until the evaporation of the solvent is complete. The espirulin is allowed to cool to room temperature as the solvent evaporates.较佳 Preferably, the evaporation of the solvent is prevented for a period of time after the application of the laser pulse is started. The solvent is then evaporated while continuing to apply a laser pulse. Preferably, the amorphous aspirin of the present invention is prepared by a method comprising: passing laser radiation through a Strachan device, wherein the Strachan device comprises a first diffraction grating and a second diffraction grating and is located at the first And a refractive element between the second diffraction grating. This offsets a portion of the laser radiation by destructive interference and produces a pulse of laser radiation by constructive interference. The laser light through the Strachan device is then applied to the aspirin solution dissolved in solvent and the solvent is evaporated to yield the amorphous aspirin of the present invention. Preferably, the pulse of laser radiation has an effective average pulse length of no more than about 1 〇 9 seconds after passing through the strachan device. [Embodiment] The term "amorphous aspirin" as used herein refers to any form of aspirin that provides substantially no peak pattern in powder ray diffraction (PXRD) knives, such A typical peak of the pXRD peak crystal form of the aspirin PXRD pattern. The present invention relates to amorphous ethyl succinic acid or s. 135497.doc 200930379, which is stable at room temperature, and to a process for preparing the stabilized amorphous aspirin. The amorphous aspirin of the present invention is stable for at least about 24 hours, preferably at least about 3 days, more preferably at least 3 months, and most preferably > about 6 at about "it" to its temperature. month. A sample of the amorphous aspirin of the present invention is about 2 Torr.保持 Stable for at least about 1 year at temperatures up to 30 °C. Without wishing to be bound by theory, it is believed that the amorphous form of the compound has a higher free energy in the intermolecular lattice than any crystalline form of the compound. This imparts an amorphous φ shape which has a relatively high solubility in water which is about 2 to 8 times higher than that of the crystal form, wherein the amorphous and crystalline forms have similar particle sizes. This increase in solubility translates into faster dissolution, absorption and clinical effects, as well as significantly greater bioavailability. Thus, the amorphous aspirin of the present invention provides a faster dissolution rate of crystalline aspirin and provides higher solubility and biological properties after oral ingestion or transmucosal delivery (for example, sublingually). Utilization. Thus, the present invention has a clinical and other advantage at about 2 (TC to about 3 (a stable amorphous aspirin at rc temperature) which is superior to the crystalline form. The crystalline form of aspirin and the amorphous form of the invention Pearson powder X-ray diffraction (PXRD) analysis shows the difference in molecular arrangement between the two forms. The PXRD pattern of the crystalline compound is typical at a specific angle of reflection of the X-ray beam (measured as 2 theta) Generally, the measurement resolution is about ± 〇 2. 2 Θ. The result of regular arrangement of molecules in the reflection system crystal. Conversely, the PXRD case of a part of the amorphous compound sample has a substantially blunt peak or a reduced peak, and pure The PXRD pattern of the amorphous compound sample generally does not have any typical peaks. The molecular structure of the amorphous compound is randomly arranged, and thus no reflection peak is observed in the pxRD pattern. It can be observed in some amorphous compounds at 135497.doc -10- 200930379 Intensity changes and baseline noise in a wide range. The typical PXRD pattern of crystal form aspirin is shown in circle 1. The PXRD pattern in Figure 1 has several peaks, which are crystalline aspirin. In contrast, Figure 2 provides the pxRD pattern of the amorphous aspirin of the present invention. The PXRD pattern of the amorphous aspirin is substantially opposite to the crystalline form of the crystalline form of Aspirin shown in Figure 1. The crystalline form of aspirin is essentially absent • High-intensity PXRD peaks, indicating that there is only a very short