Stability Orders of Acetaminophen and Theophylline Co-crystals Determined by Co-crystal Former Exchange Reactions and Their Correlation With In Silico and Thermal Parameters

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• 关键词：co-crystals ; crystal engineering ; crystal structure ; physicochemical ; solid state ; stability
• 刊名：Journal of Pharmaceutical Sciences
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：106
• 期：1
• 页码：258-263
• 全文大小：1108 K
• 卷排序：106

文摘

The aim of this study was to determine the thermodynamic stability order of co-crystals using co-crystal former exchange reactions and to validate 2 in silico parameters for predicting co-crystal formation. Co-crystal former exchange reactions were performed using acetaminophen (AC) co-crystals of oxalic acid (OX), maleic acid (MA), and theophylline (TH). The addition of TH to an AC-MA co-crystal (AC-MA) afforded AC-TH, suggesting that AC-TH was more stable than AC-MA. The stability order among the other co-crystals was determined in the same manner. The stability order of the AC co-crystals was determined to be AC-TH > AC-MA ≈ AC-OX. Interestingly, the addition of TH to AC-OX afforded TH-OX. The stability order of the TH co-crystals was also determined (OX-TH > AC-TH ≈ MA-TH). Although the stability order of the AC co-crystals was consistent with the differences in their hydrogen bond energy (ΔE), an in silico parameter for predicting co-crystal formation, it showed no relationship to the excess enthalpy (Hex). These results suggest that co-crystal formation can be predicted with greater accuracy using ΔE rather than Hex for AC co-crystals. The stability orders of the AC and TH co-crystals also correlated well with their melting points and disintegration temperatures.