[Downloaded free from http://www.japtr.org on Friday, August 05, 2016, IP: 180.241.146.

41]

J. Adv. Pharm. Tech. Res. Vol. 1 (2), Apr-Jun, 2010 ISSN 0976-2094

DEVELOPMENT, CHARACTERIZATION AND SOLUBILITY STUDY OF SOLID

DISPERSIONS OF AZITHROMYCIN DIHYDRATE BY SOLVENT EVAPORATION
METHOD
S.C. Arora*1, P.K. Sharma2, Raghuveer Irchhaiya3, Anurag Khatkar1, Neeraj Singh1,
Jagbir Gagoria1
1. R.K.S.D. College of Pharmacy, Kaithal, Haryana, (India)
2. Dept. of Pharmaceutical Technology, MIET, Meerut, Uttar Pradesh, (India)
3. Institute of Pharmacy, Bundelkand University, Jhansi, Uttar Pradesh, (India)
Corresponding Authors E-mail: - scarora_1952@rediffmail.com
Received: 08th April 2010 Revised: 01st June 2010 Accepted: 07th June 2010

ABSTRACT
Azithromycin Dihydrate (Poorly water soluble drug), when prepared as solid dispersion
showed improved solubility and dissolution. So the main purpose of this investigation
was to increase the solubility and dissolution rate of Azithromycin Dihydrate by the
preparation of its solid dispersion with urea using solvent evaporation method. Physical
mixtures and solid dispersions of Azithromycin Dihydrate were prepared by using urea
as water-soluble carrier in various proportions (1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7 by
weight), by employing solvent evaporation method. The drug release profile was studied
and it was found that the dissolution rate and the dissolution parameters of the drug
from the physical mixture as well as solid dispersion were higher than those of the
intact drug. FT- IR spectra revealed no chemical incompatibility between drug and urea.
Drug-polymer interactions were investigated using differential scanning calorimetry
(DSC) and Powder X-Ray Diffraction (PXRD).

Keywords: Azithromycin Dihydrate; Urea; Solvent Evaporation Method; Solid dispersion.

INTRODUCTION hexopyranosyl]oxy]-1-oxa-6
Azithromycin Dihydrate ((2R, 3 S, 4 R, 5 azacyclopentadecan-15-one) (Figure 1) a
R, 8 R, 10 R, 11 R, 12 S, 13 S, 14 R)- macrolide antibiotic of the azalide
13-[(2, 6-di deoxy-3-C methyl-3-O- subclass, exerts its antibacterial action
methyl-a-L-ribo-hexopyranosyl) oxy]-2- by binding to the 50s ribosomal
ethyl-3, 4, 10-trihydroxy-3, 5, 6, 8, 10, subunits of susceptible bacteria and
12, 14-heptamethyl-11-[[3, 4, 6, - suppressing protein synthesis; however,
trideoxy-3(dimethylamino)--D-xylo it differs chemically from erythromycin

JAPTR, All Rights Reserved 221 Available online on www.japtr.org

[Downloaded free from http://www.japtr.org on Friday, August 05, 2016, IP: 180.241.146.41]