range of ordering in the amorphous aspirin of the present invention. It is important to note the PXRD pattern of Figure 1. The resolution is more than 7 times greater than the resolution of the pattern depicted in circle 2. Therefore, it is observed in the pattern of the crystalline form of Aspirin in Figure 1 and is also in the amorphous form in Figure 2. The intensity of any peak in the PXRD pattern of spirin is in fact no greater than the baseline noise in Figure 1. This clearly demonstrates that aspirin analyzed by PXRD is essentially pure amorphous as depicted in Figure 2. Spirin. There is essentially no sorting of aspirin molecules in the sample producing the PXRD peak. φ Considering the strong thermodynamic trend of aspirin crystals at room temperature, in the sample depicted in Figure 2. There may be microcrystalline formation in a very short range. However, 'amorphous at room temperature The pXRD pattern of aspirin indicates that microcrystalline structures with at most a short range of no more than a few aspirin molecules can be randomly scattered throughout the sample. Substantially the entire sample is completely randomized by the actual glass. A typical continuous phase composition, which may contain a small number of random microcrystalline structures with a very short range of ordering. It is believed that the physical and chemical properties of the amorphous aspirin of the present invention are substantially inferior to those of pure glass. The same. The arrangement of the molecules is essentially random, which may make the amorphous 135497.doc 200930379 spearin more soluble than the crystalline form. Since the typical reflection + of the PXRD pattern disappears, when the amount of amorphous compound in the sample increases, Fourier transform infrared (FIRIER Infrared (FTIR)) spectral absorption band broadens. This provides additional evidence of the presence of amorphous. The infrared spectrum of a crystalline material typically exhibits an absorption band that is more amorphous or more well resolved. Some bands in the infrared spectrum can also be slightly displaced, which is caused by a change in the form between the crystalline material of the same compound and the amorphous form. The results of FTIR analysis of ❹ crystal form and amorphous form of aspirin are shown in Figures 3 and 4, respectively. Aspirin samples were analyzed by pxRD in Figures 2 and 2. The absorption peak of the FTIR pattern of crystalline form of aspirin is relatively well defined in Figure 3. In contrast, the FTIR pattern of amorphous aspirin is shown in Figure 4 for a relatively wide absorption band. A comparison of the crystalline form of aspirin with the FTIR spectrum of the amorphous aspirin of the present invention indicates that the two samples are the same chemical entity. However, the ftr peak broadening of the sample analyzed in Figure 4 is consistent with the amorphous form of the compound.差异 The difference in crystal structure between the prior art crystalline form of aspirin and the amorphous aspirin of the present invention can also be observed in crystalline and amorphous polarized light microscopy (PLM) micrographs. In a polarized light microscope, the crystalline form of aspirin produces birefringence. Birefringence occurs in an anisotropic material in which the crystalline molecules are arranged in a highly ordered pattern that is not present in the amorphous form. Therefore, the polarized light microscopy photomicrograph of the crystalline form of aspirin shows the high birefringence not observed in pure amorphous aspirin. The pure amorphous aspirin has no ordered arrangement of molecules found in the crystal form. . The birefringence is clearly visible in the entire highly crystalline sample in the polarized light microscopy of the crystalline form of aspirin, 135497.doc -12-200930379 showing advanced white interference color. In contrast, S' did not observe birefringence in the polarized light microscopy photomicrograph of the purely isotropic amorphous aspirin particles of the present invention. The absence of birefringence demonstrates evidence of the amorphous aspirin of the present invention. As mentioned above, birefringence requires an ordered arrangement of molecules 'which is found in the crystal form but not in the amorphous form. The amorphous aspirin of the present invention is produced by exposing the aspirin solution to ultrashort pulses