Orthosilicate Prodrug Models: Synthesis, Hydrolysis, and Encapsulation in Block Copolymer Nanoparticles

A fundamental drawback hindering the development and clinical application of many new drugs is limited aqueous solubility. An emerging technology, termed flash nanoprecipitation (FNP), relies on the rapid impingement mixing of water and a miscible organic solvent in which an amphiphilic block copolymer and an organic active are co-dissolved. In the resulting aqueous solution, the organic compound and hydrophobic block are encapsulated within the newly formed nanoparticle, which is effectively solubilized by the hydrophilic block. FNP studies using β-carotene as a highly hydrophobic model have resulted in high encapsulation efficiencies, high drug loading, and controllable nanoparticle sizes of approximately 100 nm.

Attempts to encapsulate drug molecules that are not sufficiently water soluble for clinical applications have been less successful due to the tendency of the drugs to crystallize outside of the nanoparticle upon aging via Ostwald ripening. To create more stable nanoparticles, we are investigating novel orthosilicate prodrugs that would increase the hydrophobic nature of the drug (and presumably its tendency to remain in the nanoparticle core). Furthermore, altering the steric character of these hydrolytically labile prodrugs would provide a means to manage the hydrolysis rates and thus drug release. With this goal in mind, we have investigated orthosilicate models to document hydrolytic stabilities by varying the nature of the orthosilicate, acid catalyst strength, and solvent composition. The information obtained from model studies has been applied to hydrocortisone as a representative drug-containing orthosilicate in encapsulation and release studies.