Investigation of meropenem stability after reconstitution: the influence of buffering and challenges to meet the NHS Yellow Cover Document compliance for continuous infusions in an outpatient setting

Objectives To determine the influence of different buffers, pH and meropenem concentrations on the degradation rates of meropenem in aqueous solution during storage at 32 degrees C, with the aim of developing a formulation suitable for 24-hour infusion in an ambulatory elastomeric device, compliant with the latest National Health Service Pharmaceutical Quality Assurance Committee Yellow Cover Document (YCD) requirements. Methods Meropenem was diluted to 6.25mg/mL and 25mg/mL in aqueous solutions adjusted to various pH with phosphate or citrate buffer and assessed for stability. Meropenem concentrations were determined using a validated stability-indicating high-performance liquid chromatography method at time 0 and following storage for up to 24hours at 32 degrees C as per the YCD requirements. Results Degradation was observed to be slowest in citrate buffer around pH 7 and at a meropenem concentration of 6.25mg/mL; however, losses exceeded 10% after storage for 24hours at 32 degrees C in all of the diluents tested in the study. Conclusions Meropenem at concentrations between 6.25mg/mL and 25mg/mL as tested is not sufficiently stable to administer as a 24-hour infusion in ambulatory device reservoirs. If the YCD 95% minimum content limit is applied, the infusion period must be reduced to less than 6hours for body-worn devices, especially at the higher concentration studied (25mg/mL). This limits the possibility of using elastomeric devices to deliver continuous infusions of meropenem as part of a wider outpatient parenteral antimicrobial therapy service.