Template-induced nucleation for controlling crystal polymorphism: from molecular mechanisms to applications in pharmaceuticals processing

Jose V. Parambil,a Sendhil K. Poornachary,*b Jerry Y. Y. Hengc and Reginald B. H. Tanb, d

aDepartment of Chemical and Biochemical Engineering, Indian Institute of Technology Patna, Bihta, Patna 801106, Bihar, India

bInstitute of Chemical and Engineering Sciences, A*STAR (Agency for Science, Technology and Research), 1 Pesek Road, Jurong Island, Singapore 627833

cDepartment of Chemical Engineering, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom

dDepartment of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117576

Abstract

Over the last two decades, the use of template surfaces to induce heterogeneous crystal nucleation has been explored primarily to address two different goals: first, as an alternative to the conventional seeding technique used for polymorph control and, second, as a technique to promote nucleation rate in novel crystallisation processes and formulations. The former need conceivably arises due to the risk of crystallizing a new polymorph despite pre-seeding the solution with the desired crystal form. In this context, we review ongoing efforts in the research area of template-induced crystallisation, covering both experimental and simulation studies directed towards deeper understanding of the underpinning mechanisms. In addition, we report on the use of template-induced crystal nucleation as a process intensification technology for formulating drug substances and as a technique for enabling nucleation and polymorphic control during continuous manufacturing of active pharmaceutical ingredients.

Introduction

Controlling crystal polymorphism of active pharmaceutical ingredients (APIs) is an important attribute in pharmaceutical crystallisation as the polymorphs exhibit different physico-chemical properties, and, in turn, profoundly affect the efficacy and bioavailability of the drug.1 Additionally, crystal polymorphism can influence product isolation, downstream operations and formulation of solid dosage forms.2 In current industry practice, various methods including seeding, temperature cycling, supersaturation control and altering the solvent composition are considered for selective crystallisation of polymorphs. Despite using one or more of these control parameters, the targeted product crystal properties could at times be inaccessible. To address this issue, recent studies has focused on developing new techniques to control crystallisation process – particularly, to promote crystal nucleation kinetics and preferential nucleation of a desired crystal polymorph on templates.3–5

Template-induced nucleation refers to heterogeneous nucleation of the solute crystal on a template surface, introduced into the solution intentionally or naturally encountered during the crystallisation process. A template surface can be an organic or inorganic material, amorphous or crystalline with two- or three-dimensional order. Fluid interfaces such as emulsions and bubbles can also act as a template inducing crystal nucleation. In this review, we use the term ‘template-induced nucleation’ specifically to refer to those instances where a foreign surface often chosen or designed for its chemical and physical properties of interest is introduced into the solution to study its influence on heterogeneous crystal nucleation.

A literature search on template-induced crystal nucleation reveals both experimental and modelling studies that provide insights into the kinetic, thermodynamic and structural aspects of template-induced crystallisation process.6,7 Notably, a recent article reviewed different types of templates ranging from inorganic surfaces to self-assembled monolayers (SAMs) to polymers and functionalised substrates for crystallisation of various pharmaceutical and biopharmaceutical compounds, both small organic and protein molecules.7 In this Highlight, we provide an overview on the use of templates specifically for polymorphic control of small organic molecules alongside the conceptual crystal nucleation mechanisms involved. We first discuss the major factors that influence template-induced crystal nucleation, with illustrative case studies. We then discuss the mechanisms involved, and the challenges associated with designing ad conducting experimental/ modelling studies towards deeper understanding of the underpinning mechanisms. Finally, we highlight applications in pharmaceutical manufacturing and formulation processes where templating effect is used to promote crystal nucleation, and for polymorphic control.

Factors governing template-induced nucleation

Heterogeneous crystallisation on a template surface depends on various factors that strongly influence molecular aggregation of the solute en route to crystal nucleation. As such, the major surface factors are epitaxy, surface topography, and surface chemistry. As depicted schematically in Figure 1, these factors often interact with each other leading to template-induced crystal nucleation. Furthermore, in combination with these surface factors, the solution conditions, as determined by supersaturation and solvent properties, and hydrodynamics in the crystalliser also influence the polymorphic outcome. The latter factors hold significance from the viewpoint of crystallisation process development using template-induced nucleation technique. However, except for a few studies including those from our group, the combined effects of surface and solution factors on template-induced nucleation has not been investigated in detail.

Figure 1 Schematic representation of the factors that affect template-induced nucleation process in solution crystallisation.

Epitaxial relationship between the template and nucleating crystal

Epitaxy denotes the similarity in ordered molecular arrangement between the crystal structure of the nucleating solute and that of the heterogeneous surface where nucleation occurs.8 A good epitaxial relationship between these surfaces favours heterogeneous nucleation by reducing the interfacial free energy requirement for the formation of crystal nuclei.9–11 Complementing planes of the nucleating crystal facets and the template can interact through periodic hydrogen bonds, van der Waals and electrostatic forces, thereby lowering to the solid-liquid interfacial energy. Several examples of epitaxial nucleation are well documented in the literature since the first report by Boistelle and Rinaudo in 1981.12

