Once-Daily Tablet Formulation and In Vitro Release Evaluation of
Cefpodoxime Using Hydroxypropyl Methylcellulose: A Technical Note
Submitted: February 13, 2006; Accepted: June 5, 2006; Published: September 22, 2006
Hamid A. Merchant,1
Harris M. Shoaib,1
Jaweria Tazeen,1
and Rabia I. Yousuf1
1
Department of Pharmaceutics, Faculty of Pharmacy, University of Karachi, Karachi-75270, Pakistan
INTRODUCTION
Hydrophilic polymer matrix systems are widely used in
oral controlled drug delivery because they make it easier
to achieve a desirable drug-release profile, they are costeffective,
and they have broad US Food and Drug Administration
acceptance.1
The hydrophilic polymer matrix system
consists of hydrophilic polymer, drug, and other excipients
distributed throughout the matrix. This dynamic system is
dependent on polymer wetting, hydration, and dissolution
for controlled release of drug. At the same time, other soluble
excipients or drug substances will also wet, dissolve,
and diffuse out of the matrix, whereas insoluble excipients
or drug substances will be held in place until the surrounding
polymer, excipients, or drug complex erodes or dissolves
away.2
Hydroxypropyl methylcellulose (HPMC), which is commonly
used in hydrophilic matrix drug delivery systems, is
a mixed alkyl hydroxyalkyl cellulose ether containing
methoxyl and hydroxypropyl groups. The hydration rate
of HPMC depends on the nature of these substituents, such
as the molecular structure and the degree of substitution.
Specifically, the hydration rate of HPMC increases with an
increase in the hydroxypropyl content. The solubility of
HPMC is pH independent.1
HPMC has been found to be a
very versatile material for the formulation of soluble matrix
tablets. It is a widely accepted pharmaceutical excipient
and is included in all major compendia. Because HPMC is
available in a wide range of molecular weights, effective
control of gel viscosity is easily provided.2
Cefpodoxime proxetil is an orally administered, extendedspectrum,
semisynthetic antibiotic of the cephalosporin
class. Cefpodoxime is a prodrug; its active metabolite is
cefpodoxime.3
Cefpodoxime proxetil, a relatively new broadspectrum
third-generation cephalosporin, has very good in
vitro activity against Enterobacteriaceae, Hemophilus spp,
and Moraxella spp, including lactamase producers and many
strains resistant to other oral agents. It also has activity
against Gram-positive bacteria, especially against Streptococci.
It is well tolerated and is one of the first thirdgeneration
cephalosporins to be available in oral form. While
the compound has been used most widely in the treatment
of respiratory and urinary tract infections, its utility
has also been demonstrated in the treatment of skin structure
infections, acute otitis media, pharyngitis, tonsillitis,
and sexually transmitted diseases.4
In a multicenter study,
the in vitro activity of cefpodoxime was compared with
that of cefixime, cefuroxime, cefaclor, cefadroxil, and clarithromycin
against 5556 recent clinical isolates. Cefpodoxime
demonstrated potent activity against members of the
Enterobacteriaceae, in particular against species generally
resistant to the established oral cephalosporins such as
Proteus vulgaris (minimum inhibitory concentration (MIC)
50, 0.12 g/mL), Providencia rettgeri (MIC50, 0.015 g/mL),
and Serratia marcescens (MIC50, 2 g/mL). Cefpodoxime
was very effective against the fastidious organisms most
frequently associated with respiratory infections, such as
Streptococcus pneumoniae (MIC90, 0.12 g/mL), Hemophilus
influenzae (MIC90, 0.12 g/mL), and Moraxella
catarrhalis (MIC90, 1 g/mL). In contrast to other orally administered
third-generation cephalosporins (cefixime or
ceftibuten), cefpodoxime demonstrated reasonable activity
against oxacillin-susceptible Staphylococci, with MIC90
ranging from 1 to 2 g/mL. All cephalosporins tested demonstrated
poor activity against Pseudomonas spp, Xanthomonas
spp, Enterococcus spp, and oxacillin-resistant Staphylococci.
Cefpodoxime had the widest spectrum of activity of all
tested oral cephalosporins.5
Considering the wide range of activity of cefpodoxime
proxetil, the objective of this study was to decrease the dose
frequency and increase the speed of recovery from the indications
by increasing the rate of bacterial killing and thereby
increasing patient compliance. The prospective sustainedrelease
formulation of cefpodoxime proxetil named Cefpo
SR is expected to produce a peak plasma concentration of
1.2 mg/L and then sustain that concentration for 24 hours.
