Lyophilisation: difference between revisions
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| 11 | The process is used because peptides in aqueous solution degrade by hydrolytic routes — [[deamidation]] of asparagine and glutamine, backbone cleavage, [[Peptide aggregation|aggregation]] — whose rates depend strongly on molecular mobility and on the availability of water. Removing water and holding the residue in an amorphous glass suppresses those routes by orders of magnitude, converting a product with a shelf life of days at ambient temperature into one with a shelf life measured in years.{{r|wang2000,chang2009}} | 11 | The process is used because peptides in aqueous solution degrade by hydrolytic routes — [[deamidation]] of asparagine and glutamine, backbone cleavage, [[Peptide aggregation|aggregation]] — whose rates depend strongly on molecular mobility and on the availability of water. Removing water and holding the residue in an amorphous glass suppresses those routes by orders of magnitude, converting a product with a shelf life of days at ambient temperature into one with a shelf life measured in years.{{r|wang2000,chang2009}} |
| 12 | 12 | ||
| + | 13 | A lyophilisation cycle has three phases: freezing, primary drying in which ice is sublimed, and secondary drying in which water sorbed to the solid is desorbed. Each phase is bounded by a physical constraint. Freezing determines the ice-crystal structure and therefore the resistance the vapour must overcome later; primary drying must be conducted below the temperature at which the freeze-concentrated matrix loses rigidity; secondary drying must reach a residual moisture low enough for stability without over-drying a solid that may require a small amount of water for conformational integrity.{{r|tang2004,carpenter1997}} | |
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| 13 | == Physical basis == | 15 | == Physical basis == |
| 14 | Water can pass directly from solid to vapour only at pressures below its triple point, which lies at 611.657 Pa and 0.01 °C. Above that pressure, warming ice produces liquid; below it, warming ice produces vapour. Every lyophilisation cycle therefore operates at a chamber pressure well beneath 611 Pa, typically between 5 and 20 Pa, so that heat supplied to the product drives sublimation rather than melting.{{r|nail2002}} | 16 | Water can pass directly from solid to vapour only at pressures below its triple point, which lies at 611.657 Pa and 0.01 °C. Above that pressure, warming ice produces liquid; below it, warming ice produces vapour. Every lyophilisation cycle therefore operates at a chamber pressure well beneath 611 Pa, typically between 5 and 20 Pa, so that heat supplied to the product drives sublimation rather than melting.{{r|nail2002}} |
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| 30 | <ref name="nail2002">Nail SL, Jiang S, Chongprasert S, Knopp SA. "Fundamentals of freeze-drying." ''Pharmaceutical Biotechnology'' 14:281–360 (2002).</ref> | 32 | <ref name="nail2002">Nail SL, Jiang S, Chongprasert S, Knopp SA. "Fundamentals of freeze-drying." ''Pharmaceutical Biotechnology'' 14:281–360 (2002).</ref> |
| 31 | <ref name="wang2000">Wang W. "Lyophilization and development of solid protein pharmaceuticals." ''International Journal of Pharmaceutics'' 203(1–2):1–60 (2000).</ref> | 33 | <ref name="wang2000">Wang W. "Lyophilization and development of solid protein pharmaceuticals." ''International Journal of Pharmaceutics'' 203(1–2):1–60 (2000).</ref> |
| + | 34 | <ref name="tang2004">Tang X, Pikal MJ. "Design of freeze-drying processes for pharmaceuticals: practical advice." ''Pharmaceutical Research'' 21(2):191–200 (2004).</ref> | |
| + | 35 | <ref name="carpenter1997">Carpenter JF, Pikal MJ, Chang BS, Randolph TW. "Rational design of stable lyophilized protein formulations: some practical advice." ''Pharmaceutical Research'' 14(8):969–975 (1997).</ref> | |
| 32 | <ref name="chang2009">Chang LL, Pikal MJ. "Mechanisms of protein stabilization in the solid state." ''Journal of Pharmaceutical Sciences'' 98(9):2886–2908 (2009).</ref> | 36 | <ref name="chang2009">Chang LL, Pikal MJ. "Mechanisms of protein stabilization in the solid state." ''Journal of Pharmaceutical Sciences'' 98(9):2886–2908 (2009).</ref> |
| 33 | 37 |