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Acta Poloniae Pharmaceutica Drug Research, Vol. 62 No. 3 pp.

183187, 2005

ISSN 0001-6837
Polish Pharmaceutical Society

BIOPHARMACY

THE STABILITY OF CEFUROXIME AXETIL IN TABLETS


ANNA JELISKA1*, IZABELA DUDZISKA2, MARIANNA ZAJC1,
IRENA OSZCZAPOWICZ3 and WALDEMAR KRZEWSKI4
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Medical Sciences
6 Grunwaldzka Str., 60-780 Pozna, Poland; 2GlaxoSmithKline Pharmaceuticals S.A.
189 Grunwaldzka Str., 60-322 Pozna, Poland
3
Department of Modified Antibiotics, Institute of Biotechnology and Antibiotics,
5 Starociska Str., 02-515 Warszawa, Poland
4
Bioton Sp. z o.o., 12 Poznaska Str., 05-850 Oarw Mazowiecki, Poland

Abstract: The stability of cefuroxime axetil in BIORACEF tablets was studied by means of long term
(298 K/60% RH), intermediate (303 K/65% RH), accelerated (313 K/75% RH) and stress stability tests.
Changes in the concentration of cefuroxime axetil diastereoisomers A and B and their total was determined
using the RP-HPLC method, as described in a monograph of Cefuroxime axetil tablets in the British
Pharmacopoeia 2003. After 2 years of storage under long term, 1 year under intermediate and 6 months under
accelerated storage conditions, the preparation of BIORACEF meets the quality requirements as regards both,
the active substance content and chromatographic purity. Under stress conditions the decomposition of
cefuroxime axetil diastereoisomers follows the first-order reversible autocatalytic reaction with 3-isomers of
cefuroxime axetil as the main product. The kinetic parameters of the decomposition reaction were calculated
and compared with analogical parameters obtained for ZINNAT tablets stored in the same conditions.
Keywords: Cefuroxime axetil; stability; tablets

tric purposes is also available as granules in multidose bottles and sachets. The constitution gives a suspension containing 125 or 250 mg of cefuroxime
(as cefuroxime axetil). Tablets should be stored below 250C in airtight containers and protected from
light. For the preparation of pharmaceutical forms,
only the amorphous form of cefuroxime axetil is
used. In comparison with crystalline form the amorphous from has better physicochemical and biological properties (5-6).
The aim of the present study was to evaluate
the stability of CFA in BIORACEF under long
term, intermediate, accelerated and stress storage
conditions. Under stress conditions the stability of
CFA in ZINNAT tablets was also studied and compared with the stability of CFA in BIORACEF tablets.

Cefuroxime axetil (1-acetoxyethyl ester of cefuroxime, CFA), commonly used in therapy, is


a prodrug of cefuroxime. This second-generation cephalosporin is active against a wide range of Gram-positive and Gram-negative organism and is resistant to most -lactamases.

Cefuroxime axetil is indicated for the treatment


of infections caused by sensitive bacteria (1-4). The
ester (CFA) is applied in therapy (Zinnat, Bioracef,
Elobact, Cepazine) as tablets containing 125, 250 or
500 mg of cefuroxime (as cefuroxime axetil). The
compositions of ZINNAT and BIORACEF are the
same. The form of oral suspension dosage for pedia-

EXPERIMENTAL
Chemicals and reagents
The amorphous form of cefuroxime axetil
(CFA), cefuroxime, -3 isomers of cefuroxime axetil and E-isomers of cefuroxime axetil were obtained
from the Institute of Biotechnology and Antibiotics
in Warsaw. BIORACEF tablets (batch 20010102),

* Corresponding author: e-mail address ajelinsk@amp.edu.pl

183

184

ANNA JELISKA et al.