After 100 mg of the conventional-release dosage form of
cefpodoxime is administered, the peak plasma concentration
achieved is 1.2 mg/L, and this concentration slowly
declines below minimum effective concentration (MEC)
within 12 hours.6,7
The steady-state maintenance of plasma
KEYWORDS: Cefpodoxime proxetil, hydroxypropyl methylcellulose
(HPMC), hydrophilic matrix tablets, in vitro sustained
drug release, once-daily tablet, Cefpo SR.
AAPS PharmSciTech 2006; 7 (3) Article 78 (http://www.aapspharmscitech.org).
E1
Corresponding Author: Harris M. Shoaib, Assistant
Professor, Faculty of Pharmacy, University of Karachi,
Department of Pharmaceutics, University Road, Karachi-
75270, Pakistan. Tel: +9221-4816410; Fax: +9221-
4987344; E-mail: harrisshoaib2000@yahoo.com
concentration will increase the rate of bacterial killing and
more quickly relieve the excruciating symptoms of bacteremia.
One tablet of Cefpo SR will be sufficient for 24 hours’
maintenance where 100 mg twice-daily doses of conventional-release
dosage forms are recommended for conditions
such as pharyngitis, tonsillitis, uncomplicated urinary
tract infections, uncomplicated gonorrhea, and rectal gonococcal
infections. Two tablets of Cefpo SR taken as a
straight dose can replace a 200 mg twice-daily dose regimen
in acute community-acquired pneumonia and acute
bacterial exacerbations of chronic bronchitis. However, this
will not be suitable for indications like skin/skin structure
infections requiring higher doses, such as 400 mg every
12 hours.3
In the present study, the formulation (Cefpo SR) was designed
for 24-hour sustained release of cefpodoxime proxetil,
and the sustained pattern was evaluated by in vitro
drug release for 24 hours. The drug release data were plotted
using various kinetic equations (zero order, first order, Higuchi’s
kinetics, Korsmeyer’s equation, and Hixson-Crowell
cube root law) to evaluate the drug release mechanism and
kinetics. In vivo drug release, biopharmaceutical evaluation,
and in vivo/in vitro correlations were beyond the scope of
this study and will be considered in future work.
MATERIALS AND METHODS
Materials
HPMC 4000 cps (USP Type-2208) was purchased from Dow
Chemicals (Midland, MI); Avicel PH-101 from FMC Biopolymer
Corporation (Philadelphia, PA); and magnesium
stearate from Merck KGaA (Darmstadt, Germany). Cefpodoxime
proxetil (Orchid Chemical, India) was a gift from
S.J. and G. Fazul Ellahie (Pvt) Ltd (Karachi, Pakistan). All
other materials used in analysis of Cefpo SR were of analytical
grade.
Methods
Calculation of the Sustained Dose
Per the zero-order release principle, the rate of delivery must
be independent of the amount of drug remaining in the dosage
form and constant over time. The release from the dosage
form should follow zero-order kinetics, as shown by the
following equation:
K0
r ¼ Rate in ¼ Rate out ¼ ke:Cd:Vd ð1Þ
where Kr
0
is the zero-order rate constant for drug release
(amount/time), ke is the first-order rate constant of overall
drug elimination (h–1
), Cd is the desired drug level in the
body (amount/volume), and Vd is the volume in which the
drug is distributed.8
If the elimination half-life of cefpodoxime
proxetil is 2.4 hours (ke = 0.693/2.4), Cd is 1.4 mg/L,
and Vd is 32.3 L, then Kr
0
is 13.05 mg/h.6
The elimination
constant (Kr
0
) calculated was 13.05 mg/h, so the drug release
constant should also have been equal to the elimination constant
so as to maintain the steady-state condition. Cefpodoxime
is not completely absorbed if taken orally; only
50% of the drug is absorbed in fasting conditions. The
percent absorbed is improved if the drug is taken with food,
to ~75% of the dose administered.9
Hence, the drug release
rate should be 25% more than the elimination rate, which
would be 13.05 mg/h  125/100, or 16.32 mg/h.
For a system in which the maintenance dose releases drug
by a zero-order process for a specified period of time, the
total dose is as follows:
W ¼ ðDi − K0
r TpÞ þ K0
r Td ð2Þ
where Di is the initial dose, Kr
0
is the same zero-order rate
constant, and Td is the total time desired for sustained
release from 1 dose (ie, 24 hours). If the maintenance dose
begins release of the drug at the time of dosing (t = 0), it
will add to that which is provided by the initial dose, thus
increasing the initial drug level. In this case, a correction
factor is needed (Kr
0
Tp) to account for the added drug from
the maintenance dose. This correction factor is the amount
of drug provided during the period from t = 0 to the time of
the peak drug level, Tp.8
If Di is 100 mg, Kr
0
is 16.32 mg/h, Tp is 2.5 hours, and Td
is 24 hours, then per Equation 2 the total dose would be
450.88 mg of cefpodoxime. Since 130 mg of cefpodoxime
proxetil is equivalent to 100 mg of cefpodoxime,10
the required
quantity of cefpodoxime proxetil would be (450.88 Â
1.3), or 586 mg (the quantity used was 590 mg/tablet).
