Supramolecular architectures in multicomponent crystals of imidazole-based drugs and trithiocyanuric acid

The structures of three distinct forms (cocrystal, salt and a hybrid cocrystal of salt) of multicomponent crystals of imidazole-based drugs (metronidazole, ketoconazole and miconazole) with trithiocyanuric acid as coformer are characterized. Their supramolecular architectures reflect the interplay between different molecular species.


Introduction
Crystal engineering, that is the design of desirable crystal architectures (Desiraju, 1989(Desiraju, , 2007)), has been attracting increasing attention for decades as it offers endless ways of creating new substances.Thanks to the combination of the wide range of ingredients and variety of synthetic methods, there has been rational development in this area (Haskins & Zaworotko, 2021).Recent years in particular have seen great interest in the use of cocrystallization methods to obtain multicomponent crystals (Haskins & Zaworotko, 2021;Saha et al., 2023).Such complex systems, based on noncovalent interactions, are a source of fascination because of possibilities presented by combining several components with each other.Cocrystallization allows systems to be obtained consisting of two or more neutral molecules (cocrystals) or ionized species (salts) and their mixtures (including solvates or polymorphs) (Aitipamula et al., 2012).All mentioned types of multicomponent crystalline structures containing an active pharmaceutical ingredient (API) have great potential in the pharmaceutical industry because (along with improved physicochemical properties) they essentially preserve or even enhance the inherent pharmacological properties of the active substance (Almarsson & Zaworotko, 2004;Yousef & Vangala, 2019;Bolla et al., 2022).Among the APIs, some of the most frequently explored forms are combinations of those based on N-heterocyclic bases, such as imidazoles, with simple aromatic or aliphatic carboxylic acids (Martin et al., 2013(Martin et al., , 2020;;Zheng et al., 2019;Drozd et al., 2021).Imidazole-based compounds are of particular interest in medicinal chemistry as they can have properties such as anticancer, antifungal, antibacterial, anti-tubercular, anti-inflammatory, antineuropathic, antihypertensive, antihistaminic, antiparasitic, antiobesity, antiviral, and others (Zhang et al., 2014;Tolomeu & Fraga, 2023).This study explores the multicomponent crystals of three imidazole-containing drugs, namely, metronidazole (MTZ), ketoconazole (KTZ) and miconazole (MIC), with an effective cocrystallizing agent, trithiocyanuric acid (TTCA) (see Scheme 1).
The unique structural motifs formed between imidazolecontaining drugs and TTCA coformer molecules are promising for the crystal engineering of similar systems; our study therefore looks more closely at the crystal architecture of new multicomponent modifications.It thus provides new insights into the rational design of drugs using potential Ndonor and N-acceptor groups.Our observations are supported by analyses of structural motifs from the geometrical and energetic point of view, and the structural findings are supported by an natural bond orbital (NBO) analysis of the optimized gas-phase structures of TTCA-coformer molecules.
Preparation of MTZ•TTCA.Equimolar amounts (0.05 mmol in a 1:1 molar ratio) of metronidazole and trithiocyanuric acid were dissolved in a water-methanol (1:2, v/v) solution, and left to evaporate in the refrigerator.Crystals suitable for X-ray measurements were obtained in two weeks.
Preparation of MIC•MIC(+)•TTCA(À ).Equimolar amounts (0.05 mmol in a 1:1 molar ratio) of miconazole and trithiocyanuric acid were mixed in ethanol (3 ml) and left to evaporate slowly at room temperature.After two weeks, crystals suitable for X-ray measurements were obtained.

