Skip to main content
NCBI home page
ACS AuthorChoice logoLink to ACS AuthorChoice
. 2023 Jul 19;23(8):5446–5461. doi: 10.1021/acs.cgd.2c01403

Exploring the Crystal Structure Landscape of Sulfasalazine through Various Multicomponent Crystals

Shan Huang †,‡, Vinay K R Cheemarla †, Davide Tiana †, Simon E Lawrence †,‡,*
PMCID: PMC10401639  PMID: 37547882

Abstract

graphic file with name cg2c01403_0020.jpg

Sulfasalazine is used as an anti-inflammatory drug to treat large intestine diseases and atrophic arthritis. In the solid state, two tautomers are known: an amide tautomer (triclinic polymorph) and an imide tautomer (monoclinic polymorph). Crystallization of six new multicomponent solids of sulfasalazine with three cocrystal formers and three salt formers has been achieved by slurry, liquid-assisted grinding and slow evaporation methods. All of the solid forms are characterized by X-ray diffraction techniques, thermal analysis, and Fourier transform infrared spectroscopy. The crystal structural analysis reveals that two sulfasalazine molecules or anions arrange in a head-to-head fashion involving their pyridyl, amide, and sulfonyl groups in an R22(7):R2(8):R22(7) motif. This is the key structural unit appearing in both sulfasalazine imide polymorph and all six multicomponent crystals. In addition, sulfasalazine exists in the amide form in all unsolvated multicomponent crystals obtained in this work and adopts the imide tautomer in the solvated cocrystals and salt. Hirshfeld surface analysis and the associated two-dimensional (2D) fingerprint plots demonstrate that sulfasalazine has significant hydrogen bond donor capability when cocrystallized and is a significant hydrogen bond acceptor in the salts. The frontier molecular orbital analysis indicates that sulfasalazine cocrystals are chemically more stable than the salts.

Short abstract

The key structural unit in three cocrystals and three salts of sulfasalazine is a head-to-head orientation of the sulfasalazine molecules along a short axis of the molecule involving the pyridyl and sulfonamide groups in an R22(7):R2(8):R22(7) motif. Hirshfeld surface and frontier molecular orbital analyses investigated the differences between the cocrystals and salts.

Introduction

Sulfasalazine (SSZ, Figure 1), a conjugate of an anti-inflammatory drug, 5-aminosalicylic acid, and an antibacterial drug, sulfapyridine, is successfully used as a disease-modifying anti-rheumatic drug to treat large intestine diseases and atrophic arthritis.1 As one of the sulfonamide compounds containing a pyridine or pyrimidine moiety, SSZ can adopt two different tautomeric conformations in its crystal forms. The first reported tautomer of SSZ was the triclinic amide form, which was obtained from ethanol by recrystallization,2 while the monoclinic imide tautomer was obtained by cooling after heating an ethanolic solution of SSZ in a Teflon-lined stainless steel autoclave.3 The migration of a hydrogen atom, accompanied by the switch of a single bond and adjacent double bond, significantly alters the crystal packing and intermolecular interactions of these two tautomers.

Figure 1.

Figure 1

Open in a new tab

Amide form of sulfasalazine observed in the triclinic polymorph (left) and the imide form seen in the monoclinic polymorph (right).

To further investigate the molecular arrangements and hydrogen bonding motifs in different SSZ crystal forms, a detailed analysis of the crystal structures of the known SSZ amide and imide forms was conducted. The hydrogen bond network and π–π interactions of the amide polymorph are shown in Figures 2 and S6a, respectively, and the corresponding hydrogen bond and π–π interaction data are displayed in Table S2. Two SSZ molecules are assembled in a head-to-tail fashion through discrete N–H···O and O–H···N hydrogen bonds (taking the pyridyl group as the head and the carboxyl acid group as the tail), generating binary level R22(8) and R2(28) motifs (Figure 2a). The structure is extended through C–H···O discrete hydrogen bonds, forming an R22(14) motif (Figure 2b).

Figure 2.

Figure 2

Open in a new tab

Crystal packing and intermolecular interactions in the SSZ amide form: (a) R22(8) and R2(28) motifs and (b) R22(14) motif.

In contrast, in the structure of the imide form, pairs of SSZ molecules are arranged in a head-to-head manner (Figure 3 and Table S3). The two SSZ molecules are linked via a N–H···N discrete hydrogen bond and a C–H···O discrete hydrogen bond, generating an R22(7):R2(8):R22(7) motif (Figure 3a). Additional C–H···O discrete hydrogen bond forms an R2(14) motif (Figure 3b). Furthermore, the π–π interactions between two pyridyl rings from SSZ also contribute to the extended crystal packing (Figure S7b).

Figure 3.

Figure 3

Open in a new tab

Crystal packing and intermolecular interactions in the SSZ monoclinic imide form: (a) R22(7):R2(8):R22(7) motif and (b) R2(14) motif.

Sulfasalazine has low solubility and permeability and is a class IV drug4 according to the Biopharmaceutics Classification System.5 Different approaches have been investigated to improve its bioavailability. For example, Shadid et al. successfully improved the solubility and bioavailability of SSZ by ionic liquid formation.6 Priyam and co-workers synthesized an amphiphilic derivative of SSZ to modify the solubility by conjugating it with polyethylene glycol.7 In addition, nanocrystallization,8 solid dispersion,9 and noisome techniques10 have been explored to improve the solubility and/or dissolution performance of SSZ.

During the past few decades, crystal engineering has developed for predicting and designing the crystals that contain more than one molecule, for example, cocrystals and salts.11−14 A significant driver has been the design of improved drugs with optimal physicochemical properties. Cocrystals are multicomponent crystalline materials of two or more different molecular and/or ionic compounds in a stoichiometric ratio that are neither solvates nor simple salts.15 They are generally assembled via hydrogen bonds,16 halogen bonds,17 or π–π stacking.18 The term pharmaceutical cocrystal has been used when at least one component is an active pharmaceutical ingredient and the others are pharmaceutically acceptable.19 Similarly, the term pharmaceutical salt has been used for related systems where intermolecular proton transfer has occurred between complementary acid and basic functional groups.20 Empirically, when ΔpKa [ΔpKa = pKa (base) – pKa (acid)] is greater than 4, the two components form a salt, and when ΔpKa is less than −1, the system results in a cocrystal. For systems with ΔpKa between −1 and 4, a linear relationship between ΔpKa and the probability of proton transfer between two components was derived.21,22 Other techniques are used for distinguishing crystal forms, for instance, solid-state nuclear magnetic resonance,23 vibrational spectroscopy,24 and single crystal X-ray diffraction (SCXRD).25

From the crystal engineering perspective, SSZ would be expected to readily form cocrystals or salts because it has multiple functional groups, with multiple hydrogen bond donor and acceptor sites. Four multicomponent crystalline materials of SSZ have been reported: SSZ-trimethoprim (one cocrystal and one salt), SSZ-nicotinamide cocrystal, and SSZ-theobromine cocrystal. They all have enhanced dissolution performance compared with pure SSZ;26,27 however, none of their crystal structures are available in version 2022.2.0 of the Cambridge Structural Database (CSD).28

