Optimizing the lyophilization cycle and the consequences of collapse on the pharmaceutical acceptability of Erwinia L-asparaginase

Journal of Pharmaceutical Sciences
G D Adams, J R Ramsay

Abstract

The antileukemia enzyme, Erwinia L-asparaginase, occurs as a tetramer which can be dissociated by the stresses of lyophilization into four subunits (subunit M(r) 34 000 Da). Dissociation can be reduced by adding protectants to the formulation to stabilize the biopolymer, while the product should dry to form a pharmaceutically elegant, shelf-stable cake which is readily soluble. Using analytical ultracentrifugation, HPLC, and circular dichroism we have related structural dissociation of the enzyme during lyophilization to biological activity. Additives such as mannitol prevent ablation loss of vial contents and dry to form cosmetically elegant cakes but provide little biological protection, since during freezing they crystallize and are removed from the preparation. Excipients persisting throughout the cycle in the amorphous state provide improved biological protection, although high molecular weight compounds such as Dextran (M(r) 70000 Da) are most effective only during product freezing or storage. Low molecular weight sugars are protective throughout the cycle although formulations containing monosaccharides often exhibit low collapse temperatures (Tc) measured using a freeze-drying microscope or glass transition temperatures...Continue Reading

References

Dec 12, 1983·Biochimica Et Biophysica Acta·K HellmanK A Cammack
Jan 1, 1993·Journal of Chemical Technology and Biotechnology·G D Adams, L I Irons

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Citations

May 17, 2005·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Stéphanie PassotMichèle Marin
Sep 1, 2000·International Journal of Pharmaceutics·W Wang
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May 8, 2015·Chemical & Pharmaceutical Bulletin·Kahori FujiiKatsuhide Terada

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