Study of Extractables in High-Density Polyethylene Packaging: Evaluation of the Impact of Excipients Propylene Glycol, Mint Flavor, and Benzalkonium Chloride on the Leaching Process of Semi-volatile Additives

The study of extractables and leachables has become increasingly important in the pharmaceutical industry, with growing concerns about minimizing impurity risks in final products. Polymeric materials are widely used in pharmaceutical packaging due to their many advantages, but they can also introduce impurities. These materials often contain low molecular mass additives that may migrate into the product during storage and shelf life. This issue is particularly critical in liquid pharmaceutical formulations, which are more prone to interactions with packaging materials. In this context, the present work evaluates the extractive potential of selected excipients - benzalkonium chloride, propylene glycol, and mint flavor - in aqueous formulations stored in high-density polyethylene (HDPE) containers. The main goal is to compare the physicochemical properties of these excipients in the formulation with the additives extracted from the packaging. In summary, benzalkonium chloride (the excipient with the highest log P value) demonstrated the greatest extraction power, through the extraction of 7,9-di-tert-butyl-1-oxaspiro(4,5)deca-6,9-diene-2,8-dione, palmitic acid, and stearic acid. The mint aroma and propylene glycol contributed only to the extraction of 7,9-di-tert-butyl-1-oxaspiro(4,5)deca-6,9-diene-2,8-dione (the additive with the lowest log P value). Therefore, the novelty of this study lies in its empirical approach to correlating the physicochemical parameters of excipients with leachables, providing a predictive framework for leaching behavior in the pharmaceutical industry.