Crystallization of Paracetamol under Oscillatory Flow Mixing Conditions

Abstract

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.

Determination of metastable zone width, mean particle size and detectable number density using video imaging in an oscillatory baffled crystallizer

“…However, we chose an oscillatory baffled crystallizer (OBC) because it has previously been shown to produce uniform mixing, [16][17][18][19] improved heat and mass transfer 20,21 and crystals of consistent properties 22,23 in an environment of consistent fluid mechanical conditions. We also estimate the sensitivity of this technique by utilising the minimum detectable number density.…”

Oscillatory Flow Reactors (OFRs) for Continuous Manufacturing and Crystallization

“…Various crystal systems have been investigated in batch OBC platforms including paracetamol, 86,207,208 LGA 209-211 and sodium chlorate. 101,212,213 These studies (largely cooling crystallization) have included the effects of strain and shear on crystal suspensions and it is evident that the hydrodynamic environment of oscillatory mixing offers significant advantages, see Figure 15.…”

Application of Continuous Preferential Crystallization to Efficiently Access Enantiopure Chemicals

“…To combat this drawback mixing elements, such as the Kenics type static mixers 43 can be included or differential fluid flow can be utilized, as is seen with oscillatory baffled crystallizers. 44 …”