Steger P J, Martinelli E F, Mühlebach S F
Department of Pharmacy, Kantonsspital Aarau, Switzerland.
J Clin Pharm Ther. 1996 Apr;21(2):73-8. doi: 10.1111/j.1365-2710.1996.tb00003.x.
The stability of a preservative-free morphine chloride solution for intravenous or intrathecal use manufactured at a concentration of 40 mg/ml, near the solubility limit in water, was studied. The influence of heat and oxygen on morphine content was measured with and without autoclaving, and after additional thermal and oxidative stress. The morphine injection was stable during steam sterilization at 121 degrees C for up to 180 min if the solution was adjusted to a pH of 3.2 and if oxygen was eliminated by saturating the solution and flushing the vial with nitrogen before sealing. By adding an oxidizing agent (200 microliters H2O2 3% per 20 ml vial) before 15 min of sterilization, a decomposition of approximately 20% of morphine resulted when compared to oxygen-free control samples (P < 0.01, n = 3) High-performance liquid chromatography with UV detection (HPLC) and direct UV spectroscopy (UV) (the latter available in most hospital pharmacies for analytical purposes) were compared for specificity, precision and appropriateness for content and stability assessment of morphine solutions. UV could only be used for quantification of undecomposed morphine. Morphine degradation products of stressed solutions interfered with the direct UV assay of morphine at 286 nm, whereas these interfering components were separated by the ion-pair reversed-phase HPLC used. The results demonstrate that even in the absence of stabilizers, morphine chloride solutions may safely be sterilized for 15 min at 121 degrees C. The HPLC method was shown to be sufficiently sensitive and specific for quality control and stability assessment of morphine preparations, and, therefore, appropriate for the validation of the manufacture of morphine injection solutions in hospital pharmacies, where morphine solutions are manufactured in special strengths and volumes for individual patients' needs.
对一种浓度为40mg/ml、接近在水中溶解度极限的用于静脉或鞘内注射的无防腐剂吗啡氯化物溶液的稳定性进行了研究。在有无高压灭菌以及额外的热和氧化应激后，测量了热和氧对吗啡含量的影响。如果将溶液的pH值调节至3.2，并且在密封前通过使溶液饱和并用氮气冲洗小瓶来消除氧气，那么吗啡注射液在121℃蒸汽灭菌长达180分钟的过程中是稳定的。在灭菌前15分钟加入一种氧化剂（每20ml小瓶加入200微升3%的过氧化氢），与无氧对照样品相比，吗啡分解约20%（P<0.01，n = 3）。比较了采用紫外检测的高效液相色谱法（HPLC）和直接紫外光谱法（UV）（后者在大多数医院药房可用于分析目的）在吗啡溶液含量和稳定性评估方面的特异性、精密度和适用性。紫外法只能用于未分解吗啡的定量。应激溶液中的吗啡降解产物干扰了在286nm处对吗啡的直接紫外测定，而使用的离子对反相HPLC可分离这些干扰成分。结果表明，即使在没有稳定剂的情况下，吗啡氯化物溶液也可在121℃安全灭菌15分钟。HPLC法对吗啡制剂的质量控制和稳定性评估具有足够的灵敏度和特异性，因此适用于医院药房吗啡注射液生产的验证，在医院药房中，吗啡溶液是根据个体患者的需求以特殊的浓度和体积制备的。
