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Weak Interactions Cause Packing Polymorphism in Pharmaceutical Two-Component Crystals. The Case Study of the Salicylamide Cocrystal Artem O. Surov,† Alex N. Manin,† Alexander P. Voronin,† Andrei V. Churakov,§ German L. Perlovich,† and Mikhail V. Vener*,‡ †

G.A. Krestov Institute of Solution Chemistry of the Russian Academy of Sciences, 1, Akademicheskaya St., 153045 Ivanovo, Russia Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russia ‡ Mendeleev University of Chemical Technology, 9, Miusskaya Square, 125047 Moscow, Russia §

S Supporting Information *

ABSTRACT: Two polymorphs of the salicylamide cocrystal with oxalic acid have been obtained and described. Form I of the cocrystal was prepared by three alternative methods in various solvents, while formation of form II was achieved only by a special crystallization procedure. Single-crystal X-ray analysis has revealed that polymorphs consist of conformationally identical salicylamide and oxalic acid molecules, which are assembled into supramolecular units connected via a network of very similar hydrogen bonds. The packing arrangements of the cocrystal polymorphs, however, were found to be different, suggesting a rare example of packing polymorphism. The stability relationship between the polymorphs has been rationalized by using a number of experimental methods, including thermochemical analysis, solubility, and solution calorimetry measurements. Similarities and differences in intermolecular contacts across two polymorphs have been visualized using the Hirshfeld surface analysis. The Bader analysis of the theoretical electron density has enabled us to quantify the pattern of noncovalent interactions in the considered cocrystals. Applicability of different theoretical schemes for evaluation of the lattice energy of the two-component organic crystals has been discussed.

1. INTRODUCTION Polymorphism is of interest in crystallization, phase transition, material synthesis, and the pharmaceutical industry because differences in the crystal packing and/or conformation of compounds with the same formula can change the chemical and physical properties, including solubility and bioavailability.1−3 Generally, polymorphic structures can be divided into two main categories, i.e., packing and conformational polymorphs.4 The conformational polymorphism is associated with molecules that contain one or more flexible fragments with a relatively low energy barrier for rotation around covalent bonds. Such molecules are able to adopt a suitable conformation for different crystalline surroundings.5 Packing polymorphism mainly occurs for conformationally rigid molecules which have a large energy penalty for conformational change.6 However, for the most polymorphic systems the distinction between packing and conformational polymorphism is not obvious, since both types of changes (i.e., conformation and packing) are usually observed during polymorphic transition. In the case of cocrystals, the difference between polymorphism types is even more unclear. For example, the polymorphic cocrystals of ethenzamide−ethylmalonic acid (1:1)7 and caffeine−glutaric acid (1:1)8 contain different © 2017 American Chemical Society

conformers of only one component of the cocrystal. Moreover, polymorphism in multicomponent crystals can be accompanied by a change in primary hydrogen bond motifs, leading to synthon polymorphism.9 Therefore, polymorphic forms of a cocrystal can be classified as packing polymorphs if the following conditions are fulfilled: (i) both polymorphs should be constructed from the components with minor differences in their conformations, (ii) both polymorphs should be sustained by the same synthons of hydrogen bonds. Obviously, simultaneous realization of these two conditions seems unlikely. Thus, descriptions of packing polymorphism for cocrystals are limited by only few examples.10 In this work we report the results of the combined experimental and theoretical study of the cocrystal of salicylamide (SAM) with oxalic acid (Ox) having a 2:1 molar ratio (Figure 1), which is found to exist in two polymorphic forms. Single-crystal X-ray analysis has revealed that the cocrystal polymorphs consist of conformationally identical molecules connected by similar hydrogen bond synthons but show difference in their overall packing arrangements. These Received: January 5, 2017 Revised: February 2, 2017 Published: February 6, 2017 1425

