Regina Moog

Time domain NMR as a new process monitoring method for characterization of pharmaceutical hydrates

&NA; Hydrates are of great pharmaceutical relevance and even though they have been characterized thoroughly by various analytical techniques, there is barely literature available on molecular mobility of the hydrate water studied by NMR relaxation in the time domain. The aim of this work was to examine the possibility of differentiating hydration states of drugs by 1H time domain NMR (TD‐NMR) regarding spin‐spin and spin‐lattice relaxation times (T2 and T1) using benchtop equipment. Caffeine and theophylline were selected as model compounds and binary mixtures of hydrate to anhydrate were analyzed for each drug using a spin echo and inversion recovery pulse sequence. It was possible to extract a signal that was specific for the water in the hydrates so that differentiation from anhydrous solid forms was enabled. Excellent calibrations were obtained for quantitative analysis of hydrate/anhydrate mixtures and predicted water contents were in good agreement with water amounts determined in desiccator sorption experiments. TD‐NMR was therefore found to be a suitable new technique to characterize pharmaceutical hydrates in a non‐invasive and hence sample‐sparing manner. Quantification of the hydrate content in pharmaceutical mixtures appears highly attractive for product development and process monitoring. TD‐NMR provides here a valuable and complementary technique to established process analytics, such as for example Raman spectroscopy. Highlights1H time domain NMR (TD‐NMR) provides valuable information on molecular water mobility in hydrates.Methods of spin echo and inversion recovery were suitable to quantify the model hydrates.TD‐NMR is a non‐destructive method with high potential for process analytics of hydrates. Graphical abstract Figure. No caption available.

Process and scaling parameters for wet media milling in early phase drug development: A knowledge based approach

Abstract Wet media milling is a well‐established unit operation for the manufacturing of suspension formulations during early phase pharmaceutical development. However, knowledge about the kinetics of particle breakage is limited, although the impact of hydro‐mechanical process parameters on the mean particle size of finished suspensions has been thoroughly investigated. We performed in this work milling trials with two different compounds on two milling devices with different mechanical design and volume scale. We analyzed our data in terms of a kinetic milling model where we included the milling speed as an explicit process parameter in addition to the process duration. We show, that the milling kinetics can be fairly well predicted for a wide range of these operating parameters. The proposed milling model may therefore be useful for rational process planning and scale‐up considerations in the industrial setting. Graphical Abstract Figure. No caption available.