Evaluation of Current Compendial Physiochemical Test Procedures for Pharmaceutical Elastomeric Closures and Development of an Improved HPLC Procedure

Abstract

The interaction between elastomeric container closures and the solutions they confine presents a potential hazard to the consumer due to extraction of closure ingredients into the dosage form. Each of the major Pharmacopeias, the United States, the European, and the Japanese, prescribe testing procedures for elastomeric closures. These consist of a series of non-specific wet chemical analyses performed on samples extracted into water or, in some cases, isopropanol (IPA) or the drug product vehicle. No consideration is given to the extracting potential of the drug product. Results from our testing on ten randomly selected closure samples indicated that these tests are not sensitive or specific enough to accurately measure the levels of extractables. Therefore, an HPLC gradient method was developed which had the required sensitivity and specificity. The prescribed compendial extractions, when performed on the various stopper types, proved inefficient and experiments were conducted in an attempt to improve them. These included increasing the time of the extractions, increasing the closure surface area, and increasing the strength of the extracting solvent (methylene chloride). The HPLC gradient method and the compendial wet chemical tests were then used to evaluate the stopper extractables. Results of the compendial analyses on the prescribed aqueous extractions were inconclusive as the number and relative amount of extractables in the closure could not be measured. The results of the compendial testing were only marginally improved using the stronger extraction conditions. Testing was dramatically improved, however, using the HPLC gradient method. As many as twenty extractables were detected in some of the samples and, unlike the compendial analysis, low level extractables were detected in the water samples. Identification of some of the extractables was accomplished via GC/MS.