Understanding the interactions between Terfenadine, Indomethacin and Fenofibrate in Co-Amorphous systems by comparing the experimental data with prediction models

Co-amorphous systems have emerged as an advanced strategy to enhance the apparent solubility of poorly soluble drugs. This strategy offers the benefit of addressing stability challenges that often hinder conventional amorphous formulations. Fenofibrate can be converted to the amorphous phase, but it is highly unstable. The manuscripts assess the antiplasticising effects of indomethacin and terfenadine when co-amorphous mixtures were created. Binary and ternary co-amorphous systems of terfenadine, indomethacin and fenofibrate were produced and analysed in situ using Differential Scanning Calorimetry. The glass transition temperatures of the binary and ternary systems were predicted using the Gordon-Taylor equation, and the deviation from the model was used to investigate the characteristics of co-amorphous systems. The strongest positive interaction with the highest T _g amongst the binary mixtures was observed in terfenadine-indomethacin systems at a 1:1 molar ratio (72.2°C) and therefore, presented a promising co-amorphous to incorporate fenofibrate. Ternary mixtures with a higher molar proportion of terfenadine and a lower molar proportion of fenofibrate exhibited positive deviations, which were attributed to the molecular interactions between terfenadine and indomethacin. However, ternary mixtures with a high molar proportion of fenofibrate demonstrated negative deviation, indicating non-ideal mixing behaviour. The Gordon-Taylor model underestimated the plasticising effect of amorphous fenofibrate when present in higher proportions, leading to lower actual glass transition temperatures. Consequently, the system exhibits greater molecular mobility than expected, resulting in lower physical stability of CAMs. This finding highlights the importance of experimental data that signifies the lack of the Gordon-Taylor model for predicting the plasticising influence of amorphous fenofibrate, leading to less stable CAMs.