MTDSC

Craig et al. [1.176] assessed the behavior of amorphous lactose by MTDSC. The relaxation time of 10% freeze-dried amorphous lactose as a function of the difference between annealing (storage) temperature and is given in Figure 1.48.4 The relaxation time 15 K below is 10 h and 35 K below it is -250 h. The authors dis-... 

Van Winden et al. [1.161] used MTDSC in lyoprotected liposomes to detect the glass transition in samples in which it overlaps with the bilayer melting endotherm. 

Kett et al. [1.162] studied Tg in freeze-dried formulations containing sucrose as a function of relative humidity and temperature during storage by TMDSC and ther-mogravimetric analysis. Craig et al. [1.163] found it helpful to asses the relaxation behavior of freeze-dried amorphous lactose by MTDSC. Relaxation times were calculated from measurements of Tg, and the magnitude of the relaxation endotherm. Scannnig was performed at 2°C/min with a modulation amplitude of 0.3 °C and a period of 60 s. 

More complex temperature programmes are sometimes useful. These might combine periods of variable heating and cooling rates with isothermal periods. For example, stepwise heating can be used to detect the onset of melting under quasi-isothermal conditions (Laye, 2002). Modulated temperature DSC (MTDSC), in which the linear temperature scan is perturbed by a sinusoidal, square or saw-tooth wave, or other modulation of temperature, has a number of potential advantages over the conventional linear scan. These include increased sensitivity and resolution, and the ability to separate multiple thermal events (Laye, 2002). 

The evolution in calorimetry technology has also led to the development of protocols for quantitative analysis (Buckton and Darcy 1999). Fiebich and Mutz (1999) determined the amorphous content of desferal using both isothermal microcalorimetry and water vapour sorption gravimetry with a level of detection of less than 1 per cent amorphous material. The heat capacity jump associated with the glass transition of amorphous materials MTDSC was used to quantify the amorphous content of a micronised drag substance with a limit of detection of 3 per cent w/w of amorphous... 

Bottom, R. The role of MTDSC in the characterisation of a drug molecule exhibiting polymorphic and glass forming tendencies. Int. J. Pharm. 1999,192 (1), 47-53. 

Manduva R, Keti VL. Banks SR. et al. Calorimetric and spatial characterisation of polymorphic transitions in caffeine using quasi-isothermal MTDSC and localised thermo-mechanical analysis. J Wiarm Sci 2007 97(2008) 1285-1300,... 

Heat Capacity = Heat Flow/Heating Rate or for MTDSC experiments... 

An additional calibration constant is required for accurate MTDSC experiments this is the heat capacity calibration. The heat capacity constant is calculated as the ratio of the theoretical heat capacity of a known standard to the measured heat capacity of the material. The heat capacity constant is sensitive to changes in the modulation conditions, especially the frequency of modulation. 

The chapter is arranged in three sections. First, we outline the principles of MTDSC, including a discussion of the practicalities of running MTDSC experiments. Second, we outline the typical thermal events and systems for which MTDSC is well suited, and finally we review some of the applications of MTDSC within the pharmaceutical sciences to date. 

MTDSC was introduced by Reading et al. (1-4) and is an extension of conventional DSC. In essence, the technique involves the application of a perturbation to the heating program of a conventional DSC (a sinusoidal wave in most cases, but sawtooth and square waves are also used) combined with a mathematical procedure designed to separate different types of sample behavior. The separation (also called deconvolution) procedure can most easily be understood in terms of a simple equation (5,6), that is,... 

The basis of the separation or deconvolution procedure can be illustrated by a few simple equations. When used with a sinusoidal perturbation, the temperature program for an MTDSC experiment is given by ... 

FIGURE 4.2 Flowchart representing the simple deconvolution procedure for TA Instruments MTDSC signals. (From Jiang, Z., Imrie, C.T., and Hutchinson, J.M., Thermochim. 

The simple deconvolution process outlined earlier is the typical methodology used for most MTDSC analysis. However, it is possible to further analyze the signals to take into account the phase lag. Before describing the more complex deconvolution the phase lag itself warrants further explanation. 

FIGURE 4.3 Flowchart representing the complete deconvolution procedure for TA Instruments MTDSC signals. 

Advantages and Disadvantages of MTDSC Compared to the Conventional Technique... 

As can be seen from the previous discussion, MTDSC offers the possibility of analyzing samples with varying degrees of sophistication. However, there are inevitably concomitant disadvantages associated with the technique, and hence it is useful to briefly summarize what we consider to be the main advantages and disadvantages of the method. 

Calibration is a potentially complex subject as there can be cell asymmetries in terms of heat capacity, thermal resistances, and other effects such as convection and emissivity. However, here we shall confine ourselves to a simple procedure that will be effective in most cases. We can consider that calibration of an MTDSC consists of three steps (1) heat flow calibration (by calculation of a cell constant), (2) baseline calibration, and (3) heat capacity calibration (10). 

For MTDSC, it is also essential to calibrate for the reversing heat capacity to allow quantification of the deconvoluted results. There are several approaches by which this may be achieved, with more accurate methods requiring greater sophistication and more time hence, a decision needs to be made with regard to how important accurate heat capacity data are to the objectives of the study. For most pharmaceutical applications, fairly simple calibration procedures such as those about to be outlined are usually sufficient. However, for more accurate work it is essential to use more detailed approaches such as that described in Reference 11. In this summary, we outline only the simple approaches, but readers should be aware of the availability of more complex methods that yield more reliable results. 

---