Although a template surface with well-ordered molecular arrangement generally refers to crystalline phase of three-dimensional (3D) order, two-dimensional (2D) interfaces with orderly molecular arrangement can also result in epitaxial nucleation. These templates typically include self-assembled-monolayers (SAMs) and Langmuir-Blodgett (LB) films. We highlight some case studies from recent literature work to illustrate epitaxial nucleation on SAMs. Solution crystallisation of entacapone (a drug used for the treatment of Parkinson’s disease) on the SAM of the solute molecules formed on Au (100) surface lead to preferential nucleation of the stable form A crystals; in the absence of the template surface, under similar solution conditions, the metastable form D crystals were formed.13 Nucleation of form A crystals on the template and of form D crystals in the bulk solution concomitantly clearly demonstrated the importance of template surface in altering polymorphic outcome. Likewise, SAMs of analogous molecules of 2-iodo-4-nitroaniline (INA) was used to selectively crystallise the metastable polymorph of INA as opposed to concomitant nucleation of the stable and metastable polymorphs in the absence of the template.14 Hiremath et al.3 reported the selective nucleation of three polymorphs of 1,3-bis(m-nitrophenyl) urea on three different 4’-X-4-mercaptobiphenyl (X=H, I, and Br) SAMs on gold surface, utilising 2-D geometric lattice matching and complementary chemical interactions. Many more examples of crystal growth occurring on SAMs are documented in the review by Singh et.al.6 A review by Harding et. al. provides a comprehensive view of the experimental and computational results pertaining to nucleation and growth of inorganic crystals on SAMs.15

Figure 2 (a) Similarity between the molecular conformations of FFA I (blue) and MFA I (red) in comparison to that of FFA III (green). Molecular packing diagrams: (b) FFA I and MFA I interface; (c) FFA III and MFA I interface. Reprinted with permission from ref. 11. Copyright 2010 American Chemical Society.

In addition to templatecrystal lattice matching, epitaxial crystallisation of organic molecules with torsional degrees of freedom can benefit from favourable interaction due to matching between the conformation of molecule present on the template surface and that of the nucleating crystal. . We illustrate this mechanism of template-induced nucleation with the case of mefenamic acid (MFA).11 Crystallisation of MFA vapour (generated by sublimation) on flufenamic acid (FFA) seed crystal (a structurally related molecule) resulted in oriented growth of form I crystals on the (011) facet of FFA crystal polymorphs. Furthermore, MFA crystals nucleated faster on the surface of FFA I polymorph than on FFA II polymorph. These experimental observations were rationalised based on the similarity in conformation between MFA and FFA molecules within their respective crystal structures (see Figure 2a). As shown in Figures 2b and 2c, this can also be evidenced from the molecular packing diagrams of the nucleating crystaltemplate crystal interface, which reveals a good conformational match between the substrate (FFA I and FFA II) crystal and deposited crystal (MFA form I). Initially, the authors reasoned that hydrogen bonding would be the determining factor for this epitaxial crystallisation behaviour. However, the experimental results and lattice calculations showed that a high degree of conformational matching plays a significant contributor. Note that, in this case, epitaxial crystallisation occurs in the absence of solvent environment (via sublimation), and hence, the conclusions derived from this study may not be extrapolated to a solution crystallisation process.

A variation to the general 2D epitaxial nucleation mechanism is template-induced nucleation via ledge-directed epitaxy (LDE), where a ledge corresponds to the intersection of a terrace plane and a step plane on a crystal surface. LDE occurs when the interplanar dihedral angles between the planes on a ledge site matches with the planes of a prenucleation crystalline aggregate. Using this conceptual mechanism, a metastable polymorph of the complex salt (DMTC+)(TMO-)-CHCl3 (where DMTC is 3,3'-dimethylthiacarbocyanine and TMO is 3,3',5,5'-tetramethyltrimethine oxonol) was preferentially nucleated along the ledges of succinic acid (substrate) crystal.16 However, as compared to 2D epitaxy, only fewer instances of LDE resulting in preferential polymorphic nucleation is reported in the literature. A definitive advantage of 2D epitaxy over LDE is the large surface area of the templating plane, possibly resulting in higher probability of crystal nucleation induced through enhanced solute-template interaction.

Crystallisation of 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile, a compound known to exhibit six conformational polymorphs (commonly termed as the ROY polymorphs due to their distinguished colours), by sublimation on freshly cleaved faces of pimelic acid crystal led to preferential growth of the unstable yellow polymorph.8 By carrying out AFM goniometry indexing and lattice matching studies using the GRACE (Geometric Real-space Analysis of Crystal Epitaxy) program, the authors inferred that the LDE mechanism did not contribute to the polymorphic selectivity. On the other hand, the 2D epitaxial mechanism resulted in selective nucleation of ROY polymorph.

