Crystallization of paracetamol under oscillatory flow mixing conditions

There has been an increasing effort in designing pharmaceutical particles with controllable properties (quality) such as chemical purity, morphology, size distribution, surface characteristics, and microstrain content. In this paper, we explore the feasibility of oscillatory flow mixing (OFM) in improving the quality of pharmaceutical precipitates, using paracetamol (4-acetamidophenol) as a model system. In-situ atomic force microscopy (AFM) and optical microscopy were applied to observe the growth of {110} faces of single paracetamol crystals. These studies showed that (a) the bunching and macrostep formation occur at all values of supersaturation; and (b) the oscillation of solution with respect to the growing interface and its relative velocity are the critical parameters for the minimization of the interfacial instabilities, and in turn, for maintaining structural quality. These findings were tested in a conventional impeller driven batch crystallizer (IDBC) and in an oscillatory baffled batch crystallizer (OBBC), in which, apart from hydrodynamics, all external conditions such as initial supersaturation and crystallization temperature were kept constant. The physical properties (the quality) of the precipitates were characterized by low angle laser light scattering (LALLS), scanning electron microscopy (SEM), and X-ray powder diffraction (XRPD), respectively. The analysis of obtained results and their comparison for these two types of mixing shows clearly that particles precipitated in OBBC are of significantly higher quality than those produced in IDBC. A computational fluid dynamics (CFD) software package, Fluent 5, was used to model dynamical fluid patterns in both crystallizers.