Lyophilisation: difference between revisions
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| 5 | | Physical requirement = Pressure below the triple point of water | 5 | | Physical requirement = Pressure below the triple point of water |
| 6 | | Typical cycle length = 20–70 hours | 6 | | Typical cycle length = 20–70 hours |
| + | 7 | <!-- Representative process conditions --> | |
| + | 8 | | Freezing shelf temperature = −40 to −50 °C | |
| + | 9 | | Chamber pressure, primary drying = 5–20 Pa (roughly 40–150 mTorr) | |
| + | 10 | | Product temperature, primary drying = −40 to −20 °C | |
| + | 11 | | Shelf temperature, secondary drying = 20–40 °C | |
| 7 | }} | 12 | }} |
| 8 | 13 | ||
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| 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}} | 18 | 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}} |
| 14 | 19 | ||
| + | 20 | The finished cake is characterised by appearance, residual moisture, reconstitution time and the chemical purity of the reconstituted solution. None of these is visible from a purity figure alone, which is one reason a [[certificate of analysis]] that reports only [[Area percent purity|area percent purity]] leaves the physical quality of the vial undocumented.{{r|usp1207}} | |
| + | 21 | ||
| 15 | == Physical basis == | 22 | == Physical basis == |
| 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}} | 23 | 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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| 32 | 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}} |
| 33 | 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}} | |
| + | 42 | ||
| 34 | == Freezing == | 43 | == Freezing == |
| 35 | 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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| 39 | 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. |
| 40 | 49 | ||
| + | 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 | | |
| + | 62 | ||
| 41 | == References == | 63 | == References == |
| 42 | {{reflist}} | 64 | {{reflist}} |
| ⋮ | ⋮ | ||
| 50 | <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> | 72 | <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> |
| 51 | <ref name="murphy2005">Murphy DM, Koop T. "Review of the vapour pressures of ice and supercooled water for atmospheric applications." ''Quarterly Journal of the Royal Meteorological Society'' 131(608):1539–1565 (2005).</ref> | 73 | <ref name="murphy2005">Murphy DM, Koop T. "Review of the vapour pressures of ice and supercooled water for atmospheric applications." ''Quarterly Journal of the Royal Meteorological Society'' 131(608):1539–1565 (2005).</ref> |
| + | 74 | <ref name="usp1207">United States Pharmacopeia, General Chapter <1207>, "Package Integrity Evaluation — Sterile Products". USP–NF, current revision.</ref> | |
| 52 | 75 | ||
| 53 | {{DEFAULTSORT:Lyophilisation}} | 76 | {{DEFAULTSORT:Lyophilisation}} |