Herein, the crystalline form diversity of SSZ with a series of pharmaceutically relevant cocrystal/salt formers (Figure 4) was explored. Three cocrystals of SSZ with 4,4′-bipyridine (BPY), 1,2-bis(4-pyridyl) ethane (BPE), and phenazine (PHE) and three salts of SSZ with 4-aminopyridine (4AP), 4,4′-trimethylenedipyridine (TMD), and imidazole (IMZ) were successfully prepared and fully characterized, and their crystal structures were obtained. Four more products of SSZ with piperazine (PPZ), 2-aminopyrimidine (2-APM), 4-dimethylaminopyridine (4-DMP), and acridine (ACRI) were determined as new multicomponent crystalline solids by powder X-ray diffraction (PXRD) (Figure S5). However, multiple attempts to grow suitable crystals for analysis were unsuccessful.

Figure 4.

Figure 4

Open in a new tab

Cocrystal formers and salt formers investigated in this study (successful cocrystal/salt formers analyzed by SCXRD in blue, successful cocrystal/salt formers based on PXRD in orange, and unsuccessful cocrystal/salt formers in black).

Experimental Section

Materials

Sulfasalazine (monoclinic imide form) was purchased from Fluorochem and used as received without further purification. Isonicotinamide, mefenamic acid, and picolinamide were purchased from TCI chemicals; other cocrystal/salt formers were obtained from Sigma-Aldrich and used as received. Solvents were purchased from commercial sources and used as received.

Solid Form Screening and Crystallization Experiments

Liquid-Assisted Grinding (LAG) Method

Mechanical grinding experiments were conducted in a Retsch Mixer Mill MM 400, equipped with 5 mL stainless steel grinding jars and one 2.5 mm stainless steel grinding ball per jar. The mill was operated at a rate of 30 Hz for 30 min, and the ratio of 1:1/1:2/2:1 of SSZ with cocrystal/salt formers was used. The powdered products were isolated and analyzed by PXRD.12 Experimental details are provided in Table S1.

Slurry Method

SSZ and cocrystal/salt formers in a 1:1/1:2/2:1 molar ratio were slurried in methanol or ethanol for 2–3 days. The resulting suspension was filtered and allowed to dry in the fume hood for up to 24 h. The powdered products were isolated and analyzed by PXRD. Experimental details are provided in Table S1.

Solution Crystallization

(SSZ)2·BPY·(Tol)0.8 Cocrystal Solvate

The powdered product from the 2:1 SSZ: BPY slurry experiment (48.6 mg) was dissolved in 20 mL of toluene–ethanol (1:1, v/v) in a sample vial, covered with perforated parafilm, and kept at room temperature until the solvent had almost completely evaporated (∼1 week). Red plate-like single crystals were obtained.

(SSZ)2·BPE·(EtOH)2 Cocrystal Solvate

The powdered (SSZ)2·BPE·(EtOH)2 (51.1 mg) obtained from slurry experiments was dissolved in 10 mL of ethanol in a sample vial, covered with perforated parafilm, and kept at room temperature until the solvent had almost completely evaporated (1–2 weeks). Orange plate-like single crystals were obtained.

(SSZ)2·PHE Cocrystal

The powdered (SSZ)2·PHE (50.8 mg) obtained from slurry experiments was dissolved in 10 mL of ethanol in a sample vial, covered with perforated parafilm, and kept at room temperature until the solvent had almost completely evaporated (1–2 weeks). Orange needle-like single crystals were obtained.

SSZ·4AP Salt

The powdered SSZ·4AP (49.6 mg) obtained from slurry experiments was dissolved in 5 mL of methanol in a sample vial, covered with perforated parafilm, and kept at room temperature until the solvent had almost completely evaporated (∼1 week). Red plate-like single crystals were obtained.

SSZ·TMD Salt

SSZ (19.9 mg, 0.05 mmol) and TMD (9.9 mg, 0.05 mmol) in a 1:1 molar ratio were dissolved in 10 mL of deionized water in a sample vial and left at room temperature until the solvent had almost completely evaporated (3–4 months). The orange plate-like single crystals of SSZ·TMD salt were obtained on one occasion. Attempts to obtain other crystals or bulk material were unsuccessful.

SSZ·IMZ·MeCN Salt Solvate

The powdered product from the 1:1 SSZ: IMZ LAG experiment (49.2 mg) was dissolved in 15 mL of acetonitrile in a sample vial, covered with perforated parafilm, and kept at room temperature until the solvent had almost completely evaporated (1–2 weeks). Orange needle-like single crystals were obtained.

Physical Measurements

Differential scanning calorimetry (DSC) data were collected using a TA Instruments Q1000. Samples (2–6 mg) were crimped in nonhermetic aluminum pans and scanned from 25 to 300 °C at a heating rate of 10 °C min–1 under a continuously purged dry nitrogen atmosphere. Thermogravimetric analysis (TGA) data were collected using a TA Instruments Q500 thermogravimetric analyzer. The sample was placed in an aluminum sample pan and heated under nitrogen at a rate of 20 °C min–1 from 25 to 500 °C. IR spectra were recorded on a PerkinElmer UATR Two spectrophotometer using a diamond-attenuated total reflectance accessory over a range of 400–4000 cm–1. An average of four scans was taken for each spectrum obtained with a resolution of 4 cm–1. PXRD data were collected using a STOE STADI MP diffractometer with Cu Kα radiation using a linear position-sensitive detector over the 2θ range of 3.5–45.5° with an increment of 0.05° at a rate of 2° min–1. The samples were prepared as transmission foils and the data were viewed via STOE WinXPOW POWDAT software.29 SCXRD data of (SSZ)2·BPY·(Tol)0.8 and (SSZ)2·BPE·(EtOH)2 were collected using a Bruker APEX II DUO with monochromated Cu Kα radiation (λ = 1.54178 Å). SCXRD data of the other SSZ cocrystals and salts were collected on a Bruker Quest D8 diffractometer with monochromated Cu Kα radiation (λ = 1.54184 Å). All calculations and refinements were made using Bruker APEX software with the SHELX suite of programs.30,31 Nonhydrogen atoms were refined anisotropically. For (SSZ)2·BPY·(Tol)0.8 and (SSZ)2·BPE·(EtOH)2, the N–H hydrogen atoms were located and refined. All other hydrogen atoms were placed in geometrically calculated positions using the riding model, with C–H = 0.93–0.97 Å and N–H = 0.86–0.89 Å, and Uiso (H) (in the range of 1.2–1.5 times Ueq of the parent atom). DIAMOND was used for creating figures,32 and PLATON was used for the analysis of potential hydrogen bonds and short ring interactions.33,34 Crystallographic parameters are provided in Table 1.

