Implications of formulation change on the in-use stability of compounded pemetrexed infusion bags: Impact of excipients, solvent and storage conditions.

Pemetrexed diluted infusions are often prepared in advance for hospital use. Since patent expiry of the originator, several generics with different formulations and stability claims have become available, but the influence of formulation variables on in-use stability remains unclear. We compared the pharmaceutical quality and in-use stability of seven pemetrexed injectable products. Products were diluted to 5 mg/mL in 0.9% sodium chloride or 5% dextrose, filled into polypropylene infusion bags, and stored at 2-8 °C or 20-25 °C for 28 days. At predefined time points, samples were analyzed for pH, assay and related impurities using the European Pharmacopoeia method complemented by Orbitrap high-resolution mass spectrometry for degradant identification. Although assay remained acceptable, in-use quality was formulation dependent. Hydroxypropyl-β-cyclodextrin appeared to improve stability, and storage at 2-8 °C in 0.9% sodium chloride under light and oxygen protection minimized degradation. High-resolution mass spectrometry identified ketopemetrexed-related degradants, and a new degradation product whose exact mass is consistent with a pemetrexed dextrose adduct product. This study highlights the need for systematic in-use stability assessment whenever the summary of product characteristics' recommendations cannot be followed, even when stability data exists for other formulations containing the same active pharmaceutical ingredient.