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

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 pK_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 pK_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 D₂O and was found to be more consistent with stacking complex formation than micelle formation. The stability ofN-Gly-CBZ makes a ready-to-use parenteral formulation impractical, but a freeze-dried preparation for reconstitution appears to be feasible.