J. Adv. Pharm. Tech. Res. Vol. 1 (2), Apr-Jun, 2010 ISSN 0976-2094

in that a methyl-substituted nitrogen hydrophilic matrix and a hydrophobic

atom is incorporated into the lactone drug. The matrix can be either
ring. Azithromycin, as the dihydrate, is crystalline or amorphous. The drug can
a white crystalline powder with a be dispersed molecularly, in amorphous
molecular formula of C38H72N2O122H2O particles (clusters) or in crystalline
and a molecular weight of 785.0. It is particles [2]. Solid dispersion technique
used orally for the treatment of has been used for a wide variety of
bronchitis, certain types of skin poorly soluble drugs such as nimesulide
infections, sore throat (pharyngitis, [3], ketoprofen (4), tenoxicam (5),
tonsillitis), and pneumonia. One of the nifedipine [6], nimodipine [7],
major problems with this drug is its ursodeoxycholic acid [8], and
very poor solubility in biological fluids albendazole [9]. Various hydrophilic
that results into poor bioavailability carriers, such as polyethylene glycols
after oral administration. It shows [10], polyvinylpyrrolidone [11],
erratic dissolution problem in gastric hydroxypropyl methylcellulose [12],
and intestinal fluid due to its poor water gums [6], sugar [13], mannitol [14], and
solubility. Rate of absorption and/or urea [8], have been investigated for
extent of bioavailability for such improvement of dissolution
insoluble drugs are controlled by rate of characteristics and bioavailability of
dissolution in gastrointestinal fluids [1]. poorly aqueous soluble drugs.
The peak plasma concentration (Cmax) Solid dispersion can be prepared by
and the time taken to reach Cmax (tmax) various methods such as solvent
depend upon extent and rate of evaporation and melting method. Solid
dissolution of drug respectively. The dispersion technique has been
effort to improve the dissolution and extensively used to increase the
solubility of a poorly water-soluble drug solubility of a poorly water-soluble drug.
remains one of the most challenging According to this method, a drug is
tasks in drug development. Several thoroughly dispersed in a water-soluble
methods have been introduced to carrier by suitable method of
overcome this problem like solid preparation. The mechanism by which
dispersions, complexation, Zydis the solubility and the dissolution rate of
technology, and by the use of the drug are increased includes:
hydrophilic carriers. reduction of the particle size of drug to
Solid dispersion, which was introduced submicron size or to molecular size in
in the early 1970s [2], refers to a group the case where solid solution is
of solid products consisting of at least obtained. The particle size reduction
two different components, generally a generally increases the rate of

JAPTR, All Rights Reserved 222 Available online on www.japtr.org

[Downloaded free from http://www.japtr.org on Friday, August 05, 2016, IP: 180.241.146.41]

J. Adv. Pharm. Tech. Res. Vol. 1 (2), Apr-Jun, 2010 ISSN 0976-2094

dissolution; secondly, the drug is Chemicals Pvt. Ltd., New Delhi. All
changed from amorphous to crystalline other chemical reagents were of
form, the high energetic state which is analytical grade.
highly soluble; finally, the wettability of
the drug particle is improved by the Methods
hydrophilic carrier. Azithromycin Preparation of Physical Mixture
Dihydrate-urea systems, prepared by Accurately weighed amount of
solvent evaporation method, showed an Azithromycin Dihydrate and urea
improvement in dissolution rates of the (carrier) in various drug-to-carrier
drug from the solid dispersions as weight ratios were thoroughly blended
compared with the pure drug and in glass mortar for 5 min. The
physical mixtures. This study presents composition of various batches is shown
formulation of solid dispersions of in Table 1. The products were kept in
Azithromycin Dihydrate with urea as desiccator for further study.
the hydrophilic carrier.
Preparation of Solid Dispersion
The solid dispersions of Azithromycin
Dihydrate and urea (carrier) in various
drug-to-carrier weight ratios were
prepared by solvent evaporation
method. The 100 mg of Azithromycin
Dihydrate was dissolved in 20 ml of
methanol in a beaker and carrier was
added and mixed to dissolve at 40C on
a hot plate to get a clear solution. Then
the solvent was allowed to evaporate.
The process of evaporation was opted
until the constant weight was obtained.
Fig. 1: Chemical structure of Solid Dispersions prepared were
Azithromycin Dihydrate crushed, pulverized and sifted through
mesh number 80 and stored in
MATERIALS AND METHODS desiccators.
Materials
Azithromycin Dihydrate was obtained as Estimation of Azithromycin
generous gift from FDC Limited, Dihydrate
Mumbai. Urea (Analytical grade) was Azithromycin Dihydrate was estimated
purchased from Qualikems Fine at 215 nm [15] using UV

JAPTR, All Rights Reserved 223 Available online on www.japtr.org

[Downloaded free from http://www.japtr.org on Friday, August 05, 2016, IP: 180.241.146.41]

