Lyophilisation: difference between revisions
Diff·revision 14 → 15·13:47, 9 Feb 2025
Difference between revision 14 and revision 15 of Lyophilisation. 4 lines changed; the page grew by 766 bytes.
| Revision 14 — 17:15, 23 Jan 2025 SurmountSurma (talk) correct the freezer temperature range given for long-term storage 16,876 bytes +1,442 | Revision 15 — 13:47, 9 Feb 2025 EmptyingElke (talk) convert the storage conditions to a table 17,642 bytes +766 | ||
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| 89 | Vials do not all behave alike. Those at the edge of a shelf receive additional radiant heat from chamber walls and door, sublime faster, and reach higher product temperatures; this edge-vial effect can amount to several degrees and is the usual reason a cycle validated on a laboratory dryer fails at production scale.{{r|rambhatla2003}} | 89 | Vials do not all behave alike. Those at the edge of a shelf receive additional radiant heat from chamber walls and door, sublime faster, and reach higher product temperatures; this edge-vial effect can amount to several degrees and is the usual reason a cycle validated on a laboratory dryer fails at production scale.{{r|rambhatla2003}} |
| 90 | 90 | ||
| + | 91 | {{note|Product temperature during primary drying is below shelf temperature, sometimes by 20 °C or more. Shelf temperature is not a proxy for product temperature, and a cycle described only by its shelf settings cannot be evaluated.}} | |
| + | 92 | ||
| 91 | === Collapse and eutectic melting === | 93 | === Collapse and eutectic melting === |
| 92 | Two distinct structural failures bound primary drying. In a system whose freeze-concentrate crystallises, exceeding the eutectic melting temperature produces liquid, and the vial dries as a shrunken residue or a glassy shell — usually described on inspection as melt-back. In an amorphous system, exceeding a temperature a few degrees above Tg′ allows viscous flow of the freeze-concentrated matrix into the pores that the sublimed ice has vacated. The dried layer loses its structure, and the result is a shrunken, sometimes glassy or foamed cake. The temperature at which this becomes observable by freeze-drying microscopy is the collapse temperature, Tc, conventionally 1–3 °C above Tg′ for small-molecule and peptide systems.{{r|tang2004}} | 94 | Two distinct structural failures bound primary drying. In a system whose freeze-concentrate crystallises, exceeding the eutectic melting temperature produces liquid, and the vial dries as a shrunken residue or a glassy shell — usually described on inspection as melt-back. In an amorphous system, exceeding a temperature a few degrees above Tg′ allows viscous flow of the freeze-concentrated matrix into the pores that the sublimed ice has vacated. The dried layer loses its structure, and the result is a shrunken, sometimes glassy or foamed cake. The temperature at which this becomes observable by freeze-drying microscopy is the collapse temperature, Tc, conventionally 1–3 °C above Tg′ for small-molecule and peptide systems.{{r|tang2004}} |
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| 107 | 109 | ||
| 108 | The heating ramp matters because the glass transition temperature of the partially dried solid rises as water leaves it. Early in secondary drying the solid is plasticised by residual water and its glass transition may be only slightly above the product temperature; heating too quickly can carry the product above the moving glass transition and cause the same collapse phenomenon seen in primary drying, at a much higher temperature. Conventional practice ramps shelf temperature at 0.1–0.5 °C per minute for this reason.{{r|tang2004}} | 110 | The heating ramp matters because the glass transition temperature of the partially dried solid rises as water leaves it. Early in secondary drying the solid is plasticised by residual water and its glass transition may be only slightly above the product temperature; heating too quickly can carry the product above the moving glass transition and cause the same collapse phenomenon seen in primary drying, at a much higher temperature. Conventional practice ramps shelf temperature at 0.1–0.5 °C per minute for this reason.{{r|tang2004}} |
| + | 111 | ||
| + | 112 | Residual moisture specifications for lyophilised peptides commonly sit below 3% w/w, and frequently below 1% for products intended for long ambient storage. Lower is not always better. For some proteins a monolayer of water appears to be required for conformational stability, and over-dried preparations have shown reduced stability relative to preparations dried to an intermediate moisture. The relationship between residual moisture and degradation rate is not monotonic and is formulation-specific.{{r|chang2009,wang2000}} | |
| 109 | 113 | ||
| 110 | == References == | 114 | == References == |