Stability of Drugs and Dosage Forms Sumie Yoshioka

2.1. • Pathways of Chemical Degradation 33
Scheme 64. Representative drug substances susceptible to substitution and addition reactions by bisulfite.
undergo this addition/rearrangement reaction, also called the “browning” reaction because
of the resulting discoloration. Examples are the reaction of amphetamine, 233 isoniazid, 234
dextroamphetamine sulfate, 235,236 and norphenylephrine 237 with sugars such as lactose and
the degradation products of sugars, such as 5-(hydroxymethyl)furfural. Sulpyrine forms an
addition product with glucose. 238
2.1.7.3. Transesterification Reactions
In the presence of drug substances with hydroxy groups, aspirin undergoes a reversible
transacylation reaction to form salicylic acid, while acetylating the drug substance. For
example, codeine 239 and sulfadiazine 240 are acetylated by aspirin, as shown in Scheme 65.
Similar acetylation reactions with aspirin have been reported for acetaminophen 241 and the
excipient polyethylene glycol. 242,243 Another example of transesterification is the reaction
of benzocaine with polyvinyl acetate phthalate (Scheme 66). 244
Scheme 65. Representative drug substances susceptible to acetylation by aspirin.