Lyotherm determines endothermic and exothermic events within a freeze drying formulation, to understand its behavior during and after the freeze drying process.

1. An Introduction to Lyotherm2

10. What is Lyotherm2 ? Lyotherm2 provides an integrated Differential Thermal Analyser (DTA) and an Electrical Impedance (Zsinφ) capability in one instrument.

13. System Components Aluminium heating block minimises variation between samples Liquid N 2 Dewar for rapid cooling Lyotherm2 Control Box Impedance probe (ZSin φ ) DTA Probes (Sample and Reference)

15. Assay Procedure (2) 5. Run Lyotherm2 software to start data recording 6. Lower heating block into Dewar half filled with LN2 7. When sample and reference are within 1°C of each other and below -150°C, switch on heating.

16. Data Recording Graphical plots of both the Zsin  and DTA values are available tracking the raw data. Near-linear cooling rates are provided by the thermally distributing design of the sample holding block.

17. Data Analysis Real-time updates of both Zsin  and DTA data indicates results before the analysis run is complete

18. Data Analysis Events of interest in the analysis profiles can be examined from the data by simply highlighting potential areas of interest using the zoom function.

22. Initial Warming The blue line represents the initial warming of the solution. An exotherm is observed at -25°C which is characteristic of a re-organisation within the frozen material. This is likely to be a result of the crystallisation of amorphous phase mannitol. The presence of amorphous mannitol can cause a weakness in the frozen structure and defects in your product during freeze-drying

23. Heat Annealing Freeze-drying microscopy image of a 4% mannitol solution showing product weakness that occurs due to amorphous phase mannitol present To avoid this collapse we can apply an annealing step to encourage the amorphous mannitol to crystallise before drying As the temperature increases the structure shows evidence of collapse As the amorphous phase mannitol crystallises the sample regains structure Dried amorphous phase mannitol Frozen mannitol

24. Second Warming The red line represents the second warming of the solution. This time no exotherm is observed The annealing step encourages the mannitol to crystallise, so when the sample is cooled and re-warmed there is no amorphous mannitol remaining to cause the exotherm.

25. Problem Solved Intelligently ‘ Trial and Error’ Cycle resulting in loss of product ‘ Determination of critical temperatures and / or annealing step requirement New cycle based on actual parameters Lyotherm2 provides essential information about the critical temperatures of your cycle, enabling you to achieve target product formulation profile

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