Papers

Shelf-life prediction of intravenous busulfan by isothermal calorimetry

By Simon Gaisford, PhD, MRSC, Michael O’Neill, PhD, Lucy Thompson, BSc, MRPharmS,
and Kai-Loke Chan, BPharm, PGDip, MRPharmS

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Simon Gaisford is a lecturer in pharmaceutics and Michael O’Neill is a senior post-doctoral research fellow at the University of London School of Pharmacy.

Lucy Thompson is associate director of pharmacy, aseptic services, and Kai-Loke Chan is associate director of pharmacy, training and development, at King’s College Hospital, London.

Correspondence to Dr Gaisford at the Department of Pharmaceutics, School of Pharmacy, University of London, 29–39 Brunswick Square, London WC1N 1AX.

ABSTRACT

OBJECTIVE — To use isothermal calorimetry to measure the degradation of reconstituted busulfan at a number of elevated temperatures and to use these data to determine whether the shelf-life of the product could safely be increased from its current period of 15h.

METHODS — Busilvex (60mg busulfan in 10ml non-aqueous solvent) was diluted to 50ml or 100ml with 0.9 per cent w/v saline. Power/time data were recorded at 25C, 30C, 37C and 45C using isothermal calorimetry. Degradation rate constants were determined from the slopes of ln (power) versus time graphs and an Arrhenius plot was used to extrapolate the stability data to 6C (the storage temperature of the reconstituted solution).

RESULTS — Busulfan degradation was found to be first-order at all study temperatures and linear Arrhenius plots were obtained. Extrapolation of the data to 6C gave predicted rate constants of 3.9 x 10^–7s^–1 and 9.7 x 10^–7 s^–1 for dilution to 50ml and 100ml, respectively.

CONCLUSIONS — The percentages of drug remaining following storage in the current schedule were calculated to be 95.6 per cent and 91.1 per cent for dilution to 50ml and 100ml, respectively. Extending the period of storage at 6C to 24h would result in 94 per cent and 87.3 per cent of drug remaining for dilution to 50ml and 100ml, respectively. The data indicate that a 24h shelf-life would be inappropriate for the current schedule (dilution to 100ml) but would be appropriate if dilution to 50ml was adopted as a new reconstitution schedule.