Mechanistic Elucidation of Hard Agglomerate Formation from Drying Kinetics in the Integrated Sorption Chamber

The formation of hard agglomerates during drying has impacts on the product quality, particle size distribution, and downstream formulation. Hence, understanding the cause of hard agglomerates and determining a remedy for them or preventing their formation are necessary. The integrated sorption chamber (ISC) has been successfully applied to the study of hard agglomerate formation. The design and development of this ISC are briefly described. The vapor-phase profile of a binary mixture of acetone and water without active pharmaceutical ingredient (API) was predicted using an analytical solution of a batch distillation and verified via mass spectrometry (MS). The drying of the API wet cake, which is very soluble in water, using a starting point of 5 wt % water in acetone was conducted in the ISC. A significant delay in water removal was observed from both the weight measurement and the MS signal. The slow removal of water was attributed to diffusion of water from a thin crust layer induced by the solution of the API in water and drying, resulting in the formation of hard agglomerates at the end of drying. A wet-cake solvent composition change following a cake wash with acetone reduced the initial water content from 5.5 to 0.5 wt %. This altered wet-cake solvent composition changed the behavior of water removal, leading to a significant reduction of the diffusion time. The dried API contained soft lumps without hard agglomerates.