Relating induction time and metastable zone width

© 2017 The Royal Society of Chemistry. A relation between induction time and metastable zone width in cooling crystallization has been developed based on the correlation between temperature and supersaturation with the induction time in the classical nucleation theory. By this relation, the nucleation times in linear cooling experiments and the induction times at constant temperature can be estimated from each other, i.e. estimating metastable zone widths from experimental induction times or interfacial energy and the pre-exponential factor from metastable zone widths. Ascorbic-water system, with 120 induction times and 192 metastable zone widths determined, and several systems reported in the literature, have been investigated to compare the estimated values of metastable zone width/induction time with experimental values, respectively. The estimated metastable zone widths are fairly consistent with the experimental values. The differences between experimental literature values of metastable zone widths and the estimated values using the literature induction times range from 0.1 K to 10 K with an average of 2.5 K. For two systems (paracetamol in ethanol and salicylic acid in ethyl acetate), estimated and experimental results are of very good consistency with an average uncertainty of only about 5%. More accurate extrapolations of the induction times from metastable zone widths have been investigated. The potential utilities of this approach in crystallization research and process understanding are discussed

Review on life cycle of parabens: synthesis, degradation, characterization and safety analysis

In this review, we show the life cycle of parabens, commonly used preservatives that exist in nature and commercial products. Typical synthetic methods to produce parabens, and a set of complimentary characterization techniques to monitor the composition of parabens are also highlighted. This includes solid state analysis using Scanning Electron Microscope (SEM), Differential Scanning Calorimetry (DSC) and X-Ray Diffraction (XRD), in-situ monitoring of crystallization process using Focused Beam Reflectance Measurement (FBRM), Particle Vision Measurement (PVM), quantitative detection via High Performance Liquid Chromatography (HPLC), and Gas Chromatography (GC). An improved understanding of the overall physical, biophysical and chemical properties of parabens and their life cycle, summarized in this article, are vital for the safety control and extensive applications of relevant products in food, cosmetic and pharmaceutical industries

Jumping into metastable 1:1 urea-succinic acid cocrystal zone by freeze-drying

Aqueous solutions with molar ratios between urea and succinic acid from 0.3:1 to 3:1 were evaporated at room temperature, and products were pure or mixtures of stable 2:1 urea-succinic acid cocrystals, urea or succinic acid. By freeze-drying, metastable 1:1 urea-succinic acid cocrystal formed. The different mixtures of the 1:1 cocrystals reveal several "hidden" metastable zones in a ternary phase diagram of the 2:1 cocrystal. The formation of the 1:1 cocrystal indicated that the solution composition points in the phase diagram "jump" over the stable zone into the metastable zones

Development and workflow of a continuous protein crystallization process: A case of lysozyme

In the present work, a workflow on the development of a continuous protein crystallization is introduced, with lysozyme as a model protein, from microliter screening experiments, to small scale batch crystallization experiments in a shaking crystallization platform, and to batch and continuous crystallization experiments in an oscillatory flow platform. The lysozyme crystallizations investigated were for a concentration range from 30 to 100 mg/mL, shaking conditions from 100 to 200 rpm in the batch shaking crystallization platform, and oscillatory conditions with amplitude (x 0 ) from 5 to 30 mm and frequency (f) from 0.1 to 1.0 Hz in the batch oscillatory flow crystallization platform. We propose the use of the Reynold's number (R e ) for scaling up of the process from the shaking batch to the continuous oscillatory flow platform. Additionally, it is shown that the nucleation rate increased with increase in concentration of initial lysozyme solution, or increase in shear rate, inducing smaller size of lysozyme crystals. The properties and qualities of the crystal products indicate that continuous crystallization platforms may offer advantages to the downstream bioprocessing of proteins

Continuous protein crystallisation platform and process: Case of lysozyme

© 2018 Institution of Chemical Engineers In this work, we designed and built a continuous crystallisation oscillatory flow platform. The lysozyme crystallisation behaviours were investigated at concentrations from 30 to 100 mg/mL, under oscillatory conditions with amplitude (x0) from 10 to 25 mm and frequency (f) from 0.05 to 0.25 Hz in a batch oscillatory flow crystallisation platform. The nucleation rate increased with increase in concentration of initial lysozyme solution, and was also found to increase with increase in shear rate. By learning the thermodynamics and kinetics of lysozyme crystallisation in batch oscillatory flow, the batch crystallisation process was successfully transferred to a continuous oscillatory flow crystallisation process. The equilibrium state of continuous crystallisation reached at residence time 200 min, and the final product crystals shape and size were consistent during the continuous process. This work demonstrates the feasibility of oscillatory flow based platforms for the development of continuous protein crystallisation as for downstream bioseparation

Selective crystallisation of carbamazepine polymorphs on surfaces with differing properties