Refinement
Crystal data, data collection and structure refinement details for the three compounds are summarized in Table 1.The H atoms bonded to C atoms were included in the refinement using riding models, with constrained distances set to 0.95 A ˚(aromatic), 0.98 A ˚(R-CH 3 ), 0.99 A ˚(R 2 -CH 2 ) and 1.0 A ˚(R 3 -CH) (for R = C,N,O), and with U iso (H) = 1.2U eq or 1.5U eq (for R-CH 3 only) of the attached C atom.
The hydrogen atoms bonded to heteroatoms (N, O), involved in hydrogen bonds, were located in difference Fourier maps and refined freely.
During the refinement of KTZ(+)•TTCA(À )•0.16H 2 O, the (1,3-dioxolan-4-yl)methoxy fragment was found to be disordered and refined with two alternative positions with the final site-occupancy factors A to B components: k A :k B = 0.625 (7):0.375(7).Additionally, geometrical similarity constraints were applied to the O3A-C15 and O3B-C15 bond lengths using the SADI instruction (in SHELXL).The RIGU command (in SHELXL) was used to maintain the structural integrity of disordered groups.
In KTZ(+)•TTCA(À )•0.16H 2 O, one partially occupied water molecule is present in the crystal structure.The occupancy ratio was refined to 0.160 (8); (O)À H atoms were constrained (AFIX 6) and their U iso was fixed to 1.5U eq (O).The stoichiometry of water was identified by occupancy refinement of electron density located in a solvent-accessible pocket in close proximity to the disordered (1,3-dioxolan-4yl)methoxy fragment.This partially occupied water is engaged in the hydrogen-bonding network.

Pairwise model energies
CrystalExplorer software was used to estimate pairwise model energies (Turner et al., 2014) between molecules within clusters: within a radius of 5 A ˚, for a cocrystal of MTZ-TTCA or 25 A ˚, for a salt of KTZ(+)•TTCA(À )•0.16H 2 O and a cocrystal of salt of MIC•MIC(+)•TTCA(À ) (Spackman et al., 2021).The computational approach uses a B3LYP/6-31G(d,p) molecular wavefunction calculated for the respective molecular arrangement in the crystal.The total interaction energy between any nearest-neighbour molecular pairs was estimated in terms of four components: electrostatic, polarization, dispersion and exchange-repulsion; the calculation employed scale factors of 1.057, 0.740, 0.871 and 0.618, respectively.
Please note that the energy values computed for ionized pairs should be interpreted with care, and thus the approximate set of energies is used to show the energetic trends rather than exact values.

Theoretical calculations
Full geometry optimizations of the trithiocyanuric acid molecule [TTCA] and an anion [TTCA(À )], and of the corresponding hydrogen-bonded dimers TTCA-TTCA, TTCA(À )-TTCA(À )_ortho and TTCA(À )-TTCA(À )_para were performed using the density functional theory (DFT) method with Gaussian16 software (revision C.02; Frisch et al., 2016).The calculations were conducted in the gas phase at the M06L/6-311++G(3df,3pd) level of theory; the meta exchangecorrelation functional M06L is known to have comparable accuracy to CCSD calculations performed on small noncovalently interacting systems (Remya & Suresh, 2013).The harmonic vibrational calculations indicate an absence of imaginary frequencies, thus confirming that the analysed Natural atomic charges and intermolecular donor-acceptor orbital interactions were determined based on NBO calculations, which were performed at the same level of theory as the geometry optimizations.The significance of the orbital interactions was quantified by the stabilization energy E(2) associated with the electron delocalization from the donor orbital (i) to the acceptor (j).This energy was assessed using secondorder perturbation theory, as follows: where q i is the donor orbital occupancy, " j ," i is the diagonal elements (orbital energies), F(i,i) is the off-diagonal NBO Fock matrix element (Foster & Weinhold, 1980;Reed & Weinhold, 1983;Reed et al., 1985).The NBO calculations were performed using NBO3.1 software implemented in the Gaussian16 package.

