Challenges in assigning purity to certified reference materials

摘要

Fulfilling the mandate of the NMISA "to maintain and develop primary methods for chemical analysis to certify reference materials for SA and the region", the Organic Metrology Group recently participated in an international intercomparison (CCQM P20.e) for the purity assignment of theophylline (1, 3-dimethylxanthine). Theophylline is a widely used anti-asthmatic medication routinely tested by clinical and diagnostic laboratories. No pure substance CRM is currently available for theophylline. Two possible routes to purity assignment may be followed, namely 1) quantitate the major analyte (the assay approach), or 2) subtract the sum of all impurities from 100 percent. The route taken is often determined by the assortment of analytical instrumentation available. Assays of relatively pure substances generally require a primary method of measurement e.g. titrimetry, particularly when there is no CRM available for the measurand. This approach has to demonstrate specificity, i.e. ensure that only the major analyte is being measured. Furthermore, excellent repeatability is essential in order to achieve small uncertainties in the final measurement. The second approach requires a suite of analytical instrumentation to ensure that all possible impurities are measured, because missed impurities will lead to errors. However, the final result will not be affected by large relative uncertainties in the individual impurity measurements. For purity assessment of a substance, the challenge lies in ensuring traceability for a material for which there is no CRM, using only the available instrumentation. For the intercomparison study, high performance liquid chromatography with diode array detection was used to quantitate the individual components of the drug material. Trace level impurities could be measured in the presence of excess theophylline with a (percent)RSD of less than 0.5percent. Method development and intercomparison results will be shown.