Acceptor Ratios of the Coformers: Do They

Article pubs.acs.org/crystal

Cite This: Cryst. Growth Des. 2018, 18, 5254−5269

Hydrogen Bond Donor/Acceptor Ratios of the Coformers: Do They Really Matter for the Prediction of Molecular Packing in Cocrystals? The Case of Benzamide Derivatives with Dicarboxylic Acids Alex N. Manin,† Ksenia V. Drozd,† Andrei V. Churakov,§ and German L. Perlovich*,† †

G.A. Krestov Institute of Solution Chemistry of the Russian Academy of Sciences, 1, Academicheskaya, 153045 Ivanovo, Russia Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russia

§

Crystal Growth & Design 2018.18:5254-5269. Downloaded from pubs.acs.org by UNIV OF SUNDERLAND on 10/01/18. For personal use only.

S Supporting Information *

ABSTRACT: Seven new 4-aminobenzamide cocrystals/salts with dicarboxylic acids and one 4-hydroxybenzamide/malonic acid 1:1 cocrystal have been obtained and characterized. Analysis of the Cambridge Structural Database of para-substituted benzamide derivatives cocrystals with dicarboxylic acids has been carried out to understand the influence of hydrogen bond donor/acceptor ratios of the coformers on molecular packing similarity in cocrystals. The concept of supramolecular constructs has been used to compare 37 benzamide derivatives cocrystals/salts. Common zero- to three-dimensional structure fragments have been identified and discussed. Two types of zero-dimensional and two types of one-dimensional fragments of closely para-substituted benzamide derivatives have been identified as the dominating motifs. It has been identified that a deviation from the ratio of hydrogen bond donors and acceptors in cocrystal formers increases the probability of formation of multicomponent crystal solvates. In a number of groups of similarly packed crystals, the minimal values of dissimilarity index X (which means maximal likelihood) are observed for the pairs of structures with halogen-substituted benzamide cocrystals. This study is helpful for understanding cocrystal formation mechanisms and has a high significance for crystal engineering.

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of the functional groups, their form, and size.15−17 Tothadi and Desiraju have published a number of works devoted to the studies of synthon modularity in binary and ternary cocrystals of benzamide derivatives with dicarboxylic acids.18−21 The authors supposed that it was possible to introduce dicarboxylic acid between the molecules of benzamide derivatives bound via an amide−amide homosynthon, in order to realize singlecomponent diphenol crystal packing.18 Indeed, this design strategy allowed them to use synthon modularity to obtain a number of cocrystals of benzamide para-derivatives with dicarboxylic acids in the stoichiometric ratio of 2:1. Quite often researchers investigate the hierarchy of supramolecular heterosynthons focusing mainly on the analysis of robust heterosynthons between the most popular functional groups, such as amide, acide, pyridine, and other ones.22−25 In turn, the supramolecular synthon approach fails when the molecular structure does not have such groups26 or when the coformer molecules have several types of functional groups with competing hydrogen bond donors and acceptors. In such cases, an especially important role in cocrystal design is played

INTRODUCTION Cocrystals are multicomponent crystals that consist of two or more neutral molecules interacting with each other via noncovalent bonds1,2 Cocrystals attract a lot of attention of representatives of the pharmaceutical industry as an alternative method of obtaining new drug forms with improved pharmaceutically relevant physicochemical properties.3−5 The main principle of selecting coformers is based on the possibility to form supramolecular synthons. Supramolecular synthons are structural units within supermolecules that can be formed and/ or assembled by known or conceivable synthetic operations involving intermolecular interactions.6 Supramolecular synthons are further categorized into (a) supramolecular homosynthons: composed of identical self-complementary functionalities or (b) supramolecular heterosynthons: composed of different but complementary functionalities.7,8 This method is established from the work by Etter9,10 and the proposed rules for organic compounds which were formulated based upon the predictability of hydrogen bonds. For example, in the process of acid and amide cocrystallization, the homosynthons between, respectively, the −COOH (acid) and −CONH2 (amide) functional groups are replaced with the acid−amide heterosynthon.11−14 That is why one of the main principles of cocrystal design is selecting coformers taking into account complementarity © 2018 American Chemical Society

Received: May 9, 2018 Revised: July 12, 2018 Published: July 17, 2018 5254

DOI: 10.1021/acs.cgd.8b00711 Cryst. Growth Des. 2018, 18, 5254−5269

Crystal Growth & Design

Article

4-Aminobenzamide, (1). 4-Aminobenzamide (30 mg, 0.22 mmol) was dissolved in a minimum amount of acetone. The resulting solution was left for the solvent to evaporate under ambient conditions. Small, colorless plate crystals of 4-aminobenzamide formed after 3 days. 4-Aminobenzamide+/Oxalic Acid− 2:1 Salt, (2). 4-Aminobenzamide (30 mg, 0.22 mmol) and oxalic acid (19.83 mg, 0.22 mmol) were dissolved in ethanol and left for the solvent to evaporate under ambient conditions. Small, colorless needles of the 2:1 salt formed after 4 days. 4-Aminobenzamide +/Oxalic Acid− 2:1 Salt Hydrate, (3). 4-Aminobenzamide (30 mg, 0.22 mmol) and oxalic acid (19.83 mg, 0.22 mmol) were dissolved in acetone and then left for the solvent to evaporate under ambient conditions. Small, colorless blocks of the 2:1 hydrate salt formed after 3 days. 4-Aminobenzamide/Malonic Acid 1:1 Cocrystal, (4). 4-Aminobenzamide (19.83 mg, 0.22 mmol) and malonic acid (22.93 mg, 0.22 mmol) were dissolved in acetonitrile. The dilute solution was left for the solvent to evaporate under ambient conditions. Small, colorless plates of the 1:1 cocrystal formed after 5 days. 4-Aminobenzamide/Succinic Acid 2:1 Cocrystal, (5). 4-Aminobenzamide (30 mg, 0.22 mmol) and succinic acid (26.02 mg, 0.22 mmol) were dissolved in methanol and left to evaporate under ambient conditions. Small, colorless blocks of the 2:1 cocrystal formed after 4 days. 4-Aminobenzamide Acid/Maleic Acid 1:1 Cocrystal, (6). 4-Aminobenzamide (30 mg, 0.22 mmol) and maleic acid (25.6 mg, 0.22 mmol) were dissolved in acetonitrile and left for the solvent to evaporate under ambient conditions. Small, colorless prisms of the 1:1 cocrystal formed after 3 days. 4-Aminobenzamide/Fumaric Acid 2:1 Cocrystal, (7). 4-Aminobenzamide (40 mg, 0.29 mmol) and fumaric acid (17.04 mg, 0.15 mmol) were dissolved in acetonitrile. The resulting solution was left for the solvent to evaporate under ambient conditions. Small colorless prisms of the 2:1 cocrystal formed after 5 days. 4-Aminobenzamide/Pimelic Acid 1:1 Cocrystal, (8). 4-Aminobenzamide (18 mg, 0.13 mmol) and pimelic acid (42.33 mg, 0.26 mmol) were dissolved in acetonitrile. The dilute solution was left for the solvent to evaporate under ambient conditions. Small, colorless prisms of the 1:1 cocrystal formed after 5 days. 4-Hydroxybenzamide/Malonic Acid 1:1 Cocrystal, (9). 4-Hydroxybenzamide (30 mg, 0.22 mmol) and malonic acid (22.76 mg, 0.22 mmol) were dissolved in acetonitrile and left to evaporate under ambient conditions. Small, colorless prisms of the 1:1 cocrystal formed after 8 days. Single Crystal X-ray Diffraction. The single crystal X-ray diffraction data were collected on a Bruker SMART 6K (for 1) and Bruker SMART APEX II (for compounds 2−9) diffractometers using graphite-monochromated Mo−Kα radiation (λ = 0.71073 Å) in the ω-scan mode. Absorption corrections based on measurements of equivalent reflections were applied.31 The structures were solved by direct methods and refined by the full matrix least-squares method on F2 with anisotropic thermal parameters for all the non-hydrogen atoms.32 In the structures 1, 4, 5, 6, 7, and 9 all the hydrogen atoms were found from the difference Fourier synthesis and refined with isotropic thermal parameters. As for 8, all carbon H atoms were placed in calculated positions and refined using a riding model, while amino and hydroxy hydrogen atoms were located from difference map and refined isotropically. In the structures 2 and 3, all carbon H atoms were placed in calculated positions and refined using a riding model; amino and hydroxy hydrogen atoms were located from difference map but were also refined using a riding model due to the low reflectivity of both crystals. High final R-values for compound 2 were the result of its poor crystallinity (very broad and weak diffraction peaks). The crystallographic data were deposited with the Cambridge Crystallographic Data Centre as supplementary publications under the CCDC numbers 1841931−1841939. This information can be obtained free of charge from the Cambridge Crystallographic Data Centre at www. ccdc.cam.ac.uk/data_request/cif.

by weaker noncovalent interactions (H-bonds, C−H···O contacts, or π−π stacking), by which cocrystal molecular packing is realized (hydrogen-bonded dimer or trimer) of cocrystal formers) in the crystal lattice. In our work, we decided to continue Tothadi and Desiraju’s studies and to analyze how an additional hydrogen bond donor in the benzamide molecule can affect the packing of cocrystals with dicarboxylic acids. We chose 4-aminobenzamide as the object of our studies. Chemical structures of the benzamide derivatives and coformers are shown in Figure 1. It should be said

Figure 1. Chemical structures of the compounds used in this study.

that up to now the molecule of 4-aminobenzamide has been not well studied in the context of crystal engineering. Only four hits can be seen in the Cambridge Structural Database (CSD) corresponding to the pure compound27 and three cocrystals (with sulfathiazole,28 sulfamethizole,29 and 3,5-dihydroxybenzoic acid30).