of different wavelengths of laser light from at least two sources at a relatively high pulse repetition rate and evaporating the solvent. Pulses of laser light can be applied simultaneously or in an alternating sequence. The effective length of the laser pulse is preferably no greater than the picosecond range (10 to 10 seconds) and can be in the femtosecond range (1 〇 丨 5 to 10 seconds) or sub femtosecond (sub -femtosecond) Range (<10-丨5 seconds). Preferably, a laser has an emission concentrated in the lower half of the visible spectrum, i.e. between about 400 and about 550 nm, preferably in the near ultraviolet (uv) to blue range - preferably better From about 400 to about 470 nm. Another laser preferably has an emission concentrated in the upper half of the visible spectrum, i.e. between about 550 and about 700 nm, preferably in red to near infrared (IR), more preferably at about 620. To a wavelength of about 680 nm. The use of two lasers with emission concentrated at similar wavelengths (i.e., two short-wave lasers, two long-wave lasers, or two lasers concentrated at approximately 550 nm) can be used in some applications. However, a good result has been obtained using a laser having a center wavelength of about 4 Å to about 47 Å and a second laser having a center wavelength of about 400 to about 470 nm. 135497.doc 13 200930379 Without wishing to be bound by theory, it is believed that the output bandwidth of the laser is broadened by the effective short pulse length. This follows the Uncertainty Principle. Thus, it is believed that short pulses of laser light provide photons that interact with multiple oscillatory and/or electronic states of aspirin to provide an amorphous shape. Therefore, it is not necessary to have a lightning radiation corresponding to the emission of a specific absorption band of aspirin. Preferably, the ultrashort laser pulse is produced by a sparse node that improves the output of the laser to produce constructive interference of the electromagnetic (EM) wave, as described in U.S. Patent Nos. 6,064,500 and 6,811, to Strachan. The disclosures of the entire disclosure of which is hereby incorporated by reference. The term "Strachan device" as used herein refers to a device of the type disclosed by Strachan in their patents. The Strachan device as defined in the '500 and the '564 patents and used herein includes a first diffraction grating and a second diffraction grating and a refractive element between the first and second diffraction gratings. When a continuous or pulsed laser beam passes through the first diffraction grating, the refractive element, and the second diffraction grating, at least a portion of the beam is substantially offset by destructive interference. When the beam passing through the Strachan device leaves the Strachan device, its interaction produces substantially canceling the destructive interference of the beams. The refractive elements cause cancellation within a small percentage of the laser source rather than at a single critical wavelength. The relatively sparse zone of constructive interference occurs between the high frequency and low frequency channels of the counteracting element in the selected direction. A sparse node in which constructive interference occurs only in the case where the output of the device (10) produces constructive interference at a distance from the device. Constructive interference occurs only in a very short time and thus produces ultrashort pulses of light. It is believed that the effective pulse length of the pulse does not exceed approximately 135497.doc 14 200930379 ίο·9 seconds. With the Strachan device, small changes in the relative amplitudes of the laser wavelength or laser wavelength cause the positions of the nodes to move rapidly, as in the case of, for example, small changes in current in the laser diode and junction temperature fluctuations leading to the laser center. The frequency changes the same. As a result, the continuous laser beam is converted into a series of very short duration pulses by a relatively simple method of low frequency amplitude modulation. The amplitude modulation of the diode laser at frequencies greater than "MHz" is within the skill of those skilled in the art. Thus, the pulse length of the duration in the picosecond range can be easily obtained, and femtosecond or sub-flight pulses can be obtained with a suitably prepared Strachan device