Thermodynamic approaches for the prediction of oral drug absorption

Abstract

The present study is a comparative study of three equations, namely the Clausius-Clapeyron, Van't Hoff and Hildebrand (to calculate crystal-liquid fugacity ratio (CLFR) of drug compounds), to select the best model in predicting the intestinal absorption and develop a new classification system based on dose number (D (o)) and CLFR. The required thermodynamic parameters [melting point, enthalpy of fusion (Delta H (m)) and the differential molar heat capacity (a dagger C (pm))] were experimentally obtained by differential scanning calorimetry. Pharmacokinetic data [the human intestinal absorption (F (a)) and apparent permeability of Caco-2 (P (app) _Caco-2)] and D (o) were obtained from the literature. The highest value of CLFR was found for diclofenac with the value of 88.78, 87.29, and 87.84 mol% from Clausius-Clapeyron, Van't Hoff, and Hildebrand approaches, respectively. The lowest CLFR value was seen for memantine with the value of 14.3 x 10(-17) and 26 x 10(-12) mol% from Van't Hoff and Hildebrand equations, respectively. Statistical comparison with the Wilcoxon signed rank test showed that the CLFR values calculated by three equations are different. CLFR values of more than 1 mol% correspond to the complete intestinal absorption (F (a)). There was a sigmoidal dependency between CLFR and F (a), similar to the dependency between P (app) _Caco-2 and F (a). In these modeling, the excellent correlations were obtained in all three models as evidenced by a good coefficient of determination (r (2) ) without a significant difference in the average absolute error. A new classification system from Hildebrand model based on D (o) and CLFR was developed and was in agreement with the biopharmaceutics classification system (70.5%) and the biopharmaceutical drug disposition system (65.6%). This modeling approach can be a valuable tool for scientists as an alternative for intestinal permeability in the biopharmaceutical classification system to develop new oral drugs. The CLFR obtained from Hildebrand model is also more convenient than the Clausius Clapeyron model, because the former does not need to calculate a dagger C (pm) (difficult step in calculating CLFR) for drug compounds. This new classification can help to develop the new drug product in industrial and academic research, without necessary in vivo experiments.