were obtained from Bioton Sp. z o.o in Oarw Mazowiecki, Zinnat tablets (batch 2M10A), were produced by Glaxo. Other chemical substances and reagents were products of Sigma Chemical Co.
Chromatographic conditions
The method used in the experiments is a modification of the procedure presented in the British
Pharmacopoeia 2003 for Cefuroxime axetil tablets.
The only modification introduced was the internal
standard, methyl hydroxybenzoate (Nipagine M),
used to determine the CFA in tablets. Changes in the
concentration of the two diastereoisomers (A and B)
of CFA were recorded using the HPLC method.
Chromatography was carried out on a Hypersil C1
HS 16 column (250 4 mm, 5 m particle size). The
mobile phase consisted of a mixture of 38 volumes
of methanol and 62 volumes of a 23 g/L solution of
ammonium dihydrogen phosphate. The flow rate was
1.0 mL/min. The detection wavelength was 278 nm.
The injector was a Rheodyne 7120 with a noose of
50 mL. The internal standard was a solution of nipagine M in a mixture (1: 1) of acetonitrile and water
at a concentration of 0.26 mg/mL. The study was
performed at ambient temperature.
Conditions of kinetics studies
In order to determine the kinetic mechanism of
CFA decomposition in BIORACEF and ZINNAT,
their tablets were studied at 333 K and at a relative
humidity of ~75%. The required air humidity was
achieved using saturated NaCl solutions. At the gi-

Figure 1. HPLC chromatogram of the cefuroxime (1), nipagine M


(2), cefuroxime axetil diastereoisomer B (3), cefuroxime axetil
diastereoisomer A (4), -3 isomers of cefuroxime axetil (5) and Eisomers of cefuroxime axetil (6, 7).

ven conditions, both preparations were stored out of


their commercial pack. Depending on the decomposition rate of CFA the testing frequency was established and the tablets were removed from a desiccator.
The tablets were triturated after cooling down, and
the mass of powdered tablets corresponding to 10 mg
of CFA was weighed out into 25 mL measuring flasks. 15 mL of the acetonitrile: water (1: 1) mixture
was added to the mass, mixed in a ultrasound bath for
10 minutes, filled to volume with the same mixture
and filtered. To 1.0 mL of the sample taken, 0.5 mL
of internal standard solution was added. 50 mL samples of the solutions were injected onto the column.
In order to determine the stability of CFA in
BIORACEF tablets, the tablets were stored in their
commercial pack in climate chambers under the following conditions: 298 K/60% RH (long term test),
303 K/65% RH (intermediate test) and 313 K/75%
RH (accelerated test). The cefuroxime content (as
cefuroxime axetil) in one tablet was tested at 3month time intervals in the first year and at 6-month
time intervals in the second year, taking 3 tablets for
each testing. The cefuroxime content (as cefuroxime
axetil) was calculated using the same procedure as
in the determination of the kinetic mechanism of
CFA decomposition in tablets. 0.4 mg/mL of comparative solution of CFA was prepared at the same

Figure 2. Semilogarithmic plots of Pt = f(t) characterizing the


degradation of cefuroxime axetil in BIORACEF (B) and ZINNAT
(Z) at 333 K and RH ~ 75% (A and B CFA diastereoisomers).

The stability of cefuroxime axetil in tablets

185

Figure 3. Semilogarithmic plots of Pt P = Pt = f(t) for the


degradation of cefuroxime axetil in BIORACEF (B) and ZINNAT
(Z) at 333 K and RH ~ 75% (A and B CFA diastereoisomers).

Figure 4. Semilogarithmic plots of Pt/(P0 Pt) = f(t) for the


degradation of cefuroxime axetil in BIORACEF (B) and ZINNAT
(Z) at 333 K and RH ~ 75% (A and B CFA diastereoisomers).

time. From the peak sum of CFA diastereoisomers


A and B were obtained for the tablets and from the
peak sum of the CFA comparative substance, the cefuroxime content (as cefuroxime axetil) in the tablets was calculated.
Chromatographic purity (related substances)
was studied according to the British Pharmacopoeia
2003 at the end-point of each storage test, i.e., after
6 months of storage at 313 K/75% RH, 12 months of
storage at 303 K/65% RH and 24 months of storage
at 298 K/60% RH, using only one tablet, but each
test was made twice.

Semilogarithmic plots (Pt P) = Pt = f (t) are


typical of autocatalytic reaction (Figure 3), where Pi
is the proportion of the CFA peak size to the internal standard peak size. To evaluate the rate constants
of the first-order autocatalytic reaction, the curves of
ln Pt/(P0 Pt) = f (t) were plotted. They are
straight lines and their slopes correspond to the rate
constants of the decomposition of CFA (Figure 4);
Pt substrate concentration after time t, (P0 Pt)
product concentration after time t.

