Prediction of benzodiazepines solubility using different cosolvency models

The solubility of four benzodiazepines (BZPs) including diazepam (DIZ), lorazepam (LRZ) clonazepam (CLZ), and chlordiazepoxide

(CHZ) in water-cosolvent (ethanol propylene glycol and polyethylene glycol 200) binary systems were studied. In

general, increasing the volume fraction of cosolvents resulted in an increase in the solubility of benzodiazepines. The mole fraction

solubilities were fitted to the various cosolvency models, namely extended Hildebrand approach (EHA), excess free energy (EFE),

combined nearly ideal binary solvent/Redlich-Kister (CNIBS/R-K), general single model (GSM), mixture response surface

(MR-S), double log-log (DL-L), and linear double log-log (LDL-L). The results showed that DL-L model was the best model in

predicting the solubility of all drugs in all the water–cosolvent mixtures (OAE%=4.71). The minimum and maximum errors were

observed for benzodiazepine’s solubility in water–propylene glycol and water–ethanol mixtures which were 2.67 and 11.78%,

respectively. Three models (EFE, CNIBS/R-K and LDL-L) were chosen as general models for solubility descriptions of these

structurally similar drugs in each of the solvent systems. Among these models, the EFE model was the best in predicting the

solubility of benzodiazepines in binary solvent mixtures (OAE%=11.19). © 2002 E´ ditions scientifiques et me´dicales Elsevier SAS.