Crystal nucleation from solutions – transition states, rate determining steps and complexity

Abstract

This introductory paper offers a contemporary view of crystal nucleation. We begin with a molecular interpretation of the transition state and then revisit the use of classical nucleation theory as a means of obtaining molecular scale information from kinetic data. Traditional physical organic chemistry has always utilised the combination of kinetics and thermodynamics in order to gain insight over reaction pathways. Here we demonstrate for the cases of sucrose and p-aminobenzoic acid how solution chemistry, crystallography and kinetics come together to provide self-consistent pictures of the molecular scale processes occurring during nucleation. In this and a number of other systems desolvation of specific functional groups is highlighted as the rate determining step. Finally we move on to discuss the question of complexity, both from a phase and molecular perspective.

Promotion of Mefenamic Acid Nucleation by a Surfactant Additive, Docusate Sodium

“…In fact, in the present work, the growth time t g is decreased in the presence of DOSS in 40 % DMA -% water over the entire supersaturation range examined. The same relation has been found previously 40 for paminobenzoic acid in different solvents, and it was concluded that desolvation of the carboxylic acid group and formation of carboxylic acid dimers is the rate limiting step for nucleation as well as for crystal growth. Studies showing molecular additives to increase the nucleation rate are rather scarce, but it has been found 41 that tailor-made additives can accelerate the growth of γglycine along the fast growing pole by disruption of the solvation, and that crystal growth of Lalanine 42 is accelerated in the presence of L-valine enhancing the rate of surface diffusion.…”

“…Similarly, in 70 % DMA -30 % water at S I =1.75 in the absence of DOSS, the habit of the Form I crystals was plate-like, and did not change upon the addition of 1 mg/mL or 5 mg/mL DOSS(Figure 4.) SEM images of MEF crystals prepared in the absence or presence of DOSS in 40 % DMA -60 % water, at S II =4 40. (isolated at 8 min) and at S II =2.20 (isolated at 15 min).…”

The role of solvent in the self-assembly of m-aminobenzoic acid: a density functional theory and molecular dynamics study

“…by the properties of the solvation environment, there is considerable interest, both fundamental and technological, in understanding how the processes of clustering, nucleation and subsequent growth of a molecular crystal are affected by the solution chemistry. 7,8 However, even advanced spectroscopic techniques such as synchrotron radiation x-ray scattering or atomic force microscopy cannot give a complete understanding of these processes. 9 The interpretation of experimental measurements and, most importantly, the ability to predict how a new crystal phase nucleates and then grows increasingly depends on the use of computer simulations.…”

Reducing the Induction Time Using Ultrasound and High-Shear Mixing in a Continuous Crystallization Process

“…This leaves the nucleation of molecules with slow nucleation kinetics as one of the key challenges for tubular crystallizers. APIs typically belong to this last category due to their high molecular complexity, which is still increasing for recently developed drugs as indicated by their increasing molecular weights [11]. Slow nucleation kinetics can cause difficulties in tubular crystallizers, as residence times are limited and the stochastic nature of crystallization can make the induction times in the small volume of tubular crystallizers excessively long.…”