Physicochemical Stability and Compatibility Testing of Voriconazole in All-in-One Parenteral Nutrition Admixtures

Abstract

(1) Drug compatibility with all-in-one (AiO) parenteral nutrition (PN) admixtures is a very important pharmaceutical quality issue to be answered based on appropriate laboratory testing. We assessed voriconazole (V), a poorly water-soluble (logP ≈ 1) single-daily dosed antifungal drug monitored in patients and thus candidate for AiO PN admixing for convenient and safe patient care. We evaluated V compatibility and stability in AiO PN admixtures through adapted therapeutic drug monitoring method (drug stability) and visual microscopic emulsion stability by lipid droplets analysis improved by an automated microscopic digital assessment. (2) V was added in concentrations of 0.05/0.25/0.5 mg/mL (143.1/715.7/1431.5 µM), correlating to daily therapeutic dosing, to three commercially available industrial AiO PN admixtures. Three aliquots were stored in the refrigerator (4 °C), at room temperature (24 °C) and under stress conditions in a water bath (37 °C). Samples taken at 0/24/48/72/168 h after admixing were subjected to a stability-indicating one-week analysis. Assessment included visual examination, lipid droplet measurement according to an established and validated method (bright-field microscopy using oil immersion), pH measurement (glass electrode) and V identification/quantification (LC–MS/MS). (3) After one week, all samples at 37 °C showed slight yellow discoloration. The pH values remained stable. All samples met specifications for lipid droplets according to size (upper size ≤8 µm, mean size <4.5 ± 2 µm) and number (n ≤ 9 lipid droplets >5 µm). V concentrations were within an acceptable range, calculated for every timepoint as percent of the theoretical concentration spiked into the AiO PN. The median recovery was 98.2% (min–max, 90–112%). (4) At therapeutic doses, commercial V formulations were compatible and stable within specifications over one week in commonly used volumes of commercial AiO PN admixtures at 4–37 °C.