University of Limerick
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The influence of solvent on the nucleation of mediums-sized flexible organic molecules from solution

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posted on 2022-09-19, 14:59 authored by Manuel Kuhs
In this thesis the influence of solvents on crystal nucleation is probed to progress understanding of crystal nucleation from solution. Induction times of two solutes in different solvents and at different thermodynamic driving forces were measured using a custom 20 mL multireactor system. To account for the wide distribution of induction times under identical conditions, around 2,000 induction times were collected, covering 25 combinations of solute, solvent and thermodynamic driving force. Both the thermodynamic driving force required to achieve median induction times of 2 hours, and the interfacial energies calculated using the Classical Nucleation Theory, were found to decrease in the order ethanol > isopropanol > toluene > ethyl acetate for fenoxycarb, and [n-propanol & toluene] > ethyl acetate > acetonitrile for tolbutamide. Thus both solutes nucleate more easily in ethyl acetate than in either toluene or the alcohols. Absolute values of interfacial energies ranged from 0.5 to 5 mJ/m2 in line with results of similar experiments in the literature. For fenoxycarb these correlated quite well with solvent-solute interaction enthalpies (with the exception of toluene) such that stronger binding of the solute by the solvent corresponded to more difficult nucleation. This trend has recently also been reported for salicylic acid and risperidone. In the case of tolbutamide the same relationship appeared to be complicated by a second mechanism, whereby tolbutamide assumes different solvent-dependent conformers in solution that hinder nucleation relative to the energy barrier of rotating to the conformer found in the crystal. While collecting induction times for fenoxycarb in isopropanol, a history of solution effect on the nucleation rate was discovered whereby nucleation becomes more difficult with increasing pretreatment temperature and time. Such an effect has been sporadically reported for the past 100 years, but its cause remains unsolved. In order to quantify this effect, the influence of solution pretreatment on the nucleation was measured by collecting 1,800 induction times spanning 17 combinations of pretreatment time and temperature. The influence of pretreatment time and temperature on the induction time was found to follow a first order rate reaction with an activation energy of over 260 kJ mol-1. On the basis of modelling it has previously been suggested for this system that the molecular packing in the crystal lattice is not the thermodynamically stable configuration at the level of simple dimers in solution, and that solute aggregation must exist in solution due to the low solvent-tosolute molecular ratio. It is thus hypothesized that the dissolution of crystalline material at first leaves molecular assemblies in solution that retain features of the crystalline structure, which facilitates subsequent nucleation. However, the longer the solution is kept at a temperature above the saturation temperature and the higher the temperature, the more these assemblies disintegrate and transform into molecular structures less suited to form critical nuclei. Thus a third mechanism affecting nucleation from solution may exist, involving the structure of solute clusters. Solubilities, required to estimate thermodynamic driving forces and interfacial energies, were experimentally determined in several organic solvents using a gravimetric method. Temperature ranges of 2-8 °C for tolbutamide and 5-45 °C for fenoxycarb were investigated, with resulting solubilities ranging from 0.002 to 0.05 g tolbutamide / g solvent, and from 0.06 to 29 g fenoxycarb / g solvent. As solubility is a function of the solid-state structure, the latter was carefully identified using powder XRD, SEM, NMR and DSC. Deviations from linearity in a solubility van’t Hoff plot were observed for fenoxycarb, and demonstrated to arise from the van’t Hoff enthalpy of solution containing temperaturedependent heat capacity and activity coefficient terms.



  • Doctoral

First supervisor

Rasmuson, Åke C.





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