DOI: 10.1021/acs.cgd.7b00019 Cryst. Growth Des. 2017, 17, 1425−1437

Crystal Growth & Design

Article

collected on a Bruker SMART APEX II diffractometer using graphitemonochromated Mo Kα radiation (λ = 0.71073 Å) at 150 K. Absorption corrections based on measurements of equivalent reflections were applied.20 The structures were solved by direct methods and refined by full matrix least-squares on F2 with anisotropic thermal parameters for all non-hydrogen atoms.21 All hydrogen atoms were found from a difference Fourier map and refined isotropically. The crystallographic data for form I and form II of [SAM+Ox] (2:1) have been deposited with the Cambridge Crystallographic Data Centre as supplementary publications under the CCDC numbers 1525077 and 1525078. This information can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/ data_request/cif. 2.3.2. Powder X-ray Diffraction. X-ray powder diffraction (XRPD) data of the bulk materials were recorded under ambient conditions in Bragg−Brentano geometry with Bruker D8 Advance diffractometer with Cu Kα1 radiation (λ = 1.5406 Å). The voltage and current applied were 40 kV and 40 mA, respectively. The data were collected in the range of 2θ = 5−30° with a step size 0.03°. 2.3.3. Differential Scanning Calorimetry (DSC). Thermal analysis was carried out using a PerkinElmer DSC 4000 differential scanning calorimeter with a refrigerated cooling system (USA). The sample was heated in sealed aluminum sample holders at the rate of 10 °C min−1 in a nitrogen atmosphere. The unit was calibrated with indium and zinc standards. The accuracy of the weighing procedure was ±0.01 mg. 2.3.4. Thermogravimetric Analysis (TGA). TGA was performed on a TG 209 F1 Iris thermomicrobalance (Netzsch, Germany). Approximately 10 mg of the sample was added to a platinum crucible. The samples were heated at a constant heating rate of 10 °C·min−1. The samples were purged with a stream of flowing dry Ar at 30 mL· min−1 throughout the experiment. 2.3.5. Solution Calorimetry Experiments. The polymorphs solution enthalpies were measured by using an ampule-type isoperibolic calorimeter with a 50 cm3 titanium reaction vessel at 25.0 °C The automated control scheme allowed the temperature to be maintained with the accuracy over 6 × 10−4 °C. The temperature and thermal sensitivities of the calorimeter measuring cell were 10−4 K and 10−3 J, respectively. The instrumental errors were 0.6−1%. The accuracy of weight measurements corresponded to ±10−5 g. Due to small values of the solution heat effects, a correction (q(T)) was introduced to account for the heat of ampule breaking and evaporation of the solvent in the ampule free volume: q(20.0 °C) = 0.034 J, q(30.0 °C) = −0.018 J, q(45.0 °C) = −0.059 J. Other corrections were negligibly small. The calorimeter was calibrated using KCl (Merck analysis grade >99.5%) in water over a wide concentration interval with more than 20 measurements made. The obtained standard value of solution enthalpy was 17 240 ± 36 J·mol−1, which was in good agreement with the value 17 241 ± 18 J·mol−1 recommended by IUPAC.22 The results are stated as the average of at least six replicated experiments. 2.3.6. Dissolution Experiments. Dissolution measurements were carried out by the shake-flask method in acetonitrile at 25 ± 0.1 °C. The excess amount of each sample was suspended in 5 mL of the acetonitrile solution in Pyrex glass tubes. Aliquots of the suspension were withdrawn at predetermined intervals, filtered through a 0.22 μm PTFE syringe filter (Rotilabo), and the concentration of salicylamide was determined with a suitable dilution by a Cary 50 UV−vis spectrophotometer (Varian, Australia) at the reference wavelength. The results are stated as the average of at least four replicated experiments. The polymorphs stability during the solubility experiments was monitored by analyzing samples of the bottom phase after 10, 120, and 360 min using XRPD.

Figure 1. Molecular structures of salicylamide (SAM) and oxalic acid (Ox). Flexible torsion angle in the salicylamide molecule is numbered and indicated by τ.

facts unambiguously suggest that polymorphic forms of the [SAM+Ox] (2:1) cocrystal should be considered as a rare case of packing polymorphism. It is evident that packing polymorphism is mainly associated with distribution of weak intermolecular interactions in polymorph crystals. It has been reported that the charge density analysis based on experimental11 or theoretical12 calculations is a powerful tool for investigation into polymorphism phenomena of single component crystals.13−15 In addition, the quantum theory of atoms in molecules and crystals (Bader analysis) based upon the topological properties of the periodic electron density gives a possibility to establish a network of intermolecular contacts in crystals of polymorphs and describe quantitatively the contributions of these contacts to their lattice energies.16 This approach, however, is poorly applicable to weak intermolecular interactions, the energy of which does not exceed ∼2 kJ·mol−1.17 Therefore, crystal lattice energies of the [SAM+Ox] (2:1) cocrystal polymorphs were also estimated using the CLP (Coulomb-London-Pauli) calculation method based on classical atom−atom potentials.18 In order to visualize the similarities and differences in intermolecular contacts across the two polymorphs, the Hirshfeld surface analysis19 was also performed.

2. EXPERIMENTAL METHODS 2.1. Compounds and Solvents. Salicylamide (2-hydroxybenzamide) (C7H7NO2, MW 137.14, purity 99%) was purchased from Sigma-Aldrich. Oxalic acid (C2H2O4, MW 90.04, purity 98%) was purchased from Acros Organics. All the solvents were of analytical grade and used as received without further purification. 2.2. Preparation and Crystallization Procedures. 2.2.1. Solvent-Drop Grinding. Solvent-drop grinding experiments were performed using a Fritsch planetary micromill, model Pulverisette 7, in 12 mL agate grinding jars with a total of 10 agate balls, 5 mm in diameter, with a few drops of different solvents at a rate of 600 rpm for 60 min containing salicylamide (SAM) and oxalic acid (Ox) in varying stoichiometric ratios at room temperature. 2.2.2. Slurry Sonication Technique. Stable form I was obtained by solution-mediated phase transformation as follows: several drops of acetonitrile were added to a mixture of salicylamide and oxalic acid in a 1:1 molar ratio to form a slurry, the mixture was treated by ultrasound for 30−45 min and stirred overnight in a magnetic stirrer at 300 rpm at room temperature. 2.2.3. Crystallization Procedure. [SAM+Ox] (2:1) form I. Equimolar amounts of salicylamide and oxalic acid were dissolved in ethanol and stirred at room temperature. The resulting clear solution was filtered and allowed to evaporate. Diffraction quality crystals were grown over a few days. [SAM+Ox] (2:1) form II. Approximately 100 mg of salicylamide was added to 5 mL of the saturated ethanol solution of oxalic acid and stirred at room temperature. The resulting clear solution was filtered, covered by parafilm perforated with a few small holes, and allowed to evaporate slowly. Diffraction quality crystals were grown over a few days. 2.3. Characterization of Cocrystal Polymorphs. 2.3.1. SingleCrystal X-ray Diffraction. Single-crystal X-ray diffraction data were

