C haracterization of Azithromycin hydrates

European Journal of Pharmaceutical Sciences 16 (2002) 175–184
www.elsevier.nl / locate / ejps
Characterization of Azithromycin hydrates q
Rajesh Gandhi a , Omathanu Pillai a , Ramasamy Thilagavathi b , Bulusu Gopalakrishnan b ,
a
a,
Chaman Lal Kaul , Ramesh Panchagnula *
a
Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research ( NIPER), Sector-67, SAS Nagar—160 062 Punjab,
India
b
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research ( NIPER), Sector-67,
SAS Nagar—160 062 Punjab, India
Received 15 November 2001; received in revised form 3 April 2002; accepted 21 May 2002
Abstract
Azithromycin (AZI) is a macrolide antibiotic with an expanded spectrum of activity that is commercially available as a dihydrate. This
study was carried out to characterize hydrates of azithromycin. A commercial dihydrate sample was used to prepare monohydrate from
water / ethanol (1:1) mixture. Hydrates were characterized using DSC, TGA, KFT, XRD, HSM, SEM and FT-IR. TGA showed that the
commercial samples are dihydrate and the sample prepared from water / ethanol (1:1) was a monohydrate. Solubility studies revealed that
monohydrate converted to dihydrate during solubility studies and as a result there was no significant difference in the equilibrium
solubility of MH and DH. Thermal analysis under various conditions revealed that dehydration and melting took place simultaneously.
Anhydrous AZI was found to be hygroscopic and converted to DH on storing at room temperature. Molecular modeling studies revealed
the probable sites of attachment of water molecules to AZI.
 2002 Elsevier Science B.V. All rights reserved.
Keywords: Azithromycin; Pseudopolymorphism; Thermal analysis; Powder X-ray diffraction; Molecular modeling
1. Introduction
Polymorphism and pseudopolymorphism are important
solid state properties that influence the performance and
processing of solid dosage forms (Morris et al., 2001).
Polymorphism deals with difference in the internal structure of crystals, and pseudopolymorphism is existence of
different solvates of the same chemical compound (Vippagunta et al., 2001). The most common solvate encountered in pharmaceutical compounds is hydrate. Water
in hydrates can be present either in stoichiometric or in
nonstoichiometric ratio depending on the crystal lattice
arrangement as well as the nature of binding of water
molecules (Jeffery, 1969). Hydrates of drug can influence
physicochemical properties, processing, mechanical and
compaction behavior of a drug. In addition, water in
q
Niper communication no. 73.
*Corresponding author. Tel.: 191-172-214682x87; fax: 191-172214692.
E-mail address: [email protected] (R. Panchagnula).
hydrates can also influence the intermolecular interactions,
crystalline disorder, changes in free energy, thermodynamic activity, solubility, dissolution rate, stability and
bioavailability (Khankari and Grant, 1995). Therefore,
characterization of solid state properties at an early stage
using appropriate analytical methodology is an essential
prerequisite in the development of solid dosage forms both
from scientific and regulatory points of view (Byrn et al.,
1995). Azithromycin (AZI) is a semisynthetic acid-stable
erythromycin derivative (Fig. 1) with an expanded spectrum of activity and improved pharmacokinetic characteristics (Dunn and Barradell, 1996). It is reported to exist as a
dihydrate (USP, 1995). Azithromycin samples from different manufacturers were found to exhibit variable thermal
behaviour with either single or two endotherms as shown
in Table 1. Most of them exhibited two endotherms, while
the USP reference standard showed a single endotherm.
Therefore, this study was carried out to investigate the
presence of different solid state forms of azithromycin and
further there is no literature report on the solid state
behaviour of azithromycin. In this preliminary study,
0928-0987 / 02 / $ – see front matter  2002 Elsevier Science B.V. All rights reserved.
