A Proton Magnetic Resonance Study of Fexofenadine/β-Cyclodextrin Inclusion Complexes in Aqueous Solution

Abstract

Fexofenadine hydrochloride (FFN), (±)-4-[1-hydroxy-4[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethyl benzeneacetic acid hydrochloride, is a second generation antihistamine that is used to treat allergies. It is a racemate and exists as zwitter ion in aqueous media at physiological pH. It belongs to the group of amine compounds bearing diphenylmethyl functionality. Like other members of this group, the drug is highly hydrophobic and slightly soluble in water. The study of inclusion complexes of cyclodextrins (CDs) is a subject of great interest. CDs are oligosaccharides composed of six to eight glucopyranose units bound by α(14) linkages that are commonly named α-, β-, and γ-CD, respectively. β-CD, in particular, has an internal cavity shaped like a truncated cone. The interior of the cavity is relatively hydrophobic while the outer surface is quite hydrophilic because of the presence of numerous hydroxyl groups. CDs can accommodate a variety of guests into its cavity through non-covalent interactions. These complexes serve as models to mimic enzyme activity and to provide understanding of the molecular recognition. Moreover, the physical properties, such as solubility, stability, volatility, sublimation, etc, of the guest molecule are modified upon complexation with CDs, and the resulting inclusion complexes have found numerous practical applications in pharmaceutical sciences and in several other areas of chemistry ranging from analytical to synthetic chemistry. Inclusion complexes of pharmaceutical compounds with CDs have been extensively studied and utilized to improve the solubility, dissolution rate and bioavailability of poorly water-soluble drugs. Other applications of CD complexes of pharmaceuticals include elimination of undesirable drug properties, such as irritation and unpleasant odor or taste. CDs have also been used to stabilize and protect degradation of unstable compounds. In addition, they have shown a potential for improving the stability of light and oxygen sensitive drugs. Various techniques are used to study the CD inclusion complexes but NMR spectroscopy has been found to be most useful in this type of studies. Evidence for the inclusion of the guest into the CD-cavity is obtained by simple NMR titration experiments. NMR spectra of mixtures of CD and guest molecule are recorded and changes in the chemical shifts of both the host and guest are studied. The formation of the inclusion complex results in upfield shift changes in the CD protons situated inside the cavity, namely H-3' and H-5'. On the other hand, guest protons generally experience downfield shift changes but sometimes upfield shifts are also observed. These shift changes are attributed to the anisotropic ring current effect of the aromatic guests. Moreover, the magnitude of the chemical shift changes for the CD-cavity protons have been shown to be a qualitative measure of the stability of the complex while their ratio, ΔδH-5'/ΔδH-3', gives information about the depth of penetration. Also, information regarding the mode of penetration of the guest into the cavity, i.e. from narrower or wider rim side, can be obtained from these shift changes. A typical inference is that ΔδH-5' > ΔδH-3' if the guest enters the cavity from narrower side and vice versa but there are exceptions and these conclusions can only be drawn when only one complex in formed while in cases where multiple equilibria exist these shift changes can only be used as an evidence for the formation of inclusion complexes. Information regarding the stoichiometry and association and/or dissociation constant of the complex can also be obtained by the treatment of simple H NMR titration data. 2D NMR spectroscopy has recently become an important tool for the investigation of the interactions between CDs and guest molecules since the NOE cross peaks between the protons that are closer than 4 A in space are observed in ROESY spectrum. The relative intensities of these cross peaks depend on the spaces between the corresponding protons. The height and the diameter of the β-CD cavity are about 7.9 ± 0.1 A and 6.0-6.5 A, respectively. Therefore, while the guest molecule is included into the β-CD cavity, NOE correlation peaks between the protons of the guest and protons of the β-CD cavity (H-3' and H-5') are observed by means of ROESY experiment. According to the relative intensities of these cross peaks, it is possible to estimate the orientation of the guest molecule within the CD cavity. In continuation of our work on the NMR studies of inclusion complexes of pharmaceutical compounds with βCD, we report herein our results on the detailed study of the complexation between fexofenadine hydrochloride (FFN) and β-CD in aqueous solution using high resolution NMR spectroscopy.