Department of Pharmaceutical Chemistry, University of Kansas, 2095 Constant Avenue, Lawrence, Kansas 66047, USA.
J Pharm Sci. 2010 Apr;99(4):1810-25. doi: 10.1002/jps.21952.
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 degrees 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 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.
卡马西平（CBZ）的 N-酰基脲衍生物是通过亚胺基苯乙烯与酰基异氰酸酯反应合成的，形成 N-甘氨酰卡马西平（N-Gly-CBZ，经过脱保护步骤）或 N-乙酰基卡马西平（N-乙酰基-CBZ）。N-Gly-CBZ 被分离为其水溶性盐酸盐，并被设计为通过酰基脲键的酶促裂解在体内充当前药并转化为 CBZ 和甘氨酸。确定了 N-Gly-CBZ 和 N-乙酰基-CBZ 的稳定性 pH 速率曲线。发现 N-Gly-CBZ 的稳定性在四个数量级范围内，在 pH 3-4 时稳定性最大，在 25°C 时 pH 4 下的 t(90)值为 5.9 天。从 pH 速率曲线的拟合中估计出两个 pK(a)值分别为 7.2（末端胺）和 10.0（酰亚胺），这两个值使用紫外可见光谱分析独立验证。在 pH 5.5-7.5 的范围内确定了 N-Gly-CBZ 在水溶液中的溶解度。发现中性前药形式的固有溶解度为 4.4mg/mL，并且当 pH 低于其 pK(a1)值时，前药的溶解度呈指数增加（对数线性）。在 pH 4 时，N-Gly-CBZ 的水溶性超过 50mg/mL。发现 N-Gly-CBZ 的存在增加了 CBZ（一种降解产物）在水中的溶解度。与单独在水中相比，含有 23mg/mL N-Gly-CBZ 的水溶液中 CBZ 的溶解度增加了 8.6 倍。通过检查 D(2)O 中主要物种的扩散系数研究了 N-Gly-CBZ 对 CBZ 的增溶作用，发现与胶束形成相比，更符合堆积配合物的形成。N-Gly-CBZ 的稳定性使得现成的可注射制剂不切实际，但冻干制剂用于重组似乎是可行的。
