Stability of Drugs and Dosage Forms Sumie Yoshioka

2.3. • Stabilization of Drug Substances against Chemical Degradation 127
The term [D–L] represents the concentration of the complex, D–L, [D] ƒ is the concentration
of free or uncomplexed drug, and [L] ƒ is the concentration of free ligand. In Scheme 76, k ƒ
represents the rate constant for the degradation of the drug in the absence of complexation,
and k, is the rate constant for the degradation of the drug in its complexed form. As can be
seen, the drug will be stabilized by the presence of L if k c < k ƒ . The degree of stabilization
will also depend on the relative amounts of free and complexed drug, which in turn depends
on the concentrations of D and L and the magnitude of K. Conversely, if k c > k ƒ , complex
formation will result in acceleration of the degradation. Differing ligands (L) in a series can
affect the degradation rate in two ways: first, by affecting the degree of complexation, as
measured by K, and, second, by affecting k c .
Stabilization of esters such as benzocaine (Fig. 120), procaine, and tetracaine by
complex formation with caffeine was reported in the 1950s. 513-515 The stabilization of drugs
by caffeine is thought to result from the formation of “stacking” complexes. Thus, attack by
water or hydroxide ion on the ester bonds of benzocaine is hindered when the benzocaine
molecules are sandwiched between caffeine molecules. Similar stabilization by caffeine has
been reported for base-catalyzed degradation of riboflavin. 516
Ampicillin, cephalexin, and bacampicillin are stabilized by complex formation with
aldehydes such as benzaldehyde and furfural, 517-522 altho ugh this stabilization involves
reversible formation of covalent species. Even though these interactions involve covalent
bond formation, they follow Scheme 76, because the covalent association and dissociation
(defined by the equilibrium constant K) is fast relative to k c and k ƒ . The greater stability of
N-nitrosoureas in Tris buffers than in carbonate buffers has been ascribed to complex
formation with tris(hydroxymethyl)aminomethane. 523
Figure 120. Stabilization of benzocaine by complex formation with caffeine (30°C, 0.04 N hydroxide ion).
Caffeine concentration: (1) 0.25%; (2) 0.50%; (3) 1.00%; (4) 1.50%; (5) 2.00%; (6) 2.50%. (Reproduced from Ref.
5 13 with permission of the American Pharmaceutical Association.)