Bridging in vitro dissolution and in vivo exposure for acalabrutinib. Part I. Mechanistic modelling of drug product dissolution to derive a P-PSD for PBPK model input.

Drug product dissolution for four batches of acalabrutinib 100 mg capsules were analyzed with in vitro dissolution in various pH conditions and in media containing synthetic surfactant micelles or biorelevant micelles. Non-sink conditions, where the drug is unionized, were used to derive a batch specific drug product particle size distribution (P-PSD). The purpose of this P-PSD is to serve as an input in physiological based pharmacokinetic (PBPK) models to calculate in vivo dissolution in various administration conditions.

Coupling and optimisation of online nuclear magnetic resonance spectroscopy and mass spectrometry for process monitoring to cover the broad range of process concentration.

Real time online monitoring of chemical processes can be carried out by a number of analytical techniques, including optical and vibrational spectroscopies, nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS). As each technique has unique advantages and challenges, combinations are an attractive option. The combination of a 500-MHz H NMR and a small footprint mass spectrometer to monitor a batch reaction at process concentration was investigated.