SOME PHYSICAL-CHEMICAL PROPERTIES OF DANTROLENE AND 2 OF ITS ANALOGS

Some physical-chemical properties of dantrolene (1-[[5-(p-nitrophenyl)furfurylidene]amino]hydantoin), p-chlorodantrolene ((des-p-nitro)-p-chlorodantrolene) and o-nitrodantrolene ((des-p-nitro)-o-nitrodantrolene) have been studied. The solubility was measured in the range 20-37-degrees-C, at pH 5.4, 7.4 and 9.4. The solubility was found to increase as a function of pH and temperature. The thermodynamic solubility parameters were determined. Distribution experiments in the system octanol-buffer (20-degrees-C) yielded a value for the logarithm of the partition coefficient of the neutral compound of 1.70 +/- 0.05 and a pK value of 7.5. In the presence of cyclodextrins the solubility increased, indicating complex formation. The corresponding complex formation constants were highest for beta-cyclodextrin, with no detectable pH dependence. The inclusion of p-Cl-dantrolene was also studied using modelling experiments and molecular mechanics calculations. Inclusion of the chlorophenyl group proved to be possible in all cyclodextrins studied; inclusion of the hydantoin part was only feasible with beta- and gamma-cyclodextrin. The calculated energy of interaction indicated that Cl-dantrolene has complete rotational freedom in gamma-cyclodextrin, but limited freedom in alpha- and beta-cyclodextrin.