利用量子力學溶合計算預測藥物在混合溶劑中的溶解度

Prediction of Drug Solubility in Mixture Solvents Based on First Principle Solvation Calculations

疏俊傑(Chun-Chieh Shu)

指導教授 ： 林祥泰

國立臺灣大學/工學院/化學工程學研究所/碩士(2009年)

https://doi.org/10.6342/NTU.2009.03249

摘要

溶解度對於工廠在藥物研究與開發中，甚至於大量生產製造時扮演著一個重要角色。當結晶過程可以利用更加便宜和更好的溶劑，便可以對於整體製造省下許多金錢。 在此研究中，我們依據COSMO理論基礎來針對混合物溶劑的溶解度提供一個簡易的方法。研究中我們考慮了33種藥物化合物的溶解度［從最小的2個原子(碘)，到最大的49個原子(睪甾酮)］在37種不同溶劑的混合溶劑情況下。我們針對總共127個固液平衡系統，包括123個雙成分的溶劑混合物、3個三成份的溶劑混合物和1個四成分的溶劑混合物。溫度範圍從273.15K到323.315K［如果我們將一種混合溶劑在不同溫度算成一個不同的系統的情況下有235個系統］。在這研究中我們利用NRTL-SAC模型在57個系統與COSMOSAC模型和PR+COSMOSAC在235個系統的計算結果進行比較。結果報告的誤差是根據自然對數單位的方均根錯誤(RMSE)來做為計算的方法。我們可以獲得從NRTL-SAC在57個系統的計算結果RMSE是0.58［相當於百分誤差79%］；同時，COSMO-SAC和PR+COSMOSAC在235個系統的計算結果分別為1.60和1.42的RMSE值［相當於百分誤差395%與314%］。研究中我們分別針對COSMOSAC和PR+COSMOSAC利用純溶劑下的溶解度實驗值最為一個修正，同時可以是COSMO-SAC+Corr和PR+COSMOSAC+Corr兩種模型的RMSE降低到0.59［相當於百分誤差80%］。

關鍵字

溶解度 ； 預測 ； 溶質模型 ； COSMOSAC ； Peng-Robinson Equation

並列摘要

Solubility plays an important role in drug research and development especially in the factory with massive manufactures. When there is a cheaper and better solvent for crystalline process, there saves lots of money. In this research, we provide an easy method for solubility prediction in mixture solvents based on COSMO theory. In this study, we have considered the solubility of 33 drug compounds [from 2 atoms (iodine), for the smallest, to 49 atoms (testosterone), for the largest] in (the mixture of) 37 different solvents. We have studied a total of 127 solid-liquid equilibrium systems, including 123 binary solvent mixtures, 3 ternary solvent mixtures, and 1 quaternary solvent mixture. The temperature ranges from 273.15K to 323.15K. [There are 235 systems if we consider a mixture at a different temperature to be a different system.] We compare the model used in this research with Nonrandom Two Liquid Segment Activity Coefficient (NRTL-SAC) model in 57 systems, COnductor-like Screening MOdel Segment Activity (COSMOSAC) model, and Peng-Robinson equation of state with COnductor-like Screening MOdel Segment Activity (PR+COSMOSAC) in 235 systems. The results are calculated based on different model and reported with nature logarithm unit of root mean square error (RMSE). We can obtain the RMSE from NRTL-SAC is 0.58 (77% error) with 57 of 235 systems for the restriction of parameters in molecules; meanwhile, the COSMO-SAC and PR+COSMOSAC are reported the RMSE with 1.60 (395%) and 1.42 (314%) in 235 systems. Also as we apply a correction with pure solvent solubility, the COSMO-SAC+Corr and PR+COSMOSAC+Corr would both reduce the RMSE to 0.59 (80%). It excites us that the method we applied improves the prediction of solubility.

並列關鍵字

solubility ； prediction ； solvation model ； COSMOSAC ； Peng-Robinson Equation

參考文獻

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