Arlin et al. and Srirambhatla et al. found that computationally predicted form V polymorph of carbamazepine can be obtained through epitaxial nucleation by solvent-free crystallisation (via sublimation) of carbamazepine on form II dihydroxycarbamazepine (analogous molecule) crystal.17,18 These works, along with other studies,19–21 established that isomorphous crystal structures can potentially be used as template substrates to obtain elusive crystal forms. Other than crystalline substrates, polymers such as poly(butylene adipate),22 poly(1-butene),23 and polylactides24, either dissolved or suspended in solution, have been reported to act as templates for epitaxial nucleation of specific polymorphs. Talc, an excipient included in the GRAS (generally regarded as safe) list, was found to preferentially nucleate a new metastable crystal form of fenofibrate, with an epitaxial relationship between the (001) face of talc and (100) face of the solute crystal.25

Chadwick et. al.26 studied the nucleation of acetaminophen from ethanol solution on crystalline substrates such as graphite, L-histidine, sodium chloride, α-lactose monohydrate, and D-mannitol. The effectiveness of the substrates to induce heterogeneous crystal nucleation was assessed through induction time measurements. From the experimental observations and molecular modelling, they concluded that functionality matches between the nucleating molecule and the crystalline substrate is more important than lattice matching. Furthermore, hydrogen bonding between the solute and molecules present on the template surface stabilised prenucleation clusters formed in the solution and thereby resulted in oriented growth of specific crystalline facets on the substrate. Olmstead and Ward explored the use of inorganic crystalline templates such as galena, highly ordered pyrolitic graphite (HOPG), molybdenite, muscovite, and phlogopite to investigate crystallisation behaviour of several polymorphic compounds.27 Epitaxial relationships between the solute crystal structures and the template were predicted through geometric lattice matching using the GRACE program. However, the experimental results were found to vary considerably from the predicted solute crystal orientations on the templates. This lead to the suggestion that though epitaxy can generally be attributed to crystal nucleation occurring on crystalline templates, chemical interactions between the template and solute molecule may at times be the dominant factor.

In addition to the aforementioned studies, where epitaxial nucleation occurred on template substrates introduced intentionally into the crystallising medium, several instances of inadvertent epitaxial cross-nucleation of one polymorphic form over another have been reported. The crystallisation of sulfathiazole, which is known to exhibit 5 polymorphic forms, is one such curious case where the less-stable form IV crystals were surrounded by a shell of more-stable form II crystals.28 Experimental and modelling studies revealed that the kinetically favoured form IV crystals nucleated first and subsequently form II nucleated on the existing form IV crystals due to epitaxial interaction. In contrast, the metastable form of a steroid molecule 7-α-methyl-Δ5,10-norethindrone crystallised on the stable form through epitaxial nucleation.29 This cross-nucleation behaviour, in contrast to the Ostwald’s rule of stages, is attributed30 to both epitaxial nucleation (by lowering thermodynamic barrier to 2-D nucleation) and competitive crystal growth kinetics of the stable versus metastable forms. Melt-crystallisation of D-mannitol9 and polymers10 such as poly(1-butene) and polypivalolactone have also exhibited similar cross-nucleation of polymorphs. However, as reported in the case of ROY polymorphs,31 the kinetics of nucleation and crystal growth of different polymorphs play a significant role in such the cross-nucleation behaviour, with epitaxy playing a complementary role.

Topography of heterogeneous template

Topography refers to 2D/3D features such as pores, (polymer) matrices and engineered patterns on the nucleating template surface. Molecular simulations have provided insights into the role of such topographic features on crystal nucleation. For instance, when crystal nucleation takes place inside nanosized pores, the pores with size corresponding to that of the critical nucleus of the solute enhanced the nucleation rate through ‘pore-filling’ mechanism.32 Similarly, when topographic features like edge geometry and angle are complimentary to the macroscopic (nucleating) crystal, it is more likely that nucleation will be promoted by stabilising the prenucleation molecular aggregates. In the case of nucleation induced within pores, contributions from both small-volume confinement effects and specific molecular interactions between the solute and pore matrix will be influential.

Conceptually, relating the size/geometry of the crystal nucleus to that of geometric features on the template surface appears to be similar to the ledge-directed epitaxial (LDE) nucleation mechanism. However, in the case of LDE, lattice matching, i.e., similarity in atomic/molecular arrangement is as important as geometric complementarity. Thus, LDE can be considered as a specific case of topography-induced nucleation mechanism that is observed mostly in the case of crystalline templates. Having said that, this section deals with heterogeneous crystal nucleation induced by topographic features on non-crystalline surfaces.

Literature studies provide comprehensive insights into the effects of pore size and shape and wedge angle on template-induced nucleation. In the study by Hamilton et al., 33 the highly metastable β-glycine nanocrystals formed inside porous polymer template exhibited oriented growth, with the [010] axis aligned parallel to the pore axis. Also, in pores smaller than 24 nm, the β glycine crystals were found to be stable, whereas in pores greater than 55 nm, the metastable β form transformed to the stable form, in accordance with the Ostwald’s rule of stages.34 Towards rationalising these experimental observations, the authors hypothesized that crystal nuclei formed in other crystallographic orientations will not be able to grow to their critical size inside the pores. Besides, the pore-size dependent polymorphic stability was attributed to the absence of form crystal nuclei in the smaller pores. In a related study, Ward and co-workers35 investigated the effect of pore size on selective nucleation of anthranilic acid and ROY polymorphs. In their study, form II anthranilic acid crystals preferentially nucleated over form III crystals in porous glass with pore size ≤23 nm. In case of ROY polymorphs, the R-nanocrystals were found inside the pores with their (111) planes in alignment with the pore axis whereas a-ROY crystals were present on the surface outside the pores. Moreover, crystallisation of ROY was suppressed in 20 nm pores compared to 30 nm pores.

