Characterization and Physical Stability of Spray Dried Solid Dispersions of Probucol and PVP-K30

Abstract

The main purpose of this study was to obtain stable, well-characterized solid dispersions (SDs) of amorphous probucol and polyvinylpyrrolidone K-30 (PVP-K30) with improved dissolution rates. A secondary aim was to investigate the flow-through dissolution method for in-vitro dissolution measurements of small-sized amorphous powders dispersed in a hydrophilic polymer. SDs were prepared by spray drying solutions of probucol and different amounts of PVP-K30. The obtained SDs were characterized by dissolution rate measurements in a flow-through apparatus, X-ray Powder Diffraction (XRPD), Differential Scanning Calorimetry (DSC), Scanning Electron Microscopy (SEM), particle sizing (laser diffraction) and Brunauer-Emmett-Teller Method (BET) and results were compared with starting material and a physical mixture. The physical stability was monitored after storage at 25°C and 60% RH for up to 12 weeks. The flow-through method was found suitable as dissolution method. All SDs showed improved in-vitro dissolution rates when compared to starting material and physical mixtures. The greatest improvement in the in-vitro dissolution rate was observed for the highest polymer to drug ratio. By means of the results from XRPD and DSC, it was argued that the presence of amorphous probucol improved the dissolution rate, but the amorphous state could not fully account for the difference in dissolution profiles between the SDs. It was suggested that the increase in surface area due to the reduction in particle size contributed to an increased dissolution rate as well as the presence of PVP-K30 by preventing aggregation and drug re-crystallization and by improving wettability during dissolution. The stabilizing effect of the polymer was verified in the solid state, as all the SDs retained probucol in the amorphous state throughout the entire length of the stability study.

Keywords:

• amorphous
• flow-through dissolution
• solid dispersion
• stability
• spray drying
• probucol

ACKNOWLEDGMENTS

The Drug Research Academy and GEA Pharmaceutical A/S are acknowledged for financial support. The authors would like to thank Niro A/S for use of their SDMicro^TM Spray dryer and Michelle Milling Madsen for helping with the spray drying experiments. Erling B. Jørgensen and Lene Olsson are greatly appreciated for help with the X-ray diffractrograms and Ragna Berthelsen for carrying out a substantial number of the solubility and dissolution measurements.

Notes

*Work was performed at: Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.