What are critical temperatures?

Every formulation has a critical temperature, below which it should be cooled for complete solidification and maintained below during primary drying in order to prevent processing defects. To design a freeze drying cycle on a rational basis such information should be identified (Pikal 1990, Frank 1990).

Tc - Collapse temperature, this is the temperature at which the material softens to the point of not being able to support its own structure.

Teu - Eutectic temperature, this is the temperature at which the solute material melts, preventing any structure forming after the solvent has been removed.

Tg’ - Glass transition, the temperature of the frozen material changes from a brittle to flexible structure.

Why identify critical temperatures?

Use of Lyostat2 (FDM) and Lyotherm2 (DTA and Impedance analysis) enables the development of safe and efficient freeze drying cycles for a wide range of formulations.

Benefits

Once analysis has been carried out a cycle can be developed that is:

•Cost efficient •Economic •Safe •Robust

And produces a product that has:

•A cosmetically acceptable cake •Good stability •Long shelf life •High activity rate •Low moisture •Rapid rehydration

BTL has used this scientific approach to analyse and develop efficient freeze drying cycles for hundreds of samples from small drug molecules to large complex bio-molecules for many companies worldwide .

How do you determine critical temperatures?

Freeze drying microscopy (FDM) can be used to identify temperatures at which visible changes occur, together with relative drying rates (Zhai et al 2003) BTL have developed Lyostat2 for this purpose.

Historically it was believed that Tg’ and Tc occur at the same temperatures, this is not always the case and can be missed even with sensitive methods. BTL has developed Lyotherm2 to measure Zsinφ — a function of electrical impedance (Martin et al 2007) and differential thermal analysis (DTA). This has enabled mobility increases to be identified below traditional critical temperatures.

Lyotherm2— differential thermal analyser (DTA) and impedance analyser (Zsinφ)

Lyotherm2 Allows detection of thermal events (Tg’) in the frozen material (figure 3) and enables characterisation of the freezing parameters essential for a successful freeze drying cycle.

Figure 2

Dried Dried MaterialMaterial

Frozen Frozen MaterialMaterial

Collapsed Collapsed MaterialMaterial

As a result of sublimation cooling the product temperature is below the shelf temperature for the

beginning of primary drying

Freeze dried with product temperature above Tc Shelf = -10.0oC Tc = -20.0oC Product = -15.0oC Result is a collapsed cake

Freeze dried with product temperature at Tc Shelf = -15.0oC Tc = -20.0oC Product = -20.0oC Result is a partially collapsed cake

Freeze dried with product temperature below Tc Shelf = -20.0oC Tc = -20.0oC Product = -25.0oC Result is an excellent cake

www.biopharma.co.uk

Winchester, United Kingdom, 2008

The Importance of Critical Temperatures in the Freeze Drying of

Pharmaceutical Products

Lyostat2

Allows observation of the sample structure during drying (figure 1), as the temperature is raised, the exact point of collapse (Tc/ Teu) can be determined (figure 2). Dried Dried

MaterialMaterial

Frozen Frozen MaterialMaterial

Movement of Movement of sublimation frontsublimation front

Figure 1

Sublimation Sublimation

Lyostat2

Lyotherm2

Acknowledgements Thomas Peacock, Isobel Cook, Sophie Koenig and Prof Louis Rey

References Franks, F. (1990) “Freeze drying: from empiricism to predictability” Cryo-letters, 11, 93-110 Martin, C., Ross, C., Peacock, T. and Ward, K. R. (2007). “Application of Electrical Impedance Analysis for Investigation of Nutraceutical Formulation Stability in the Frozen State”. SET for Britain presented at the House of Commons, London,

Monday 19th March 2007: E2-28. Poster presentation. Pikal, M. J. (1990) “The collapse temperature in freeze drying: Dependence on measurement methology and rate of water removal from

the glassy phase” International journal of Pharmaceutics, 62, 165-186. Zhai, S. et al, (2003) “Measurement of lyophilisation primary drying rates by freeze drying microscopy” Chemical Engineering Science

58, 2313 – 2323

Case study BTL was asked to reduce the freeze drying time for a product that currently had a cycle duration of 61 hours. The formulation was analysed - Lyostat2 identified a Tc range of –18.6oC to –17.4oC (see figures 1 and 2), while Lyotherm2 identified a softening event in the impedance at –25.0oC (see figure 3). A freeze drying cycle was carried out that was designed to maintain the product temperature below –30.0oC (allowing a 5.0oC safety margin below the lowest critical temperature identified). BTL was able to design a cycle that was 45 hours long therefore saving 16 hours of freeze drying compared to the original cycle.

Figure 3

The effects of freeze drying at different

temperatures

Clare Ross, Tony Gaster and Kevin Ward Biopharma Technology Limited

Lyostat2—freeze drying microscope

Shelf Temperature

Product Temperature

Chamber Pressure

The freeze drying cycle graph

Tc