Table 1. Crystallographic Data for SSZ Cocrystals and Salts.

crystallographic data (SSZ)2·BPY·(Tol)0.8 (SSZ)2·BPE·(EtOH)2 (SSZ)2·PHE SSZ·4AP SSZ·TMD SSZ·IMZ·MeCN
chemical formula C51.6H42.4N10O10S2 C26H26N5O6S C24H18N5O5S C23H20N6O5S C31H28N6O5S C23H21N7O5S
formula weight 1026.67 536.58 488.49 492.51 596.65 507.53
crystal system monoclinic triclinic monoclinic triclinic triclinic monoclinic
space group, Z P2/n, 2 P1̅, 2 C2/c, 8 P1̅, 4 P1̅, 2 P21/c, 4
temperature (K) 296.(2) 296.(2) 293(2) 293(2) 298(2) 302(2)
a (Å) 14.2397(5) 8.7750(7) 7.683(5) 10.7519(17) 7.826(13) 25.134(3)
b (Å) 6.4706(2) 12.8102(10) 33.62(3) 15.5563(18) 13.715(17) 10.0917(14)
c (Å) 26.7698(9) 12.9300(10) 22.610(9) 15.7326(17) 15.243(18) 9.409(2)
α (deg) 90 68.159(3) 90 64.838(7) 64.54(10) 90
β (deg) 90.5000(10) 77.234(4) 98.78(2) 74.725(10) 81.12(7) 91.511(12)
γ (deg) 90 82.571(4) 90 87.389(10) 75.13(12) 90
volume (Å3) 2466.46(14) 1313.99(18) 5771(6) 2290.9(5) 1426(4) 2385.8(7)
ρ calcd (g cm–3) 1.382 1.356 1.124 1.428 1.390 1.413
μ (mm–1) 1.571 1.524 1.320 1.678 1.449 1.640
reflns measured 30288 16382 20087 73865 11530 54017
reflns independent 4321 4409 2835 8952 6638 4714
Rint 0.0220 0.0201 0.0491 0.0887 0.0738 0.0629
significant [I > 2σ(I)] 4140 3996 2277 5947 1163 4055
parameters refined 338 366 319 628 390 328
Δρmax, Δρmin (e Å–3) 0.484, −0.355 0.508, −0.422 0.198, −0.300 1.050, −0.526 0.137, −0.204 0.508, −0.287
F(000) 1068 562 2024 1024 624 1056
R1 [I > 2σ(I)] 0.0473 0.0673 0.0512 0.0872 0.0593 0.0573
wR2 (all data) 0.1492 0.1988 0.2007 0.2842 0.1647 0.1829
CCDC 2109809 2109810 2109811 2064484 2109807 2109808
Open in a new tab

Computational Studies

Density functional theory (DFT) calculations using the Gaussian 09 program package employing the M06-2X functional with the 6-31+G (d,p) basis set were performed on the six obtained crystals without conducting structural optimization.13,35 The molecular orbitals were viewed using the Multiwfn 3.8 program and plotted by VMD.36,37 Hirshfeld surface analysis and two-dimensional (2D) fingerprint plots were carried out using the CrystalExplorer 21.5 program.38

Results and Discussion

Physical Characterization

The thermal behavior of the SSZ cocrystals/salts was assessed using DSC and TGA techniques. The melting points of (SSZ)2·BPY·(Tol)0.8, (SSZ)2·BPE·(EtOH)2, SSZ·4AP, SSZ·TMD, and SSZ·IMZ·MeCN are in between those of the individual components, while (SSZ)2·PHE cocrystal melts at a lower temperature than the starting materials (Figure S1). Additionally, small endothermic peaks before the melting peaks were observed in the DSC traces for (SSZ)2·BPY·(Tol)0.8, (SSZ)2·BPE·(EtOH)2, and SSZ·IMZ·MeCN, indicating the presence of solvent within the crystal lattice, which is consistent with the SCXRD data. This is also supported by the TGA results (Figure S2). A weight loss of 6.8% is observed for (SSZ)2·BPY·(Tol)0.8, which corresponds to 0.8 equiv of toluene (calculated as 6.7%). For (SSZ)2·BPE·(EtOH)2, a weight loss of 8.7%, corresponding to 1 equiv of EtOH (calculated as 8.6%), is observed. Similarly, SSZ·IMZ·MeCN exhibits a significant weight loss of 7.8%, which corresponds to 1 equiv of MeCN (calculated value is 8.1%). No significant weight loss before the decomposition temperature is observed for the other SSZ solids, suggesting that they are not solvated or hydrated. After cocrystallization of SSZ, the Fourier transform infrared (FTIR) spectrum (Figure S3) of cocrystals and salts showed the shifts in the hydroxyl peak of SSZ from 3027 to 2974 [(SSZ)2·BPY·(Tol)0.8], 2978 [(SSZ)2·BPE·(EtOH)2], 3059 [(SSZ)2·PHE], 2980 (SSZ·4AP), 3058 (SSZ·IMZ·MeCN), 3052 (SSZ·TMD) cm–1, suggesting the formation of new crystalline forms of SSZ, respectively. The PXRD patterns of the (SSZ)2·BPY·(Tol)0.8, (SSZ)2·BPE·(EtOH)2, (SSZ)2·PHE, SSZ·4AP, and SSZ·IMZ·MeCN (Figure S4) matched with the theoretical patterns obtained from the SCXRD analysis, demonstrating that these cocrystals can be reproduced in bulk quantities by the slurry or LAG method. The PXRD pattern of SSZ-TMD cannot be obtained since attempts to synthesize crystals or bulk material of SSZ·TMD were unsuccessful.

As for the solid states of these obtained new crystals, according to the ΔpKa rule, (SSZ)2·PHE is expected to be a cocrystal (ΔpKa <−1), while SSZ·4AP and SSZ·IMZ·MeCN are expected to be salts (ΔpKa > 4), which are confirmed by the SCXRD results (Table 2). The solid state of (SSZ)2·BPY·(Tol)0.8, (SSZ)2·BPE·(EtOH)2, and SSZ·TMD could be either salt or cocrystal (−1 < ΔpKa < 4), and SCXRD data confirm that (SSZ)2·BPY·(Tol)0.8 and (SSZ)2·BPE·(EtOH)2 are cocrystals and SSZ·TMD is a salt, which follows the linear relationship proposed by Cruz-Cabeza.22

Table 2. pKa Values of SSZ, Cocrystal/Salt Formers, and ΔpKa Values of the New Solid Forms.

  pKa ΔpKa solid state
SSZ 2.70a    
BPY 3.27a 0.57 2:1 cocrystal solvate
BPE 6.13a 3.43 2:1 cocrystal solvate
PHE 1.60a –1.10 2:1 cocrystal
4AP 9.1739 6.47 1:1 salt
TMD 6.30a 3.60 1:1 salt
IMZ 6.9740 4.27 1:1:1 salt solvate
Open in a new tab
a

pKa was obtained from CAS SciFindern.