and an amplitude modulated diode laser. For example, with a continuous diode laser, the pulse repetition frequency of a very short duration pulse train is defined by the direct laser diode drive or the amplitude modulation frequency of the acoustic-optical or electro-optic modulation device. The inherent current modulation of the direct laser driving method will result in a large fluctuation of the laser center enthalpy and the time of the multi-beat coincidence pulse, and if the aperture of the modulated beam is larger than the straight φ diameter of the crystal optimally modulating the opening, The acoustic_light modulation provides a similar effect because the outer diameter will be less modulated than the inner diameter, which results in a functional change in the effective opening. In the method of the present invention for producing amorphous aspirin _, applying a fast, parent-subsequent ultrashort laser pulse from at least two different lasers to aspirin as discussed above, it is believed that the output bandwidth of the laser It is widened by the length of the short pulse. This is based on the principle of uncertainty. Thus, it is believed that short pulses of laser light provide photons that interact with multiple vibrational and/or electronic states of aspirin to produce an amorphous shape. Therefore, the emission of the laser corresponding to the specific absorption band of aspirin is not required, and thus the choice of laser is not •35497.do, 200930379 is the key. Lasers that emit in blue-purple bands (preferably from about 400 to about 470 nm) and lasers that emit in the red to near-infrared wavelength band (preferably from about 620 to about 680 nm) have achieved good results. Preferably, the preferred alternate sequence includes sparse knowledge of constructive interference of ultra-short durations in two wavelength regions produced using one or more Strachan devices. Without wishing to be bound by theory, it is believed that an alternating sequence of ultrashort laser pulses interacts with the electronic state and/or vibrational dynamics of aspirin, which disrupts intermolecular interactions and thus prevents crystal formation and/or Destroy ^ 曰曰 a body structure. The amorphous aspirin stabilized at room temperature of the present invention is preferably produced by alternately applying amplitude modulated sparse construct nodes from at least two different lasers which are passed through a Strachan device and applied to the solution. Aspirin solution in solvent. Preferably, the alternating application is applied frequently in a repetitive manner. Useful solvents are usually organic solvents in which aspirin is at least moderately soluble and can evaporate from about room temperature to about 13 (TC is toxic and non-toxic. Preferably the aspirin is soluble) Alcohols, and more preferably in ethanol. The solvent is preferably anhydrous, and the most preferred solvent is anhydrous ethanol. Preferably, laser radiation is applied to the aspirin solution until the solvent is substantially evaporated. Preferably, the aspirin solution is heated during application of the laser radiation and evaporation of the solvent. Preferably, the laser radiation is first applied to the aspirin solution, wherein the solution is covered with a transparent cover that substantially prevents evaporation of the solvent. The transparent cover is removed and the application of laser radiation continues as the solvent evaporates. 135497.doc 16- 200930379 Preferably, the laser comprises a laser that emits in the blue-violet wavelength and emits in the red-orange wavelength band. More preferably, the lasers are preferably emitted in the range of from about 400 to about 470 nanometers and in the range of from about 62 angstroms to about 68 nanometers. The invention may use more than two at different wavelengths. Laser launched below. Adopt S The trachan device and the diode laser emitted at 408 nm and 674 nm have obtained good results. Although the method of the present invention has been shown to provide amorphous amorphine in the presence of a standard atmosphere, the method It can also be carried out in an inert atmosphere. The inert atmosphere can be supplied using nitrogen, helium, argon or other inert gases. For reasons of cost, nitrogen is preferred. The use of inert gas will eliminate the oxidation of aspirin during processing. The following non-limiting examples