Manufacturing of Tablets
Tablets were prepared by direct compression, the recommended
process for working on a matrix system with HPMC;
in wet granulation, unwanted swelling of HPMC could occur
because of granulation fluid.11
The tablet formula consisted
of cefpodoxime proxetil (53.6%), HPMC 4000 cps
(35%), Avicel PH 101 (10.4%), and magnesium stearate
(1%). The HPMC manufacturer JRS (Rosenberg, Germany)
recommended 20% to 50% matrix former for optimum
release.11
Materials were blended in a polybag using the
geometric dilution principle. The blend was compressed
using a single-punch tablet machine (KORSCH Erweka,
Frankfurt, Germany) using 19.0 mm  8.8 mm capletshaped
concave punches (although we recommend using
22 mm  10 mm punches for ease of filling) with a target
weight of 1.1 g/tablet.
AAPS PharmSciTech 2006; 7 (3) Article 78 (http://www.aapspharmscitech.org).
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Evaluation of Tablets
Physical Evaluation. Using official British Pharmacopoeia
methods, we evaluated tablets’ physical parameters, including
weight (Mettler Toledo B204-S, Zurich, Switzerland)
and hardness (OSK Fujiwara Hardness Tester, Tokyo, Japan)
variation, thickness, length, breadth, and friability (H. Jurgens
GmbH and Co, Bremen, Germany).12
Assay for Cefpodoxime. An assay was performed on
HPLC as per the official monograph requirement for cefpodoxime
proxetil in USP 27.13
System suitability was
checked prior to sample injections. Resolution factor R between
the cefpodoxime proxetil S and R epimer peaks, and
tailing factor t for cefpodoxime R epimer, were calculated.
In Vitro Dissolution Studies. In vitro drug release of
Cefpo SR was evaluated using USP official method Drug
Release G7249 Method A using USP Apparatus-II, following
general dissolution procedure USP G7119. The only
exception was that a stationary basket was suspended in the
vessel of Apparatus-II (Erweka ZT-2, Heusenstamm, Germany)
because of the floating character of the tablet in the
dissolution medium during paddle rotation at 100 rpm. The
tablet was placed in a specially made basket of stainless
steel wire gauze (8 mesh) with rod assembly through the
cover of the dissolution vessel and fixed at 3.2 cm away
from the center of the vessel; the lower end of the bottom
of the basket was adjusted to ~1 cm above the top of the
paddle blade. The largest side of the basket was oriented
tangentially to the flow stream, with the tablet standing on
its edge.13
Qiu et al found that factorial studies have indicated that
higher pH, addition of sodium lauryl sulfate (SLS) to the
dissolution medium, and higher agitation intensity increased
the release rate from the matrix tablet. Use of SLS led to not
only increased release rates that were closer to in vivo absorption
rates but also improved differentiation among
formulations with varying release rates.14
Hence, drug release
for Cefpo SR was studied for the first 45 minutes in an
acidic medium containing 1% SLS and then for the rest of
the 24-hour period in phosphate buffer (pH 6.8 ± 0.05)
having 0.75% SLS. A 10-mL aliquot was withdrawn from
the dissolution medium at predetermined intervals throughout
the 24-hour period; at each interval, the withdrawn medium
was replaced with blank dissolution medium. Drug
release was then analyzed by measuring the absorbance
through a spectrophotometer (UV 150-02, Shimadzu Corporation,
Kyoto, Japan) at wavelength 259 nm after suitable
dilution. Drug content (assay) was determined through
High Performance Liquid Chromatography (HPLC) (LC-5A,
SPD-2A, Shimadzu Corporation, Kyoto, Japan) using official
methods for cefpodoxime proxetil tablets.13
Drug Release Kinetics. To study the release kinetics, data
obtained from in vitro drug release studies were plotted in
various kinetic models: zero order (Equation 3) as cumulative
amount of drug released vs time, first order (Equation 4)
as log cumulative percentage of drug remaining vs time, and
Higuchi’s model (Equation 5) as cumulative percentage of
drug released vs square root of time.
