Combined X-ray Crystallographic, IR/Raman Spectroscopic, and Periodic DFT Investigations of New Multicomponent Crystalline Forms of Anthelmintic Drugs: A Case Study of Carbendazim Maleate

Synthesis of multicomponent solid forms is an important method of modifying and fine-tuning the most critical physicochemical properties of drug compounds. The design of new multicomponent pharmaceutical materials requires reliable information about the supramolecular arrangement of molecules and detailed description of the intermolecular interactions in the crystal structure. It implies the use of a combination of different experimental and theoretical investigation methods. Organic salts present new challenges for those who develop theoretical approaches describing the structure, spectral properties, and lattice energy Elatt. These crystals consist of closed-shell organic ions interacting through relatively strong hydrogen bonds, which leads to Elatt > 200 kJ/mol. Some technical problems that a user of periodic (solid-state) density functional theory (DFT) programs encounters when calculating the properties of these crystals still remain unsolved, for example, the influence of cell parameter optimization on the Elatt value, wave numbers, relative intensity of Raman-active vibrations in the low-frequency region, etc. In this work, various properties of a new two-component carbendazim maleate crystal were experimentally investigated, and the applicability of different DFT functionals and empirical Grimme corrections to the description of the obtained structural and spectroscopic properties was tested. Based on this, practical recommendations were developed for further theoretical studies of multicomponent organic pharmaceutical crystals.


S1.1 Periodic (solid-state) DFT calculations and lattice energy calculation
Periodic DFT computations with all-electron Gaussian-type orbitals (GTO) were performed using Crystal17 [1]. The 6-31G** basis set was used. The tolerance on energy controlling the self-consistent field convergence for geometry optimizations and frequency computations was set to 10 −10 and to 10 −11 Hartree, respectively. The number of points in the numerical firstderivative calculation of the analytic nuclear gradients equals 2. The shrinking factor reflecting the density of the k-points grid in the reciprocal space was set to 4. K-space sampling was limited to the  point. Raman intensities were calculated using the "RAMANEXP" keyword. For isolated molecules and ions in periodic DFT calculations with plane-wave basis set was used cubic box with edge length 60 a.u. The cut-off energies were the same as in calculations of crystal.
Lattice energy calculation using GTO require taking into account the basis set superposition error (BSSE), which requires modification of eq. (s1): Computations of Emol were performed in CRYSTAL17 using the keyword MOLECULE.
BSSE was computed using the Boys-Bernardi counterpoise correction scheme with the S3 MOLEBSSE option [4]. The standard molecular extraction procedure built in CRYSTAL17 does not treat the charged species correctly. This leads to the situation where ions exist instead of neutral molecules. For single point SCF calculations and geometry relaxation, no problems occurred; however, BSSE calculations of ions failed with following error message: ERROR **** GHOSTD **** MOLECULE -SET UHF AND SPINLOCK -ODD NUMBER

OF ELECTRONS
We followed the recommendation of the program and added UHF and SPINLOCK 2 to the input file for MOLEBSSE calculation. This resulted in normal program termination. In order to obtain comparable SCF energies for neutral molecules in gas phase, SCF computations without counterpoise correction were also performed using UHF/SPINLOCK 2 keywords, and BSSE correction was calculated as the difference between the total electronic energies of MOLEBSSE and SCF computations.
The computations using eq. (s2) with neutral molecules in the gas phase were not 'straightforward' as well. Since we could not transform an ion to the corresponding neutral molecule by program means, the molecular structures of pure components (extracted from crystalline CRB/ refcode SEDZUW01, and MLE/ refcode MALIAC12) were used as initial points for Emol calculation. We had to consider BSSE energy for molecular species equal to that for ionic species calculated in UHF approximation.

S1.2. Non-covalent interaction energies
In order to quantify the energies of particular non-covalent interactions in crystal, Bader analysis of crystalline electron density was performed in the TOPOND software [5] currently built into CRYSTAL suit. The search for (3;-1) critical points was conducted between the pairs of atoms within the 5Å radius, and the interactions with electron density ρb in the (3;-1) point higher than 0.003 a.u. were taken for consideration.
The energy of the particular noncovalent interaction, Eint, was evaluated from the local kinetic energy density in the (3;-1) critical point (Gb) according to following equation [6]: Eq. (2) yields reasonable Eint values for molecular crystals with different types of intermolecular interactions: H-bonds, C−H···O, Hal···Hal contacts, etc. [7][8][9]. The additive scheme based on equation (2) provides lattice energies that are close to experimental sublimation enthalpies for single-and multicomponent molecular crystals, as shown in Refs. [10][11][12] S4 Energies of conventional intermolecular H-bonds were also estimated by several correlation equations based either on metric or spectroscopic parameters. For instance, Rozenberg equation [13] (s3) allows estimating the hydrogen bonding energy EHB (kJ· mol -1 ) in liquids, solids and solutions using only the distance between hydrogen and acceptor atoms RHA expressed in nm: Here Dhb = 39.75 kJ· mol -1 , Rhb = 2.75 Å, RDA is the distance between heavy atoms involved in hydrogen bonding in angstroms.  a) Oxygen atom involved in the formation of the intra-and intermolecular H-bonds is denoted as Ob; b) PW stands for plane-wave basis set with cut-off energy 100 Ry. PAW pseudopotentials [15] were taken from pslibrary-1.0.0 (http://quantumespresso.org, Andrea Dal Corso, 2013); S6 a) Oxygen atom involved in the formation of the intra-and intermolecular H-bonds is denoted as Ob; b) all-electron Gaussian-type orbital calculations were performed with the 6-31G** basis set; c) abbreviations used for relative intensities: vs, very strong; s, strong; m, medium; d) non-periodic computations of the CRB dimer in water (PCM); e) IR intensities are given in parenthesis; f) PW stands for plane-wave basis set with cut-off energy 100 Ry and PAW pseudopotentials; g) in the calculations, this is a doublet of bands with almost identical wave numbers and IR intensities S7  Figure S1. Part of the crystal structure with notable non-conventional H-bonds.     S15