Pinnamaneni Swathi, Rinaldi Frank A, Jayawickrama Dimuthu A, Li Jinjiang, Dali Mandar V
a Drug Product Science and Technology and.
b Analytical and Bioanalytical Development, R&D, Bristol-Myers Squibb Co. , New Brunswick , NJ , USA.
Pharm Dev Technol. 2016;21(3):311-20. doi: 10.3109/10837450.2014.1003653. Epub 2015 Feb 24.
The impact of pepsin on the maintenance of supersaturated solution of the HCl salt of a weakly basic drug was evaluated in simulated gastric fluid by monitoring the drug solubility in the absence and presence of pepsin. In the presence of pepsin, the HCl salt maintained its apparent solubility through 24 h, whereas, no such solubility advantage was seen in the absence of pepsin. Consequently, a minimum inhibitory concentration of pepsin is required for maintenance of supersaturation. In addition, NMR study seems to indicate a molecular level interaction between pepsin and HCl salt leading to a weak binding between the two. Therefore, for the HCl salts of weak bases having disproportionation potential, it is preferred that preformulation solubility studies are conducted in the presence of pepsin to reflect their in vivo behavior in maintaining supersaturation solubility.
通过监测在无胃蛋白酶和有胃蛋白酶存在的情况下药物的溶解度，在模拟胃液中评估了胃蛋白酶对弱碱性药物盐酸盐过饱和溶液维持的影响。在有胃蛋白酶存在的情况下，盐酸盐在24小时内保持其表观溶解度，而在无胃蛋白酶的情况下则没有观察到这种溶解度优势。因此，维持过饱和需要胃蛋白酶的最低抑制浓度。此外，核磁共振研究似乎表明胃蛋白酶与盐酸盐之间存在分子水平的相互作用，导致两者之间的弱结合。因此，对于具有歧化潜力的弱碱盐酸盐，最好在胃蛋白酶存在的情况下进行制剂前溶解度研究，以反映它们在体内维持过饱和溶解度的行为。
