Abstract
The ability to grow properly sized and good quality crystals is one of the cornerstones of single-crystal diffraction, is advantageous in many industrial-scale chemical processes1,2,3, and is important for obtaining institutional approvals of new drugs for which high-quality crystallographic data are required4,5,6,7. Typically, single crystals suitable for such processes and analyses are grown for hours to days during which any mechanical disturbances—believed to be detrimental to the process—are carefully avoided. In particular, stirring and shear flows are known to cause secondary nucleation, which decreases the final size of the crystals (though shear can also increase their quantity8,9,10,11,12,13,14). Here we demonstrate that in the presence of polymers (preferably, polyionic liquids), crystals of various types grow in common solvents, at constant temperature, much bigger and much faster when stirred, rather than kept still. This conclusion is based on the study of approximately 20 diverse organic molecules, inorganic salts, metal–organic complexes, and even some proteins. On typical timescales of a few to tens of minutes, these molecules grow into regularly faceted crystals that are always larger (with longest linear dimension about 16 times larger) than those obtained in control experiments of the same duration but without stirring or without polymers. We attribute this enhancement to two synergistic effects. First, under shear, the polymers and their aggregates disentangle, compete for solvent molecules and thus effectively ‘salt out’ (that is, induce precipitation by decreasing solubility of) the crystallizing species. Second, the local shear rate is dependent on particle size, ultimately promoting the growth of larger crystals (but not via surface-energy effects as in classical Ostwald ripening). This closed-system, constant-temperature crystallization driven by shear could be a valuable addition to the repertoire of crystal growth techniques, enabling accelerated growth of crystals required by the materials and pharmaceutical industries.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Data availability
All data used in the calculations are available in GitHub repository (https://doi.org/10.5281/zenodo.3533635).
Code availability
All computer codes and COMSOL project files used in the calculations are available in GitHub repository (https://doi.org/10.5281/zenodo.3533635).
References
Shekunov, B. Y. & York, P. Crystallization processes in pharmaceutical technology and drug delivery design. J. Cryst. Growth 211, 122–136 (2000).
Variankaval, N., Cote, A. S. & Doherty, M. F. From form to function: crystallization of active pharmaceutical ingredients. AIChE J. 54, 1682–1688 (2008).
Ulrich, J. & Frohberg, P. Problems, potentials and future of industrial crystallization. Front. Chem. Sci. Eng. 7, 1–8 (2013).
Censi, R. & Di Martino, P. Polymorph impact on the bioavailability and stability of poorly soluble drugs. Molecules 20, 18759–18776 (2015).
Lee, E. H. A practical guide to pharmaceutical polymorph screening & selection. Asian J. Pharm. Sci. 9, 163–175 (2014).
ICH Q6A Specifications: Test Procedures And Acceptance Criteria For New Drug Substances And New Drug Products: Chemical Substances Report CPMP/ICH/367/96 (European Medicines Agency, 2000); https://www.ema.europa.eu/en/ich-q6a-specifications-test-procedures-acceptance-criteria-new-drug-substances-new-drug-products.
Guidance For Industry. ANDAS: Pharmaceutical Solid Polymorphism Chemistry, Manufacturing, And Controls Information (Food and Drug Administration, 2007); http://academy.gmp-compliance.org/guidemgr/files/POLYMORPHISM_7590FNL.PDF
Shamlou, P. A. & Titchener-Hooker, N. Turbulent aggregation and breakup of particles in liquids in stirred vessels. In Processing of Solid-Liquid Suspensions 1–25 (Butterworth–Heinemann, 1993).
Wang, J. & Estrin, J. Secondary nucleation of sucrose by fluid shear in aqueous solutions. Chem. Eng. Commun. 152/153, 275–286 (1996).
Forsyth, C. et al. Influence of controlled fluid shear on nucleation rates in glycine aqueous solutions. Cryst. Growth Des. 15, 94–102 (2015).
Forsyth, C., Burns, I. S., Mulheran, P. A. & Sefcik, J. Scaling of glycine nucleation kinetics with shear rate and glass–liquid interfacial area. Cryst. Growth Des. 16, 136–144 (2016).
Botsaris, G. D. Secondary nucleation—a review. In Industrial Crystallization 3–22 (Springer, 1976).
McCabe, W. L., Smith, J. C. & Harriott, P. Unit Operations Of Chemical Engineering 1130 (McGraw-Hill, 1993).
Sung, C. Y., Estrin, J. & Youngquist, G. R. Secondary nucleation of magnesium sulfate by fluid shear. AIChE J. 19, 957–962 (1973).