RESULTS AND DISCUSSION


Under the conditions given, the separation of
cefuroxime axetil (diastereoisomers A and B), cefuroxime, -3 isomers of cefuroxime axetil, E-isomers of CFA and internal standard (Nipagine M)
was achieved (Figure 1). The decomposition of
CFA in BIORACEF and ZINNAT tablets at 333 K
and 75% RH (stress test) occurred according to the
model of the first-order reversible autocatalytic reaction depending on the substrate concentration (Figure 2).
A, B

k1
k2

Products

A and B CFA diastereoisomers

Figure 5. Semilogarythmic plot of Pt = f(t) for the reaction of


formation and decomposition of -3 isomers of CFA in
BIORACEF at 333 K and RH ~ 75%.

186

ANNA JELISKA et al.

Table 1. Kinetic parameters for the degradation of cefuroxime axetil in BIORACEF and ZINNAT at 333 K and RH ~ 75%

Kinetic parameters

Diastereoisomer A

Diastereoisomer B

Sum of diastereoisomers

-0.0225 0.0015
6.6710-4
428 2
0.217
(6.26 0.42) 10-6
11.1
5.1610-7
5.7410-6
-0.996
11

-0.0134 0.0023
2.2310-6
116 1
0.0766
(3.73 0.38) 10-6
2.84
9.7010-7
2.7610-6
-0.999
12

-0.0159 0.0013
5.7010-4
138 2
0.196
(4.42 0.35) 10-6
4.84
7.5610-7
3.6610-6
-0.994
12

-0.0216 0.0024
1.0310-3
492 2
0.274
(5.99 0.66) 10-6
10.4
5.2510-7
5.3710-6
-0.991
10

-0.0144 0.0019
8.7210-4
73.7 1.8
0,259
(3.99 0.54) 10-6
2.31
1.2010-7
2.7810-6
-0.982
12

-0.0161 0.0018
7.8110-4
162 2
0.220
(4.46 0.49) 10-6
4.05
8.8210-7
3.5810-6
-0.990
11

BIORACEF
a a, h-1
Sa
b b
Sb
(ks k), s-1
K
k1, s-1
k2, s-1
r
n
ZINNAT
a a, h-1
Sa
b b
Sb
(ks k), s-1
K
k1, s-1
k2, s-1
r
n

Table 2. The cefuroxime content (as cefuroxime axetil) in BIORACEF tablets stored under described conditions

Storage time
(Months)

Cefuroxime content (as cefuroxime axetil)


298 K/60% RH

303 K/65% RH

313 K/75% RH

0.2514

0.2514

0.2514

0.2512

0.2509

0.2498

0.2507

0.2508

0.2493

0.2501

0.2503

0.2505

0.2503

0
x
3
x
6
x
9
x
12
x
18
x

0.2501

24
x

0.2503

The slope of the curve of ln Pt/(P0 Pt) = f (t)


is equal to the sum of reaction rate constants k1 and
k2. Partial reaction rate constants k1 and k2 were calculated using the following equations (7):

k2 = ks/(1 + K); k1 = ks k2
where: ks = k1 + k2; K (equilibrium constant) = k1/k2
= (P0 P)/P.
The studies showed that the decomposition of

The stability of cefuroxime axetil in tablets

diastereoisomer B is faster than that of diastereoisomer A, but the differences in the decomposition rates of CFA in BIORACEF and ZINNAT are statistically insignificant (Table 1).
The main products of the decomposition of
CFA under stress storage conditions are -3 isomers
of CFA. The reaction of formation and decomposition of -3 isomers of CFA is the first-order reversible autocatalytic reaction, too (Figure 5).
The autocatalytic character of CFA degradation in BIORACEF tablets under stress conditions
suggests the necessity of performing stability test
under long-term and intermediate conditions to confirm the stability of CFA.
Under long-term, intermediate and accelerated
stability tests, the CFA content (92.5% 105.0%)
(Table 2), the amount of -3 isomers of CFA
( 2%), the amount of the E-isomers ( 1.5%) and the
sum of other impurities ( 1%) meet the requirements
of Cefuroxime axetil tablets monograph (BP 2003).

187

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Received: 28.12.2004