are merely illustrative of the preferred embodiments of the invention and are not to be construed as limiting the scope of the invention, which is defined by the scope of the accompanying claims. As discussed above, amorphous Aspen Pilling is far below the thermodynamic equilibrium at room temperature and has previously been found to crystallize or crystallize at temperatures above the glass transition temperature (which is well below room temperature) up to the melting temperature. Repeated application of laser radiation in accordance with the present invention results in a crystalline form of Aspen (tetra), which has been found to be as long as about 1 year at room temperature. Example 1 Long Waves from Strachan Devices Long (red) 674 nm followed by short wavelength (purple) 408 nm amplitude modulation and a single sequence of structured laser light (each light ^ min) applied to a solution of aspirin in absolute ethanol. 135497.doc •17· 200930379 3 cm extended beam slowly rotates over a sample 25 cm from the Strachan device. Analysis of treated aspirin using a plane polarized light microscope shows occasionally a small portion of tiny isotropic aspirin Minor droplets (usually less than 1 mm (1 mm) in size), these droplets are stable at room temperature after evaporation of the solvent. Most of the droplets have the core of the birefringent crystalline material and the isotropic A. Halo, but a few droplets are purely isotropic. The ability of the isotropic material to resist crystallization when formed adjacent to the leading edge of the crystalline material indicates that the amorphous aspirin of the present invention produced by the method of hydrazine is implemented. Stabilization Example 2 after desolvation to produce a stable amorphous glassy aspirin, frequent, repeated sequencing • Application of laser radiation to produce up to about 80 to about 90. /. Or more transparent glassy amorphous aspirin. It has been found that droplets of pure glassy material of about 2 to 3 mm or more and glazed aspen lakes of several tens of millimeters are stable at room temperature for about one year. Ο As discussed above, the reference standard crystal form aspirin is analyzed by PXRD. The pattern of the reflection peak of the standard aspirin is shown in the figure. The crystal form of aspirin is also analyzed by Fourier transform infrared spectroscopy as shown in Fig. 3. Since the pxRD pattern of the amorphous form of the compound causes the typical reflection peak to disappear, the FTIR spectrum determines the identity of the compound, and the broadening of the absorption band appearing in the amorphous form as compared with the positive state further proves to be amorphous. The austenitic glassy state of aspirin is produced by repeated application of several cycles of the 135497.doc -18.200930379 sequence of long wavelength followed by short wavelength laser light modulated and structured by the trachan device. A sample of 10 mg of the crystalline aspirin reference standard was cooled in 450 mg of absolute ethanol while being stoppered by a magnetic stirrer at 9 rpm (4). Heat and heat to 14G °C for Ι2·5 minutes. The solution was transferred to a (9) mm (1) mm glass Petri dish and covered with a glass lid. Heat the petH dish to 100 °C on a hot plate. The Aspen E-linger solution was treated with repeated cycles of laser radiation modified by the 'Stratra' device. The first cycle is an amplitude modulated diode laser that is derived from a diode laser with a center wavelength of 674 nm. The second cycle is an amplitude modulated diode laser that is derived from a diode laser with a center wavelength of 408 nm. The sample was rotated slowly through 25 cm from the Strachan device through each of the approximately 3 cm expanded bundles. The peak power of the 674 nm laser diode bundle is 4.80 in the absence of optics and the peak power is reduced by approximately 5〇% after passing through the Thorlabs 5x beam expander and (10) device. The 奈 nanobeam was adjusted to 80% phase cancellation using a Strachan device to obtain a 3 cm diameter beam of approximately 0,48 mW. The peak power of the 408 nm beam is approximately 4.8 mW without additional optics. After passing through the Thorlabs 5x beam expander and the Strachan device, the peak power is reduced by approximately 50%. Using a Strachan device, the 4 〇 8 nm beam was adjusted to 80% phase cancellation to obtain a beam