Roy S D, Flynn G L
College of Pharmacy, University of Michigan, Ann Arbor 48109-1065.
Pharm Res. 1989 Feb;6(2):147-51. doi: 10.1023/a:1015932610010.
The pH dependence of the aqueous solubility of morphine, fentanyl, and sufentanil was investigated at 35 degrees C. Dissociation constants and corresponding pKa' values of the drugs were obtained from measured free-base solubilities (determined at high pH's) and the concentrations of saturated solutions at intermediate pH's. Morphine, fentanyl, and sufentanil exhibited pKa' values of 8.08, 8.99, and 8.51, respectively. Over the pH range of 5 to 12.5 the apparent solubilities are determined by the intrinsic solubility of the free base plus the concentration of ionized drug necessary to satisfy the dissociation equilibrium at a given pH. Consequently, the drug concentrations of saturated aqueous solutions fall off precipitously as the pH is raised and ionization is suppressed. Further, at low pH's the aqueous solubility of morphine increased in a linear fashion with increases in the molar strength of citric acid which was added to acidify the medium, suggesting the formation of a soluble morphine-citrate complex.
在35摄氏度下研究了吗啡、芬太尼和舒芬太尼在水中溶解度的pH依赖性。通过测量游离碱溶解度（在高pH值下测定）和中间pH值下饱和溶液的浓度，获得了药物的解离常数和相应的pKa'值。吗啡、芬太尼和舒芬太尼的pKa'值分别为8.08、8.99和8.51。在pH值为5至12.5的范围内，表观溶解度由游离碱的固有溶解度加上在给定pH值下满足解离平衡所需的离子化药物浓度决定。因此，随着pH值升高和电离受到抑制，饱和水溶液的药物浓度急剧下降。此外，在低pH值下，加入柠檬酸以酸化介质，吗啡在水中的溶解度随柠檬酸摩尔浓度的增加呈线性增加，表明形成了可溶性的吗啡柠檬酸盐复合物。
