Inhibition of Nucleation Using a Dilute, Weakly Hydrogen-Bonding Molecular Additive

The effect of a weakly interacting dilute complexing agent on the nucleation rates of a small-molecule solute was explored using the model system of 3-nitrophenol as the inhibited molecule in a toluene solution with a 3-aminobenzoic acid inhibitor. Induction times were measured experimentally using the probability distribution of the solute crystals nucleation events as a function of time. Experimental results demonstrated that a small concentration of inhibitor (0.25% molar with respect to solute) led to a 230% increase in induction times with respect to noninhibited controls at identical super-saturation. Product crystal growth rates, polymorphism, and purity were found to be unaffected by the complexing agent, confirming that the change in nucleation rate was only due to nucleation inhibition. The nucleation rate kinetics of the solute were studied as a function of supersaturation, with and without the inhibitor. Data indicated that upon the addition of the inhibitor, there is a sharp decrease in the pre-exponential factor for the nucleation rate correlation, while there is minimal change on the activation energy. The experimental data were rationalized using a nucleation kinetics model based on the two-step nucleation theory. Analysis of the parameters defined in the nucleation rate equation for the two-step model indicated that the change in rates came from suppression of the ordering kinetic constant for the transition from a prenucleation cluster to a nucleus. A mechanism for the inhibition was proposed in which the formation of intermolecular complexes between solute and additive disrupts the ordering step by hindering the rearrangement of molecules within clusters.