Spray congealing with solid lipid materials: Rheological, solid state and drug release investigations

摘要

This study seeks to explore spray congealing as an efficient technology to embed drugs in meltable lipid matrices such as fatty alcohols, fatty acids, fatty esters and glycerides, and produce solid lipid microparticles. These meltable materials from different chemical classes possess a variety of physicochemical properties. Polymeric additives, polyvinyl-2-pyrrolidonevinyl- acetate (PVP/VA) and ethyl cellulose (EC) were added to the lipid matrix to act as release- modifying agents by their effects on matrix viscosity and characteristics of the resultant spray-congealed microparticles. Intermolecular interactions between the lipid-based material and additive were also investigated using spectroscopic techniques.;The viscosity-temperature relationship of the lipid-based materials was investigated, culminating in the development of a new model which could better describe the relationship than existing viscosity-temperature models. A temperature-independent rheological parameter, Tp, was derived. The Tp values were found to correlate better than viscosity with the size of the resultant spray-congealed microparticle. The Tp value, which is characteristic of the lipid-based material, was affected by the polymeric additives. It can therefore be used for the optimization of lipid-based formulations to produce spray-congealed microparticles of the desired size range.;The spray congealing process caused polymorphic changes to glyceryl dibehenate and the model drug, ibuprofen. Further changes during storage for up to a year were monitored. The polymeric additives were found to affect the stability of the polymorphs to different extents. PVP/VA and EC expanded the unit cell dimensions of cetyl alcohol but had negligible effect on stearic acid. They can also either accelerate or decelerate the polymorphic transformations in glyceryl dibehenate.;The different solid lipid microparticles showed varying ability to sustain the release of ibuprofen. The effect on drug release was influenced by the nature of lipid-based material, microparticle size, drug-matrix miscibility and nature of additives added. Unlike cetyl alcohol, stearic acid and glyceryl dibehenate were useful as lipid matrix materials for the production of sustained release microparticles. Larger solid lipid microparticles (with higher additive concentration) generally led to slower drug release. PVP/VA and EC were useful as release modifying agents but their effects were not easily generalizable. From the scanning electron microscope (SEM) images of the microparticles taken pre- and post-dissolution together with drug release modelling, it appeared that the drug release mechanisms differed for the microparticles prepared using different lipid matrices. For solid lipid microparticles prepared using stearic acid or glyceryl dibehenate, diffusion was found to be the main release mechanism. For cetyl alcohol, drug release was characterized by an initial burst release of the bulk of the encapsulated drug followed by a loss of integrity of the microparticle structure which led to a generally fast release rate.