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RESEARCH ARTICLE
Development and
Characterization of Poloxamer Solid Dispersions of Cefuroxime Axetil
Alladi Saritha1,
Praveenachary A2
1SSJ
College of Pharmacy, Hyderabad, Andhra Pradesh, India
2Krupanidhi
College of Pharmacy, Bangalore (Karnataka), India
*Corresponding Author E-mail: alladis1@gmail.com
The
objective of the present investigation was to improve the dissolution rate of
cefuroxime axetil, a BCS class-II drug by solid dispersion technique using a
water soluble carrier, poloxamer 188(PXM). The solid dispersions were prepared
by solvent evaporation method and the prepared systems showed an enhancement in
dissolution. Solid dispersions characterized with Fourier transform infra red
spectroscopy (FTIR) revealed no interaction between CA and poloxamer.
Differential scanning calorimetry and X-ray diffraction revealed that the
enhanced dissolution of CA from solid dispersion is due to a decrease in
crystallinity of drug and additive and due to dissolution of cefuroxime axetil
in the form of solid dispersion. In conclusion preparation of cefuroxime axetil
dispersion with hydrophilic polymer could be a promising formulation approach
to improve the dissolution rate.
KEYWORDS: Cefuroxime Axetil, solid dispersions, Poloxamer, dissolution rate,
crystallinity.
INTRODUCTION:
Cefuroxime
Axetil (1-(acetyloxy) ethyl ester of cefuroxime is a second
generation semi-synthetic cephalosporin effective against Gram-positive and Gram-negative
microorganisms.
One of the major problems of this drug is its very poor solubility in
biological fluids, which results in poor bioavailability after oral
administration. Cefuroxime Axetil (CA)
shows erratic dissolution problems in the gastric and intestinal fluids, due to
its poor water solubilityI.
It is broad spectrum
cephalosporin ester pro drug, which is hydrolyzed by intestinal esterase prior
to absorption, leading to poor and variable bioavailability. The rate of
absorption and / or extent of bioavailability for such insoluble drugs are
controlled by the rate of dissolution in the gastrointestinal fluids2.
To
improve the dissolution of poorly water soluble drugs various approaches have
employed such as micronization, solubilization, solid dispersions, salt
formation, complexation with polymers, alteration of pH, drug derivatization
and others3. Several approaches
such as nano particles, spherical agglomeration, Super critical
technology and solid dispersion using urea, mannitol, poly vinyl pyrrolidine
are reported for the dissolution enhancement of cefuroxime axetil4-8.
Solid dispersions (SDs) represent a useful pharmaceutical
technique for increasing the dissolution, absorption, and therapeutic efficacy
of drugs in dosage forms. The term “solid dispersion” refers to the dispersion
of one or more active ingredients in an inert carrier or matrix in the solid
state prepared by the melting, solvent, or melting solvent methods2. Among all the methods solid dispersion
technique has proved to be the most successful, simple, economical method in
improving the dissolution and bioavailability of poor water soluble drugs3.
Many water soluble
carriers have been employed for the
preparation of dispersions of poor water soluble drugs. The most commonly used
carriers are poly vinyl pyrrolidine, β-cyclodextrin, hydroxyl propyl
methyl cellulose, poly ethylene glycols. Recently pluronics or Poloxamers, a
group of block copolymers has been exploited in pharmaceutical formulation for
poor water soluble drugs. Polaxomer consists of hydrophilic poly oxy ethylene
chain, and hydrophobic core (poly propylene), arranged in a tri block structure
to give an amphiphilic structure. These polymers are widely used as
emulsifiers, solubilizing agents, wetting agents and stabilizers. The
hydrophobic drug may be solubilized with in the core of micelle or conjugated
to the micelle forming polymer to increase dissolution of poor water soluble
drugs9-11.
In the present study attempts
were made to increase the dissolution of cefuroxime axetil using a solid
dispersion technology. Solid dispersions of PXM and CA were prepared using the
solvent evaporation method and physico chemical characterization was performed
to evaluate the chemical interaction between the drug and polymer.
MATERIALS AND METHODS:
Cefuroxime axetil was a gift
sample from Ranbaxy Laboratories, Guargaon, India. Poloxamer was kindly
supplied by DR. Reddy’s Laboratory, Hyderabad. All the solvents used were of
analytical grade.
Preparation of
poloxamer dispersions
The poloxamer solid
dispersions of cefuroxime axetil were prepared by solvent evaporation method.
