Continuous Crystallization of Proteins in a Tubular Plug-Flow Crystallizer

Abstract

Protein crystals have many important applications in many fields, including pharmaceutics. Being more stable than other formulations, and having a high degree of purity and bioavailability, they are especially promising in the area of drug delivery. In this contribution, the development of a continuously operated tubular crystallizer for the production of protein crystals has been described. Using the model enzyme lysozyme, we successfully generated product particles ranging between 15 and 40 μm in size. At the reactor inlet, a protein solution was mixed with a crystallization agent solution to create high supersaturations required for nucleation. Along the tube, supersaturation was controlled using water baths that divided the crystallizer into a nucleation zone and a growth zone. Low flow rates minimized the effect of shear forces that may impede crystal growth. Simultaneously, a slug flow was implemented to ensure crystal transport through the reactor and to reduce the residence time distribution.

Continuous Generation of Millimeter-Sized Glycine Crystals in Non-Seeded Millifluidic Slug Flow

“…Continuous crystallization has received increasing research interests in both academia and industry for controlling crystal qualities, including polymorphic form, size, and morphology [1][2][3][4][5][6][7][8][9][10][11][12][13]. Many types of continuous crystallizers have been designed to meet different product quality requirements, with representative examples: (a) multi-stage mixed-suspension mixed-product removal (MSMPR) crystallizers [14][15][16][17]; (b) fluidized bed crystallizers [18][19][20][21][22]; (c) oscillatory baffled crystallizers [23][24][25]; (d) unbaffled crystallizers with an interior tubing mixing enhancer [8] (such as static mixers [11,26,27]); and (e) segmented/slug-flow crystallizers [3,[26][27][28][29].…”

Ultrasound Assisted Particle Size Control by Continuous Seed Generation and Batch Growth

“…Furthermore, the solubility, disintegration, and dissolution rate of medicines in the human body depend on this parameter [5,6]. The batch processes, often used in industry, suffer from batch-to-batch variabilities in particle size distributions, growth rates, and crystal habits [1,2,7,8]. In addition, scale up is not straight forward as large-scale systems create inhomogeneous conditions with a noticeable impact on the product quality.…”

“…The most important advantages are: more reproducible PSDs, smaller particle sizes, more robust scale-up, shorter downtimes, and easier control over the supersaturation ratio by better temperature control [1,2,7,8]. These continuous crystallizers suffer, nevertheless, from clogging and blocking of their channels by the attachment of crystals to the walls or agglomeration of these crystals [1,4,5,9].…”

Designs of continuous-flow pharmaceutical crystallizers: developments and practice

“…10,14,17,26,29,[93][94][95][96] Each liquid segment/slug is a functional crystallizer itself, with mixing from recirculation (intrinsic properties of slug flow) without requiring mixing blades. 9,10,14,29,97 Reactive precipitation, 17,26,30,[93][94][95][96] cooling crystallization, 10,14,29,98,99 and anti-solvent crystallization, 100 have all been demonstrated for milli-fluidic flow systems (that is, the tubing inner diameter and slug size is on the scale of millimeters), with residence time on the order of minutes or longer, depending on the production purposes. Alternating segments/slugs of slurry and a non-miscible phase (liquid or gas) have been formed using segmenters 17,94,101,102 (aka flow cutters) or simple tubing fittings 9,10,14,29,97 (e.g., Fig.…”