Changes in recovery due to drug product matrix ageing as a source of mass imbalances

Abstract

An important quality feature of stability testing of drug products is mass balance. Besides several known or anticipated causes for mass imbalances, a further potential cause that has not yet been systematically assessed might be incomplete recovery due to the influence of matrix ageing. The genotoxic degradation product 4-chloroaniline (PCA) and the unstable drug substance estradiol (E2) that is known to be difficult to extract from matrices in low-dose solid formulations were chosen as examples. A marketed product containing E2 as well as two marketed products that potentially contain PCA were investigated together with experimental formulations containing E2 or PCA that were produced for this study. To accelerate drug product matrix ageing, samples were stored at different conditions for defined storage periods. PCA and E2 recovery was determined at all sampling time points, respectively. In comparison to unstressed samples, significant changes in recovery were observed in 67% of the formulations investigated. Consequently, the outlined procedure can be regarded as a promising approach to reveal potential reasons for mass imbalance.