Development of improved physicochemical test procedures for pharmaceutical elastomeric closures.

摘要

Due to their unique physical and chemical properties, elastomers have been used as closures for pharmaceuticals since the early 1900's. Over the years, however, extractables from elastomeric closures have been the cause of stability failures and product recalls.1--8 The current compendial physiochemical test requirements for elastomeric closures are a combination of non-specific wet chemical analyses performed on samples extracted into either water, isopropanol (IPA) or the drug product vehicle. Preliminary results from our testing indicated that these tests did not accurately measure the levels of extractables in the closures.; A partition chromatographic method was utilized which estimated the relative partition coefficients (K) of the elastomeric extractables and the formulation components. The relative affinity between the extractables and the formulation was then determined based on the similarities of these partition coefficients. It is hypothesized that extractables with partition coefficients similar to a formulation will have a greater probability of interacting (absorption or desorption).; An HPLC gradient method was developed which had the required sensitivity and specificity to perform the analysis and which was a strong predictor of partition coefficients (r ≈ 0.9). Extractions were performed on various stopper types. Experiments were also performed in an attempt to improve these extractions. This was accomplished by increasing the time of the extractions, increasing the closure surface area and by extracting with a stronger non-polar solvent; methylene chloride (CH2Cl2). The HPLC gradient method and the compendial wet chemical tests were then used to evaluate the stopper extractables.; Results of the compendial analyses were insignificant as the number and relative amount of extractables in the closure could not be measured. Testing was dramatically improved using the HPLC gradient method. As many as twenty extractables were detected in some of the IPA and CH2Cl2 samples and, unlike the compendial analysis, low level extractables were detected in the water samples. Identification of some of the unknown elastomeric extractables was accomplished via GUMS utilizing electron impact ionization.; Interaction studies were initiated in which stopper - parenteral formulation mixtures (having various values for K) were stored at both ambient and accelerated conditions and assayed over a two month period. Results indicated that pharmaceutical compounds with high partition coefficients were absorbed by hydrophobic stoppers and that hydrophobic extractables were leached into formulations which had components with high partition coefficients. There was no interaction observed between formulation components and extractables with partition coefficients lower than 3.