Strategy for Fast Decision on Material System Suitability for Continuous Crystallization Inside a Slug Flow Crystallizer

Abstract

There is an increasing focus on two-phase flow in micro- or mini-structured apparatuses for various manufacturing and measurement instrumentation applications, including the field of crystallization as a separation technique. The slug flow pattern offers salient features for producing high-quality products, since narrow residence time distribution of liquid and solid phases, intensified mixing and heat exchange, and an enhanced particle suspension are achieved despite laminar flow conditions. Due to its unique features, the slug flow crystallizer (SFC) represents a promising concept for small-scale continuous crystallization achieving high-quality active pharmaceutical ingredients (API). Therefore, a time-efficient strategy is presented in this study to enable crystallization of a desired solid product in the SFC as quickly as possible and without much experimental effort. This strategy includes pre-selection of the solvent/solvent mixture using heuristics, verifying the slug flow stability in the apparatus by considering the static contact angle and dynamic flow behavior, and modeling the temperature-dependent solubility in the supposed material system using perturbed-chain statistical associating fluid theory (PC-SAFT). This strategy was successfully verified for the amino acids l-alanine and l-arginine and the API paracetamol for binary and ternary systems and, thus, represents a general approach for using different material systems in the SFC.

Keywords

• continuous crystallization
• microfluidics
• slug flow
• contact angle
• solid–liquid interaction
• solubility modeling