3. CALCULATION PROCEDURES 3.1. Solid-State DFT Followed by Bader Analysis of the Periodic Electronic Density. Density functional theory computations with periodic boundary conditions (solid-state DFT) were performed in the Crystal1423 software package using B3LYP in the localized basis set 6-31G**. The B3LYP/631G** approximation provides reliable and consistent results in 1426



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studying the intermolecular interactions in crystals.24 London dispersion interactions were included using the semiempirical D2 scheme.25 The details of solid-state DFT calculations are given in SI. Bader analysis of periodic electron density26,27 was performed in TOPOND14.28 The following electron-density features at the bond critical point were computed: the values of the electron density, ρb, the Laplacian of electron density, ρb, and the positively defined local electronic kinetic energy density, Gb. Noncovalent (intermolecular) interactions with ρb < 0.003 au were not considered in the present work, as their value is too small for determination by the existing experimental and computational methods.29,30 The energy of the particular single noncovalent interaction Eint was estimated as31 E int = 0.429·G b

(in atomic units)

salicylamide to form an acid−amide heterosynthon, which is one of the most popular synthons found in cocrystals.39,44−46 Oxalic acid was chosen as the coformer because it has −COOH functional groups. It is known that DSC analysis of the physical mixtures of coformers may indicate cocrystal formation if (a) the physical mixture melting produces two peaks corresponding to the eutectic mixture and cocrystal melting (with their temperatures being different from the melting temperatures of individual components); (b) the eutectic melting (the first peak) is followed by a small exoeffect.47 The results of the DSC analysis of SAM and Ox physical mixture in stoichiometry 1:1 are presented in Figure 2. The

(1)

Equation 1 yields reasonable Eint values for molecular crystals with H-bonds, C−H···O and π-stacking contacts, and so forth.17,32,33 3.2. Lattice Energies Evaluation. There are several theoretical approaches to evaluation of lattice energy Elatt in crystalline materials. The first one explores the total energy of the unit cell and relaxed energies of the molecule(s) forming the crystal. The computed Elatt values are very sensitive to the level of theory (the particular functional and the basis set) and the dispersion corrections accounting method.34−36 To the best of our knowledge, this approach has not been used for evaluation of the relative stabilities of different polymorphic forms of two-component molecular crystals. The second approach views the lattice energy as a sum of the energies of intermolecular (noncovalent) pairwise interactions between the considered molecule and its neighbors.37,38

Figure 2. DSC curves of SAM (black), Ox (red), and binary mixture of SAM and Ox (blue).

E latt = −∑ ∑ E int, j , i i

j 2σ(I)) Final wR(F2) values (I > 2σ(I)) Final R1 values (all data) Final wR(F2) values (all data) Goodness of fit on F2

Form II

1525077 1525078 2(C7H7NO2)·C2H2O4 Monoclinic Monoclinic 12.8855(13) 6.848(4) 5.0100(5) 3.7481(19) 25.327(3) 30.232(15) 101.422(2) 95.186(8) 1602.6(3) 772.7(7) C2/c P21/c 4 2 1.510 1.566 7909 4330 1935 1436 0.0190 0.0798 0.0375 0.0701 0.0974 0.1367 0.0417 0.1210 0.1004 0.1553 1.055 1.029 1428



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Figure 5. View of the hydrogen-bonded ribbons formed by the salicylamide and oxalic acid molecules in the crystals of (a) form I and (b) form II. The trimeric units in the structures are shown in ball and stick style. The energies of hydrogen bonds (blue) and C−H···O contacts (green) in the highlighted area of the crystal are shown on the right. The interaction energies are given in kJ·mol−1.

flat ribbons (Figure S4a). In the cocrystals formed by 4methylbenzamide and 4-hydroxybenzamide, the molecular conformations of the benzamide constituents are considerably twisted from planarity, which promotes hydrogen bonding between the trimers located in parallel ribbons (Figure S4b,c). However, the main difference between the cocrystals of benzamide derivatives and the studied structure is observed in the overall packing arrangement. In contrast to the zigzag packing in the [SAM+Ox] (2:1) polymorphs, the neighboring ribbons in the [4-chlorobenzamide + oxalic acid] (2:1) and [4methylbenzamide + oxalic acid] (2:1) cocrystals are paralleloriented (Figure S5a,b). The crystal structure of [4hydroxybenzamide + oxalic acid] (2:1) can be described as parallel chains of trimers connected by a complex network of hydrogen bonds (Figure S5c). The mentioned examples allow us to propose a number of important structural features in the [SAM+Ox] (2:1) cocrystal: (i) the presence of the intramolecular H-bond in salicylamide holds the molecule in its relatively flat conformation, which, in turn, prevents hydrogen bonding between the molecules located in parallel ribbons; (ii) the absence of bulk substituents and H-bond sites in the molecule periphery does not suppress mobility of neighboring ribbons and allows them to have different spatial orientation relative to each other. We assume that all the mentioned

