Control of API release with matrix polymorphism in tristearin microspheres

Glycerides are widely employed as solid matrices in a range of pharmaceutical intermediates and dosage forms. Diffusion-based mechanisms are responsible for drug release, with both chemical and crystal polymorph differences in the solid lipid matrix cited as controlling factors in drug release rates. This work uses model formulations composed of crystalline caffeine embedded in tristearin to study the impacts to drug release from the two primary polymorphic states of tristearin and dependencies on the conversion routes between them. Using contact angles and NMR diffusometry, this work finds that drug release from the meta-stable alpha-polymorph is rate limited by a diffusive mechanism relating to its porosity and tortuosity, but initial burst release occurs due to ease of initial wetting. Poor wettability resulting from surface blooming can be rate limiting for the 13-polymorph, resulting in slower initial drug release relative to the alpha-polymorph. The route to achieve the 13-polymorph strongly impacts the bulk release profile due to differences in crystallite size and packing efficiency. API loading enhances the effective porosity, leading to enhanced drug release at high loadings. These findings offer generalizable principles to guide formulators on the types of impacts to drug release rates that one may expect due to triglyceride polymorphism.

Automated summary

Glycerides are commonly used as solid matrices in pharmaceutical intermediates and dosage forms. The release of drugs from these matrices is controlled by diffusion-based mechanisms, with chemical and crystal polymorph differences of the lipid matrix influencing the release rates. This study focuses on the impacts of tristearin polymorphism on drug release using model formulations containing crystalline caffeine. The results show that the release rates are influenced by the polymorphic states of tristearin and the conversion routes between them. The findings provide valuable insights for formulators in understanding the impacts of triglyceride polymorphism on drug release rates.