Critical concentrations in the dilution of oral self-microemulsifying drug delivery systems

Abstract

Background: Self-microemulsifying drug delivery systems provide a key technology to formulate challenging drugs. These formulations are commonly screened in early development by simple in vitro dilution tests. However, there is often a lack of rationale of how these tests are performed; so this article aims to improve this situation by studying critical concentrations in the dilution of self-microemulsifying formulations. Methods: Dynamic laser light backscattering, conductivity measurements, and electron paramagnetic resonance spectroscopy were conducted. Results: All model formulations exhibited profound changes at a similar aqueous dilution, which was interpreted as a percolation threshold of the formulation in water. It marked the change of a bicontinuous microemulsion to discrete micelles. The systems exhibited at this point maximal particle dispersion with a threshold of polydispersity. A marked change was also observed in the paramagnetic resonance spectra and with the conductivity measurements. This altered microenvironment can be relevant for solubilized drugs. Conclusions: Future dilution tests should include a formulation-to-water ratio of roughly 1:5 (w/w), which is in the proximity of the individual threshold concentration. Additional dilutions may be tested below and clearly above this value to reflect the physiological dilution process.