Cocrystal and salt, and their hybrid
Among multicomponent crystals, cocrystals and salts can be distinguished by the location of the proton between an acid and a base in their structure.A salt is formed by proton transfer from an acid to a base; in this case, ionized molecules are present in the crystal structure; while for a cocrystal, no proton transfer is observed, the proton remains on the acid, and the crystal is composed of neutral molecules.In this study, the location of the hydrogen atom was confirmed from the difference Fourier maps of the single-crystal structures.Thus, both neutral metronidazole (MTZ) and trithiocyanuric acid (TTCA) molecules were found to form a cocrystal, whereas the ketoconazole [KTZ(+)] and trithiocyanuric acid [TTCA(À )] molecules formed a salt; these were ionized by the transfer of one proton from TTCA to the basic imidazole-N atom of KTZ.Additionally, the presence of a partially occupied water molecule, 0.16 (1)H 2 O, indicates the salt is hydrated.
The multicomponent crystal of the third drug, miconazole, is not a typical cocrystal or salt by definition: its asymmetric unit consists of ionized species of miconazole [MIC(+)] and trithiocyanuric acid [TTCA(À )] through analogous proton transfer to that observed in the KTZ salt.However, the crystal structure also contains an additional neutral miconazole molecule (MIC); such a ternary adduct is difficult to categorize.While the debate regarding such classification remains on-going, such molecular complexes can for now be classified as a cocrystal of a salt or a cocrystal salt (Aitipamula et al., 2012;Odiase et al., 2015;Grothe et al., 2016;Zhoujin et al., 2022), or a salt cocrystal (or a salted cocrystal) (Cherukuvada et al., 2013;Yu et al., 2021;Zhang et al., 2023).In this study, the multicomponent crystal of MIC•MIC(+)•TTCA(À ) is classified as a cocrystal of a salt.
There is also another terminology, ionic cocrystals (ICs), which can be used for mixed species observed in MIC•MIC(+)•TTCA(À ).Although originally ionic cocrystals were formed by ionic salts (with an inorganic counterion) and an organic molecule (Braga et al., 2010(Braga et al., , 2011)), recently this concept has been applied to organic salts and a neutral conformer (Wang et al., 2018;Rahmani et al., 2022).However, this nomenclature seems to be less used in the literature.
Additionally, in all studied drug molecules, the imidazole N atom was confirmed to be protonated, as indicated by the analysis of the C-N-C angle in the heterocyclic ring.The C-N-C angle in the neutral metronidazole molecule was found to be 105.74(11) � , which is similar to that found in the neutral miconazole moiety, 105.0 (2) � ; however, both values differ significantly from those found in ionized molecules of miconazole and ketoconazole, these being 109.4(2) � and 107.9 (3) � , respectively.The obtained C-N-C angle values correspond well with the geometry of the imidazole ring found in the various crystal structures of MTZ, MIC and KTZ deposited in the Cambridge Structural Database (CSD version 5.44, September 2023; Groom et al., 2016).For the analysed imidazole-based drugs, the cationic forms were found to exhibit higher values (109-111 � ) than the corresponding neutral moieties (103-106 � ) (Figs. S1-S3 in the supporting information).Only one exception from the rule has been recognized: the first determination of the miconazole hemihydrate from 1979 (MICONZ; Peeters et al., 1979) indicated extremely high C-N-C angles in two independent neutral molecules, these being 107.260 � and 108.516 � .
In addition, while the formation of cocrystals and salts can be predicted by the �pK a rule, [�pK a = pK a (base) À pK a (acid)], this approach cannot be used for testing the multicomponent crystals considered in this study.According to this empirical rule, the cocrystal formation can be expected at �pK a < À 1 and salt formation at �pK a > 4; however, acidbase pairs with �pK a values that lie in-between are difficult to clearly classify (Cruz-Cabeza, 2012).As such, based on the calculated �pK a values for the MTZ (pK a = 2.62), KTZ (pK a = 6.51) and MIC (pK a = 6.91) imidazole bases and trithiocyanuric acid (pK a = 6.35),only the TTCA-MTZ pair meets the criterion for cocrystal formation (�pK a = À 3.73).The remaining two acid-base pairs, namely, TTCA-KTZ and TTCA-MIC, have �pK a values close to 0. Interestingly, the literature pK a value for MTZ differs considerably from those of KTZ and MIC; this reflects a fundamental difference between the substituted nitroimidazole base moiety of MTZ and the pure (unsubstituted) imidazole base of KTZ and MIC drugs.