Andereck, C. D., Liu, S. S. & Swinney, H. L. Flow regimes in a circular Couette system with independently rotating cylinders. J. Fluid Mech. 164, 155–183 (1986).
Hasell, T., Chong, S. Y., Jelfs, K. E., Adams, D. J. & Cooper, A. I. Porous organic cage nanocrystals by solution mixing. J. Am. Chem. Soc. 134, 588–598 (2012).
Antonietti, M., Kuang, D., Smarsly, B. & Zhou, Y. Ionic liquids for the convenient synthesis of functional nanoparticles and other inorganic nanostructures. Angew. Chem. Int. Ed. 43, 4988–4992 (2004).
Zhen, M., Yu, J. & Dai, S. Preparation of inorganic materials using ionic liquids. Adv. Mater. 22, 261–285 (2010).
Gao, M. R., Yu, S. H., Yuan, J., Zhang, W. & Antonietti, M. Poly(ionic liquid)-mediated morphogenesis of bismuth sulfide with a tunable band gap and enhanced electrocatalytic properties. Angew. Chem. Int. Ed. 55, 12812–12816 (2016).
Berry, G. C. & Fox, T. G. The viscosity of polymers and their concentrated solutions. Fortsch. Hochpolym. Adv. Polymer Sci. 5, 261–357 (1968).
Szymański, J., Patkowski, A., Wilk, A., Garstecki, P. & Holyst, R. Diffusion and viscosity in a crowded environment: from nano-to macroscale. J. Phys. Chem. B 110, 25593–25597 (2006).
De Gennes, P. G. Coil-stretch transition of dilute flexible polymers under ultrahigh velocity gradients. J. Chem. Phys. 60, 5030–5042 (1974).
Cottrell, F. R., Merrill, E. W. & Smith, K. A. Conformation of polyisobutylene in dilute solution subjected to a hydrodynamic shear field. J. Polym. Sci. A 7, 1415–1434 (1969).
Larson, R. G. Constitutive Equations For Polymer Melts And Solutions (Butterworth–Heinemann, 1988).
Link, A. & Springer, J. Light scattering from dilute polymer solutions in shear flow. Macromolecules 26, 464–471 (1993).
Lee, E. C., Solomon, M. J. & Muller, S. J. Molecular orientation and deformation of polymer solutions under shear: a flow light scattering study. Macromolecules 30, 7313–7321 (1997).
Smith, D. E., Babcock, H. P. & Chu, S. Single polymer dynamics in steady shear flow. Science 283, 1724–1727 (1999).
Sun, J. K. et al. General synthetic route toward highly dispersed metal clusters enabled by poly(ionic liquid)s. J. Am. Chem. Soc. 139, 8971–8976 (2017).
Burrell, G. L., Dunlop, N. F. & Separovic, F. Non-Newtonian viscous shear thinning in ionic liquids. Soft Matter 6, 2080–2086 (2010).
Del Galdo, S. & Amadei, A. The unfolding effects on the protein hydration shell and partial molar volume: a computational study. Phys. Chem. Chem. Phys. 18, 28175–28182 (2016).
Norman, A. I., Yiwei, F., Ho, D. L. & Greer, S. C. Folding and unfolding of polymer helices in solution. Macromolecules 40, 2559–2567 (2007).
Noyes, A. A. The physical properties of aqueous salt solutions in relation to the ionic theory. Science 20, 577–587 (1904).
Lewis, G. N. & Randall, M. Thermodynamics And The Free Energy Of Chemical Substances (McGraw-Hill, 1923).
Cohn, E. J. The physical chemistry of the proteins. Physiol. Rev. 5, 349–437 (1925).
Miller, S. A., Dykes, D. D. & Polesky, H. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 16, 1215 (1988).
Schmid, D. W. Finite and infinite heterogeneities under pure and simple shear. PhD thesis, ETH Zurich (2002).
Nesbitt, W. S. et al. A shear gradient-dependent platelet aggregation mechanism drives thrombus formation. Nat. Med. 15, 665–673 (2009).
Ramel, P. R., Campos, R. & Marangoni, A. G. Effects of shear and cooling rate on the crystallization behavior and structure of cocoa butter: shear applied during the early stages of nucleation. Cryst. Growth Des. 18, 1002–1011 (2018).
Marcus, Y. The Properties Of Solvents (Wiley, 1998).
