Novel Synthons in Sulfamethizole Cocrystals - ACS Publications

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Novel Synthons in Sulfamethizole Cocrystals: Structure−Property Relations and Solubility Kuthuru Suresh,† Vasily S. Minkov,‡,§ Kranthi Kumar Namila,† Elizaveta Derevyannikova,‡,§ Evgeniy Losev,‡,§ Ashwini Nangia,*,† and Elena V. Boldyreva*,‡,§ †

School of Chemistry, University of Hyderabad, Central University P.O., Prof. C. R. Rao Road, Hyderabad 500 046, India Novosibirsk State University, 2 Pirogov str., 630090 Novosibirsk, Russian Federation § Institute of Solid State Chemistry and Mechanochemistry SB RAS, 18 Kutateladze, 630128 Novosibirsk, Russian Federation ‡

S Supporting Information *

ABSTRACT: The sulfamethizole antibiotic drug has rich hydrogen bond functionalities (donors: amine NH2 and imine NH; acceptors: sulfonyl O, thiazolidine N and S, and imidine N), which makes it a functionally diverse molecule to form cocrystals. A cocrystal screen of sulfamethizole (SMT) with COOH, NH2, pyridine, and CONH2 functional group containing coformers, e.g., p-aminobenzoic acid (PABA), vanillic acid (VLA), p-aminobenzamide (ABA), 4,4-bipyridine (BIP), suberic acid (SBA), oxalic acid (OA), and adipic acid (ADP), resulted in six cocrystals and one salt, namely, SMT−ADP (1:0.5), SMT−PABA (1:1), SMT−VLA (1:1), SMT−ABA (1:1), SMT−BIP (1:1), SMT−SBA (1:0.5), and SMT−OA (1:1). The novel crystalline adducts were synthesized by liquid-assisted cogrinding and isothermal solvent crystallization. In addition to single-crystal X-ray diffraction, the phase composition of the powder samples was confirmed by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). Hydrogen bonding interactions between the coformers and SMT are analyzed as six different synthons. In addition to strong N−H···O and O−H··· N hydrogen bonds, the cocrystal structures are sustained by weak C−H···O hydrogen bonds. The not so common chalcogen− chalcogen (S···O) type II intermolecular interaction in SMT−ADP cocrystal and chalcogen−nicogen (S···N) type II interaction in SMT−BIP cocrystal were observed. The products were characterized by vibrational spectroscopy to obtain information on the strengths of the intermolecular interactions. Solubility and dissolution experiments on SMT−ADP, SMT−SBA, and SMT−OA showed a lower intrinsic dissolution rate (IDR) and equilibrium solubility compared to SMT in 0.1 N HCl medium, which is ascribed to stronger N−H···O, N−H···N, and O−H···O hydrogen bonds and better crystal packing. The decreased IDR could be useful in controlled/extended release of SMT to improve therapeutic activity of the drug by minimizing its fast systemic elimination in vivo. Furthermore, we observed that SMT−OA salt is formed spontaneously when the components were mixed in acidic medium (0.1 N HCl), whereas in neutral medium (phosphate buffer) no SMT−OA salt formation was observed.

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complexes has been reported.17 Most sulfonamide class drugs exhibit moderate to high solubility, but bioavailability is limited due to fast elimination half-life. As a result the dose strength of sulfonamide drugs has to be higher.18 SMT has good solubility (1.05 g/L at 37 °C in water),19 but it has a short half-life (2.1 h) due to rapid metabolism and systematic elimination.20 To improve the concentration of SMT in the blood, an extended release of lipase-SMT granule system is reported,21 with the SMT concentration in blood of Cmax 1.05 mg/mL at 6 h after oral administration of 43 mg/kg SMT dose in dogs. This is because rapid metabolism of SMT is reduced by lipase which controls the digestion of glyceryl trilaurate and glyceryl tristearate and subsequent release of the embedded drug

INTRODUCTION

The goal in crystal engineering is the design of periodic structures with a target supramolecular assembly that enacts the network approach between molecular and supramolecular structure on the basis of intermolecular interactions.1,2 Synthon strategies guided by hydrogen bonding rules are the primary tool in crystal engineering to design cocrystals with superior properties and improved pharmaceutics.3−6 Cocrystals of active pharmaceutical ingredients (APIs) termed pharmaceutical cocrystals have gained increased importance and popularity for improving the physicochemical properties of drugs, such as solubility,7,8 tabletability,9,10 stability,11−13 hydration,14 etc. Sulfamethizole (SMT) is a sulfonamide class antibiotic that acts through the competitive inhibition of folate synthesis in microorganisms.15 The crystal structure of SMT (reported in 1987) shows that the molecule exists as the imidine tautomer (Scheme 1).16 Solubility improvement of SMT by cyclodextrin © 2015 American Chemical Society

