Ionization and Partitioning Profiles of Zwitterions: The case of the anti‐inflammatory drug azapropazone

Azapropazone (1) is a non‐steroidal anti‐inflammatory drug (NSAID) whose chemical structure is markedly different from that of other agents in this class and challenges our understanding of structure‐activity and structure‐permeation relationships. Using a variety of experimental and computational techniques, we studied 1 for its molecular structure in the gas phase and non‐protic polar solvents, protonation/deprotonation equilibra, tautomerism, and pH‐lipophilicity profiles (octan‐1‐ol/H2O and dodecane/H2O). Other NSAIDs and model compounds were also examined for comparison. Due to its very low acidic pKa1, 1 exists in the physiological pH range as a zwitterion and as an anion. Some pharmacological implications of these findings are discussed.