Zeng Pengyun, Zhang Guifang, Rao Aruna, Bowles Walter, Wiedmann Timothy Scott
Department of Pharmaceutics, University of Minnesota, 308 Harvard St. SE, Minneapolis, MN 55455, United States.
Int J Pharm. 2009 Feb 9;367(1-2):73-8. doi: 10.1016/j.ijpharm.2008.09.031. Epub 2008 Sep 25.
Chlorhexidine (CHX), a chemical antiseptic, is known to bind to dentin and has been shown to be effective in treating bacterial infections caused by microbes. The solubility and aggregation properties of CHX salts were determined to guide the development of a sustained release formulation for long-term disinfection.
The amount of CHX in solution was determined as a function of counterion concentration (chloride, acetate (Ac) or gluconate (G)) by UV spectrophotometry at 255nm. The weight average molecular weight was determined from the angular dependence of the scattered light. Proton NMR spectroscopy was used to investigate the dependence of the peak intensity and chemical shift on solution concentration and diffusion measurements were performed by Fourier-transform pulsed-field gradient spin-echo (PFG-SE) (1)H NMR.
The observed CHX concentration was highly dependent on the type and concentration of salt present in solution with the greatest CHX concentration achieved with gluconate, moderate to low with diacetate, and very low with dichloride solutions. Addition of sodium gluconate enhanced the amount of CHX-Ac(2) in solution; however, only low concentrations of chlorhexidine can be achieved in the presence of chloride ions. For solutions of CHX-G(2), the aggregate number appeared to range from a dimer at 40mM to perhaps a pentamer at 150mM. In contrast, no aggregation of CHX-Cl(2) or CHX-Ac(2) was detected, which was corroborated by diffusion NMR results. The change in chemical shift of protons is consistent with association of the phenyl group of one CHX with the hexamethylene chain of a second CHX. Based on the analysis of NMR peak intensities of CHX, gluconate, and acetate in saturated solutions, it appears that solubilization of the diacetate species occurs within digluconate aggregates, since the solubility product of chlorhexidine diacetate is such that the concentration of CHX will exceed the critical micelle concentration (CMC). However, no solubilization of CHX-Cl(2) occurs because the solubility product falls below the CMC.
The low concentration of CHX that can be achieved in physiological concentrations of chloride in the oral cavity may be problematic for dental and slow release formulations. Achieving a high concentration of CHX appears to require that the monomer be present at a concentration greater than that required to produce self-association.
洗必泰（CHX）是一种化学防腐剂，已知其可与牙本质结合，并已证明对治疗由微生物引起的细菌感染有效。测定CHX盐的溶解度和聚集特性，以指导长效消毒缓释制剂的开发。
通过在255nm处的紫外分光光度法测定溶液中CHX的量，作为抗衡离子浓度（氯离子、醋酸根（Ac）或葡萄糖酸根（G））的函数。由散射光的角度依赖性测定重均分子量。利用质子核磁共振光谱研究峰强度和化学位移对溶液浓度的依赖性，并通过傅里叶变换脉冲场梯度自旋回波（PFG-SE）（1）H NMR进行扩散测量。
观察到的CHX浓度高度依赖于溶液中存在的盐的类型和浓度，葡萄糖酸盐溶液中CHX浓度最高，二醋酸盐溶液中CHX浓度中等至低，二氯化物溶液中CHX浓度非常低。添加葡萄糖酸钠可提高溶液中CHX-Ac(2)的量；然而，在存在氯离子的情况下，只能达到低浓度的洗必泰。对于CHX-G(2)溶液，聚集体数量似乎从40mM时的二聚体到150mM时可能的五聚体不等。相比之下，未检测到CHX-Cl(2)或CHX-Ac(2)的聚集，扩散核磁共振结果证实了这一点。质子化学位移的变化与一个CHX的苯基与另一个CHX的六亚甲基链的缔合一致。基于对饱和溶液中CHX、葡萄糖酸盐和醋酸盐的核磁共振峰强度的分析，似乎二醋酸盐物种的增溶发生在二葡萄糖酸盐聚集体内，因为洗必泰二醋酸盐的溶度积使得CHX的浓度将超过临界胶束浓度（CMC）。然而，由于溶度积低于CMC，CHX-Cl(2)不会发生增溶。
在口腔生理浓度的氯离子中可达到的低浓度CHX可能对牙科和缓释制剂存在问题。要达到高浓度的CHX，似乎需要单体的浓度大于产生自缔合所需的浓度。