cocrystal was considered for “corresponding ordered sets of points”. The filter setting was set to medium (a/p/d, 10/14/ 1.50) according to default option in the program. The Xpac analysis of the polymorphs identified a 1D structural construct comprising only three molecules with dissimilarity index of 2.1.53 All the salicylamide molecules are located within the hydrogen-bonded ribbon. This result indicates that despite the similarity in hydrogen bonding, crystal structures of the polymorphs are considerably different in terms of 3D packing arrangement, which is expected in the case of packing polymorphism. In order to compare crystal structures of the [SAM+Ox] (2:1) polymorphs with the known cocrystals of oxalic acid and different benzamide analogs, a CSD (version 5.37, May 2016 update) survey was performed. A search in the CSD has yielded four two-component cocrystals with benzamide derivatives, namely, 4-chlorobenzamide, 4-methylbenzamide, and 4-hydroxybenzamide. All the retrieved cocrystals consist of benzamide and oxalic acid in a 2:1 molar ratio. It has been found that in each structure, the benzamide and oxalic acid molecules are linked via conventional amide−acid heterosynthons with R22(8) graph set notation and form a supramolecular trimeric unit, similar to that in [SAM+Ox] (2:1). In the [4-chlorobenzamide + oxalic acid] (2:1) cocrystal, the trimers are essentially planar and interact through side N−H···O hydrogen bonds to form 1429



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Figure 6. Molecular packing projections for (a) form I and (b) form II of the title cocrystal along the crystallographic a axis. The stacks of ribbons discussed in the text are separated by blue dashed lines.

Table 2. X···O Distances, Where X = O, N, and C, and Energies, Eint, of the Intermolecular O−H···O and N−H···O Bonds of the Acid-Amide Heterosynthon and Selected Intraribbon Interactions in Forms I and II Computed Using the B3LYP-D2/6-31G** Approximation Form I

a

Form II

Fragment

D(X···O), Å

Eintb, kJ·mol−1

D(X···O), Å

Eintb, kJ·mol−1

O4−H1···O1 N1−H11···O3 N1−H12···O4 N1−H12···O3 C5−H5···O2 C6−H6···O4

2.587 2.924 3.332 2.883 3.244 3.500

50.5 22.3 9.4 11.1 7.5 6.1

2.508 2.927 3.360 2.886 3.231 3.477

66.6 22.3 9.1 11.0 7.7 6.4

Atomic numeration is introduced in Figure 5. bEq 1.

geometric and packing features in the cocrystal provide favorable conditions for packing polymorphism to appear. 4.3. Localization of the Intermolecular Interactions and the Assessment of Their Energy. According to section 4.2, intermolecular (noncovalent) interactions in the polymorphs can be divided into four types: (a) the intermolecular O−H···O and N−H···O bonds of the acid−amide heterosynthon; (b) the N−H···O bonds and C−H···O contacts within the infinite ribbon, which is expanded along the a-axis (Figures 5 and 6); (c) the interlayer contacts consisting of C−

H···O and C−H···C interactions between the molecules located in the wave-shaped 2D-layer perpendicular to b-axis (Figure 6); (d) the intralayer contacts include π-stacking and other nondirectional interactions between the molecules located in the neighboring 2D-layers. 4.3.1. Bader Analysis. Both polymorphs have a similar Hbond network; however, the energy of the particular intermolecular interactions in these forms may differ significantly. In order to quantify the strong and weak noncovalent interactions found in the polymorphs, the Bader analysis of the 1430



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to the interlayer interactions. The values of the lattice energy evaluated using eq 2 were found to be −167.3 kJ·mol−1 and −174.2 kJ·mol−1 for forms I and II, respectively. Consequently, Bader analysis predicts that form II is energetically more stable than form I. 4.3.2. CLP Calculations. As the next step, the intermolecular interaction energies in the polymorphs were analyzed according to the CLP-PIXEL program package developed by Gavezzotti.18 Unfortunately, the PIXEL approach is restricted to the crystals with two molecules per asymmetric unit and cannot be used in the case of cocrystals with 2:1 stoichiometry. Thus, the AA-CLP model was applied to estimate the lattice energies of the [SAM+Ox] (2:1) polymorphs. All the calculations were performed with the optimized geometrical parameters of the crystals. The calculation results are summarized in Table 3.

