Stability of Drugs and Dosage Forms Sumie Yoshioka

2.2. • Factors Affecting Chemical Stability 109
Figure 93. Effect of surface area on the reaction between sulfacetamide andphthalic anhydride. The plotted values
are the percentages of the drug that reacted during 3 h at 95°C. (Reproduced from Ref. 415 with permission.)
hydration, isomerization, or other bimolecular chemical reactions. In these cases, the
degradation rate is directly affected by the concentrations of water, hydronium ion, or
hydroxide ion according to Eq. (2.4). Second, water adsorbs onto the drug surface and forms
a moisture-sorbed layer in which the drug is dissolved and degraded. Water adsorption may
also change the physical state of drugs, thereby affecting their reactivity. Thus, water affects
drug degradation indirectly by providing a favorable environment for degradation.
The mechanisms for these effects of water are complicated and are determined by the
physical state of water molecules. For example, for drugs that form hydrates, water of
crystallization is trapped in the crystals and, generally, cannot participate in chemical
reactions. This is exemplified by the discoloration of glucuronic acid derivatives. 423 As
shown in Fig. 95, addition of water in amounts that form water of crystallization does not
cause discoloration; however, addition of excess water does accelerate the discoloration at
a rate proportional to the amount of water not involved in hydrate formation.
Figure 94. Effect of water content on the degradation of vitamin A tablets. (Reproduced from Ref. 421 with
permission.)