Theoretical Prediction of (pKa) and Thermodynamic Parameters Using Dft and PM3 Methods: Application to NSAIDs

In this study, the thermodynamic functions of six pharmaceutical chemical compounds were calculated, and their theoretical ionization constants were determined, including enthalpy change (ΔH), Gibbs free energy change (ΔG), and entropy change (ΔS). These calculations were performed using different theoretical methods, namely the DFT/6-31G method, which is classified as an ab initio computational approach, and the PM3 method, which belongs to the semi-empirical computational methods. A statistical correlation was conducted between the calculated thermodynamic functions (ΔH, ΔG, ΔS) and the experimentally determined ionization constants. The results showed that the DFT/6-31G method yielded the best correlation coefficient between enthalpy values and experimental ionization constants, with a value of R² = 0.9396. Similarly, for the PM3 method, the highest correlation coefficient obtained was R² = 0.9392, also between enthalpy values and experimental ionization constants. An increase in the thermodynamic functions leads to an increase in pKa values, indicating a decrease in acidity, whereas a decrease in the thermodynamic functions results in lower pKa values, corresponding to increased acidity. Hence, the relationship between thermodynamic functions and acidity is inverse.This method is an effective tool for drug and understanding its properties, offering high precision (R² > 0.93).