Omari Mahmoud M Al, Badwan Adnan A, Zughul Mohammad B, Eric J, Davies D
The Jordanian Pharmaceutical Manufacturing Company, Naor, Jordan.
Drug Dev Ind Pharm. 2007 Nov;33(11):1205-15. doi: 10.1080/03639040701377672.
Interactions of fexofenadine (Fexo) with cyclodextrins (CDs: alpha- beta-, gamma-, and HP-beta-CD) were investigated by several techniques including phase solubility, differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), (1)H-nuclear magnetic resonance ((1)H-NMR) and molecular mechanical modeling (MM(+)). The effects of CD type, pH, ionic strength, and temperature on complex stability were also explored. Fexo/CD complex formation follows the decreasing order: beta-CD > HP-beta-CD > gamma-CD > alpha-CD (i.e., at pH 7.0 and 30 degrees C, K(11) = 1139, 406, 130, and 104 M(-1), respectively). The linear correlation of the free energy of Fexo/beta-CD complex formation (DeltaG(11)) with the free energy of inherent Fexo solubility (DeltaG(So)), obtained from the variation of K(11) with inherent Fexo solubility (S(o)) at different pHs and ionic strengths, was used to measure the contribution of the hydrophobic character of Fexo to escape from water by including into the hydrophobic CD cavity. The hydrophobic effect (desolvation) contributes about 76% of the total driving force towards inclusion complex formation, while specific interactions contribute -7.7 kJ/mol. Moreover, Zwitterionic Fexo/beta-CD complex formation appears to be driven both by favorable enthalpy (DeltaH degrees = -23.2 kJ/mol) and entropy (DeltaS degrees = 15.2 J/molxK) changes at pH 7.0. (1)H-NMR and MM(+) studies indicate multimodal inclusion of the piperidine, carboxypropylphenyl, and phenyl moieties into the beta-CD cavity. MM(+) computations indicate that the dominant driving force for complexation is Van der Waals force with very little electrostatic contribution. (1)H-NMR, DSC, and XRPD studies indicate the formation of inclusion complex in aqueous solution and the solid state.
通过多种技术研究了非索非那定（Fexo）与环糊精（CDs：α-、β-、γ-和HP-β-CD）的相互作用，这些技术包括相溶解度、差示扫描量热法（DSC）、X射线粉末衍射法（XRPD）、氢核磁共振（¹H-NMR）和分子力学建模（MM⁺）。还探讨了CD类型、pH值、离子强度和温度对复合物稳定性的影响。Fexo/CD复合物形成顺序为：β-CD＞HP-β-CD＞γ-CD＞α-CD（即在pH 7.0和30℃时，K₁₁分别为1139、406、130和104 M⁻¹）。通过在不同pH值和离子强度下K₁₁随非索非那定固有溶解度（Sₒ）的变化，得到非索非那定/β-CD复合物形成的自由能（ΔG₁₁）与非索非那定固有溶解度的自由能（ΔGₛₒ）之间的线性相关性，用于衡量非索非那定通过进入疏水性CD腔从水中逸出的疏水特性的贡献。疏水效应（去溶剂化）对包合物形成的总驱动力贡献约76%，而特异性相互作用贡献-7.7 kJ/mol。此外，在pH 7.0时，两性离子非索非那定/β-CD复合物的形成似乎受到有利的焓变（ΔH° = -23.2 kJ/mol）和熵变（ΔS° = 15.2 J/mol·K）的驱动。¹H-NMR和MM⁺研究表明哌啶、羧丙基苯基和苯基部分以多模式方式包合进入β-CD腔。MM⁺计算表明，络合的主要驱动力是范德华力，静电贡献很小。¹H-NMR、DSC和XRPD研究表明在水溶液和固态中形成了包合物。
