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The stability of AG337, a selective thymidylate synthase inhibitor, in 5% Dextrose in Water (D5 W) PVC infusion bags and sodium bicarbonate treated D5W infusion bags was studied at 30°C for seven days. AG337 Solution for Injection, 2% was diluted in D5W infusion bags to yield final AG337 concentrations of 4 mg/mL, 1 nig/mL and 0.1 mg/mL. For the sodium bicarbonate treated D5W infusion bags, the final concentrations of AG337 used were 4 mg/mL, 1 mg/niL and 0.2 mg/mL. The bags were prepared in triplicate and stored at 30°C. At predetermined time intervals, each bag was visually examined for presence of precipitates and samples were withdrawn for HPLC assay and pH testing. No precipitation was observed in any of the samples. The pH of the sodium bicarbonate treated D5W infusion bags remained constant throughout the study. The recovery of AG337 was greater than 93% in all samples tested. The recovery of methyl and propylparaben, used as preservatives in the formulation, however, decreased over time probably due to adsorption in the PVC bags. This study demonstrated that AG337 was stable at 30°C for up to seven days, in D5W infusion bags and in the presence of sodium bicarbonate treated D5W infusion bags. Figure 1) is a selective inhibitor of the enzyme, thymidylate synthase (TS)'. It has shown potent anti-tumor activity in uiuo against both intraperitoneal and intramuscularly implanted murine tumors2. AG337 is formulated for parented administration as a 2% buffered aqueous concentrate solution. The concentrate AG337 solution contains 50% propylene glycol as a co-solvent and parabens (methyl and propyl) as preservatives3. The aqueous solution is administered as an infusion in 5% Dextrose in Water (D5W). The concentration of AG337 in the infusion bags may range as high as 4 mg/mL. The pH of the AG337 infusion solution is typically around 3.8. To minimize irritation 1773 Copyright 0 1995 by Marcel Dekker, Inc. Drug Dev Ind Pharm Downloaded from informahealthcare.com by Nyu Medical Center on 02/02/15 For personal use only. JNTRODUCTION AG337 (

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Unclassified _________________________ 2a. SECURITY CLASSIFICATION AUTHORITY 3. DISTRIBUTION 1AVAaLAatW OF REPORT 2b. ECLSSIFCATON DOWGRAING CHEULEApproved for public release; Zb. ECLSSIICATON DOWGRADNG CHEULEdistribution un1.dted 4. PERFORMING ORGANIZATION REPORT NUMBER(S) S. MONITORING ORGMIAWZA REPORT NUMBER(S) Ga. NAME OF PERFORMING ORGANIZATION 6b. OFFICh SYMBOL 7a. NAME OF MONITOUNAIVANIZATION 6c. ADDRESS (City, State, and ZIP Code) 7b. ADDRESS(Cify, SUaMe WBCod@

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