Influence of temperature and hydrophobic group-associated icebergs on the activation energy of drug decomposition and its implication in drug shelf-life prediction.

The Ea values of aspirin hydrolysis, as a result of hydronium-ion catalysis, intramolecular-nucleophilic catalysis, and hydroxyl-ion catalysis, were significantly different from each other when determined in the 30-40, 45-55, and 60-70 degrees C ranges. The different Ea values were attributed to differences in both delta H* and delta S*, which could be accounted for by the various activated complexes formed in the hydrolysis of aspirin for each mechanism and the disruptive effect of temperature on the iceberg structures of water present around the phenyl group and the methyl group of aspirin at 42 and 58 degrees C, respectively. A linear relationship observed between the calculated "differential" enthalpy and entropy values, with a slope (compensation temperature) value of about 307 degrees K, supported a role for icebergs associated with hydrophobic groups in the formation of the activated complexes. This study illustrates that the predicted shelf life of a drug at room temperature could be erroneous if estimated from a single Ea value which is calculated from the decomposition rate constants determined at widely spaced temperatures in the range of 10-70 degrees C, using the Arrhenius relationship.