PII: S0928-0987( 02 )00087-8
R. Gandhi et al. / European Journal of Pharmaceutical Sciences 16 (2002) 175 – 184
176
therms in DSC was used in this study. CS when kept under
85% relative humidity (saturated KCl) at room temperature
for 2 weeks in a dessicator and then subjected to DSC
analysis showed a single endotherm and the sample was a
dihydrate (DH). Monohydrate (MH) was prepared by
dissolving an excess amount of CS with continuous stirring
in a water / ethanol mixture (50:50) and warming the
solution in a water bath at 60 8C. The undissolved drug
from the saturated solution was filtered and then the filtrate
was cooled at room temperature. AZI crystals obtained
were stored in a vacuum dessicator till further analysis.
Anhydrous AZI was prepared by heating the CS, DH and
MH in a hot-air oven at 100 8C for 30 min and also by
storing under phosphorus pentoxide.
Fig. 1. Chemical structure of azithromycin.
2.3. Differential scanning calorimetry ( DSC)
thermal methods, FT-IR, X-ray diffraction, microscopy,
solubility studies and molecular modeling were used for
solid state characterization of AZI.
2. Materials and methods
2.1. Materials
Azithromycin was procured as gratis sample from seven
different manufacturers in India (JK Pharmaceuticals, New
Delhi; Sarabhai Chemicals Ltd., Baroda; Pfizer India Ltd.,
Mumbai; Alembic Chemicals Ltd., Baroda; Kopran India
Ltd., Mumbai; Pradeep Drugs Company Ltd., Chennai; Bal
Pharma, Mumbai). The solvents and reagents used were
either HPLC grade or analytical reagent-grade.
2.2. Preparation of AZI hydrates
A commercial sample (CS) which exhibited two endoTable 1
Thermal behavior of azithromycin samples supplied by different manufacturers
Azithromycin
samples a
AZI 1
AZI 2
AZI 3
AZI 4
AZI 5
AZI 6
AZI 7
(USP reference)
a
b
DSC analysis b
Temperature range (8C)
Heat of fusion (J / g)
133.78–143.08
149.58–156.97
137.88–146.75
133.27–144.49
145.24–150.60
129.60–142.41
148.15–154.40
132.91–145.38
149.58–156.97
132.90–145.39
149.39–157.69
137.66–147.89
63.54
30.71
95.83
61.13
31.44
65.10
29.99
61.46
31.44
56.53
30.09
91.63
Azithromycin obtained from different sources.
DSC thermograms were recorded in sealed pans.
The thermograms of hydrates were recorded on a DSC
(Mettler, Toledo DSC 821 e Switzerland) using the Mettler
Star e system. The temperature axis and cell constant of
DSC cell were calibrated with indium. A heating rate of
10 8C / min was employed over a temperature range of
25–250 8C with nitrogen purging (80 ml / min). The sample
(1–5 mg) was weighed into an aluminum pan and analysed
either in open condition or sealed with and without pin
holes and an empty aluminum pan was used as the
reference. To further characterize the melting endotherm of
AZI, the samples were held in the DSC pan for 30 min at
102 8C and then heated at 10 8C / min up to 200 8C.
2.4. Thermogravimetric analysis ( TGA)
Thermogravimetric analysis was carried out using TGA
(Mettler, Toledo TGA / SDTA 851 e , Switzerland) with the
Mettler Star e system. The water loss was determined by
placing the sample (1–5 mg) in alumina crucibles and
heating up to 250 8C at a rate of 10 8C / min under nitrogen
purge (20 ml / min). The pan was either open or closed with
a lid in order to compare the results from DSC studies. To
further characterize the melting endotherm of AZI, the
samples were held in the TGA pan for 30 min at 102 8C.
Samples were then cooled in the pan to room temperature
and again heated at 10 8C / min from 25 to 200 8C with
simultaneous recording of TGA and DTA.
