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The use of growth modifiers in natural, biological, and synthetic crystallization is a ubiquitous strategy for controlling growth and achieving desired physicochemical properties. For crystals that grow classically (i.e., monomer-by-monomer addition), theories of crystallization are well established and the field of growth modification is rather mature, although many questions remain regarding the molecular driving forces of modifier–crystal interactions. A new frontier in crystallization is the application of classical methods to tailor materials that grow nonclassically (i.e., growth by the addition of species more complex than monomers). A recent surge of interest and activity in this field has been driven by mounting evidence of both inorganic and organic materials that grow via nonclassical pathways. In these systems, the challenge of elucidating the mechanism(s) of crystallization is underscored by a diversity of growth units that far outnumber those available for classical routes. In this Perspective, we discuss growth modification in nonclassical crystallization, including examples in the literature, the challenges associated with elucidating the modes of modifier action, and to what degree classical theories can be applied to these complex problems as a means of establishing versatile blueprints for crystal engineering.

Advanced methods of identifying therapeutics for kidney stone disease have created a greater awareness of the potential impact of crystal modifiers in pathological crystallization. Many natural and synthetic species have the capacity to act as growth inhibitors; however, the challenge of bridging in-vitro and in-vivo evidence has proven to be difficult. Future effort to better integrate laboratory research, clinical trials and animal studies has the potential to broaden our understanding of crystal growth modification and its role in mitigating pathological crystallization.

Analysis of the probability distribution of induction times for acetaminophen and glycine supersaturated solutions showed that reduction in sample volume results in an exponential increase in induction times. It approximately increased by a factor of 55 when the volume was reduced from 1000 to 25 μL. To elucidate the use of confinement as an approach to nanocrystal development and polymorph access, we demonstrated the effect of volume reduction on the nucleation of two model compounds, acetaminophen and glycine. Using supersaturated solutions of both compounds at volumes ranging from 1000 to 25 μL, induction time statistics were obtained experimentally. Image analysis revealed that form I acetaminophen and β-glycine formed as the initial primary nucleation event, with β-glycine sometimes followed by a polymorph transformation to γ-glycine shortly after. Image analysis showed no variation in polymorphism occurring for acetaminophen systems across all volumes. However, it was revealed that at volume sizes below 100 μL, primary nucleation in glycine systems shifts toward γ-glycine nucleation. These results demonstrate the effects of volume reduction on nucleation induction times, its implications on polymorphism, and the extent of lessening the probability of a nucleation event.

We show that alkali metals function as effective modifiers of calcium oxalate monohydrate (COM) crystallization wherein alkali-oxalate ion parings reduce the rate of crystal growth by as much as 60%. Our findings reveal a distinct trend in alkali metal efficacy that cannot be explained by colloidal theories or simple descriptors, such as ion size, but is consistent with a theoretical model that accounts for the ion pair's affinity for water.

The synthesis of biocompatible polymers for coating applications has gained significant attention in recent years due to the increasing spread of infectious diseases via contaminated surfaces.

Calcium oxalate crystals are ubiquitous minerals in biogenic, geological, and synthetic systems. It has been shown that the most naturally abundant form of these crystals, calcium oxalate monohydrate (COM), grows via a classical pathway that can be regulated by crystal growth modifiers. One of the most important occurrences of COM is during human kidney stone disease where the role of zinc in pathological stone formation is not fully understood. There are conflicting claims in the literature that zinc functions either as a promoter or inhibitor of COM stone formation. Here, we examine the role of zinc ions in COM crystal growth using a combination of experimental and modeling techniques to elucidate ion−crystal interactions at macroscopic to atomic length scales. From this, we show that zinc reduces the rate of crystal growth and also induces morphological transformations via the introduction of intergrowths that can potentially accelerate crystal growth. Density functional theory calculations indicate high energetic barriers for zinc incorporation in COM crystals, suggesting that changes in crystal growth are related to zinc interactions with COM crystal surfaces. This was confirmed by in situ atomic force microscopy measurements showing a unique ability of zinc ions to truncate the height of layers on the (100) face, which concomitantly affects both the morphology of surface features and the kinetics of layered growth. Collectively, our study suggests that the role of zinc in pathological crystallization is potentially bimodal, consistent with opposing theories in the literature.

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