Emulsion preparation using β-cyclodextrin and its derivatives acting as an emulsifier

Article abstract of DOI:10.1248/cpb.56.1335

The preparation and formation mechanism of n-hexadecane/water emulsions using natural β-cyclodextrin (β-CD) and chemically modified β-CDs (triacylated β-cyclodextrins) as an emulsifier were investigated. The stable water/oil (W/O) emulsion was formed using tripropanoyl-β-CD (TP-β-CD). From observation using the contact angle (θ_ow) of precipitates derived from CD, it was clarified that oil/water (O/W) emulsion at θ_ow<90° and (W/O) emulsion at θ _ow>90° are formed when the composition of each oil and water was mixed with natural β-CD or triacylated β-CDs.

Full text of DOI:10.1248/cpb.56.1335

September 2008
Notes
Chem. Pharm. Bull. 56(9) 1335—1337 (2008)
1335
b
Emulsion Preparation Using -Cyclodextrin and Its Derivatives Acting as
an Emulsifier
Motoki INOUE, Kaname HASHIZAKI, Hiroyuki TAGUCHI, and Yoshihiro SAITO*
College of Pharmacy, Nihon University; 7–7–1 Narashinodai, Funabashi, Chiba 274–8555, Japan.
Received April 7, 2008; accepted June 12, 2008; published online June 16, 2008
The preparation and formation mechanism of n-hexadecane/water emulsions using natural b-cyclodextrin
(b-CD) and chemically modified b-CDs (triacylated b-cyclodextrins) as an emulsifier were investigated. The sta-
ble water/oil (W/O) emulsion was formed using tripropanoyl-b-CD (TP-b-CD). From observation using the con-
tact angle (qow) of precipitates derived from CD, it was clarified that oil/water (O/W) emulsion at qowꢂ90° and
(W/O) emulsion at qowꢀ90° are formed when the composition of each oil and water was mixed with natural b-
CD or triacylated b-CDs.
Key words cyclodextrin; phase diagram; oil/water emulsion; water/oil emulsion; Pickering emulsion; contact angle
C84H112O56: C, 50.00; H, 5.59. Found: C, 49.62; H, 5.71.
Cyclodextrins (CDs) have a hydrophobic cavity and form
TP-b-CD: 1H-NMR (DMSO) d: 1.00—1.07 (9H, m), 2.21—2.40 (6H,
m), 3.83—3.87 (1H, t), 4.10—4.13 (1H, q), 4.25—4.28 (1H, d), 4.39—4.42
(1H, d), 4.72—4.75 (1H, t), 5.05—5.06 (1H, d), 5.22—5.26 (1H, t). 13C-
NMR (DMSO) d: 8.61, 26.60, 62.19, 69.31, 69.75, 70.09, 76.02, 96.27,
172.42, 173.23, 173.93. IR (KBr) cmꢁ1: 1750, 1470, 1360, 1180, 1050.
FAB-MS m/z: 2312. Anal. Calcd for C105H154O56: C, 54.54; H, 6.71. Found:
C, 54.59; H, 6.83.
an inclusion complex with a hydrophobic guest molecule; as
a result, these have found a number of applications in the
pharmaceutical field.1) We have recently reported the prepa-
ration and formation mechanism of emulsions using natural
CDs as an emulsifier.2,3) In these studies, it was suggested
that the formation of a dense film at the oil–water interface
and a three-dimensional structural network in the continuous
phase by precipitated complexes derived from CD are neces-
TB-b-CD: 1H-NMR (DMSO) d: 0.83—0.90 (9H, m), 1.49—1.56 (6H,
m), 2.28—2.31 (6H, m), 3.84—3.85 (1H, t), 4.07—4.09 (1H, q), 4.24—4.26
(1H, d), 4.36—4.39 (1H, d), 4.67—4.70 (1H, t), 5.02—5.03 (1H, d), 5.20—
sary for the formation of a stable emulsion. Consequently, we 5.25 (1H, t). 13C-NMR (DMSO) d: 13.20, 17.48—35.13, 62.10, 69.32,
69.69, 70.17, 76.05, 96.22, 171.38, 172.25, 172.30. IR (KBr) cmꢁ1: 1750,
concluded that the formed emulsions are a kind of Pickering
emulsion, which is stabilized by solid particles. Furthermore,
we clarified that the prepared emulsion using natural CDs
1180, 1050. FAB-MS m/z: 2606.8. Anal. Calcd for C126H196O56: C, 58.05; H,
7.58. Found: C, 58.01; H, 7.75.
Preparation of Emulsion and Phase Diagram The composition with
forms the oil/water (O/W) type only because the contact
angle (qow), which the precipitate derived from CD makes
with the oil–water interface, is less than 90°. In consideration
of the above results, it is thought that water/oil (W/O) emul-
sion must be formed at qowꢀ90°. However, there is no report
in the literature on the preparation of W/O emulsion using
CDs as an emulsifier.
different levels of CD, oil, and water was placed in a sealed container and
mixed at 10000 rpm for 5 min using a homogenizer (Excel Auto Homoge-
nizer, Nihon Seiki Seisakusyo Co., Tokyo, Japan) at 25 °C. Phase diagrams
of oil/CD/water systems were obtained using visual and microscopic obser-
vations 1 h after preparation. The type of emulsion was determined by elec-
tric conductivity measurement and dilution testing.5)
Contact Angle The contact angle measurement was the same as de-
scribed previously.3) Briefly, the emulsion was centrifuged and the obtained
precipitate was molded into a pellet-like shape and immersed in oil. Two mi-
In this paper, we attempted to prepare W/O emulsion using
triacylated b-CDs, which are hydrophobic compounds.
croliters of water was dropped onto the pellet, and the contact angle (qow
)
which the precipitate makes with the oil–water interface at 25 °C was im-
aged using a microcamera. The contact angle was then determined by an
image analysis system (Visual Scalar MCP-550, Moritex Co., Tokyo, Japan).
The measurements were repeated three times.
Experimental
Materials b-cyclodextrin (b-CD) was purchased from Nihon Shokuhin
Kako Co., Ltd. (Tokyo, Japan) and used after drying in a vacuum. Acetic an-
hydride, propionic anhydride, and butyric anhydride were purchased from
Kanto Chemical Co., Inc. (Tokyo, Japan) and used without further purifica-
tion. Other reagents were the purest grade supplied by Wako Pure Chemical
Industries Ltd. (Osaka, Japan). Distilled water for injection JP (Japanese
Pharmacopoeia) was obtained from Otsuka Pharmaceutical Co., Ltd.
(Tokyo, Japan).
Results and Discussion
Phase diagrams of the ternary components of oil/CD/water
systems were investigated. The oil phase used n-hexadecane,
which formed the most stable emulsion in n-alkanes used as
the oil phase in a previous paper.3) Figure 1 shows phase dia-
Preparation of Triacylated b-CDs Triacylated b-CDs (triacetyl-b-CD
(TA-b-CD), tripropanoyl-b-CD (TP-b-CD), and tributanoyl-b-CD (TB-b-
CD)) were prepared using the corresponding acid anhydrides in pyridine.4)
NMR spectra were measured on a JEOL JNM-LA400 spectrometer (Tokyo,
Japan) operating at 400 and 100 MHz for protons and carbons, respectively.
Chemical shifts (d) are given in ppm relative to TMS as an external stan-
dard. FAB-MS spectra were measured in positive ion mode by a JEOL GC-
mate (Tokyo, Japan). Chart 1 shows the chemical structures of triacylated b-
CDs. NMR spectroscopic data and some analytical data of triacylated b-CDs
are described below.
TA-b-CD: 1H-NMR (DMSO) d: 2.02—2.10 (9H, m), 3.84—3.89 (1H, t),
4.10—4.13 (1H, q), 4.25—4.29 (1H, q), 4.42—4.44 (1H, d), 4.74—4.77
(1H, q), 5.09 (1H, d), 5.21—5.26 (1H, t). 13C-NMR (DMSO) d: 20.49,
62.32, 69.36, 69.92, 69.99, 76.52, 96.55, 169.28, 169.99, 170.03. IR (KBr)
cmꢁ1: 1750, 1380, 1240, 1040. FAB-MS m/z: 2017.8. Anal. Calcd for Chart 1. Chemical Structures of Triacylated-b-CDs
∗ To whom correspondence should be addressed. e-mail: ysaito@pha.nihon-u.ac.jp
© 2008 Pharmaceutical Society of Japan

