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.

We show that the growth recovery mechanism of the {110} faces on crystals of the pharmaceutical paracetamol in the presence of its intrinsic impurity acetanilide occurs in the same way as in the growth of inorganic KH 2 PO 4 (KDP) crystals with Fe(III) and Al(III) impurities, by initial movement of macrosteps while elementary steps remain pinned. This suggests that the mechanism of recovery by activation of elementary step motion assumed by Cabrera and Vermilyea (C-V) is not applicable to a diverse set of common and technologically important crystal systems. Recognizing that impurity-driven macrostep formation depends on an imbalance in the concentration ahead and behind the step, we propose a general condition that must be met for a crystal-impurity system to behave according to the C-V predictions.