Stability of extemporaneously prepared cytarabine, methotrexate sodium, and methylprednisolone sodium succinate

Abstract

Purpose: The short-term stability of extemporaneously prepared triple intrathecal therapy, containing cytarabine, methotrexate sodium, and methylprednisolone sodium succinate, was evaluated.

Methods: Three batches of triple intrathecal solution were prepared using commercially available products and stored in three different packaging materials (plastic syringe system, brown glass vials, and brown glass vials filled with metal needles). The solutions were protected from light and stored at 5 °C, 25 °C, and 40 °C or exposed to ultraviolet and visible light at 25 °C, compliant with the International Conference on Harmonisation. Samples were taken immediately before and after 4, 8, 24, 32, and 48 hours of storage. Simultaneous high-performance liquid chromatography- ultraviolet light/diode array detector assay of cytarabine, methotrexate sodium, and methylprednisolone sodium succinate was performed using a fused-core stationary phase and an acetonitrile-based gradient. First-order kinetic degradation values were calculated, and temperature dependence was evaluated using the Arrhenius equation.

Results: Cytarabine was stable under all storage conditions. Methotrexate sodium displayed significant degradation after light exposure but remained stable under the other storage conditions. Methylprednisolone sodium succinate was found to be the most labile component in the triple intrathecal solution. Temperature-dependent degradation was observed, resulting in 46% degradation after 48 hours at 40 °C. Two degradants were formed: methylprednisolone and methylprednisolone hydrogen succinate. Packaging material and batch-to-batch variability did not significantly influence the stability of the triple intrathecal solution.

Conclusion: Triple intrathecal solution of cytarabine, methotrexate sodium, and methylprednisolone sodium succinate was stable for up to 12 hours when stored at 5 °C and protected from light.