C ¼ K0 t ð3Þ
where K0 is the zero-order rate constant expressed in units
of concentration/time and t is the time in hours. A graph of
concentration vs time would yield a straight line with a
slope equal to K0 and intercept the origin of the axes.15
LogC ¼ LogCo−kt=2:303 ð4Þ
where C0 is the initial concentration of drug, k is the first
order constant, and t is the time.16
Q ¼ Kt1=2
ð5Þ
where K is the constant reflecting the design variables of
the system and t is the time in hours. Hence, drug release
Figure 1. Cefpo SR release profile vs theoretical profile and
zero order plot.
Figure 2. First-order kinetics (log cumulative percent drug
remaining vs time).
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rate is proportional to the reciprocal of the square root of
time.17
To evaluate the drug release with changes in the surface
area and the diameter of the particles/tablets, the data were
also plotted using the Hixson-Crowell cube root law:
3
ffiffiffiffiffiffi
Q0
p
À 3
ffiffiffiffiffiffi
Qt
p
¼ kHC Â t ð6Þ
where Qt is the amount of drug released in time t, Q0 is the
initial amount of the drug in the tablet, and KHC is the rate
constant for the Hixson-Crowell rate equation,18
as the cube
root of the percentage of drug remaining in the matrix vs time.
Mechanism of Drug Release. To evaluate the mechanism
of drug release from Cefpo SR, data for the first 60% of
drug release were plotted in Korsmeyer et al’s equation
(Equation 7) as log cumulative percentage of drug released
vs log time, and the exponent n was calculated through the
slope of the straight line.
Mt=M∞ ¼ Ktn
ð7Þ
where Mt/M∞ is the fractional solute release, t is the release
time, K is a kinetic constant characteristic of the drug/
polymer system, and n is an exponent that characterizes the
mechanism of release of tracers.19
For cylindrical matrix
tablets, if the exponent n = 0.45, then the drug release
mechanism is Fickian diffusion, and if 0.45 G n G 0.89,
then it is non-Fickian or anomalous diffusion. An exponent
value of 0.89 is indicative of Case-II Transport or typical
zero-order release.20
RESULTS AND DISCUSSION
Manufacturing and Evaluation of Tablets
The physical attributes of the tablet were found to be satisfactory.
Typical tablet defects, such as capping, chipping,
and picking, were not observed, but for ease of filling we
recommend using 22 mm  10 mm instead of 19 mm Â
8.8 mm punches. Results for other physical evaluations
were also found to be within an acceptable range. For instance,
weight variation was calculated as 1.68% (range ±
5%), where average weight was 1.1015 ± 0.0185 g (n = 20).
Hardness of the tablet was found to be 18.5 ± 5 kg (n = 20).
Thickness, length, and breadth were found to be fixed during
the compression cycle; values were 9.8 mm, 19.0 mm, and
8.8 mm, respectively. Friability of the tablet was calculated
as 0.1613% (n = 10), which was well within the acceptable
range of 1% and indicates that tablet surfaces are strong
enough to withstand mechanical shock or attrition during
storage and transportation and until they are consumed.12
Assay for Cefpodoxime Proxetil
The resolution factor R between the cefpodoxime proxetil
S and R epimer peaks was 2.538 (not less than (NLT) 2.5),
and the tailing factor for cefpodoxime proxetil R epimer
was 1.04 (not more than (NMT) 1.5). The assay percentage
was 90.04% (90% to 110%), with relative standard deviation
(RSD) of 1.06% (NMT 1%). The fact that the assay
results were close to the lower limit of the range may have
been due to manual bag blending of the formula ingredients.
In Vitro Dissolution Studies
Ideally, an extended-release tablet should release the required
quantity of drug with predetermined kinetics in order to
maintain an effective drug plasma concentration. To achieve
this, the tablet should be formulated so that it releases the
drug in a predetermined and reproducible manner. By considering
the drug’s biopharmaceutic and pharmacokinetic
profile, one can determine the required release from the
tablet.21
Figure 1 shows the in vitro drug release profile of
Cefpo SR. It was found that ~99.45 mg (16.86%) of the
drug was released during the first hour, which is in accordance
with the conventional dose of a 100-mg tablet. During
the initial 9 hours, ~50% of the drug was released.
After 9 hours, the release rate increased slightly, until the
21st hour, and then release slowed but continued until the
Figure 3. Higuchi (square root) kinetics (cumulative percent
drug released vs square root of time). SQRT indicates square root.