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Vol. 56, No. 9
Fig. 3. Formation Mechanism of Pickering Emulsion
Fig. 1. Phase Diagrams of n-Hexadecane/CD/Water Systems at 25 °C.
(a) n-Hexadecane/b-CD/water system, (b) n-hexadecane/TA-b-CD/water system, (c)
n-hexadecane/TP-b-CD/water system, and (d) n-hexadecane/TB-b-CD/water system.
Fig. 4. Relationship between the Contact Angle (qow) Which the Precipi-
tate Makes with the Oil–Water Interface and Interfacial Tension (gow) of
Various Compounds Used as an Oil Phase at 25 °C
(a) n-Octanol, (b) methyl n-octanoate, (c) isopropyl myristate, (d) poly(dimethyl-
siloxane), (e) n-octane, (f) n-dodecane, and (g) n-hexadecane. The gow values of various
compounds are from refs. 9 and 10.
formed using b-CD and TA-b-CD, while the stable W/O
emulsion was formed using TP-b-CD. For TB-b-CD, only
the unstable W/O emulsion was formed. In the low volume
fraction of the dispersed phase in the system, the emulsion
was liable to be unstable regardless of the kind of b-CDs. In
addition, in the low volume fraction of the continuous phase
and in the high volume fraction of CD in the system, the for-
mation of precipitates was confirmed in all systems. In addi-
tion, the phase inversion in the emulsion by the change in the
volume fraction of oil and water did not occur in all systems.
The surface state of W/O emulsion droplets was investigated
using polarized light microscopy. From the photograph, it
was clear that the precipitates contributed to the formation of
Fig. 2. Microphotographs of n-Hexadecane/CD/Water Systems
(a) Stable O/W emulsion phase, (b) unstable O/W emulsion phase, (c) precipitated
phase, (d) stable W/O emulsion phase, (e) unstable W/O emulsion phase, and (f) stable
W/O emulsion phase taken under cross nicol polarization. (a), (b) and (c) are emulsified
using TA-b-CD, and (d), (e) and (f) are emulsified using TP-b-CD.
grams of the ternary components of n-hexadecane/CD/water the emulsion because polarized light originating from precip-
systems. In the phase diagrams, ‘O/W (S)’ is a stable O/W itates was observed on the surface of droplets (see Fig. 2f).
emulsion, ‘O/W (U)’ is an unstable O/W emulsion, ‘W/O Consequently, it was thought that the formed W/O emulsion
(S)’ is a stable W/O emulsion, ‘W/O (U)’ is an unstable W/O is a kind of Pickering emulsion, similar to the O/W emulsion
emulsion, ‘O’ is the separated oil phase, ‘W’ is the separated previously reported.2,3)
water phase, and ‘P’ is the precipitate phase.
The type of Pickering emulsion is governed by the wetta-
Figure 2 shows the microphotographs and the microphoto- bility of the solid particles at the oil–water interface6,7); that
graph under crossed nicol polarization for each phase in n- is to say, a solid particle of qowꢂ90° stabilizes O/W emul-
hexadecane/CD/water systems. Stable O/W emulsions were sion, and that of qowꢀ90° stabilizes W/O emulsion, as shown