Diao et al. studied the combined effects of pore size and shape on the nucleation (template-induced) rate of aspirin crystals. They found that aspirin nucleation was hindered on surfaces with cylindrical pores in the size range 15 to 120 nm.36 Further, as compared to circular pores, hexagonal and square pores reduced the nucleation induction time drastically (Figure 3a). As shown in Figures 3b and 3c, the aspirin crystals nucleated inside the square pores aligned their crystal faces with the pore walls indicating the wedge effect on crystal nucleation. In addition to these effects, favourable solute-template intermolecular interactions influenced the molecular conformation in the pre-nucleation clusters as they approached the pore walls. Validating this hypothesis, upon changing the surface chemistry inside the pores, the nucleation rates decreased due to less favourable solute-template interactions.

Polymeric templates comprising patterns of varying angles has been shown37 to enhance nucleation of acetaminophen over flat templates. Particularly, when the angle of the topographic pattern was closest to the angle between the solute crystal faces, the nucleation rate was highest. Computer simulation38 of heterogeneous crystal nucleation on wedge-shaped grooves has shown similar results grooves of a specific angle increased nucleation rate by several times in comparison with a flat surface. When the wedge angle and the intrinsic lattice angle between the close-packed planes are similar, nucleation rate peaks due to maximum interaction between the solute and wedge surface. Such a mechanism was reported in the case of selective nucleation of metastable form II crystals of mefenamic acid on patterned templates containing square shaped nanopores.39

Even the presence of an airliquid interface can act as a nucleation trigger, as it was shown in the case of glycine crystallisation in both batch and continuous processes.40,41 These studies highlighted the role of surface interactions in promoting crystal nucleation. A related study42 on interfacial crystallisation of caffeine and hydroxy-2-naphtolic acid has shown that polymorphic nucleation of cocrystals can be controlled by regulating thermodynamic conditions at the solution interface formed by two immiscible solvents.

Figure 3: (a) Influence of pore size and shape no average nucleation induction time (τ) of aspirin. (b) AFM image of the square pores on polymer film with (100) layers of aspirin crystals nucleated at the ledges. (c) Schematic of a possible configuration of aspirin crystal facets in the square pore. Reprinted by permission from Springer Nature: Macmillan Publishers Limited ref 36. Copyright 2011.

Surface metal organic framework (SURMOF) templatesthe latest addition to the range of templates used to regulate polymorphic crystallisationoffer the features of both SAMs and metal organic frameworks (MOFs) to enable heterogeneous nucleation control.43 As with porous templates, SURMOFs combine the benefits of both 2-D and 3-D templating effects; as with SAMs, they enhance chemical interactions between the solute and template surface, alongside geometric/ lattice matching.

Several studies have demonstrated the use of soft substrates such as emulsions and gels to induce crystal nucleation. Water-in-oil emulsions with specific template molecules at the emulsion interface has shown to produce pure β form of glycine over the α/β mixture that nucleated in the absence of such additives.44 Similarly, metal-phenolic gels with specific compositions and additives have been shown to regulate the size, morphology, and polymorphism of crystals formed inside the gel.45 In polymeric gels, the void volume could be altered by changing the amount of branching polymer chains or cross-linking agents. As a result, polymeric gels could be formulated to produce matrices with specific confinement sizes and chemistry. Besides polymorph control, the technique of crystallisation within gel matrix could possibly be used for controlled drug delivery application.

Diao et. al., demonstrated the use of microgels to control polymorphic nucleation of CBZ and ROY crystals.46 By altering the mesh size in polyethylene glycol diacrylate (PEGDA) microgels (produced through stop-flow lithography technique), the form II CBZ crystals and R form ROY crystals were selectively crystallised. The authors reasoned that, two factors primarily influence the nucleation process within the gel. Firstly, the localised solute density is increased due to favourable solutepolymer interactions, thereby enhancing the probability for cluster formation. As depicted schematically in Figure 4, the polymer chemistry can influence cross-linking of the gel structure and, in turn, the mesh size. Consequently, it affects the effective volume available for aggregation of the solute molecules as well as their molecular conformation inside the gel. Secondly, specific chemical interactions between the solute and polymer matrix contributes to lowering the nucleation barrier. This effect can also be fine-tuned by altering the polymer chemistry, say by providing more hydrogen-bond acceptor and/or donor functional groups. In a recent study,47 using this concept, supramolecular gel containing specific targeted gelator has been designed to preferentially nucleate the metastable R polymorph of ROY.

Figure 4 Schematic illustration of the effect of gel mesh size of crystal nucleation. At high cross-linking, the mesh size is small that they confine too few solute molecules to form a nucleus (a). When the mesh size is too big, then the solute molecules are not significantly confined and the number of solute-solute interactions may dominate the polymer-aided solute-solute interactions (c). At the optimum mesh size of the gel, the meshes are able to confine and align the right amount of polymer-aided solute-solute interactions to create a stable nuclei (b). Reprinted with permission from ref 46. Copyright 2012 American Chemical Society.

Surface chemistry of heterogeneous template

Intermolecular interactions that occur during template-assisted nucleation include solutesolute, solutesolvent, solutetemplate, and that of templatesolvent. The template surface chemistry can significantly alter the landscape of these intermolecular interactions by influencing both the templatesolvent and solutetemplate interactions.48 Specific molecular interactions between functional groups present on the template surface and solute molecule lead to reduction in the interfacial surface energy associated with crystal nucleation.49 In addition, these interactions can influence the diffusion of solute molecules towards the template surface.

