Measurement, Prediction, and Control of the Physical Stability of a Hygroscopic API

The selection of hygroscopic crystalline forms is sometimes necessary to enable the clinical development of API. In this work the drug substance isolated from the manufacturing process is isolated as an anhydrous crystalline form which readily converts to a hydrate under environments of moderate relative humidity. Form control during storage and drug product manufacture was necessary to ensure process robustness. This presentation will focus upon experimental and modeling studies to enable definition of a control strategy which preserves the anhydrous form of the API. This strategy was applied to packaging and storage of the drug substance as well as processing and sampling of the drug product.

The talk will discuss a experimental set up designed to measure the dynamic hydration under different relative humidity environments by automatically recording the relative humidity, temperature, and sample mass. Different geometries were used to examine the impact of cake length on hydration rate.

Finally, a model incorporating solid state reaction kinetics and powder vapor diffusion was developed from the experimental data. The model allowed for a quantitative assessment of the risk and impact of hydration under different manufacturing and storage environments.