2.5. Hot-stage microscopy ( HSM)
Thermal events were observed on a hot stage (Mettler,
FP 80) under a polarized light microscope (Leitz, Germany) equipped with a 35-mm camera (Leica, MPS 52).
The sample was placed over a drop of silicone oil, covered
with a cover slip and heated at a rate of 10 8C / min. The
temperature at which liberation of bubbles corresponding
to escape of water vapor and melting events occurred were
observed to characterize the hydrates.
R. Gandhi et al. / European Journal of Pharmaceutical Sciences 16 (2002) 175 – 184
177
Fig. 2. DSC thermograms of different forms of AZI. Upper curve depicts the commercial sample (CS) of AZI; middle curve shows the endotherm of
dihydrate (DH) and lower curve shows the endotherm of monohydrate (MH). The thermograms were generated using a sealed pan.
2.6. Karl Fischer titration ( KFT)
2.8. Powder X-ray diffraction ( XRD)
Water content in different forms of AZI was determined
using a Karl Fischer titrimeter (Metrohm, 716 DMS,
Switzerland). Samples (20–25 mg) were accurately
weighed and quickly transferred to the titration vessel
containing anhydrous methanol.
Powder X-ray diffraction patterns for different forms of
AZI were acquired at room temperature on an X-ray
diffractometer (Siemens, D-5000, Germany) using Cu Ka
radiation (tube operated at 40 kV, 30 mA). Data were
collected over an angular range from 2 to 508 2u in
continuous scan mode using a step size of 0.038 2u and a
step time of 0.5 s.
2.7. Fourier transform infrared spectroscopy ( FT-IR)
Spectra were recorded in a FT-IR spectrophotometer
(Nicolet, Impact 410, USA) using the KBr pellet method in
the region of 4000–400 cm 21 .
2.9. Scanning electron microscopy ( SEM)
AZI samples were viewed by scanning electron micro-
Table 2
Thermal analysis and KFT of different forms of AZI
Sample
name
DSC analysis a
Temperature range (8C)
Heat of fusion (J / g)
TGAd (%)
KFT e (%)
CS
132.29–143.09 b
149.83–155.48 c
134.65–141.35
139.88–156.31
62.7367.13 b
30.4162.93 c
92.9968.58
92.8362.41
4.45260.18
4.5760.03
4.15560.41
2.47260.41
4.3560.28
2.3960.79
DH
MH
a
DSC thermograms were recorded in sealed pans.
First endotherm.
c
Second endotherm.
d
Thermogravimetric analysis; mean6S.D.; n53.
e
Karl Fischer analysis; mean6S.D.; n53.
b
Water content
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R. Gandhi et al. / European Journal of Pharmaceutical Sciences 16 (2002) 175 – 184
Fig. 3. DSC thermograms of DH with different pan types. From top to bottom sealed pan, sealed pan with pin hole and open pan.
Fig. 4. TGA thermograms of different forms of AZI. Upper curve indicates stoichiometric weight loss of two water molecules in CS; middle curve
indicates weight loss of two water molecules in DH and lower curve indicates weight loss of one water molecule in MH.
R. Gandhi et al. / European Journal of Pharmaceutical Sciences 16 (2002) 175 – 184
scopy (Jeol electron microscope, D-6000, Japan). The
samples were sputter coated with gold before examination.
2.10. Solubility studies
An excess amount of CS, DH and MH were placed in
glass vials with 5 ml of water in a shaker water bath at 100
rpm and 37 8C. Samples were withdrawn at specified time
intervals till equilibrium was reached and analyzed using
the HPLC method which is described elsewhere (Gandhi et
al., 2000). Excess solid remaining after the last sample was
subjected to DSC and TGA analysis.
2.11. Molecular modeling
Molecular modeling studies were carried out using
SYBYL  (version 6.6) molecular modeling software (TRIPOS Associates, USA) installed on a Silicon Graphics
power ONYX workstation using IRIX 6.5. The AZI
structure was sketched and energy minimization was
carried out using Tripos force field for 1000 cycles. The
charges were calculated using the Gasteiger–Huckel method. Docking of water molecules to AZI structure was done
using the ‘Dock’ option in SYBYL  and the energy of the
docked complex was minimized using conjugate gradients
(Powell, 1977).