computed periodical electron density was performed, and the energies of intermolecular interactions were calculated according to eq 1. The energies of the intermolecular Hbonds and the selected C−H···O contacts are given in Table2, while the rest of the data are collected in Table S2. The O4−H1···O1 bond is the strongest intermolecular interaction in the crystals of both polymorphs. In form II, this bond is characterized by a remarkably high electron density at the bond critical point (ρb = 0.082 au) and a short O···O distance (2.508 Å), which results in the energy value of 66.6 kJ· mol−1 (Table 2). The same interaction in polymorph I has a lower ρb value at the bond critical point (0.062 au), and its energy is calculated to be ∼20% lower than that in form II. The O4−H1···O1 bond falls into the intermediate region, separating the ideal shared and closed shell interactions in crystals.54,55 The electron-density parameters and the energy of the N1− H11···O3 bond in the acid−amide heterosynthon have similar values in both forms (∼22 kJ·mol−1) (Figure 5). The energy of the acid−amide heterosynthon equals 72.8 kJ·mol−1 in form I and 88.9 kJ·mol−1 in from II. The latter value seems somewhat overestimated. The reasons for this result are discussed in section 5. The N1−H12···O4 side bond, which connects the neighbor trimers with each other, is characterized by ρb values slightly above 0.01 au (Table 2). This H-bond corresponds to the closed-shell interactions49,50 and its energy is slightly larger in form I (9.4 kJ·mol−1) than in form II (9.1 kJ·mol−1). We also localize the (3; −1) critical point indicating the existence of an additional N1−H12···O3 side bond between the molecules of salicylamide and oxalic acid. This intermolecular H-bond is far from linearity, the N1−H12···O3 angle equals 108.1° and 107.6° in forms I and II, respectively. However, its energy is greater than the energy of the quasi-linear N1−H12···O4 bond (Figure 5). In addition, the Bader analysis reveals that the O4 atom of oxalic acid and the O2 atom of salicylamide act as acceptors of relatively weak C−H···O interactions (∼5−8 kJ· mol−1); see Figure 5. The total energy of intermolecular interactions within the ribbon is nearly identical in the considered crystals and equals 34.2 kJ·mol−1 (form I) and 34.3 kJ·mol−1 (form II). A number of the (3; −1) bond critical points corresponding to the interlayer contacts are observed in form II. The first one corresponds to the C3−H3···O2 interaction with the energy of 7.9 kJ·mol−1, while the second is the C4−H4···C4 contact with the energy of 3.7 kJ·mol−1 (Figure S6). A relatively large number of these contacts is localized in form I; however, the energy of the particular interactions is quite small (2.6−5.2 kJ· mol−1). The total energy of the interlayer interactions equals 16.7 kJ·mol−1 (form I) and 11.7 kJ·mol−1 (form II). Topological analysis has also revealed a set of the critical points (3, −1) between the molecules located in the 2D-layers. Most of these contacts can be attributed to π-stacking and other nondirectional interactions. The energy of the particular interaction is relatively small and varies within 3−8 kJ·mol−1 (Figure S7). The total energy of intralayer interactions, however, equals 43.7 kJ·mol−1 in form I and 39.5 kJ·mol−1 in form II. The obtained values are comparable with the total energy of the intermolecular interactions within the ribbon. Both polymorphic forms have the following distribution of the energy of intermolecular interactions: about 50% of the total energy is associated with the acid−amide heterosynthon, the intermolecular interactions within the ribbon and interlayer interactions contribute ∼20%, and only about 10% corresponds

Table 3. Results of AA-CLP Calculations (in kJ·mol−1)a Form I Form II

Ecoul

Epol

Edisp

Erep

Elatt

−73.1 −64.4

−62.4 −65.3

−152.1 −171.6

114.9 152.3

−172.8 −149.0

a

Lattice energies (Elatt), coulombic energies (Ecoul), polarization energies (Epol), dispersion energies (Edisp), and repulsion (Erep) terms.

According to AA-CLP calculations, the total lattice energy for form I is ca. 24 kJ·mol−1 more stabilizing than that for form II, suggesting the opposite rank order of stabilities of polymorphs I and II compared to the results of the Bader analysis. Table 3 shows that the dispersion interactions dominate the structures of the polymorphs, while the Coulombic term is almost two times less significant. An analysis of different energy contributions to the total lattice energy indicates that the main difference between the polymorphs is observed for the repulsion term, which is calculated to be significantly larger in form II. However, the packing arrangement of form II is more favorable compared to that of form I in terms of the attractive energy contributions (Coulombic, polarization, dispersion). In other words, AA-CLP calculations suggest that the lattice energy gain for form I is obtained mainly by decreasing the repulsive interactions between the molecules in the crystal. Relevant information can also be obtained by analyzing sums of the intermolecular interaction energies between different types of constituents in the crystal structure (Table 4). According to AA-CLP, in both polymorphs, the SAM-Ox and SAM-SAM interactions have closely comparable contributions, each comprising approximately half of the total energy. The results of Bader analysis indicate that almost 70% of the crystal energy is provided by interactions between salicylamide and oxalic acid, while the SAM−SAM interactions comprise only ca. 22%. 4.3.3. Hirshfeld Surface Analysis. Hirshfeld surface analysis19,56 has proven to be an effective tool to analyze the differences in crystal packing between structurally related compounds, especially effective in studying molecular polymorphism and multicomponent crystals of a single component with variable coformers, solvents, or counterions.15,57 The difference in 3D maps of Hirshfeld surfaces and fingerprint plots provides valuable information on noncovalent interactions and close contacts at a low computational cost. The 2D fingerprint plots and the relative contribution of the important intermolecular contacts of salicylamide in the cocrystal polymorphs are shown in Figure 7. For both polymorphs, the most significant contributions come from 1431



