INTERACTION OF NSA WITH CYCLODEXTRINS AND HYDROXYPROPYL CYCLODEXTRIN DERIVATIVES

The effects of hydroxyalkylated cyclodextrins (CD) on the solubility and stability of the nonsteroidal antirheumatics (NSA) diclofenac, piroxicam and indomethacin were investigated. The stability constants of the indomethacin complexes calculated from the slope and the intercept of the phase solubility diagram are larger in the non-ionized form whereas the number of mol indomethacin per mol CD is much more pronounced in basic media. The pH profile of indomethacin at 21 and 41-degrees-C shows four straight lines indicating no change in the degradation reaction on addition of CD. At both temperatures, hydroxypropyl-beta-cyclodextrin (HP-beta-CD) decreases the hydrolysis by one half. The influence of beta-cyclodextrin (beta-CD) and HP-beta-CD on the stability of diclofenac solutions with and without oxygen at a stress temperature of 71-degrees-C showed that the CD derivative has the most stabilizing effect. At room temperature the decrease was not significant, even when the solutions without CD were physically unstable due to recrystallization of the drug. In contrast to indomethacin and diclofenac, the CD have a destabilizing effect on the stability of piroxicam. Computer models of the complexes of indomethacin and diclofenac based on H-1-NMR measurements are shown.