Myrdal P B, Simamora P, Surakitbanharn Y, Yalkowsky S H
Department of Pharmaceutical Sciences, College of Pharmacy, University of Arizona, Tucson 85721, USA.
J Pharm Sci. 1995 Jul;84(7):849-52. doi: 10.1002/jps.2600840713.
We describe a computational model and an in vitro experiment for assessing whether or not a pH-solubilized drug has the potential to precipitate upon dilution with blood. The computational model enables an efficient means of selecting buffer concentration and pH, and the in vitro test provides a simple experimental validation. Both means of screening are applied to the formulation of the weakly basic drug levemopamil-HCI. A buffered formulation of levemopamil is chosen from the computational model and shown to be free of precipitation upon dilution in vitro and to not produce phlebitis in the rabbit ear model. In comparison, an unbuffered formulation at the same pH and drug concentration precipitates in vitro and causes significant phlebitis in vivo. The results of this study reinforce the importance of buffering parenteral formulations instead of simply adjusting the pH of the formulation.
我们描述了一种计算模型和一项体外实验，用于评估pH溶解的药物在与血液稀释时是否有沉淀的可能性。该计算模型提供了一种选择缓冲液浓度和pH值的有效方法，体外试验则提供了一种简单的实验验证。这两种筛选方法均应用于弱碱性药物盐酸乐卡地平的制剂研究。从计算模型中选择了一种缓冲型乐卡地平制剂，结果表明其在体外稀释时无沉淀，在兔耳模型中也不产生静脉炎。相比之下，相同pH值和药物浓度的非缓冲制剂在体外会沉淀，并在体内引起严重的静脉炎。本研究结果强调了对注射用制剂进行缓冲的重要性，而不是简单地调节制剂的pH值。