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EXPERIMENTAL SECTION

Materials. 4-Aminobenzamide, 4-hydroxybenzamide, and pimelic acid were purchased from Sigma-Aldrich. The oxalic, fumaric, and glutaric acids were purchased from Acros Organics, and the succinic, adipic, and malonic acids were purchased from Merck. All of them were used as received without further purification. Analytical grade solvents were used for the crystallization experiments. Screening by Solvent-Drop Grinding. 4-Aminobenzamide (or 4-hydroxybenzamide) and coformer were added to 12 mL agate grinding jars with 5 mm agate balls and ground for 30 min at a rate of 500 rpm using a Fritsch planetary micro mill (model Pulverisette 7). For solvent-drop grinding, ca. 0.05 mL of the selected solvent was added to the jars before the grinding started. A total of 50 mg of the sample was used in each ball milling run. Differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) were used to characterize the materials produced with reference to the starting materials to identify whether there had been any changes, and, hence, whether a new solid form had been produced. Single Crystal Preparation by Solution Crystallization. The solvent evaporation method was used to prepare single crystals of the new materials that were identified as promising ones from the screening by grinding. These were used in single crystal X-ray diffraction experiments. 5255



Article

Table 1. ΔpKa Values of Combinations of 4-AmBZA and Coformers

Powder X-ray Diffraction (PXRD). For the samples generated through grinding screening experiments, the data were collected using a Bruker D8 Advance powder X-ray diffractometer with Cu−Kα radiation (λ = 1.54060 Å), applying a 40 kV voltage and a 40 mA current. The data were collected over an angle of 5−30° 2θ with a 0.03° step size. OriginPro 8.5 was used to plot the PXRD patterns obtained. Differential Scanning Calorimetry (DSC). A PerkinElmer DSC 400 differential scanning calorimeter with a refrigerated cooling system (USA) was used to measure the thermal behavior of all the samples. The dried samples (free from the residual solvent), with a mass of 2−5 mg, were placed into an aluminum pan. The heating range was set from 20 °C to 200−300 °C depending on the sample, with a heating rate of 10 °C min−1, and nitrogen gas was used for purging. The unit was calibrated with indium and zinc standards. The accuracy of the weighing procedure was ±0.01 mg. XPac Analysis. The crystal packing similarities which exist between the observed crystals structures have been analyzed quantitatively using the XPac 2.0.2.33,34 It provides information about the extent of dissimilarity (dissimilarity index X) as well as the dissimilarity parameters (stretch parameter, change in angles and planes) between the two crystal structures. For XPac analysis, we took all the atomic coordinates (in crystal geometry) of 4-aminobenzamide. Hirshfeld Surface Analysis. The molecular Hirshfeld surfaces calculations were performed using the CrystalExplorer35 program. The principles of Hirshfeld surfaces were reported in the literature.36−39 In this study, all the Hirshfeld surfaces were generated using a standard (high) surface resolution. The three-dimensional (3D) dnorm surfaces were mapped by using a red-white-blue color scheme, where the red color highlights shorter contacts, the white color represents the contact around van der Waals (vdW) separation, and the blue one is for longer contacts. The two-dimensional (2D) fingerprint plots are shown by using the standard 0.6−2.6 Å view with the de and di distance scales displayed on the graph axes. Crystal Lattice Energy Calculations. The intermolecular interaction energies were calculated using the PIXEL approach developed by Gavezzotti.40,41 This method allows quantitative determination of crystal lattice energies and pairwise intermolecular interactions, with a breakdown of these energies into Coulombic, polarization, dispersion, and repulsion terms. The molecular electron densities for the cocrystals were calculated at the MP2/6-31G** level of theory in the GAUSSIAN09 program. All the hydrogen atoms in the structures were set to the standard neutron values according to the default procedure in the PIXEL program.

compound 4-AmBZA oxalic acid malonic acid succinic acid maleic acid fumaric acid glutaric acid adipic acid pimelic acid

pKa (base)a

pKa (acid)b

ΔpKa

PXRD

2.17, −0.79 0.57, −2.29 −0.79, −2.08 1.47, −3.18 0.37, −1.14 −0.94, −2.02 −1.02, −2.01 −1.08, −2.02

+ + + + + + − +

nature of molecular complex

3.4 1.23, 2.83, 4.19, 1.93, 3.03, 4.34, 4.42, 4.48,

4.19 5.69 5.48 6.58 4.54 5.42 5.41 5.42

salt/salt hydrate cocrystal cocrystal cocrystal cocrystal

cocrystal

a

pKa value calculated using ACE and JChem acidity and basicity calculator.46 bFirst and second pKa values obtained from pKa data compiled by Williams.47

same intermediate zone, in which the nature of the molecular complex is difficult to predict based only on the ΔpKa value. In all the other cases, the ΔpKa values suggest that combinations of 4-AmBZA with the corresponding acid would result in cocrystals (ΔpKa < −1). PXRD was used as the primary analytical method to identify new solid forms of 4-AmBZA with dicarboxylic acids. The solid form screening resulted in a total of seven new solids with all CFs, except adipic acid (Figure S1). Single crystal X-ray diffraction was used to confirm the nature of multicomponent crystals. As a result, salt formation was observed in the case of oxalic acid, and a cocrystal was formed with malonic acid, succinic acid, maleic acid, fumaric acid, and pimelic acid, which is consistent with the ΔpKa values. As for the combination of 4-AmBZA with glutaric acid (Figure S2), any attempts to prepare a single crystal of cocrystal by crystallization resulted in single crystals of a certain individual component. Crystal Structure Analysis. Single crystal X-ray diffraction analyses were performed for one single-component and eight multicomponent crystals. The crystallographic data are detailed in Table 2. The hydrogen bond table (Table S1) and the ORTEP diagrams (Figure S3) for all the solid forms are included in the Supporting Information. 4-Aminobenzamide, (1). The crystal structure of 4-AmBZA was previously reported in the literature by Alleume in 1967 (CSD refcode AMBZAM10).48 The temperature of AMBZAM10 crystal structure determination was ambient, in the 283−303 K range with a high R-factor (7.6%). The 4-AmBZA crystal structure was redetermined at 120 K to make a consistent comparison of all the structures reported in this work. Plate-shaped crystals grown from acetone were found to have a monoclinic, P21 space group with one molecule of 4-AmBZA in the asymmetric unit. By comparing the simulated PXRD patterns of the 4-AmBZA single crystal structures obtained in this study and by Alleaume (Figure S4), we obtained identical diffraction peaks but with some displacement toward higher theta angles of the peak position. Nevertheless, the hydrogen bond patterns in the crystal structure were significantly different from the structure reported in the previous paper.48 The amide functional group of 4-AmBZA now formed hydrogen bonded trimers with the R23(8) ring motif involving N1−H11(syn-oriented)···O1 and N1−H12(anti-oriented)··· O1 (2.02 and 2.52 Å, respectively) interactions. On the other hand, the amine group generated an N2−H21···N2 (2.25 Å) hydrogen bond, resulting in an infinite zigzag C(2) chain along the b-axis, which led to the formation of a 2D

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RESULTS AND DISCUSSION Screening for Multicomponent Crystal Formation Using the ΔpKa Rule. 4-Aminobenzamide is a weak base with the amine group pKa of 3.4. The compound was screened for salt/cocrystal formation with dicarboxylic acids (Figure 1). Dicarboxylic acids are a class of compounds that exhibit a large range of pKa values.42 The nature of a multicomponent crystal (salt or cocrystal) involving acid and base moieties can be predicted by the difference of pKa (ΔpKa = pKa(base) − pKa(acid)) values.43−45 Salt formation is expected if the ΔpKa is greater than 4, and a cocrystal is formed when the ΔpKa is less than −1. In the intermediate ΔpKa range of −1 and 4, the nature of a multicomponent crystal is difficult to predict (salt− cocrystal continuum). Table 1 lists the pKa and ΔpKa values of 4-AmBZA combinations with the coformers (CFs) used in this study. The difference between the pKa value of 4-AmBZA and the first ionization constant of oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, and glutaric acid is found to be within the range of the salt−cocrystal continuum. But analyzing the difference between the pKa of 4-AmBZA and the second ionization constant of CFs, only the combination of 4-AmBZA and oxalic acid gives the value remaining in the 5256


CCDC No. emp. form. form. wt. cryst syst sp. gr. cryst. size, mm a, Å b, Å c, Å α, ° β, ° γ, ° V, Å3 Z Dcalc, g·cm−3 T, K μ, mm−1 Data collection meas rflns ind rflns rflns with I > 2σ(I) Rint Θmax, ° Refinement no. of parameters R1 wR2 GOF, F2 largest diff peak and hole, e·Å−3

