Investigation of the effect of formulated sodium lauryl sulfate on microenvironment-driven dissolution of...

Repotrectinib is a poorly water-soluble tyrosine kinase inhibitor formulated as an immediate-release capsule containing a high level of sodium lauryl sulfate (SLS, approximately 48% w/w of capsule fill) to enhance drug solubility and dissolution. This study investigated the influence of formulation-derived SLS on dissolution behavior and evaluated the mechanistic basis for its impact on dissolution method discrimination. An optimized dissolution method was developed using USP Apparatus II with pH 6.8 phosphate buffer containing 0.3% (w/v) SLS. The influence of formulation variables on dissolution performance was evaluated using capsules containing different drug substance particle sizes and SLS levels. Equilibrium solubility studies, capsule blend suspension experiments, and USP Apparatus IV open-loop and closed-loop configurations were employed to characterize SLS-mediated microenvironmental dissolution behavior. Repotrectinib and SLS concentrations were quantified using chromatographic methods with UV and mass spectrometric detection. The optimized dissolution method provided complete and reproducible drug release and was sensitive to changes in drug substance particle size and substantial reductions in formulation SLS content. Repotrectinib solubility increased proportionally with SLS concentration, reaching approximately 51 mg/mL at high SLS levels. Suspension studies demonstrated a direct relationship between dissolved SLS and repotrectinib concentrations, indicating that localized surfactant enrichment substantially enhanced drug solubilization. USP Apparatus IV experiments showed rapid generation of a transient SLS-rich microenvironment immediately following capsule rupture, resulting in an initial burst of dissolved repotrectinib prior to dilution into the bulk dissolution medium. Formulation-derived SLS plays a dominant role in the early-stage dissolution of repotrectinib capsules by creating a transient microenvironment that substantially enhances drug solubilization. This mechanism provides a scientific basis for understanding dissolution behavior in highly surfactant-loaded formulations and explains the reduced sensitivity of conventional dissolution testing to moderate formulation changes. The findings provide important considerations for dissolution method development, interpretation of discriminating capability, and regulatory assessment of surfactant-containing oral drug products.