September 2008
1337
Acknowledgment This work was supported in part by “High-Tech Re-
search Center” Project for Private Universities: matching fund subsidy from
MEXT (Ministry of Education, Culture, Sports, Science and Technology),
2007 and Nihon University Research Grant for 2007.
in Fig. 3. In addition, it is known that the qow varies with the
oil-water interfacial tension (gow) of the compound used as
the oil phase.8) Figure 4 shows the correlation between the
qow which the precipitate makes with the interface and the
g
ow of various compounds. In the TB-b-CD, the qow values in References
1) Frömming K.-H., Szejtli J., “Cyclodextrins in Pharmacy,” Kluwer Aca-
demic Publishers, Dordrecht, 1994.
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Chem. Pharm. Bull., 55, 1620—1625 (2007).
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668—671 (2008).
4) Hirayama F., Yamanaka M., Horikawa T., Uekama K., Chem. Pharm.
Bull., 43, 130—136 (1995).
oils having a low gow were not measured because the hy-
drophobicity of precipitates derived from TB-b-CD is very
high. The qow values increased with increasing hydrophobic-
ity of CD and decreasing interfacial tension of the compound
used as the oil phase. Furthermore, O/W emulsion at
qowꢂ90° and W/O emulsion at qowꢀ90° were formed when
the composition of each compound (oil) and water was
mixed with natural b-CD or triacylated b-CDs. In the TA-b-
CD, it is particularly interesting that W/O emulsion is formed
using oils having a low gow, while O/W emulsion is formed
using oils having a high gow.
5) Martin A., Swarbrick J., Cammarata A., “Physical Pharmacy,” 3rd ed.,
Lea & Febiger, Philadelphia, 1983, pp. 553—554.
6) Schulman J. H., Leja J., Trans. Faraday Soc., 50, 598—605 (1954).
7) Binks B. P., Lumsdon S. O., Langmuir, 16, 8622—8631 (2000).
8) Binks B. P., Lumsdon S. O., Langmuir, 16, 2539—2547 (2000).
9) “Kagaku Binran Kisohen II,” ed. by The Chemical Society of Japan,
Maruzen, Tokyo, 1988, pp. 88—89.
In conclusion, the present findings suggest that both O/W
and W/O emulsions can be prepared using appropriate b-
CDs and oils.
10) Binks B. P., Lumsdon S. O., Phys. Chem. Chem. Phys., 2, 2959—2967
(2000).