Modeling the Migration Behavior of Extractables from Mono- and Multilayer Polyolefin Films to Mathematically Predict the Concentration of Leachable Impurities in Pharmaceutical Drug Products. Part 1: Experimental Details and Modeling Experimental Results.

An important step in the development of a pharmaceutical drug product is to demonstrate acceptable levels of leachable impurities during the shelf-life and therapeutic use of the drug product. If the diffusion and partition coefficients are known, the concentration profile of a leachable impurity in the drug product can be predicted theoretically at a given temperature and time. With this objective in mind, kinetic experiments were performed to study the migration of low- to high-molecular-weight organic compounds from mono- and multilayer polyolefin films. Migration curves at different temperatures were generated for each compound when these films were brought in contact with aqueous solutions with varying pH or with another plastic film made from a different polyolefin material. "Best fit" migration curves and the corresponding diffusion and partition coefficients (about 300 pieces) were obtained by using numerical software developed by FABES. The results obtained show that, in general, the correlation between the calculated diffusion and partition coefficients and temperature, between 30°C and 85°C, obeys the Arrhenius and Van't Hoff equations. In this temperature range, the diffusion and partition coefficients can be used to model and predict migration of the investigated compounds from the same pharmaceutical packaging materials. A comparison of these coefficient values with other polyolefin films also provides insights into the chemistry of the mono- and multilayers and the impact it has on the migration behavior of the compounds. In a consecutive paper, an approach to overestimate the diffusion and partition coefficients to account for the variability in experimental data is explained and finally, the use of these overestimated parameters to predict the concentrations for other compounds leaching from the multilayer films into aqueous drug product formulations is discussed.

Modeling the Migration Behavior of Extractables from Mono- and Multilayer Polyolefin Films to Mathematically Predict the Concentration of Leachable Impurities in Pharmaceutical Drug Products. Part 2: Conservative Diffusion and Partition Coefficient Determinations.

In the development of a pharmaceutical drug product packaging, an important step is to demonstrate acceptable levels of leachable impurities migrating from the packaging material into the drug product during its shelf life and therapeutic use. Such migration processes can be quantified either by analytical methods (which is often challenging and labor intensive) or (in many cases) through theoretical modeling, which is a reliable, quick, and cost-effective method to forecast the level of leachable impurities in the packaged drug when the diffusion and partition coefficients are known. In the previous part, it was shown how these parameters can be determined experimentally, and subsequent theoretical fitting of the results for a series of low- and high-molecular-weight organic compounds (known leachables) in a series of polyolefin materials was performed. One of the interpretations of these results is that a theoretical calculation can be made only for organic compounds and materials whose diffusion/partition/solubility coefficients were determined experimentally and theoretical fitting was achieved. However, in practice, there will be situations in which other leachable compounds may have to be investigated. In such cases, strictly speaking, it would be necessary to perform the whole experimental and fitting procedure for the new compound before a proper theoretical modeling is possible. But this would make the theoretical calculation of a leaching process from a pharmaceutical packaging material a cumbersome and cost intensive procedure. To address this problem, the pools of diffusion and partition coefficients were used to develop an approach that allows the estimation, without any additional experimentation, of so-called "conservative" diffusion and partition coefficients for a much wider range of potential leachables in the polyolefin pharmaceutical packaging materials and aqueous solutions investigated previously.