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

Jeffrey N. Hemenway, Pekka Jarho, John T. Henri, Sajiv K. Nair, David Vandervelde, Gunda I. Georg, Valentino J. Stella

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20 Scopus citations


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 pKa 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 pKa1 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.

Original languageEnglish (US)
Pages (from-to)1810-1825
Number of pages16
JournalJournal of Pharmaceutical Sciences
Issue number4
StatePublished - Apr 2010

Bibliographical note

Funding Information:
The authors would like to gratefully acknowledge Dr. Serena Tongiani for her assistance in the NMR diffusion experiments and Dr. Brian Carlson for his assistance with the LC/MS/MS analysis used to identify the rearrangement product. This work was supported in part by The American Foundation for Pharmaceutical Education Pre-Doctoral Fellowship and a Tuition Fellowship from Perdue Pharma.

Copyright 2017 Elsevier B.V., All rights reserved.


  • Carbamazepine
  • Glycine
  • Prodrug
  • Solubility
  • Stability
  • pH-rate profile


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