Lyophilisation: difference between revisions
Diff·revision 17 → 18·04:46, 8 Nov 2024
Difference between revision 17 and revision 18 of Lyophilisation. 15 lines changed; the page grew by 1,105 bytes.
| Revision 17 — 14:15, 3 Nov 2024 Chromatokid (talk) expand §Why lyophilised material tolerates ambient shipping 8,247 bytes ±0 | Revision 18 — 04:46, 8 Nov 2024 PharmDrafts (talk) copyedit 9,352 bytes +1,105 | ||
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| 39 | Sublimation is strongly endothermic. The enthalpy of sublimation of ice is approximately 2.83 MJ·kg⁻¹, about 13% greater than the enthalpy of vaporisation of liquid water, so the shelf must supply a large heat flux for a modest mass flow. That heat must cross a gas gap between shelf and vial base, and the efficiency of that transfer — conventionally expressed as a vial heat transfer coefficient — is itself a function of chamber pressure, because conduction through rarefied gas falls as pressure falls.{{r|rambhatla2003}} | 39 | Sublimation is strongly endothermic. The enthalpy of sublimation of ice is approximately 2.83 MJ·kg⁻¹, about 13% greater than the enthalpy of vaporisation of liquid water, so the shelf must supply a large heat flux for a modest mass flow. That heat must cross a gas gap between shelf and vial base, and the efficiency of that transfer — conventionally expressed as a vial heat transfer coefficient — is itself a function of chamber pressure, because conduction through rarefied gas falls as pressure falls.{{r|rambhatla2003}} |
| 40 | 40 | ||
| + | 41 | Two consequences follow and recur throughout the article. First, product temperature is not a set point but a result: it emerges from the balance between heat supplied and heat consumed by sublimation, and it is lower than the shelf temperature throughout primary drying. Second, anything that changes the resistance of the dried layer to vapour flow changes the product temperature, which is why the freezing step — which sets that resistance — governs the behaviour of the two steps that follow.{{r|searles2001}} | |
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| 41 | == Freezing == | 43 | == Freezing == |
| 42 | Cooling an aqueous solution below 0 °C does not immediately produce ice. Nucleation requires supercooling, and in clean pharmaceutical solutions supercooling of 10–20 °C below the equilibrium freezing point is routine. The temperature at which nucleation happens to occur determines the number and size of the ice crystals formed: nucleation close to 0 °C produces few, large crystals and a coarse, low-resistance dried structure, whereas deep supercooling produces many small crystals and a fine structure that impedes vapour escape.{{r|searles2001,kasper2011}} | 44 | Cooling an aqueous solution below 0 °C does not immediately produce ice. Nucleation requires supercooling, and in clean pharmaceutical solutions supercooling of 10–20 °C below the equilibrium freezing point is routine. The temperature at which nucleation happens to occur determines the number and size of the ice crystals formed: nucleation close to 0 °C produces few, large crystals and a coarse, low-resistance dried structure, whereas deep supercooling produces many small crystals and a fine structure that impedes vapour escape.{{r|searles2001,kasper2011}} |
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| 46 | As ice forms, solutes are excluded from the crystal lattice and concentrate in the remaining liquid. This freeze concentration continues until the residual phase either crystallises at a eutectic temperature or becomes so viscous that it vitrifies. The temperature at which the maximally freeze-concentrated amorphous phase undergoes its glass transition is written Tg′ and is a formulation property, not a process setting. | 48 | As ice forms, solutes are excluded from the crystal lattice and concentrate in the remaining liquid. This freeze concentration continues until the residual phase either crystallises at a eutectic temperature or becomes so viscous that it vitrifies. The temperature at which the maximally freeze-concentrated amorphous phase undergoes its glass transition is written Tg′ and is a formulation property, not a process setting. |
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| + | 50 | |+ Thermal behaviour of common lyophilisation solutes | |
| + | 51 | | !Solute | Critical temperature | Behaviour on freezing | | |
| + | 52 | |---|---|---| | |
| + | 53 | | Sucrose | Tg′ ≈ −32 °C | Amorphous | | |
| + | 54 | | Trehalose | Tg′ ≈ −29 °C | Amorphous | | |
| + | 55 | | Sorbitol | Tg′ ≈ −44 °C | Amorphous | | |
| + | 56 | | Glycerol | Tg′ ≈ −65 °C | Amorphous | | |
| + | 57 | | Dextran 40 | Tg′ ≈ −11 °C | Amorphous | | |
| + | 58 | | Povidone K30 | Tg′ ≈ −23 °C | Amorphous | | |
| + | 59 | | Mannitol | Eutectic ≈ −1.5 °C | Crystallises | | |
| + | 60 | | Glycine | Eutectic ≈ −3.6 °C | Crystallises | | |
| + | 61 | | Sodium chloride | Eutectic ≈ −21.1 °C | Crystallises | | |
| 47 | 62 | ||
| 48 | == References == | 63 | == References == |