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Figure 3.3 Example o f a typical DSC glass transition calculation

3.5.4 Microcalorimetric study of physical mixes of amorphous salbutamol sulphate and different types of lactose

Increasing amounts (20, 40 and 80 mg) of: a-lactose monohydrate (DMV, The Netherlands); Zeparox® [partially amorphous (~ 15 %) a-lactose monohydrate]; or 100 % amorphous spray dried lactose; were added to 20 mg samples of amorphous salbutamol sulphate in a 3 mL glass vial and microcalorimetric determinations were carried out at 85 %RH. Similar experiments were carried out using lactoseisalbutamol sulphate (3:1) mixes which had been tumbled at 42 rpm for 40 min in a Turbula* mixer (Bachofen AG, Switzerland).

Chapter 3_________________________________________________Investigation ofpf^ ical stability

3.6 Results and discussion

The spray drying parameters used were derived from a series of experiments outlined in chapter 2. All spray dried and micronised salbutamol sulphate samples used had a mass median diameter less than 5 pm as determined by laser diffraction analysis. Micronised salbutamol sulphate (Batch X) had a MMD of 4.4 pm. The MMD o f the spray dried salbutamol sulphate ranged from 3.1 to 3.7 pm. The median size was dependent on the temperature of the initial feed solution and the location of the yield (chapter 2).

3,6,1 D ifferential scanning calorimetry profile

Typical DSC profiles for micronised and original salbutamol sulphate material are shown in figures 3.4 and for spray dried salbutamol sulphate in figure 3.5. At the start of any run an artefactual small exothermic or endothermie drift occurred, thought to be related to the non-identical heat input to the sample pans due to differences in heat capacity, thermal conductivity and sample size. This was to some extent minimised by holding at the starting temperature for 1 min but, having disregarded the existence of a peak in this region, only the areas of interest post artefact are presented in the traces.

The DSC run rate of 10 ®C/min gave greater peak resolution than the 20 °C/min rate previously used for salbutamol sulphate (Chawla, 1993). The traces were reproducible, though greater reproducibility was shown by the original and micronised material than with the spray dried material. Slow scanning speeds (e.g., 2 °C/min) allow greater equilibration of the sample and thus resolution of non-reversing changes such as melting and decomposition. Faster scanning speeds can uncover new signals relating to solid state transformations, such as the glass transition temperature (Tg ), but unfortunately, faster speeds can also shift the position of transition temperatures. Solid state phase changes, such as those occurring at the Tg, are not seen at the slower speeds which tend to show melt mediated transformations (Ford and Timmins, 1989). In this study, running the samples at 2°C/min drastically changed the position and nature o f established peaks and so all the traces presented are 10 °C/min DSC runs. Care is taken when analysing samples which have low thermal conductivity since temperature gradients may occur in

Chapter 3_________________________________________________Investigation o f physical stability

temperature indicated by the platinum thermocouple is not necessarily the average temperature of the sample.

The original material exhibited two major endotherms as did the micronised material (Table 3.4). It was assumed that the endotherm seen around 207-210 °C © corresponded to the fusion of salbutamol sulphate (Figures 3.4 and 3.5). Most organic materials do not melt isothermally and thus the peak is often broad. As samples become increasingly impure due to decomposition (drying at elevated temperatures, e.g., 150 °C for 48 h) the shape of the melting peak changes. A second endothermie peak thought to be related to degradation of the salbutamol sulphate occurred between 286-295 ®C (D). Only this peak (D) was seen when running the dark brown material recovered after vacuum drying at

temperatures > 100°C (Figure 3.6).

Melt mediated degradation of salbutamol sulphate has been reported around 200 °C by Ward and Schultz (1995) but the present study has shown a separate primary peak for this drug which was assumed to relate only to a melting endotherm. Prior to this no exothermic events were noted for the micronised drug which indicated that if amorphous surface material was present in the micronised sample, it was in very small amounts and thus its crystallisation signal would be below the sensitivity of detection of the DSC. On the other hand, it may be that prior to receiving the micronised batch it had been subjected to adverse environmental conditions or “thermal history” which would have induced an amorphous to crystalline conversion.

On analysis of the spray dried material (Figure 3.5), the integrated exothermic signal corresponding to crystallisation (A) was poorly reproducible but was generally in the range 20-40 J/g (with a few exceptions, table 3.4). Prior to melting © a series of sharp discrete endotherms are seen in the 100-150 °C area (B), thought to indicate the release of adsorbed or absorbed water. The sample pans were crimped to avoid problems with thermal emissivity, sublimation and sample shape changes. This seal was not hermetic, however, and a certain degree of water vapour loss could have occurred resulting in weight loss and a constantly changing baseline.

Chapter 3 Investigation o f physical stability