The observed release pattern from different pellets can be attributed to polymer permeability. The relatively higher permeability
of Eudragit RL (16) to the dissolution medium could be considered responsible for the observed fast release of KT from the
pellet coated only with Eudragit RL (see Figure 1). Including Eudragit RS, which is known to be of lower permeability (16),
in the coat composition (Eudragit RL:Eudragit RS = 1:2) led to a reduction in drug release. Increasing the proportion of the
less-permeable polymer Eudragit RS in the coating blend to 1:3 (Eudragit RL:Eudragit RS, respectively) resulted in a further
reduction in drug release as a result of hindered permeation of the dissolution medium. This effect is most pronounced when
the coat is made totally of Eudragit RS, where maximum retardation of drug release is observed (see Figure 1). Drug-release
profiles also depend to a great extent on the integrity of the film surrounding the pellets, which is affected by the presence
of plasticizer in the coating dispersion (17).
It seems from the present results that Formula III (Eudragit RL:Eudragit RS = 1:3) is of appropriate drug release such that
the release of KT is extended over the test period in addition to a 100% release after 12 h. Although formula II and formula
IV had similar release pattern, they showed only 92% and 86% release after 12 h. Therefore formula III was selected for the
release kinetics study.
The release data from the selected pellets (Formula III) coated with Eudragit RL:Eudragit RS (1:3) were fitted to various
release models (zero order, first order, and Higuchi models). Table II summarizes the correlation coefficients of these models.
A plot of %-KT released over time (see Figure 1) indicated a nonlinear correlation, thereby suggesting that the release pattern
from pellets doesn't follow the zero-order kinetic model. Drug release from Eudragit-coated pellets is expected to follow
a diffusion-controlled model in accordance with the Higuchi equation (18).
Table II: The correlation coefficients and release rate constants of ketorolac tromethamine observed for zero-order, first-order,
and Higuchi equation.
The plot of the amount of KT released from pellets versus the square-root of time indicated that the amount of drug released
increased linearly (r = 0.981) with the square-root of time. However, both the square-root of time and first-order release plot were linear, as
indicated by the correlation coefficients derived from first-order and Higuchi equations (see Table II). The first-order release
curve, however, showed biphasic release profiles with two distinct regions, in agreement with previous reports (19). The first
region in the release occurs at a relatively fast rate (0.461 h–1), and a terminal region in which a reduction in drug release is observed (0.345 h–1) (see Table II). However, the Higuchi equation yielded a correlation coefficient value almost similar to that of the first-order
equation (see Table II).
To further distinguish the exact mechanism of release, the differential form was performed. For a diffusion-controlled mechanism,
the rate will be inversely proportional to the total amount of drug released Q, according to the following equation:
dQ/dt = K
in which dQ/dt is the release rate, K
is the rate constant calculated from Higuchi equation, S is the surface area, and Q is the amount of drug released. The plot of release rate (dQ/dt ) versus 1/Q was linear (r = 0.994), indicating that the release of KT from the pellets was governed by the Higuchi square-root of time kinetics equation.
It could, therefore, be concluded that the apparent release of KT from the prepared pellets coated with Eudragit RL:Eudragit
RS 1:3 appears to follow both diffusion-controlled and first-order kinetics. However, differential rate treatment confirmed
that release was governed by a diffusion-controlled mechanism.