Journal of Inclusion Phenomena and Macrocyclic Chemistry
Preparation and characterization of the inclusion complexes of equol
with sulfobutylether-β-cyclodextrin: their antioxidant activity
and dissolution evaluation
· Sakiko Obata
· Hirokazu Nakayama
Received: 24 February 2018 / Accepted: 22 May 2018
© Springer Science+Business Media B.V., part of Springer Nature 2018
The formation of inclusion complexes between S-(−)-equol (SEq) and cyclodextrins (CDs) was investigated. The binding
) of the SEq/sulfobutylether-β-cyclodextrin (SBE-β-CD) inclusion complex was determined to be 1600 L/mol
based on UV data. The phenyl ring of the SEq molecule was found to be inserted from the secondary hydroxyl face of the
SBE-β-CD as evidenced from
H rotating frame nuclear Overhauser eﬀect spectroscopy (ROESY) NMR. The ther-
mal properties of the solid SEq/SBE-β-CD inclusion complexes prepared by physical mixing, kneading and freeze-drying
methods were studied by diﬀerential scanning calorimetry. For the solid complex obtained by the freeze-drying method, the
endothermic peak corresponding to the melting point of SEq disappeared. The solid SEq/SBE-β-CD complexes exhibited a
high score in antioxidant activity evaluation tests compared to SEq alone. Dissolution test revealed that the solid complex
obtained by freeze-drying method had improved dissolution of SEq.
Keywords S-(−)-Equol · Sulfobutylether-β-cyclodextrin · Inclusion complexes · Antioxidant activity · Dissolution
7-Hydroxy-3-(4′-hydroxyphenyl)-chroman (Equol) is an
isoﬂavone and is known to be a nonsteroidal estrogen .
Intestinal bacteria enantioselectively synthesize S-(−)-equol
rather than R-(+)-equol when metabolizing 7-hydroxy-3-(4′-
hydroxyphenyl)-4H-1-benzopyran-4-one (daidzein) because
S-(−)-equol (SEq) has a high aﬃnity for binding to estrogen
receptor-β . However, some people cannot produce
SEq in their intestines and recently it has become popular to
take SEq as a supplement for postmenopausal women .
Since it is diﬃcult to dissolve SEq in water, the development
of a product with higher solubility is desired .
Cyclodextrin (CD) is a cyclic oligosaccharide synthesized
by the action of cyclodextrin glycosyltransferase (CGTase)
on starch. CD contains a hydrophobic cavity and can form
inclusion complexes with hydrophobic molecules [5–7].
It is therefore used to stabilize pharmaceutics [8–11] and
improve their bioavailability [12, 13]. Various CD-contain-
ing drugs are currently on the market. Moreover, the useful-
ness of cyclodextrins has been shown in the food industry
This is the ﬁrst report to measure the binding constant (K
of SEq with various CDs at constant pH using spectroscopic
data. Natural CDs and synthetic CDs, [sulfobutylether-β-
cyclodextrin (SBE-β-CD), hydroxypropyl-α-cyclodextrin
(HP-α-CD), hydroxypropyl-β-cyclodextrin (HP-β-CD),
hydroxypropyl-γ-cyclodextrin (HP-γ-CD) and methyl-β-
cyclodextrin (Me-β-CD)] were used.
Solid SEq/CD inclusion complexes were prepared by
physical mixing, kneading, and freeze-drying methods,
and the antioxidant activities of the solid complexes were
examined. Also, the improvement in solubility of SEq was
examined in the dissolution test.
* Hideko Maeda
Laboratory of Functional Molecular Chemistry, Kobe
Pharmaceutical University, 4-19-1 Motoyamakita-machi,
Higashinada-ku, Kobe 658-8558, Japan