Table 1. Release Kinetics of Cefpo SR
Zero Order First Order Higuchi Korsmeyer-Peppas Hixson-Crowell
r2
Ko (h–1
) r2
K1 (h–1
) r2
KH (h-1/2
) r2
n KKP (h–n
) r2
KHC (h–1/3)
0.9708 3.7574 0.9091 0.1582 0.9734 23.753 0.9006 0.57 0.1309 0.9878 0.1325
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24-hour mark. Hence, a sustained-release pattern was observed
throughout the 24-hour dissolution study. The in
vitro release behavior of Cefpo SR was also compared
with the theoretical (predictive) profile and found to be quite
similar; a very close relationship was noted between the
test and theoretical release patterns (Figure 1).
Drug Release Kinetics
The zero-order rate (Equation 3) describes the systems where
the drug release rate is independent of its concentration.
Figure 1 shows the cumulative amount of drug release vs
time for zero-order kinetics. The first order (Equation 4),
which describes the release from systems where the release
rate is concentration dependent, is illustrated by Figure 2,
which shows the log cumulative percent drug remaining vs
time. Higuchi’s model (Equation 5) describes the release
of drugs from an insoluble matrix as a square root of a
time-dependent process based on Fickian diffusion. Figure 3
illustrates the Higuchi square root kinetics, showing the
cumulative percent drug release vs the square root of time.22
The release constant was calculated from the slope of the
appropriate plots, and the regression coefficient (r2
) was
determined (Table 1). It was found that the in vitro drug
release of Cefpo SR was best explained by Higuchi’s equation,
as the plots showed the highest linearity (r2
= 0.9734),
followed by zero order (r2
= 0.9708) and first order (r2
=
0.9091). This explains why the drug diffuses at a comparatively
slower rate as the distance for diffusion increases,
which is referred to as square root kinetics (or Higuchi’s
kinetics). However, drug release was also found to be very
close to zero-order kinetics, indicating that the concentration
was nearly independent of drug release. Figure 1 also
verifies the correlation of the Cefpo SR release profile with
the theoretical profile.
The dissolution data were also plotted in accordance with
the Hixson-Crowell cube root law (Equation 6). The applicability
of the formulation to the equation indicated a
change in surface area and diameter of the tablets with the
progressive dissolution of the matrix as a function of time
(Figure 4).
Mechanism of Drug Release
The corresponding plot (log cumulative percent drug release
vs time) for the Korsmeyer-Peppas equation19
indicated a
good linearity (r2
= 0.9006). The release exponent n was
0.57, which appears to indicate a coupling of the diffusion
and erosion mechanism—so-called anomalous diffusion—
and may indicate that the drug release is controlled by more
than one process (Figure 5). Reddy et al observed similar
results with a matrix tablet of nicorandil with an n value
of 0.71,23
and Fassihi and Ritschel with a matrix tablet of
theophylline with an n value of 0.7.24
Both these groups of
researchers also considered the corresponding n values to
indicate an anomalous release mechanism.
SUMMARY AND CONCLUSIONS
Decreasing the dose frequency of cefpodoxime proxetil increases
patient compliance; patients prefer to take the drug
once daily. It also improves the rate of bacterial killing
and hastens the cure from the indications, and therefore
increases compliance. The hydrophilic matrix of HPMC
controlled the cefpodoxime proxetil release effectively for
24 hours; hence, the formulation can be considered as a
once-daily sustained-release tablet of cefpodoxime proxetil.
The formulation showed acceptable pharmacotechnical
properties and assay requirements. In vitro dissolution studies
indicated a sustained-release pattern throughout 24 hours
of the study that was comparable to the theoretical release
profile. Drug release kinetics indicated that drug release was
best explained by Higuchi’s equation, as these plots showed
the highest linearity (r2
= 0.9734), but a close relationship
was also noted with zero-order kinetics (r2
= 0.9708).
Figure 4. Korsmeyer et al kinetics (log cumulative percent
drug released vs log time).
Figure 5. Hixson-Crowell cube root plots (CBR percent drug
remaining vs time). CBR indicates cube root, W0 indicates initial
drug load at time zero, taken as 100%, and Wt indicates percentage
drug undissolved at time t.
AAPS PharmSciTech 2006; 7 (3) Article 78 (http://www.aapspharmscitech.org).
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Korsmeyer’s plots indicated an n value of 0.57, which was
indicative of an anomalous diffusion mechanism or diffusion
coupled with erosion; hence, the drug release was
controlled by more than one process. Hixson-Crowell plots
indicated a change in surface area and diameter of the
tablets with the progressive dissolution of the matrix as a
function of time.
ACKNOWLEDGMENT
The authors gratefully acknowledge the support of M/s S.J.
and G. Fazul Ellahie (Pvt) Ltd (Karachi, Pakistan), which
provided cefpodoxime proxetil for this research.
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