of about 48 mW 23 cm diameter. The two beams are electronically amplitude modulated at 6.25 Hz. As discussed above, without wishing to be bound by theory, it is believed that the output bandwidth of the laser is broadened by the length of the short pulses produced by the Straehan device, which follows the principle of uncertainty 135497.doc •19-200930379. This provides for the interaction of photons in the laser light with multiple electron and/or vibration modes of the aspirin molecule. The aspirin solution was treated with 674 nm on a hot plate in a covered glass Petri dish for 1 minute, followed by a 4 〇 8 nm configuration! The minutes are as described above. Thereafter, an amplitude modulation and structured 674 nm configuration, another cycle of the subsequent 4 〇 8 nm laser configuration was implemented, and each laser system implemented i minutes. The third sequence of the 674 nm laser followed by the 408 nm laser treatment was performed using each laser system for 2 minutes. φ After this cycle, the glass cover was removed from the Petri dish to evaporate the ethanol. Regarding the duration of the laser treatment, the solution of aspirin in ethanol was kept on a hot plate in more than 5 cycles. 674 nm followed by 4 〇 8 nm. One cycle of laser processing was performed using each laser system for 2 minutes. Four cycles of 674 nm followed by 408 nm laser treatment were then applied, each cycle being 2 minutes with each laser system applying 丨 minutes per cycle. After the last laser treatment cycle is completed, the laser-treated aspirin sample is removed from the hot plate to continue the solvent evaporation process at a room temperature of about 18 ° C to 2 ° C and a humidity of 35%. . At the end of the laser treatment, most of the solvent has evaporated, producing a clear, transparent glassy aspirin about 3 cm wide, and the narrow crystalline edge around the outer edge of the lake has formed an equivalent circumference circumference. 3〇% of the belt. Although the active crystallization front is formed, the extension of the leading edge is negligible after each cycle of the sequencing laser processing is completed. Evaporate the solvent removal process after laser processing! Within a few hours, a stable system of 8〇% or higher quality is solidified into a clear amorphous glass. 135497.doc -20· 200930379 Amorphous. Continue to store at room temperature of about 18 ° C to 22 ° C and about 30 to 40% humidity for more than 6 months 'The appearance of the sample does not change, and the transparent glassy aspirin is maintained even if the adjacent crystalline edge is maintained. Wide expansion. After 6 months of storage, the laser treated aspirin was studied by PXRD. The pattern shown in Figure 2 indicates that the material is highly χ-radial amorphous-shaped, which is in contrast to the highly crystalline pattern of the aspirin as shown in Figure 1. Compared to the high-intensity reflection peaks seen by the crystalline form of aspirin, 该 for the laser-treated aspirin, the peaks are substantially completely eliminated, indicating that at most only the amorphous glass form produced There is a very short range of sorting. No crystallization was observed after another 6 months of storage. These observations indicate the stability of the amorphous aspirin produced by the method of the present invention. A _-ray amorphous aspirin sample was then scanned using a Fourier transform infrared (FTIR) spectrometer as shown in FIG. Compared with the FTIR spectrum of the aspirin reference crystalline material shown in Figure 3, the aspirin ray-radial sample is relatively wide compared to the more defined bands of the crystalline aspirin reference sample. The absorption band is obvious. The infrared spectrum of the crystalline material generally exhibits an absorption band that is more amorphous or better resolved. This is because some of the bands in the infrared spectrum can be slightly displaced due to the reduced freedom of molecular movement in the crystal lattice. The change in form between the crystalline material and the amorphous form. Comparison of the crystalline form of aspirin with the FTIR spectrum of laser-treated aspirin, which is the same chemical entity as the moon. The widening of the spectral peaks in the laser-treated aspirin is another feature consistent with amorphous aspirin. Example 3 is then tested in the reverse order of long wavelength and short wavelength (ie, short wavelength followed by long wave 135497.doc 21 - 200930379. This square-shaped glassy aspirin will contain this amorphous A long cycle sequencing laser treatment Repeating with the Example 2 protocol also produced room temperature stable non-lingering with a yield of up to 90%, which remained stable for more than 23 months at room temperature. . The Petri dish of the spirulin sample was not observed to stand sideways for about 6 weeks. Comparative example
