An investigation into the thermal behaviour of a model drug mixture with amorphous trehalose.

The thermal and structural properties of amorphous trehalose mixed with a model drug, paracetamol, have been studied with a view to developing understanding of the thermal events undergone by such binary systems. A physical mixture of paracetamol and spray dried trehalose (1:9 weight ratio) was studied using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot stage microscopy (HSM), and variable temperature powder X-ray diffraction (VTPXRD). The presence of the drug resulted in a lower temperature recrystallization exotherm for the trehalose compared to the disaccharide alone. Evidence is presented for the trehalose recrystallization being triggered by the melting rather than simply the presence of the paracetamol particles. HSM studies indicated that the trehalose recrystallized around the drug on heating, with the recrystallization temperature again corresponding to the melting of the drug. VTPXRD indicated that the presence of the drug again lowered the recrystallization temperature of the trehalose, although the trehalose anhydrate diffraction peaks were discernible at a lower temperature for both the pure trehalose and the mixed systems than was observed for the DSC studies, suggesting that the association between recrystallization and drug melting was not apparent when using this approach. It is suggested that while the trehalose recrystallization process is not significantly influenced by the presence of the drug when studied over relatively long time periods such as those used for the VTPXRD studies, the process is triggered by the melting of the paracetamol when short experimental times and scanning conditions are used such as those relevant to DSC studies. These data have implications for the quality control of trehalose products using DSC, the characterisation of the physical structure of the binary systems and the prediction of the corresponding physical stability.

Thermal behaviour of diclofenac sodium: decomposition and melting characteristics.

The thermal behaviour and melting characteristics of diclofenac sodium were investigated using various instrumental techniques--differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier-transform infrared (FT-IR) spectroscopy and thin layer chromatography (TLC). DSC analysis of diclofenac sodium performed under dynamic flow of either synthetic air or helium or nitrogen did not produce any sharp endothermic peak characteristic of melting peak of a pure substance. Both the rate of scanning of the sample and the environmental atmospheric condition significantly affected the thermographic profile of diclofenac sodium. An exothermic peak prior to an endothermic peak corresponding to melting of the substance appeared when heated under dynamic flow of synthetic air suggesting oxidation (decomposition) of diclofenac sodium before reaching its melting point. In fact, at a scanning rate of 1 degree C/min only the exothermic peak appeared in the thermogram, suggesting complete decomposition prior to melting under the dynamic flow of synthetic air. DSC, FT-IR and TLC data obtained from samples heated under the dynamic flow of either helium or nitrogen revealed formation of a related compound, 1-(2,6-dichlorophenyl)-indolin-2-one, an indol-cyclic amide, as a result of an intramolecular cyclization reaction during the heating process. TGA data demonstrated a loss of 11.4-20.2% of the mass of diclofenac sodium when heated under various environmental conditions, and also supported the oxidative nature of degraded product(s) when the thermal process occurred slowly under a dynamic flow of synthetic air.

Paracetamol-propyphenazone interaction and formulation difficulties associated with eutectic formation in combination solid dosage forms.

Polymorphic behaviours of paracetamol and propyphenazone and interaction between these two compounds were investigated using differential scanning calorimetry (DSC), X-ray powder diffraction and Fourier transform-infrared (FT-IR)-spectroscopy. Binary mixtures containing various ratios of the compounds were prepared as physical and fused mixtures and analysed by DSC to study their thermal behaviours. Phase diagrams obtained from the melting endotherms of the binary mixtures demonstrated formation of an eutectic mixture at a paracetamol-propyphenazone combination of about 35:65 (w/w) with an eutectic temperature of 56 degrees C. The FT-IR spectroscopy revealed no chemical interaction due to eutectic formation, and a lower degree of crystallinity of the eutectic mixture than individual substances was observed by X-ray powder diffraction analysis. The DSC and X-ray powder diffraction data demonstrated a polymorphic change in propyphenazone as a result of melting of the compound. Tablets, containing both paracetamol and propyphenazone in a combination formulation and prepared using standard wet granulation technology, were found to have physical instability when packed in either polyvinylchloride// aluminium or polyvinylchloride/polyvinyldienechloride// aluminium blisters and stored for one month at 40 degrees C with either 75% relative humidity or without any humidity control. The instability of the tablets was more apparent under the high humidity condition.