Stability in Frozen Solutions

Freezing of phosphate buffer solutions may affect drug stability by lowering the micro-pH of the condensed aqueous phase. The degradation rate of mitomycin C in frozen phosphate buffer solutions was faster than in solutions.353 

Care should be taken when storing, under freezer conditions, drug substances whose degradation is dependent on concentration and pH. Decreased degradation due to the decreased temperature cannot always be assumed. 

Degradation rates of drug substances are generally affected by pH because most degradation pathways are catalyzed by hydronium and/or hydroxide ions. Water itself is also a critical reactant. If the critical path in a reaction involves a proton transfer or abstraction step, other acids and bases present in solution (usually buffer species) can affect the reaction rate. These reactions will also be pH-dependent because the fraction of any species present in its acid or base form will be dependent on its dissociation constant and the solution pH. Also, for ionizable drugs, the fraction of drug present in any particular form will depend on the solution pH. Therefore, if the reactivity of the drug depends on its form, its reactivity will be pH-dependent. 

When a reaction dependent on hydronium and hydroxide ion activity is performed at constant pH, it usually follows pseudo-first-order kinetics, which can be described by a first-order rate constant kQbs. A reaction in which hydronium ion, hydroxide ion, and water catalysis are observed can be described by 

If the contributions of the first and second terms in Eq. (2.93) are larger than that of the third term, the pH-rateprofile shown in panel 1 of Fig. 50 is seen. If the second and third terms are dominant, then the profile illustrated in panel 2 is observed. If the first and third 

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