Molecular structures of imidazole-based drugs
The asymmetric units of the three considered structures of imidazole-based drugs with trithiocyanuric acid, namely, MTZ•TTCA, KTZ  Symmetry codes: (i) À x + 1, y À 1 2 , À z + 1 2 ; (ii) x, À y À 1 2 , z À 1 2 ; (iii) À x, À y À 2, À z.In the cocrystal of salt, MIC•MIC(+)•TTCA(À ), a rootmean-square (RMS) deviation of 0.183 A ˚(Spek, 2020) was calculated for an overlay of 25 non-hydrogen atoms of two MIC molecules (one neutral and one ionized in the asymmetric unit.This reflects a high similarity between the two independent miconazole molecules (one neutral and one ionized) in the asymmetric unit.A molecular overlay is presented in Fig. S4.
In the KTZ(+)•TTCA(À )•0.16H 2 O salt, the cation and anion from the asymmetric unit are linked by a charge-assisted N2(+)-H2� � �N5(À ) hydrogen bond, for which the protonated imidazole-N atom of KTZ acts as a donor (Table 3).Two ionic pairs are joined into a supramolecular motif [presented in green in Fig. 2(b)] by the centrosymmetric N6-H6� � �S3(À x + 1, À y, À z) interaction between two TTCA anions.The C-H� � �O contacts propagate the characteristic motif into a tri-periodic network.A partially occupied water molecule can also be seen in the crystal structure: it appears approximately three times every 20 unit cells.This water molecule does not disturb the formation of the supramolecular motif, being incorporated into the gaps between the molecules interacting with TTCA anions and KTZ cations via O5-H5A� � �O4(À x + 1, À y + 1, À z) and O5-H5B� � �S1(xÀ 1, y, z) hydrogen bonds.If water were not included in the crystal structure, the supramolecular motifs would cluster into (001) di-periodic layers.
On the other hand, in the case of MIC•MIC(+)•TTCA(À ) cocrystal of salt (or ionic cocrystal), the presence of a neutral MIC molecule can be justified by donor-acceptor mismatch compared to the MTZ cocrystal and the KTZ salt.The N atom in the imidazole ring of the neutral miconazole molecule plays an important role as the only strong acceptor of the N-H� � �N hydrogen bond, replacing the oxygen atom in the N-H� � �O interactions in MTZ and KTZ crystals reported here.Summarizing, an additional molecule of MIC is required in the crystal structure to complement and stabilize the supramolecular motif built by the ionic pair.

Hirshfeld surface analysis
To provide further insight into the packing and intermolecular contacts in the analysed structures of multicomponent crystals, the imidazole-based drugs and TTCAcoformer molecules were separately subjected to Hirshfeld surface analysis.Figs.S5 and S6 show the respective percentage contributions of various intermolecular contacts to the Hirshfeld surface area for the two types of molecules.At first glance, it can be seen that the metronidazole moiety has a Hirshfeld fingerprint breakdown different from that of the ketoconazole and miconazole molecules; this is due to the fact that a variety of functional groups (nitro, hydroxyethyl and methyl) are substituted into the imidazole ring of MTZ in contrast to an unsubstituted imidazole moiety and a few other ring fragments in KTZ and MIC drugs.Therefore, the O� � �H contacts represent one of the most important groups on the Hirshfeld surface of MTZ; they are less important in KTZ and disappear for MICs.In turn, contacts with terminal chlorine atoms, such as Cl� � �H, Cl� � �Cl or C� � �Cl, play a dominant role on the Hirshfeld surface of both miconazole molecules, constituting 49.7% of the surface for MIC and 40.7% for MIC(À ), and are also noticeable for KTZ (�16%).In all cases, the next most dominant group of close interactions (30-50%) is represented by H� � �H and C� � �H contacts, although in variable proportions.Surprisingly, S� � �H contacts make a significant contribution to the MTZ area; however, this may be due to the relatively smaller number of atoms and, therefore, the smaller surface area of the MTZ molecule compared to other drugs.The breakdown diagram of contact shares for TTCA differs between the examined structures: the S� � �H contacts clearly dominate, the percentage of H� � �H maintains stable, but the remaining shares (�40%) are significantly diversified.
An analysis of normalized contact distances in two-dimensional fingerprint plots (Figs.S7 and S8) indicates that O� � �H and N� � �H interactions compete with each other to be the shortest for the drug molecules, whereas the S� � �H contacts also become important for TTCA molecules.
In summary, it is difficult to identify trends resulting from the similarity of supramolecular motifs.Rather, differences are observed because of different tri-periodic crystal architectures.

