## Hydrolysis

Hydrolysis of the drug entity can be a major factor in the instability
of solutions. Aspirin, for example, undergoes hydrolysis with the resultant
degradation products being salicylic acid and acetic acid. The rate of
this reaction is said to be second order, since it is dependent not only
upon the aspirin concentration, but upon solution pH (i.e. the hydronium
ion concentration at solution pH values less than approximately 2.5 or
the concentration of hydroxyl ion at solution pH values greater than approximately
7.0). At pH = 7.5, the rate expression for the hydrolysis of aspirin may
be written:

where,

If the solution is buffered so that the hydroxyl ion concentration remains
essentially constant, the rate expression may be rewritten as:

where,

Since two constants can always be combined into one constant, the above
expression is equal to:

where,

From the above equation, it can be seen that the degradation of aspirin in a
solution buffered at pH = 7.5 will follow first order kinetics; that is,
the reaction will appear to be a first order reaction, dependent only on
the concentration of one reactant; i.e. aspirin.

The integrated form of a first order rate expression is:

where,

This equation is of the form:

where,

For the hydrolysis of aspirin in buffered solution (pH = 7.5), a semi-log
plot of the aspirin concentration remaining versus time should yield a
straight line with a negative slope equal to -K_{app}.

The experimentally determined first order rate constant () can be
related to the true second order rate constant by the expression:

The pseudo first order degradation of aspirin in a solution buffered
at pH = 7.5 can be followed by measuring the increasing concentration of
salicylic acid spectrophotometrically.

One mole of salicylic acid is produced when one mole of aspirin degrades;
so, using the ratio of the molecular weights of aspirin to salicylic acid,
we can determine the weight of aspirin degraded for each mg of salicylic
acid produced.

Thus, each milligram of salicylic acid present represents the degradation
of 1.304 milligrams of aspirin. Since the amount of aspirin initially present
is known and since the amount of aspirin which has degraded can be determined,
the amount of aspirin remaining can be calculated.