3.2.2. Molecular Electrostatic Potential Surface

MEPs can provide some clear information in terms of the electrophilic and nucleophilic attack region of the molecule. The values of MEP, related to the strength of intermolecular interactions, can predict the formation possibility of multicomponent crystals. The MEPs mapped on van der waals (VDW) surface of ARI, SAL, and ADI are given in Figure 6, where the red color represents a positive electrical potential and the blue color represents a negative electrical potential. The pKa values were calculated by MarvinSketch and are presented in the black color.

**Figure 6.** Electrostatic potential mapped onto the 0.001 a.u. electron density isosurface of ARI, SAL, and ADI. The maximal and minimal extreme points of electrical potential are marked with red and blue, repectively. The pKa values are presented in black.

As reported by Zhao Yanxiao [18], the global maxima and minima values of the electrostatic potential on the surface in ARI were +36.98 and −41.23 kcal/mol, which corresponded to carbonyl and amino group of the lactam ring, respectively, and formed the N-H··· O homodimers as evidenced in this study. The N2 and N3 atoms of the piperazinyl group had little difference in electrical potential, but the N3 atom had the strong p-π conjugative effect with adjacent benzene ring. As a result, the N2 atom was vulnerable to electrophilic attack, and no ARI variant containing an exclusive protonation of the N3 atom was observed [16]. The global maxima value of the electrostatic potential on the surface in SAL was +53.86 kcal/mol, which corresponded to carboxylate group with a low pKa value (pKa = 2.79). As result, the deprotonated N+-H··· O hydrogen bond was formed in ARI-SAL salt. For ADI, the global and secondary maxima values were +49.71 and +49.66 kcal/mol, which corresponded to both of the carboxylate groups with identical nucleophilic reactivity, respectively. As expected, the deprotonated N+-H··· <sup>O</sup> hydrogen-bonding contacts occurred in real ARI-ADI salt, where the stoichiometric ratio of ARI to ADI was 1:0.5.
