RESUMO
In pharmaceutical oral drug delivery development, about 90% of drugs in the pipeline have poor aqueous solubility leading to severe challenges with oral bioavailability and translation to effective and safe drug products. Amorphous solid dispersions (ASDs) have been utilized to enhance the oral bioavailability of poorly soluble active pharmaceutical ingredients (APIs). However, a limited selection of regulatory-approved polymer excipients exists for the development and further understanding of tailor-made ASDs. Thus, a significant need exists to better understand how polymers can be designed to interact with specific API moieties. Here, we demonstrate how an automated combinatorial library approach can be applied to the synthesis and screening of polymer excipients for the model drug probucol. We synthesized a library of 25 random heteropolymers containing one hydrophilic monomer (2-hydroxypropyl acrylate (HPA)) and four hydrophobic monomers at varied incorporation. The performance of ASDs made by a rapid film casting method was evaluated by dissolution using ultra-performance liquid chromatography (UPLC) sampling at various time points. This combinatorial library and rapid screening strategy enabled us to identify a relationship between polymer hydrophobicity, monomer hydrophobic side group geometry, and API dissolution performance. Remarkably, the most effective synthesized polymers displayed slower drug release kinetics compared to industry standard polymer excipients, showing the ability to modulate the drug release profile. Future coupling of high throughput polymer synthesis, high throughput screening (HTS), and quantitative modeling would enable specification of designer polymer excipients for specific API functionalities.
RESUMO
Recent advances in oxygen-tolerant controlled/living radical polymer chemistry now enable efficient synthesis of diverse and combinatorial polymer libraries. While library synthesis has been dramatically simplified, equally efficient purification strategies for removal of small-molecule impurities are not yet established in high throughput settings. It is shown that gel filtration columns for chromatography frequently used in the protein science community are well suited for high throughput polymer purification. Using either single-use columns or gel filtration plates, the purification of 32 diverse polymers is demonstrated in a library with >95% removal of small molecule impurities and >85% polymer retention in a single purification step. Doing so replaces the typical procedure of polymer precipitation, which requires solvent optimization for each polymer in a complex library. Overall, this work raises awareness in the polymer science community that gel filtration is amenable to purification of large polymer libraries and can speed up the progress of combinatorial polymer chemistry.