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Table 4. Sums of Intermolecular Interaction Energies (kJ·mol−1) between Different Types of Constituents Calculated Using Different Methods SAM-SAM AA-CLP QTAIMC

Form Form Form Form

I II I II

−77.7 −71.3 37.2 35.2

SAM-Ox −93.6 −72.4 120.9 133.2

(44.9%) (47.9%) (22.3%) (20.2%)

(54.2%) (48.6%) (72.3%) (76.5%)

Ox-Ox −1.5 −5.3 9.1 5.8

(0.9%) (3.5%) (5.5%) (3.3%)

Elatt −172.8 −149.0 −167.3 −174.2

Figure 7. 2D fingerprint plots for the salicylamide molecule in the cocrystal polymorphs. The lower diagram shows the relative contribution of the intermolecular contacts to the Hirshfeld surface area.

shows clearly that the contributions of the H···C and C···C contacts to the Hirshfeld surface are the main difference between the polymorphs. In form I, C···H contacts occupy twice as much area as in Form II (21.7% against 10.8%), while Form II is characterized by a much larger contribution of C···C contacts, which are nearly absent in Form I (12.1% versus 3.6%). The bright-colored area in the upper right part of the fingerprint plot for Form II clearly corresponds to π-stacking interaction between the parallel SAM located in parallel ribbons. These π···π contacts are found to be much shorter in Form II than those in Form I. The main part of C···H contacts in form I corresponds to C−H···π interactions between SAM molecules of the neighboring layers. These contacts are seen as wide areas on each side of the Form I fingerprint plot. In Form II, however, C−H···π interactions spread only in the range between 1.8 and 2.0 Å. 4.4. Thermal Analysis. Differential scanning calorimetry (DSC) was conducted to compare the melting properties of the polymorphs. For each polymorphic form, melting temperature

H···O and H···H contacts, which correspond to the hydrogen bonds/C−H···O contacts and van der Waals interactions, respectively. Since the dnorm values for these contacts are close (32.6−33.8% in Form I and 34.9−35.9% in Form II), the lattice is stabilized equally by both H-bonds and dispersion forces. The synthon interactions, which have the closest interatomic distance of all the noncovalent interactions, are seen on the fingerprint plot as two distinct spikes. The distances of N1− H11···O3 contact are nearly equal in both polymorphs; the O4−H1···O1 bond is observed at a shorter distance in Form II. It is interesting to note that all the H-bonds and C−H···O contacts found using the Bader analysis are visible on the 3D plots as areas with negative dnorm (Figure S8). The H···H contacts, being less directed, are presented on 2D fingerprint plots as bulk central areas. In contrast to H···O contacts which are always attractive, the H···H contacts occupy the part of the Hirshfeld surface with positive dnorm, and thus should be considered repulsive.58 A similar balance between Coulombic and repulsive forces is observed in CLP calculations. Figure 7 1432



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and fusion enthalpy were stated as the average of at least five replicated experiments. The results of DSC experiments are shown in Figure 8, and the thermal data are given in Table 5.

Therefore, in order to rationalize the thermodynamic relationships between the polymorphs, a set of experimental techniques were applied, including solubility and solution calorimetry measurements. It is well-known that the difference in free energy between polymorphs is directly proportional to their relative equilibrium solubilities4 as expressed by the following equation: ⎛S ⎞ ΔGtrT(I → II) = RT ln⎜ II ⎟ ⎝ SI ⎠

where SI and SII are the solubilities of forms I and II, respectively. Solubility implies the equilibrium between a solid phase and a solution. It means that both polymorphs should possess longterm stability in the solvent in order to reach the equilibrium state. Preliminary solubility experiments with methanol, ethanol, acetonitrile, and ethyl acetate at 25 °C have shown that form II is unstable in all the tested solvents and undergoes a solution-mediated transformation to form I in the bottom phase. It should be noted that the conversion from form II to form I in methanol, ethanol, and ethyl acetate occurs in less than 2 h time, since no reflections of form II are detected by XRPD analysis in the residual materials. However, after 2 h of dissolution in acetonitrile, the bottom phase has been found to contain a mixture of polymorphic forms (Figure S10), and the transformation process is completed after 6 h of experiment (Figure S11). These observations unambiguously suggest that form II of the [SAM+Ox] (2:1) cocrystal is the least thermodynamically stable polymorph under the current conditions. In order to compare thermodynamic stability of the polymorphs quantitatively, we estimate apparent solubility of form II from its dissolution profile in acetonitrile (Figure 9). It is seen that the dissolution profile of form II of [SAM + Ox] (2:1) demonstrates “spring and parachute” behavior.60

Figure 8. DSC traces for polymorphs of [SAM+Ox] (2:1) cocrystal.

Table 5. Thermophysical Data for Polymorphs of [SAM +Ox] (2:1) Tfus, °C (onset)a Form I Form II a

167.7 ± 0.2 (n = 5) 167.5 ± 0.8 (n = 5)

ΔHTfus, kJ·mol−1 ΔHTtr, kJ·mol−1 (I→II) 80.7 ± 0.6 68.2 ± 2.1

(3)

12.5 ± 2.7

n = number of independent DSC measurements.

