What Are the Important Factors That Influence API Crystallization in Miscible Amorphous API-Excipient Mixtures during Long-Term Storage in the Glassy State?

In this Perspective, the authors examine the various factors that should be considered when attempting to use miscible amorphous API-excipient mixtures (amorphous solid dispersions and coamorphous systems) to prevent the solid-state crystallization of API molecules when isothermally stored for long periods of time (a year or more) in the glassy state. After presenting an overview of a variety of studies designed to obtain a better understanding of possible mechanisms by which amorphous API undergo physical instability and by which excipients generally appear to inhibit API crystallization from the amorphous state, we examined 78 studies that reported acceptable physical stability of such systems, stored below T-g under "dry" conditions for one year or more. These results were examined more closely in terms of two major contributing factors: the degree to which a reduction in diffusional molecular mobility and API-excipient molecular interactions operates to inhibit crystallization. These two parameters were chosen because the data are readily available in early development to help compare amorphous systems. Since T-g - T = 50 K is often used as a rule of thumb for the establishing the minimum value below T-g required to reduce diffusional mobility to a period of years, it was interesting to observe that 30 of the 78 studies still produced significant physical stability at values of T-g - T < 50 K (3-47 degrees C), suggesting that factors besides diffusive molecular mobility likely contribute. A closer look at the T-g - T < 50 systems shows that hydrogen bonding, proton transfer, disruption of API-API self-associations (such as dimers), and possible pi-pi stacking were reported for most of the systems. In contrast, five crystallized systems that were monitored for a year or more were also examined. These systems exhibited T-g - T values of 9-79, with three of them exhibiting T-g - T < 50. For these three samples, none displayed molecular interactions by infrared spectroscopy. A discussion on the impact of relative humidity on long-term crystallization in the glass was included, with attention paid to the relative water vapor sorption by various excipients and effects on diffusive mobility and molecular interactions between API and excipient.