Solubilization Strength Characterization of Parenteral Solutions Containing Polysorbate 80 in Support of Extractable & Leachable Studies

Leaching of chemical constituents from pharmaceutical polymeric contact materials to clinically relevant solutions including process streams, drug products, or body compartments, is a physicochemical process demanding expert analysis to ensure the safety and efficacy of a medicinal or medical product. Regulatory agencies require information generated by safety assessment that typically include experimental data supporting the suitability of a given contact material for the marketing authorization of a product. The extraction propensity of a parenteral solution towards polymers, and hence the profile of leachables in e.g. a drug product at the end of its shelf life, depends on its qualitative and quantitative composition of excipients. Thermodynamic partition coefficients describe the extraction propensity of a contact solution through equilibrium concentrations in solution and polymer. Simulating solvent mixtures containing a fixed amount of alcohol and water are regularly employed in experimental studies supporting authorization to facilitate experimental procedures when collecting data on extractable (i.e., potential leachable) and leachable compounds.

Here, simulating solvent mixtures are utilized with the intention of mimicking the extraction propensity of a drug product. In this work, a linear solvation energy relationship (LSER) was established to calculate the solubilization strength of polysorbate 80 (PS 80), a frequently formulated solubilizing excipient, in water. The system parameters of the LSER model were reported, discussed, and a critical examination of data sourced from the literature and determined here was provided.  The individual solubilizing mechanism of other relevant excipients, as well as their effect on aqueous solubilization in combination with each other and PS 80, was explored. It was found that solubilizing excipients such as PS 80 dominate aqueous solubilization in drug product solutions, and therefore dominate a drug product’s extraction propensity.  In an exercise to generate appropriate simulating solvent compositions for individual drug products, the solubilization strength of simulating solvent mixtures containing either ethanol or isopropanol were aligned with the solubilization strength of PS 80 solutions representing drug products by applying LSER equations from literature and this work. Chemical identity of a leachable and PS 80 concentration in solution were shown to dictate the suitable alcohol concentration in the simulating solvent. By utilizing simulating solvents with aligned solubilization, a better representation of drug product solutions and, consequently, a more representative extraction profile in simulation studies is expected.

Finally, migration of model leachables from loaded polymer disks into pharmaceutically relevant solutions was determined in a case study. By means of LSER predicted partition coefficients and a thermodynamic cycle, equilibrium leachable concentrations in solution were successfully forecast. Predictions were solely based on the total amount of loaded leachable, volume of contact phases, and calculated partition coefficients between polymer and solution.  This thesis demonstrated the practicability of LSER predictions to align the solubilization strength of simulating solvents with drug products and to determine equilibrium leachable concentrations in a drug product from chemical extraction data.

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Information: Adrian Benedict Strobel. Johannes Gutenberg-Universität, Mainz. 2021.