+

2 −

5309 1412 1224

0.0359 25.05

120

0.0952 0.2564 1.066 0.620/−0.399

2700 958 904

0.0199 28.99

120

0.0316 0.0889 1.104 0.311/−0.171

4-AmBZA 4-AmBZA /Oxl 1841931 1841934 C7H8N2O 2(C7H9N2O)·C2O4 136.15 362.34 monoclinic monoclinic P21 C2/c 0.40 × 0.40 × 0.15 0.38 × 0.34 × 0.05 7.8133(5) 29.799(11) 5.2554(4) 5.732(2) 8.4547(6) 10.015(4) 90.00 90.00 108.798(2) 106.165(5) 90.00 90.00 328.65(4) 1643.0(10) 2 4 1.376 1.465 120(2) 123(2) 0.096 0.114

1

3 −

5257

0.0705 0.1882 1.052 0.456/−0.390

246

0.0270 25.05

3912 2735 1967

4-AmBZA /Oxl /H2O 1841933 2(C7H9N2O)·C2O4·H2O 380.36 triclinic P1̅ 0.30 × 0.14 × 0.06 3.7159(12) 12.030(4) 18.705(6) 75.522(5) 87.603(5) 89.565(5) 808.9(4) 2 1.562 150(2) 0.124

+

0.0336 0.0951 1.048 0.339/−0.217

202

0.0304 28.00

20546 2539 2153

4-AmBZA/Mlo 1841932 C7H8N2O·C3H4O4 240.22 orthorhombic Pbca 0.35 × 0.20 × 0.07 7.1013(4) 10.3160(5) 28.7193(15) 90.00 90.00 90.00 2103.89(19) 8 1.517 150(2) 0.123

4

0.0526 0.1408 1.009 0.617/−0.246

511

0.0469 26.00

16603 5362 3639

4-AmBZA/Suc 1841936 2(C7H8N2O)·C4H6O4 390.40 monoclinic P21/c 0.20 × 0.15 × 0.10 26.0487(19) 5.1440(4) 21.8997(16) 90.00 111.694(2) 90.00 2726.6(4) 6 1.427 120(2) 0.109

5

Table 2. Crystallographic Data for Refinement of the Crystal Structures Reported in This Paper

0.0405 0.1073 1.120 0.253/−0.222

211

0.0150 27.00

5251 2398 2147

4-AmBZA/Mle 1841935 C7H8N2O·C4H4O4 252.23 triclinic P1̅ 0.35 × 0.30 × 0.20 5.7127(7) 6.7687(8) 14.8950(18) 89.2159(18) 85.9346(17) 73.3493(17) 550.40(11) 2 1.522 150(2) 0.122

6

0.0352 0.1001 1.053 0.422/−0.227

167

0.0162 30.00

10107 2573 2352

4-AmBZA/Fum 1841937 2(C7H8N2O)·C4H4O4 388.38 monoclinic P21/n 0.35 × 0.25 × 0.10 8.7001(6) 5.3133(3) 19.0805(12) 90.00 92.8958(9) 90.00 880.89(10) 2 1.464 150(2) 0.112

7

0.0278 0.0717 1.050 0.131/−0.208

214

0.0250 26.00

6301 1456 1348

4-AmBZA/Pim 1841939 C7H8N2O·C7H12O4 296.32 monoclinic P21 0.40 × 0.40 × 0.22 5.1674(5) 19.3418(19) 7.4638(7) 90.00 106.797(1) 90.00 714.16(12) 2 1.378 150(2) 0.105

8

0.0341 0.0954 1.085 0.388/−0.193

198

0.0154 30.00

12429 3082 2765

4-OHBZA/Mlo 1841938 C7H7NO2·C3H4O4 241.20 monoclinic P21/n 0.42 × 0.20 × 0.15 5.3417(3) 9.8721(5) 20.1592(10) 90.00 97.4124(7) 90.00 1054.19(10) 4 1.520 150(2) 0.128

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Crystal Growth & Design Article



Article

Figure 2. 2D packing structure of 1.

Figure 3. Crystal structure of salt 2 (a) 1D chain (b) 2D structure showing the intersection of chains.

4-AmBZA. Upon salt formation with 4-AmBZA, the Oxl− adopts a twisted conformation (the dihedral angle between the planes of carboxylic groups −33.9°). The 4-AmBZA+ cations form a nonplanar dimeric unit via an amide−amide R22(8) homosynthon involving N1−H11···O1 (1.96 Å) hydrogen bonding. The adjacent dimer units are interconnected to each other via Oxl− dianions constructing tetramers with the R44(14) ring motif through strong N2+−H21···O3− (1.84 Å) and N2+− H23···O2− (1.90 Å) interactions and form an infinite onedimensional (1D) chain (Figure 3a). In the crystal structure, the chains propagate parallel to the two crystallographic planes that have an intersecting angle of nearly 90° between them, resulting in a 3D network structure (Figure S7). The perpendicular chains are interconnected with each other via N1− H12···O1 (1.99 Å) (R46(16) ring motif) hydrogen bonding between the 4-AmBZA+ homosynthons and through the

nonplanar structure (Figure 2). Finally, the 2D structures arranged into a 3D architecture via N2−H22(amine)··· O1(amide) (2.16 Å) hydrogen bonding between them (Figure S5). Generally, the way of 4-AmBZA crystal packing was analogous to that of the corresponding 4-hydroxybenzamide (CSD refcode VIDMAX0218). The similarity in the unit cell and isostructurality index of the 4-AmBZA and 4-OHBZA crystal structures was quantified by the XPac method. The dissimilarity index for the structures was 0.4, which is indicative of 3D isostructurality of the given BZA derivatives (Figure S6). 4-Aminobenzamide+/Oxalic acid− 2:1 Salt, (2). It crystallizes in the monoclinic, C2/c space group with Z = 4 (Z″ = 1.5).49 The asymmetric unit consists of one cation of 4-AmBZA+ and half a dianion of Oxl−. The proton of the carboxyl group has transferred to the amine group of 5258



Article

Figure 4. Crystal structure of salt hydrate 3 (a) 1D chain (b) 2D structure.

formation of the R44(14) tetramers involving 4-AmBZA+ (N2+− H21···O3− and N2+−H23···O2− hydrogen bonds) between the same tetramers of adjacent chains (Figure 3b). 4-Aminobenzamide+/Oxalic Acid− 2:1 Salt Hydrate, (3). It crystallizes in the triclinic, P1̅ space group with Z = 2 (Z″ = 4). The asymmetric unit consists of two cations of 4-AmBZA+, one dianion of Oxl−, and one molecule of H2O. Proton transfer from the carboxyl group of Oxl to the amine group of 4-AmBZA is clearly evident. In contrast to the previous case, the Oxl− adopts a nearly planar conformation (the dihedral angle between the planes of carboxylic groups is 4.6°). In the crystal structure, the crystallographically different 4-AmBZA+ cations are engaged in the amide−amide R22(8) homosynthon involving N11−H11a···O21 (1.95 Å) and N21−H21a···O11 (2.28 Å) hydrogen bonds. The adjacent dimeric units are interconnected with each other by alternating different types of tetramers with R44(14) (N22+−H22b···O1− (1.78 Å), N22+− H22c···O2− (1.80 Å)), and R24(8) (N12+−H12a···O3− (1.93 Å), N12+−H12c···O3− (1.93 Å)) ring motifs resulting in an infinite 1D chain (Figure 4a). The chains are stacked along the ab-axis to form a 2D structure (Figure 4b). The connection between the 4-AmBZA+ dimers of the adjacent chains is established by the alternation of the R46(12) ring motif (O5− H5b···O21 (1.95 Å), N11−H11b···O5 (2.07 Å)) with two incorporated H2O molecules and a tetramer with the R24(8) ring

motif involving N21−H21b···O11 (2.12 Å) hydrogen bonding. The paralleled 2D structures arrange into a 3D architecture only due to interactions between the Oxl− tetramers (Figure S8). 4-Aminobenzamide/Malonic Acid 1:1 Cocrystal, (4). It crystallizes in the orthorhombic, Pbca space group with Z = 8 (Z″ = 2). The asymmetric unit consists of one 4-AmBZA and one Mlo molecule. The molecules adopt a nearly planar conformation. The Mlo molecule is stabilized via a strong intramolecular O3−H31···O4 (1.63 Å) hydrogen bond to form a S(6) ring motif. The two-component adduct (4-AmBZA and Mlo molecules) is held together by the expected acid-amide R22(8) heterosynthon involving strong O5−H51···O1 (1.53 Å) and N2−H22···O4 (1.99 Å) hydrogen bonding. These dimeric units are associated through weak bifurcated N1−H12···O2 and N1−H12···O3 (2.24 and 2.64 Å, respectively) hydrogen bonds of the R21(4) ring motif, building an infinite corrugated 1D chain along the c-axis (Figure 5a). The adjacent chains connect via the N1−H11···O2 (2.239 Å) hydrogen bond between the amine group of 4-AmBZA and the carbonyl oxygen atom of Mlo, which results in an infinite zigzag C(3) chain along the b-axis and formation of a 2D wave-like structure (Figure 5b). The corrugated layers stack along the a-axis in an antiparallel fashion via the weak N2−H21(anti-oriented)···O1 (2.41 Å) interaction between the 4-AmBZA molecules (Figure S9). 5259



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Figure 5. Crystal structure of cocrystal 4 (a) 1D chain (b) 2D structure.

