On The Polymorph-Selective Role of Hydrogen Bonding and π - π Stacking in Para-Aminobenzoic Acid Solutions

Abstract

<div><div><div><p>Understanding molecular self-association in solution is vital for uncovering polymorph- selective crystal nucleation pathways. In this paper, we combine solution NMR spectroscopy and molecular dynamics simulations to shed light on the structural and dynamical features of para-aminobenzoic acid (pABA) in solution, and on their role in pABA crystals nucleation. pABA is known to yield different crystal forms (α, and β) depending on solvent choice and su- persaturation conditions. NMR reveals that dominant interactions stabilising pABA oligomers are markedly solvent-dependent: in organic solvents, hydrogen bonds dominate, while water promotes π - π stacking. Despite this clear preference, both types of interactions contribute to the variety of self-associated species in all solvents considered. MD simulations support this observation and show that pABA oligomers are short-lived and display a fluxional character, therefore indicating that the growth unit involved in pABA crystallisation is likely to be a single molecule. Nevertheless, we note that the interactions dominating in pABA oligomers are indicative of the polymorph obtained from precipitation. In water, at low pABA concen- trations - conditions that are known to yield crystals of the β form - carboxylic-carboxylic hydrogen bonds are exclusively asymmetric. At higher pABA concentration conditions in which the crystallisation is known to yield the α form - a small but statistically significant fraction of symmetric carboxylic-carboxylic hydrogen-bonded dimers is present. We interpret the presence of these interactions in solvated pABA oligomers as indicative of the fact that a simultaneous and complete desolvation of two carboxylic groups, necessary to form the sym- metric hydrogen-bonded dimer typical of the α crystal form, is accessible, therefore directing the nucleation pathway towards the nucleation of α-pABA.</p></div></div></div>

Using HOESY NMR Spectroscopy to Characterize Prenucleation Aggregates

“…At highest BA/pFBA concentrations, the HOE signal ratio shows only minor preference for specific associates (red dashed line in Figure 1E). This is in line with our previous studies, 21 showing a great variety of self-associates present in paraaminobenzoic acid solutions in organic solvents, with comparable fractions of various π−π stacked and hydrogenbonded self-associates. Such scenario is likely in this system and would appear as almost random distribution.…”

“…Preference for hydrogen bonding in low-concentration solutions is also supported by NMR dilution experiments (Figure SI3), which show that 13 C chemical shift changes match the hydrogen bonding model systemcyclohexane carboxylic acid. 21 Our MD simulation data support these observations. BA and pFBA molecules in a 2 M methanol solution are densely packed (see the MD simulation snapshot in Figure SI4B), thus satisfying the 19 F− 1 H internuclear distance requirements necessary to observe the HOEs.…”

Reducing Crystal Structure Overprediction of Ibuprofen with Large Scale Molecular Dynamics Simulations

“…The use of highly polar solvents that preclude H-bonding interactions could favour the formation of these structures. 52 In Fig. 4A, the states that are effectively persistent at finite temperature and pressure are shown as blue dots.…”

Combined Use of Structure Analysis, Studies of Molecular Association in Solution, and Molecular Modelling to Understand the Different Propensities of Dihydroxybenzoic Acids to Form Solid Phases

“…The solute’s center of mass and the vector connecting atoms C4 to C7 were used to define the position and absolute orientation of the solute molecules. An in-house python script [ 45 ] was used for collecting and plotting the data. The analysis of probability density distribution of hydrogen-bonded dimers and hydrogen-bonded associates with solvent molecules was performed using the VMD [ 49 ] HBonds plugin by counting the number of hydrogen bonds between the respective oxygen atoms that have a geometry corresponding to a conventional hydrogen bond (the distance between the donor (D) and acceptor (A) is less than 3.0 Å, and the angle D-H-A is 180 ± 20°).…”

“…In our research, we focus on the determination of causes and the mechanism of how the location of the phenolic hydroxyl groups affects the diversity of solid phases formed by the diOHBAs, and in contrast to the previously published studies, we consider all six isomers of diOHBA. We employ a combined use of crystal structure analysis [ 23 , 40 ] and an analysis of molecule electrostatic potential surfaces [ 22 , 41 , 42 ], molecular behaviour, and association studies in solution using vibrational and NMR spectroscopy [ 43 , 44 ] and molecular dynamics simulations [ 45 ] to rationalize molecular interactions and hydrogen-bond formation propensity and to evaluate how the differences present as a result of a change of hydroxyl group position affect the diversity of solid phases formed by the diOHBAs.…”