J. Adv. Pharm. Tech. Res. Vol. 1 (2), Apr-Jun, 2010 ISSN 0976-2094

spectrophotometer (Systronics Double press. The scanning range was 400 to

Beam Spectrophotometer 2202). 4000 cm1 and resolution was 2 cm1.
Standard curve for the estimation was
prepared in phosphate buffer pH 6.0 in Differential scanning calorimetric
concentration range of 2-30 g/ml. In studies
this concentration range good linearity Differential scanning calorimetry (DSC)
was observed with the correlation measurements were carried out on a
coefficient (R2) 0.9939. The graph scanning calorimeter (DSC Q10 V9.0
obeyed the Beer-Lamberts law in the Build 275, Universal V4.1D TA
selected concentration range. Instruments). The instrument was
calibrated using indium as standard.
Table 1: Composition of Batches Samples (5-10 mg) were placed in
Containing Azithromycin Dihydrate and sealed aluminium pans and heated
Urea from 70oC to 150oC at a rate of
Batches 10oC/min under nitrogen atmosphere
Azithromycin Drug : Batches
for Urea
Dihydrate Carrier for Solid (60 ml/min), with empty pan as
Physical (mg)
(mg) Ratio dispersion reference.
Mixture
PM1 100 100 1:1 SD1
X-Ray Diffraction Studies
PM2 100 200 1:2 SD2
The powder x-ray diffraction (XRD) was
PM3 100 300 1:3 SD3
performed by Xpert Pro with Spinner
PM4 100 400 1:4 SD4
PW3064 using Ni-filtered, CuK
PM5 100 500 1:5 SD5
radiation, a voltage of 45 kV, and a
PM6 100 600 1:6 SD6
current of 40 mA with a scintillation
PM7 100 700 1:7 SD7
counter. The instrument was operated
in the continuous scanning speed of
Characterization of Samples
4o/min over a range of 5oC to 40oC.
Fourier Transform Infrared
Spectroscopy Drug Content
All prepared solid dispersions were Solid dispersions equivalent to 100 mg
subjected to FTIR spectroscopic studies of Azithromycin Dihydrate were weighed
to determine drug-carrier interaction. accurately and dissolved in a suitable
FTIR spectra were recorded on samples quantity of phosphate buffer pH 6.0.
prepared in potassium bromide (KBr) The solutions were filtered and drug
disks using Fourier Transform IR content was determined at 215 nm by
spectrophotometer (Perkin Elmer, RXI UV spectrophotometer (Systronics
FTIR System). Samples were prepared Double Beam Spectrophotometer 2202)
in KBr disks by means of a hydrostatic after suitable dilution. The percentage

JAPTR, All Rights Reserved 224 Available online on www.japtr.org

[Downloaded free from http://www.japtr.org on Friday, August 05, 2016, IP: 180.241.146.41]

J. Adv. Pharm. Tech. Res. Vol. 1 (2), Apr-Jun, 2010 ISSN 0976-2094

yield of each formulation was also Azithromycin Dihydrate and urea. The
calculated. characteristic peaks of Azithromycin
Dihydrate, urea and physical mixtures
Saturation Solubility
are presented in Table 2. It was revealed
To evaluate the increase in solubility of
that there were no differences in the
Azithromycin Dihydrate, physical
positions of the absorption bands,
mixture and solid dispersions,
hence providing evidence for the
saturation solubility measurements
absence of interactions in the solid state
were conducted. The known excess
between Azithromycin Dihydrate and
(approximately 50 mg) of Azithromycin
urea.
Dihydrate was added to 100 mL of
phosphate buffer (pH 6.0). Samples Table 2: FT-IR peaks of pure
were rotated at 20 rpm in a water bath Azithromycin Dihydrate, urea and
(37.0 0.5oC) for 48 hours. The samples physical mixture of Azithromycin
were then filtered, suitably diluted, and Dihydrate and urea.
analyzed by UV spectrophotometer at Description Characterization (cm-1)
215 nm. Azithromycin
2973.8, 1469.3, 1050.8 and 993.6.
Dihydrate
Dissolution Studies
The dissolution studies were performed Urea 3335.8, 1150.6, 787.1 and 556.9.

