Towards a Better Understanding of Verapamil Release from Kollicoat SR:IR Coated Pellets Using Non-Invasive Analytical Tools

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.

Keywords: coated pellet; controlled release; drug release mechanisms; film coating; non-invasive analytical tools; polyvinyl acetate; weakly basic drug.

Figure 1

Verapamil release in acetate buffer pH = 3.5 and phosphate buffer pH = 7.4 from pellets coated with: (a) Kollicoat SR:IR 95:05 (coating level: 5%), or (b) Kollicoat SR:IR 90:10 (coating level: 10%).

Figure 2

Solubility (c_s) of verapamil HCl at 37 °C, as a function of the pH in different aqueous release media: 0.1 N HCl, acetate buffer pH = 3.5 and phosphate buffer pH = 7.4. The pH was optionally adjusted with varying amounts of sodium hydroxide or HCl.

Figure 3

Drug release (blue curves, right y-axes) from single pellets coated with Kollicoat SR:IR 95:05 (coating level: 5%) upon exposure to acetate buffer pH = 3.5 (left column) or phosphate buffer pH = 7.4 (right column). The orange curves (left y-axes) show the pH values determined by fluorescence spectroscopy inside the pellet cores. Each diagram shows the drug release from/pH changes within the same single pellet.

Figure 4

Drug release (blue curves, right y-axes) from single pellets coated with Kollicoat SR:IR 90:10 (coating level: 10%) upon exposure to acetate buffer pH = 3.5 (left column) or phosphate buffer pH = 7.4 (right column). The orange curves (left y-axes) show the pH values determined by fluorescence spectroscopy inside the pellet cores. Each diagram shows the drug release from/pH changes within the same single pellet.

Figure 5

Dynamic changes in the size of single pellets coated with Kollicoat SR:IR 95:5 (5% coating level (cl), left hand side) or Kollicoat SR:IR 90:10 (10% coating level, right hand side) upon exposure to acetate buffer pH = 3.5 (top row) or phosphate buffer pH = 7.4 (bottom row).

Figure 6

Theory (curves) and experiments (symbols): (a) Drug release from free verapamil HCl-loaded films in acetate buffer pH = 3.5 (initial drug loading: 1%, w/w). The curves show the fittings of Equation (1). Drug release from 3 individual films is shown (red, blue and green). (b) Drug release from verapamil HCl-loaded, coated pellets. The curves show the theoretical predictions obtained using Equation (6). The free films and film coatings were based on Kollicoat SR:IR 95:5 or 90:10 blends. The film thickness was about 100 µm in the case of free films, and about 8 and 15 µm in the case of the film coatings based on Kollicoat SR:IR 95:5 and 90:10 blends, respectively (corresponding to 5% and 10% coating level).

Figure 7

SEM images of pellets coated with Kollicoat SR:IR 95:5 (5% coating level, left column) or Kollicoat SR:IR 90:10 (10% coating level, right column) before and after exposure to acetate buffer pH = 3.5 or phosphate buffer pH = 7.4 (as indicated).

Figure 8

Raman images of cross sections of pellets coated with 5% Kollicoat SR:IR 95:5 after exposure to different release media for varying time periods (as indicated). The cross sections were obtained: (a) invasively (by cutting with a scalpel), or (b) non-invasively (virtually by confocal Raman spectroscopy). False colors depict the matrix in blue, the film coating in yellow and the drug in red.

Figure 9

Raman images of pellets coated with 10% Kollicoat SR:IR 90:10 before and after exposure to different release media for varying time periods (as indicated): (a) cross sections (obtained invasively by cutting with a scalpel), (b) surfaces and virtual cross sections of the film coatings (obtained non-invasively by confocal Raman spectroscopy). False colors depict the matrix in blue, the film coating in yellow and the drug in red.

Figure 9

Raman images of pellets coated with 10% Kollicoat SR:IR 90:10 before and after exposure to different release media for varying time periods (as indicated): (a) cross sections (obtained invasively by cutting with a scalpel), (b) surfaces and virtual cross sections of the film coatings (obtained non-invasively by confocal Raman spectroscopy). False colors depict the matrix in blue, the film coating in yellow and the drug in red.