Volume 21 Nr. 1 1999 Pharmacy World & Science 35 stance, its concentration in 5-FC intravenous solutions must be kept to a minimum in order to reduce the exposition of this drug to patients treated with 5-FC. Until so far there have only been shelf life studies with 5-FC in extemporaneously compounded oral liq- uids [4 5] and according to our knowledge published data for the stability of 5-FC in intravenous solutions is lacking. However, for the preparation and storage of 5-FC intravenous solutions at our pharmacy, informa- tion about the 5-FC stability in infusion fluids is war- ranted. We studied the stability of 5-FC in intravenous solu- tions by an accelerated stability testing experiment and selectively measured the concentrations of 5-FC as well as 5-FU in 5-FC intravenous solution. Materials and methods Drugs and chemicals 5-FC (Ancotil ® ) infusion solution was obtained from Roche (Roche Nederland B.V., Mijdrecht, The Nether- lands). 5-FU (C 4 H 3 FN 2 O 2 ) and 5-FC (C 4 H 4 FN 3 O) (Figure 1) were purchased from Sigma Chemical Co. (St. Louis, USA). The ion-pare reagent used for HPLC, 1-heptanesulfon- ic acid (sodiumsalt, monohydrate; C 7 H 15 O 3 SNa.H 2 O) was obtained from Sigma-Aldrich Chemical Co. (St. Louis, USA). Ammonium dihydrogen phosphate ((NH 4 )H 2 PO 4 ) was purchased from Merck (Merck, Darmstadt, Germany) and distilled water was obtained from Braun-NPBI (Medispoel ® , Emmer-Compascuum, The Netherlands). Assay For the heating of the 5-FC intravenous solution waterbaths with Type EM Jujabo heating elements (Jujabo labortechnik, Seelbach, Germany) and two stoves (Model 400 Memmert; Memmert GmbH, Schwabach, Germany and Heraeus; Dijkstra B.V., The Netherlands) were used. The concentrations of 5-FU and 5-FC were deter- mined using a newly developed HPLC method with UV detection. A Supelcosil LC-18-DB column (150 mm x 4.6 mm I.D.) (Art. No. 5-8348; Supelco Inc., Supelco Park, Bellefonte, USA), a Model 7125 Rheodyne Injector system (Rheodyne Inc., Cotati, USA), a Shimadzu ® LC-6A Liquid Chromatograph (Shimadzu Co., Kyoto, Japan) (flow rate 1 ml/min; pressure 120 kgf/cm 2 ), a Shimadzu ® C-R6A Chromatograph (Shimadzu Co., Kyoto, Japan) and a Shimadzu ® SPD-6A UV Spectrophotometric Detector (Shimadzu Co., Kyoto, Japan) were used. Absorption was measured at a wavelength of 266 nm. The mobile phase consisted of 0.03 M (3.45 g/l) ammonium dihydrogen phosphate (pH 3.5) and 0.005 M (1.1015 g/l) 1-heptanesulfonic acid, filtered before use over a SM-11117 0.2 μM filter (Sattorius GmbH, Göttingen, Germany). Articles Introduction Flucytosine (5-FC) is a systemic antimycotic drug which is active against mycotic infections caused by Candida-species and Cryptococcus neoformans as well as in chromoblastomycosis [1]. The drug can be administered both orally and by intermittent or con- tinuous infusion. For the intravenous route of admin- istration 5-FC is marketed as Ancotil ® which is an iso- tonic solution existing of 1.0% 5-FC (10 mg 5-FC/ml) and 0.805% NaCl [1]. At temperatures below 18 °C 5-FC is known to pre- cipitate which can be reversed by heating the solution at 80 °C. The manufacturer advices to heat the solu- tion under these circumstances for a maximum of half an hour. Storage of the solution above a temperature of 25 °C however is known to cause degradation of 5- FC into 5-fluorouracil (5-FU) [1]. 5-FU is a widely used antineoplastic drug mainly prescribed for the palliative treatment of carcinoma of the colon, rectum and mammae [1 2]. Furthermore, it is known that 5-FU is not only formed as a decompo- sition product of 5-FC but it is also used as precursor in the synthesis of 5-FC [3]. These two reasons might explain the presence of 5-FU impurities in 5-FC prod- ucts. As 5-FU is a heavily toxic and teratogen sub- An accelerated stability study of 5-flucytosine in intravenous solution • Andras Vermes, Heleen van der Sijs and Henk-Jan Guchelaar Pharm World Sci 1999;21(1): 35-39. © 1999 Kluwer Academic Publishers. Printed in the Netherlands. Andras Vermes, Heleen van der Sijs and Henk-Jan Guchelaar (correspondence): Department of Clinical Pharmacy, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; Tel: + 31 20 566 3474, Fax: +31 20 697 2291, E-mail: H.J.GUCHELAAR@AMC.UVA.NL Keywords Ancotil ® intravenous solution Flucytosine 5-Fluorouracil High-performance liquid chromatography (HPLC) Accelerated stability study Drug stability Abstract The stability of the antimycotic drug flucytosine (5-FC) and the extent of 5-fluorouracil (5-FU) formation in 5-FC intravenous solution was studied in an accelerated stability experiment. 5-FC intravenous solution (10 mg/ml) was heated at 40, 60, 70, 80 and 90 °C for a maximum of 131 days. At appropriate time intervals samples were taken and the concentrations of 5-FC and 5-FU were determined using a newly developed, stability indicating HPLC-UV method. Heating the 5-FC intravenous solution at 40, 60, 70, 80 and 90 °C lead to 5-FC decomposition of respectively 0, 8.9, 14.4, 52.5 and 61.6%. The Arrhenius plot of the 5-FC decomposition is described by: Lnk 5-FC decomposition = 80.1892 * 1/T - 0.2396 and the 5-FU formation is described by Lnk 5-FU formation = -13087 * 1/T + 34.4028. It is concluded that 5-FC is very stable in intravenous solution at regular storing temperatures and can therefore be stored at ambient temperatures for several years before the critical limit of 95% 5-FC is reached. However, the toxic and terato- gen degradation product 5-FU may be present in considerable amounts in the product, due to both impurities in the raw material and the formation from 5-FC upon sterilisation and storage. Accepted January 1998