Stability of sulfadiazine oral liquids prepared from tablets and powder.

Umma Pathmanathan, David Halgrain, Fouad Chiadmi, Joël Schlatter, Norbert Vermerie
Pharmacy Department, University Hospital of Jean Verdier, Bondy, France.
Received 04 February 2004, Revised 02 April 2004, Accepted 02 April 2004, Published 22 April 2004
Abstract Purpose: To assess the stability of sulfadiazine
(SDZ) oral liquids prepared from tablets and powder
at two temperatures. Methods: Solutions of SDZ
200 mg/mL were prepared from commercially available
500 mg tablets and powder in sterile water for irrigation.
They were stored in amber glass bottles at 4°C
and 23°C. The concentrations of SDZ were determined
in duplicate by high-performance liquid chromatography
at 0, 1, 3, 7 and 14 days. The initial and
final pH of solutions was compared. The recovery of
SDZ from tablets was determined. A loss exceeding
10% of the initial concentration of SDZ was considered
excessive degradation. Results: The recovery of
SDZ from tablets was 100 ± 3%. The initial pH values
were significantly different between solutions prepared
from tablets and powder, 6.9 and 9.8 respectively. No
significant difference was found between initial and
final pH values for the two all formulations. Detectable
change in odor was observed for the solutions
stored at 23°C. The solution prepared from powder
was stable 3 days stored at 4°C. Other formulations
lost over 10% of the initial SDZ concentration within
2 days. Conclusions: SDZ 200 mg/mL oral solution
prepared from powder could be used to facilitate drug
administration to very young children by nurses but
by taking account of its fast degradation.
INTRODUCTION
Toxoplasmosis is caused by the protozoan parasite
Toxoplasma gondii. Congenital infection with this
germ may result in spontaneous abortion, fetal death
or severe disease (1, 2). The sequelae in live-born
infants with signs of infection are generally severe and
include a potentially fatal syndrome in which hydrocephalus,
mental retardation and chorioretinitis may
occur (3-7). The recommended dose of sulfadiazine in
children is to 25 to 50 mg/kg four times daily (8). Sulfadiazine,
a 2-sulfanilamidopyrimidine (SDZ), is a sulfonamide
anti-infective agent available in compressed
tablets only. SDZ is a white or yellow crystalline powder
insoluble in water and very slightly soluble in ethanol.
It is slowly darkening on exposure to light with
decomposition (9). A liquid dosage form would be
highly desirable for pediatric patients and allows the
dose to be easily adjusted. Because of the lack of published
data on the stability of SDZ in oral liquid dosage
form, we designed a study to determine the stability of
the drug in liquid prepared from commercially available
tablets and powder at two controlled temperatures.
MATERIALS AND METHODS
Materials
Sulfadiazine powder1 was of analytical grade. Sulfadizaine
500-mg tablets2 were obtained commercially.
They were consisted of potato starch 17.5 mg, magnesium
stearate 1.15 mg, corn starch 135 mg and talc 6
mg. Ranitidine 50 mg/2 ml for injection3 (internal
standard) and sterile water for irrigation4 were
obtained commercially. Methanol5 and diethylamine6
were HPLC grade.
Formulations
A suspension of SDZ 200 mg/ml was prepared by
crushing 100 500-mg tablets using a glass mortar and
pistil and diluting with sterile water for irrigation to
make a paste. Sterile water for irrigation was then
added and mixed to a 250 ml final volume. The suspension
was transferred in twelve amber glass prescription
bottles. The recovery of SDZ obtained from tablets
was also studied from five suspensions prepared independently.
Another oral liquid of SDZ 200 mg/ml was
prepared with SDZ powder. A sufficient quantity was
weighed and mixed with sterile water for irrigation.
This solution was transferred in twelve amber glass
prescription bottles. Duplicate 1 mL samples were
removed from each bottle and analyzed immediately.
stable 3 days stored at 4° C. The formulation prepared
using the tablet lost over 10% of the initial SDZ concentration
within 2 days (Table 1). SDZ can be prepared
extemporaneously in liquid formulations from
tablets or powder. However, the SDZ oral liquids are
not stable for long time and cannot be prepared by
pharmacists. Excipients and pH of suspensions prepared
from tablets could explain the difference in stability
with solutions prepared from powder. SDZ is
not available in a liquid dosage form for the management
of paediatric patients. SDZ 200 mg/mL oral solution
prepared from powder was stable 3 days at 4° C
and could be used to facilitate drug administration to
very young hospitalized children by taking account of
her fast degradation. However, the formulations are
not suitable for preparation in large batches.
