Understanding and Designing Tailor-Made Additives for Controlling Nucleation: Case Study of p-Aminobenzoic Acid Crystallizing from Ethanolic Solutions

Abstract

A workflow for tailor-made additive screening and crystallisation control using a combination of molecular modelling and experimental techniques is presented. The impact of seven structurally analogous additives, the majority of which containing a carboxylic acid group, on the nucleation of alpha-para-aminobenzoic acid is assessed. Intermolecular grid-search modelling is used to determine dimer interaction energies. Of these, three tailor-made additives are found to form stronger carboxylic group dimer interactions with the compound. Solvation energy calculations demonstrate the stability of these dimers in solution. Subsequent intermolecular interaction assessment demonstrates an ability of one of the tailor-made additives to interfere with the molecular preassembly route to nucleation, with molecular charge distributions providing an insight into this effect. Polythermal crystallisation experimental screening confirms the effectiveness of these tailor-made additives to inhibit nucleation. Interestingly, the nucleation mechanism is found to change from instantaneous to progressive nucleation in the absence and presence of the tailor-made additives in solution, respectively, together with an increase in the effective interfacial tension.It includes: pABA crystallisation background science, grid optimization, intermolecular interaction energies and contributions, dimer interaction geometries, dimer solvation and pABA interaction energies, TMAs within pABA crystal structure, statistical T-test, TMA screen MSZWs, pABA optical micrographs, crystallisation and dissolution temperatures, crystallisability and van't Hoff analysis and nucleation kinetic analysis.

Influence of solution chemistry on the solubility, crystallisability and nucleation behaviour of eicosane in toluene : acetone mixed-solvents

“…The resulting changes in nucleation behaviour and mechanism as a function of mixed-solvent composition, also align well with previous studies that have demonstrated that, in single solvent solutions, the IN mechanism is associated with stable prenucleation clusters in solution 24 and a shift towards a PN pathway can be associated with a disruption of the ability of solutions to form stable clusters prior to nucleation. 23 This demonstrates a wider applicability of the results outlined in this study towards other crystallising systems.…”

“…In the PN case, the number of crystallites increases as a function of time, with a large distribution of crystallite sizes, whereas in the IN case there are a fixed number of crystallites of equal sizes, assuming a consistent growth rate. IN occurs when a number of strongly active nucleation sites are present in solution, which can occur due to foreign particles within solution, resulting in heterogeneous nucleation, or when solutions are seeded with crystallites, either externally or self-seeded, or when, as previous studies have highlighted, 23,24 solutions are subject to strong solute clustering, resulting in a number of prenucleation clusters that nucleate at once. Regardless of the mechanism by which nucleation occurs, the solution remains apparently unaffected until a critical level of undercooling is reached corresponding to the limit of the MSZW, at which point the amount of formed crystallites are detectable by the monitoring technique.…”

“…IN could, in principle, result in a more uniform crystal size distribution of product. Previous studies in other organic solvents have highlighted the fact that changes in solution environment, relating to solution solvent and concentration 20,22 as well as the inclusion of nucleation inhibition additives, 23 can alter the mechanism of nucleation. The IN mechanism has been shown to occur when solute clustering is present in solution prior to the nucleation stage, 24 in line with van't Hoff isotherms suggesting strong solute : solute interactions within solution.…”

Energetic and Topological Supramolecular Study and Nucleation Mechanism Proposal of Halogenated Phenols

“…The concept of supramolecular cluster creates the idea of a fixed number of molecules that provide information to help understand the supramolecular interactions of the crystalline system, that is, a cluster formed by the first coordination sphere [11] . Recently, remarkable studies have advanced and correlated theoretical and experimental data for nucleation proposals [17] …”

“…[11] Recently, remarkable studies have advanced and correlated theoretical and experimental data for nucleation proposals. [17] Non-covalent interactions involving aromatic rings play an important role in many chemical [18] and biochemical processes. [19,20] A good understanding of the nature of these non-covalent interactions play a crucial role in many contexts and these energies, in turn, are used to assess the relative importance of the different intermolecular interactions identified in a crystal.…”