Formulation development of anticancer drug: FB642

Abstract

Carbendazim (methyl-2-benzimidazolecarbamate), a well known anti-fungal agent that may have significant anti-cancer activity, is a poorly water-soluble ampholyte. Unfortunately its projected oral dose up to hundred mg per day is far greater than its water solubility of 6 μg/ml. The overall aim of this research was to conduct preformulation studies and develop therapeutically viable oral and parenteral formulations. The solubility of carbendazim was altered by using both solute and solvent modification approaches. The solvent modification was carried out by investigating the solubilization of carbendazim by pH in combination with cosolvents, surfactants or complexants. At pH 7 the total drug solubility is 6.11 ± 0.45 μg/ml which increases by 1 to 7 fold with cosolvent, surfactant or complexant. However, at pH 2 the solubility increases by 400 times and at pH 1.3 over 3000 times. Both cosolvents and non-ionic surfactants have a negligible effect on the total drug solubility at pH 2, whereas the total drug solubility increases by combining pH 2 with anionic surfactants or complexants. The solute modification was accomplished by preparing different salts of carbendazim. In all six different salts, viz., hydrochloride dihydrate, phosphate, hemisulfate hydrate, mesylate, besylate, and tosylate were prepared. Their structures were determined using single crystal x-ray diffraction. The developability attributes (i.e. hygroscopicity, thermal behavior, aqueous solubility, solid state stability, and dissolution rate) of these compounds were evaluated. The dissolution studies showed that all the salts had better dissolution rate than the free base, the mesylate salt been the best. Based on the preformulation studies, two formulations were chosen for oral dosing in mice. The proposed oral formulation of 9.4 mg/ml carbendazim at pH 1 in phosphate buffer and 20% SBEβCD phosphate buffer, respectively, did not precipitate on in vitro static serial dilution with water and seven up. However, the formulation containing only phosphate buffer showed activity in mice by significantly reducing the tumor growth in B-16 melanoma injected mice. Also, it gave active blood levels, which were comparable to IV dosing.