The dispersions of CA are prepared using increased proportions of poloxamer.
Solid dispersions with different drug to polymer ratios were prepared.
Accurately weighed drug was dissolved in di chloromethane and mixed thoroughly.
Poloxamer was dissolved in methanol and mixed with the drug solution. The blend
was evaporated at a temperature of 45ºC±2ºC using rota evaporator. The
evaporated mass was then removed and then pulverized, sifted through a #100
sieve, and stored at in tightly stopper, type 1 glass vials at dry, ambient
temperature (25-27°C)
till further use12,13.
Evaluation and characterization
of poloxamer dispersion
Drug content
An equivalent weight of 100 mg
of cefuroxime axetil was dissolved in the 50 ml of methanol. From this 1ml was
taken in 100ml volumetric flask and made up to the mark with 0.1 N HCL. The absorbance was measured at 281 nm using 0.1 N HCL as blank. The drug content was estimated
using slope of calibration curve.
Dissolution characteristics
Dissolution
studies of pure cefuroxime axetil and solid dispersion formulations with
poloxamer were conducted using an USP apparatus-II (paddle type) with three
triplicates. The dissolution studies were conducted in 0.1N HCL solution at 37°C at a rotation
speed of 50 rpm. In all experiments 5ml of dissolution medium was withdrawn at
predetermined intervals. An equal amount of fresh dissolution medium was
replaced immediately after withdrawal of the test sample. Test samples were
filtered through a membrane filter and suitably diluted. The absorbance of
diluted samples was estimated for amount of cefuroxime axetil dissolved by
measuring in UV/VIS spectrophotometer at 281 nm.
The prepared cefuroxime axetil
and poloxamer systems were evaluated for assay and dissolution studies. Based
on the dissolution data the optimized formulations were selected for further
studies and were characterized using XRD, DSC and FT-IR spectroscopy.
Fourier Transform Infra Red
Spectroscopy
The FTIR spectra of
Cefuroxime axetil, poloxamer and its dispersion were obtained using Schimadzu
model 8033 IR equipment. About 5 mg of sample was mixed thoroughly with KBr IR
powder and compacted under vacuum at a pressure of about 6000kg/cm² for 3 min.
The resultant disc was mounted in a suitable holder in a Schimadzu model 8033
IR spectrophotometer and the IR spectrum was recorded from 4000 cm-1
to 625 cm-1 in a scan time of 12 minutes. The resultant spectra were
compared for any spectral changes.
X-ray diffraction
X-ray diffraction
pattern of Cefuroxime axetil, poloxamer and its dispersion were obtained on a
powder X-ray diffractometer (Seifer 3003TT) using Cu kα
radiation at 30ma and 450kv. The angular range was set from 0-60° with a step
of 0.03/0.5 sec. The relative intensity I/Io and inter planar distance (d)
corresponding to 2θ values were obtained and compared.
Differential
Scanning Calorimetry
Differential
scanning calorimetry thermo grams of sample were recorded in Mettler Toledo
Analyzer equipped with a monitor and printer. The instrument was calibrated
with indium as a standard. Accurately weighed 2.5 mg of samples were placed in
open flat bottom, pierced aluminum sample pan. Thermo grams were obtained by
heating the sample a constant rate 100c/min.
A dry purge of nitrogen gas (20ml/min) was used for all runs. Samples were
heated from 350c to 4000c. The melting point, peak
maxima, appearance of any new peak and peak shape was noted to determine the
interaction between the drug and carrier.
RESULTS AND DISCUSSIONS:
In vitro release studies for solid dispersion
formulations with different carriers conducted in 0.1N HCl are given in
Figure-1. The solid dispersion of Cefuroxime axetil- poloxamer 188 showed a
significant dissolution enhancement than the pure drug Cefuroxime axetil.
Incorporation of Poloxamer 188 in solid dispersion formulation of Cefuroxime
axetil showed a drastic increase in dissolution rate. Pure Cefuroxime axetil
showed 17.45% of drug release in 180 min while all the formulations of
Poloxamer 188 showed more than 75% of drug release in 180 min. The formulation
CP1 (1:1) ratio showed highest drug release of 99.45% drug release
in 180 min indicating the remarkable influence of poloxamer in dissolution
enhancement.