A key aspect to the effect of surface chemistry on template-induced nucleation is that different facets of a crystal expose different functional groups leading to facet-specific interactions with the template surface. Literature studies point out that, in several instances, template surface chemistry plays a complementary role, alongside factors like epitaxy and topography, to influence heterogeneous crystal nucleation. A recent work49 reported the use of biocompatible crystalline substrates sugars like galactose, mannitol, α-lactose monohydrate, and xylitol to induce crystallisation of acetaminophen. Computational modelling of the interactions between the solute and template crystal highlighted that chemical interactions had a greater impact on the template-induced nucleation compared to epitaxial relationship. To illustrate, Figure 5 shows hydrogen-bonding sites engaged in the solute (crystal)template interaction for the case of acetaminophenxylitol system. The abundance of such favourable interactions can play a vital role in increasing the interfacial concentration of the solute molecules and thereafter in tethering the crystal nuclei onto the template surface. Further insights into this mechanism, in the context of classical and two-step nucleation theories, will be provided in the next section.

In certain systems, template surfaces without any molecular order have influenced polymorphic crystallisation, thus highlighting the significance of surface chemistry (rather than epitaxy) on template-induced nucleation. Our recent work on carbamazepine (CBZ) crystallisation on surface functionalised glass templates (through silanisation procedure) was associated with this mechanism. In that study, templates with mercapto and fluoro functional groups induced the nucleation of CBZ form III crystals, whereas cyano functional groups induced form II nucleation.50 In the absence of 2D molecular order, the occurrence of epitaxial nucleation was ruled out; instead, molecular interactions between the solute and functional groups on the template surface was reasoned to be the major factor determining polymorphic nucleation. Likewise, in the case of microgel-induced nucleation of CBZ, which was discussed earlier in section 2.2 and Figure 4, formation of C-H···O hydrogen-bonds between the polymer substrate and CBZ molecules was proposed as a factor contributing to preferential nucleation, in addition to the effect of polymeric gel mesh size on crystal nucleation.46

Figure 5 H-bonding sites involved in the interaction between acetaminophen and xylitol crystal faces. Reprinted with permission from ref 51. Copyright 2017 American Chemical Society.

Whilst it is conceivable that surface chemistry of the template affects the interfacial interactions during template-induced nucleation, the solute concentration, vis-à-vis supersaturation, can influence the extent of solutetemplate interaction considerably, thereby impacting template-induced crystal nucleation. In the case of tolbutamide crystallisation on SAMs, the polymorph obtained was dependent on the supersaturation level: at low supersaturation, phenyl-terminated SAMs nucleated the least stable form IV polymorph whereas methyl- and trifluoromethyl-terminated SAMs resulted in nucleation of form II polymorph due to favourable hydrogen bonding interactions.52 However, at higher supersaturation, different polymorphs nucleated concomitantly on the templates with the same surface chemistry. Through molecular modelling, it was inferred that favourable van-der-Waals, hydrogen bonding, and electrostatic interactions contributed to the solutetemplate interactions, resulting in preferential polymorphic nucleation.

In our previous studies,53 we observed a similar effect of solute concentration on template-induced nucleation of carbamazepine. By constructing template-induced polymorphic domain (TiPoD) plots, we established that the templates were effective in altering the polymorph crystallised only within an intermediate supersaturation region. Under these solution conditions, the solutetemplate interactions are strong enough to tilt the thermodynamics or kinetics of the nucleation process to favour one polymorph over another. With the development of computational models that can factor-in the effect of supersaturation and solvent type on solutetemplate interactions, we could possibly predict surface chemistries for templateinduced polymorphic nucleation control.

In a typical crystallisation process, the solution will be in contact with surfaces made of varied materials such as glass, metals, and polymers. The effect of these materials on the solute crystal nucleation needs to be evaluated before employing a suitable control strategy. In this context, Yang et al.4 studied selective nucleation of carbamazepine (CBZ) in the presence of glass, tin and PTFE surfaces. The experimental results showed that stable form III crystals nucleate more on tin surface than on glass and PTFE surfaces. In addition, at higher supersaturation, increasing the area of accessible template surface for nucleation promoted crystallisation of metastable form II polymorph. Based on the overall results, it was inferred that nucleation of CBZ crystal polymorphs is influenced by template surface chemistry, template area, and solution supersaturation, in the order of decreasing significance.

In the above discussion, the template surface is typically a solid or liquid interface. However, there are examples in the literature where heterogeneous molecules present in the solution (other than the primary solute) act as templates to induce crystal nucleation. Zhang et al.54 studied crystallisation of pyrazinamide (PZA) in the presence of additives that form supramolecular synthon with PZA, resulting in preferential nucleation of chain structured γ form crystals instead of a polymorph with dimer-based crystal structure. In view of ‘molecular templates’ influencing polymorphic nucleation, the underpinning nucleation mechanisms could be studied in the light of several studies that have well documented the effect of impurities and additives on crystal nucleation and growth.55–57

On a related note, interestingly, when additives that typically inhibit crystal growth are present in an immobilised phase, such as a constituent of a polymeric heteronuclei, they promote nucleation due to strong molecular interaction with the solute molecules.58 Matzger and co-workers59,60 used this approach to design polymeric templates with different functional groups and demonstrated their use for polymorph control in pharmaceutical actives like acetaminophen and sulfamethoxazole.

