Monday, 05 October 2020 21:25

Development of a surface coating technique with predictive value for bead coating in the manufacturing of amorphous solid dispersions

Written by Eline Boel
Rate this item
(0 votes)

The aim of this research was to investigate whether a surface coating technique could be developed that can predict the phase behavior of amorphous solid dispersions (ASDs) coated on beads. ASDs of miconazole (MIC) and poly(vinylpyrrolidone-co-vinyl acetate) (PVP-VA) in methanol (MeOH) were studied as a model system.

First, the low crystallization tendency of the model drug in MeOH was evaluated by means of spray drying and subsequent modulated differential scanning calorimetry (mDSC) analysis. With respect to the classification of Van Eerdenbrugh et al., it can be concluded that MIC also exhibits a low crystallization tendency in MeOH [1]. It was however striking that the obtained melting point onsets did not correspond to the melting point onsets of any known MIC polymorph [2]. Our data suggest the formation of a MIC solvate and further investigations, encompassing the implementation of single crystal analysis, are currently ongoing. In a next step, a drug loading screening was performed on casted films and coated beads in order to define the highest possible MIC loading that still results in a one-phase amorphous system (see Figure 1). For the film casted MIC-PVP-VA formulations, 30% was determined as the highest possible drug loading that still results in a one-phase amorphous system. In contrast, for MIC-PVP-VA formulations coated on beads, even 50% drug loading resulted in the formation of one-phase amorphous systems. These results thus indicate that film casting, which is often used as a screening test to assess drug-polymer miscibility, is not suitable for phase behavior predictions of ASDs coated on beads, most likely because of the low rate of solvent evaporation.

Figure 1. mDSC thermograms of (A) film casted (FC) MIC-PVP-VA systems, increasing the drug loading from 30% (black) to 45% (pink) by intermediate steps of 5%. The reversing heat flow (RHF) signals are shown as arbitrary units; (B) milled MIC-PVP-VA coated beads (BC), with drug loadings from 30% (black) to 50% (green) by intermediate steps of 5%. The RHF signals are shown as arbitrary units.

Therefore, it was examined whether and how a surface coating technique can be developed that can predict the phase behavior of MIC-PVP-VA ASDs coated on beads. For this purpose, the drying chamber of the spray dryer was flattened at the bottom so that a glass cylinder could be inserted. This cylinder serves as supporting plate for an MCC tablet, which is prepared by milling MCC beads, a subsequent sieving step and compression of the resulting MCC powder. The dimensions of the cylinder were chosen in such a way that the setup still allows for sufficient air flow for the simultaneous production of spray dried powder that can be collected in the collection vessel (see Figure 2). The operational conditions were related as closely as possible to the parameter settings of the bead coating process.

Figure 2. Schematic illustration of the surface coating setup.

When coating the surface of an MCC tablet, either a continuous or an intermittent spraying procedure can be applied. With the former procedure, 20.0 mL of MIC-PVP-VA_MeOH solution is continuously sprayed onto the tablet’s surface, followed by an additional drying step of 5 min. This procedure was found to be highly variable due to a lack of kinetic trapping and the resulting phase behavior was similar to what was obtained from film casting experiments (see Figure 3A). In contrast, when an intermittent spraying procedure is employed, spraying alternates with drying, followed by an additional drying step of 5 min at the end. The mDSC thermograms of Figure 3B illustrate that, with the intermittent spraying procedure, one-phase amorphous systems are produced up to 50% drug loading. Hence, it can be concluded that the newly developed surface coating technique can predict the phase behavior of MIC-PVP-VA ASDs coated on beads, but only if an intermittent spraying procedure is applied.

Figure 3. mDSC thermograms of (A) MCC tablets surface coated (TC) with MIC-PVP-VA, applying a continuous spraying procedure; (B) MCC tablets surface coated with MIC-PVP-VA, employing an intermittent spraying procedure (20 s–20 s). The RHF signals are shown as arbitrary units.

Finally, spray drying was also evaluated for its ability to manufacture high drug-loaded ASDs. The highest possible drug loadings that still result in a one-phase amorphous system were obtained for bead coating and its predictive intermittent surface coating technique, followed by spray drying and finally by film casting and the continuous surface coating technique, thereby underlining the importance for further research into the underexplored bead coating process.

The full version of the article can be consulted at https://www.mdpi.com/1999-4923/12/9/878.

This research was funded by Fonds Wetenschappelijk Onderzoek (FWO), grant number 1S06120N.

  1. Van Eerdenbrugh, B.; Baird, J.A.; Taylor, L.S. Crystallization tendency of active pharmaceutical ingredients following rapid solvent evaporation - Classification and comparison with crystallization tendency from undercooled melts. J. Pharm. Sci. 2010, 99, 3826–3838.
  2. Guns, S.; Dereymaker, A.; Kayaert, P.; Mathot, V.; Martens, J.A.; Van den Mooter, G. Comparison Between Hot-Melt Extrusion and Spray-Drying for Manufacturing Solid Dispersions of the Graft Copolymer of Ethylene Glycol and Vinylalcohol. Pharm. Res. 2011, 28, 673–682.

 

 

Read 215 times