4-Aminobenzamide/Succinic Acid 2:1 Cocrystal, (5). It crystallizes in the monoclinic, P21/c space group with Z = 6 (Z″ = 4.5). The asymmetric unit consists of three molecules of 4-AmBZA and one-and-a-half molecules of Suc. The general way of formation of a 2D structure of the 4-AmBZA cocrystal with Suc is the formation of three-component base−acid−base supramolecular units with an inversion center at the center of the Suc molecule. Since there are three crystallographically different molecules of 4-AmBZA in the asymmetric unit, in the crystal structure there are two types of three-component supramolecular units bonded via acid-amide R22(8) heterosynthons and arranged into different 2D structures (Figure 6a). The first type of base−acid−base units is formed from crystallographically identical 4-AmBZA molecules involving O52− H52···O11 (1.67 Å) and N11−H11a···O51 (2.10 Å) hydrogen bonds (Figure 6a) linked to each other through N11− H11b(antioriented)···O11 (2.23 Å) and N12−H12a···N12 (2.29 Å) interactions between the 4-AmBZA molecules to form infinite C(4) and C(2) chains, respectively (Figure S10a). The second type of base−acid−base unit is formed from crystallographically different 4-AmBZA molecules via different acid-amide R22(8) heterosynthons involving O44−H44···O21 (1.64 Å), N21−H21a···O43 (2.10 Å), and O42−H42···O31 (1.59 Å), N31−H31a···O41 (2.17 Å) hydrogen bonds (Figure 6b). The resulting units are self-assembled into a 2D nonplanar structure via N21−H21b(anti-oriented)···O21 (2.23 Å), N31−H31b(anti-oriented)···O31 (2.22 Å), and N22−H22b···N32 (2.29 Å) interactions between the 4-AmBZA molecules to form infinite C(4), C′(4), and C(3) chains, respectively (Figure S10b). The 2D structures arrange into a 3D architecture (Figure 6b). The identical 2D structures interconnect in the slipped manner via the N22−H22a···O44 (2.38 Å) hydrogen bond. The different 2D structures pack through the N32−H32a···O52 (2.42 Å) hydrogen bond. 4-Aminobenzamide/Maleic Acid 1:1 Cocrystal, (6). It crystallizes in the triclinic, P1̅ space group with Z = 2 (Z″ = 2). The asymmetric unit consists of one 4-AmBZA and one Mle molecule. The cis-orientation of both carboxylic groups of Mle predisposes this compound in planar conformation to

form a strong intramolecular O14−H14···O12 (1.51 Å) hydrogen bond with the S(7) ring motif. The cocrystal is composed of corrugated chains (Figure 7a) that consist of repeating dimeric units via an acid−amide R22(8) heterosynthon of O11− H11···O1 (1.49 Å) and N1−H1···O12 (2.09 Å) hydrogen bonds. The two-component units are linked to each other through N2−H21···O13 (2.20 Å) between the amine group of 4-AmBZA and the carbonyl oxygen atom of Mle and the weaker N1− H2(anti-oriented)···O1 (2.708 Å) interactions between 4-AmBZA molecules along the a-axis to form infinite C(3) and C(4) chains, respectively, which results in a 2D structure (Figure 7b). 4-Aminobenzamide/Fumaric Acid 2:1 Cocrystal, (7). It crystallizes in the monoclinic, P21/n space group with Z = 2 (Z″ = 1.5). The asymmetric unit consists of one molecule of 4-AmBZA and half a molecule of Fum. The two carboxylic acid groups of Fum are involved in the acid−amide R22(8) heterosynthon with 4-AmBZA through O21−H21···O11 (1.603 Å) and N11−H11···O22 (2.084 Å) hydrogen bonds. This hydrogen-bonded motif generates a three-component base− acid−base supramolecular unit with an inversion center at the center of the Fum molecule (Figure 8a) as in the [4-AmBZA + Suc] cocrystal. The resulting three-component supramolecular units are self-assembled into a 2D nonplanar structure via N11−H12(antioriented)···O11 (2.352 Å) and N12−H2···N12 (2.334 Å) interactions between the 4-AmBZA molecules to form infinite C(4) and C(2) chains, respectively (Figure 8b). The 2D structures are then fitted into the 3D architecture in a slipped manner via the weaker N12−H1(amine)···N11(amide) (2.730 Å) interaction between the 4-AmBZA molecules (Figure 11). The [4-AmBZA + Suc] and [4-AmBZA + Fum] cocrystals are 3D isostructural with the XPac dissimilarity index value of 8.8 (Figure S12). 4-Aminobenzamide/Pimelic Acid 1:1 Cocrystal, (8). It crystallizes in the monoclinic, P21 space group with Z = 2 (Z″ = 2). The asymmetric unit consists of one molecule each of 4-AmBZA and Pim. The molecules of 4-AmBZA and Pim form a zigzag hydrogen bonded 1D chain that consists of repeating dimeric units formed via acid-amide R22(8) heterosynthon of O11− H11···O1 (1.53 Å) and N1−H1···O12 (2.03 Å) hydrogen 5260



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Figure 6. Crystal structure of cocrystal 5 (a) types of the three-component supramolecular units (b) 3D architecture.


bonds linked through weak bifurcated N2−H22···O14 (2.35 Å) and N2−H22···O13 (2.627 Å) interactions of the R21(4) ring motif as in 4 (Figure 9a). The chains are stacked along the ac-axis by two alternating R24(8) ring motif (N2−H21···O12,

N1−H2···O14 (2.27 and 2.28 Å, respectively)) and O13− H13···O11 (1.91 Å) interactions in a staggered arrangement to form a 2D flat structure due to the planar conformation of the molecules (Figure 9b). 5261



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4-Hydroxybenzamide/Malonic Acid 1:1 Cocrystal, (9). It crystallizes in the monoclinic, P21/n space group with Z = 4 (Z″ = 2). The asymmetric unit consists of one 4-OHBZA and one Mlo molecule. Similar to cocrystal 4, the Mlo molecule is stabilized via the strong intramolecular O14−H14···O12 (1.66 Å) hydrogen bond forming the S(6) ring motif. The crystal structure is composed of hydrogen bonded 1D chains held together by the acid−amide R22(8) heterosynthon of O1−H11···O1 (1.47 Å) and N1−H1···O12 (2.015 Å) interactions and linked to each other via the

O2−H5···O13 (1.805 Å) hydrogen bond (Figure 10a). The chains run in two nearly perpendicular directions hydrogen bonded through the N1−H2···O2 (2.125 Å) interaction between the 4-OHBZA molecules to form a 3D network structure (Figure 10b). Interestingly, the way of crystal packing of cocrystal 9 is analogous to that of the corresponding [4-OHBZA + Mle] (1:1) cocrystal obtained by Tothadi et al.18 Conformational Analysis. Considering that the amide functional group can rotate via the C−C bond, the BZA derivatives (4-AmBZA and 4-OHBZA) can adopt different 5262



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Figure 10. Crystal structure of cocrystal 9 (a) 1D chain (b) 3D network structure.

to 28.5° (4-OHBZA forms). A statistical analysis has shown that cocrystal formation in all cases leads to a decrease in the amide group rotation angle due to the formation of an acid− amide heterosynthon with dicarboxylic acid and N−H(antioriented)−O hydrogen bonds between the 4-AmBZA or 4-OHBZA molecules compared to their parent structures. 4-AmBZA and 4-OHBZA molecules adopt a nearly planar conformation in the [4-AmBZA + Pim] (β1 = 1.4°) and [4-OHBZA + Mle] (β1 = 2.5°) cocrystals. In contrast, 4-AmBZA salt formation affects the conformation states of both the BZA derivative and the coformer. Formation of a homosynthon between the 4-AmBZA ions leads to an increase in the amide group rotation angle compared to the β1 value in the 4-AmBZA parent structure. The values of the dihedral angle (β2) between the planes of the carboxylic group of dicarboxylic acids in multicomponent crystals are summarized in Table S2. Salt formation has resulted in twisting of the oxalate ion away from its normal planar geometry (β2 = 33.9°) as in the [4-OHBZA + Oxl] cocrystal (β2 = 0°). However, in the [4-AmBZA+ + Oxl− + H2O] salt hydrate, the oxalate ion adopts a slightly twisted conformation with β2 = 4.6°. It can be explained by different ways of crystal packing in oxalate salts of 4-AmBZA. In all the other cases, the conformation of dicarboxylic acid in cocrystals with 4-AmBZA and 4-OHBZA depends on its carbon chain length. Even-chain acids adopt planar or slightly twisted conformations, while odd-chain acids display twisted conformations as in their parent structures.50 Hirshfeld Surface Analysis. Hirshfeld surface analysis is an effective method used to characterize different types of intermolecular interactions and to obtain additional information in crystal structure analysis.36−39 This approach is often applied for quantitative determination and comparison of intermolecular interactions of structurally similar compounds including multicomponent crystals (salts, cocrystals, and solvates) and polymorphs. Any crystal structure has unique 3D Hirshfeld surface and 2D fingerprint plots, which allows making a

conformations in the crystal structure. Figure 11 shows the overlay diagrams of different 4-AmBZA and 4-OHBZA conformers

