Stability of Drugs and Dosage Forms Sumie Yoshioka

120 Chapter 2 • Chemical Stability of Drug Substances
Figure 111. Effect of water content on the dehydration of misoprostol dispersed in hydroxymethyl cellulose
(55°C) at a function of water content. (Reproduced from Ref. 465 with permission.)
dehydration rate of misoprostol dispersed in hydroxymethyl cellulose increased significantly
as water content increased, presumably due to the plasticizing effect of water. Drugs in
polymer matrices in a glassy state with low water content exhibit high stability owing to the
restricted mobility, whereas those in polymer matrices plasticized by water exhibit increased
degradation. Few studies have been performed on the plasticizing effect of water on the
chemical degradation of pharmaceuticals. However, there are some studies on the plasticizing
effect of water on physical degradation in relation to glass-transition temperature. This
effect will be described in Chapter 3. It is difficult to make generalizations about the role of
water in chemical degradation because of the multiple roles (reactant, plasticizer etc.) that
water can play.
2.2.13.4. Other Properties of Excipients
Excipients can also affect drug stability by altering microclimate pH. The surface acidity
of excipients has been reported to be a factor contributing to drug degradation, for example,
in the isomerization of vitamin D 2 . 466 Carboxylic acid groups on the solid surface furnish a
representative example. Lomustine exhibited faster degradation in poly( d,l-lactide) microspheres
than in its pure crystalline state. 467 Although this enhanced degradation has been
attributed to molecular dispersion of the drug in the microspheres, the possibility that the
terminal carboxylic acid groups of poly( d,l-lactide) effect micro-pH changes cannot be
excluded. Degradation of etoposide entrapped in poly( l-lactide) microspheres increased as
the number of terminal carboxylic acid groups increased during poly( l-lactide) decomposition,
suggesting the degradation enhancing effect of these groups. 468 Enhanced degradation
of solid oxazolam in the presence of microcrystalline cellulose may be attributed to
carboxylic acid groups on the cellulose surface in addition to the effect of moisture. 469,470
Excipients affect drug degradation via various mechanisms other than pH changes. The
effect of stearate on the degradation of aspirin has been explained by a change in melting
behavior rather than pH changes (Fig. 112). 471 Dye excipients may enhance oxidation and
photodegradation of drugs by producing singlet oxygen that participates in chain reactions.
Examples are enhancement of the oxidation of phenylbutazone 472 and ascorbic acid 473 by
dye excipients.