Polymorph-Selective Role of Hydrogen Bonding and π–π Stacking in p-Aminobenzoic Acid Solutions

Abstract

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 p-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 supersaturation conditions. NMR reveals that dominant interactions stabilizing 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 crystallization 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 concentrations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 crystallization 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 symmetric hydrogen-bonded dimer typical of the α crystal form, is accessible, therefore directing the nucleation pathway toward the nucleation of α-pABA.

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. 56 In Fig. 4A, the states that are effectively persistent at finite temperature and pressure are shown as blue dots.…”

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

“…Evaporation crystallization experiments were performed by preparing saturated solutions (in water, acetonitrile, 1,4-dioxane, tetrahydrofuran, and 2-propanol) at room temperature; the obtained solutions were filtered and slowly evaporated at ambient conditions. For cooling crystallization, saturated solutions were prepared at elevated temperature (40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50) • C; the obtained solutions were filtered and crystallized in a closed vial at 5 • C. The obtained products were collected by filtration, air-dried, and analyzed by recording powder X-ray diffraction (PXRD) pattern.…”

“…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.…”