Crystal Structures

The structure analyses of the six multicomponent systems are presented below. Hydrogen bond and π–π interaction data are displayed in Tables S4–S9.

(SSZ)2·BPY·(Tol)0.8 Cocrystal Solvate

The (SSZ)2·BPY·(Tol)0.8 crystal has one SSZ molecule and half of the BPY molecule in the asymmetric unit. Disordered toluene is present in voids in the structure. An R22(7) motif is formed by SSZ and BPY through O1–H1···N5 and C23–H23···O2 discrete hydrogen bonds, and the BPY molecule links another SSZ molecule via a discrete C20–H20···O4 hydrogen bond. The latter SSZ molecule is involved in two hydrogen bonds (N4–H4N···N3 and C18–H18···O5) with the adjacent SSZ molecule, forming an R2(7):R22(8):R2(7) motif, which leads to the formation of three-dimensional (3D) hydrogen bond layers (Figure 5). The structure is further stabilized by the π–π interactions between the SSZ and SSZ, SSZ and BPY, and SSZ-toluene molecules (Figure S8 and Table S4).

Figure 5.

Figure 5

Open in a new tab

Crystal packing and intermolecular interactions in the (SSZ)2·BPY·(Tol)0.8 cocrystal solvate (pink is SSZ, green is BPY, and blue is toluene).

(SSZ)2·BPE·(EtOH)2 Cocrystal Solvate

The (SSZ)2·BPE·(EtOH)2 cocrystal solvate crystallizes in the triclinic P1̅ space group with one SSZ molecule, half of the BPE molecule, and one EtOH molecule in the asymmetric unit. The SSZ molecule is disordered over the N=N group (75:25), and the EtOH molecule is disordered (75:25). As shown in Figure 6a, the BPE molecule links two SSZ molecules through discrete O2–H2···N5 and C22–H22···O5 hydrogen bonds, and the EtOH molecule links one SSZ molecule via C16–H16···O31A hydrogen bonds. Along the a-axis, the 3D hydrogen bonding network is further stabilized by the R22(7):R2(8):R22(7) motif between two adjacent SSZ molecules. Along the c-axis, the voids containing EtOH molecules can be observed (Figure 6b). Additional π–π interactions between the phenyl rings from SSZ and the pyridyl rings from BPE (Cg2–Cg3, Cg2–Cg4, and Cg4–Cg4) contribute to the extended 3D structure (Figure S9 and Table S5).

Figure 6.

Figure 6

Open in a new tab

Crystal packing and intermolecular interactions in the (SSZ)2·BPE·(EtOH)2: (a) along the a-axis (pink is SSZ, green is BPE, and blue is EtOH) and (b) along the c-axis. The minor component of the disordered structure has been omitted for clarity.

(SSZ)2·PHE Cocrystal

The asymmetric unit of (SSZ)2·PHE has one SSZ molecule and half of the PHE molecule. PHE and two SSZ molecules form an R22(6):R2(8) motif through C6–H6···O1, O1–H1···N1 and C3–H3···O2 discrete hydrogen bonds (Figure 7a). The hydrogen bond network is extended through N4–H40···N5 and C24–H24···O4 hydrogen bonds, resulting in the same R22(7):R2(8):R22(7) motif between adjacent SSZ molecules as mentioned previously (Figure 7b). In addition, an R6(32) ring is formed via the C22–H22···O3 interaction between two SSZ molecules, and an R88(54) ring is formed between six SSZ molecules and two PHE molecules. The π–π interactions between two phenyl rings from SSZ and PHE (Cg2–Cg2, Cg3–Cg5) also contribute to the extended crystal packing (Figure S10 and Table S6).

Figure 7.

Figure 7

Open in a new tab

Crystal packing and intermolecular interactions in the (SSZ)2·PHE: (a) asymmetric unit (pink is SSZ and green is PHE) and (b) hydrogen bond network.

SSZ·4AP Salt

The SSZ·4AP salt crystallizes with two SSZ– anions and two 4AP+ cations in the asymmetric unit. The proton is transferred from the carboxylic acid group of SSZ to the pyridyl ring of 4AP. SSZ– and 4AP+ are linked through N1–H1N···O2, C7–H7···O9, N2–H2A···O10 and C3–H3···O9 discrete hydrogen bonds, the latter two forming an R22(8) motif (Figure 8a). The assembly is further sustained by intermolecular interactions (C9–H9···O5, N4–H4B···O4, N2–H2B···O5, N3–H3N···O6, N4–H4A···O10, and N3–H3N···O7) between two SSZ– anions and two 4AP+ cations in the same manner. The two adjacent SSZ– interact via N–H···N and C–H···O hydrogen bonds, which constitute an R2(7):R22(8):R2(7) motif (Figure 8b). Additional π–π stacking interactions between adjacent phenyl rings from SSZ– also contribute to the extended structure (Figure S11 and Table S7).

Figure 8.

Figure 8

Open in a new tab

Crystal packing and intermolecular interactions in the SSZ·4AP: (a) asymmetric unit (pink is SSZ and green is 4AP) and (b) three-dimensional hydrogen bond network.

SSZ·TMD Salt

SSZ and TMD form a salt that crystallizes with one TMD+ cation and one SSZ– anion in the asymmetric unit. The two components interact with each other through the N5–H5···O5 discrete hydrogen bond (Figure 9a). What is interesting is that only in this crystal is the N atom of the azo group from the SSZ– anion involved in the formation of intermolecular hydrogen bonds, producing an R22(26) motif between two asymmetric units via the C24-H24B···N4 hydrogen bond. Two adjacent SSZ– anions connect through N2–H2···N1 and C1–H1···O2 hydrogen bonds, forming the same R2(7):R22(8):R2(7) motif as the previously described crystals (Figure 9b). As shown in Figure S12 and Table S8, the packing is further stabilized by the π–π interactions between the phenyl rings from SSZ– and the pyridyl rings from TMD+ (Cg2–Cg3, Cg4–Cg4, and Cg5–Cg5).

Figure 9.

Figure 9

Open in a new tab

Crystal packing and intermolecular interactions in the SSZ·TMD: (a) asymmetric unit (pink is SSZ and green is TMD) and (b) hydrogen bond network.

SSZ·IMZ·MeCN Salt Solvate

SSZ·IMZ·MeCN crystallizes with one SSZ– anion, one IMZ+ cation, and one acetonitrile molecule in the asymmetric unit. The proton is transferred from the carboxylic acid of SSZ– to the basic nitrogen of the imidazole ring (Figure 10a). Along the b-axis, the IMZ+ cation acts as hydrogen bond donors and interacts with SSZ– and MeCN through N5–H5A···O3, N6–H6···O2, and C21–H21···N100 discrete hydrogen bonds, respectively (Figure 10b). In addition, R53(14) and R4(25) motifs are formed via the above interactions and C100–H10B···N100, C100–H10C···O5, and C22–H22···O3 hydrogen bonds. The two adjacent SSZ– anions interact with each other through C5–H5···O5 and N1–H1A···N2 hydrogen bonds, forming a related R22(7):R2(8):R22(7) motif, which differs due to the position of the hydrogen atom. As shown in Figure S13 and Table S9, the 3D structure is further stabilized by the π–π interactions between the phenyl rings and pyridyl rings from SSZ (Cg1–Cg1 and Cg2–Cg3).

