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Heterogeneous Nucleants for Crystallogenesis and Bioseparation
Umang V. Shaha, Christian Ambergb, Ying Diaoc, Zhongqiang Yangd, Jerry Y. Y. Henga*
a
Surfaces and Particle Engineering Laboratory (SPEL), Department of Chemical Engineering, Imperial
College London, South Kensington Campus, London SW7 2AZ, United Kingdom.
b
Engineering Formulation Europe, Syngenta Crop Protection Münchwilen AG, Breitenloh 5,
CH-4333 Münchwilen, Switzerland.
c
Department of Chemical and Biomolecular Engineering, University of Illinois, Urbana, IL 61801,
United States of America.
d
Key Laboratory of Organic Optoelectronics & Molecular Engineering of the Ministry of Education,
Department of Chemistry, Tsinghua University, Beijing 100084, P. R. China.
*Corresponding Author: [email protected]
Phone: +44-(0)207-594-0784. Fax: +44-(0)207-594-5700 Web: www.imperial.ac.uk/spel
Keywords: nucleation; crystallisation; nanoparticles; bioseparation; proteins
Highlights
1. An insight into nucleation mechanism, with brief review of current nucleation theories.
2. Description of selective nucleant approaches for controlling crystallisation.
3. Essential components for successful crystallisation – the Crystallisation Triangle concept.
4. Outlook of crystallisation for biocrystallisation and bioseparation.
5. Emerging approaches to include soft materials.
1
Abstract
Crystallisation is a widely used separation step for both isolation and purification of products, for a wide
range of chemical processes. Nevertheless, there remains a great challenge in controlling the onset of
crystallisation - nucleation. Heterogeneous nucleation has been investigated over the last three decades
to determine physico-chemical relationships between nucleant and solute properties, which may be key
for controlling nucleation. This can lead to rational design of nucleants facilitating selective
crystallisation of particles with desired properties. In this opinion, a review on recent advances in
developing mechanistic understanding of the role of interfacial properties, mainly nano-scale surface
topography, surface chemistry and the combination of both features, in controlling nucleation is
presented. An outlook for the development of next generation nucleants and the potential application
areas are presented.
2
Introduction
Crystallisation is often considered an essential separation step for many different chemical processes
ranging from producing simple compounds such as salt and sugar to large complex macromolecular
biotherapeutics such as insulin. Controlling crystallisation has been a topic of interest for many areas of
science and technology including environmental sciences [1], pharmaceuticals [2], semiconductors [3],
non-linear optics [4], food products [5], neutraceuticals [6], minerals in biological and synthetic systems
[7, 8]. Protein crystallisation is often considered more of an art than a science, relying on empirical
approaches and hampered by lack of mechanistic understanding [9]. Nucleation is the governing step for
controlling crystallisation. However, it is extremely difficult to control nucleation considering that in
most practical circumstances, nucleation is initiated on foreign interfaces, i.e. heterogeneous nucleation.
Over the last decade, considerable progress has been made in understanding the role of interfacial
properties in controlling heterogeneous nucleation [10]. Among the proposed mechanisms, favourable
specific molecular interactions for the crystallising molecule and an epitaxial match between the
molecule and the substrate have been demonstrated to aid nucleation [11-13]. Furthermore, nucleant
surface topography at the nanometre length scale has been reported to affect nucleation [14]. However
the contributions from these surface attributes are seldom quantified in isolation, combination of these
attributes has been neglected until very recently [15], resulting in a limited mechanistic understanding.
Here, recent advances in mechanistic understanding of nucleation and how such advancements have
aided the insight into the role of nucleant surface properties in controlling nucleation are presented.
Selected literature also highlights mechanisms by which interfacial properties governing heterogeneous
nucleation, presenting opportunities for targeted/selective nucleation by specifically designed nucleant,
opening up new applications for crystallisation, such as biocrystallisation, bio-separation, water
softening, and scale prevention, etc.
