數種茶鹼共結晶及茶鹼水合物之製備及特性探討

Preparation and Characterization of Several Cocrystals of Theophylline and Theophylline Monohydrate

胡博智(Po-Chih Hu)

指導教授 ： 謝學真

國立臺灣大學/工學院/化學工程學研究所/碩士(2020年)

https://doi.org/10.6342/NTU202100080

摘要

共結晶(cocrystal)藥物是一種將共構物(coformer)與活性藥物成分(active pharmaceutical ingredients, 縮寫API)結合形成共結晶來調整藥物的熱穩定性、抗溼性、溶解度、溶離速率、壓錠性等物理性質同時維持原有治療效果的藥物固體型式。依據API的官能基、立體結構不同，可挑選合適的共構物與之形成共結晶以達成改善藥物物化性質之目的。
結晶工程研究常用的溶劑蒸發法可製備出完整且均勻的共結晶，但此方法的實驗成果往往受限於各成分對溶劑的溶解度而不得不大量使用高生物毒性的有機溶劑。期刊文獻指出，多種有效成分與共構物均勻混和後在常溫常壓的儲存下即可緩慢形成共結晶，因而發展出眾多固相的共結晶製備方法，其中又以研磨法為最常用的製備法。
本研究選擇茶鹼(theophylline)做為模式藥物(model drug / model API)，因它可做為支氣管擴張劑，且易與多種物質形成共結晶。在研究中使用乙醇輔助研磨法製備茶鹼/乙醯胺酚、茶鹼/菸鹼醯胺、茶鹼/DL-蘋果酸、茶鹼/D-酒石酸、茶鹼/檸檬酸、茶鹼/草酸二水合物總共六種共結晶，製備過程中依據後續物性檢測結果，討論總研磨時間對共晶化程度的影響，進而決定出六種共結晶各自的最少需研磨時間。製備出的樣品使用X光繞射分析比對茶鹼、共構物、共結晶的特徵峰，使用差示掃描量熱法比對茶鹼、共構物、物理混合物、共結晶的熔化峰判斷共結晶的完成度，亦嘗試使用尚未普及的兆赫茲時域光譜，評估其作為判斷藥物共晶化程度的檢測技術的可行性。另以同為振動光譜的拉曼光譜與兆赫茲時域光譜比較，討論兩者對於共結晶資訊判讀的特性。
X光繞射分析與差示掃描量熱法的結果顯示，乙醇輔助研磨法製備的茶鹼/菸鹼醯胺樣品研磨30分鐘後即形成共結晶並達平衡，茶鹼/DL-蘋果酸樣品研磨45分鐘後即形成共結晶並達平衡；茶鹼/乙醯胺酚、茶鹼/檸檬酸樣品在研磨的第30-60分鐘內共晶化比例仍在提高，尚需要改善研磨的製程；茶鹼/草酸二水合物樣品雖能在X光繞射分析與差示掃描量熱法的結果中明顯看出少量共結晶的形成但共晶化程度未能隨研磨時間提升，茶鹼/D-酒石酸的結果則顯示樣品研磨後大部分仍為物理混合物而非共結晶，因此以上二者可能不適合以研磨法製備，應考慮改用其他製備法。在兆赫茲光譜應用於共結晶測定方面，茶鹼/DL-蘋果酸的共結晶在1.24 THz具有可與物理混合物區別的特徵峰，茶鹼/乙醯胺酚的共結晶未有明顯可辨識的獨立特徵峰，不易辨識樣品中共晶化程度，茶鹼/D-酒石酸因實驗結果不佳使共結晶與混合物的兆赫茲光譜無顯著差異，至於茶鹼/菸鹼醯胺、茶鹼/檸檬酸、茶鹼/草酸二水合物此三種共結晶與其各自的物理混合物有差異，但共結晶的兆赫茲光譜訊號非常微弱，現階段若要在共結晶與混合物混雜的樣品中辨識其中共晶化程度相當困難，有待後續進一步研究。
本研究除了測定共結晶的光譜，也測定了六種共結晶以及茶鹼水合物的溶解度與熱穩定性。實驗結果顯示，六種茶鹼共結晶的裂解起始溫度下降了約20-50°C，裂解結束溫度則幾乎不變，茶鹼水合物的裂解起始與結束溫度則上升了約15°C。本研究測得的茶鹼在常溫的水中溶解度為6.86毫克/毫升，茶鹼水合物為5.62毫克/毫升，茶鹼/乙醯胺酚共結晶為8.78毫克/毫升，茶鹼/菸鹼醯胺共結晶為8.03毫克/毫升，茶鹼/DL-蘋果酸共結晶為4.76毫克/毫升，茶鹼/檸檬酸共結晶為5.79毫克/毫升，茶鹼/草酸二水合物系統為4.10毫克/毫升。整體而言，茶鹼/乙醯胺酚共結晶、茶鹼/菸鹼醯胺共結晶提升了茶鹼溶解度，但茶鹼/DL-蘋果酸共結晶、茶鹼/檸檬酸共結晶、茶鹼/草酸二水合物系統則降低了茶鹼的溶解度，未來可考慮選用其他共構物製備共結晶以改善茶鹼溶解度。

