Solvation and Aggregation of Meta-Aminobenzoic Acid in Water: Density Functional Theory and Molecular Dynamics Study.

Etienne Gaines,Devis Di Tommaso

doi:10.3390/pharmaceutics10010012

Etienne Gaines, Devis Di Tommaso

Open Access

https://doi.org/10.3390/pharmaceutics10010012

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Journal: Pharmaceutics	Publication Date: Jan 23, 2018
Citations: 8	License type: CC BY 4.0

Affiliation: Queen Mary University of London

Abstract

Meta-aminobenzoic acid, an important model system in the study of polymorphism and crystallization of active pharmaceutical ingredients, exist in water in both the nonionic (mABA) and zwitterionic (mABA±) forms. However, the constituent molecules of the polymorph that crystallizes from aqueous solutions are zwitterionic. This study reports atomistic simulations of the events surrounding the early stage of crystal nucleation of meta-aminobenzoic acid from aqueous solutions. Ab initio molecular dynamics was used to simulate the hydration of mABA± and mABA and to quantify the interaction of these molecules with the surrounding water molecules. Density functional theory calculations were conducted to determine the low-lying energy conformers of meta-aminobenzoic acid dimers and to compute the Gibbs free energies in water of nonionic, (mABA)2, zwitterionic, (mABA±)2, and nonionic-zwitterionic, (mABA)(mABA±), species. Classical molecular dynamics simulations of mixed mABA–mABA± aqueous solutions were carried out to examine the aggregation of meta-aminobenzoic acid. According to these simulations, the selective crystallization of the polymorphs whose constituent molecules are zwitterionic is driven by the formation of zwitterionic dimers in solution, which are thermodynamically more stable than (mABA)2 and (mABA)(mABA±) pairs. This work represents a paradigm of the role of molecular processes during the early stages of crystal nucleation in affecting polymorph selection during crystallization from solution.

Highlights

The substance meta-aminobenzoic acid is of considerable importance in the pharmaceutical industry, widely used in the synthesis of analgesics, antihypertensives, vasodilators, and other drugs [1]
Are denoted by Om and Nm, the hydrogen of amino group are denoted by Ha, the hydrogen atoms of carboxylic group are denoted by Hc, and oxygen and hydrogen of water are denoted by Ow and Figure 3 reports the time evolution of the intra- (Om–Hc and Nm–Ha) and inter-molecular (Om···Hw and Nm···Hw) distances during the Ab initio (Born-Oppenheimer) molecular dynamics (AIMD) simulations of the more stable than (mABA) and mABA± species in water
Both mABA and mABA± molecules are stable in water and should be considered when modeling the aggregation of meta-aminobenzoic acid in aqueous solution

Summary

Introduction

The substance meta-aminobenzoic acid is of considerable importance in the pharmaceutical industry, widely used in the synthesis of analgesics, antihypertensives, vasodilators, and other drugs [1]. This molecules represents a fascinating model system for polymorphic research because it can crystallize in five different crystal structures (I–V) [2]. In Form II, two mABA molecules interact through the O−H···O acid dimer of an R22(8) ring motif (Figure 2a). In Form III, the mABA± molecules form ionic N+−H···O− interactions in an R44(8) ring motif (Figure 2b). In Form IV, two independent molecules form a linear C(7) chain through ionic N+−H···O− interactions (Figure 2c). The nature of the Pharmaceutics 2018, 10, 12; doi:10.3390/pharmaceutics10010012 www.mdpi.com/journal/pharmaceutics

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