In previous work, it has been shown that the crystal nucleation of salicylic acid (SA) in different solvents becomes increasingly more difficult in the order: chloroform, ethyl acetate acetonitrile, acetone, methanol, and acetic acid. In the present work, vibration spectroscopy, calorimetric measurements, and density functional theory (DFT) calculations are used to reveal the underlying molecular mechanisms. Raman and infrared spectra suggest that SA exists predominately as dimers in chloroform, but in the other five solvents there is no clear evidence of dimerization. In all solvents, the shift in the SA carbonyl peak reflecting the strength in the solvent-solute interaction is quite well correlated to the nucleation ranking. This shift is corroborated by DFT calculated energies of binding one solvent molecule to the carboxyl group of SA. An even better correlation of the influence of the solvent on the nucleation is provided by DFT calculated energy of binding the complete first solvation shell to the SA molecule. These solvation shell binding energies are corroborated by the enthalpy of solvent-solute interaction as estimated from experimentally determined enthalpy of solution and calculated enthalpy of cavity formation using the scaled particle theory. The different methods reveal a consistent picture and suggest that the stronger the solvent binds to the SA molecule in solution, the slower the nucleation becomes.

Over 2100 induction time experiments were carried out for the medium-sized, antipsychotic drug molecule, risperidone in seven different organic solvents. To reach the same induction time the required driving force increases in the order: cumene, toluene, acetone, ethyl acetate, methanol, propanol, and butanol, which reasonably well correlates to the interfacial energies as determined within classical nucleation theory. FTIR spectroscopy has been used to investigate any shifts in the spectra and to estimate the interaction of solute and solvent at the corresponding site. The solution condition has also been investigated by Density Functional Theory (DFT) calculations over (1 : 1) solvent-solute binding interactions at 8 different sites on the risperidone molecule. The DFT computational results agree with the spectroscopic data suggesting that these methods do capture the binding strength of solvent molecules to the risperidone molecule. The difficulty of nucleation correlates reasonably to the DFT computations and the spectroscopic measurements. The results of the different measurements suggest that the stronger the solvent binds to the risperidone molecule in solution, the slower the nucleation becomes.

Nucleation of salicylic acid in different solvents becomes gradually more difficult in the order: chloroform, ethyl acetate, acetonitrile, acetone, methanol and acetic acid. By comparing the results of metastable zone width and induction time experiments new insights are obtained.

Molecular clustering and solvent-solute interactions in isopropanol solutions of fenoxycarb have been thoroughly and systematically investigated by dynamic light scattering, small-angle X-ray scattering, and nanoparticle tracking, supported by infrared spectroscopy and molecular dynamics simulations. The existence of molecular aggregates, clusters, ranging in size up to almost a micrometre is clearly recorded at undersaturated as well as supersaturated conditions by all three analysis techniques. The results systematically reveal that the cluster size increases with solute concentration and time at stagnant conditions. For most concentrations the time scale of cluster growth is of the order of days. In undersaturated solutions the size appears to eventually reach a maximum value, higher the higher the concentration. Below a certain concentration threshold clusters are significantly smaller. Clusters are found to be smaller in solutions pre-heated at a higher temperature, which offers a possible explanation for the so-called "history of solution" effect. The cluster distribution is influenced by filtration through membranes with a pore size of 0.1 μm, offering an alternative explanation for the "foreign particle-catalysed nucleation" effect. At moderate concentrations larger clusters appear to be sheared into smaller ones, but the original size distribution is rapidly re-established. At higher concentrations, although still well below solubility, the cluster size as well as solute concentration are strongly affected, suggesting that larger clusters contain at least a core of more organized molecules not able to pass through the filter.