3
Insight into nucleation mechanisms
Classical Nucleation Theory
The fundamental framework used in describing nucleation is known as the Classical Nucleation Theory
(CNT). This theory assumes that local concentration fluctuates intermittently form clusters that grow
through monomer additions until a critical size is reached. As per CNT, critical cluster size is inversely
proportional to the level of supersaturation. It is thus clear that as supersaturation increases, the critical
size decreases and the solute is more likely to successfully form nucleus. However, in practice, this
expression oversimplifies the nucleation process and fails to account for several aspects of experimental
measurements of nucleation rate [16], although is widely applied
Two-step Nucleation Model
The two-step nucleation model differs fundamentally from the CNT in that solution molecules are not
assumed to exchange directly with a cluster. Instead, first an intermediate dense liquid droplet is formed,
followed by nucleation of an ordered crystalline structure [17]. At sufficiently high supersaturation and
low temperature, the critical nucleus size is unity, such that every molecule in the solution can be a seed.
Here, the thermodynamic nucleation barrier is zero and generation of new crystalline phase is only
limited by kinetics of cluster growth. Thus, nucleation rate is no longer increased by increasing
concentration or lowering temperature, in agreement with experimental nucleation rates [18]. Based on
the assumption that formation of crystal nuclei in the dense liquid phase is rate limiting, an improved
kinetic rate law was presented [19]. These findings highlight that heterogeneous nucleants do not result
in the lowering of the free energy barrier to induce nucleation, but instead in assisting the formation of
ordered cluster by influencing the rate of nucleation [20, 21]. The most obvious role for heterogeneous
nucleation is the stabilisation of an intermediate en-route to the right crystal structure [22]. This is very
similar to the pathway followed by enzymes in stabilising a transition state and not the final products of
the enzyme-catalysed reactions.
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Both theories remain widely adopted. However, the two-step nucleation mechanism not only predicts
more realistic nucleation rates, but also provides insight on the nuclei formation from solution [18-20,
22].
Towards developing mechanistic understanding on the role of different surface properties
Surface Topography
Surface Porosity
Nucleants with pore diameter of nanometre length scale were employed for promoting nucleation of
biological macromolecules [23, 24], crystallisation of different polymorphs of organic crystals,
investigating nucleation kinetics of organic molecules [2], biomineralisation [7, 25] and nucleation of ice
[26]. For biological macromolecules, it was hypothesised that a higher local supersaturation within the
confinement resulted in a thermodynamic drive for nucleation within the pores. Here, nucleation follows
two steps; first, capillary condensation of protein solution in the pores, followed by rapid nucleation.
The maximum rate of nucleation was obtained when pore diameter is equivalent to the size of the
protein’s critical nucleus [27]. The systematic use of different pore size with narrow size distribution
[14], further confirms the existence of such a relationship. Such nanotemplates have the potential of
selective nucleation for bioseparation.
Surfaces exhibiting topological features have also been applied to controlling crystallisation of organic
electronics. Bao’s group reported the use of rough patches of octadecyltriethoxysilane (OTS)
functionalized dielectric surfaces (average roughness 10-15nm) for templating single-crystal growth of
various organic semiconductors [28, 29]. For morphology control of solution processed solar cells and
electronics, Treat et al. applied organic additives to control the nucleation density and domain size [30].
During material processing, these additives crystallise first to provide nanostructured nucleation
templates and subsequently induce nucleation. The mechanism of these nanotemplates is probably
5
consistent with the capillary condensation picture discussed above, however, has not been investigated in
this light.
Crystallisation of organic molecules from a same solvent in nanoscale confinements demonstrated that
crystal nucleation and polymorph selectivity are also affected by pore sizes. It was proposed that
nanoscale confinement results in stabilising metastable crystal forms by melting point depression and
that this effect is more dominant at lower crystal size [31]. Other applications include the use of porous
metallic organic framework, modified acrylic copolymer or styrenic copolymer or combination of both
[32]. Electrospun cellulose resins with rough surfaces [33] were used for crystallisation of inorganic salts
containing calcium and magnesium ions from waters, a “template induced crystallisation” approach for
domestic and industrial water softening.
Employing Monte Carlo simulations, it was proposed that nucleation rates are theoretically maximum at
an angle at which the crystal lattice matches the pore wedge angle [34]. On the basis of experimental
evidences, angle-directed nucleation mechanism was proposed where an angle characteristic of the
topological feature of the substrate controls nucleation in a minimum strain configuration. This
demonstrates the geometrical match between nucleant surface and molecular arrangement in a crystal
lattice [35-37].
