Complexation of Mefenamic Acid by Low‐Generation PAMAM Dendrimers: Insight from NMR Spectroscopy Studies and Molecular Dynamics Simulations

Abstract

The complexation of mefenamic acid (MA) with poly(amido amine) dendrimers of the second and third generation (PAMAM‐G2 and PAMAM‐G3) at pH 7.0 is studied by aqueous solubility experiments, DOSY and 2D‐NOESY spectroscopy, and fully atomistic molecular dynamics (MD) simulations. Solubility profiles account for the formation of MA:PAMAM complexes of the type 10:1 and 15:1, for PAMAM‐G2 and PAMAM‐G3, respectively, with a maximum solubilization enhancement of 14.6 mol of MA per mol dendrimer. Diffusion ordered sepectroscopy (DOSY) and nuclear Overhauser effect spectroscopy (NOESY) experiments suggest that MA association occurs through both external electrostatic interactions with the PAMAM surface and internal encapsulation into the deep dendrimer cavities. MD simulations are consistent with these experimental findings and show that the internal drug encapsulation is enhanced as the dendrimer generation increases. The involvement of internal and external interactions in the complexation of MA with low‐generation PAMAM dendrimers differs from the general behavior expected for acidic anionic guests, for which external electrostatic contacts with the positively charged PAMAM surface have been postulated as the most relevant factor for drug association. image