Lyophilisation: difference between revisions
Diff·revision 25 → 26·13:46, 28 Dec 2024
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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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| 76 | 79 | ||
| 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}}} |
| + | 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}} | |
| 78 | 83 | ||
| 79 | === Collapse and eutectic melting === | 84 | === Collapse and eutectic melting === |