關鍵字

茶鹼 ； 共結晶 ； X光繞射分析 ； 差示掃描量熱法 ； 兆赫茲時域光譜

並列摘要

Cocrystal drug is composed of coformer and active pharmaceutical ingredients (API) in order to adjust the thermal stability, moisture resistance, solubility, dissolution rate, and compressibility of the drug, while maintaining the original therapeutic effect. According to the functional groups and three-dimensional structure of API, suitable coformers can be selected to form cocrystals with improved physical and chemical properties.
In this study, theophylline was selected as the model drug because it can be used as a bronchodilator and also it can form cocrystals with many substances. Ethanol-assisted grinding method was used to prepare six cocrystals including theophylline/acetaminophen, theophylline/nicotinamide, theophylline/DL-malic acid, theophylline/D-tartaric acid, theophylline/citric acid, theophylline/oxalic acid dehydrate. Powder X-ray diffraction, differential scanning calorimeter and thermogravimetric analysis were used to determine the minmum grinding time requied for cocrystallization. In addition, terahertz time-domain spectroscopy and Raman spectroscopy were utilized to examine the differewnce between physical mixture and cocrystal. Further, the information extracted from these two vibrational spectra was discussed. The solubilities of theophylline, theophylline monohydrate, and theophylline cocrystal samples were also measured.
Experimental results showed that theophylline/nicotinamide were highly cocrystalized after being ground for 30 minutes and theophylline/DL-malic acid were highly cocrystalized after being ground for 45 minutes. The degree of cocrystalization in theophylline/acetaminophen and theophylline/citric acid systems continuously increased when prolonging the grinding time from 30 to 60 minutes. In contrast, theophylline/oxalic acid dehydrate were partly cocrystalized and the degree of cocrystalization could not be increased by prolonged grinding. Lastly theophylline/D-tartaric acid were not cocrystalized by ethanol-assisted grinding method. The use of terahertz time-domain spectroscopy indicated that only theophylline/DL-malic acid system had distinguishable characteristic peak at 1.24 THz. Theophylline/acetaminophen system exhibited slight difference between physical mixture and cocrystal. Surprisingly, theophylline/nicotinamide, theophylline/citric acid and theophylline/oxalic acid dihydrate systems displayed weak terahertz signals. The starting temperatures of thermal decomposition of theophylline cocrystals were 20-50°C lower than theophylline and there was no significantly change in the ending temperatures. The measured solubility of theophylline was 6.86 mg/ml, theophylline monohydrate 5.62 mg/ml, theophylline/acetaminophen 8.78 mg/ml, theophylline/nicotinamide 8.03 mg/ml, theophylline/DL-malic acid 4.76 mg/ml, theophylline/citric acid 5.79 mg/ml, and theophylline/oxalic acid dehydrate 4.10 mg/ml. Overall, theophylline/acetaminophen and theophylline/nicotinamide cocrystals increased the solubility of theophylline, but theophylline/DL-malic acid, theophylline/citric acid and theophylline/oxalic acid dihydrate cocrystals decreased the solubility of theophylline.

並列關鍵字

theophylline ； cocrystal ； powder X-Ray diffraction ； differential scanning calorimeter ； terahertz time-domain spectroscopy

參考文獻

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