Surface-induced nucleation of carbamazepine (CBZ) in ethanol was investigated with different surface materials: glass, polytetrafluoroethylene (PTFE) and tin. The introduction of foreign surfaces with different areas and surface chemistries into the solution has an impact on the crystal morphology and polymorphic form (Form II or III). With an increase in supersaturation, a higher possibility of crystallisation of CBZ metastable Form II was observed, as expected. Increasing the number of inserts resulted in a direct increase in the surface area available for heterogeneous nucleation. The increase in surface area resulted in the greater possibility of obtaining the metastable Form II of CBZ. The stable Form III preferred to nucleate on tin rather than on glass and PTFE. The results indicate that the two different polymorphs of CBZ can be selectively crystallised out from solution with the aid of a foreign surface. The kinetic mechanism of heterogeneous nucleation of the different polymorphs induced by foreign surfaces was discussed. The potential applications will be used to control and design the crystallisation process

Optimization of vapor diffusion conditions for anti-CD20 crystallization and scale-up to meso batch

© 2019, MDPI AG. All rights reserved. The crystal form is one of the preferred formulations for biotherapeutics, especially thanks to its ability to ensure high stability of the active ingredient. In addition, crystallization allows the recovery of a very pure drug, thus facilitating the manufacturing process. However, in many cases, crystallization is not trivial, and other formulations, such as the concentrate solution, represent the only choice. This is the case of anti-cluster of differentiation 20 (anti-CD20), which is one of the most sold antibodies for therapeutic uses. Here, we propose a set of optimized crystallization conditions for producing anti-CD20 needle-shaped crystals within 24 h in a very reproducible manner with high yield. High crystallization yield was obtained with high reproducibility using both hanging drop vapor diffusion and meso batch, which is a major step forward toward further scaling up the crystallization of anti-CD20. The influence of anti-CD20 storage conditions and the effect of different ions on the crystallization processes were also assessed. The crystal quality and the high yield allowed the first crystallographic investigation on anti-CD20, which positively confirmed the presence of the antibody in the crystals

Optimization of vapor diffusion conditions for anti-CD20 crystallization and scale-up to meso batch

© 2019, MDPI AG. All rights reserved. The crystal form is one of the preferred formulations for biotherapeutics, especially thanks to its ability to ensure high stability of the active ingredient. In addition, crystallization allows the recovery of a very pure drug, thus facilitating the manufacturing process. However, in many cases, crystallization is not trivial, and other formulations, such as the concentrate solution, represent the only choice. This is the case of anti-cluster of differentiation 20 (anti-CD20), which is one of the most sold antibodies for therapeutic uses. Here, we propose a set of optimized crystallization conditions for producing anti-CD20 needle-shaped crystals within 24 h in a very reproducible manner with high yield. High crystallization yield was obtained with high reproducibility using both hanging drop vapor diffusion and meso batch, which is a major step forward toward further scaling up the crystallization of anti-CD20. The influence of anti-CD20 storage conditions and the effect of different ions on the crystallization processes were also assessed. The crystal quality and the high yield allowed the first crystallographic investigation on anti-CD20, which positively confirmed the presence of the antibody in the crystals

Protein crystallisation with air bubble templates: Case of gas-liquid-solid interfaces

Heterogeneous surfaces, such as solid particles, are known to efficiently increase nucleation rates during crystallisations from solution. In this work, air bubbles have been used to act as heterogeneous surfaces, to facilitate the critical nuclei formation of large protein molecules. Protein crystallisation experiments were performed using the hanging-drop method, to investigate the effects of concentrations of lysozyme and sodium chloride, and air bubbles on the nucleation of crystals. The introduction of an air bubble template resulted in an overall reduction in the nucleation induction time, over the majority of test conditions. With air bubbles in the hanging droplets, the population density of the lysozyme crystals was up to 1.5 times higher than that in the droplets that contained no bubbles. For the studied experimental conditions, the mass yield was also found to increase by adding air bubbles into the droplet

Freeze-dissolving method: a fast green technology for producing nanoparticles and ultrafine powder

A new technology, a freeze-dissolving method, has been developed to isolate nanoparticles or ultrafine powder and is a more efficient and sustainable method than the traditional freeze-drying method. In this work, frozen spherical ice particles were produced with an aqueous solution of sodium bicarbonate or ammonium dihydrogen phosphate at various concentrations to generate nanoparticles of NaHCO3 or (NH4)(H2PO4). The freeze-drying method sublimates ice, and nanoparticles of NaHCO3 or (NH4)(H2PO4) in the ice templates remain. The freeze-dissolving method dissolves ice particles in a low freezing point solvent at temperatures below 0 °C, and then, nanoparticles of NaHCO3 or (NH4)(H2PO4) can be isolated after filtration. The freeze-dissolving method is 100 times faster with about 100 times less energy consumption than the freeze-drying method as demonstrated in this work with a much smaller facility footprint and produces the same quantity of nanoparticles with a more uniform size distribution.</p