Figure 11. Overlay diagrams of different conformers found in (a) 4-AmBZA and (b) 4-OHBZA multicomponent crystals. Color code: (a) red [4-AmBZA+ + Oxl−], green [4-AmBZA+ + Oxl− + H2O], magenta [4-AmBZA + Mlo], cyan [4-AmBZA + Suc], blue [4-AmBZA + Mle], yellow [4-AmBZA + Fum], orange [4-AmBZA + Pim]; (b) red [4-OHBZA + Oxl], magenta [4-OHBZA + Mlo], cyan [4-OHBZA + Suc], blue [4-OHBZA + Mle], yellow [4-OHBZA + Fum], green [4-AmBZA + Glu] Form I, orange [4-OHBZA + Pim].

found in their multicomponent crystals with dicarboxylic acids. The values of the dihedral angle (β1) between the planes of the amide group (in both 4-OHBZA and 4-AmBZA molecules) and the benzene ring are summarized in Table S2. The molecules of 4-AmBZA and 4-OHBZA adopt a twisted conformation in their parent structures with similar values of β1 ≈ 28°. In multicomponent crystals of BZA derivatives with dicarboxylic acids, β1 variations show an almost free rotation of the amide group relative to the benzene ring, and the values vary from 1.4° to 33.8° (4-AmBZA forms) and from 2.5° 5263



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which the H···O/O···H interactions are shown separately, we can notice in most cases but in different degrees the asymmetry of these spikes, which indicates different molecule donor− acceptor hydrogen bonding types. The biggest asymmetry of H···O and O···H contributions is observed in the salts [4-AmBZA+ + Oxl−] and [4-AmBZA+ + Oxl− + H2O] because 4-AmBZA is in the protonated form and is most likely to act as the hydrogen bond donor than the acceptor. The third in magnitude contribution is made by the C···H/H···C contributions which are shown as wings on the 2D fingerprint plots. A comparative analysis of the contributions of intermolecular interactions of the cocrystals of 4-AmBZA and 4-OHBZA shows that for cocrystals with aminobenzamide, the contribution of the H···O/O···H interactions is much smaller that for the corresponding cocrystals with 4-hydroxybenzamide. This is explained, first of all, by the fact that the O−H (hydroxyl)···O hydrogen bond energy is higher than that of one N−H(amine)···O and even two N−H(amine)···O hydrogen bonds.51 Thus, analyzing the influence of the number of donors and acceptors of hydrogen bonds in benzamide derivatives on the molecule packing in the crystal, we should also take into account the nature of these functional groups. Crystal Lattice Energy Calculations. The intermolecular interaction energies in 4-AmBZA or 4-OHBZA cocrystals with 1:1 stoichiometry were analyzed according to the PIXEL approach developed by Gavezzotti.40 Four different types of forces calculated by PIXEL are summarized in Table 3, and the

conclusion about the nature and type of intermolecular interactions in the crystal. In this work, we analyzed the Hirshfeld surfaces of multicomponent crystals of BZA derivatives with dicarboxylic acids in order to evaluate the effect of the hydroxyl and aminegroups in the para-position of the benzamide molecule on the intermolecular interactions. The 3D Hirshfeld surfaces of the systems being studied are shown by 2D fingerprint plots (Figures S13 and 14). The quantitative comparisons of all the contributions of the intermolecular interactions of the 4-AmBZA and 4-OHBZA molecules in multicomponent crystals with dicarboxylic acids are shown in Tables S3 and S4, respectively. Figure 12 represents diagrams of relative

Table 3. Results of PIXEL Calculations (kJ·mol−1): Lattice Energies (Elatt), Coulombic (Ecoul), Polarization (Epol), Dispersion (Edisp), and Repulsion (Erep) Terms [4-AmBZA + Mlo] (1:1) [4-AmBZA + Mle] (1:1) [4-AmBZA + Pim] (1:1) [4-OHBZA + Mlo] (1:1) [4-OHBZA + Mle] (1:1)

Ecoul

Epol

Edisp

Erep

Elatt

−222.4 −221.0 −245.6 −252.6 −235.8

−95.4 −98.0 −107.8 −124.6 −103.6

−172.4 −182.2 −216.8 −159.4 −162.6

238.0 254.8 283.2 289.2 251.2

−252.4 −246.2 −294.6 −247.4 −251.0

sum of these four terms provides the total intermolecular interaction energy. The calculations show that the lattice energy value obtained for [4-AmBZa + Pim] is ca. 45 kJ·mol−1 more stabilizing than that for other cocrystals. However, PIXEL gives an opportunity not only to estimate the total lattice energy of the studied systems but also to partition the total energy into electrostatic, polarization, dispersion, and repulsion terms. Table 4 shows that the Coulombic

Figure 12. Relative percentage contributions to the Hirshfeld surface area for various intermolecular contacts in (a) 4-AmBZA and (b) 4-OHBZA multicomponent crystals.

contributions of the most valuable intermolecular interactions of 4-AmBZA or 4-OHBZA in multicomponent crystals. The main contribution to all the considered crystal structures is made by three types of interactions: H···H, H···O/O···H, and H···C/C···H, and the crystals are therefore stabilized mainly by hydrogen bonding and van der Waals interaction. For all the multicomponent crystals of 4-AmBZA, except the [4-AmBZA+ + Oxl−] salt and for most cocrystals with 4-OHBZA, the main contribution to the Hirshfeld surfaces is made by H···H interactions which occupy the central part on the 2D fingerprint plots. It should be said that the H···H interactions contribution grows along with the increase in the alkyl chain length of dicarboxylic acids. In addition to the H···H interactions, a considerable contribution to all the considered structures is made by H···O/O···H interactions shown as two separate spikes. If we take a closer look at the 2D fingerprint plots on

Table 4. Sums of Intermolecular Interaction Energies (kJ·mol−1) between Different Types of Molecules Calculated Using the PIXEL Method (A-BZA Derivative, B-Dicarboxylic Acid) A−A [4-AmBZA + Mlo] (1:1) [4-AmBZA + Mle] (1:1) [4-AmBZA + Pim] (1:1) [4-OHBZA + Mlo] (1:1) [4-OHBZA + Mle] (1:1) 5264

A−B

B−B

total

−70.8 (28.1%) −155.0 (61.4%) −26.6 (10.5%) −252.4 −57.3 (23.3%) −168.0 (68.2%) −20.9 (8.5%)

−246.2

−31.7 (10.7%) −197.5 (67.1%) −65.4 (22.2%) −294.6 −85.5 (34.6%) −127.5 (51.5%) −34.4 (13.9%) −247.4 −51.4 (20.5%) −172.4 (68.7%) −27.2 (10.9%) −251.0



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Figure 13. DSC traces of (a) 4-AmBZA and (b) 4-OHBZA multicomponent crystals.

and repulsion interactions dominate the structures of the cocrystals, while the dispersion term also significantly contributes to the lattice energy of the [4-AmBZA + Pim] cocrystal. Table 4 shows the sums of the intermolecular interaction energies between different types of molecules. In all cases, the BZA derivative−dicarboxylic acid (A−B) interactions provide the largest contribution to the lattice energy (more than 50%). The minimum contribution of such interactions (A−B) to the crystal lattice energy is found for the [4-OHBZA + Mlo] cocrystal. The additional unit in the carbon chain of maleic acid in comparison with malonic acid increases the contribution of the A−B interactions. If the energies of crystal lattice are similar, the contribution of the A−B interactions for cocrystals with maleic acid are 7% (for 4-AmBZA) and 15% (for 4-OHBZA) higher, respectively. For cocrystals with 4-AmBZA, the increase in the A−B interactions contribution is mainly caused by a decrease in the B−B interactions role, while for 4-OHBZA cocrystals, the contribution of the interactions between the 4-OHBZA molecules becomes smaller. Thermal Analysis. DSC measurements were conducted to investigate the thermal behavior of BZA derivatives (4-AmBZA and 4-OHBZA) salt/cocrystals. All the samples for thermal analysis were prepared by solvent drop grinding of physical mixtures in stoichiometries corresponding to those of single crystals. The purity of the obtained samples was monitored by comparing the experimental and simulated PXRD patterns from crystal structures of 4-AmBZA and 4-OHBZA salt/ cocrystals (Figures S15−27). The DSC traces are shown in Figure 13, and the thermal data are represented in Table 5. The DSC thermograms of 4-AmBZA and all its nonhydrate forms (Figure 13a) show a single sharp endothermic transition corresponding to the homogeneity of the samples. In all cases, the 4-AmBZA salt/cocrystal formation leads to a decrease in the melting point compared to the pure 4-AmBZA melting point. The 4-AmBZA salt with Oxl shows the smallest melting point drop (ca. 2 °C) compared to pure 4-AmBZA which could be due to stronger ionic hydrogen bonds in the crystal structure. Moreover, all the 4-AmBZA multicomponent crystals melt at a lower temperature compared to the melting points of both 4-AmBZA and CF, except that the melting point of the [4-AmBZA + Pim] cocrystal is in-between the melting points of the 4-AmBZA and Pim as in case of most cocrystals.52 For 4-AmBZA cocrystals with stoichiometry 1:1, the fusion enthalpy