重複實例2及3之方案，只是未施加雷射輻射。所產生材 料顯然為晶形，其由！>則分析來確^。未施加雷射轄射 所獲得之晶形阿斯匹靈的PXRD圖案缔示於圖5巾。圖5之 PXRD圖案具有與圖⑽示對照樣品相同的峰。亦對所 產生晶形阿斯匹靈實施打汛分析。所產生光譜繪示於圖6 中且實質上與圖3中所繪示者相同。彼等結果清楚地表 明，非晶形阿斯匹靈並非實驗假像，而係在本發明方法中 施加雷射輻射之直接結果。 本發明穩定之非晶形玻璃狀阿斯匹靈在室溫下長期儲存 期間保持非晶形。因此，非晶形之使用使得用於臨床使用 或其他應用首次可行。舉例而言，由於據信化合物之非晶 形較相同化合物之晶形更易溶解，因此非晶形阿斯匹靈應 溶解更快且在較低劑量下更具活性。具體而言，此形式為 快速起作用的阿斯匹靈提供可能，該阿斯匹靈以較低劑量 更快地減輕臨床症狀且降低對黏膜刺激之傾向。 為達成此形式之大規模生產，微膠囊化容許生產及密封 較小粒#的非晶形阿斯匹靈，其固有地較由非晶形阿斯匹 靈、且成之較大顆粒更穩定。微膠囊化將有助於在長時間儲 135497.doc -22· 200930379 存期間於寬溫度及濕度範圍下保持穩定性本發明非晶形 阿斯匹靈亦可增強快速吸收黏膜或局部遞送系統之實用 性。微膠囊化技術在此項技術中眾所周知。 儘管本文所揭示本發明明顯完全適合實現上述目的但 吾人應瞭解彼等熟習此項技術者可設計多種修改及實施 . 例。因此，隨附申請專利範圍意欲涵蓋屬於本發明實際精 • 神及範圍之所有此等修改及實施例。 【圖式簡單說明】 ® 圖1繪示對照晶形阿斯匹靈樣品之粉末X-射線繞射 (PXRD)圖案； 圖2綠示本發明非晶形阿斯匹靈之粉末χ射線繞射 (PXRD)圖案； 圖3繪不對照晶形阿斯匹靈樣品之紅外光譜圖案； 圖4緣示本發明非晶形阿斯匹靈之紅外光譜圖案其相 對於參照晶形阿斯匹靈樣品展示加寬之吸收帶； φ 圖5纷示以類似於本發明之方法、但不施加雷射輻射所 形成之晶形阿斯匹靈的粉末X-射線繞射（PXRD)圖案；及 圖6繪不圖5晶形阿斯匹靈樣品之紅外光譜圖案。 135497.doc -23·The schemes of Examples 2 and 3 were repeated except that no laser radiation was applied. The material produced is clearly in the form of a crystal, which is made up of! > Analysis to confirm ^. The PXRD pattern of the crystalline form of aspirin obtained without the application of a laser is shown in Figure 5. The PXRD pattern of Figure 5 has the same peak as the control sample shown in Figure (10). A snoring analysis was also performed on the crystalline form of aspirin. The resulting spectrum is depicted in Figure 6 and is substantially the same as that depicted in Figure 3. Their results clearly show that amorphous aspirin is not an experimental artifact and is a direct result of the application of laser radiation in the method of the invention. The stabilized amorphous glassy aspirin of the present invention remains amorphous during long-term storage at room temperature. Therefore, the use of amorphous makes it feasible for clinical use or other applications for the first time. For example, since the amorphous form of the compound is believed to be more soluble than the crystalline form of the same compound, the amorphous aspirin should dissolve more quickly and be more active at lower doses. In particular, this form provides the possibility for fast-acting aspirin, which lowers clinical symptoms and reduces the propensity for mucosal irritation at lower doses. To achieve this form of mass production, microencapsulation allows the production and sealing of the smaller particles of amorphous aspirin, which is inherently more stable than amorphous aspirin and larger particles. Microencapsulation will help maintain stability over a wide temperature and humidity range during long periods of storage 135497.doc -22· 200930379. The amorphous aspirin of the present invention also enhances the utility of rapid absorption of mucosal or local delivery systems. Sex. Microencapsulation techniques are well known in the art. Although the present invention is clearly adapted to achieve the above objects, it should be understood that those skilled in the art can devise various modifications and embodiments. Accordingly, the appended claims are intended to cover all such modifications and embodiments, BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 shows a powder X-ray diffraction (PXRD) pattern of a comparative crystalline form of aspirin; Figure 2 shows green powdered astigmatism diffraction of the amorphous aspirin of the present invention (PXRD) Figure 3 depicts the infrared spectrum pattern of the sample aspirin sample; Figure 4 shows the infrared spectrum pattern of the amorphous aspirin of the present invention which exhibits broadening absorption relative to the reference crystal form of aspirin. Figure 5 shows a powder X-ray diffraction (PXRD) pattern of a crystalline form of aspirin formed by a method similar to the method of the present invention but without the application of laser radiation; and Figure 6 depicts the crystal form of Figure 5 Infrared spectral pattern of the sample of spirulin. 135497.doc -23·