where Z is the collision frequency, R is the gas constant, and E is the activation energy. Thereafter, Eyring developed the theory of absolute reaction rates by introducing the concept of the formation and breakdown of an activated complex. This so-called transition-state model, defined by the reaction illustrated in Fig. 5, is represented by

where Qa, Qb, and Q* are the partition functions of A, B, and the activated complex, respectively, and E0 is the energy required for the formation of 1 mol of the activated complex at 0°K. Replacing partition functions in Eq. (2.9) by thermodynamic functions yields Eq. (2.7).

Because chemical reaction rates depend not only on the concentrations (more accurately, the activities) of participating species but also on temperature and the free energy of reaction, AG*, as represented by Eqs. (2.4), (2.6), and (2.7), the reaction rate is strongly influenced by those factors affecting AG*.

With respect to degradation of drug substances in solutions, any observed rate or rate constant can be calculated according to Eqs. (2.4), (2.6), and (2.7), and factors affecting the degradation can be related to the terms in these equations. In other words, the stability of drug substances does not change unless the key parameters appearing in these equations change owing to changes in reaction condition/media, etc. For a more comprehensive review of chemical kinetics in solution, the book by Connors245 is highly recommended.

Equations (2.4), (2.6), and (2.7) are also applicable to the degradation of drug substances in the solid state. However, the factors affecting the reaction rates become more complex because reactions often proceed in heterogeneous physical states. For example, apparent reaction rates depend on solubility and dissolution rates of drug substances when degradation proceeds in water layers adsorbed on the surface of solid drugs. Therefore, these and other additional factors need to be considered.

In the following sections, factors affecting drug degradation in solutions are discussed, especially as they relate to basic kinetic concepts. Later sections discuss drug degradation in more complex heterogeneous states such as solid-state decomposition.

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