Preparation and physicochemical characterization of a novel water‐soluble prodrug of carbamazepine

Abstract N -Acyl-urea derivatives of carbamazepine (CBZ) were synthesized through the reactions of iminostilbene with acyl-isocyanates to form N -glycyl-carbamazepine ( N -Gly-CBZ, after a deprotection step) or N -acetyl-carbamazepine ( N -acetyl-CBZ). N -Gly-CBZ was isolated as its water-soluble HCl salt and was designed to act as a prodrug and convert to CBZ and glycine in vivo by enzymatic cleavage of the acyl-urea bond. The stability pH-rate profiles for N -Gly-CBZ and N -acetyl-CBZ were determined. The stability of N -Gly-CBZ was found to range over four orders of magnitude with its greatest stability at pH 3–4 and a t 90 value of 5.9 day at pH 4 at 25°C. From the fit of the pH rate profile two p K a values were estimated to be 7.2 (terminal amine) and 10.0 (imide), which were independently verified using UV–visible spectroscopic analysis. The solubility of N -Gly-CBZ in aqueous solution was determined in the range of pH 5.5–7.5. The intrinsic solubility of the neutral form of the prodrug was found to be 4.4 mg/mL, and the solubility of the prodrug increased exponentially (log linear) as pH was decreased below its p K a1 value. N -Gly-CBZ was found to have an aqueous solubility in excess of 50 mg/mL at pH 4. The presence of N -Gly-CBZ was found to increase the aqueous solubility of CBZ, a degradation product. CBZ showed an 8.6-fold greater solubility in an aqueous solution containing 23 mg/mL of N -Gly-CBZ than in water alone. The solubilization of CBZ by N -Gly-CBZ was investigated by examining the diffusion coefficients of the predominant species in D 2 O and was found to be more consistent with stacking complex formation than micelle formation. The stability of N -Gly-CBZ makes a ready-to-use parenteral formulation impractical, but a freeze-dried preparation for reconstitution appears to be feasible. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1810–1825, 2010