An inspection of the DSC curves shows that the major endotherm which corresponds to the melting of the cocrystal is followed by unknown endoevents. According to TG analysis, the latter process is accompanied by a weight loss and starts at the end of melting (Figure S9). It might be reasonable to assume that the weight loss may be attributed to the sublimation or evaporation of salicylamide as it is released from the crystal, since salicylamide is known to have a relatively high vapor pressure especially at elevated temperatures.59 Therefore, the absolute value fusion enthalpy ΔHfusT of the cocrystal can be estimated only roughly. However, assuming that in both forms the contribution to the total thermal effect from evaporation of salicylamide is equal, the difference between ΔHfusT of the polymorphs should be considered as a reliable value which can be used in further discussion. The polymorphs melt without other phase transitions. It is interesting to note that the onset temperature of form II is only marginally lower and practically identical to that of form I. This thermal behavior makes the polymorphs almost indistinguishable in the DSC experiment. The difference in the heat of fusion between these two forms, however, is found to be ca. 12.5 kJ·mol −1 , which is considerably larger than the experimental error. Since no thermal events occur below the melting points of the polymorphs, forms I and II of [SAM+Ox] (2:1) should be considered monotropically related. 4.5. Thermodynamic Relationships between Polymorphs. As shown earlier, different calculation schemes were not able to provide consistent results for lattice energies of the polymorphs and their relative stability. On the other hand, thermochemical studies also involve some difficulties, namely, virtually equal thermal stability of the polymorphs and evaporation of salicylamide during the melting process.

Figure 9. Dissolution profile of title crystal forms in acetonitrile at 298.2 K plotted as SAM concentration in solution against time.

The PXRD analysis of the solid material taken after 10 min of dissolution (the time roughly corresponds to the concentration maximum on the dissolution curve of form II) shows no evidence of form II conversion at that time. The concentration level of SAM for form II remains higher than that of form I for the next 4 h, indicating a relatively slow rate of polymorphic transition in acetonitrile. The results of solubility (S) and solution calorimetry (ΔHsol ° ) studies in acetonitrile and the calculated thermodynamic parameters of the polymorphic 1433



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Table 6. Solubilities (S), Solution Enthalpies (ΔHsol ° ) of [SAM + Ox] (2:1) Polymorphs in Acetonitrile at 25.0 °C and Thermodynamic Parameters of Polymorphic Transitions S −1

mol·L Form I Form II a

(1.96 ± 0.02) × 10−1 (2.40 ± 0.10) ×·10−1b

ΔHsol °a

ΔGtr° (I→II)

ΔHtr° (I→II)

ΔStr° (I→II)

kJ mol−1

kJ mol−1

kJ mol−1

J mol−1 K−1

71.9 ± 0.1 55.5 ± 0.6

0.5 ± 0.4

16.4 ± 0.7

55 ± 4

See Table S3 in the Supporting Information for the full data set. bApparent solubility.

parameters of H-bonded fragments by different functionals and basis sets. Such work cannot be successfully done as there is little reliable data on the energy of strong intermolecular hydrogen bonds in crystals. Relatively simple organic molecules, considered in the present study, have proven to be very complex systems for the Elatt evaluation using the electron density distribution (the Bader analysis) or the CLP method. Both methods have failed to correctly assess the stability of polymorphs. In the case of CLP, the lattice energy of form I was calculated to be larger than that of form II, only due to the lower contribution of the repulsion. This fact indicates the imperfection of the parametrization method rather than the actual physical picture. According to ref 79, the existing force fields systematically underestimate the absolute lattice energy. In the case of Bader, the lattice energy of form II was greater than that of form I only because of the energy of one hydrogen bond. This result may be due to the overestimation of the H-bond energy, evaluated using the electron density distribution. A characteristic feature of the two-component pharmaceutical crystals is the presence of intermolecular O−H···O/N−H··· O bonds with the O···O/N···O distance shorter than 2.60/2.65 Å79−86 and the energies higher than 40.0 kJ/mol.87 Such crystals are not included in the benchmark sets for noncovalent interactions in solids.88,89 The mean absolute deviation of the sublimation energy varies from 5 to 13 kJ/mol for the subset X12/Hydrogen dominated by weak and moderate H-bonds depending on the functional and basis sets.34 The applicability of the approaches developed in34,36,88,89 to the evaluation of the relative stability of polymorph modifications of the twocomponent pharmaceutical crystals requires a special investigation. We conclude that comprehensive theoretical approaches are hardly applicable to a quantitative description of the polymorph phenomenon in multicomponent molecular crystals. Solving this problem requires further development of the dispersion corrected quantum mechanical methods (see, e.g., ref 36) and implementation of energy decomposition schemes (SAPT,90,91 NBO,92 etc.) into the Crystal code. A reliable source of information on the relative stability of polymorphs is experimental methods, such as solubility, thermochemical investigations, and so forth.

transition between the different forms are summarized in Table 6. The experimental data show that the free energy of polymorphic transition (ΔGtr°(I → II)) calculated from the solubility of form I and apparent solubility of form II is found to be close to zero and comparable with the experimental error. According to the solution calorimetry results, form I is confirmed to be thermodynamically most stable, while the crystal lattice energy of form II is found to be 16.4 ± 0.7 kJ· mol−1 less stabilizing than form I. This value qualitatively agrees with the transition enthalpies obtained by DSC method.