Figure 10.

Figure 10

Open in a new tab

Crystal packing and intermolecular interactions in the SSZ·IMZ·MeCN: (a) asymmetric unit (pink is SSZ, green is IMZ, and blue is MeCN) and (b) hydrogen bond network.

Overall, the introduction of cocrystal/salt formers has disrupted the hydrogen bonds involving the pairs of SSZ molecules in the imide SSZ, forming six multicomponent systems with different molecular arrangements and crystal packings with the R22(7):R2(8):R22(7) motif of pairs of SSZ molecules maintained (Figure 11).

Figure 11.

Figure 11

Open in a new tab

Hydrogen bonds in pure SSZ (starting material) (left) and the different arrangements with the head-to-head SSZ pairs of molecules (right).

Conformation of SSZ

The starting material SSZ used in this work is in conformation A, where the two intramolecular hydrogen bonds (C–H···O and O–H···O) form an S21(9) motif and direct the orientation of the carboxylic acid group (Figure 12). The oxygen atom of the sulfonyl group in the amide tautomer of SSZ (conformation B) is involved in one intramolecular hydrogen bonding, forming a four-membered N–S=O···H intramolecular hydrogen bond. SSZ exists in different conformations when cocrystallized with the different cocrystal/salt formers, with the amide tautomer seen in three unsolvated crystals and the imide tautomer seen in the solvated cocrystals and salt. For the (SSZ)2·BPY·(Tol)0.8 cocrystal solvate, the intramolecular hydrogen bonds C–H···O=S=O···H–C involving both oxygen atoms of the sulfonyl group lock the conformation of the SSZ molecules (conformation C), while in (SSZ)2·BPE·(EtOH)2 SSZ, the conformation is the same as the pure starting material (imide form, conformation A). In the solvated salt SSZ·IMZ·MeCN, the SSZ exists in conformation F, which only differs by the absence of the S(5) motif due to proton transfer. For (SSZ)2·PHE cocrystal (conformation D), SSZ·4AP salt and SSZ·TMD salt (conformation E), only one oxygen atom of the sulfonyl group is utilized, leading to an S2(9) motif, and the carbonyl oxygen atom form has an intramolecular interaction with the hydroxyl group, creating an S(6) motif. The only difference between conformations D and E is whether the hydroxyl group from the carboxyl group is involved in the formation of an S(5) motif.

Figure 12.

Figure 12

Open in a new tab

Molecular conformations of SSZ/SSZ– in solid forms.

Molecular overlay (Figure 13a) indicates that the bulk of the molecule (including the sulfur atom, the phenyl ring, the azo bridge, and the hydroxybenzoic acid segment) is almost planar, while the orientation of the (2-pyridylamino) sulfonyl group varies significantly. In the imide form, both C1–N2 and N2–S1 bond lengths [1.35 (4) and 1.59 (3) Å] are much shorter than those in the amide form [1.43 (2) and 1.65 (16) Å], revealing conjugation between the pyridine ring and the side chain. Moreover, the N1–C1–N2–S1 and N2–S1–C2–C3 torsion angles of the two tautomers differ.2,3 Regardless of the conformation of SSZ, the C1–N2 and N2–S1 bond lengths of SSZ in the six systems are closer to those of the pure imide SSZ, and no general rule in the N1–C1–N2–S1 and N2–S1–C2–C3 torsion angles can be found (Table S10).

Figure 13.

Figure 13

Open in a new tab

(a) Molecular overlay of SSZ: SSZ (starting material, imide form) purple, SSZ (amide form) green, (SSZ)2·BPY·(Tol)0.8 blue, (SSZ)2·BPE·(EtOH)2 pink, (SSZ)2·PHE yellow, SSZ·4AP light green, SSZ·TMD red, and SSZ·IMZ·MeCN cyan, and (b) selected bonds and torsions in the SSZ molecule.

Array of SSZ

There are two scenarios of the R22(7):R2(8):R22(7) motif involving two adjacent SSZ molecules observed in the six multicomponent crystals. These arise due to the different positions of the hydrogen atom: the imide tautomer leads to the AADD array (Figure 14, left) and the amide tautomer leads to the ADAD array (D: hydrogen bond donor, A: hydrogen bond acceptor) (Figure 14, right). The three unsolvated SSZ multicomponent materials in this work have the ADAD array in their crystal structures. In contrast, the AADD array is observed in the solvated SSZ multicomponent materials, and this array is also present in the pure imide form of SSZ.3

Figure 14.

Figure 14

Open in a new tab

AADD/ADAD array (from the sulfonyl group to the pyridyl group) observed between two SSZ molecules/SSZ– anions in SSZ solids.

To further investigate the occurrence of these two kinds of array in other multicomponent crystalline materials of sulfonamide compounds, a CSD search was conducted using ConQuest (version 2022.2.0) and the results were filtered by “3D coordinates determined,” “only single crystal structures,” and “only organics.” Both of the arrays can be found in multicomponent crystalline materials of sulfapyridine (Figure 15, left), which is not surprising since the molecular structure of sulfapyridine is a substructure of SSZ. The AADD array is found in sulfapyridine 1,3-dioxane and sulfapyridine tetrahydrofuran solvate,41 while the ADAD array is observed in sulfapyridine oxalic acid dibutyl ester cocrystal.42 In addition to this, the ADAD array also exists in three complexes of SSZ with calcium, magnesium, and strontium, and a methanol solvate of a sulfonamide compound (Figure 15, right). Therefore, it appears that the pyridine-2-amine moiety in sulfonamide compounds plays an important role in the formation of the AADD or ADAD array in the crystal structures.

Figure 15.

Figure 15

Open in a new tab

Chemical structure of sulfapyridine and 4,5-dimethoxy-2-(3-(1,4-oxazinan-4-yl)-3-oxopropyl)-N-(2-pyridyl)benzenesulfonamide.

Hirshfeld Surface Analysis

Hirshfeld surfaces have proven to be a unique tool to investigate and visualize different types of intermolecular interactions in the crystal, and the 2D fingerprint plots provide quantitative information on these interactions.43,44 To investigate the influence of different cocrystal/salt formers on the intermolecular interactions of SSZ in different cocrystals/salts, the Hirshfeld surface analysis was performed using the CrystalExplorer 21.5 program. Figures S14 and 16 illustrate the Hirshfeld surfaces of SSZ that have been mapped over dnorm and the corresponding 2D fingerprint plots, respectively. Table S11 summarizes the main close contact contributions to the SSZ Hirshfeld surface area in different SSZ solids.

Figure 16.

