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Enhancing crystal growth using polyelectrolyte solutions and shear flow

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.

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Fig. 1: Shear-enhanced growth of TA crystals in the presence of an ionic polymer.
Fig. 2: Various polymers used for shear-enhanced crystallization.
Fig. 3: Shear-enhanced growth of additional 19 different crystals in the presence of polyionic liquids.
Fig. 4: Effects of shear rates and polymer’s chain length on crystal growth.
Fig. 5: Effects of particle size on local shear rates.

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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

  1. Shekunov, B. Y. & York, P. Crystallization processes in pharmaceutical technology and drug delivery design. J. Cryst. Growth 211, 122–136 (2000).

    Article  ADS  CAS  Google Scholar 

  2. Variankaval, N., Cote, A. S. & Doherty, M. F. From form to function: crystallization of active pharmaceutical ingredients. AIChE J. 54, 1682–1688 (2008).

    Article  CAS  Google Scholar 

  3. Ulrich, J. & Frohberg, P. Problems, potentials and future of industrial crystallization. Front. Chem. Sci. Eng. 7, 1–8 (2013).

    Article  Google Scholar 

  4. Censi, R. & Di Martino, P. Polymorph impact on the bioavailability and stability of poorly soluble drugs. Molecules 20, 18759–18776 (2015).

    Article  CAS  Google Scholar 

  5. Lee, E. H. A practical guide to pharmaceutical polymorph screening & selection. Asian J. Pharm. Sci. 9, 163–175 (2014).

    Article  Google Scholar 

  6. 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.

  7. 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

  8. 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).

  9. Wang, J. & Estrin, J. Secondary nucleation of sucrose by fluid shear in aqueous solutions. Chem. Eng. Commun. 152/153, 275–286 (1996).

    Article  Google Scholar 

  10. Forsyth, C. et al. Influence of controlled fluid shear on nucleation rates in glycine aqueous solutions. Cryst. Growth Des. 15, 94–102 (2015).

    Article  CAS  Google Scholar 

  11. 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).

    Article  CAS  Google Scholar 

  12. Botsaris, G. D. Secondary nucleation—a review. In Industrial Crystallization 3–22 (Springer, 1976).

  13. McCabe, W. L., Smith, J. C. & Harriott, P. Unit Operations Of Chemical Engineering 1130 (McGraw-Hill, 1993).

  14. Sung, C. Y., Estrin, J. & Youngquist, G. R. Secondary nucleation of magnesium sulfate by fluid shear. AIChE J. 19, 957–962 (1973).

    Article  CAS  Google Scholar 

  15. 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).

    Article  ADS  Google Scholar 

  16. 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).

    Article  CAS  Google Scholar 

  17. 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).

    Article  CAS  Google Scholar 

  18. Zhen, M., Yu, J. & Dai, S. Preparation of inorganic materials using ionic liquids. Adv. Mater. 22, 261–285 (2010).

    Article  Google Scholar 

  19. 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).

    Article  CAS  Google Scholar 

  20. Berry, G. C. & Fox, T. G. The viscosity of polymers and their concentrated solutions. Fortsch. Hochpolym. Adv. Polymer Sci. 5, 261–357 (1968).

    Article  Google Scholar 

  21. 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).

    Article  Google Scholar 

  22. De Gennes, P. G. Coil-stretch transition of dilute flexible polymers under ultrahigh velocity gradients. J. Chem. Phys. 60, 5030–5042 (1974).

    Article  ADS  Google Scholar 

  23. 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).

    Article  CAS  Google Scholar 

  24. Larson, R. G. Constitutive Equations For Polymer Melts And Solutions (Butterworth–Heinemann, 1988).

  25. Link, A. & Springer, J. Light scattering from dilute polymer solutions in shear flow. Macromolecules 26, 464–471 (1993).

    Article  ADS  CAS  Google Scholar 

  26. 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).

    Article  ADS  CAS  Google Scholar 

  27. Smith, D. E., Babcock, H. P. & Chu, S. Single polymer dynamics in steady shear flow. Science 283, 1724–1727 (1999).

    Article  ADS  CAS  Google Scholar 

  28. 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).

    Article  CAS  Google Scholar 

  29. Burrell, G. L., Dunlop, N. F. & Separovic, F. Non-Newtonian viscous shear thinning in ionic liquids. Soft Matter 6, 2080–2086 (2010).

    Article  ADS  CAS  Google Scholar 

  30. 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).

    Article  Google Scholar 

  31. Norman, A. I., Yiwei, F., Ho, D. L. & Greer, S. C. Folding and unfolding of polymer helices in solution. Macromolecules 40, 2559–2567 (2007).

    Article  ADS  CAS  Google Scholar 

  32. Noyes, A. A. The physical properties of aqueous salt solutions in relation to the ionic theory. Science 20, 577–587 (1904).

    Article  ADS  CAS  Google Scholar 

  33. Lewis, G. N. & Randall, M. Thermodynamics And The Free Energy Of Chemical Substances (McGraw-Hill, 1923).

  34. Cohn, E. J. The physical chemistry of the proteins. Physiol. Rev. 5, 349–437 (1925).

    Article  CAS  Google Scholar 

  35. 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).

    Article  CAS  Google Scholar 

  36. Schmid, D. W. Finite and infinite heterogeneities under pure and simple shear. PhD thesis, ETH Zurich (2002).

  37. Nesbitt, W. S. et al. A shear gradient-dependent platelet aggregation mechanism drives thrombus formation. Nat. Med. 15, 665–673 (2009).

    Article  CAS  Google Scholar 

  38. 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).

    Article  CAS  Google Scholar 

  39. Marcus, Y. The Properties Of Solvents (Wiley, 1998).

  40. 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).

    Article  ADS  CAS  Google Scholar 

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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

Authors

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

Correspondence to Bartosz A. Grzybowski.

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.

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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

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