Stability of Drugs and Dosage Forms Sumie Yoshioka

2.1. • Pathways of Chemical Degradation 5
Scheme 4. Oxidation of epinephrine to the highly colored adrenochrome.
stages of drug development, in identifying ways in which problematic drugs could be
formulated to minimize chemical degradation. The immense chemical and pharmaceutical
literature is probably underutilized as a source of such information. Expert systems are also
being developed for predicting stability.
Below, the major-degradation pathways in relation to molecular structure are discussed
and examples provided.
2.1.1. Hydrolysis
For most parenteral products, the drug comes into contact with water and, even in solid
dosage forms, moisture is often present, albeit in low amounts. Accordingly, hydrolysis is
one of the most common reactions seen with pharmaceuticals. Many researchers have
reported extensively on the hydrolysis of drug substances. In the 1950s, elegant studies,
especially considering the lack of high-throughput analytical techniques, concerning the
hydrolysis of procaine, 9,10 aspirin, 11,12 chloramphenicol, 13-15 atropine, 16-18 and methylphenidate
19 were reported. Hydrolysis is often the main degradation pathway for drug
substances having ester and amide functional groups within their structure.
2.1.1.1. Esters
Many drug substances contain an ester bond. Traditional esters are those formed
between a carboxylic acid and various alcohols. Other esters, however, include those formed
between carbamic, sulfonic, and sulfamic acids and various alcohols. These ester compounds
are primarily hydrolyzed through nucleophilic attack of hydroxide ion or water at the ester,
as shown in Scheme 5 for the case of a carboxylic acid ester.
The degradation rate depends on the substituents R 1 and R 2 , in that electron-withdrawing
groups enhance hydrolysis whereas electron-donating groups inhibit hydrolysis. As
shown in Table 1, substituted benzoates having an electron-withdrawing group, such as a
nitro group, in the para position of the phenyl ring (R 1 ) exhibit higher decomposition rates
than the unsubstituted benzoate. On the other hand, the decomposition rate decreases with
increasing electron-donating effect of the alkyl group (in the alcohol portion of the ester
(R 2 )) (e.g., it decreases in the order methyl > ethyl > n-propyl). Replacing a hydrogen atom
Scheme 5. Hydrolysis of a carboxylic acid ester.