(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 ≤8µm, 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.

中文翻译：

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伏立康唑在多合一肠外营养混合物中的理化稳定性和相容性测试

(1) 与多合一 (AiO) 肠外营养 (PN) 混合物的药物相容性是一个非常重要的药物质量问题，需要根据适当的实验室测试来回答。我们评估了伏立康唑 (V)，这是一种水溶性差 (logP ≈ 1) 的每日单剂量抗真菌药物，在患者中进行监测，因此是 AiO PN 混合的候选药物，以方便和安全地护理患者。我们通过适应的治疗药物监测方法（药物稳定性）和通过自动显微数字评估改进的脂滴分析的视觉显微乳液稳定性评估了 AiO PN 混合物中的 V 相容性和稳定性。(2) V 以 0.05/0.25/0.5 mg/mL (143.1/715.7/1431.5 µM) 的浓度添加到三种市售工业 AiO PN 混合物中，与每日治疗剂量相关。三等分试样分别储存在冰箱 (4 °C)、室温 (24 °C) 和压力条件下的水浴 (37 °C) 中。在混合后 0/24/48/72/168 小时采集的样品进行为期一周的稳定性指示分析。评估包括目视检查、根据已建立和验证的方法（使用油浸的明视野显微镜）进行的脂滴测量、pH 测量（玻璃电极）和 V 识别/定量（LC-MS/MS）。(3) 一周后，所有样品在 37°C 下均出现轻微的黄色变色。pH值保持稳定。根据尺寸（上尺寸≤8μm，平均尺寸<4.5±2μm）和数量（在混合后 0/24/48/72/168 小时采集的样品进行为期一周的稳定性指示分析。评估包括目视检查、根据已建立和验证的方法（使用油浸的明视野显微镜）进行的脂滴测量、pH 测量（玻璃电极）和 V 识别/定量（LC-MS/MS）。(3) 一周后，所有样品在 37°C 下均出现轻微的黄色变色。pH值保持稳定。根据尺寸（上尺寸≤8μm，平均尺寸<4.5±2μm）和数量（在混合后 0/24/48/72/168 小时采集的样品进行为期一周的稳定性指示分析。评估包括目视检查、根据已建立和验证的方法（使用油浸的明视野显微镜）进行的脂滴测量、pH 测量（玻璃电极）和 V 识别/定量（LC-MS/MS）。(3) 一周后，所有样品在 37°C 下均出现轻微的黄色变色。pH值保持稳定。根据尺寸（上尺寸≤8μm，平均尺寸<4.5±2μm）和数量（pH 测量（玻璃电极）和 V 鉴定/定量（LC-MS/MS）。(3) 一周后，所有样品在 37°C 下均出现轻微的黄色变色。pH值保持稳定。根据尺寸（上尺寸≤8μm，平均尺寸<4.5±2μm）和数量（pH 测量（玻璃电极）和 V 鉴定/定量（LC-MS/MS）。(3) 一周后，所有样品在 37°C 下均出现轻微的黄色变色。pH值保持稳定。根据尺寸（上尺寸≤8μm，平均尺寸<4.5±2μm）和数量（n ≤ 9 个脂滴 >5 µm)。V 浓度在可接受的范围内，针对每个时间点计算为掺入 AiO PN 的理论浓度的百分比。中位数回收率为 98.2%（最小-最大，90-112%）。(4) 在治疗剂量下，商业 V 制剂在 4–37 °C 下在常用体积的商业 AiO PN 混合物中相容并在规格范围内稳定超过 1 周。