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.