Abstract
The aim of this study was to gain deeper insight into the mass transport mechanisms controlling drug release from polymer-coated pellets using non-invasive analytical tools. Pellet starter cores loaded with verapamil HCl (10% loading, 45% lactose, 45% microcrystalline cellulose) were prepared by extrusion/spheronization and coated with 5% Kollicoat SR:IR 95:5 or 10% Kollicoat SR:IR 90:10. Drug release was measured from ensembles of pellets as well as from single pellets upon exposure to acetate buffer pH = 3.5 and phosphate buffer pH = 7.4. The swelling of single pellets was observed by optical microscopy, while dynamic changes in the pH in the pellet cores were monitored by fluorescence spectroscopy. Also, mathematical modeling using a mechanistically realistic theory as well as SEM and Raman imaging were applied to elucidate whether drug release mainly occurs by diffusion through the intact film coatings or whether crack formation in the film coatings plays a role. Interestingly, fluorescence spectroscopy revealed that the pH within the pellet cores substantially differed upon exposure to acetate buffer pH = 3.5 and phosphate buffer pH = 7.4, resulting in significant differences in drug solubility (verapamil being a weak base) and faster drug release at lower pH: from ensembles of pellets and single pellets. The monitoring of drug release from and the swelling of single pellets indicated that crack formation in the film coatings likely plays a major role, irrespective of the Kollicoat SR:IR ratio/coating level. This was confirmed by mathematical modeling, SEM and Raman imaging. Importantly, the latter technique allowed also for non-invasive measurements, reducing the risk of artifact creation associated with sample cutting with a scalpel.
Highlights
Sink conditions were provided in the well stirred release medium throughout the experiments. As it can be seen, verapamil release was faster in acetate buffer pH = 3.5 than in phosphate buffer pH = 7.4, irrespective of the type of coating. This might eventually be attributable to the fact that the solubility of verapamil is strongly pH dependent: Figure 2 shows the dependence of the solubility of the drug as a function of the pH of the bulk fluid at 37 ◦ C
The fluorescence markers Oregon green and BCECF dextran were incorporated into the systems’ cores to allow for pH measurements by phosphate buffer pH = 7.4 were used, the pH was optionally adjusted with sodium droxide or HCl) at 37 °C
The present study highlights the importance of the pH of the liquid within the pellets cores and of crack formation in the film coatings for verapamil release from systems coated with different Kollicoat SR:IR blends
Summary
Pellets are promising therapeutic formulations for oral administration since these small spherical multiparticulates offer multiple advantages compared to single unit dosage creativecommons.org/licenses/by/ 4.0/). It is desirable to know which mass transport mechanisms play a role in the coated pellet formulation of interest: The knowledge on the underlying drug release mechanisms contributes to an improved device optimization during product development as well as quality control. The elucidation of the drug release mechanisms from these multiple unit dosage forms can be challenging, since one mechanism might be of importance and since generally ensembles of pellets are observed (e.g., hundreds of pellets) at the same time, the measurements are the sums of the behaviors of the various individual pellets, and the latter might substantially differ [16,21]
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