Table 5. Thermophysical Data of 4-AmBZA and 4-OHBZA, Crystalline Forms, and Salt/Cocrystal Formers Used in This Study Tfus (CF), °C (onset) 4-AmBZA [4-AmBZA+ + Oxl−] (2:1) [4-AmBZA + Mlo] (1:1) [4-AmBZA + Suc] (2:1) [4-AmBZA + Mle] (1:1) [4-AmBZA + Fum] (2:1) [4-AmBZA + Pim] (1:1) 4-OHBZA [4-OHBZA + Oxl] (2:1) [4-OHBZA + Mlo] (1:1) [4-OHBZA + Suc] (2:1) [4-OHBZA + Mle] (1:1) [4-OHBZA + Fum] (2:1)

181.6 189 136 184 139 287 104 158.4 189 136 184 139 287

Tfus (CC), °C (onset) 179.6 121.6 146.3 135.5 162.7 119.3 183.9 123.5 166.6 158.3 198.6

ΔHTfus, kJ·mol−1 32.7 89.3 39.1 82.3 48.7 80.1 60.7 26.0 50.2 49.9 48.1 82.0 43.6

values growth is similar to the growth in the carbon chain length ([4-AmBZA + Mlo] < [4-AmBZA + Mle] < [4-AmBZA + Pim]). The fusion enthalpy values of 4-AmBZA cocrystals with stoichiometry 2:1 are close to each other due to the equal carbon chain length of CFs, while ΔHTfus for [4-AmBZA+ + Oxl−] (2:1) is found to be the highest value (89 kJ·mol−1). The melting temperature of 4-OHBZA is ca. 23 °C lower than that of 4-AmBZA, and in all cases the melting point of the 4-OHBZA cocrystals is intermediate compared to the melting points of individual compounds, except for the [4-OHBZA + Mlo] cocrystal. The thermal analysis was not done for 4-OHBZA cocrystals with Glu and Pim as any attempts to prepare powders with PXRD patterns corresponding to the simulated PXRD patterns of already known crystal structures were unsuccessful (Figures S26 and 27). Thermal analysis of the BZA derivatives cocrystals and comparison of the melting points of the cocrystals with the melting points of the coformers revealed a direct correlation between the melting points of CF and CC: the higher the melting point of the CF is, the higher is the melting point of the CC is (Figure 14). The attempts to find correlations between the structural and thermophysical characteristics of the studied cocrystals were 5265



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Figure 14. Correlation plots between the melting points of (a) 4-AmBZA and (b) 4-OHBZA cocrystals vs coformers.

unsuccessful. The only trend confirming the influence of structural parameters on the thermophysical properties was found by comparing the contributions of intermolecular interactions calculated from the Hirshfeld surfaces and the melting temperatures of the 4-AmBZA and 4-OHBZA cocrystals (Figure S28). It is seen that the cocrystal melting temperature changes are similar to the contributions of the H···C/C···H interactions. For the systems with malonic and maleic acids, for which the contribution of the H···C/C···H interactions is lowest, the melting temperature decreases both in the case with cocrystals of 4-aminobenzamide and with 4-hydroxybenzamide. Cambridge Structural Database Study. The ratio of hydrogen bond donors and acceptors in cocrystal formers can both facilitate cocrystal formation and make this process impossible. As a rule, the fewer donors and acceptors of hydrogen bonds a compound has, the less probable cocrystal formation is and the more difficult it is to find a suitable coformer.26 We have analyzed all known cocrystals and salts of paraderivatives of benzamide with dicarboxylic acids in order to confirm this hypothesis in the series under study. In the Cambridge Structural Database (CSD version 5.39 updates (November 2017)), a total of 37 cocrystals/salts of para-derivatives of BZA have been reported so far.18−21,53−55 The total number of the cocrystals and salts, including those found by us, reaches 45, among which 15 compounds are cocrystals/salts with three or more components (Table S5). The ratios of the number of the two-components cocrystals/ salts in the stoichiometric ratio 1:1, 2:1, 4:1, and multicomponent cocrystals (including solvates and hydrates) are shown in Figure 15. It should be said that only 4-aminobenzamide has four acceptors for four hydrogen bond donors in the studied dicarboxylic acids, and the number of hydrogen bond acceptors of 4-aminobenzamide corresponds to the number of donors of dicarboxylic acids. It is of interest that it is for the salt of 4-aminobenzamide with oxalic acid and its hydrate ([4-AmBZA+ + Oxl−] and [4-AmBZA+ + Oxl− + H2O]) that an acid−amide heterosynthon is not produced. It can be explained by the presence of competing hydrogen bond donors and acceptors, which in this case are more favorable centers of formation of intermolecular hydrogen bonds. Cocrystals of 4-aminobenzamide are equally likely to form systems with 1:1 and 2:1 stoichiometries. Cocrystals of

Figure 15. Ratio of cocrystals and salts of the studied systems with dicarboxylic acids with different stoichiometric ratios and coformer numbers (the blue color − 1:1 stoichiometry; the red color − 2:1 stoichiometry; the green color − 4:1 stoichiometry; the yellow color − three-component cocrystals and hydrates and solvates of the cocrystals/salts).

4-hydroxibenzamide with the stoichiometric ratio of 1:1 are formed much more seldomonly in two cases out of 14, while cocrystals with the 2:1 stoichiometry are formed three times more often. The number of cocrystal hydrates significantly growsalmost half of the known cocrystals with 4-OHBZA are in the hydrated form, where the water molecule acts as an additional donor of hydrogen bonds. The molecules of halogen derivatives of benzamide have two hydrogen bond donors and two acceptors, which hinders the formation of all possible hydrogen bonds with dicarboxylic acid in the stoichiometric ratio of 1:1. It is the reason why there are no cocrystals of these benzamide derivatives with dicarboxylic acid in the 1:1 stoichiometry. The most frequent stoichiometric ratio of coformers is 2:1. A group of authors have also found cocrystals of 4-bromobenzamide with fumaric and succinic acids with the rare stoichiometric ratio of 4:1.19 Changes in the hydrogen bond donor/acceptor ratio in coformers increases the probability of multicomponent crystal solvate formation. The Xpac analysis was performed to analyze the influence of hydrogen bond donors and acceptors ratios on the molecular packing predictability of nonsolvated cocrystals and salts of para-substituted benzamide derivatives with dicarboxylic acids. 5266



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The Xpac method makes it possible to identify similar “supramolecular constructs”33 in the crystal structures of similar molecules (families) and to quantitatively describe the similarity of molecular packets. The chosen common set of points for the studied compounds includes all heavy atoms of 4-aminobenzamide with no substituents in the molecular structure (see Scheme S1). For the data set of 34 crystal structures under study, a matrix of [34 × (34 − 1)/2] = 561 unique pairs of crystals was considered and packing dissimilarity index X and stretch parameter D were investigated for each pair. The results of the XPac analysis are given in Scheme 1 and in Figure S29.

for the structures is 2.0. Compounds 20 and 22 belong to this group (Figure S35). (5) Pairs of cocrystals of para-substituted benzamides (Br− and Cl−) with fumaric acid in the 2:1 stoichiometry crystallizing in the P1 space group. The dissimilarity index for the structures is 2.9. Compounds 21 and 28 belong to this group (Figure S36). (6) Pairs of cocrystals of para-substituted benzamides (Br− and Cl−) with sebacic acid in the 2:1 stoichiometry crystallizing in the P1 space group. The dissimilarity index for the structures is 1.1. Compounds 26 and 29 belong to this group (Figure S37). The dominant constructs in packing cocrystals of halogen derivatives of benzamide are zero-order constructs SC3, 4, and 6 formed via π−π interactions and weak halogen···halogen contacts (Figure S38). The dominant constructs for the cocrystals of hydroxy- and amido-derivatives of benzamide are zero-order constructs SC3 (C−H···O(amide) and π−π stacking (type 1) dimer, respectively) (Figure S38). The 1D level more often has N−H···O bonded chains than the other supramolecular constructs (SC 1D (Figure S39)). Scheme 1 shows that the pairs of isostructural cocrystals of halogen derivatives 4, 5, and 6 are formed directly from zero-dimensional (0D) constructs without passing through the one dimensionality level. Within a row of groups of similarly packed crystals, minimal values of X (which means maximal likelihood) are observed for the pairs of structures with the halogen-substituted benzamide cocrystals. This feature is explained by low variation in the ways of hydrogen bond formation with coformers. In the series of compounds being studied, the largest number of isostructural cocrystals has the multicomponent crystals with succinic and fumaric acids. However, the expected 3D isostructurality between [4-BrBZA + Suc] (2:1) and [4-BrBZA + Fum] (2:1) is not observed. This is probably explained by the difference in the direction of C−H···O contacts between the acid molecules in cocrystals [4-BrBZA + Suc] (2:1) and [4-BrBZA +Fum] (2:1). In the cocrystals with fumaric acid, the C−H···O contacts take place in the molecule plane, in contrast to the cocrystals with succinic acid. In the cocrystals with 4-AmBZA and 4-OHBZA, this difference is not of primary importance as the main forces holding the molecules of the cocrystal formers in the crystal lattice are strong N−H··· O and O−H···O hydrogen bonds, but in the cocrystals with halogen derivatives of benzamide, the structure forming agents are the C−H···O hydrogen bonds. That is why the [4-BrBZA + Fum] cocrystal (2:1) is 3D isostructural to the [4-ClBZA + Fum] cocrystal (2:1). It is interesting to note that the molecules in cocrystals with short aliphatic dicarboxylic acids (with oxalic (2, 9, 27, 30), maleic (5, 12) and malonic acid (3, 10, 18) (Scheme 1)) are packed into crystal lattices through the most infrequent 0D and 1D supramolecular constructs. Moreover, the molecule packing of the cocrystal [4-AmBZA + Mlo] (2:1) (3) is not observed in any of the studied systems. It is also of interest that it is in this cocrystal that one molecule in the asymmetric unit has the biggest number of unique hydrogen bonds (Table S6). On average, one molecule of the cocrystal component for aminobenzamide cocrystals has 3.43 hydrogen bonds of different strengths. There are approximately equal numbers of unique hydrogen bonds3.52for one molecule of component in the asymmetric unit in the cocrystals with 4-hydrobenzamide

Scheme 1. Diagram Showing the Structural Relationship between 34 Para-Substituted Benzamide Derivatives with Dicarboxylic Acids Cocrystals/Salts with Determined Crystal Structuresa

a

The numeration used is consistent with Figure S29.

