(198y) Probing Nanoclustering of Fenoxycarb in Isopropanol Solutions

Crystal nucleation is a widely occurring phenomenon in nature, e.g. in the formation of bones, shells and ice, is of significant industrial importance in the manufacturing of many inorganic and organic materials, and has medical implications, e.g. in the formation of kidney stones and precipitates of amyloid proteins. Despite its importance, the current molecular level understanding of the mechanisms of crystal nucleation from solution is poor, and consequently, there are features of crystal nucleation that still lack proper explanation, e.g. the so-called “history of solution” effect and the influence of filtration on nucleation. Classical theory of nucleation originally developed early in the last century¹ has been used for years to understand primary nucleation. Conventionally crystallization is assumed to proceed via the attachment of ions/molecules to a primary molecule. In recent years, experimental evidence for the existence of various kinds of clusters without crystalline structure in both supersaturated and undersaturated solutions, with sizes of the order of ~100 nm, has started to accumulate^2-7. This has led to development of alternative nucleation theories^{8, 9}, which take their point of origin in the various concepts of clusters. These clusters are proposed to be thermodynamically stable entities without a defined phase boundary, which can be present also in undersaturated solutions. According to the two-step theory of nucleation, originally proposed for nucleation of proteins, concentration fluctuations result in the nucleation of a kind of clusters having a liquid-like structure with a higher concentration of the solute compared to the bulk solution. Final crystal nucleation then takes place within the clusters^{10, 11}. The extent of applicability of these models, and the underlying molecular level mechanisms, are still focal points of investigation and debate.

In the present work, we have investigated the molecular association and clustering of fenoxycarb molecules in isopropanol solution at room temperature with DLS (Dynamic Light Scattering, Malvern Zetasizer ZSP Nano), and verified further using SAXS (Small Angle X-ray Scattering, I22 beamline, Diamond Light Source, UK) and NTA (Nanoparticle Tracking Analysis, Malvern Nanosight LM14). As opposed to most of the molecules so far featured in studies on clustering in solution the fenoxycarb molecule is bigger and have conformational flexibility. Fenoxycarb solutions of various concentrations (x) were very carefully prepared, systematically and periodically analysed with DLS, SAXS and NTA at 25 °C. The presence of clusters in isopropanol solutions of fenoxycarb has been clearly established in this work, using three different analytical techniques. Clusters are found in both under- and supersaturated solutions. There is a good correspondence between the three analytical techniques in terms of cluster size, which ranges up to several hundred nanometers at undersaturated conditions and a few micrometers at supersaturated conditions. The cluster size is found to increase with solute concentration at constant residence time. The observations of the NTA and SAXS experiments on solutions pre-treated at an elevated temperature are consistent with experimental observations of primary nucleation under different conditions, and help explain the strong solution history effects exhibited by this system¹².

Acknowledgments: We gratefully acknowledge the financial support of the Synthesis and Solid State Pharmaceutical Centre, funded by Science Foundation Ireland (grant no. 12/RC/2275), as well as support from the Bernal Institute and the Department of Chemical Sciences, University of Limerick.

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