Incorporation of Salicylic Acid Molecules into the Intermolecular Spaces of γ-Cyclodextrin-Polypseudorotaxane

Abstract

Sealed-heating of salicylic acid (SA) and polyethylene glycol (PEG)/γ-cyclodextrin (CD)-polypseudorotaxane induced a novel complex formation wherein SA was inhabited in the intermolecular spaces formed by the γ-CD/polypseudorotaxane columns. Incorporation of SA into the PEG/γ-CD-polypseudorotaxane structure was clarified by powder X-ray diffraction measurements and 13 C-solid-state NMR spectroscopy. Different water vapor adsorption and desorption behaviors between the novel complex and PEG/ γ-CD-polypseudorotaxane confirmed the incorporation of SA molecules into the intermolecular spaces in the complex.Cyclodextrins (CDs), which are host molecules, are known to include various kinds of guest molecules in their cavities. 1 Inclusion complex formations with active pharmaceutical ingredients (APIs) have been widely studied because inclusion complex formations improve physicochemical properties such as solubility, dissolution rate, bioavailability, and stability of APIs. Guest molecules were reported to be able to exist both in the cavities of CDs and in the intermolecular spaces formed by CDs. 2 Indeed, Harata et al. described that in the evaporated sample of p-nitrophenol/dimethyl-β-CD, p-nitrophenol existed in the interstitial sites of the molecular arrangement of dimethyl-β-CD molecules. 2 In the case of m-nitrophenol or m-bromophenol, the guest molecules were located not only in the cavity of R-CD but also in the intermolecular spaces of R-CD columns. 2 However, there have been few publications that have discussed the existence of guest molecules outside the CD cavities.Recently, a large number of studies on the inclusion complexes of CDs with polymers, named CD-polypseudorotaxanes, have been published. 3,4 CD-polypseudorotaxanes have received a great deal of interest because of their unique structural, electrical, and mechanical properties. Their applications in the pharmaceutical field, however, have been extremely limited because the CD cavities are filled with polymers and no more space in the cavity remains for the inclusion of drugs.Herein we report a novel complex prepared by utilizing the sealed-heating technique, in which both the guest and host molecules are only heated in an enclosed space. 5 In this novel complex, it was found that salicylic acid (SA) molecules were inhabited in the intermolecular spaces formed by polyethylene glycol 2000 (PEG)/γ-CD-polypseudorotaxane columns. A novel inclusion complex was prepared in two steps. In step 1, conventional PEG/γ-CD-polypseudorotaxane was prepared by the coprecipitation method. 3 PEG and γ-CD were suspended in distilled water. The suspension was stirred at 25°C for 2 days and then stored for 1 day at 25°C. The precipitate was filtrated and dried for 1 day at 25°C to obtain PEG/γ-CD-polypseudorotaxane. In step 2, SA and the polypseudorotaxane were sealedheated in order to incorporate SA molecules into the intermolecular spaces of the γ-CD molecules.

Rapid quantification of 2-hydroxypropyl-β-cyclodextrin in liquid pharmaceutical formulations by 1H nuclear magnetic resonance spectroscopy

“…Furthermore, some interesting abilities of cyclodextrins, such as permeability enhancer, could be evaluated by quantifying cyclodextrin content before and after their passage through a cell layer (Matilainen et al, 2008). Since Nuclear Magnetic Resonance (NMR) spectroscopy is one of the most widely used techniques for understanding the interaction between CD and guest compounds (Bertholet et al, 2005;Higashi et al, 2009;Lis-Cieplak et al, 2014;Malet-Martino and Holzgrabe, 2011;Schneider et al, 1998;Vogt and Strohmeier, 2012;Yang et al, 2009) and to evaluate the number of substituted glucopyranose units (molar substitution), we aim to apply 1 H nuclear magnetic resonance spectroscopy ( 1 H NMR) to quantify 2-HP-b-CD in pharmaceutical solutions. Under controlled conditions, 1 H NMR spectroscopy is considered as quantitative given that the intensity of a signal is directly related to the amount of resonant nuclei (Holzgrabe et al, 2005).…”

Salicylic Acid/γ-Cydodextrin 2:1 and 4:1 Complex Formation by Sealed-Heating Method

“…23 Our recent study showed that sealedheating of salicylic acid (SA) with PEG/g-CD polypseudorotaxane induced a novel complex formation. 24 In this complex, each g-CD molecule can be inhabited by two SA molecules in the intermolecular spaces between the PEG/g-CD-polypseudorotaxane columns.…”

Simultaneous Dissolution of Naproxen and Flurbiprofen from a Novel Ternary .GAMMA.-Cyclodextrin Complex

“…In our recent study, it was found that the sealed-heating of salicylic acid (SA) with polyethylene glycol (PEG)/g-CDpolypseudorotaxane induced complex formation. 14) In this complex, two SA molecules for each g-CD molecule were incorporated into the intermolecular spaces between the columns of g-CD stacks, while double-stranded PEG chains were included in the g-CD cavity. Although a large number of studies have been carried out on the inclusion complexes of CDs, there are only a few reports on the existence of guest molecules outside the CD cavity.…”

“…The diffraction pattern of the SH was similar to that of the monoclinic columnar form reported previously. 14,25) We have proposed that the transformation from the hexagonal columnar form to the monoclinic columnar form takes place upon the complex formation of SA/(PEG/g-CD-polypseudorotaxane) by the sealed-heating method.…”

“…This might result in the faster dissolution of NPX than the crystalline NPX. 14,[26][27][28] The dissolution profiles of NPX and FBP from the PM and ternary complex were compared (Fig. 3c).…”