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

Abstract

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.

New Bench-Scale Method To Elucidate Active Pharmaceutical Ingredient Drying Mechanisms

“…Drying is an important unit operation in the pharmaceutical industry and because of the complex nature of the compounds under development, the variety of drying behaviors encountered, and the specific critical attributes targeted, researchers in the field have developed many different tools to study the aspects of interest. − For drying kinetics, these include experimental methods ranging from small scale dynamic vapor sorption chambers and flow cells to larger scale pilot plant agitated dryers and, in some cases, mechanistic models are provided. − Often, to minimize system disturbances and material requirements, in-line process analytical technology is used to supplement or in lieu of off-line testing of in process samples. Common examples include near infrared (NIR) or RAMAN probes, in contact with the solids, to determine the solvent content or physical form of the solids as well as mass spectroscopy to monitor components leaving in off gas streams. − The current work introduces another experimental tool for inclusion in the drying process development toolbox.…”

Monitoring Drug Substance Drying with Online GC

“…Data collected throughout the drying process can inform analysts if and when to apply external stimuli, such as heat or agitation, to promote drying without compromising CQAs. Thermogravimetric analysis, , dynamic vapor sorption, and integrated sorption chambers are all techniques capable of collecting data throughout the drying process. A limitation to these mass-based techniques is their inability to distinguish the drying behavior between different solvents, as only an aggregate drying curve is reported.…”