Pairwise model energies
These findings raise the question of the role of hydrogenbonded motifs in the formation of the supramolecular architecture of multicomponent crystals from the viewpoint of the energy of the intermolecular interactions.
The interaction energies for the most important molecular pairs in the examined crystal structures are given in Table 5.In a cocrystal form of MTZ•TTCA, the molecular pair connected by the N-H� � �O(imidazole) hydrogen bond has slightly higher energy than the pair from the asymmetric unit (TTCA-MTZ) binding through the N-H� � �N(imidazole) hydrogen bond, which has a less negative value; in third position is the MTZ-MTZ pair with the O-H� � �O hydrogen bond.However, the difference between the first and last positions does not exceed 5 kJ mol À 1 .It can clearly be seen that the magnitudes of the total energies differ significantly between completely ionized species in a salt and the cocrystal form.The highest attractive pairwise energy is nearly eight times greater for the acid-base pair connected by the N(+)À H� � �N(À ) charge-assisted hydrogen bond (�À 400 kJ mol À 1 ) than for the neutral form.The hybrid structure of the cocrystal of salt, MIC•MIC(+)•TTCA(À ), is confirmed by the observed energetic trends, i.e.À 407 kJ mol À 1 for pairs of molecules with proton transfer compared to À 43 kJ mol À 1 for those without.Thus, it seems that the energetic hierarchy in salts and salt adducts is more varied, and appears to be more transparent than in cocrystals.
In the case of TTCA molecules which are centrosymmetrically related through the N-H� � �S hydrogen bond, those built from neutral molecules have a much lower total attractive energy (À 26.6 kJ mol À 1 ) compared to the acid-base pair in the same cocrystal form, while dimers of TTCA(À ) anions are characterized by a repulsive energy around 150 kJ mol À 1 .

