Stability of Drugs and Dosage Forms Sumie Yoshioka

52 Chapter 2 • Chemical Stability of Drug Substances
Scheme 69. Degradation of NSC-373965 catalyzed by its degradant, formaldehyde. (Reproduced from Ref. 265
with permission.)
An example that closely follows this scheme is the hydrolysis of NSC-373965 (Scheme 69),
a water-soluble prodrug of NSC-284356, where P, in this case, is formaldehyde. 265
Initial
hydrolysis of D in this example to generate formaldehyde was not dependent on formaldehyde
being present in the starting solution.
2.2.3.2. Kinetic Models Describing Chemical Drug Degradation in the Solid State
The rate equations used to describe drug degradation in solution can be derived
theoretically on the basis of the proposed degradation mechanisms. Data can then be tested
to see if they conform to the proposed scheme. When the scheme is validated, the appropriate
rate constant can be calculated and used to further refine the model. Similar theoretical rate
equations for drug degradation in the solid state have been derived. Because drug degradation
in the solid state generally occurs in a heterogeneous system where the physical state of the
drug and other components varies with time, the rate equations describing solid-state
degradation are much more complicated than those for degradation in solution.
A descriptor rate constant for solid-state degradation can be obtained once a theoretical
rate equation has been derived and the data have been tested to see if they conform to the
proposed model. However, for solid-state degradation in which the factors affecting the
degradation mechanism have not been elucidated, because of the complexity involved, often
an apparent constant (or constants) obtained by fitting the observed degradation curve to an
empirical equation or equations is utilized. Such constants and the empirical relationships
themselves can sometimes be used for stability prediction purposes. This section first
discusses various theoretical equations used to describe the solid-state stability of drugs and
introduces an empirical equation that can often describe the data adequately.
2.2.3.2.a. Diffusion-Controlled Reaction—The Jander Equation (Three-Dimensional
Diffusion). For a model in which a sphere of a reactant B exists in another reactant A (Fig.
18), a rate equation for reaction between A and B at the interface was derived by Jander in