179
3. Results and discussion
DSC thermograms of CS, DH and MH are shown in Fig.
2 and the thermal characteristics are shown in Table 2. The
CS sample showed two endothermic peaks, while DH and
MH showed single endotherms. DSC analysis using different pan types showed a shift in the melting endotherm of
AZI (Fig. 3). Since melting is preceded by release of
water, the dehydration temperature shifts with increase in
pressure from open pan to sealed pan. As can be seen from
the thermograms (Fig. 3), the melting peak is sharp in the
sealed pan due to the rapid attainment of equilibrium under
the ‘pressurized’ pan conditions and the same was also
observed in the case of MH (data not shown). When all
three samples were observed in HSM, it was found that in
the case of DH and MH, release of bubbles started at
around 100 8C and continued up to 120–130 8C, where
crystals were found to melt simultaneously with generation
of bubbles. But, in the case of CS, water release was
accompanied by partial melting of some of the crystals at
around 120 8C and the complete melting of all the crystals
took place at 130 8C.
A stoichiometric weight loss of two water molecules
(theoretical weight loss 4.58%) was found for CS and DH
by TGA, while MH showed a weight loss corresponding to
one molecule of water (theoretical weight loss 2.29%) as
shown in Fig. 4. The results were in good agreement with
Fig. 5. Simultaneous TGA and DTA scans of different hydrates of AZI (see details for text). Upper two thermograms depict TGA and DTA curves for
DH; Lower two thermograms depict TGA and DTA curves for MH. The straight line indicates that there is negligible water loss in TGA.
180
R. Gandhi et al. / European Journal of Pharmaceutical Sciences 16 (2002) 175 – 184
those found by KFT as shown in Table 2. Since release of
water and melting took place simultaneously, it was
difficult to interpret the thermal features, therefore, TGA
and DTA were recorded simultaneously (Fig. 5) after
holding the sample in the TGA pan for 30 min at 102 8C to
release the water, cooling followed by reheating at 10 8C /
min from 25 to 200 8C. As can be seen from Fig. 5, TGA
showed negligible water loss (,0.3%) while DTA showed
an endotherm corresponding to the melting temperature of
AZI. There was a difference in the melting temperature
between DSC scans and simultaneous TGA / DTA scans
due to the difference in pan type and the ‘pressure’ inside
the pan (Byrn et al., 1995). In CS, there were two
endothermic peaks (Fig. 2), which is indicative of dehydra-
tion and melting of anhydrous form, respectively, whereas
in DH and MH there were single peaks. The first endotherm in CS had an enthalpy of 62.73 J / g (Table 2), which
was in good agreement with the reported enthalpy values
for dehydration which generally lie in the range 60–80
J / g, depending upon the nature of binding of water (Han
and Suryanarayanan, 1997; Khankari et al., 1992). The
second endotherm was indicative of melting as was found
from HSM and the enthalpy of fusion was 30 J / g. On the
other hand, in the case of DH and MH, dehydration and
melting took place simultaneously as is evident from the
enthalpy values which is additive of dehydration and
melting enthalpy values. In SEM, it was found that
although the crystal habits of all three samples of AZI
Fig. 6. SEM of different forms of azithromycin. Microphotographs are arranged from top to bottom in the following order: CS, DH and MH.
R. Gandhi et al. / European Journal of Pharmaceutical Sciences 16 (2002) 175 – 184
181
Fig. 7. DSC thermograms of anhydrous azithromycin prepared by keeping the samples under phosphorus pentoxide overnight. From top to bottom: CS,
DH and MH.
were similar, MH was found to contain more irregular
particles which can probably explain the slight shift in the
melting temperature of MH compared to DH and CS (Fig.
