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Preparation of Azithromycin Microcapsules by A Layer-By-Layer Self-Assembly Approach and Release Behaviors of Azithromycin
Preparation of Azithromycin Microcapsules by A Layer-By-Layer Self-Assembly Approach and Release Behaviors of Azithromycin
Preparation of Azithromycin Microcapsules by A Layer-By-Layer Self-Assembly Approach and Release Behaviors of Azithromycin
a r t i c l e
i n f o
Article history:
Received 13 January 2010
Received in revised form 17 March 2010
Accepted 5 April 2010
Available online 13 April 2010
Keywords:
Azithromycin
Microcapsule
Layer-by-layer self-assembly
Polyelectrolyte
Dissolution
a b s t r a c t
A novel preparation method of azithromycin (AZI) microcapsules based on hollow polyelectrolyte (PE)
microcapsules, which were prepared by layer-by-layer self-assembly onto the surface of silica microsphere (SiO2 ) followed by core dissolution has been investigated. The prepared AZI/PE microcapsules
with an average diameter 1.2 m possess homogeneous size and regular spherical shape. FTIR spectra
and XRD patterns indicated that AZI molecular structure was not changed and AZI crystal state changed
from monohydrate to dihydrate. The drug release experimental results showed an obvious improvement
in the dissolution rate of the prepared AZI/PE microcapsules in comparing with AZI raw material drug
powder.
2010 Elsevier B.V. All rights reserved.
1. Introduction
Azithromycin (AZI) is a semi-synthetic acid-stable macrolide
antibiotic with a 15-membered azalactone ring. It shows a broad
spectrum of bacteriostatic activity, and is proved to be clinically
effective against not only Gram-positive but also Gram-negative
bacteria and atypical pathogens, which make up the deciency of
erythromycin, the rst macrolide used clinically as an antibiotic
[1]. Although AZI is derived from erythromycin, it differs by the
insertion of a methylsubstituted nitrogen on the lactone ring at
position 9-a of the large macrolactone ring. This modication produces an enhanced spectrum and potency against bacteria, and a
superior stability in acidic environment [2]. Besides, AZI is available in immediate oral or intravenous release, and has a longer
half-life period, fewer side-effects, and higher concentration in tissue than erythromycin, and can even be applied to children or
pregnant women [3]. So AZI and other newer macrolides, such as
larithromycin, dirithromycin and roxithromycin, are regarded as an
advanced-generation for erythromycin [4]. As for bacteriostatic
mechanism, like erythromycin, it appears to bind to the same receptor, 50 S ribosomal subunits of susceptible bacteria and suppresses
protein synthesis [1]. AZI plays a leading role in the treatment or
prophylaxis of common respiratory tract infections, skin structure
infection and several other clinical diseases, such as opportunistic
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Fig. 4 displays the FTIR spectra of SiO2 (a), SiO2 /PE composite
microspheres (b), hollow PE microcapsules (c), AZI raw material
drug (d) and AZI/PE microcapsules (e). In the silica microspheres
spectra, the peak 1097.6 cm1 is the SiOSi anti-symmetric
stretching vibration absorption, the peaks 802.4 and 468.9 cm1
are related respectively to the symmetrical stretching vibration and
the bending vibration, and the peaks 1631.5 and 3451.4 cm1 represent respectively the characteristic water absorption peak and
the OH radicals of silica microspheres. However, the FTIR spectra
of hollow PE microcapsules, SiO2 /PE composite microspheres and
silica microspheres were nearly unchanged, which is owing to the
residues of SiO2 disposed by HF solution. Moreover, residues of SiO2
are the support materials to prevent microspheres collapsing. The
FTIR spectra of AZI raw material drug and AZI/PE microcapsules are
very similar, except part of the H2 O-correlated characteristic FTIR
peaks. So in the preparation process of AZI/PE microcapsules, the
basic groups and AZI intramolecular structures were unaltered.
However, the crystal state of the prepared AZI/PE microcapsules
has been changed. AZI is found to exhibit polymorphism, pseudopolymorphism and amorphism. Pseudopolymorph AZI can exist
as monohydrate and dihydrate [15]. The anhydrous form of AZI
seems to be unstable since it converts to dihydrate on storage at
room temperature, and the monohydrate form converts to the more
stable dihydrate form in the presence of moisture [16]. The structural change that occurred in the AZI/PE microcapsules during the
preparation process can be conrmed as follows:
On one hand, the FTIR spectra of AZI raw material drug and
AZI/PE microcapsules revealed distinct differences within the OH
stretching region (3450 cm1 ), which contributed to the change of
AZI crystal lattice structure. The presence of a sharp high frequency
peak at 3494 cm1 in the case of AZI raw material is indicative of the
presence of tightly bound water in the crystal lattice, while the
broad band at 33003600 cm1 in AZI/PE microcapsules is due to
the OH stretching for self associated water that may be loosely
bounded [16].
On the other hand, by comparing the X-ray diffraction (XRD)
patterns of AZI raw material drug and AZI/PE microcapsules, as
shown in Fig. 5, it is fair to say that the crystal state of AZI had
been changed during the preparation of AZI/PE microcapsules. The
XRD spectral characteristic of AZI raw material is very complex with
many diffraction peaks, while the XRD pattern of AZI/PE microcapsules basically corresponds with XRD spectra of AZI monohydrate.
Some studies show that AZI monohydrate has a faster dissolution
rate at the initial 48 h [16], which is one of the reasons that dissolution rate of AZI/PE microcapsules increases. Moreover, Zhao et al.
[9] have conrmed that the AZI monohydrate prepared by goodpoor solvent method demonstrate a much-improved antibacterial
activity.
3.3. Release behavior of AZI raw material drug and AZI/PE
microcapsules
The release curves of the AZI raw material drug and the
AZI/PE microcapsules prepared under the conditions of pH = 6.0 and
pH = 2.0 are presented in Fig. 6. As shown in this gure, AZI is lowly
soluble in water and highly soluble in acid solution. Thus, the pH
condition plays a very important role in the AZI dissolution rate,
as evidenced by the releasing results. For AZI raw material drug
and AZI/PE microcapsules, the dissolution rate in the dissolution
medium under pH = 2.0 is obviously better than it is under pH = 6.0,
respectively. Under the same pH condition, pH = 2 or pH = 6, the
prepared AZI/PE microcapsules show an apparent improvement
in dissolution rate compared with AZI raw material drug. AZI/PE
microcapsules cost about 4 h to release 80%, while AZI raw mate-
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Z. Zhang et al. / Colloids and Surfaces A: Physicochem. Eng. Aspects 362 (2010) 135139
Fig. 2. TEM images of SiO2 microspheres (a), SiO2 /PE composite microspheres (b), hollow PE microcapsules (c), and AZI/PE microcapsules (d).
Fig. 4. FTIR spectra of SiO2 microspheres (a), SiO2 /PE composite microspheres (b),
hollow PE microcapsules (c), AZI raw material drug (d), and AZI/PE microcapsules
(e).
Z. Zhang et al. / Colloids and Surfaces A: Physicochem. Eng. Aspects 362 (2010) 135139
139
This work was supported by the National Natural Science Foundation of China (20925621, 20976054), the Key Project of Science
and Technology for Ministry of Education (107045), the Innovation
Program of Shanghai Municipal Education Commission (09ZZ58),
the Program of Shanghai Subject Chief Scientist (08XD1401500)
and the Shanghai Leading Academic Discipline Project (project
number: B502).
References
Fig. 6. Releasing curves of AZI raw material drug and AZI/PE microcapsules in
pH = 6.0 and pH = 2.0, respectively.