Improvement in solubility and dissolution rate of 1, 2-dithiole-3-thiones upon complexation with beta-cyclodextrin and its hydroxypropyl and sulfobutyl ether-7 derivatives

J Pharm Sci. 1999 Sep;88(9):889-95. doi: 10.1021/js990067o.


Inclusion complexes between beta-cyclodextrin derivatives and 1, 2-dithione-3-thiones were studied in aqueous solution and in the solid state. Phase solubility study was used to evaluate the complexation in solution, at 37 degrees C, of three cyclodextrins, i. e., beta-cyclodextrin (betaCD), hydroxypropyl-beta-cyclodextrin (HPbetaCD), sulfobutyl ether-7-beta-cyclodextrin (SBE7betaCD), and four 1,2-dithiole-3-thiones, i.e., the parent compound dithiolethione (DTT), dimethyldithiolethione (DMDTT), 5-phenyldithiolethione (5PDTT), and anetholetrithione (ATT). Stability constants of the DTT complexes with HPbetaCD and SBE7betaCD were also determined spectrophotometrically using a nonlinear least-squares methodology. Differential scanning calorimetry (DSC) and scanning electronic microscopy (SEM) were used to characterize spray-dried complexes formed between 5PDTT and SBE7betaCD, ATT and SBE7betaCD. Dissolution studies using the USP paddle method were carried out in water at 37 degrees C for both ATT and 5PDTT binary systems with HPbetaCD and SBE7betaCD. Solubility enhancements were much greater with the more lipophilic ATT and 5PDTT compared to DTT and DMDTT, whatever the cyclodextrin used, in the rank order SBE7betaCD > HPbetaCD >> betaCD. Stability constants obtained (between 120 and 12800 mol(-1)) were also the highest for the more lipophilic drugs and in the same rank order SBE7betaCD > HPbetaCD >> betaCD. Results obtained by UV spectrophotometry were in good agreement with those obtained by phase-solubility study. DSC thermograms of spray-dried complexes of ATT and 5PDTT with HPbetaCD and SBE7betaCD lacked the endothermal peak of pure drug peak which was found for the physical mixtures (107 degrees C and 125 degrees C for ATT and 5PDTT, respectively). Finally, dissolution profiles of spray-dried inclusion complexes studied displayed a faster dissolution rate compared to physical mixtures and pure drugs. The present study showed that complexation of 1,2-dithiole-3-thiones with beta-cyclodextrin derivatives resulted in an increase in solubility, allowing intravenous formulation for bioavailability and metabolism studies and an increase in the dissolution rate of the drugs, which should be of interest for oral absorption of these lipophilic compounds.

MeSH terms

  • 2-Hydroxypropyl-beta-cyclodextrin
  • Calorimetry, Differential Scanning
  • Chromatography, High Pressure Liquid
  • Cyclodextrins / chemistry*
  • Hydrogen-Ion Concentration
  • Kinetics
  • Microscopy, Electron, Scanning
  • Particle Size
  • Solubility
  • Spectrophotometry, Ultraviolet
  • Thiones / chemistry*
  • beta-Cyclodextrins*


  • Cyclodextrins
  • Thiones
  • beta-Cyclodextrins
  • 2-Hydroxypropyl-beta-cyclodextrin
  • SBE4-beta-cyclodextrin
  • betadex