Physicochemical properties of tadalafil solid dispersions - Impact of polymer on the apparent solubility and dissolution rate of tadalafil

Eur J Pharm Biopharm. 2015 Aug;94:106-15. doi: 10.1016/j.ejpb.2015.04.031. Epub 2015 May 19.

Abstract

To improve solubility of tadalafil (Td), a poorly soluble drug substance (3μg/ml) belonging to the II class of the Biopharmaceutical Classification System, its six different solid dispersions (1:1, w/w) in the following polymers: HPMC, MC, PVP, PVP-VA, Kollicoat IR and Soluplus were successfully produced by freeze-drying. Scanning electron microscopy showed a morphological structure of solid dispersions typical of lyophilisates. Apparent solubility and intrinsic dissolution rate studies revealed the greatest, a 16-fold, increase in drug solubility (50μg/ml) and a significant, 20-fold, dissolution rate enhancement for the Td/PVP-VA solid dispersion in comparison with crystalline Td. However, the longest duration of the supersaturation state in water (27μg/ml) over 24h was observed for the Td solid dispersion in HPMC. The improved dissolution of Td from Td/PVP-VA was confirmed in the standard dissolution test of capsules filled with solid dispersions. Powder X-ray diffraction and thermal analysis showed the amorphous nature of these binary systems and indicated the existence of dispersion at the molecular level and its supersaturated character, respectively. Nevertheless, as evidenced by film casting, the greatest ability to dissolve Td in polymer was determined for PVP-VA. The crystallization tendency of Td dispersed in Kollicoat IR could be explained by the low Tg (113°C) of the solid dispersion and the highest difference in Hansen solubility parameters (6.8MPa(0.5)) between Td and the polymer, although this relationship was not satisfied for the partially crystalline dispersion in PVP. Similarly, no correlation was found between the strength of hydrogen bonds investigated using infrared spectroscopy and the physical stability of solid dispersions or the level of supersaturation in aqueous solution.

Keywords: Amorphous drug; Apparent solubility; Dissolution rate; Freeze-drying; Polymer; Solid dispersion; Supersaturation; Tadalafil.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calorimetry, Differential Scanning
  • Capsules
  • Chemistry, Pharmaceutical
  • Crystallography, X-Ray
  • Drug Stability
  • Freeze Drying
  • Hydrogen Bonding
  • Hypromellose Derivatives / chemistry*
  • Kinetics
  • Microscopy, Electron, Scanning
  • Powder Diffraction
  • Powders
  • Pyrrolidines / chemistry*
  • Solubility
  • Spectroscopy, Fourier Transform Infrared
  • Tadalafil / chemistry*
  • Technology, Pharmaceutical / methods
  • Temperature
  • Vinyl Compounds / chemistry*

Substances

  • Capsules
  • Powders
  • Pyrrolidines
  • Vinyl Compounds
  • poly(vinylpyrrolidone-co-vinyl-acetate)
  • Hypromellose Derivatives
  • Tadalafil