Stability of Drugs and Dosage Forms Sumie Yoshioka

104 Chapter 2 • Chemical Stability of Drug Substances
Figure 86. Effect of dielectric constant changes on the degradation rate of hexobarbiturate at 50°C. The plotted
values are the apparent rate constants obtained by extrapolating to zero ionic strength. ∆, C2H5OH/H2O system; ,
CHO3OH/H2O system. (Reproduced from Ref. 399 with permission.)
A complication in interpreting the effect of solvent dielectric constants on kinetic data
is that the dissociation constants of various species can change with changing solvent
properties. Also, the possible role that a solvent modifier plays in the reaction must be
considered. For example, an alcohol or glycol or some other co-solvent might be used to
modify the dielectric constant of water. The co-solvent molecule may react with the drug in
question, thus complicating the interpretation of the solvent dielectric effect.
An alternative qualitative approach to the use of Eq. (2.111) is to consider the differences
in solvation between the ground state and the transition state of a particular reaction. For
example, in an S N 1 reaction, a molecule may go from a neutral ground state to a transition
state with a great deal of charge separation. The stability of the highly polar transition state
would be enhanced by a solvent that has a high dielectric constant whereas the free energy
of the ground-state reactant may be only slightly affected. As the dielectic constant of the
solvent is decreased, for example, by addition of a co-solvent, the transition state would be
relatively destabilized, resulting in a decrease in the reaction rate. By considering the
expected polarity of the ground state of a molecule and possible transition states, the effect
of changes in solvent dielectic constant can often be rationalized.
2.2.9. Oxygen
The kinetics of the oxidation of drug substances can be affected by the availability of
oxygen. Also, some photodegradation reactions involve photooxidative mechanisms that are
dependent on oxygen concentration. An example is the increased photodegradation of
cianidanol with increasing oxygen concentration. 402 Oxygen participates in Eq. (2.4) as a
reactant and alters the degradation rate. Although the concentration of oxygen in the
atmosphere and in various solutions is known to often affect drug degradation significantly,
only a few studies relating drug degradation kinetics and oxygen concentration are available.
The rate of oxidation of ascorbic acid depends on oxygen concentration, as shown in Fig. 87. 177