Dynamic self-assembled meso-structures formed across a wide concentration range in aqueous solutions of propranolol hydrochloride

Hypothesis: Nanoscale characterisation of the self-associated species formed by amphiphilic pharmaceuticals in aqueous solution carries relevance across their entire journey from development through to manufacture - relevant, therefore, not only as regards formulation of the drug products as medicines, but also potentially relevant to their bioavailability, activity, and clinical side effects. Such knowledge and understanding, however, can only be fully secured by applying a range of experimental and theoretical methodologies.

Experiments: Herein, we apply a synergistic combination of solubility, surface tension, SANS, NMR and UV spectroscopic studies, together with MD simulation and QM calculations, to investigate the meso-structures of propranolol hydrochloride aggregates in bulk aqueous solutions, at concentrations spanning 2.5 mM to > 200 mM. In addition, we explore the effects of adding NaCl to mimic the ionic strength of physiological fluids, and the differences between racemate and single enantiomer.

Findings: There is a continuum of particle sizes shown to exist across the entire concentration range, with molecules joining and leaving on the nanosecond timescale, and with the distributions of aggregate sizes varying with drug and salt concentration. Given that propranolol is a highly prescribed (WHO essential) medicine, disfavouring aggregators from consideration in high-throughput screening for potential new drug candidates - as many have advocated - should thus be done cautiously.