Template-induced nucleation mechanism: CNT or two-step nucleation theory?

In the above case studies, template-induced nucleation is usually discussed in the context of the classical-nucleation theory (CNT). In particular, for the computational modelling studies, the nucleus interacting with the template surface is assumed to possess 3D molecular arrangement similar to the crystal structure. In addition, analysis of induction time measurements is largely based on the CNT construct. Nonetheless, proposals to view template-induced heterogeneous nucleation under the aegis of two-step nucleation mechanism are gaining traction.

Initial studies pertaining to two-step nucleation mechanism mostly focused on macromolecules such as proteins.61 Nevertheless, recent works has reported the occurrence of two-step nucleation mechanism in small molecule crystallisation.62,63 Atomic force microscopy (AFM) studies on the transformation of olanzapine anhydrous to dihydrate crystal form in water revealed formation of dense nanodroplets at the step sites of the dominant (100) face of olanzapine form I crystal prior to nucleation of the hydrate crystalan observation consistent with the two-step nucleation pathway.64 Under unstirred condition, the (100) template surface of olanzapine form I crystal induced nucleation of the stable dihydrate crystal form. However, under stirred conditions, the template effect was weakened possibly due to liquid shearing that dislocated the prenucleation droplets from the crystal surface. Consequently, the kinetic dihydrate crystal form nucleated in the bulk solution. Computational modelling showed that the (100) surface favoured heterogeneous nucleation of the stable (dihydrate) form over the kinetic form.

The work by Cui et al.65 probed into the mechanism of contact-induced heterogeneous nucleation by crystallising isonicotinamide and ROY polymorphs respectively on SAMs with contact force applied to induce nucleation. Their study suggested that templates control polymorphic nucleation by influencing the formation of prenucleation clusters with definite ordering/ orientation through direct interaction with the solute molecules. In contact-induced heterogeneous nucleation, while the early stages follow a similar pathway mechanism, in the later stage, the crystal aggregates may not form chemical interactions with the template surface and eventually detach upon application of contact force.

From both experimental (spectroscopic analysis of saturated and supersaturated solutions) and computational studies, it is known that, induced by the solvent, solute molecules undergo self-association to form specific molecular motifs in the crystallising solution; in turn, these solute clusters can significantly influence nucleation kinetics of the crystal polymorphs. The work by Caridi et al.66 demonstrated that, in the case of isonicotinamide (INA), the presence of template surfaces altered the course of polymorph crystallisation as determined by self-association of the solute. In ethanol solution, while INA is present as both head-to-head dimer and head-to-tail chain motifs, the head-to-head associates dominate the nucleation kinetics, thus resulting in the formation of stable form II crystals. However, in the presence of TiO2 templates (anatase phase), the metastable form I and form III crystals were formed. This shift in the polymorphic outcome may suggest preferential association of INA molecules at the template surface to form head-to-tail motif Analysis of the kinetics data based on the CNT theory indicated that the activity factor (of the template) plays a significant role in altering the polymorphic nucleation.

Hydrogen bond interaction often plays a major role in the self-association of solute molecules leading to crystal nucleation. Using microcrystalline cellulose (MCC) as heterogeneous template, Verma et. al.67 showed that crystal nucleation of API molecules that lack hydrogen bond donors (HBD) is significantly enhanced in the presence of the template. On the other hand, in the case of API molecules that possess both HBD and hydrogen-bond acceptor (HBA) functionalities, the nucleation enhancement is considerably less. Density functional theory (DFT) and molecular dynamics (MD) simulations showed that the polar hydroxyl groups present on MCC efficiently formed H-bonds with those API molecules (for example, fenofibrate) possessing only HBAs. As shown schematically in Figure 6, these interactions aid in adsorption and stabilisation of the solute (fenofibrate) molecules on the MCC surface. Under these conditions, the H-bond lifetime between the solute and template molecules are much greater than the H-bonds involved in APIAPI interaction in the solution. It is envisaged that these molecular events follow the two-step nucleation model, wherein API clusters adsorbed on the template surface when reaching sufficient stability, subsequently convert into crystalline phases.

Figure 6 Schematic representation of solute (fenofibrate) molecules adsorbing and stabilizing on the template surface (microcrystalline cellulose) by forming hydrogen bonds over time. Adapted with permission from ref 67. Copyright 2018 American Chemical Society.

Unique challenges to address in template-induced crystal nucleation studies

The high number of publications over the last decade, including recent reviews,6,7 clearly indicate active research in the area of template-assisted crystallisation. However, mechanistic studies on template-induced crystal nucleation are confronted with some unique challenges. The first challenge pertains to characterisation of interfacial interactions that occur during heterogeneous crystal nucleation on a template surface. Unlike the case with proteins and other macromolecules, direct observation of small molecule clusters (which maybe in the sub-nanometer size range) during the early stages of crystal nucleation is quite challenging. Hence, interaction between the template surface and nucleating crystal are mostly inferred from preferred orientation effects that are observed during template-induced crystallisation. Alternatively, computational models based on molecular simulations has provided insights into the template-induced nucleation process. However, the modelling studies mostly have not accounted for the effect of solvent on template-induced nucleation. With that said, at this stage, it may not be possible to draw far-fetched conclusions on template-induced polymorphic selectivity.

