Professional Documents
Culture Documents
183187, 2005
ISSN 0001-6837
Polish Pharmaceutical Society
BIOPHARMACY
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.
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),
183
184
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-
185
k1
k2
Products
186
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)
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
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
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
REFERENCES
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2000 (in Polish).
5. Polish Patent No. 156001.
6. Oszczapowicz I., Maafiej E., Szelachowska M.,
Horoszewicz-Maafiej A., Kuklewicz C., Sieraska E., Denys A., Niedworok J.: Acta Polon.
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(in Polish).
Received: 28.12.2004