We can single out six sets of crystals with a determined 3D isostructurality (Figures S6, S12, S30−37): (1) The above-mentioned isostructural 4-AmBZA (1) and 4-OHBZA (8) types crystallizing in P21 space group. The dissimilarity index for the structures is 0.4 (Figure S6). (2) A set of para-substituted benzamides (OH− and NH2−) cocrystals with fumaric and succinic acids in (2:1) stoichiometry crystallizing in the P21/n and P21/c space groups. Compounds 4, 6, 11, and 13 belong to this group (Figure S12, Figures S30−33). (3) Pairs of cocrystals with pimelic and glutaric acid in (2:1) stoichiometry crystallizing in the C2/c space group. The structure of the hydrogen bonding network is similar to the second group of isostructural cocrystals. The distinguishing feature of the packing in this cocrystal pair consists in the fact that the benzamide molecules linked via dicarboxylic acid are located at the angle of 70° in relation to each other, whereas the dicarboxylic acid is the twisted state. The dissimilarity index for the structures is 5.3. Compounds 14 and 16 belong to this group (Figure S34). (4) Pairs of cocrystals of 4-bromobenzamide with succinic and fumaric acids in the 4:1 stoichiometry crystallizing in the P21/c space group. The molecules in the cocrystal are packed so that the trimers formed by bromobenzamide molecules linked via dicarboxylic acids alternate with 4-bromobenzamide dimers. The dissimilarity index 5267



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(Table S6). There are much fewer hydrogen bonds for one molecule in the asymmetric unit of cocrystals with bromobenzamide and chlorobenzamide2.91 and 2.42, respectively. The cocrystals with nitrobenzamide have more unique hydrogen bonds for one molecule in the asymmetric unit4.11than in the others, but these bonds are mostly weak C−H···O and C−H···N contacts. Indeed, the lack of hydrogen bond donors is compensated by the formation of weak hydrogen bonds of the C−H···A (AO, N) type. (Table S6) The fewer donors a molecule of the benzamide para-derivative has, the more C−H···A (AO, N) contacts one coformer molecule has in the asymmetric units: 0.72 for 4-AmBZA cocrystals; 0.93 for 4-OHBZA cocrystals, 1.1 and 1.08 for 4-BrBZA and 4ClBZA cocrystals, respectively, and 2.15 for 4-NO2BZA cocrystals. The cocrystals with a large number of unique strong hydrogen bonds are highly likely to have similar supramolecular constructs of the 1D level, while the cocrystals with a large number of weak C−H···O/C−H···N contacts are more likely to have isostructural packing of the molecules formed by similar 0D level constructs.

This work was supported by the Russian Science Foundation (Grant No. 17-73-10351). Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Russian Science Foundation (Grant No. 17-73-10351). We thank “the Upper Volga Region Centre of Physicochemical Research” for technical assistance with the PXRD experiments. The X-ray diffraction studies for compounds 2−9 were performed at the Centre of Shared Equipment of IGIC RAS. X-ray data for compound 1 were collected at The Durham X-ray Centre (Durham University, UK). We thank Dr. Alexander P. Voronin for useful discussions regarding XPac analysis.

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CONCLUSIONS The hydrogen bond donor/acceptor ratios of the coformers have a significant influence on molecular packing in cocrystals. Despite the fact that in most cases cocrystallization of benzamide derivatives with dicarboxylic acids produces an acid−amide heterosynthon, the replacement of the substituent in the paraposition changes the cocrystal molecule environment. Structurally similar coformers with a small number of hydrogen bond donors/acceptors are more likely to form isostructural cocrystals. But the lack of hydrogen bond donors/acceptors increases the probability of cocrystal solvate formation. When the total number of hydrogen bond donors in the coformers is equal to the total number of hydrogen bond acceptors, the risk of obtaining solvated cocrystal forms is lower. The lack of hydrogen bond donors is compensated for by the formation of weak hydrogen bonds of the C−H···A (AO, N) type. The dominant constructs in packing cocrystals of halogen derivatives of benzamide are formed via π−π interactions and weak halogen···halogen contacts.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.8b00711. Specifics concerning the synthesis of cocrystals, their crystallographic, XPac and Hirshfeld surface analysis (PDF) Accession Codes

CCDC 1841931−1841939 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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REFERENCES

(1) Bond, A. D. What is a co-crystal? CrystEngComm 2007, 9, 833− 834. (2) Childs, S. L.; Zaworotko, M. J. The reemergence of cocrystals: The crystal clear writing is on the wall: Introduction to virtual special issue on pharmaceutical cocrystals. Cryst. Growth Des. 2009, 9, 4208− 4211. (3) Schultheiss, N.; Newman, A. Pharmaceutical cocrystals and their physicochemical properties. Cryst. Growth Des. 2009, 9, 2950−2967. (4) Thakuria, R.; Nangia, A. Olanzapinium salts, isostructural solvates, and their physicochemical properties. Cryst. Growth Des. 2013, 13, 3672−3680. (5) Drozd, K. V.; Manin, A. N.; Churakov, A. V.; Perlovich, G. L. Novel drug-drug cocrystals of carbamazepine with para-aminosalicylic acid: screening, crystal structures and comparative study of carbamazepine cocrystal formation thermodynamics. CrystEngComm 2017, 19, 4273−4286. (6) Desiraju, G. R. Supramolecular synthons in crystal engineering a new organic synthesis. Angew. Chem., Int. Ed. Engl. 1995, 34, 2311− 2327. (7) Walsh, R. D. B.; Bradner, M. W.; Fleischman, S.; Morales, L. A.; Moulton, B.; Rodríguez-Hornedo, N.; Zaworotko, M. J. Crystal engineering of the composition of pharmaceutical phases. Chem. Commun. 2003, 2, 186−187. (8) Almarsson, Ö .; Zaworotko, M. Crystal engineering of the composition of pharmaceutical phases. Do pharmaceutical co-crystals represent a new path to improved medicines? Chem. Commun. 2004, 17, 1889−1896. (9) Etter, M. C. Encoding and decoding hydrogen-bond patterns of organic compounds. Acc. Chem. Res. 1990, 23, 120−126. (10) Etter, M. C.; Frankenbach, G. M. Hydrogen-bond directed cocrystallization as a tool for designing acentric organic solids. Chem. Mater. 1989, 1, 10−12. (11) Adalder, T. K.; Sankolli, R.; Dastidar, P. Homo- or heterosynthon? A crystallographic study on a series of new cocrystals derived from pyrazinecarboxamide and various carboxylic acids equipped with additional hydrogen bonding sites. Cryst. Growth Des. 2012, 12 (5), 2533−2542. (12) Vener, M. V.; Levina, E. O.; Koloskov, O. A.; Rykounov, A. A.; Voronin, A. P.; Tsirelson, V. G. Evaluation of the lattice energy of the two-component molecular crystals using solid-state density functional theory. Cryst. Growth Des. 2014, 14 (10), 4997−5003. (13) Steiner, T. Reviews: The hydrogen bond in the solid state. Angew. Chem., Int. Ed. 2002, 41, 48−76. (14) Manin, A. N.; Voronin, A. P.; Manin, N. G.; Vener, M. V.; Shishkina, A. V.; Lermontov, A. S.; Perlovich, G. L. Salicylamide cocrystals: screening, crystal structure, sublimation thermodynamics, dissolution, and solid-state DFT calculations. J. Phys. Chem. B 2014, 118, 6803−6814.