Epitaxy
Epitaxy is a mechanism responsible for nucleation and growth of many organic and inorganic
compounds such as semi-conductors [38], pharmaceuticals [39], ice [1] and proteins [40]. It has been
demonstrated that if the crystallising molecule is presented with the nucleant having similar unit cell
parameters and molecular functionality, nucleant selective polymorphic control can be achieved. The
proposed mechanism is that the nucleant stabilises the pre-nucleation aggregates by epitaxial ordering
directed by lattice matching and the intermolecular interactions [11, 39, 41]. Recently, the epitaxial
6
effect was incorporated into predictions from crystal energy landscape for selective formation of a
metastable polymorph [42].
Surface Chemistry
Also relevant in nucleation is the specific chemical interaction between nucleant substrate and
crystallising molecule, which may well dominate [43]. In solution phase crystallisation, when both the
solute and solvent are polar, the polarisation effect governs the ability of solute molecule to adsorb on
the nucleant surface. By adjusting nucleant surface potential, adsorption selectivity can be obtained
resulting in surface induced/promoted nucleation phenomenon [44-46]. For organosilane grafted
surfaces, the molecular interactions at the polymer-solute interfaces were reported to control nucleation
of pure stable form or its nucleant kinetics. The governing surface specific electrostatic interactions
involve mainly the hydrogen bonding, dipole moments or acid-base interactions between template
surface functional end-groups and solute molecule [37, 47].
Surface chemistry has also played a critical role in controlling the morphology of organic semiconductor
thin films, although mechanistic studies have been rare. Gundlach et al. reported crystallisation of
fluorinated 5,11-bis(triethylsilylethynyl) anthradithiophene (diF-TES-ADT) by pentafluorobenzene thiol
(PFBT) templated gold electrodes. The templating effect may be guided by the F-S or F-F interactions
between diF-TES-ADT and PFBT [48]. Self-assembled monolayers on dielectric surfaces have been
extensively used for facilitating the growth of the semiconductor layer [49-52]. The intermolecular
interactions are typically non-specific in these cases since the SAM layers used are predominantly
aliphatic. Amongst possible templating mechanisms are interfacial free energy matching [51, 53] and in
some cases, epitaxy between the 2D lattice formed by crystalline SAM layer and the crystal lattice of the
semiconducting layer [49]. Recently, organic small molecules that form an amorphous insulating layer
between the semiconductor and the dielectric have been explored for controlling crystallisation of the
semiconducting layer as well [54, 55].
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Parambil et al. investigated the effect of template surface chemistry and supersaturation on nucleation of
organic molecules, reporting a template induced polymorphic occurrence domain (POD). The POD
concept highlights the role of template surface chemistry in mediating preferential nucleation [56]. As
depicted schematically in Fig 1, the metastable zone width, wherein crystallisation can occur is affected
by a combination of i) solution properties [57], such as solvent and salt type, concentration and
supersaturation, ii) having a nucleation promoter such as external stimulus (magnetic field, ultrasound,
etc) or through surfaces/heteronucleants and iii) process conditions, influenced by hydrodynamics and
mass transfer which may also affect rate of achieving supersaturation.
Figure X: Crystallisation Triangle
Nucleation Promoter
Precipitation
Controlled
Crystallisation
Zone
Nucleation
Promoter
Solution Properties
Process Conditions
Figure 1: A diagram for the “Crystallisation Triangle” concept.
8
Combined Effect of Surface Topography and Surface Chemistry
Recently Diao et al. investigated the combination of both surface chemistry and topography by
employing different polymeric surfaces for investigating the nucleation kinetics of aspirin. Diao et al.
reports that active polymer surfaces with nanoscale porosity were able to increase the nucleation of polar
facets of aspirin by an order of magnitude [15].
Different Approaches using Combined Effect of Surface Porosity and Surface Chemistry
Selective Nucleant Approach
By employing surfaces with narrow pore size distribution and specific surface chemistry as nucleants,
Shah et al. reported a selective nucleant approach demonstrating that nucleant with a pore diameter
similar to the protein’s hydrodynamic diameter were successful in nucleation of a specific target protein.
