Elucidating the Solvent‐Dependent Solvation and Structural Stability of Irinotecan: A Molecular Simulation Study

The clinical application of the chemotherapeutic agent irinotecan is critically hindered by its low and variable solubility. To provide a fundamental understanding of this issue, we employed molecular dynamics simulations and free energy calculations to detail the solvation thermodynamics of irinotecan. Our analysis reveals that irinotecan's solvation preference is governed by a delicate and often competitive balance between two fundamental physical contributions: the Lennard–Jones term (representing cavity formation and dispersion) and favorable solute–solvent electrostatic interactions. We demonstrate that while polar protic solvents (e.g., water) provide the strongest electrostatic stabilization, their high energetic cost for cavity formation severely limits overall solvation favorability. Conversely, polar aprotic solvents (e.g., pyridine and DMSO) optimize this balance by facilitating easier cavity formation while still providing strong electrostatic interactions, resulting in the most favorable solvation profiles. Notably, irinotecan's unexpectedly high relative solubility in cyclohexane compared to water underscores the critical role of solvent reorganization energy in dictating solution‐phase behavior. These molecular‐level findings are rigorously validated by structural analyses (connection matrices and radial distribution functions) and a complementary macroscopic solubility parameter analysis (MOSCED framework). This study offers a robust, integrated, and predictive physicochemical framework for understanding and optimizing the formulation of complex, flexible drug molecules.