title: Can we estimate the critical micelle concentration of amphiphilic drug bases from molecular connectivity indices?
abstract: Self-aggregation of drugs is since many years an important topic in the pharmaceutical sciences. Drugs can aggregate similar to surfactants and thereby exhibit a critical micelle concentration (CMC). The present work focused on amphiphilic drug bases and it was aimed to predict log(CMC) based on chemical structure alone. A dataset of 35 compounds was gathered mostly form the literature and complemented with own measurements based on ultrasonic resonator technology. The hydrophilic-lipophilic balance (HLB) values of the protonated bases were calculated and provided a range of 22.9-27.4. Based on a hypothesis from surfactant sciences, it was tried to predict log(CMC) with connectivity and shape indices as well as molecular dipole moment. A fairly good model was obtained using the Randix index (RI), 3 D Wiener number (WN) and molecular dipole moment (DM) (R2= 0.824). Interestingly, a simple linear regression of log(CMC) with the Randic index alone, resulted in an acceptable model (R2= 0.755). The present work should help with early identification of drug bases that exhibit surfactant-like behavior and an estimation of log(CMC) values is proposed. An improved understanding of drug aggregation and prediction of log(CMC) helps to better cope with physical consequences like, for example, "anomalous" drug solubility in drug discovery and development.
authors.affiliation: a University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences, Institute of Pharma Technology , Muttenz , Switzerland.|b University of Basel, Institute of Pharmaceutical Technology , Basel , Switzerland.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Saal
authors.affiliation: c Roche Pharmaceutical Research and Early Development, Pre-Clinical CMC, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd , Basel , Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Wyttenbach
authors.affiliation: c Roche Pharmaceutical Research and Early Development, Pre-Clinical CMC, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd , Basel , Switzerland.
authors.forename: Jochem
authors.initials: J
authors.lastname: Alsenz
authors.affiliation: a University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences, Institute of Pharma Technology , Muttenz , Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Kuentz
mesh_terms: D057927:Hydrophobic and Hydrophilic Interactions; D008823:Micelles; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D012995:Solubility; D013501:Surface-Active Agents / Q000737:chemistry
chemical_list: D008823:Micelles; D004364:Pharmaceutical Preparations; D013501:Surface-Active Agents
keywords: Solubility; micelle; molecular modeling; physicochemical properties; surface active