Preformulation 1文档.ppt

Hydrolysis and the Role of Excipients One of the most common pathways of drug product degradation is hydrolysis. Flutamide, a non-steriodal anti-androgen, is an acetanilide derivative and undergoes acid and base catalysed amide hydrolysis (43), at the extremes of pH to form 4-nitro-3-trifluoromethylaniline (NTMA). Solutions of flutamide stored at pH 1 for 2 weeks at 45?C gave 39% of NTMA; whereas, solutions at pH 10 gave 21% of NTMA (same storage conditions). Neutral solutions of flutamide were stable (<0.4% NTMA). The source of the excipients can greatly influence hydrolytic reactions. This is exemplified by Gold and Campbell (44) where talc obtained from different sources impacts markedly on the overall stability of the aspirin tablet formulation. This is possibly attributable to the affect of different types and amounts of surface impurities, which are dissolved in the adsorbed moisture layer, where they subsequently react with the API. It could also influence the pH of the micro-environment. (43). R Sternal and N Nigura, Anal. Prof. of Drug Subs. and Excip., 27 (2001) 115. (44). G. Gold and J. Campbell, J. Pharm. Sci., 53 (1964) 52. Oxidation and the Role of Excipients Oxidation is broadly defined as a loss of electrons in a system, but it can be restated as an increase in oxygen or a decrease in hydrogen content (45). Oxidation always occurs in tandem with reduction; the so called REDOX reaction couple. More generally, it can be defined as the loss of an electron positive atom, radical or electron, or the addition of an electronegative moiety. Oxidation reactions can be catalysed heavy metals, light, leading to free radical formation (initiation). Free radicals then react with oxygen to form peroxy radicals, which react with the oxidative substrate to yield further complex radicals (propagation), finally the reaction ceases (termination). Excipients play a key role in oxidation; either as a primary source of oxidants, trace amounts of metal