NBO calculations for the TTCA coformer
The study also examined the preferred site of deprotonated nitrogen atom in TTCA, i.e. a site where the proton transfer occurs, in respect to the hydrogen-bonded synthon in the dimer formed by TTCA anions.This was confirmed using NBO analysis, which allows atomic charges to be calculated.As the charge acquired by an atom reflects the extent of electron repositioning, an analysis of atomic charges can provide an insight into the reactivity of the interacting molecular fragments, based on their electronic density distribution.
The TTCA molecule has a specific symmetric structure, with three sulfur atoms bonded to a triazine ring.With respect to the tautomerism of TTCA, in the solid state the predominant form is that with three protonated nitrogen atoms (Scheme 1) (Wzgarda-Raj et al., 2021a); this may be supported by the fact that the N-H group has relatively stronger hydrogen-bonddonor properties than the S-H counterpart (Gilli & Gilli, 2013).
A detailed analysis of the Cambridge Structural Database (CSD) by Wzgarda-Raj et al. (2021b) found a cyclic R 2 2 ð8Þ synthon (Bernstein et al., 1995;Etter, 1990;Etter et al., 1990) formed by N-H� � �S interactions to be the most characteristic for crystal structures with TTCA.This synthon is further propagated to linear or zigzag double chains, cyclic assemblies, and di-periodic structures.In this study, for all investigated multicomponent crystals, the neutral TTCA molecules or anions form centrosymmetric dimers that can be described as a mentioned above ring R 2 2 ð8Þ motif.As a result of N-H� � �N/ N� � �H-N hydrogen bonds between TTCA dimers and imidazole moiety of drug molecules: MTZ, KTZ and MIC, the characteristic finite patterns can be found [Section 3.3; Interaction energies (kJ mol À 1 ) for selected molecular pairs.E tot is the total energy and its individual components: E ele is electrostatic (k = 1.057),E pol is polarization (k = 0.740), E dis is dispersion (k = 0.871), E rep is repulsion (k = 0.618).The TTCA dimers built from neutral and ionized moieties were subjected to NBO analysis to gain a deeper understanding of their electronic structure.For a consistent comparison of the results, the analysis was performed on optimized structures of the neutral molecule and anion, and their corresponding dimers (Fig. 5).Two dimers formed from anions can be distinguished based on the site of deprotonated nitrogen atom assigned as the ortho (N6 atom) or the para (N4 atom) positions with respect to the C-S bond involved in the hydrogen-bonded ring.

Structure
In all considered systems of TTCA, the nitrogen atoms have the most electronegative character among all elements.The charge distribution analysis confirmed that the neutral molecule has high symmetry, and that each type of atom (S, N, C, H) have the same natural atomic charges (Table S1 in the supporting information).In comparison, TTCA(À ) is a less symmetrical anion: one nitrogen atom is deprotonated and has a higher atomic charge (À 0.6030) i.e. less negative, than the other N atoms (À 0.6156).
For two centrosymmetric dimers formed by anions, Figs.5(c)-5(e), one can observe that the molecular symmetry of the anion is broken; among the three nitrogen atoms, the maximum charge is found for the N5 atom, involved in the intermolecular hydrogen bond, and the minimum for the deprotonated nitrogen atom.Applying the observed trends to the dimer formed from the neutral TTCA molecules, the discrimination of charges between N4 and N6 nitrogen atoms can be used to predict the preferred site of proton transfer between TTCA and the base molecule; this site appears to be the ortho position in respect to C-S bond involved in the N-H� � �S hydrogen bond.
Stabilization energy E( 2) Acceptor (j) TTCA TTCA(À ) TTCA-TTCA TTCA(À )-TTCA(À )_ortho TTCA(À ) -TTCA(À )_para  contrary to our observations in the crystalline state.It seems that the packing forces in crystals play a crucial role in the formation of centrosymmetric dimers from TTCA anions.The preferred site for proton transfer between TTCA and other molecules can also be predicted by analysing the donoracceptor orbital interactions within the NBO framework.This theory assumes that the interactions can be examined between the filled Lewis and empty non-Lewis orbitals.The strength of such interactions is quantified by the stabilization energy, E(2), whose highest value corresponds to the strongest interaction (Weinhold & Landis, 2001).It should be noted that the present study focuses only on the interactions involving the orbitals of the nitrogen atoms.The E(2) values are presented in Table 6.For the neutral molecule of TTCA, the orbital interactions of three N atoms have the same stabilization energy values, and this is related to the molecular high symmetry, whereas the corresponding energy values E(2) slightly differ for the TTCA anion and all dimers (Table 6).As the effect of proton transfer can be showed by the smallest stabilization energy values (i.e.below 1 kcal mol À 1 ), for the dimer TTCA-TTCA, it appears that proton transfer is most likely to occur at N6 atom, i.e. the atom involved in the weakest orbital interaction.However, as the energy difference �E(2) between �(S1-C7)!�*N6 and �(S2À C8)!�*N4 is not significant, it is possible that the transfer may also occur at N4 atom.It is highly unlikely for a proton transfer to occur at N5 atom, as its orbital is involved in the strongest interaction and N5 itself is characterized by the smallest atomic charge value [Fig.5(c), Table S1].