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*E-mail: [email protected]. ORCID

Andrei V. Churakov: 0000-0003-3336-4022 German L. Perlovich: 0000-0002-6267-5244 5268



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(15) Desiraju, G. R. Crystal engineering: From molecule to crystal. J. Am. Chem. Soc. 2013, 135 (27), 9952−9967. (16) Cincić, D.; Friscić, T.; Jones, W. Isostructural materials achieved by using structurally equivalent donors and acceptors in halogen-bonded cocrystals. Chem. - Eur. J. 2008, 14 (2), 747−753. (17) Moragues-Bartolome, A. M.; Jones, W.; Cruz-Cabeza, A. J. Synthon preferences in cocrystals of cis-carboxamides:carboxylic acids. CrystEngComm 2012, 14 (7), 2552−2559. (18) Tothadi, S.; Desiraju, G. R. Synthon modularity in 4hydroxybenzamide-dicarboxylic acid cocrystals. Cryst. Growth Des. 2012, 12, 6188−6198. (19) Tothadi, S.; Joseph, S.; Desiraju, G. R. Synthon modularity in cocrystals of 4-bromobenzamide with n-alkanedicarboxylic acids: Type I and type II halogen···halogen interactions. Cryst. Growth Des. 2013, 13, 3242−3254. (20) Tothadi, S.; Desiraju, G. R. Designing ternary cocrystals with hydrogen bonds and halogen bonds. Chem. Commun. 2013, 49, 7791−7793. (21) Tothadi, S.; Sanphui, P.; Desiraju, G. R. Obtaining synthon modularity in ternary cocrystals with hydrogen bonds and halogen bonds. Cryst. Growth Des. 2014, 14 (10), 5293−5302. (22) Melendez, R. E.; Sharma, C. V. K.; Zaworotko, M. J.; Bauer, C.; Rogers, R. D. Toward the design of porous organic solids: Modular honeycomb grids sustained by anions of trimesic acid. Angew. Chem., Int. Ed. Engl. 1996, 35 (19), 2213−2215. (23) Bis, J. A.; Vishweshwar, P.; Weyna, D.; Zaworotko, M. J. Hierarchy of supramolecular synthons: Persistent hydroxyl···pyridine hydrogen bonds in cocrystals that contain a cyano acceptor. Mol. Pharmaceutics 2007, 4 (3), 401−406. (24) Shattock, T. R.; Arora, K. K.; Vishweshwar, P.; Zaworotko, M. J. Hierarchy of supramolecular synthons: Persistent carboxylic acid··· pyridine hydrogen bonds in cocrystals that also contain a hydroxyl moiety. Cryst. Growth Des. 2008, 8 (12), 4533−4545. (25) Kavuru, P.; Aboarayes, D.; Arora, K. K.; Clarke, H. D.; Kennedy, A.; Marshall, L.; Ong, T. T.; Perman, J.; Pujari, T.; Wojtas, Ł.; Zaworotko, M. J. Hierarchy of supramolecular synthons: Persistent hydrogen bonds between carboxylates and weakly acidic hydroxyl moieties in cocrystals of zwitterions. Cryst. Growth Des. 2010, 10 (8), 3568−3584. (26) Mapp, L. K.; Coles, S. J.; Aitipamula, S. Design of cocrystals for molecules with limited hydrogen Bonding Functionalities: Propyphenazone as a Model System. Cryst. Growth Des. 2017, 17, 163−174. (27) Berkovitch-Yellin, Z.; van Mil, J.; Addadi, L.; Idelson, M.; Lahav, M.; Leiserowitz, L. Crystal morphology engineering by ″tailormade″ inhibitors; a new probe to fine intermolecular interactions. J. Am. Chem. Soc. 1985, 107 (11), 3111−3122. (28) Samanta, R.; Kanaujia, S.; Reddy, C. M. New co-crystal and salt form of sulfathiazole with carboxylic acid and amide. J. Chem. Sci. 2014, 126 (5), 1363−1367. (29) Suresh, K.; Minkov, V. S.; Namila, K. K.; Derevyannikova, E.; Losev, E.; Nangia, A.; Boldyreva, E. V. Novel synthons in sulfamethizole cocrystals: Structure-property relations and solubility. Cryst. Growth Des. 2015, 15 (7), 3498−3510. (30) Mukherjee, A.; Dixit, K.; Sarma, S. P.; Desiraju, G. R. Anilinephenol recognition: from solution through supramolecular synthons to cocrystals. IUCrJ 2014, 1, 228−239. (31) Sheldrick, G. M. SADABS, Program for Scaling and Correction of Area Detector Data; University of Göttingen, 1997. (32) Sheldrick, G. M. A short history of SHELX. Acta Crystallogr., Sect. A: Found. Crystallogr. 2008, 64, 112−122. (33) Gelbrich, T.; Hursthouse, M. B. A versatile procedure for the identification, description and quantification of structural similarity in molecular crystals. CrystEngComm 2005, 7, 324−336. (34) Gelbrich, T.; Hursthouse, M. B. Systematic investigation of the relationships between 25 crystal structures containing the carbamazepine molecule or a close analog: a case study of the XPac method. CrystEngComm 2006, 8, 448−460.

(35) Wolff, S. K.; Grimwood, D. J.; McKinnon, J. J.; Tumer, M. J.; Jayatilaka, D.; Spackman, M. A. CrystalExplorer, version 3.1; University of Western Australia, 2012. (36) Spackman, M. A.; Jayatilaka, D. Hirshfeld surface analysis. CrystEngComm 2009, 11 (1), 19−32. (37) Spackman, M. A.; McKinnon, J. J. Fingerprinting intermolecular interactions in molecular crystals. CrystEngComm 2002, 4, 378−392. (38) McKinnon, J. J.; Spackman, M. A.; Mitchell, A. S. Novel tools for visualizing and exploring intermolecular interactions in molecular crystals. Acta Crystallogr., Sect. B: Struct. Sci. 2004, 60, 627−668. (39) McKinnon, J. J.; Jayatilaka, D.; Spackman, M. A. Towards quantitative analysis of intermolecular interactions with Hirshfeld surfaces. Chem. Commun. 2007, 0, 3814−3816. (40) Gavezzotti, A. Non-conventional bonding between organic molecules. The ’halogen bond’ in crystalline systems. Mol. Phys. 2008, 106, 1473−1485. (41) Maschio, L.; Civalleri, B.; Ugliengo, P.; Gavezzotti, A. Intermolecular Interaction Energies in Molecular Crystals: Comparison and Agreement of Localized M?ller-Plesset 2, DispersionCorrected Density Functional, and Classical Empirical Two-Body Calculations. J. Phys. Chem. A 2011, 115, 11179−11186. (42) da Silva, C. C. P.; de Oliveira, R.; Tenorio, J. C.; Honorato, S. B.; Ayla, A. P.; Ellena, J. The continuum in 5-fluorocytosine. Toward salt formation. Cryst. Growth Des. 2013, 13, 4315−4322. (43) Childs, S. L.; Stahly, G. P.; Park, A. The salt-cocrystal continuum: the influence of crystal structure on ionization state. Mol. Pharmaceutics 2007, 4, 323−338. (44) Bhogala, B. R.; Basavoju, S.; Nangia, A. Tape and layer structures in cocrystals of some di- and tricarboxylic acids with 4,4′bipyridines and isonicotinamide. From binary to ternary cocrystals. CrystEngComm 2005, 7, 551−562. (45) Cruz-Cabeza, A. J. Acid-base crystalline complexes and the pKa rule. CrystEngComm 2012, 14, 6362−6365. (46) https://ace.chem.illinois.edu/ace/public/pKa.jsp. (47) https://www.chem.wisc.edu/areas/reich/pkatable/pKa_ compilation-1-Williams.pdf. (48) Alleaume, M. Thesis, University of Bordeaux, 1967. (49) Nichol, C. S.; Clegg, W. The importance of weak C-H···O bonds and π···π stacking interactions in the formation of organic 1,8bis(dimethylamino)naphthalene complexes with Z′ > 1. Cryst. Growth Des. 2006, 6, 451−460. (50) Thalladi, V. R.; Nüsse, M.; Boese, R. The melting point alternation in α,ω-alkanedicarboxylic acids. J. Am. Chem. Soc. 2000, 122, 9227−9236. (51) Manin, A. N.; Voronin, A. P.; Shishkina, A. V.; Vener, M. V.; Churakov, A. V.; Perlovich, G. L. Influence of secondary interactions on the structure, sublimation thermodynamics, and solubility of salicylate:4-hydroxybenzamide cocrystals. Combined experimental and theoretical study. J. Phys. Chem. B 2015, 119 (33), 10466−10477. (52) Perlovich, G. L. Two-component molecular crystals: evaluation of the formation thermodynamics based on melting points and sublimation data. CrystEngComm 2017, 19, 2870−2883. (53) Aakeröy, C. B.; Beatty, A. M.; Helfrich, B. A.; Nieuwenhuyzen, M. Do polymorphic compounds make good cocrystallizing agents? A structural case study that demonstrates the importance of synthon flexibility. Cryst. Growth Des. 2003, 3 (2), 159−165. (54) Edwards, M. R.; Jones, W.; Motherwell, W. D. S. Cocrystal formation of 4-methyl and 4-chlorobenzamide with carboxylic acids: chloro/methyl interchange and crystal structure. CrystEngComm 2006, 8 (7), 545−551. (55) Sanphui, P.; Tothadi, S.; Ganguly, S.; Desiraju, G. R. Salt and cocrystals of sildenafil with dicarboxylic acids: solubility and pharmacokinetic advantage of the glutarate salt. Mol. Pharmaceutics 2013, 10 (12), 4687−4697.

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Acceptor Ratios of the Coformers: Do They

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