The use of polymorphic state modifiers in solid lipid microparticles: The role of structural modifications on drug release performance

This study investigates the correlation between the structural and release properties of solid lipid microparticles (MPs) of tristearin containing 5 % w/w of four different liquid additives used as crystal modifiers: isopropyl myristate (IM), ethyl oleate (EO), oleic acid (OA) and medium chain triglycerides (MCT). All additives accelerated the conversion of the unstable alpha-form of tristearin, formed after the MPs manufacturing, to the stable beta-polymorph and the transformation was completed within 24 h (for IM and EO) or 48 h (for OA and MCT). The kinetic of polymorphic transition at 25 degrees C was investigated by simultaneous synchrotron SAXS/WAXS and DSC analysis after melting and subsequent cooling of the lipid mixture. After crystallization in the alpha-phase, additives accelerate the solid-solid phase transformation to beta-tristearin. SAXS data showed that two types of structural modifications occurred on MPs during storage: compaction of the crystal packing (slight decrease in lamellar thickness) and crystal growth (increased number of stacked lipid lamellae). The release behavior of a model hydrophilic drug (caffeine) at two different amounts (15 % and 30 %) from MPs was studied in water and biorelevant media simulated the gastric and intestinal environment. It was particularly significant that the introduction of IM, EO and MCT were able to prolong the drug release in water, passing from a diffusion-based Higuchi kinetics to a perfect zero-order kinetic. Moreover, the overall release profiles were higher in biorelevant media, where erosion/digestion of MPs was observed. After 6 months, a moderate but statistically significant change in release profile was observed for the MPs with IM and EO, which can be correlated with the timedependent structural alterations (i.e. larger average crystallite size) of these formulations; while MPs with OA or MCT displayed stable release profiles. These findings help to understand the correlation between release behavior, polymorphism and supramolecular-level structural modification of lipid formulations containing crystal modifiers.

Automated summary

This study investigated the correlation between the structure and release properties of solid lipid microparticles (MPs) with different liquid additives. The additives accelerated the conversion of the unstable alpha-form of tristearin to the stable beta-polymorph and caused structural modifications in the MPs. The presence of additives prolonged the drug release in water and resulted in higher release profiles in biorelevant media. The findings suggest that the release behavior can be influenced by the polymorphism and supramolecular-level structural modification of lipid formulations containing crystal modifiers.