Dynamics and Thermodynamics of Ibuprofen Conformational Isomerism at the Crystal/Solution Interface

Abstract

Conformational flexibility of molecules involved in crystal growth and dissolution is rarely investigated in detail, and usually considered to be negligible in the formulation of mesoscopic models of crystal growth. In this work we set out to investigate the conformational isomerism of ibuprofen as it approaches and is incorporated in the morphologically dominant {100} crystal face, in a range of different solvents -water, 1-butanol, toluene, cyclohexanone, cyclohexane, acetonitrile and trichloromethane. To this end we combine extensive molecular dynamics and well-tempered metadynamics simulations to estimate the equilibrium distribution of conformers, compute conformer-conformer transition rates, and extract the characteristic relaxation time of the conformer population in solution, adsorbed at the solid/liquid interface, incorporated in the crystal in contact with the mother solution, and in the crystal bulk. We find that, while the conformational equilibrium distribution is weakly dependent on the solvent, relaxation times are instead significantly affected by it. Furthermore, differences in the relaxation dynamics are enhanced on the crystal surface, where conformational transitions become slower and specific patways are hindered. This leads to observe that the dominant mechanisms of conformational transition can also change significantly moving from the bulk solution to the crystal interface, even for a small molecule with limited conformational flexibility such as ibuprofen. Our findings suggests that understanding conformational flexibility is key to provide an accurate description of the solid/liquid interface during crystal dissolution and growth, and therefore its relevance should be systematically assessed in the formulation of mesoscopic growth models.

Identifying conformational isomers of organic molecules in solution via unsupervised clustering

“…In the field of crystallisation, conformational rearrangements are not only relevant to polymorphism. In our previous work 6 on the study of ibuprofen conformational isomerism at the crystal/solution interface, we demonstrate how, even for relatively small systems, conformational rearrangements, crystal growth and dissolution are inherently coupled. Additionally state-to-state transitions of a molecule along its path of incorporation into the crystal from solution may be limited by conformational rearrangements.…”

“…Computational studies of conformational rearrangement in small organic molecules often use internal torsional angles to describe the adopted molecular configuration. [6][7][8][9] Torsional angles are a convenient way of describing rearrangements as they provide a fine-grained comprehensive picture of the internal molecular configuration space. To describe the conformation of larger molecules such as peptides or aliphatic chains, however, resorting to descriptors such as end-to-end distance or Root Mean Square Deviation (RMSD) 1,10 is a common choice, made necessary by the fact that the torsional angle space for these systems is high-dimensional and impractical to read and interpret.…”

“…Such tools, which allow the systematic classification of molecular configurations regardless of the dimensionality of the space of descriptors necessary to completely capture every conformational change, have the potential to improve existing methodologies for studying the effects of conformational rearrangements during crystal nucleation and growth. 6 Here, we propose a methodology which enables the study of conformational isomerism in a general way for systems with a large number of torsional degrees of freedom. Our approach, based on the application of the Fast Search and Find of Density Peaks clustering algorithm, 26 allows to define a set of conformational states that is common to multiple environments (i.e.…”

Solvent Dynamics and Thermodynamics at the Crystal–Solution Interface of Ibuprofen

“…All images have been created with VMD 19 to be stable in the presence of polar solvents, whilst solvents of low polarity cause dissolution of this surface through enhancing the interactions of neighbouring carboxyllic groups. 20 MD simulations were performed using Gromacs 5.1.4 21 in conjunction with the Generalised Amber Force Field (GAFF) 22 and an explicit representation of the solvent. Force field parameters for the solvent molecules were obtained from the Virtual Chemistry database, 23,24 except for ethanol which was parametrised following the standard GAFF 22 procedure.…”

Can molecular flexibility control crystallization? The case ofparasubstituted benzoic acids

“…This conclusion is conrmed by the conformational analysis above: in both pPENTYLBA and pBOBA the conversion between conformers involves crossing energy barriers of about 13 kJ mol À1 (ie $ 5RT). Typical conformational exchange rates for these chains calculated by molecular dynamics 32,33 suggest that such a barrier is easily crossed and that it is unlikely to limit the interconversion. Indeed our estimated value of the overall activation energy for nucleation of pBOBA (74 kJ mol À1 ) being 5 times higher than the conformational energy barriers conrms that conformational change cannot be rate determining.…”