Physicochemical study of drug binary systems. Part 3: Tolbutamide-urea and tolbutamide-mannitol systems.

The phase diagram of the tolbutamide-urea system, constructed by data obtained from the microheating table apparatus, was a peritectic type. It showed the possibility of the formation of two molecular compounds with incongruent m. p. at 112 degrees C and 123 degrees C. Metastable and stable eutectic points were observed at 63 degrees C and 92 degrees C respectively. The phase diagram of tolbutamide-mannitol system revealed that in addition to eutectic liquefaction at 102 degrees C and 6% (w/w) mannitol, there was a region [40--80% (w/w) mannitol] in which the two components were not completely miscible in the liquid state. Solubility studies showed an increase of about 2.5 fold in the solubility of tolbutamide with 0.5 g% urea and suggested the possibility of the formation of a low-solubility complex in addition to a soluble higher complex of the two components. No obvious increase in the solubility of tolbutamide was detected in the presence of mannitol. A full description of the nature and composition of the final solidified melts of the two present systems could prove to be helpful in the explanation of the dissolution behaviour of the different studied samples and their corresponding physical mixtures. The fused 90% urea and mannitol solid dispersions showed a fast rate of dissolution in the order of 15 and 10 times (respectively) greater than pure tolbutamide.