Summary
The stability of the potential antitumour agent 2,5-diaziridinyl-3,6-bis(2-hydroxyethylamino)-1,4-benzoquinone (BZQ; NSC 224070) has been investgated by high-performance liquid chromatography. At 22°C in 0.05M buffer, BZQ was most stable at pH 9 with an apparent first-order rate constant (k) of about 0.014 h−11. There was reduced stability at pH values above and below 9.0. At a pH of 3 and 12 the values of k were 38 and 0.3 h−1, respectively. Stability of BZQ was adversely affected by increased temperatures (above 0°C), increased buffer concentration and light. Solutions of BZQ could not be frozen for any length of time, as the drug precipitated out in a form that would not redissolve (possibly a polymer). For parenteral administration to patients, it is suggested that BZQ would be most stable in 1.26% sodium bicarbonate solution when at room temperature, under normal laboratory lighting, 5% of the drug degraded (t0.95) in 5.5 h. Increased stability is obtainable in this medium by refrigeration and vigorous exclusion of light. Long term (24 h) infusions of BZQ could be considered in hypotonic sodium bicarbonate (30 mM) with careful exclusion of light as long as the volume of the infusion was small, e.g. 1 ml/h. Under these conditions to.95 was 42 h at 21.5°C.
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Khan AH, Driscoll JS: Potential central nervous system antitumor agents. Aziridinylbenzoquinones. I. J Med Chem 19:313–317, 1976
Driscoll JS, Hazard GF, Jr, Wood HB, Jr, Goldin A: Structure-antitumor activity relationships among quinone derivatives. Cancer Chemother Rep Part 2 4:1–362, 1974
Chou F, Khan AH, Driscoll JS: Potential central nervous system antitumor agents. Aziridinylbenzoquinones 2. J Med Chem 19:1302–1308, 1976
Driscoll JS, Dudeck L, Congleton G, Geran RI: Potential CNS antitumor agents VI: Aziridinylbenzoquinones III. J Pharm Sci 68:185–188, 1979
Bedikian AY, Bodey GP, Burgess MA, Freireich EJ: Phase I study of aziridinylbenzoquinone (NSC 182986). Cancer Clin Trials 4:459–463, 1981
Schilsky RL, Kelley JA, Ihde DC, Howser DM, Cordes RS, Young RC: Phase I trial and pharmacokinetics of aziridinylbenzoquinone (NSC 182986) in humans. Cancer Res 42:1582–1586, 1982
Griffin JP, Newman RA, McCormack JJ, Krakoff IH: Clinical and clinical pharmacologic studies of aziridinylbenzoquinone. Cancer Treat Rep 66:1321–1325, 1982
Bender JF, Grillo-Lopez AJ, Posada JG, Jr: Diaziquone (AZQ). Investigational New Drugs 1:71–84, 1983
Eagan RT, Dinapoli RP, Hermann RC Jr, Groover RV, Layton DD Jr: Preliminary communication — treatment of primary brain tumors recurrent after irradiation with aziridinylbenzoquinone (AZQ; NSC 182986). Am J Clin Oncol 6:577–578, 1983
Allen BA, Newman RA, Griffin JP, McCormack JJ: Liquid chromatographic determination of an antineoplastic aziridinylbenzoquinone in human and murine serum. J Chromatogr 222:146–151, 1981
Curt GA, Kelley JA, Kufta CV, Smith BH, Kornblith PL, Young RC, Collins JM: Phase II and pharmacokinetic study of aziridinylbenzoquinone [2,5-diaziridinyl-3,6-bis(carboethoxyamino)-1,4-benzoquinone, diaziquone, NSC 182986] in high-grade gliomas. Cancer Res 43:6102–6105, 1983
Bachur NR, Collins JM, Kelley JA, Van Echo DA, Kaplan RS, Whitacre M: Diaziquone, 2,5-diaziridinyl-3,6-biscarboethoxyamino-1,4-benzoquinone, plasma and cerebrospinal fluid kinetics. Clin Pharmacol Ther 31:650–655, 1982
Savaraj N, Lu K, Feun LG, Leavens ME, Stewart D, Burgess MA, Benjamin RS, Loo TL: Intracerebral penetration and tissue distribution of 2,5-diaziridinyl-3,6-bis(carboethoxyamino)-1,4-benzoquinone (AZQ, NSC 182986). J Neuro-Oncol 1:15–19, 1983
Poochikian GK, Cradock JC: 2,5-diaziridinyl-3,6-bis(carboethoxyamino)-1,4-benzoquinone I: kinetics in aqueous solutions by high-performance liquid chromatography. J Pharm Sci 70:159–162, 1981
Metzler CM: NONLIN: a computer program for parameter estimation in nonlinear situations. Technical Report 7292/69/7292/005. Upjohn Co., Kalamazoo, 1969
Dien K (Ed): Documenta Geigy Scientific Tablets. Geigy Pharmaceutical Co. Ltd., Manchester, 6th Ed. 1962, pp 314–315
Poochikian GK, Kelley JA: 2,5-diaziridinyl-3,6-bis(carboethoxyamino)-1,4-benzoquinone II: isolation and characterization of degradation products. J Pharm Sci 70:162–167, 1981
Tomlinson E, Malspeis L: Concomitant adsorption and stability of some anthracycline antibiotics. J Pharm Sci 71:1121–1125, 1982
Bosanquet AG: Stability of solutions of antineoplastic agents during preparation and storage for in vitro assays. 1. General considerations; the alkylating agents and nitrosoureas. Cancer Chemother Pharmacol (in press)
Bosanquet AG; Stability of solutions of melphalan during preparation and storage for in vitro chemosensitivity assays. J Pharm Sci (in press).
Eksborg S, Ehrsson H, Wallin I, Lindfors A: Quantitative determination of adriamycin and daunorubicin — handling of blood and plasma samples. Acta Pharm Suec 18:215–220, 1981
Hoffman DM, Grossano DD, Damin LA, Woodcock TM: Stability of refrigerated and frozen solutions of doxorubicin hydrochloride. Am J Hosp Pharm 36:1536–1538, 1979
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Bosanquet, A.G., McLoughlin, S.B. Stability of 2,5-diaziridinyl-3,6-bis(2-hydroxyethylamino)-1,4-benzoquinone (BZQ; NSC 224070) in aqueous solutions by high-performance liquid chromatography. Invest New Drugs 3, 43–50 (1985). https://doi.org/10.1007/BF00176823
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DOI: https://doi.org/10.1007/BF00176823