Loss on Drying Using Halogen Moisture Analyzer: An Orthogonal Technique for Monitoring Volatile Content for In-Process Control Samples during Pharmaceutical Manufacturing
Sayyeda Zeenat A. Razvi, Isabelle Kamm, Tina Nguyen, Jackson D. Pellett, Archana Kumar
Abstract
Organic solvents and water are routinely used during the synthetic pathway of an active pharmaceutical ingredient (API) and extraction work up, respectively. Residual amounts of solvents and water tend to be strictly controlled at each step of a process as carryover can often negatively affect crystallization or the reactivity of catalysts and/or activating agents. A rapid, accurate, and precise measurement of these attributes is an important part of this overall control strategy. Here, we have developed a loss on drying (LOD) method for measuring total volatile matter for in-process control liquid and solid samples during a small molecule API manufacturing process, which relies on a halogen moisture analyzer with an integrated mass balance. Mixtures of lactose and microcrystalline cellulose with varying water content were prepared and used for evaluating the precision of the LOD technique with varying sample sizes. We have successfully demonstrated here that not only are the moisture measurements using this LOD method comparable to the traditional methods like Karl Fischer (KF) titration and/or gas chromatography (GC) for volatile solvents but also the LOD measurement process is much faster and requires little to no sample preparation. Further, we present a case study of using LOD and KF together to obtain the ratio of water and DMA (a high boiling point solvent), enabling a more efficient manufacturing process as it obviates the need for specialized HPLC or GC methods needed for measuring high boiling solvents such as DMA.