Conclusion
The study describes the successful cocrystallization of imidazole-based drugs, namely metronidazole (MTZ), ketoconazole (KTZ), and miconazole (MIC) with trithiocyanuric acid (TTCA), and presents the structural characterization of multicomponent crystals.Interestingly, three different forms were obtained: a cocrystal with MTZ, a salt with KTZ, and a hybrid, a cocrystal of salt with MIC.In the latter two cases, the proton being transferred from acid to base was localized in the difference Fourier map and was confirmed geometrically based on the analysis of the C-N-C angle of the imidazole ring.
For the three multicomponent adducts, the acid-base pair was formed by N-H� � �N hydrogen bonds between TTCA acid and an imidazole N atom; however, in the salt and cocrystal of salt, proton transfer resulted in the exchange of the roles of proton donor and proton acceptor.Regardless of whether proton transfer occurs or not, two acid-base pairs form a related secondary supramolecular motif consisting of TTCA molecules linked by a centrosymmetric N-H� � �S hydrogen bond.
Based on our analysis of supramolecular motifs combined with the analysis of atomic charges calculated for model TTCA systems, it can be seen that both acid-base pairs and the R 2 2 8 ð Þ synthon for TTCA dimers coexist in a common finite pattern.The preferred position for the deprotonated N atom of TTCA is ortho with respect to the C-S bond involved in the N-H� � �S interaction; while the N atom in the para position retains its proton-donor character.In this way, all analysed crystals, regardless of their multicomponent form, are characterized by a related robust motif.This motif is further reproduced in the crystal network in various ways depending on the drug.
The robustness of supramolecular synthons is a critical issue in crystal engineering.As such, our study of the imidazolebased drugs and TTCA molecules provides greater insight into the complex intermolecular forces shaping the architecture of pharmaceutical cocrystals and salts.

Figure 1
Figure 1 Views of the asymmetric unit of (a) MTZ•TTCA, (b) KTZ(+)•TTCA(À )•0.16H 2 O and (c) MIC•MIC(+)•TTCA(À ), with the atom-numbering schemes.In KTZ(+)•TTCA(À )•0.16H 2 O, the major disorder component is drawn using unbroken lines (atoms with A suffix) and the minor disorder component is drawn using dashed lines (atoms with B suffix).Although the partially occupied water molecule is only shown with the minor component representation, it is associated with both orientations of the disordered group.Displacement ellipsoids are drawn at the 30% probability level.H atoms are shown as spheres of arbitrary radii.

Figure 3
Figure 3Crystal packing of MTZ•TTCA cocrystal in a view along the crystallographic a axis showing a layer-cake structure; the colour code is green = MTZ and red = TTCA.

Figs. 2
Figs. 2(a)-2(c)].The common feature of the motifs observed in the crystal structures of salt, KTZ(+)•TTCA(À )•0.16H 2 O, and a cocrystal of salt, MIC•MIC(+)•TTCA(À ), is a privileged site of N atom for proton transfer between the TTCA anion and the imidazole-based drug molecule with respect to the ring synthon.The TTCA dimers built from neutral and ionized moieties were subjected to NBO analysis to gain a deeper understanding of their electronic structure.For a consistent comparison of the results, the analysis was performed on optimized structures of the neutral molecule and anion, and their corresponding dimers (Fig.5).Two dimers formed from anions can be distinguished based on the site of deprotonated nitrogen atom assigned as the ortho (N6 atom) or the para (N4 atom) positions with respect to the C-S bond involved in the hydrogen-bonded ring.In all considered systems of TTCA, the nitrogen atoms have the most electronegative character among all elements.The charge distribution analysis confirmed that the neutral molecule has high symmetry, and that each type of atom (S, N, C, et al. � Supramolecular architectures in multicomponent crystals Acta Cryst.(2024).B80, 294-304

Table 1
Experimental details.