The selective nucleant approach was employed for crystallisation of a specific protein from a binary
protein mixture [58], which is not possible using a nucleant with wide pore size distribution. Selective
nucleation provides a means of developing crystallisation for bioseparation – biocrystallisation,
potentially as an alternative downstream separation for biopharmaceuticals (Fig. 2). Recent success in
crystallising monoclonal antibodies [59], and possibilities of scaling-up, suggests that biocrystallisation
may be on the horizon [60].
The selective nucleant is developed on the basis of a relationship between the nucleant and solute surface
properties. Mechanism proposed suggests that the functional end-groups on the surface plays a key role
in attracting solute molecules to the template surface via electrostatic interaction, forming high dense
metastable liquid phase in the close vicinity of the surface [58]. It is envisaged that the design of next
generation of selective nucleants for protein crystallisation may include more complex chemistries such
as amino-acid, peptides, proteins, in very much a lock and key model for docking specific protein
regions (Fig. 3). Such selective nucleant approaches may also be applicable in a wide variety of
9
Figure
X:such
Outlook
of crystallisation
process
and scale
up using
application
areas,
as crystallisation
of organic
small development
molecule polymorphs,
prevention
of scaling by
heterogeneous nucleation for bioseparation
inorganic molecules, clathrate hydrate formation, etc.
Selective Nucleant as
Seeds – crystallising
target molecule from
protein mixture
Developing Crystallisation for Bioseparation
using Selective Nucleants
5-25 mL
Crystallisation
Condition
Identification
2-10 mL
Testing
Condition
with Seeds
50 - 500 mL
Lab Scale
Crystallisation
> 5L
Pilot & Commercial
Scale Crystallisation
Crystal Harvesting
Figure 2: The development of crystallisation as a downstream separation step.
10
SAM/ organosilane
Charged Surfaces
#"#"#"#"#"#"#"#"#"
+++++++++"
Other functional nano-materials
with selectivity
Potential
Approaches
Current
Approaches
DNA Origami
Epitaxy
Selective Nucleant
Soft Nucleant with target amino
acids/ligand functionality
Soft Templating Approach
Figure X: Summary of Current and Potential Approaches for Heterogeneous Nuclean
Figure 3: A summary of approaches for controlling nucleation with engineered heterogeneous nucleant.
Soft Templating Approaches
In contrast to the rigid materials with nanoscopic pores, soft templates have also recently been used to
crystallise proteins. Polymer surfaces with porosity and surface functionality is well advanced by Drioli
and co-workers [61], and more recently the use of molecularly imprinted polymers (MIPs) have also
been used. The MIPs were imprinted with the target protein, which were then extracted from the
imprinted polymer creating a cavity. These MIPs have been largely successful, reported to crystallise
proteins at lower concentration compared to control glass and further improve diffraction quality of
crystals [62]. Diao et al. proposed using polymer “microgels”, a biocompatible material, with tuneable
microstructures [63-65]. This approach allows the control of solute concentration within the microgel via
11
thermodynamic partitioning. A composite of hydrogel with organic phase droplets of dissolved API, was
shown to enable the control of crystal form, size and shape [66]. It is envisaged that DNA origami
structures can also be utilised for the control of protein nucleation. The ability to design a wide variety of
biocompatible polymer gel matrix ranging in mesh sizes and surface functionality, and DNA origami
structures, holds great promise in de-bottlenecking protein crystallisation.
Summary and Outlook
In summary, developing heterogeneous nucleants for controlling crystallisation is a work in progress.
Recent efforts highlight that the crystallisation community is focused on developing nucleants by
rational design adopting the basis of a systematic understanding of target molecule and nucleant
properties. While there has also been much progress in developing mechanistic understanding of
heterogeneous nucleation, investigations have been mainly focused on small lab scale, with so far
limited efforts in scale-up or process development. Interestingly, the application of heterogeneous
nucleation is not limited to protein crystallisation, but could include the prevention of scaling in
chemical process industries, water softening in domestic supplies, clathrate hydrate crystallisation for
flow assurance in the energy sector, to cloud seeding in environmental management.
Acknowledgements
ZY acknowledges the Royal Academy of Engineering – Research Exchange China and India (RECI)
programme (Reference: 1314RECI047).
12
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