SOLUBILITY OF BIOACTIVE N-(BENZENESULFONYL)-1,2,3,4-TETRAHYDROQUINOLINE AND N-BENZENESULFONYL-1H-1,2,3-BENZOTRIAZOLE IN WATER/ETHANOL MIXTURES

KOMROVSKY, F; N.R. SPERANDEO; M. MAZZIERI

Rosario

Congreso; 2° Reunión Internacional de Ciencias Farmacéuticas. RICiFa; 2012

A chemical library of N-benzenesulfonyl derivatives of heterocycles has been prepared and several of them exhibited interesting antiparasitic (1-3) and antibacterial activities. (4) A shortcoming of these compounds is their low aqueous solubility. Therefore, for biological assays and preformulation studies, it is important to know which strategies could be appropriated for enhancing solubility in aqueous media. Two compounds of the aforementioned collection were selected, N-benzenesulfonyl-1,2,3,4-tetrahydroquinoline, BSTHQ, and N-benzenesulfonyl-1H-1,2,3-benzotriazole, BSBZT, for studying their thermodynamic solubility (S) in water/ethanol mixtures. Another objective of this research was to analyze different models that could explain S behavior and evaluate their capability of prediction. (5) Materials and methods The S of BSTHQ and BSBZT was determined at 25°C in different water/ethanol mixtures. The equilibration time of both derivatives in 7 proportions of water/ethanol (100/0; 90/10; 80/20; 70/30; 50/50; 25/75; 0/100) was determined by UV-Vis spectrophotometry. Then, the S at the above solvent mixtures was assessed and set up when the difference between three consecutive measurements was  4%. (6) The analytical techniques used were RP-HPLC for BSTHQ and UV spectrophotometry (254 nm) for BSBZT. Finally, two models, Log-Lineal (LL, Ec. 1), and Jouyban-Acree (JA, Ec. 2) were considered to analyze the behavior of the S of both compounds. Their accuracy was evaluated by the average absolute error (AAE) of the experimental and the predicted S. Ec. 1 Ec. 2 To check chemical stability during the experiments and for the identification of the compounds in the supernatant, TLC tests were performed. Also, the filtered remaining solids were analyzed by Thermomicroscopy. Results BSTHQ reached the equilibrium at 72 hours, while BSBZT showed degradation products at 24 hours, therefore it was measured until 12 hours assuring its chemical stability. An important enhance of the S with the increasing of the fraction of ethanol in the mixtures was observed for both derivatives (Table 1). BSTHQ and BSBZT were approximately 12000 and 2500 times more soluble in absolute ethanol than in water, respectively. After testing the remaining solids, BSTHQ presented laminar habit and a melting range between 59-62°C, as the starting material, while prismatic crystals of BSBZT melted between 130-132°C, the same as starting material. No new particular thermal events were observed for the remaining solids, confirming their physical stability along the determinations. By using Ec. 1 and 2, the experimental data were adjusted to above mentioned selected models (Table 1). The AAE were 0.1 and 0.3 for JA and LL models, respectively, for both compounds. Therefore, JA approach was chosen, since it explained better the S behavior of BSTHQ and BSBZT in the solvent mixtures studied and provided more accurate predictions. Conclusions An enhancing of the S with the increasing of the fraction of cosolvent in the mixture water/ethanol is observed for BSTHQ and BSBZT, being more pronounced when fractions of ethanol ≥0.5. These results demonstrate the positive effect of cosolvent on the S. Furthermore, it is also confirmed the better predictions of the JA model.