using a US Pharmacopeia XXIV type II Azithromycin 3335.8, 2973.8, 1469.3, 1150.6,

dissolution test apparatus. The samples Dihydrate and Urea 1050.8, 993.6, 787.1 and 556.9.

equivalent to 100 mg Azithromycin

Dihydrate were placed in a dissolution Differential Scanning Calorimetric
vessel containing 900 mL of phosphate Studies
buffer (pH 6.0) maintained at 37.0 Differential scanning calorimetry shows
0.5oC and stirred at 100 rpm. Samples sharp endothermic fusion peak at
were collected periodically and replaced 124.9oC, which is corresponding to the
with a fresh dissolution medium. After melting point of Azithromycin Dihydrate
filtration, concentration of Azithromycin [Figure 2].
Dihydrate was determined
spectrophotometrically at 215 nm. X-Ray Diffraction Studies
The diffraction spectra of Azithromycin
RESULT AND DISCUSSION Dihydrate and urea show numerous
Fourier Transform Infrared distinct peaks indicating that both are
Spectroscopy present in a highly crystalline state. The
FT-IR studies were done to detect the XRD pattern of solid dispersion of
possible interactions between the sample SD5 exhibits all the

JAPTR, All Rights Reserved 225 Available online on www.japtr.org

[Downloaded free from http://www.japtr.org on Friday, August 05, 2016, IP: 180.241.146.41]

J. Adv. Pharm. Tech. Res. Vol. 1 (2), Apr-Jun, 2010 ISSN 0976-2094

characteristic diffraction peaks of urea **The batch having same ratio of drug:
and crystalline Azithromycin Dihydrate, urea as compared with the best batch of
but of lower intensity. This study solid dispersion (SD5) in term of drug
reveals that some Azithromycin content.
Dihydrate still exists in the crystalline Data in parenthesis represent S.D.
state in the solid dispersion. Dissolution Studies
The dissolution rate of pure
Azithromycin Dihydrate was very poor
and during 120 min a maximum about
34.22% of the drug was released. The
reason for the poor dissolution of pure
drug could be poor wettability and/or
agglomeration or particles size. It was
found that the dissolution rate of the
Fig. 2: Differential scanning calorimetry drug increased according to increasing
of Azithromycin Dihydrate. amount of hydrophilic carrier (urea) in
physical mixture batches. This was due
Drug content and saturation
to the increase in solubility of drug by
solubility
the presence of hydrophilic carrier
The drug content and saturation
surrounding the drug particles. Figure 3
solubility were determined and results
shows comparative release profile of
were presented in Table 3.
various solid dispersions of

Table 3: Drug content and saturation Azithromycin Dihydrate with urea,

solubility of different formulations. physical mixture containing 1:5 ratio of

drug: urea and pure drug. From release
Product Drug Content Saturation Solubility
Name (%)* (g/ml) profile it can be seen that dissolution of
Pure Drug -- 68.71(1.31) Azithromycin Dihydrate in solid
SD1 93.191.93 137.82(1.28) dispersions increase with increase in
SD2 95.111.01 146.65(2.11) urea up to 1:5 ratio of drug: urea. This
SD3 92.711.72 149.91(1.61) increase in the dissolution rate may be
SD4 94.601.27 157.88(1.82) due to increase in drug wettability,
SD5 97.081.58 163.32(1.34) solubilization of drug by hydrophilic
SD6 94.451.75 166.34(1.65) carrier and release of drug at molecular
SD7 93.711.13 169.29(2.02) level. From the results, it was concluded
PM5 ** 94.292.06 117.18(1.21) that the dissolution rate of
*Values represent mean of three Azithromycin Dihydrate increased by
individual experiments. preparing solid dispersion with urea.

JAPTR, All Rights Reserved 226 Available online on www.japtr.org

[Downloaded free from http://www.japtr.org on Friday, August 05, 2016, IP: 180.241.146.41]

J. Adv. Pharm. Tech. Res. Vol. 1 (2), Apr-Jun, 2010 ISSN 0976-2094

development. Drug Dev. Ind. Pharm.