FT-IR Analysis:
FTIR
studies were performed to characterize the drug-polymer interactions. The FTIR
spectra of pure Cefuroxime axetil, poloxamer and with its optimized
formulations are shown in Figure-2. In case of the pure drug, the spectrum is
characterized by the peaks at 3480-3210cm-1 due to NH-NH2
complex, 1782 cm-1 for β lactam ring, 1760 cm-1 for
acetate, 1720 cm-1 for ester group and 1676 cm-1 and 1534
cm-1 amide group. The FTIR of Poloxamer showed a characteristic peak
at 2887 cm-1, 1343 cm-1 and 1124 cm-1 due to
the C-H, O-H and C-O groups of Poloxamer. The IR spectrum of Poloxamer solid
dispersion showed the characteristic peak of Cefuroxime axetil with little
shifting of peaks. In solid dispersion formulation peaks were found at
3494-3310cm-1 due to NH-NH2 complex and
1124 cm-1 due
to the C-O groups of Poloxamer were consistent as shown in Poloxamer.
The β lactam
ring showed IR peak at 1782 cm-1. This
suggested the absence of significant interactions between drug and additive
used to make the semi solid dispersion.
Figure 1: Dissolution profile of
different ratios of poloxamer solid dispersion in 0.1N HCl.
DSC Study:
The
thermograms of Cefuroxime axetil, Poloxamer and its binary dispersion are shown
in figure- 3. The thermo gram scan of
Cefuroxime axetil showed a sharp endothermic peak at 230°c corresponding to its
fusion temperature which was due to its melting point. In case of poloxamer a
peak at 54.700c indicates the melting point of poloxamer. The optimized
dispersion of CA-Poloxamer dispersion in CP1 (1:1) ratio showed a
significant melting peak of poloxamer at 47.97°c. The poloxamer does not show a
shifting of peak which indicates the absence of interaction. The absence of peak of CA indicates the
dissolution of the drug in the poloxamer.
The CA-poloxamer solid dispersion showed a glass transition temperature
at 127°c and 161.38°c which suggests the conversion of the crystalline form of
drug to amorphous. The above studies states that drug got completely dissolved
in a carrier and also there was a conversion of crystalline nature to amorphous
form which is attributed to the dissolution enhancement.
XRD Study:
The
XRD of pure Cefuroxime axetil,
poloxame and its optimized formulations are shown in Figure 4. XRD pattern of Cefuroxime axetil shows a characteristic high intensity
diffraction peaks indicating that the drug is in crystalline form. The drug
showed high intensity peak at 400 cps. Cefuroxime axetil showed
sharp peaks at 4.30, 16.5, 19.1, 21.2, 23.45 and 24.54° (2ø) with peak
intensities of 210, 230,400, 320, 340 and 390, respectively.
KEY-A) Cefuroxime axetil(CA) B) poloxamer 188 C) CA-poloxamer 188
solid dispersion
Figure
3: Differential scanning calorimetry of Cefuroxime axetil poloxamer dispersion
The X-ray pattern of Poloxamer showed two sharp
peaks at a high intensity range of 800 to 1000cps.The solid dispersion of
CA-poloxamer showed sharp peaks at of Poloxamer with a reduced intensity range
of 300-400cps while characteristic peak of CA in dispersion was observed as
less intensity peak in a range of 100-150cps. It showed sharp peaks at 18, 24.4
and 27.0° (2ø) with peak intensities of 151, 390 and 190
respectively. The decreased intensity peak suggests the partial
conversion of crystalline to amorphous form which is responsible for
dissolution enhancement14,15.
A) Cefuroxime
axetil B) Poloxamer188 C) CA-poloxamer188 solid dispersion
Figure 4 : X-Ray Diffraction Spectra of Cefuroxime axetil poloxamer dispersion
CONCLUSION:
In the present investigation, poloxamer 407 has improved
significantly the dissolution rate of cefuroxime axetil. Characterization
studies revealed the absence of chemical interactions between the drug and
polymer, a decrease in crystallinity of cefuroxime axetil and the possibility
of the presence of the amorphous form of cefuroxime axetil in solid dispersions
systems. Among the ratios used, 1:1 ratio of solid dispersion was found to be
optimal for its superior performance in dissolution enhancement. This indicated
that an increase in the mass fraction of polymer could not offer any advantage
for dissolution enhancement. Based on these results, it can be concluded that
solid oral dosage forms of cefuroxime axetil with poloxamer 407 could be
formulated with a high dissolution rate, faster onset of action and improved
bioavailability.
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