Evaluation of the impact of formulations and preparation conditions of reconstituted pemetrexed (PEME) specialties on its stability in infusion bags

Introduction
Amid growing budgetary constraints on healthcare systems, generic drugs offer a valuable opportunity for cost savings. However, variations in pharmaceutical equivalence and stability—both between generics and compared with their reference product—may impact their clinical use. This study aims to assess and compare the In-use physicochemical stability of multiple pemetrexed (PEME) generics following reconstitution and dilution.

Materials and Methods
Seven anonymized PEME specialties, including the reference product ALIMTA^®, were evalu-ated. Each product was reconstituted in either 0.9% NaCl or 5% glucose (G5%), diluted in the same solvent to an identical concentration, and packaged in polypropylene bags (SLB^®). Samples were stored for 28 days at either 2–8 °C or 25 °C, protected from light with Opabag^® covers, resulting in 28 experimental conditions (n = 3 per condition). Physicochemical stability was assessed through: 1) HPLC-UV for active content quantification and screening of impuri-ties and degradation products; 2) pH measurement; and, LC-MS/Orbitrap^® for structural characterization of degradation products. Results were compared to the specifications in the European Pharmacopoeia (EP) monographs for the active substance and the United States Pharmacopeia (USP) monographs for the finished product. Additionally, intrinsic stability of PEME was previously investigated under isothermal conditions and photolysis using a xenon lamp (Q-SUN Xe-1).

Results
Four specialty/solvent pairs showed a reduction in active content from Day 7, rendering them non-compliant with EP criteria, although all remained within USP limits up to Day 28. For impurities and degradation products, 11 experiments were USP non-compliant at Day 7, increasing to 21 by Day 28. One generic formulation containing cyclodextrins exhibited reduced degradation compared with other products, whereas a specialty packaged in non–nitrogen-inerted vials displayed impurities from Day 0. LC-MS analysis identified three novel impurities arising from interactions between PEME, glucose and monothioglycerol. From the intrinsic stability study, Arrhenius modeling indicated higher activation energy, and thus better stability for pemetrexed in 0.9% NaCl. Moreover, PEME showed greater light sensitivity in G5% solutions.

Discussion – Conclusion
Pemetrexed stability is strongly influenced by solvent choice and formulation excipients. Reconstitution in 0.9% NaCl provides better stability than in G5%, while the use of cyclodextrins appears to enhance resistance to degradation. Nitrogen inerting is critical to prevent early impurity formation. These findings demonstrate that seemingly minor formulation differences can substantially impact stability. Therefore, any plan to prepare infusion bags in advance should be supported by systematic stability studies for each specific specialty.

Keyword: Pemetrexed, Drug stability, Generic drugs