| Summary: | BACKGROUND: Osmotic pump tablets offer highly predictable and programmable
delivery of drugs into solution, ready for absorption. The design and formulation of an osmotic
pump tablet determines the release rate of the drug and are based on exhaustive and expensive
physico-chemical testing of the system's characteristics. The results of these tests are
approximations of the real system with considerable limitations and non-negligible uncertainties.
They do not provide an understanding of the dynamics and interactions of water within the tablet
core and their influence on the drug release.
OBJECTIVES: The overall objectives of this research were first to develop a system of
measuring the percent core tablet eroded in an elementary osmotic pump tablet and to correlate it
with the percent drug released, during a 24 hour-dissolution process, using NMR Imaging
techniques which have been successfully used in the analysis of the release dynamics inside
hydrogels. Second, to propose a mechanism of drug release based on the ingredients-water
dynamics inside the tablet. The system developed constitutes a direct, qualitative and
quantitative method of analysis of an osmotic pump tablet, in a non-invasive, non-destructive
and non-interruptive way.
METHODS: First, the aqueous solubility of the model drug, triflupromazine HC1, was
determined at 37 ± 0.5 °C. Second, reference mixtures of the lactose, stearic acid and
triflupromazine HC1 blend with water were prepared, at concentrations from 2 % to 22 % by
weight, for future water proton relaxation times (T2) measurements. Then three sets of
elementary osmotic pump tablets were formulated with different membrane thicknesses. One set
of control tablets, without a drilled hole was also formulated. The percent drug released during a
24-hour dissolution at 37 ± 0.5 °C was measured for these tablets. Gray-scale NMR images and
T2 value maps of the osmotic pump tablets, were obtained every 3 hours, during a 24-hour
dissolution and the total volume of core tablet eroded at each time-point calculated and
correlated with the percent drug released. RESULTS AND DISCUSSION: The average tablet weight, thickness and hardness were
within our target specifications and thus provided batch to batch tablet uniformity in weight,
hardness and thickness. The NMR gray-scale images of the tablets during dissolution confirm
the strength and flexibility of the membrane and the unimpeded flow of water into the core
tablet, as expected. Higher percent core tablet erosion was obtained from the tablets with the
thinner membrane (73 urn) compared to the thicker one (121 Lim). This follows Fick's law as
core tablet erosion is proportional to the flux of water molecules into the tablet. The results
suggest that during dissolution, water permeates through the semi-permeable membrane, moves
between lactose particles, allowed by the tablet porosity, and dissolves the extremely watersoluble
triflupromazine HC1 independently of dissolving lactose. As dissolution progresses,
more and more triflupromazine HC1 molecules and a relatively smaller percent of lactose
molecules are dissolved.
CONCLUSION: Qualitative and quantitative analysis of osmotic pump tablets during 24-
hour dissolution testing were performed without interrupting the process or destroying the
samples. NMR axial and sagital slices of the osmotic pump tablets were taken thus allowing for
a complete and more accurate study of the system then previously possible. The percent drug
released, the water distribution inside the tablet and the rate of core tablet erosion were
determined quantitatively, while the membrane strength and permeability were evaluated
qualitatively. A tentative explanation of the drug release mechanism inside the tablet is
proposed for the first time. === Pharmaceutical Sciences, Faculty of === Graduate
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