應用COSMO-SAC模型預測藥物於高分子 之溶解度

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林筱慈(Xiao-Ci Lin) 查詢紙本館藏

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化學工程與材料工程學系

論文名稱

應用COSMO-SAC模型預測藥物於高分子之溶解度
(Prediction of Drug Solubility in Polymer with COSMO-SAC model)

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至系統瀏覽論文 (2029-6-30以後開放)

摘要(中)

由於生物製劑分類系統的第二類藥物，其低溶解度性質限制製藥發展，透過添加高分子使其改善變成無定形分散體，但分散體大多為亞穩態，可能使活性藥物傾向再結晶，產生緩慢溶解情形，為了避免再結晶或相分離，藥物/高分子相圖很重要，主要是由溶解度與玻璃轉化溫度線構成，前者可知高分子負載藥物的最大值避免發生過飽和或再結晶，後者在低於其溫度下，使分子遷移率降低，讓藥物的亞穩態無定形狀態可長時間維持穩定。然而，受到高分子的性質影響，使室溫下量測溶解度之實驗相當困難，因此透過熱力學模型估算相平衡數據，常見用於計算藥物溶解度模型為PC-SAFT以及Flory-Huggins，而玻璃轉化溫度估算可用Gordon−Taylor模型。
本研究利用量子化學計算軟體(amsterdam modeling suite, AMS)計算19種藥物與22種不同分子量與種類之高分子性質，搭配成59個固液二元相系統，使用COSMO-SAC模型探討藥物於高分子之溶解度，並比較三種COSMO-SAC模型的計算誤差值以找出最佳版本，同時與其他模型進行比較，也針對不同高分子分子量觀察溶解度之變化，此外，探討共聚物PVPVA結構排列組合差異所產生之影響，接著選擇最常使用之Gordon−Taylor模型來計算玻璃轉化溫度，最後繪製負載藥物含量與溫度關係之熱力學相圖，有益於應用藥物設計開發與優化，以及大幅降低實驗時間與成本。

摘要(英)

As a Class II drug in the Biologics Classification System, its inherently low solubility significantly hampers pharmaceutical development. These challenges can be mitigated by incorporating polymers to create amorphous dispersions. However, these solid dispersions are frequently in a thermodynamically metastable state, which can trigger the reformation of active pharmaceutical ingredients (API) crystals, resulting in a slower dissolution rate. The reliable phase diagram for the studied drug/polymer system provides essential information to prevent recrystallization or phase separation. This diagram contains the drug solubility in polymer and glass transition temperature at different amounts of a drug in a polymer. Nonetheless, conducting solubility measurements at room temperature is challenging due to the high viscosity of the polymer. Currently, commonly used models for calculating drug solubility in polymer include PC-SAFT EOS and Flory-Huggins, while the Gordon-Taylor equation is used to estimate the glass transition temperature.
In this study, the accuracy of the COSMO-SAC model in predicting drug solubility in a polymer is investigated. A total of 59 drug-polymer binary systems composed of 19 drugs and 22 polymers with varying molecular weights and types are collected from open literature. Compare the AARD calculations of the three COSMO-SAC models to identify the optimal version and contrast them with other prominent models. Additionally, observe the changes in solubility for different polymer molecular weights and explore the influence of the copolymer PVPVA on variations in structural arrangements. Subsequently, a phase diagram of a studied drug-polymer binary system is generated by the solubility predicted from COSMO-SAC and the glass transition temperature estimated from the commonly used Gordon-Taylor model. It is beneficial to apply drug design, development, and optimization as it significantly reduces the duration and costs associated with experimental procedures.

關鍵字(中)

★ COSMO-SAC
★ 藥物溶解度
★ 無定型固體分散體
★ 高分子
★ 預測

關鍵字(英)

★ COSMO-SAC
★ Drug Solubility
★ Amorphous Solid Dispersions
★ Polymer
★ Prediction

論文目次

摘要 i
Abstract ii
致謝 iv
目錄 v
圖目錄 vi
表目錄 viii
第一章、緒論 1
1-1活性藥物成分介紹 1
1-2高分子載體介紹 8
1-3藥物-高分子相行為 11
1-4回顧藥物溶於高分子之模擬方法 16
1-5回顧COSMO-SAC發展 19
1-6 COSMO-SAC模型應用藥物或高分子預測 22
1-7研究動機 23
第二章、計算原理與細節 24
2-1溶解度計算細節 24
2-2 COSMO-SAC 26
2-3 Gordon-Taylor方程式 31
第三章、結果與討論 32
3-1比較COSMO-SAC三種不同版本的預測溶解度 34
3-2比較共聚物PVPVA64結構排列差異對預測溶解度之影響 45
3-3比較其他模型預測溶解度 50
3-4高分子的分子量對預測溶解度之影響 57
3-5建構熱力學相圖 61
第四章、結論 65
參考文獻 66
附錄一、藥物物理性質 79
附錄二、藥物結構 80
附錄三、高分子物理性質 82
附錄四、預測藥物於高分子溶解度計算結果 83
附錄五、溫度與藥物重量百分比含量相圖 92

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指導教授

謝介銘(Chieh-Ming Hsieh)

審核日期

2024-7-25

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