Guest molecular size-dependent inclusion complexation of parabens with cholic acid by cogrinding

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Abstract

Effects of p-hydroxybenzoate (paraben) ester chain length on the stoichiometry and structure of grinding-induced inclusion complexes with cholic acid (CA) were investigated. Physicochemical properties of the ground mixture were evaluated by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), Fourier transform infrared (FT-IR) spectroscopy, and solid-state nuclear magnetic resonance (NMR) measurements. Ethyl-, n-propyl-, and isopropyl-parabens formed equimolar inclusion complexes with CA, and the complex structures were of the β-trans bilayer type. In contrast, the stoichiometry of the CA–paraben complex was 2:1, and the structure was of the α-gauche bilayer type when isobutylparaben was used as a guest molecule. Although the stoichiometries and structures of the complexes differed, solid-state NMR showed that the molecular states of parabens in the complexes were similar and independent of the ester chain length. Complexes between CA and parabens with longer substituent groups (C >4) were not observed. Steric effects induced by increasing the guest size are likely to influence the overall structure of inclusion complexes. Mechanical forces and thermal activation by grinding were important factors in the mechanism of CA–paraben complex formation.

Introduction

In humans, the most important bile acids are cholic acid (CA), deoxycholic acid (DCA), and chenodeoxycholic acid. Bile acids play an important role in the absorption of lipids by micellar formation. DCA can provide tunnel-like spaces called channels, in which a wide variety of organic molecules can be accommodated during complex formation (Miki et al., 1990). The channel size can be adjusted depending on the size of the guest molecules, resulting in effective complexation with many compounds (Oguchi et al., 2000). The structure of CA includes an additional hydroxyl group compared to DCA (Fig. 1). It has a facially amphiphilic molecular structure, i.e., three hydroxyl groups directed toward the steroid α-face to form a hydrophilic face and two methyl groups turned toward another face (β-face) to form a lipophilic face (Nakano et al., 2005). CA generally forms two types of host frameworks when complexed with guest molecules (Sada et al., 2001). One is a crossing-type or non-channel structure, which was reported in the case of small guest molecules such as methanol, ethanol, and 1-propanol (Johnson and Schaefer, 1972, Jones and Nassimbeni, 1990). The other is a bilayer-type or channel structure providing channels or void spaces in which larger guest molecules can be accommodated, e.g., acetophenone (Miki et al., 1988) and methyl p-hydroxybenzoate (Oguchi et al., 2002). In bilayer structures, the host frameworks were classified into four subtypes based on conformational isomerization of the steroidal side chain (gauche and trans) and stacking modes of the methyl groups in the lipophilic layer (α and β) (Nakano et al., 2001). There were α-gauche, α-trans, β-gauche, and β-trans types, which had identical host–host hydrogen-bond networks, and the lipophilic host channels with slightly different steric dimension. Bohne et al. have reported on how the hydrophobic and hydrophilic compounds can be mixed with the bile acids, such as sodium cholate in aqueous solution (Yihwa et al., 2004, Waissbluth et al., 2006).

The conventional method used to prepare complexes of bile acids is coprecipitation. However, some solvents can be preferentially included in the cavity instead of the guest compound. Cogrinding is an alternative method for preparing inclusion complexes such as DCA–naphthalene, CA–ibuprofen, and ursodeoxycholic acid–phenanthrene (Oguchi et al., 1998, Oguchi et al., 2002, Oguchi et al., 2003). Molecular complexation between bile acids and guest compounds has been explored since the 1990s. For example, the effect of guest species on the complex formation of DCA by cogrinding has been reported (Oguchi et al., 1998). In this study, parabens were used as guest molecules. Parabens are often used in the pharmaceutical formulations as preservatives. Complex formation between a paraben and the other compositions in the formulation could affect the preservation property. We investigated the grinding-induced inclusion complexes between CA and parabens with different substitute groups and examined the molecular state of the guest molecules in these complexes. We discussed mechanisms of CA–isopropylparaben and CA–isobutylparaben complex formation.

Section snippets

Materials

CA (purity 98%) was purchased from Nacalai Tesque, Inc. (Japan). Parabens used in this study were ethylparaben (EP), n-propylparaben (PP), isopropylparaben (IPP), isobutylparaben (IBP), n-pentylparaben, n-hexylparaben, n-heptylparaben, and n-nonylparaben. Their chemical structures are shown in Fig. 1. All parabens were obtained from Tokyo Chemical Industry Co., Ltd. (Japan) and were of reagent grade with a purity of >99%.

Preparation of CA–paraben physical mixtures (PMs) and ground mixtures (GMs)

CA–paraben PMs were prepared at various molar ratios using a vortex mixer

Cogrinding of CA and parabens

Effects of paraben ester chain length on inclusion complex formation with CA were investigated. We used several paraben derivatives, as mentioned in Section 2.1. The guest compounds IPP and IBP are discussed.

Fig. 2a–d shows the PXRD patterns of the CA–IPP system at a molar ratio of 1:1. Characteristic peaks were observed at 2θ = 12.0°, 13.1°, and 19.8° for CA (Fig. 2a) and 6.7° and 17.1° for IPP (Fig. 2b). The PXRD pattern of the PM was the superimposition of the diffraction peaks of CA and IPP

Conclusions

Channel-type inclusion complexes of CA and parabens were prepared by cogrinding. Ester chain length plays an important role in inclusion complexation. Parabens with different ester chain lengths form different stoichiometric and structural inclusion complexes with CA. EP, PP, and IPP formed inclusion complexes with CA at a molar ratio of CA:paraben = 1:1 with a β-trans bilayer-type structure. The 2:1 complex with an α-gauche bilayer-type structure was obtained by cogrinding CA with IBP. Although

Acknowledgement

This study was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology (Monbukagakusho), Japan (21790032, 21590038).

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