100
2003; 29: 855-864.
90 Pure Drug
80 PM5 4. Rogers JA, Anderson AJ. Physical
C u m u la tiv e % R e le a s e

70 SD1 characteristics and dissolution

60 SD2
profiles of ketoprofen-urea solid
50 SD3
40 SD4 dispersions. Pharm Acta Helv.
30 SD5 1982;57: 276Y281.
20 SD6 5. El-Gazayerly ON. Characterization
10 SD7
and evaluation of tenoxicam
0
0 20 40 60 80 100 120 coprecipitates. Drug Dev. Ind.
Time (Min) Pharm. 2000; 26: 925Y 930.
6. Vippagunta SR, Maul KA,
Fig. 3: Comparative in vitro release
Tallavajhala S, Grant DJW. Solid-
profiles of Azithromycin Dihydrate from
state characterization of nifedipine
solid dispersions and physical mixture
solid dispersions. Int. J. Pharm.
containing urea.
2002; 236:111Y123.
7. Murali Mohan Babu GV, Prasad
ACKNOWLEDGEMENT CHDS, Ramana Murthy KV.
Authors would like to thank FDC Evaluation of modified gum karaya
Limited, Mumbai for the generous gift of as carrier for the dissolution
Azithromycin Dihydrate. enhancement of poorly water soluble
drug nimodipine. Int J Pharm.
REFERENCE 2002; 234: 1Y17.
1. Reynolds, J.E.F., Eds., In; 8. Okonogi S, Yonemochi E, Oguchi T,
Martindale; The Extra Puttipipatkhachorn S, Yamamoto K.
Pharmacopoeia, 29th Edn., The Enhanced dissolution of
Royal Pharmaceutical Society of ursodeoxycholic acid from the solid
Great Britain, London, 1993, 295. dispersion. Drug Dev Ind Pharm.
2. Chiou WL, Riegelman S. 1997;23: 1115Y1121.
Pharmaceutical applications of solid 9. Torrado S, Torrado S, Torrado JJ,
dispersion systems. J Pharm Sci. Cadorniga R. Preparation,
1971; 60: 1281Y1302. dissolution and characterization of
3. Babu GV, Kumar NR, Himasankar albendazole solid dispersions. Int J
K, Seshasayana A, Murthy KV. Pharm. 1996;140:247Y250.
Nimesulide-modified gum karaya 10. Margarit MV, Rodrguez IC, Cerezo
solid mixtures: preparation, A. Physical characteristics and
characterization and formulation dissolution kinetics of solid

JAPTR, All Rights Reserved 227 Available online on www.japtr.org

[Downloaded free from http://www.japtr.org on Friday, August 05, 2016, IP: 180.241.146.41]

J. Adv. Pharm. Tech. Res. Vol. 1 (2), Apr-Jun, 2010 ISSN 0976-2094

dispersions of ketoprofen and 13. Danjo K, Nakata T, Otsuka A.

polyethylene glycol 6000. Int. J. Preparation and dissolution
Pharm. 1994; 108:101Y107. behavior of ethenzamide solid
11. Yagi N, Terashima Y, Kenmotsu H, dispersions using various sugars as
Sekikawa H, Takada M. Dissolution dispersion carriers. Chem Pharm
behavior of probucol from solid Bull (Tokyo). 1997; 45:1840Y1844.
dispersion systems of probucol- 14. Arias MJ, Gins JM, Moyano JR,
polyvinylpyrrolidone. Chem Pharm Prez-Martnez JI, Rabasco AM.
Bull (Tokyo). 1996; 44: 241Y244. Influence of preparation method of
12. Kushida I, Ichikawa M, Asakawa N. solid dispersions on dissolution
Improvement of dissolution and oral rate: study of triammterene-D-
absorption of ER-34122, a poorly mannitol. system. Int. J. Pharm.
water soluble dual 5-lipoxygenase 1995; 123: 25Y31.
/cyclooxygenase inhibitor with anti- 15. The Indian Pharmacopeia, 2007,
inflammatory activity by preparing Ministry of Health and Family
solid dispersion. J. Pharm. Sci. Welfare. Government of India.
2002; 91: 258Y266.

JAPTR, All Rights Reserved 228 Available online on www.japtr.org