Govindarajan Ramprakash, Chatterjee Koustuv, Gatlin Larry, Suryanarayanan Raj, Shalaev Evgenyi Y
Department of Pharmaceutics, University of Minnesota, 308 Harvard St. SE, Minneapolis, 55455, USA.
J Pharm Sci. 2006 Jul;95(7):1498-510. doi: 10.1002/jps.20620.
"pH memory," i.e., correlation between pH of solution before freeze-drying and chemical reactivity in the freeze-dried state, has been reported in many systems. In this study, the "pH memory" is explored by comparing the extent of protonation of sulfonephthalein probe molecules, bromophenol blue, bromocresol green, and chlorophenol red, in aqueous solution in the pH range of 3.4-6.0 and in the resulting freeze-dried amorphous matrix (lyophile) containing trehalose and sodium citrate buffer. The protonation of the probe molecules was measured in the lyophiles by diffuse reflectance visible spectroscopy, and compared with that in the solution before drying. The protonation of the indicators in the amorphous matrix correlated with solution pH, that is, an increase in solution pH resulted in a progressive decrease in the indicator protonation in the corresponding lyophile. However, the protonation was consistently higher in the lyophile than in the corresponding solution. The Hammett acidity function of lyophiles was calculated based on the extent of protonation of the probe molecules. Protonation of the probe molecules and the Hammett acidity function depended not only on prelyophilization solution pH, but also on the residual water content and the presence of amorphous sugar in the lyophile.
“pH记忆”，即冻干前溶液的pH值与冻干状态下化学反应活性之间的相关性，已在许多系统中被报道。在本研究中，通过比较在3.4 - 6.0的pH范围内水溶液中以及所得含有海藻糖和柠檬酸钠缓冲液的冻干无定形基质（冻干物）中，砜酞菁探针分子、溴酚蓝、溴甲酚绿和氯酚红的质子化程度，来探究“pH记忆”。通过漫反射可见光谱法测量冻干物中探针分子的质子化程度，并与干燥前溶液中的进行比较。无定形基质中指示剂的质子化与溶液pH相关，也就是说，溶液pH的升高导致相应冻干物中指示剂质子化程度逐渐降低。然而，冻干物中的质子化程度始终高于相应溶液中的。基于探针分子的质子化程度计算了冻干物的哈米特酸度函数。探针分子的质子化和哈米特酸度函数不仅取决于冻干前溶液的pH值，还取决于冻干物中的残余水分含量和无定形糖的存在情况。
