New thermodynamic aspects and speciation properties of the angiotensin-converting enzyme inhibitor drug, lisinopril with Cu2+, Zn2+, Ca2+, Mg2+ in sodium chloride aqueous solution

Abstract

(2S)-1-[(2S)-6-amino-2-[[(1S)-1-carboxy-3-phenylpropyl]amino]hexanoyl]pyrrolidine-2- carboxylic acid (Lisinopril) is a drug commonly used to treat hypertension and heart failure. In recent years, it has also been identified as an emerging environmental contaminant. In this study, the thermodynamic behavior of lisinopril in aqueous solution was investigated. The protonation constants of lisinopril were determined potentiometrically at different temperatures (288.15 ≤ T/K ≤ 310.15) and ionic strengths (0.16 ≤ I/mol kg⁻¹(H₂O) ≤ 0.97, NaCl). The findings indicate that the first two and the fourth protonation steps are driven by enthalpic contributions, whereas the third is slightly entropy driven. Furthermore, based on the distinct acid-base characteristics of the metal ions and the possible formation of sparingly soluble species, different speciation models were proposed for the various metal/lisinopril systems, including: ZnH₂L⁺², ZnHL⁺, CuHL⁺, CuL, CaL, CaHL⁺, MgL and MgHL⁺. The Specific Ion Interaction Theory (SIT) and a modified extended Debye–Hückel equation were employed to model the thermodynamic formation parameters as a function of ionic strength and temperature. Finally, the distribution of lisinopril species (protonation and complex formation constants) under conditions simulating real systems, such as seawater, was evaluated.