Figure 16

Open in a new tab

2D fingerprint plots of SSZ in six crystalline solids.

The large circular depressions (deep red) stand for the hydrogen bonding contacts (i.e., H···O and H···N), whereas other visible spots represent the H···H contacts (Figure S14).45 The H···H interactions have the most significant contribution to the total Hirshfeld surfaces (37.8 and 40.6%) in (SSZ)2·BPE·(EtOH)2 and (SSZ)2·PHE, while make up the second-largest proportion (32.8, 27.5, 32.2, and 27.1%) of the total Hirshfeld surfaces in (SSZ)2·BPY·(Tol)0.8, SSZ·4AP, SSZ·TMD, and SSZ·IMZ·MeCN. This could be because the ratios between SSZ and cocrystal/salt formers are 2:1 and 1:1, respectively; therefore, the more hydrophobic moiety (in the SSZ structure) in SSZ cocrystals leads to a higher proportion of H···H contacts compared with SSZ salts. In the 2D fingerprint plots, the longest upper spike (de > di) stands for the hydrogen bond donor, whereas the lower longest spike (de < di) represents the hydrogen bond acceptor.35 Therefore, when cocrystallized with BPY, BPE, and PHE, respectively, SSZ acted more as a hydrogen bond donor; when involved in salt formation, especially with TMD and IMZ, SSZ acted more as a hydrogen bond acceptor due to the proton transfer, which is in line with the crystal structure analysis.

Highest Occupied Molecular Orbital–Lowest Unoccupied Molecular Orbital (HOMO–LUMO) Analysis

The frontier molecular orbitals play an important role in the reactivity of chemical systems, and they can also be used to predict the most reactive position in the conjugated systems.46−48 In particular, the energy gap between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) can determine the kinetic stability and chemical reactivity of the system.48,49

The distributions of the HOMO and the LUMO of the imide and amide tautomers of SSZ are similar (Figure 17). For (SSZ)2·BPY·(Tol)0.8, (SSZ)2·BPE·(EtOH)2, and SSZ·4AP, the HOMOs and the LUMOs are located on the SSZ molecule/anion (Figure 18). The HOMOs are mainly localized on the azo group and hydroxybenzoic acid moiety, whereas the LUMOs mainly spread around the benzene ring and the azo group. On the contrary, for (SSZ)2·PHE, both HOMO and LUMO are distributed on the PHE skeleton. For SSZ·TMD, the HOMO is mainly localized on the azo group and hydroxybenzoate moiety of SSZ–, and the LUMO is distributed on the protonated pyridyl ring of TMD+. For SSZ·IMZ·MeCN, the HOMO mainly spreads around the carboxylate group of the SSZ– anion and the LUMO is located on the imidazolium moiety.

Figure 17.

Figure 17

Open in a new tab

HOMOs and LUMOs of the imide (left) and amide (right) tautomers of SSZ.

Figure 18.

Figure 18

Open in a new tab

HOMOs and LUMOs of (a) the SSZ cocrystals and (b) the SSZ salts.

It has been reported that larger HOMO and LUMO energy gaps lead to higher chemical stability and lower chemical reactivity, and vice versa.48 As illustrated in Figure 17, the energy gap in the imide is greater than the amide for pure SSZ, suggesting that the imide form is more stable than the amide form. This may be supported by the fact that the amide form was the first synthesized polymorph at ambient environment, while the imide form was obtained at high temperature and high pressure. The order of energy gaps in the SSZ cocrystals and salts is (SSZ)2·BPE·(EtOH)2 > (SSZ)2·BPY·(Tol)0.8 > (SSZ)2·PHE > SSZ·4AP > SSZ·TMD > SSZ·IMZ·MeCN. Notably, the cocrystals are more stable than the salts, and there is a significant difference for the solvated salt SSZ·IMZ·MeCN.

Conclusions

Sulfasalazine has a strong tendency to form multicomponent crystalline materials with a variety of cocrystal/salt formers because it has multiple hydrogen bond acceptor and donor sites in the structure and exhibits tautomerism. In these multicomponent forms, SSZ exists in different conformations. The R22(7):R2(8):R22(7) motif between two adjacent SSZ occurs in all the multicomponent forms, presenting an ADAD array in three unsolvated SSZ solids, while the AADD array is observed in solvated cocrystals and salt (SSZ)2·BPY·(Tol)0.8, (SSZ)2·BPE·(EtOH)2, and SSZ·IMZ·MeCN, which is also present in the imide form of SSZ. In addition, the azo group from SSZ participates in hydrogen bonding only in SSZ-TMD. Hirshfeld surface analysis indicates that SSZ acts as a hydrogen bond donor when forming cocrystals and as a hydrogen bond acceptor when it forms salts, which is consistent with the occurence of proton transfer determined by SCXRD results. HOMO–LUMO results suggested the cocrystals are chemically more stable than the salts.

Acknowledgments

This publication has emanated from the research conducted with the financial support of Science Foundation Ireland (Grant No. 12/RC/2275_P2). The authors thank Dr. Matteo Lusi and Dr. Chiara Cappuccino for single crystal analysis of (SSZ)2·PHE, SSZ·4AP, SSZ·TMD and SSZ·IMZ·MeCN. They wish to acknowledge the Irish Centre for High-End Computing (ICHEC) for providing the computational facilities.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.cgd.2c01403.

  • DSC traces, TGA plots, IR spectra, PXRD patterns, ellipsoid plots, diagrams of π–π interactions of pure SSZ and multicomponent crystals, 3D dnorm surfaces, a summary of experiments for SSZ cocrystals and salts, table of crystallographic parameters of pure SSZ and multicomponent forms, selected geometric parameters of pure SSZ and six cocrystals and salts, and summary of the various contact contributions to the SSZ Hirshfeld surface area in SSZ cocrystals and salts (PDF)

The authors declare no competing financial interest.

Supplementary Material

cg2c01403_si_001.pdf (3MB, pdf)