In template-mediated crystallisation studies it is often assumed that the chemical nature and morphological features on the template surface is unaltered after introducing into the crystallising solution. Although this assumption may be valid in general, it might not hold true under specific circumstances. For instance, when 1,5-diaminonaphthalene (DAN) crystals were used as heterogeneous seeds to induce epitaxial nucleation of 3-aminobenzensulfonic acid (3-ABSA), surface morphology of the DAN seed crystals changed under the solution conditions.68 While at the crystallisation temperature of 10 °C, “micro-pyramid” like morphological structures were formed on the seed crystal, at 50 °C, “micro-needle” like morphological structures were formed. Upon crystallisation, the former seeds nucleated an unreported hydrate form of 3-ABSA; the latter seeds nucleated the elusive form I crystals of 3-ABSA. Likewise, interaction of polyelectrolytes with the template surface altered the polymorphic outcome during solution crystallisation of CaCO3 on SAMs.69 These case studies illustrate that the template structure can be changed dynamically under the solution conditions and thus impact template-induced crystal nucleation.

The surface area of the “functionalised/engineered” template relative to other surfaces in contact with the crystallising solution (for example, crystalliser vessel, impeller, baffle, etc.) will be an important factor to consider when scaling up a template-induced crystallisation process. The influence of the latter surfaces on crystal nucleation is often overlooked, partly because of their wide range of chemistries and topographies that make it difficult to predict their effects on crystal nucleation a priori. In case of crystalline templates, the shape (habit) of the template crystals also becomes an important factor. Since the functional groups present on different faces of the template (seed) crystal vary, it is likely to influence the intermolecular interactions encountered during template-induced nucleation. Similarly, characterisation of the template surfaces to quantitatively access the extent of functionalisation and identify the surface functional moieties, by itself, can be quite a challenging task. However, this information is critical to modelling interaction of solute and solvent molecules with the template surface, and eventually, to predict the effect of the template on crystal polymorphism.

Applications of template-induced nucleation in pharmaceutical processing

Besides the operating conditions like supersaturation, seed loading, solvent type and temperature cycling that are conventionally used to control crystallisation processes, recent experimental studies have shown that crystal nucleation can be influenced by several other factors including gravity, pressure, ultrasound, laser light, and templates. The landscape of industrial crystallisation is also constantly changing by incorporating some of these latest developments in the manufacturing process.

Addition of a foreign component – be it a heterogeneous template surface or a solution additive – to alter the crystallisation kinetics of a pharmaceutical drug compound is usually ruled out in the manufacturing process. However, driven by the needs to reduce the manufacturing cost and improve the efficacy of formulated drug products, the pharma industry has begun to recognize the potential of using template substrates in particle formation processes. Some application areas where template-induced nucleation can be potentially employed in secondary manufacturing and formulation processes are highlighted below:

Polymorph control

The possibility of using substances/ compounds that are categorized as ‘Generally Recognized as Safe (GRAS)’ by the Food and Drug Administration (FDA) as templates for controlling crystal nucleation and polymorphism is actively being considered. For example, crystalline excipients such as D-mannitol, -lactose and talc, and amorphous excipient materials like polymers could be used as heterogeneous seeds. As we have already discussed this aspect in the preceding sections, we highlight other novel applications in the ensuing discussion.

Regulating crystal nucleation kinetics during continuous crystallisation process

In traditional batch manufacturing of pharmaceuticals, in-between the crystallisation and tableting steps, multiple secondary downstream unit operationsfiltration, drying, milling, granulation, sieving and blendingare involved. The critical quality attributes of the final dosage form (tablet), which needs to meet stringent regulatory compliance, are determined by efficient performance of each of these intermediate steps. Eliminating one or more downstream unit operations, and consequently shifting from batch to continuous processing can potentially help to increase the efficiency of pharmaceutical manufacturing process.

Various equipment designs, including mixed-suspension, mixed-product removal (MSMPR), oscillatory baffled crystalliser (OBC), and tubular crystallisers have been proposed to run a continuous crystallisation process. In order to maintain the suspension density or solid loading at an optimal level in these crystalliser configurations, it is crucial to control the crystal nucleation kinetics. Having said that, template-induced crystal nucleation can offer a promising approach not only to enhance heterogeneous crystal nucleation rate whilst operating the crystallisation process at lower supersaturation but also to achieve spatial control of crystal nucleation within the crystalliser. The latter factor, under certain crystalliser configuration and operating conditions, could help to avoid bulk nucleation and crystallisation.

From the viewpoint of reducing the process footprint – and hence the capital and operating cost – recent studies have demonstrated the usefulness of continuous heterogeneous crystallisation on excipient materials. Yazdanpanah et al.70 have developed a technique to crystallise an API (acetaminophen) directly on an excipient surface (D-mannitol) in a continuous process. The product, a composite mixture of the API and excipient, collected from the crystalliser was subsequently dried and directly formed into tablets without the need for complex downstream processing steps. By studying the influence of various factors on the continuous processing technique, the authors concluded that excipient selection and process design parameters have a significant impact on drug loading (with a maximum drug loading of 47 wt. % achieved) as well as the API crystal shape and size.

