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

Abstract

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.

Introduction

Leachable compounds can be defined as “organic and inorganic chemical entities that migrate from
the packaging/delivery system, packaging component, or packaging material of construction into the drug
under normal storage and use conditions or during accelerated stability studies of the drug”.1 Extractable
compounds, on the other hand, can be defined as “organic and inorganic chemical entities released from
a packaging system and/or packaging component through extraction under laboratory conditions”.2 These
compounds can be found in various products, including pharmaceuticals,3-7 cosmetics,8 and food,9 and may
pose health risks due to their continuous ingestion. For example, additives such as Irganox® 1010 have
been detected in ophthalmic drug products stored in plastic packaging.5 This process occurs due to the
interaction between the plastic and the formulation, which can cause the migration of low molecular mass
additives to the product. This phenomenon is dependent on the pharmaceutical form, being more relevant
in liquid/aerosol formulations and lower in solid formulations.1,10

Pharmaceutical products are formulated with excipients to provide a specific and definitive therapeutic
benefit to the user. The function of these compounds is to protect and enhance the stability of the formulation
(since some active pharmaceutical ingredients – API – do not maintain stability when isolated, either
denaturing or adhering to the walls of the container), increase the volume of the formulation, aid in solving
formulation problems such as dissolution and improve the consumer acceptance. Furthermore, they aid in
the bioavailability of the API, as in many cases, these compounds are not easily absorbed by the human
body. Thus, the mixture with an excipient can act as a solvent in this process.11 In this context, the choice
of excipients during formulation development can be crucial to the product success, potentially impacting
the leaching of packaging components. The same properties of excipients that facilitate an increase in
the solubility of the active ingredient may also facilitate the leaching of compounds in contact with various
polymeric materials.12

Plastics are widely used in packaging and the production process within the pharmaceutical industry
due to their excellent cost-effectiveness compared to other available materials, as well as their unique
characteristics. The versatility of plastic can be attributed to the different types of monomers and additives
added during the process to enhance the polymer performance and durability. Additives can be categorized
into various classes, such as: plasticizers, flame retardants, antioxidants, acid removers, light and heat
stabilizers, lubricants, pigments, antistatic agents, slip compounds, and thermal stabilizers.10,13
In this article, the focus was on evaluating the extraction potential of different excipients present in liquid
formulations stored in high-density polyethylene bottles in order to infer which excipients and concentrations
might be critical for the product. This information can support the choice of excipients during formulation
development and, subsequently, the risk analysis of extractables and leachables in the product. For this
purpose, analytical methods were developed to evaluate the semi-volatile additives from the plastic bottle
using gas chromatography coupled to mass spectrometry (GC-MS). In order to obtain realistic results, an
accelerated study was conducted to simulate the interaction between the drug and the packaging material
under storage conditions. The results were used to correlate the physicochemical characteristics of the
excipients with the concentration of additives extracted from the packaging material.

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Materials

Potassium chloride, monosodium phosphate, disodium phosphate, sodium hydroxide, dichloromethane and sodium chloride were purchased from Merck (New Jersey, USA), isopropanol and acetonitrile were purchased from J.T. Baker (Pennsylvania, USA), and hexane and hydrochloric acid were purchased from Biograde (North Carolina, USA). The high-density polyethylene packaging material purchased from Plastic Industrial Bacic (São Paulo, Brazil).

Bda Cunha, V. M. G.; de Medeiros, L. D.; Pugliesi, F.; de Oliveira, B.; Sussulini, A. 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. Braz. J. Anal. Chem. (Forthcoming). http://dx.doi.org/10.30744/brjac.2179-3425. AR-51-2025

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