The physico-chemical interactions between three model drugs and a vari
ety of surfactants were characterized by measuring the apparent permea
bility coefficients of the drugs in the presence and absence of surfac
tants in vitro. The extent of interaction between the model drugs and
the surfactants can best be described by the hydrophobic effect (prima
rily determined by the hydrophobic surface area of the drug molecule)
and the electrostatic effect (primarily determined by the charge assoc
iated with the drug molecule as well as the surfactant molecules). For
drugs that do not possess a significant hydrophobic surface area (tim
olol and cefoxitin): their interactions can best be described based on
electrostatic effects (charge effects). This interaction being strong
with oppositely charged surfactants. The interactions of L-692 585 (a
model drug with appreciable hydrophobic surface area) in the presence
of surfactants is dominated by the hydrophobic effect, with the elect
rostatic effect playing a minor secondary role. The apparent permeabil
ity coefficient of timolol as a function of the amount of surfactant i
n solution is modelled in light of micellar formation and entrapment a
nd/or interaction of free drug with this micellar structure. Briefly,
the extent of interaction as a function of amount of added surfactant
for timolol indicates that initially as surfactant is added the activi
ty of drug for transport declines significantly until a breaking point
is reached, after which the drug activity available for transport rem
ains relatively constant upon addition of more surfactant. A model is
derived which is capable of describing this behavior and provides reas
onable estimates for the critical micellar concentration of the surfac
tant, the affinity or binding constant for the interaction cf drug wit
h an equivalent micellar structure, and the loading capacity of the eq
uivalent micellar structure. These observations are potentially signif
icant for drug formulation of poorly bioavailable drugs. (C) 1997 Else
vier Science B.V.