Tapping into liquid precursors of crystals

Composite caffeine-mineral particles

The vivid colors on this issue's cover show composite caffeine-mineral particles and signify the role of liquid precursors in achieving remarkable material properties. Of recent developments in the field of particle nucleation and growth, the existence of liquid precursors challenges traditional paradigms and presents novel avenues for regulating material structure and form [1–5]. In the case of calcium carbonate (CaCO3), a ubiquitous biomineral of technological relevance, certain macromolecular additives (e.g. poly(acrylic acid)/PAA) enhance the stability of transient liquid mineral precursors and enable pseudomorphic phase transitions [3]. Liquid precursors of small organic molecules lead to complex hierarchical materials as exemplified by glutamate porous microspheres and histidine superstructures [4,5]. Exhibiting properties of a liquid such as capillarity and surface tension, liquid precursors generally lead to atypical particle morphologies distinct from those thermodynamically favored. Even in living systems, certain membraneless organelles exist as phase-separated, liquid-like droplets, suggesting an important relation between the sub-cellular liquid phase behavior and biochemical processes [6]. Such forms of physicochemical non-ideality are also prevalent during the formation of biogenic materials [7,8]. With rapid advances towards deciphering the physical nature of liquid-like inorganic and organic phases, their potential applications in material design appear to be tremendous.

The cover image demonstrates the role of liquid precursors in realizing composite particles with tuned material properties. The particles, primarily composed of a psychoactive drug, caffeine and a mineral phase, CaCO3 are produced using an organic PILP (polymer induced liquid precursor) as the mineralization additive [8]. The organic PILP is initially produced via liquid–liquid demixing [5] and is composed of caffeine and an oppositely charged polyelectrolyte, PAA. Serving as a confined source of material precursors, the organic PILP also induces manifold effects on mineral growth. The composite particles are acicular, however distinct from the high aspect ratio needles of caffeine crystals as well as the thermodynamically favored CaCO3 forms. Mineral precursors such as ions and ion-clusters as well as the physical association of mineral particles are possible factors that inhibit the elongation of caffeine crystals. Overall the morphology of the composite particles suggests that the particle growth mechanism involves (i) the destabilization of the organic PILP phase in the presence of mineral precursors and (ii) the roles of the transient organic liquid phase and subsequently formed organic crystals in modulating the maturation of the co-associated CaCO3 phase [8]. A remarkable feature is accessed via a Zeiss Axio Imager.M2m microscope equipped with a birefringence imaging system (LC-PolScope, Abrio™-Imaging) wherein retardance is determined per pixel. The lower right color map represents respective birefringence orientation. For composites grown in the presence of the organic PILP phase, individual particles exhibit uniform birefringent retardance. This suggests an effective integration of the organic and inorganic phases as well as a certain crystallographic co-orientation between the caffeine and CaCO3 crystals. Thus, mineral growth regulated by organic PILPs produces hybrid particles with tuned material properties of shape, size distribution and crystallographic orientation. With the restricted size distribution of the caffeine crystallites this synthesis approach might be ideal for enhancing the dissolution of sparingly soluble drugs (given the modest aqueous solubility of caffeine is 2 g/100 mL at room temperature). Typically applied physical means for enhancing drug solubility by particle size reduction can involve significant stress, inducing degradation of drug molecules [9]. This problem can be circumvented by utilizing a bottom-top synthesis method regulated by a PILP additive. Another inherent advantage of the PILP-based strategy presented here is the role of attached mineral particles as a filler or excipient material.

The control of particle growth achieved via organic PILPs cannot be attributed to a single physical property of the liquid-like precursor. Different organic PILP phases lead to distinct composite structures subsequent to mineralization [8]. For instance, after mineralization, a PILP phase constituted of citrate and a branched polyethylenimine leads to core–shell structures with a mineral-rich shell. These diverse outcomes of mineralization in the presence of organic PILPs are attributed to multiple factors such as (i) the stability of the organic liquid microphase in course of mineral nucleation, (ii) the fate of organic constituents subsequent to destabilization of the PILP phase, (iii) properties of the liquid–liquid interface between the bulk aqueous environment and the liquid droplets e.g. interfacial tension and charge distribution, (iv) phase behavior of mineral precursors (here Ca2+ and CO32− ions) and amorphous forms with respect to the PILP microphase and bulk aqueous environment and (v) the kinetics of mineralization [8]. Together these factors tune bi-directional interactions between the organic and inorganic players. The mineral species affect the physical properties of the organic phase including cohesiveness and stability, whereas the organic PILPs as well as its constituents spatially regulate mineral growth and structure [8]. Therefore, the phase behavior of additives applied during material formation in the form of aqueous solutes, assemblies, coacervates or PILPs is critical and significantly affects the growth of composite particles in terms of form and structure.

With traditional approaches for controlling material growth typically utilizing low to moderate additive contents in bulk solutions, the potential of non-ideal conditions in tuning particle form, structure and composition needs to be further explored. Material formation routes based on macromolecular crowding, confinement and polymorphism of organic additives emerge well-represented in Nature [7,8]. At present direct emulation of complex microenvironments associated with biomaterials is a challenging task due to significant variation in time and space in course of organism development. However, an understanding of the physicochemical aspects of the niche spaces in Nature's foundry and their corresponding impact on biogenic particle nucleation and growth will certainly advance the in vitro regulation of material form and properties.


AR thanks the Freiburg Institute for Advanced Studies and ZBSA as well as Prof. Dr. Helmut Cölfen, Department of Chemistry, University of Konstanz, Germany for their kind support.

Further reading

[1] J.J. De Yoreo, et al.
Science, 349 (6247) (2015)

[2] F.C. Meldrum, H. Cölfen
Chem. Rev., 108 (11) (2008), pp. 4332-4432

[3] L.B. Gower, D.J. Odom
J. Cryst. Growth, 210 (4) (2000), pp. 719-734

[4] Y. Jiang, et al.
Cryst. Growth Des., 11 (7) (2011), pp. 3243-3249

[5] S. Wohlrab, H. Cölfen, M. Antonietti
Angew. Chem. Int. Ed., 44 (26) (2005), pp. 4087-4092

[6] A.A. Hyman, C.A. Weber, F. Jülicher
Annu. Rev. Cell Dev. Biol., 30 (2014), pp. 39-58

[7] A. Rao, H. Cölfen
J. Struct. Biol. (2016)

[8] A. Rao, H. Cölfen
Biophys. Rev. (2016), pp. 1-21

[9] K.T. Savjani, A.K. Gajjar, J.K. Savjani
ISRN Pharm., 2012 (2012)

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DOI: 10.1016/j.mattod.2017.03.020