The influence of the solvent in nucleation of tolbutamide, a medium-sized, flexible and polymorphic organic molecule, has been explored by measuring nucleation induction times, estimating solvent-solute interaction enthalpies using molecular modelling and calorimetric data, probing interactions and clustering with spectroscopy, and modelling solvent-dependence of molecular conformation in solution. The nucleation driving force required to reach the same induction time is strongly solvent-dependent, increasing in the order: acetonitrile

Induction time experiments, spectroscopic and calorimetric analysis, and molecular modeling were used to probe the influence of solvent on the crystal nucleation of fenoxycarb (FC), a medium-sized, flexible organic molecule. A total of 800 induction times covering a range of supersaturations and crystallization temperatures in four different solvents were measured to elucidate the relative ease of nucleation. To achieve similar induction times, the required thermodynamic driving force, RT ln S, increases in the order: ethyl acetate < toluene < ethanol < isopropanol. This is roughly matched by the order of interfacial energies calculated using the classical nucleation theory. Solvent–solute interaction strengths were estimated using three methods: solvent–solute enthalpies derived from calorimetric solution enthalpies, solvent–solute interactions from molecular dynamics simulations, and the FTIR shifts in the carbonyl stretching corresponding to the solvent–solute interaction. The three methods gave an overall order of solvent–solute interactions increasing in the order toluene < ethyl acetate < alcohols. Thus, with the exception of FC in toluene, it is found that the nucleation difficulty increases with stronger binding of the solvent to the solute.

Nearly 1800 induction time experiments have been performed on crystal nucleation of fenoxycarb in isopropanol to investigate the influence of solution pretreatment. For each preheating temperature and preheating time, at least 80 experiments were performed to obtain statistically valid results. The relationship between the inverse of the induction time and the preheating time can be reasonably described as an exponential decay having time constants ranging up to days depending on the temperature. This dependence on the preheating temperature corresponds to an activation energy of over 200 kJ/mol. Given sufficiently long preheating time and high temperature, the solution appears to reach a steady-state where the "memory" effect has disappeared. Density functional theory modelling suggests that the molecular packing in the crystal lattice is not the thermodynamically stable configuration at the level of simple dimers in solution, while modelling of the first solvation shell reveals that solute aggregation must exist in solution due to the low solvent to solute 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..

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Melting temperatures and enthalpies of fusion have been determined by differential scanning calorimetry (DSC) for two polymorphs of the drug tolbutamide: FI H and FV. Heat capacities have been determined by temperature-modulated DSC for four polymorphs: FI L , FI H , FII, FV, and for the supercooled melt. The enthalpy of fusion of FII at its melting point has been estimated from the enthalpy of transition of FII into FI H through a thermodynamic cycle. Calorimetric data has been used to derive a quantitative polymorphic stability relationship between these four polymorphs, showing that FII is the stable polymorph below approx. 333 K, above which temperature FI H is the stable form up to its melting point. The relative stability of FV is well below the other polymorphs. The previously reported kinetic reversibility of the transformation between FI L and FI H has been verified using in situ Raman spectroscopy. The solid-liquid solubility of FII has been gravimetrically determined in five pure organic solvents (methanol, 1-propanol, ethyl acetate, acetonitrile and toluene) over the temperature range 278 K -323 K. The ideal solubility has been estimated from calorimetric data, and solution activity coefficients at saturation in the five solvents determined. All solutions show positive deviation from Raoult's law, and all van't Hoff plots of solubility data are non-linear. The solubility in toluene is well below that observed in the other investigated solvents. Solubility data has been correlated and extrapolated to the melting point using a semiempirical regression model.

The solubility of fenoxycarb has been determined between 278 and 318 K in several organic solvents. The solid phase at equilibrium and some indication of polymorphism has been properly examined by powder XRD, DSC, Raman and ATR-FTIR spectroscopy, solution 1 H NMR and SEM. Using literature data the activity of the solid phase within a Raoult's law definition has been calculated, based on which solution activity coefficients have been estimated. In ethyl acetate, the van't Hoff enthalpy of solution is constant over the temperature range and equals the melting enthalpy. However, it is shown that the solution is slightly non-ideal with the heat capacity difference term compensating for the activity coefficient term. In toluene, the van't Hoff enthalpy of solution is constant as well but clearly higher than the melting enthalpy. In methanol, ethanol and isopropanol, van Hoff curves are strongly non-linear, the slope however clearly approaching the melting enthalpy at higher temperatures. In all solvents, positive deviations from Raoult's law are prevailing. The activity coefficients follow a decreasing order of isopropanol > ethanol > methanol > toluene > ethyl acetate, and in all solvents decrease monotonically with increasing temperature. The highest activity coefficient is about 18 corresponding to about 2.5 kJ/mol of deviation from ideality.

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