Is There Polyamorphism in Amorphous Indomethacin? Investigating the Physicochemical Properties of Amorphous Indomethacin with Different Thermal History.

Abstract

Polyamorphism in organic molecules is a poorly understood and controversial phenomenon related to amorphous materials. Although very few studies, including our own, have demonstrated the existence of polyamorphism in drug molecules, this solid-state phenomenon is still very elusive and the investigation of its occurrence in other drugs is fundamental to understand its formation. Indomethacin (IND) has been recently discussed in the literature as a potential drug exhibiting polyamorphism. Its amorphous forms obtained by quench-cooling (QC) at different temperatures have shown distinct dissolution and physical stability properties. However, temperature can induce degradation which can potentially influence the physicochemical properties of the drugs. Here we have investigated what role degradation products may play in the physicochemical properties of amorphous IND obtained at different QC temperatures and explored the potential formation of polyamorphism in IND. Amorphous IND obtained by QC at 165-220 °C revealed similar molecular near order, suggesting lack of structural variation between the differently prepared amorphous forms. The glass transition temperature slightly decreased when the QC temperature increased. Both the onset of crystallization and relaxation time consistently increased (being more notorious at a QC temperature of 180 °C), suggesting that the amorphous IND obtained at higher QC temperatures presents lower molecular mobility and as a consequence higher physical stability. Thermogravimetric analysis revealed that IND degradation starts to occur right after its melting temperature (i.e., 165 °C), being more evident after 180 °C. Considering that a melting point depression was observed for all amorphous IND samples, especially for the ones obtained at higher temperatures (i.e., higher than 180 °C), we hypothesized that the formation of degradation products is the cause for the observed differences in the thermal and physical stability properties of the amorphous IND obtained at different QC temperatures. Moreover, real-time dissolution experiments of amorphous IND films, QC from different temperatures, demonstrated that the dissolution performance decreased gradually, but substantially, as the preparation temperature of the samples increased. Similar experiments where amorphous IND was QC from different temperatures in the absence of oxygen and where amorphous IND was spiked with highly thermally degraded amorphous IND at 2%, 5% and 10% w/w prepared by QC from 165 °C to room temperature, unequivocally demonstrated that the degradation products formed during exposure of IND to high temperatures substantially inhibit the dissolution of amorphous IND. This study demonstrates that the differences in the physicochemical properties of differently prepared amorphous forms of drugs are not necessarily a result of polyamorphism and that special attention should be paid to the potential formation of degradation products and their influence on amorphous drug performance.