Isothermal titration calorimetry vs. high performance liquid chromatography fingerprint: Prediction of adverse drug reactions of combination for Chinese medicine injections

Chinese Medicine Injections (CMIs) are powerful preparations, but adverse drug reactions can hardly be avoided. Incorrect drug combination is a major cause. Recently, insoluble particulate matter test, pH measurement, and high performance liquid chromatography (HPLC) fingerprint have been recommended as potential strategies for prediction of drug-incompatible reactions. However, these methods were complex to manipulate, subjective to judge, or were of poor relevance and low sensitivity. In this study, a novel application for the detection of compatibility of combination of CMIs based on isothermal titration calorimetry (ITC) has been proposed. Qingkailing Injection (QKL) was selected as a representative drug to blend with Potassium Chloride Injection (KCl) and Calcium Chloride Injection (CaCl 2 ). The type of reactions between them was intuitively manifested by the thermodynamic parameters including Gibbs free energy change (Δ G ), enthalpy change (Δ H ), and entropy change (Δ S ). The results indicated that when QKL mixed with CaCl 2 , Δ G T |Δ S |, which meant chemical changes happened between them and ADRs might happen in clinic. On the contrary, the reactions between QKL and KCl existed solely as physical processes, indicating that it was relatively safe. Meanwhile, HPLC fingerprint was also applied, but no significant difference was found. It is hard to distinguish whether incompatible reactions have happened during HPLC. The study suggested that with the advantages of convenience, sensitivity, and reliability, ITC could serve as an essential tool in the detection of incompatible reactions of drug combination. The described method could be used for early prediction of adverse drug reactions, which would be helpful to ensure the rationality of drug combination.