Analysis of Thermal Properties

The thermal properties of a formulation to be used for freeze-drying may be determined by a number of analytical methods. Several common methodologies are reviewed here but this list is not exhaustive.

20.4.1.1 Differential scanning calorimetry

Differential scanning calorimetry (DSC) is a powerful method for the detection of eutectic points and some glass transition temperatures. Although the quantity of sample that can be tested is small (typically less than 100 |il), and hence the thermal event signal from an aqueous solution will be much weaker than for a dry lyophilized powder, improvements on the basic technology have been suggested to allow greater sensitivity and resolution. These include modulated temperature DSC, where the weak transitions can be resolved from the stronger relaxation events which may otherwise obscure them (Kett 2001, Kett et al. 2004), and rapid heating rates as used in Hyper™ DSC (Pijpers et al. 2002) and T zero™ technology (Danley 2003).

Samples are typically frozen rapidly to below the temperature at which lyophilization is proposed (e.g. —50 °C) and then warmed at a controlled rate back to ambient conditions, using either a single oven, containing reference and sample pans, or in matched thermal ovens. The reference pan is empty and the heat required to match the temperature of the sample and reference pans is used to derive the heat flow profile of the sample. The eutectic point, glass transition point and melting point of the sample may be identified, if present.

DSC on frozen liquid samples is perhaps most informative where a clear transition or eutectic crystallization is discernible. Where no such event occurs the technique may be unrevealing (see Figure 20.3). However, for the determination of glass transition temperatures for the lyophilized product, DSC is unrivalled in its applicability. Such analyses have been shown to be of value in predicting the shelf stability of lyophilized formulation variants, hence indicating superior

Determinate Growth Curves

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Temperature (°C)

Universal V3.5B TA Instruments

Figure 20.3 DSC profile showing materials with (a) no obvious thermal event; (b) a sodium chloride eutec-tic (—21 °C) with possibly additional Tg at shoulder of the peak; (c) glass transition (—29 °C). Samples (80 |l) run in steel pans against empty reference pan at 1.5 °C/min ramping temperature with heat-only modulation on TA 2920 DSC (TA Instruments, Crawley, UK).

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Temperature (°C)

Universal V3.5B TA Instruments

Figure 20.3 DSC profile showing materials with (a) no obvious thermal event; (b) a sodium chloride eutec-tic (—21 °C) with possibly additional Tg at shoulder of the peak; (c) glass transition (—29 °C). Samples (80 |l) run in steel pans against empty reference pan at 1.5 °C/min ramping temperature with heat-only modulation on TA 2920 DSC (TA Instruments, Crawley, UK).

formulations for maximizing shelf life and providing convenient storage/shippage conditions (Duddu et al. 1997).

20.4.1.2 Electrical resistance

The electrical resistance properties of an aqueous sample change markedly on warming from the deeply frozen state (Rey 1961). The large change in electrical resistance that occurs on mobilization of water within the frozen matrix, although well below the melting temperature, can be illustrative of a suitable product temperature below which primary drying must proceed if collapse is to be avoided (Figure 20.4). In our experience this technique has wider applicability than DSC but critical temperatures will still be influenced heavily by the ionic components of the formulation.

20.4.1.3 Differential thermal analysis

Differential thermal analysis (DTA) compares the thermal properties of a sample to that of a reference material frozen and warmed in parallel with it. These techniques have long been used in the analysis of materials for freeze drying (Jennings 1999; Chang et al. 1996 a, b) and are sometimes performed with home-made systems, although commercial equipment is also available. The heat energy differences between sample and reference material are compared during warming from frozen, and again marked changes can be indicative of the maximum successful product primary drying temperature. For an example of a DTA profile, see Figure 20.4. Although simpler than DSC, electrical resistance, and DTA methods can provide useful data from a wide variety of samples.

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