Effect of Polyethylene Oxide Concentration and Particle Size on Modulating the release of diltiazem HCl From Liquisolid Tablet Matrices

Abstract

Liquisolid technique is a relatively new approach to formulating sustained release dosage forms. Polyox has been used for the preparation of sustained released tablets because of its ease of production, insensitivity to the pH of the biological medium, high water solubility, high swellability and non-toxicity. The aim of this study was to investigate the effects of Polyox (WSR 303) concentration and particle size on the tableting and dissolution properties of tablet matrices containing a model highly soluble drug, diltiazem HCl (DTZ), prepared using liquisolid technique in comparison to their physical mixture conventional counterparts. DTZ:Polyox matrices were formulated using various size-fractions of Polyox (from <63 μm to >180 μm) at three different DTZ:Polyox ratios (i.e. 1:3, 1:4 and 1:5, w:w). The results showed the hardness of liquisolid and conventional tablet matrices to increase with increasing Polyox concentration and decreasing Polyox particle size distribution. For example, the hardness of liquisolid tablets (prepared at 1:5 DTZ:Polyox ratio, w:w) increased from 14.2 N to 31.6 N when the mean diameter or Polyox decreased from 245 µm ± 4.4 µm to 75.1 µm ± 2.0 µm. The hardness of liquisolid tablets (containing <63 μm size-fraction of Polyox) increased from 10.1 N to 31.6 N when the DTZ:Polyox ratio changed from 1:3 to 1:5 (w:w). At 1:3 and 1:4 drug:Polyox (w:w) ratios, and regardless of Polyox particle size distribution, liquisolid formulations produced statistically similar release profiles compared to conventional formulations. However, liquisolid formulations produced slower release profiles compared to conventional formulations when the concentration of Polyox increased to 1:5 drug:Polyox (w:w) ratio. The release of DTZ from both liquisolid and conventional tablets showed mostly decreasing trends with increasing Polyox concentration and decreasing Polyox particle size distribution. This could be attributed to the formation of stronger and thicker gel layers on the tablet surfaces in the case of higher concentrations of Polyox. Liquisolid formulations containing Polyox particles with smaller size distributions required less time to form viscous hydrogel barrier, resulting in slower drug release by diffusion more than disintegration. Fourier transform infrared analysis showed a reduction in the absorption intensities of liquisolid formulations between 2350 cm-1 and 2400 cm-1 with the increase in Polyox concentration and the decrease in Polyox particle size distribution. This confirmed the presence of a higher degree of DTZ‒Polyox interaction (hydrogen bonding) in the case of liquisolid formulations containing higher concentrations of Polyox and smaller Polyox particles. In conclusion, concentration and particle size distribution of Polyox are important variables in determining the release of a highly soluble drug from Polyox-based liquisolid formulations.