6).
When the CS sample was gently ground before DSC
analysis, there was only one single broad endotherm at
120 8C (enthalpy value additive of dehydration and melting) similar to DH and MH. This is not unusual since the
dehydration temperature can be influenced by imperfections of a common lattice structure (Bettinetti et al., 1999)
or occluded impurities in the crystal defects (Holgado et
al., 1995) which may result in artifact peaks in DSC.
Moreover, when the samples were held at 102 8C for 30
min followed by heating at 10 8C / min up to 200 8C, there
was only one endotherm with enthalpy values of 30–45
J / g, which matched with the enthalpy values shown in
Table 2 corresponding to melting of anhydrous AZI.
Variation in enthalpy values may probably be due to a very
small amount of water still remaining in the sample as was
shown in a similar experiment with TGA as discussed
earlier. When the three samples (CS, DH, MH) were
heated in an hot-air oven at 100 8C for 30 min followed by
DSC and TGA, analysis showed similar results as described above. Further, KFT showed comparable (0.1–
0.5%) water loss as shown by TGA analysis. However,
when the samples were stored under phosphorus pentoxide
in a dessicator overnight followed by TGA and KFT,
analysis showed a complete loss of water and melting was
seen at 125–132 8C in DSC analysis (Fig. 7) with an
enthalpy value of 32–36 J / g implying the formation of the
completely anhydrous form. The same was also confirmed
by TGA and KFT analysis. But the anhydrous form was
found to be hygroscopic and convert to dihydrate on
storage at room temperature.
Equilibrium solubility of the samples in water did not
Fig. 8. Solubility of azithromycin samples as a function of time. Each
data point represents mean6S.D. (n53).
182
R. Gandhi et al. / European Journal of Pharmaceutical Sciences 16 (2002) 175 – 184
differ significantly (P.0.05), although DH (1.9860.11
mg / ml) had slightly higher solubility than MH
(1.8060.081 mg / ml). However, the solubility results at
earlier time points showed that MH was more soluble and
by 48 h converted to DH resulting in similar solubility
values to the other two samples within statistical limits
(Fig. 8). The formation of DH was confirmed by analyzing
the excess solid at the end of the solubility studies by DSC
and TGA. Earlier studies with erythromycin (Allen et al.,
1978) and nedocormil zinc hydrates (Zhu et al., 1997)
have attributed such small differences in solubility between
hydrates to the difference in particle–particle interactions
and wettability of the crystalline materials. However, such
difference in internal crystal lattice can only be revealed
using single crystal XRD which is outside the scope of this
study. FT-IR spectra of DH and MH revealed distinct
differences corresponding to O–H stretching region (3400
cm 21 ) as shown in Fig. 9. The presence of a sharp high
frequency peak at 3463 cm 21 in the case of DH and CS is
indicative of the presence of ‘tightly bound’ water in the
crystal lattice (Bettinetti et al., 1999), while the broad band
at 3000–3500 cm 21 in MH is due to the O–H stretching
for self associated water that may be ‘loosely’ bound (Zhu
et al., 1997). The difference at 1200 and 1600 cm 21 can be
attributed to the difference in the H-bonding of water to
AZI in MH and DH. An attempt was made using molecular modeling as a tool to study the interactions of water
with AZI. It was found that in the case of DH, one of the
water molecules is involved in hydrogen bonding with the
hydroxyl group at the 6th position (Fig. 10). This water
molecule further forms a hydrogen bond with another
water molecule, which in turn forms a bifurcated hydrogen
bond with oxygen at the 15th position and oxygen of
hydroxyl at the the 12th position. On the other hand, in the
case of MH, water forms a single hydrogen bond with
oxygen of the hydroxyl group at the 6th position (Fig. 10).