Table 1: Stability of SDZ 200 mg/mL oral liquids
prepared from tablets and powder at two temperatures.
a Reported as mean ± S.D. of duplicate determinations for six
samples.
b The actual mean ± S.D. initial concentration was 210.1 ±
6.3 μg/mL.
c The actual mean ± S.D. initial concentration was 213.2 ±
8.5 μg/mL.
d The actual mean ± S.D. initial concentration was 196.4 ±
6.9 μg/mL.
e The actual mean ± S.D. initial concentration was 201.3 ±
9.0 μg/mL
REFERENCES
[1] Pratlong, F., Boulot, P., Issert, E., Miska, M.,
Dupont, F., Bachelard, B., Sarda, P., Viala, J.L., Jarry,
D., Fetal diagnosis of toxoplasmosis in 190 women
infected during pregnancy. Prenat Diagn, 14:191-198,
1994.
[2] Qublan, H.S., Jumaian, N., Abu-Salem, A., Hamadelil,
F.Y., Mashagbeh, M., Abdel-Ghani, F., Toxoplasmosis
and habitual abortion. J Obstet Gynaecol,
22:296-298, 2002.
[3] Berrebi, A., Kobuch, W.E., Bessieres, M.H., Bloom,
M.C., Rolland, M., Sarramon, M.F., Termination of
pregnancy for maternal toxoplasmosis. Lancet,
344:36-39, 1994.
[4] Kutova, K., Peicheva, Z., Popova, A., Markova, V.,
Mincheva, N., Todorov, T., Congenital toxoplasmosis:
eye manifestations in infants and children. Ann
Trop Paediatr, 22:213-218, 2002.
[5] Foulon, W., Villena, I., Stray-Padersen, B., Decoster,
A., Lappalaiven, M., Pinon, J.M., Treatment of toxoplasmosis
during pregnancy: a multicenter study of
impact on fetal transmission and children’s sequelae
at age 1 year. Am J Obstet Gynecol, 180:410-415, 1999.
[6] Wilson, C.B., Remington, J.S., Stagno, S., Reynolds,
D.W., Development of adverse sequelae in children
born with subclinical congenital toxoplasma infection.
Pediatrics, 66:767-774, 1980.
[7] Mombro, M., Perathoner, C., Leone, A., Nicocia,
M., Moiraghi-Rugenini, A., Zotti, C., Congenital
toxoplasmosis: 10 year follow-up. Eur J Pediatr,
154:635-639, 1995.
[8] Kieffer, F., Thulliez, P., Brezin, A., Nobre, R.,
Romand, S., Yi-Gallimard, E., Voyer, M., Magny,
J.F., Treatment of subclinical congenital toxoplasmosis
by sulfadiazine and pyrimethamine continuously
during 1 year: apropos of 46 cases. Arch Pediatr, 9:7-
13, 2002.
[9] Reynolds, J.E.F., Sulphadiazine. Martindale, The
Extra Pharmacopoeia, The Pharmaceutical Press,
London, pp. 206-207, 1993.
[10] Kishida, K., Furusawa, N., Matrix solid-phase dispersion
extraction and high-performance liquid chromatographic
determination of residual sulfonamides
in chicken. J Chromatogr A, 937:49-55, 2001.
[11] Anaizi, H., Swenson, C., Instability of aqueous captopril
solutions. Am J Hosp Pharm, 50:486-488, 1993.
APPENDICES
1 Sulfadiazine powder, Sigma, St Quentin, France, lot
91K1044
2 Adiazine®, Bouchara, Levallois-Perret, France, lot 8647
3 Raniplex® for injection, Fournier, Dijon, France
4 Sterile water for irrigation, Fresenius, Sèvres, France, lot
0146/36
5 Methanol, Chromanorm®, Prolabo, Paris, France
6 Diethylamine, Chromanorm®, Prolabo, Paris, France
7 LC-6A, Shimadzu Corporation, Duisbourg, Germany