References

  1. Gardner G.; Furst D. E. Disease-Modifying Antirheumatic Drugs. Drugs Aging 1995, 7, 420–437. 10.2165/00002512-199507060-00003. [DOI] [PubMed] [Google Scholar]
  2. Filip L. A.; Caira M. R.; Farcas S. I.; Bojit M. T. Triclinic polymorph of sulfasalazine. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 2001, 57, 435–436. 10.1107/S0108270100020771. [DOI] [PubMed] [Google Scholar]
  3. Blake A. J.; Lin X.; Schroder M.; Wilson C.; Yuan R. X. The imide tautomer of sulfasalazine. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 2004, 60, o226–228. 10.1107/S0108270104003026. [DOI] [PubMed] [Google Scholar]
  4. Ol’khovich M. V.; Sharapova A. V.; Blokhina S. V.; Perlovich G. L. Sulfasalazine: Dissolution and Distribution in Pharmaceutically Relevant Mediums. J. Chem. Eng. Data 2016, 62, 123–128. 10.1021/acs.jced.6b00497. [DOI] [Google Scholar]
  5. Amidon G. L.; Lennernäs H.; Shah V. P.; Crison J. R. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res. 1995, 12, 413–420. 10.1023/A:1016212804288. [DOI] [PubMed] [Google Scholar]
  6. Shadid M.; Gurau G.; Shamshina J. L.; Chuang B. C.; Hailu S.; Guan E.; Chowdhury S. K.; Wu J. T.; Rizvi S. A. A.; Griffin R. J.; Rogers R. D. Sulfasalazine in ionic liquid form with improved solubility and exposure. MedChemComm 2015, 6, 1837–1841. 10.1039/C5MD00290G. [DOI] [Google Scholar]
  7. Priyam A.; Shivhare K.; Yadav S.; Sharma A. K.; Kumar P. Enhanced solubility and self-assembly of amphiphilic sulfasalazine-PEG-OMe (S-PEG) conjugate into core-shell nanostructures useful for colonic drug delivery. Colloids Surf., A 2018, 547, 157–167. 10.1016/j.colsurfa.2018.03.048. [DOI] [Google Scholar]
  8. Rao M. R.; Pawar V. M. Evaporative nanocrystallization for enhanced solubility and bioavailability of sulfasalazine. World J. Pharm. Res. 2016, 5, 814–832. [Google Scholar]
  9. Shinkar D. M.; Patil A. N.; Saudagar R. B. Solubility and Dissolution Enhancement of Sulfasalazine by Solid Dispersion Technique. Res. J. Pharm. Technol. 2018, 11, 1277–1282. 10.5958/0974-360X.2018.00237.8. [DOI] [Google Scholar]
  10. Abdolahi N.; Soltani A. Improving Drug Solubility For Inflammatory Arthritis Treatment: Sulfasalazine Niosome. Ann. Rheum. Dis. 2019, 78, 1657. 10.1136/annrheumdis-2019-eular.7821. [DOI] [Google Scholar]
  11. Desiraju G. R. Crystal engineering: from molecule to crystal. J. Am. Chem. Soc. 2013, 135, 9952–9967. 10.1021/ja403264c. [DOI] [PubMed] [Google Scholar]
  12. Khandavilli U. B. R.; Skořepová E.; Sinha A. S.; Bhogala B. R.; Maguire N. M.; Maguire A. R.; Lawrence S. E. Cocrystals and a Salt of the Bioactive Flavonoid: Naringenin. Cryst. Growth Des. 2018, 18, 4571–4577. 10.1021/acs.cgd.8b00557. [DOI] [Google Scholar]
  13. Huang S.; Xu J.; Peng Y.; Guo M.; Cai T. Facile Tuning of the Photoluminescence and Dissolution Properties of Phloretin through Cocrystallization. Cryst. Growth Des. 2019, 19, 6837–6844. 10.1021/acs.cgd.9b01111. [DOI] [Google Scholar]
  14. Huang S.; Xue Q.; Xu J.; Ruan S.; Cai T. Simultaneously Improving the Physicochemical Properties, Dissolution Performance, and Bioavailability of Apigenin and Daidzein by Co-Crystallization With Theophylline. J. Pharm. Sci. 2019, 108, 2982–2993. 10.1016/j.xphs.2019.04.017. [DOI] [PubMed] [Google Scholar]
  15. Sinha A. S.; Maguire A. R.; Lawrence S. E. Cocrystallization of Nutraceuticals. Cryst. Growth Des. 2015, 15, 984–1009. 10.1021/cg501009c. [DOI] [Google Scholar]
  16. Bolla G.; Sarma B.; Nangia A. K. Crystal Engineering of Pharmaceutical Cocrystals in the Discovery and Development of Improved Drugs. Chem. Rev. 2022, 122, 11514–11603. 10.1021/acs.chemrev.1c00987. [DOI] [PubMed] [Google Scholar]
  17. Choquesillo-Lazarte D.; Nemecb V.; Cinčić D. Halogen bonded cocrystals of active pharmaceutical ingredients: pyrazinamide, lidocaine and pentoxifylline in combination with haloperfluorinated compounds. CrystEngComm 2017, 19, 5293–5299. 10.1039/C7CE01252G. [DOI] [Google Scholar]
  18. Zhang Y.; Wang J.-G.; Wang W. Unexpected Sandwiched-Layer Structure of the Cocrystal Formed by Hexamethylbenzene with 1,3-Diiodotetrafluorobenzene: A Combined Theoretical and Crystallographic Study. Crystals 2020, 10, 379. 10.3390/cryst10050379. [DOI] [Google Scholar]
  19. Karimi-Jafari M.; Padrela L.; Walker G. M.; Croker D. M. Creating Cocrystals: A Review of Pharmaceutical Cocrystal Preparation Routes and Applications. Cryst. Growth Des. 2018, 18, 6370–6387. 10.1021/acs.cgd.8b00933. [DOI] [Google Scholar]
  20. Lemmerer A.; Govindraju S.; Johnston M.; Motloung X.; Savig K. L. Co-crystals and molecular salts of carboxylic acid/pyridine complexes: can calculated pKa’s predict proton transfer? A case study of nine complexes. CrystEngComm 2015, 17, 3591–3595. 10.1039/C5CE00102A. [DOI] [Google Scholar]
  21. 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. 10.1021/mp0601345. [DOI] [PubMed] [Google Scholar]
  22. Cruz-Cabeza A. J. Acid–base crystalline complexes and the pKa rule. CrystEngComm 2012, 14, 6362–6365. 10.1039/c2ce26055g. [DOI] [Google Scholar]
  23. Zhao L.; Hanrahan M. P.; Chakravarty P.; DiPasquale A. G.; Sirois L. E.; Nagapudi K.; Lubach J. W.; Rossini A. J. Characterization of Pharmaceutical Cocrystals and Salts by Dynamic Nuclear Polarization-Enhanced Solid-State NMR Spectroscopy. Cryst. Growth Des. 2018, 18, 2588–2601. 10.1021/acs.cgd.8b00203. [DOI] [Google Scholar]
  24. Ali H. R. H.; Alhalaweh A.; Mendes N. F. C.; Ribeiro-Claro P.; Velaga S. P. Solid-state vibrational spectroscopic investigation of cocrystals and salt of indomethacin. CrystEngComm 2012, 14, 6665–6674. 10.1039/c2ce25801c. [DOI] [Google Scholar]
  25. Mohamed S.; Tocher D. A.; Vickers M.; Karamertzanis P. G.; Price S. L. Salt or Cocrystal? A New Series of Crystal Structures Formed from Simple Pyridines and Carboxylic Acids. Cryst. Growth Des. 2009, 9, 2881–2889. 10.1021/cg9001994. [DOI] [Google Scholar]
