Sonobe T, Hasumi S, Yoshino T, Kobayashi Y, Kawata H, Nagai T
J Pharm Sci. 1980 Apr;69(4):410-3. doi: 10.1002/jps.2600690412.
The release of digoxin and its simultaneous conversion to digoxigenin bisdigitoxoside, digoxigenin monodigitoxoside, and digoxigenin in a USP dissolution test medium were followed by high-pressure liquid chromatography. Two products, Tablets A and B, were manufactured by solvent deposition and simple blending methods, respectively. Tablet A released digoxin faster than Tablet B in distilled water and in artificial intestinal juice, and no decomposition was observed. In the USP dissolution test medium, the rate of hydrolysis to digoxigenin bisdigitoxoside was almost equal to that of hydrolysis to digoxigenin monodigitoxoside, and a comparatively large formation rate of digoxigenin was observed. Concentrations of digoxin and its decomposition products were described by differential equations that included dissolution rates of digoxin (rapidly dissolving digoxin and digoxin crystals) and an apparent hydrolysis rate. In the earlier stage of dissolution, hydrolysis was rate determining; in the later stage, dissolution became the rate-determining step for overall digoxin degradation. To suppress digoxin hydrolysis in the USP dissolution test medium, a developmental formulation study was performed. The incorporation of magnesium oxide and magnesium hydroxide-aluminum hydroxide in the tablet formulations inhibited digoxin hydrolysis by 15.3 and 14.5%, respectively, after dissolution for 30 min without serious delay of drug release.
采用高压液相色谱法对去乙酰毛花苷在USP溶出度试验介质中的释放情况以及同时转化为洋地黄毒苷双洋地黄毒糖苷、洋地黄毒苷单洋地黄毒糖苷和洋地黄毒苷的情况进行了跟踪研究。两种产品，片剂A和片剂B，分别采用溶剂沉积法和简单混合法制造。片剂A在蒸馏水和人工肠液中释放去乙酰毛花苷的速度比片剂B快，且未观察到分解现象。在USP溶出度试验介质中，水解为洋地黄毒苷双洋地黄毒糖苷的速率几乎与水解为洋地黄毒苷单洋地黄毒糖苷的速率相等，且观察到洋地黄毒苷的形成速率相对较大。去乙酰毛花苷及其分解产物的浓度用微分方程描述，该方程包括去乙酰毛花苷（快速溶解的去乙酰毛花苷和去乙酰毛花苷晶体）的溶出速率和表观水解速率。在溶出的早期阶段，水解是速率决定步骤；在后期阶段，溶出成为去乙酰毛花苷整体降解的速率决定步骤。为了抑制USP溶出度试验介质中去乙酰毛花苷的水解，开展了制剂研发研究。在片剂配方中加入氧化镁和氢氧化镁 - 氢氧化铝，在溶出30分钟后，分别抑制去乙酰毛花苷水解15.3%和14.5%，且药物释放没有严重延迟。
