Lyophilisation: difference between revisions
Diff·revision 11 → 12·04:03, 28 Dec 2024
Difference between revision 11 and revision 12 of Lyophilisation. 7 lines changed; the page grew by 1,164 bytes.
| Revision 11 — 23:01, 12 Dec 2024 DiagramDelphine (talk) copyedit 12,330 bytes +1,563 | Revision 12 — 04:03, 28 Dec 2024 SupplyWatchSuri (talk) add the collapse-temperature point, sourced 13,494 bytes +1,164 | ||
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| 1 | {{Infobox method | 1 | {{Infobox method |
| 2 | | name = Lyophilisation | 2 | | name = Lyophilisation |
| + | 3 | | subtitle = Freeze-drying | |
| 3 | | image = vial.svg | 4 | | image = vial.svg |
| 4 | | caption = A lyophilised cake occupies approximately the volume of the original fill. Cake structure is a recorded quality attribute. | 5 | | caption = A lyophilised cake occupies approximately the volume of the original fill. Cake structure is a recorded quality attribute. |
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| 66 | Figures are collated from the freeze-drying literature and vary with concentration and with the measurement method.{{r|nail2002,tang2004}} The presence of sodium chloride is significant for peptide formulations because its low eutectic temperature drags the critical temperature of the whole system downward, forcing a colder and therefore longer primary drying step. A formulation carrying appreciable [[Trifluoroacetate counterion|trifluoroacetate]] or phosphate salt from purification behaves similarly. | 67 | Figures are collated from the freeze-drying literature and vary with concentration and with the measurement method.{{r|nail2002,tang2004}} The presence of sodium chloride is significant for peptide formulations because its low eutectic temperature drags the critical temperature of the whole system downward, forcing a colder and therefore longer primary drying step. A formulation carrying appreciable [[Trifluoroacetate counterion|trifluoroacetate]] or phosphate salt from purification behaves similarly. |
| 67 | 68 | ||
| + | 69 | Annealing — holding the frozen product for a period above Tg′ but below the melting point — allows small ice crystals to grow at the expense of smaller ones and permits crystallising excipients such as mannitol to complete crystallisation before drying begins. Its benefit is a more uniform and less resistant dried structure; its cost is cycle time and, for some proteins, additional exposure to the ice-water interface.{{r|kasper2011}} | |
| + | 70 | ||
| 68 | == Primary drying == | 71 | == Primary drying == |
| 69 | Primary drying removes the ice, which for a typical aqueous fill is 90–98% of the water present. Its duration is set by the sublimation rate, which in the simplest treatment follows from an energy balance across the vial base: the mass flow equals the heat flow divided by the enthalpy of sublimation. | 72 | Primary drying removes the ice, which for a typical aqueous fill is 90–98% of the water present. Its duration is set by the sublimation rate, which in the simplest treatment follows from an energy balance across the vial base: the mass flow equals the heat flow divided by the enthalpy of sublimation. |
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| 77 | {{math|dm/dt = 0.126 W ÷ 2.83 × 10^{6} J kg^{-1} = 4.4 × 10^{-8} kg s^{-1} ≈ 0.16 g h^{-1}}} | 80 | {{math|dm/dt = 0.126 W ÷ 2.83 × 10^{6} J kg^{-1} = 4.4 × 10^{-8} kg s^{-1} ≈ 0.16 g h^{-1}}} |
| 78 | 81 | ||
| + | 82 | A 2.0 mL fill therefore requires approximately 12.5 hours of primary drying under these conditions, before any safety margin is added. Doubling the shelf-to-product temperature difference halves that figure, which is why the choice of critical temperature — and how close the cycle is permitted to approach it — dominates cycle economics.{{r|tang2004,rambhatla2003}} | |
| + | 83 | ||
| 79 | === Collapse and eutectic melting === | 84 | === Collapse and eutectic melting === |
| 80 | 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}} | 85 | 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}} |
| 81 | 86 | ||
| 82 | Collapse is not necessarily a chemical failure. A collapsed cake may reconstitute and may assay within specification. Its documented consequences are elevated residual moisture, because the collapsed structure traps water; slower and sometimes incomplete reconstitution; and a cake appearance that fails a visual specification. For proteins, collapse has been associated with reduced storage stability, attributed to increased molecular mobility in the denser matrix.{{r|wang2000}} | 87 | Collapse is not necessarily a chemical failure. A collapsed cake may reconstitute and may assay within specification. Its documented consequences are elevated residual moisture, because the collapsed structure traps water; slower and sometimes incomplete reconstitution; and a cake appearance that fails a visual specification. For proteins, collapse has been associated with reduced storage stability, attributed to increased molecular mobility in the denser matrix.{{r|wang2000}} |
| + | 88 | ||
| + | 89 | Conservative practice therefore sets the target product temperature 2–5 °C below Tc and accepts the longer cycle. Aggressive cycles that run within a degree of Tc exist and are defensible when the critical temperature has been measured for the specific formulation rather than assumed from a table.{{r|tang2004}} | |
| 83 | 90 | ||
| 84 | == References == | 91 | == References == |