Nucleation control in novel drug formulations

Template-induced crystallisation has also been investigated as a process intensification technology for enabling the manufacture of drug formulations. Herein, we highlight some recent studies directed towards this application. Ling and Chadwick71 investigated a technique involving direct crystallisation of the drug (acetaminophen, sulfathiazole) inside microporous excipient particles (sodium alginate, sodium carboxymethyl cellulose). Their experimental findings showed that polymer chemistry and surface area of the polymer particles play an important role in maximizing the drug loading, encapsulation efficiency, and reducing secondary nucleation in the bulk solution. Furthermore, this method was shown to provide higher drug loadings compared to other encapsulation techniques based on crystallisation on nonporous polymer particles and molecular adsorption of drug into porous particles.

Eral et al.72 demonstrated a technique whereby hydrophilic (acetaminophen) and hydrophobic (fenofibrate) drugs can be formulated in crystalline form within biocompatible alginate microgel particles, which served both as template for heterogeneous nucleation and as encapsulating vehicle. In the case of acetaminophen, a high drug loading could be achieved by equilibrium partitioning and subsequent crystallisation within the hydrogel. On the other hand, loading of fenofibrate via equilibrium partitioning was found to be inefficient. Alternatively, incorporation of emulsion droplets of fenofibrate dissolved in a lyophilic solvent inside the hydrogel enabled higher loading (up to 80%) of the hydrophobic API.

Badruddoza et al. 73 used an emulsion-based crystallisation method to produce spherical crystalline agglomerates – with the aim to improve downstream processability of API crystals by improving flowability, compressibility and compactibility. Spherical agglomerates comprising small individual crystals can also help to enhance bioavailability of a poorly water-soluble API. In that study, silica nanoparticles modified with different functional groups were used as templates to control the polymorphic outcome of glycine (used as a model API molecule) crystallised within water-in-oil emulsion drops generated in a microfluidics setup. In a subsequent study,74 the microfluidic emulsion based-crystallisation platform was used to produce spherical agglomerates of drug crystals with co-formulated excipients. This particular study highlighted the role of process kinetics, viz., liquid-liquid phase separation and supersaturation generation rate by solvent evaporationwhich, in turn, provides sites for heterogeneous crystal nucleationin controlling the polymorphic outcome. However, the work did not provide any insight into the role of excipient (precipitated from the excipient-rich phase) in promoting nucleation kinetics or in selective nucleation of polymorphs.

Concluding remarks

In this review, we have provided an overview of the molecular/ nanoscale mechanisms underlying heterogeneous nucleation of small organic molecules on many diverse template surfaces. As literature studies reveal, template-induced crystal nucleation can be strongly influenced by an interplay of two or more factors, including epitaxial relationship between the template and a developing crystal nucleus, nanoscale topographic features on the template surface and the template surface chemistry. An in-depth understanding of these factors and associated mechanisms can help in the design of template substrates for heterogeneous nucleation control, particularly to alter the polymorphic outcome of a bulk crystallisation process. Moreover, with template surfaces often influencing the induction time and nucleation density, the method can potentially be employed as a process intensification technology to enable manufacturing of crystalline drug formulations, as well as to control product crystal yield, shape and size distribution in both conventional batch and continuous flow-based crystallisers.

From a mechanistic viewpoint, the overall phenomena of template-induced nucleation may be summarised as follows. Irrespective of the type of intermolecular interactions involved in the process, the template surface acts as an anchoring point where the solute molecules self-assemble in the right conformation, thereby leading to the formation of pre-nucleation clusters. Depending on the lifetime of templatesolute interaction and the hydrodynamic conditions prevailing at the template surface, the solute cluster may grow into a stable nucleus while still interacting with the template or may detach from the template surface and move into the bulk solution. Subsequently, the cluster either grows into a stable crystal or dissolves into the solution depending on the kinetic and thermodynamic factors that influence crystal nucleation in the bulk solution. In either case, the template catalyses the nucleation process. When highly specific interactions align the solute molecules in certain oriented conformations, the template may promote nucleation of a particular polymorph.

Despite significant advances in our understanding of the template-assisted crystallisation process, important questions remain unresolved. Foremost amongst these relates to the nature of molecular clusters that interact with the template surface are they crystalline, amorphous or a dense fluid? Data on selective nucleation of crystal polymorphs on SAM and other crystal substrates suggest that the pre-nucleation clusters are likely to possess a crystalline structure; only then can the epitaxial relationship between the template and crystal nucleus drive interfacial interactions between them. Nevertheless, as revealed by recent simulation studies, it is possible for the molecular clusters to lack a definite structure prior to interaction with the template surface. In that case, chemical interactions at the template surface promote solute adsorption followed by structural ordering to form crystal nucleus. The second question relates to the influence of solutesolvent interactions on template-induced crystal nucleation. While previous studies have mostly focused on intermolecular interactions at the template surface, there has been little attention on understanding the effects of solvent environment and solution supersaturation on template-induced crystallisation kinetics. Future studies on these aspects, using both experimental and computational approaches, will pave the way for methodological development of novel crystallisation and formulation technologies using template-induced nucleation as an enabling technique.

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TOC

We assess the major factors governing template-induced nucleation of molecular crystals by reviewing both experimental and simulation studies directed towards deeper understanding of the underpinning mechanisms. Applications in pharmaceutical manufacturing and formulation processes where templating effect is used to promote crystal nucleation and for polymorphic control are highlighted.

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