Formation of monohydrate was energetically less favorable
than dihydrate and anhydrate was found to be least stable
in molecular modeling studies. The existence of AZI in the
more stable hydrate form can be anticipated due to the
predominance of hydroxyl groups (potential hydrogen
bonding sites) compared to other macrolide antibiotics
such as erythromycin and clarithromycin. Further, clarithromycin is reported to exist only in the anhydrous form,
since one of the hydroxyl groups of erythromycin is
replaced with a methoxyl group, while erythromycin exists
both in anhydrous and hydrated forms (Stephenson et al.,
1997).
In the case of erythromycin, it is unclear as to whether
the water is present in stoichiometric (true hydrate) or
Fig. 9. FT-IR spectra of CS, DH and MH (arranged from top to bottom).
R. Gandhi et al. / European Journal of Pharmaceutical Sciences 16 (2002) 175 – 184
183
togram of CS at 9 and 14.98 u. The internal crystal
structure appears to be the same, as is evident from the
similar enthalpy of fusion for all three samples (Tiwary
and Panpalia, 1999). CHN analysis showed that the
molecular formula of both MH and DH was the same
indicating that the two differ only in their water content as
found from TGA and KFT. On the other hand, the
crystallinity of the anhydrous form formed after dehydration in DSC / TGA pans could not be characterized as the
material was hygroscopic and insufficient for characterization by XRD. Furthermore, as explained earlier the crystal
habits of all three samples were similar although, MH
consisted of a large proportion of irregularly-shaped
crystals, probably due to loosely bound water, compared to
DH (Fig. 6). Further studies are required to explain the
differences in XRD using other techniques such as variable
temperature XRD, pressure DSC (PDSC) and solid state
NMR to confirm the findings of this study. In addition,
stability of the hydrates at different relative humidities will
also form a part of the detailed studies to be reported in
future.
4. Conclusions
Fig. 10. Stereoview of molecular model of DH and MH (from top to
bottom).
nonstoichiometric amounts (pseudohydrate), as the water
bound in erythromycin (Bauer et al., 1985) can easily be
lost at temperatures as low as 40 8C. Unlike erythromycin,
the water seems to be more strongly bound in AZI as the
water is found to be lost only at temperatures around
100 8C as is found in TGA. On the other hand, the absence
of a separate dehydration peak in DSC thermograms in DH
and MH, indicates that water may be bound stoichiometrically within the crystal lattice. Powder X-ray diffractograms are shown in Fig. 11 and it was found that both
DH and MH are isostructural, but differs from the diffrac-
Azithromycin was found to exhibit pseudopolymorphism and can exist as monohydrate and
dihydrate. The anhydrous form of AZI seemed to be
unstable since it converted to dihydrate on storage at room
temperature. On the other hand, monohydrate in the
presence of moisture can convert to the more stable
dihydrate form. Therefore, the most stable form of AZI is
dihydrate. It is important to select the appropriate form of
AZI and also control the moisture levels during various
processing operations involved in the formulation of solid
dosage forms. In addition during the selection of excipient,
it is necessary to ensure the excipients do not have an
influence on the moisture content of AZI, which in turn
can induce inter conversion of one form to another
(anhydrous to dihydrate or vice versa). Future studies with
single crystal XRD, pressure DSC (PDSC), variable temperature XRD (VTXRD) and solid state NMR will provide
more insight into the stability of different forms of AZI.
Acknowledgements
We are grateful to Dr M.E. Sobhia, for her help with
modeling calculations. Vikas Grover, Technical Assistant
CIL, NIPER is acknowledged for his support in thermal
analysis. The assistance of Dr A.K. Ghosh, Polymer
Division of IIT, New Delhi, India in conducting HSM
studies is gratefully acknowledged.
184
R. Gandhi et al. / European Journal of Pharmaceutical Sciences 16 (2002) 175 – 184
Fig. 11. X-Ray diffractograms of different forms of AZI. From top to bottom, diffractograms of CS, DH and MH.
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