Integrative Approach for Improved Dofetilide Solubility Using Β-Cyclodextrin and Two Its Substituted Derivatives: Solutions and Solid Dispersions

The complexation an anti -arrhythmia drug dofetilide (DFT) with 13- cyclodextrin ( 13 - CD), 2-hydroxypropyl13- cyclodextrin (HP - 13 - CD) and sulfobutylether- 13- cyclodextrin (SBE- 13- CD) were studied using two main approaches: phase solubility diagrams and solid dispersions technique. The phase solubility diagrams were constructed in buffer solutions with physiological values pH 2.0 ii 7.4. In accordance with the protolytic properties of the drug, the solubilizing effect of cyclodextrins turned out to be more effective in a neutral environment (buffer pH 7.4): the solubility improvement of DFT in the presence of 13 - CD, HP - 13 - CD and SBE- 13- CD was 3.6, 11.8 and 18.1 times, respectively. In buffer pH 2.0, the tendency for an increase in the solubilizing effect, depending on the chemical nature of the CDs used, is maintained, but the solubility of the drug almost does not grow. The binding constants for the DFT/HP- 13- CD and DFT/SBE- 13- CD complexes equal to 344 L center dot mol - 1 and 429 L center dot mol - 1 in buffer pH 7.4 indicate the formation of stable inclusion complexes and belong to the optimal range for refinement bioavailability and stability of hydrophobic drugs. Amorphous solid dispersions DFT/ 13- CD, DFT/HP- 13- CD and DFT/SBE- 13- CD with stoichiometry 1:1 were obtained by grinding method. The combination FTIR, PXRD, DSC, TGA and SEM methods confirmed the inclusion complexes formation of the drug with cyclodextrins used. Dissolution profiles of solid dispersions DFT/ 13- CD, DFT/HP- 13- CD and DFT/SBE- 13- CD were graphing in buffer solutions pH 2.0 and 7.4. Enlargement factor of DFT solubility in the composition of solid dispersions DFT/ 13- CD, DFT/HP- 13- CD and DFT/SBE- 13- CD in the neutral medium are 3.4, 4.1 and 5.2, respectively. Whereas the formation of solid inclusion complexes DFT/CDs in an acidic buffer has virtually no effect on the increase in the equilibrium concentration of the active substance in the solution. Findings have demonstrated that the use of SBE- beta- CD shows the best solubilization potential for DFT both in solution and as a solid dispersion.