Chatterjee, S., Pedireddi, V. R., Ranganathan, A. & Rao, C. N. R. Self-assembled four-membered networks of trimesic acid forming organic channel structures. J. Mol. Struct. 520, 107–115 (2000).
Acknowledgements
We acknowledge support from the Institute for Basic Science Korea (Project Code IBS-R020-D1). We thank S. Lach for his help in the design and manufacture of the Couette cells, M. Siek for DLS measurements, C. Cahoon and K. K. Zheng for rheological measurements, J. Yuan for help with PIL synthesis, and W. Adamkiewicz for discussions.
Author information
Authors and Affiliations
Contributions
J.-K.S. designed and performed most of the experiments. Y.I.S. developed theoretical models and helped with some experiments. W.Z. and Q.Z. synthesized most of the PIL polymers. B.A.G. conceived and supervised the research. All authors wrote the paper.
Corresponding author
Ethics declarations
Competing interests
A patent application based on these results has been submitted by the Institute for Basic Science (South Korea Patent Application 10-2019-0008413; inventors J.-K.S., Y.I.S. and B.A.G.).
Additional information
Peer review information Nature thanks Andrew Cooper, Laurence Noirez and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Supplementary Information
This file contains Supplementary Sections 1-8 and includes synthesis and characterization of poly(ionic liquid)s, additional data from crystallization experiments, dynamic light scattering measurements, detailed theoretical discussion of relevant fluid dynamics and rheology, and design of magnetically-actuated Couette cells.
Supplementary Data
CIF file for trimesic acid crystallized by evaporation, crystallographic data.
Supplementary Data
CIF file for trimesic acid crystallized in the presence of PIL polymer, crystallographic data.
Supplementary Data
CIF file for trimesic acid crystallized by recrystallization, crystallographic data.
Video 1: Growing crystals in shear flow created using conventional stirring bar.
We start by pouring undersaturated solution of TA in DMF (47 mg of TA / 0.4 mL of DMF) on top of 0.35 ml of the same solvent containing a polyionic liquid polymer (300 mg of PIL-1, MW 402 kg/mol) in a glass vial containing a stirring bar and placed on a magnetic stirrer. The video begins when the stirrer is turned on (at 400 rpm). Right side of the frame shows enlarged part from the red rectangle on the left. Real time is shown in the top left corner. After the 0:30 mark, video jumps forward by increments of 10 minutes, showing 5 seconds at real-time speed after each jump. At the end of the video, microscope images (taken under crossed polarizers) of the produced crystals are shown
Video 2: Growth of TA crystals in PIL-1/DMF solution under shear.
We start by mixing undersaturated solution of TA in DMF (47 mg of TA / 0.4 ml of DMF) with 0.35 ml of the same solvent containing a polyionic liquid polymer (300 mg of PIL-1, MW 402 kg/mol). Time indicated at the top of the frame is measured from the beginning of stirring. Needle-shaped crystals become visible to a naked eye after ~30 sec of rotation. First two minutes of the experiment are presented at real-time speed. It is followed by a fast time-lapse of snapshots at one-minute intervals obtained by briefly stopping the rotation of the Couette cell (to minimize the motion blue) and taking a photo. Final snapshot of the video (at 2:39) corresponds to 63 minutes of real time after the start of Couette cell rotation. At the end of the video, microscope images (taken under crossed polarizers) of the produced crystals are shown
Video 3: Simulated evolution of local shear rate during particle rotation in the Couette flow.
Shear rate is indicated by colour (colour scale is on the left). Streamlines show velocity field. Arrow cones indicate direction and magnitude of velocity. Particle size here is L= 0.2 mm, and corner curvature rc = 2 μm, but the picture is qualitatively similar for other values of L and . This movie corresponds to Figure S46a-d. Maximum local shear rate is plotted against time in Figure S46e. For implementation details and discussion, see SI Section 4.
Rights and permissions
About this article
Cite this article
Sun, JK., Sobolev, Y.I., Zhang, W. et al. Enhancing crystal growth using polyelectrolyte solutions and shear flow. Nature 579, 73–79 (2020). https://doi.org/10.1038/s41586-020-2042-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41586-020-2042-1
This article is cited by
-
Ultra-fast supercritically solvothermal polymerization for large single-crystalline covalent organic frameworks
Nature Protocols (2023)
-
Materials, assemblies and reaction systems under rotation
Nature Reviews Materials (2022)
-
Crystallization of nanoparticles induced by precipitation of trace polymeric additives
Nature Communications (2021)
-
Ultra-fast single-crystal polymerization of large-sized covalent organic frameworks
Nature Communications (2021)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.