5. DISCUSSION The electron density distribution of a molecular crystal obtained from high-resolution X-ray diffraction experiments forms a unique physical−chemical method, which provides detailed information about the nature of intermolecular interactions in the solid state.11 Bader analysis of the periodic electronic density in conjunction with the Espinosa scheme61 reveals the energy of the particular noncovalent (intermolecular) interaction.62,63 This approach has been recently criticized.64 Indeed, the use of the Espinosa scheme exploring the local electronic potential energy density61 extracted from the experimental electron density65 may cause unreliable energies of the strong intermolecular H-bonds.66 To overcome this drawback, an approach exploring the local electronic kinetic energy density at the bond critical point Gb31 can be used.17,32,66 There are a limited number of experimental charge density studies on polymorphic systems,11,15,67−69 as it is difficult to obtain suitable crystals. The electron density distribution in molecular crystals can be obtained from the solid-state DFT computations.70,71 The use of the relaxed geometry enables computing harmonic frequencies and IR intensities.72,73 This gives a unique possibility to verify the energies of intermolecular H-bonds of different types and strength evaluated using the theoretical Gb value.24,32,74 However, this approach is not universal. It is not applicable to the extra strong intermolecular H-bonds (Eint > 85 kJ/mol) 66 in solids. These bonds exist in crystalline K+(FHF)−75 and H5O2+X−,76 where X− is the anion of a strong monobasic acid. The considered approach is not applicable to intermolecular interactions with Eint < 2 kJ/mol (section 3.1). The additional source of errors is the use of modest basis sets in solid-state computations.24,34−36,73,74,77 As a result, the calculated distance O···O may differ from the experimental values (Table 5 in ref 78). The energy of strong O−H···O bonds is very sensitive to the O···O distance (Figure 1 in ref 66), and a small error in the calculated O···O distance causes a significant error in the H-bond energy. We can speculate that the accuracy of the Bader analysis in conjunction with eq 1 for evaluation of strong H-bond energies (>60 kJ mol−1) in the solid state should be carefully studied. Special attention should be paid to the reproduction of metric

6. CONCLUSIONS In this study, a rare case of packing polymorphism in the salicylamide cocrystals with oxalic acid has been investigated. Single-crystal X-ray analysis has revealed that the two polymorphs consist of conformationally identical molecules, which are connected to each other via identical primary and secondary synthons. Both polymorphs contain a trimeric unit formed by short (strong) O−H···O and moderate N−H···O bonds between salicylamide and oxalic acid. The O···O distance in form II is ∼0.12 Å shorter than that in form I. The main 1434



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ACKNOWLEDGMENTS This work was supported by the Russian Foundation of Basic Research (No. 14-03-01031). We thank “the Upper Volga Region Centre of Physicochemical Research” for technical assistance with XRPD and TG experiments. X-ray diffraction studies were performed at the Centre of Shared Equipment of IGIC RAS.

difference between the crystal structures of the polymorphs is caused by the packing arrangements of the neighboring ribbons. In form I, the adjusted ribbons are packed in a zigzag manner to form an angle of ∼76.2°. In form II, this angle is found to be significantly smaller (∼48.6°). DSC studies have shown that the melting temperatures of the polymorphs coincide within the experimental errors. The stability relationships between the polymorphs were rationalized using different experimental methods, including solubility and solution calorimetry measurements. Both experiments indicate that form I is the thermodynamically most stable modification of the cocrystal. The lattice energy of form II is found to be 16.4 kJ mol−1 less stabilizing than form I. The similarities and differences in intermolecular contacts across two polymorphs were visualized using the Hirshfeld surface analysis. According to this, the crystal lattices of the polymorphs are stabilized equally by both H-bonds and dispersion forces. The lattice energies of the polymorphs were also evaluated using the electron density distribution (the Bader analysis) and classical force fields (the CLP approach). Both methods have failed to correctly assess the stability of the polymorphic forms. The results of the CLP calculations suggest that the lattice energy of form I has a larger value than that of form II only due to the lower repulsion contribution, although in the case of Bader analysis, the lattice energy of form I is found to be less stabilizing than that in form II only because of the energy of one hydrogen bond. We conclude that the comprehensive theoretical approaches created for the lattice energy evaluation should be used with caution for quantitative description of the polymorphism phenomenon, particularly in multicomponent molecular crystals. Therefore, the results obtained from classical experimental methods (such as solubility, thermochemical investigations, etc.) still remain the most reliable source of information on the relative stability of polymorphs.

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REFERENCES

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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.7b00019. Photomicrographs, experimental and calculated PXRD patterns of the polymorphs, thorough hydrogen bond network topology analysis and results of TG and DSC analysis of the salicylamide cocrystal, the full data set of the solution calorimetry experiments, details of the cocrystal screening and DFT calculations (PDF) Accession Codes

CCDC 1525077−1525078 contains 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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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Mikhail V. Vener: 0000-0002-0511-9903 Notes

The authors declare no competing financial interest. 1435



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