  26. Elbakush R. E.A Crystal Engineering Study of Selected Sulfa Drugs and Trimethoprim; University of the Western Cape: South Africa, 2014. [Google Scholar]
  27. Bala M.; Gautam M. K.; Chadha R. Development of non-covalent derivative of sulfasalazine with theobromine for its properties optimization. Innovations Pharm. Pharmacother. 2017, 5, 154–158. [Google Scholar]
  28. Groom C. R.; Bruno I. J.; Lightfoot M. P.; Ward S. C. The Cambridge Structural Database. Acta Crystallogr., Sect. B: Struct. Sci., Cryst. Eng. Mater. 2016, 72, 171–179. 10.1107/S2052520616003954. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Sinha A. S.; Rao Khandavilli U. B.; O’Connor E. L.; Deadman B. J.; Maguire A. R.; Lawrence S. E. Novel co-crystals of the nutraceutical sinapic acid. CrystEngComm 2015, 17, 4832–4841. 10.1039/C5CE00777A. [DOI] [Google Scholar]
  30. Sheldrick G. M. Crystal structure refinement with SHELXL. Acta Crystallogr., Sect. C: Struct. Chem. 2015, 71, 3–8. 10.1107/S2053229614024218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. APEX2 v2009.3-0; Bruker AXS, 2009.
  32. Huang S.; Venables D. S.; Lawrence S. E. Pharmaceutical Salts of Piroxicam and Meloxicam with Organic Counterions. Cryst. Growth Des. 2022, 22, 6504–6520. 10.1021/acs.cgd.2c00722. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Xu J.; Huang Y.; Ruan S.; Chi Z.; Qin K.; Cai B.; Cai T. Cocrystals of isoliquiritigenin with enhanced pharmacokinetic performance. CrystEngComm 2016, 18, 8776–8786. 10.1039/C6CE01809B. [DOI] [Google Scholar]
  34. Spek A. L. Structure validation in chemical crystallography. Acta Crystallogr., Sect. D: Biol. Crystallogr. 2009, 65, 148–155. 10.1107/S090744490804362X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Yang D.; Wang R.; Jin G.; Zhang B.; Zhang L.; Lu Y.; Du G. Structural and Computational Insights into Cocrystal Interactions: A Case on Cocrystals of Antipyrine and Aminophenazone. Cryst. Growth Des. 2019, 19, 6175–6183. 10.1021/acs.cgd.9b00591. [DOI] [Google Scholar]
  36. Lu T.; Chen F. Quantitative analysis of molecular surface based on improved Marching Tetrahedra algorithm. J. Mol. Graphics Modell. 2012, 38, 314–323. 10.1016/j.jmgm.2012.07.004. [DOI] [PubMed] [Google Scholar]
  37. Lu T.; Chen F. Multiwfn: a multifunctional wavefunction analyzer. J. Comput. Chem. 2012, 33, 580–592. 10.1002/jcc.22885. [DOI] [PubMed] [Google Scholar]
  38. Spackman P. R.; Turner M. J.; McKinnon J. J.; Wolff S. K.; Grimwood D. J.; Jayatilaka D.; Spackman M. A. CrystalExplorer: a program for Hirshfeld surface analysis, visualization and quantitative analysis of molecular crystals. J. Appl. Crystallogr. 2021, 54, 1006–1011. 10.1107/S1600576721002910. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Kostadinova I.; Danchev N. 4-aminopyridine- the new old drug for the treatment of neurodegenerative diseases. Pharmacia 2019, 66, 67–74. 10.3897/pharmacia.66.e35976. [DOI] [Google Scholar]
  40. Liang M.-K.; Patwardhan S. V.; Danilovtseva E. N.; Annenkov V. V.; Perry C. C. Imidazole catalyzed silica synthesis: Progress toward understanding the role of histidine in (bio)silicification. J. Mater. Res. 2009, 24, 1700–1708. 10.1557/jmr.2009.0223. [DOI] [Google Scholar]
  41. Pratt J.; Hutchinson J.; Stevens C. L. K. Sulfapyridine (polymorph III), sulfapyridine dioxane solvate, sulfapyridine tetrahydrofuran solvate and sulfapyridine piperidine solvate, all at 173 K. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 2011, 67, o487–o491. 10.1107/S0108270111041825. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Coles S. J.; Hursthouse M. B.; Mayer T. A.; Threlfall T. L.. Crystal Structure Report Archive; University of Southampton, 2000; Vol. 196. [Google Scholar]
  43. Yang J.; Yin L.; Gong X.-D.; Sinditskii V. P.; Zhang J.-G. Origins of Salt Formation and Cocrystallization: A Combined Experimental and Theoretical Study. Cryst. Growth Des. 2020, 20, 5834–5842. 10.1021/acs.cgd.0c00459. [DOI] [Google Scholar]
  44. Luo Y. H.; Sun B. W. Pharmaceutical Co-Crystals of Pyrazinecarboxamide (PZA) with Various Carboxylic Acids: Crystallography, Hirshfeld Surfaces, and Dissolution Study. Cryst. Growth Des. 2013, 13, 2098–2106. 10.1021/cg400167w. [DOI] [Google Scholar]
  45. Seth S. K.; Das N. K.; Aich K.; Sen D.; Fun H.-K.; Goswami S. Exploring contribution of intermolecular interactions in supramolecular layered assembly of naphthyridine co-crystals: Insights from Hirshfeld surface analysis of their crystalline states. J. Mol. Struct. 2013, 1048, 157–165. 10.1016/j.molstruc.2013.05.048. [DOI] [Google Scholar]
  46. Li K.; Ren X.; Fu S.; Zhu J. Cocrystal structure, thermal behavior, and DFT calculations between FOX–7 and 1,10–Phenanthroline. J. Mol. Struct. 2018, 1173, 26–32. 10.1016/j.molstruc.2018.06.090. [DOI] [Google Scholar]
  47. Suresh Kumar G.; Prabhu A. A. M.; Bhuvanesh N.; Ronica X. A. V.; Kumaresan S. Molecular structure investigation of organic cocrystals of 1,10-phenanthroline-5,6-dione with aryloxyacetic acid: A combined experimental and theoretical study. Spectrochim. Acta, Part A 2014, 132, 465–476. 10.1016/j.saa.2014.05.020. [DOI] [PubMed] [Google Scholar]
  48. Velmurugan V.; Nandini Asha R.; Ravindran Durai Nayagam B.; Kumaresan S.; Bhuvanesh N. Synthesis, Characterization and Biological Activity of (Phenylthio)Acetic Acid:Theophylline Cocrystal. J. Chem. Crystallogr. 2021, 51, 225–234. 10.1007/s10870-020-00847-0. [DOI] [Google Scholar]
  49. Hao L.; Wang J.; Zhai D.; Ma P.; Ma C.; Pan Y.; Jiang J. Theoretical Study on CL-20-Based Cocrystal Energetic Compounds in an External Electric Field. ACS Omega 2020, 5, 14767–14775. 10.1021/acsomega.0c01643. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

cg2c01403_si_001.pdf (3MB, pdf)

Articles from Crystal Growth & Design are provided here courtesy of American Chemical Society

RESOURCES