Stability of Drugs and Dosage Forms Sumie Yoshioka

132 Chapter 2 • Chemical Stability of Drug Substances
Scheme 77. Reaction pathway leading to melphalan degradation through a polar cyclic ethyleneimmonium
intermediate. (Reproduced from Ref. 543 with permission.)
β -CD, thalidomide by HP- β -CD, 539 tauromustine by HP-α-CD, 540 and medroxyprogesterone
acetate and megestrol acetate by HP-β -CD and methyl-β -CD. 541 The stabilizing
effect of β -CD against the oxidation of 2-[8-methyl-10,11-dihydro-11-
oxodibenz[b,ƒ]oxepin-2-yl]propionic acid in ointments has also been reported. 542
Recently, Ma et al. 543 studied the stability of the very unstable alkylating agent
melphalan in the presence of (SBE) 7M -β-CD and HP-β -CD. Melphalan undergoes an
intramolecular displacement reaction through a very polar cyclic ethyleneimmonium intermediate
(Scheme 77). The very polar transition state leading to this intermediate involves
considerable charge separation. Both (SBE), 7M -β-CD and HP-β -CD stabilized melphalan to
chemical degradation. 543 What is interesting in this case is that both (SBE) 7M -β-CD and
HP- β -CD have similar binding constants for melphalan and the same K values, as defined
in Scheme 76, but k c was significantly smaller in the case of (SBE) 7M -β-CD (Table 7). One
would intuitively feel that similar binding constants should yield similar positional binding
in the cyclodextrin cavity and perhaps similar k c values. Ma et al. 543 were able to demonstrate
that the melphalan bound to (SBE) 7M -β-CD was in a more hydrophobic environment and
that there was a small but significant difference in the position of binding of melphalan to
(SBE) 7M -β-CD versus HP-β -CD.
Although the degradation-inhibiting effects of CDs and their derivatives through
complex formation can be used as a method for stabilizing pharmaceuticals, CDs and their
derivatives may also enhance drug degradation, depending on the reaction mechanisms and
the steric arrangement of the drug in the complex. For example, β -CD inhibits the alkaline
hydrolysis of benzocaine (ethyl p-aminobenzoate) 544 but enhances that of aspirin (Table
8). 545 This has been explained by assuming that complex formation protects the ester bond
of ethyl p-aminobenzoate from attack by the hydroxide ion nucleophile. In the case of
Table 7. Estimated Values of K, k ƒ, and k c for the Degradation of Melphalan at 25°C (pH 7.5) in
the Presence of (SBE) 7M-β -CD and HP- β -CD, in Accordance with Scheme 76 a
Cyclodextrin K (M -1 ) kƒ ( h-1 ) kc ( h-1 ) kƒ/kc
(SBE)7M-β-CD 360 0.2 1.8 x 10 -3 114
HP-β -CD 382 0.2 1.1 x 10 -2 20
a
Reference 543.