Received: April 28, 2015 Revised: June 11, 2015 Published: June 12, 2015 3498

DOI: 10.1021/acs.cgd.5b00587 Cryst. Growth Des. 2015, 15, 3498−3510

Crystal Growth & Design

Article

Scheme 1. Molecular Structures and Acronyms of Sulfamethizole and Coformers

Table 1. Preparation of SMT Cocrystals and Salts solid form SMT−ADP SMT−PABA SMT−VLA SMT−ABA SMT−BIP SMT−SBA SMT−OA

SMT (mg, mmol) 270.3, 270.3, 270.3, 270.3, 270.3, 270.3, 270.3,

0.1 0.1 0.1 0.1 0.1 0.1 0.1

coformer (mg, mmol) 73.0, 0.05 137.1, 0.1 168.1, 0.1 136.1, 0.1 156.1, 0.1 87.0, 0.05 90.0, 0.1

method, solvent mortar-pestle mortar-pestle mortar-pestle mortar-pestle mortar-pestle mortar-pestle mortar-pestle

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particles. In another case, Zaworotko’s group reported that cocrystals of epigallocatechin gallate (EGCG) exhibited lower solubility compared to the parent drug, resulting in a significant increase of pharmacokinetic profile.22 The high solubility of sulfacetamide was controlled in pharmaceutical cocrystals with lower dissolution rates, reported by Goud et al.23 These results suggest that the cocrystal approach is adaptive to modulate the solubility toward higher or lower levels by the rational selection of coformers. Our goal was to optimize pharmaceutical cocrystals of sulfamethizole in this study. The strong hydrogen bonding functionalities in the drug molecule (two donors: amine NH2 and imine NH; five acceptors: two sulfonyl O atoms, thiazolidine N and S, and imidine N) make it capable of forming cocrystals with coformer partners. The aim in the present study was to cocrystallize SMT with GRAS24 (generally regarded as safe additives in pharmaceuticals) as well as nonGRAS model compounds, to analyze the X-ray crystal structures, and compare crystal packing and solubility in relation to the structure-forming synthons. A charge density analysis of sulfamethizole interactions in molecular complexes was reported in the same journal25 about the time of our manuscript submission.

grinding, grinding, grinding, grinding, grinding, grinding, grinding,

CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN

solvent of crystallization (1 (1 (1 (1 (1 (1 (1

mL) mL) mL) mL) mL) mL) mL)

CH3CN (40 mg of cocrystal in 5 mL) CH3CN (40 mg of cocrystal in 5 mL) MeOH (40 mg of cocrystal in 5 mL) Acetone (40 mg of cocrystal in 5 mL) CH3CN (40 mg of cocrystal in 5 mL) CH3CN (40 mg of cocrystal in 5 mL) acetone (40 mg of cocrystal in 5 mL)

EXPERIMENTAL SECTION

SMT and coformers (purity >99.8%) were purchased from SigmaAldrich (Hyderabad, India). Solvents (purity >99%) were purchased from Hychem Laboratories (Hyderabad, India). The preparation of cocrystals/salts and the solvents used for growing single crystals is summarized in Table 1. FT-IR Spectroscopy. Thermo-Nicolet 6700 Fourier transform infrared spectrophotometer with NXR-Fourier transform Raman module (Thermo Scientific, Waltham, Massachusetts) was used to record IR spectra. FT-IR was recorded on sample dispersed in KBr pellet. Data were analyzed using the Omnic software (Thermo

Table 2. ΔpKa Values of Dicarboxylic Acid Coformers and SMT Drug SMT OA ADP SBA

first, second pKa in water

ΔpKa

molecular complex

1.95 for aromatic aminea 1.36, 4.11 4.70, 3.92 4.90, 4.15

0.59, 2.16 2.75, 1.97 2.95, 2.20

1:1 salt 1:0.5 cocrystal 1:0.5 cocrystal

a

The pKa(1.95) of the SMT NH2 group is much less basic (almost acidic) compared to aniline (pKa 4.63). The reduced basicity by almost 3 log units is due to the electron-withdrawing sulfonyl group at the para position.26 bpKa’s were calculated using Marvin 5.10.1, 2012, ChemAxon, http://www.chemaxon.com, e.g., see ref 27. cThese values are closely matching with pKa values compiled by R. Williams.28 3499



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Table 3. Summary of Crystal Structure Parameters SMT−ADP chemical formula

(C9 H10 N4 O2 S2)· 0.5 (C6 H10 O4)

formula weight crystal system space group T [K] a [Å] b [Å] c [Å] α [°] β [°] γ [°] Z V [Å3] Dcalc [g cm−3] reflns collected unique reflns R1 [I > 2(I)] wR2 (all) goodness-of-fit diffractometer CCDC no.

343.40 monoclinic P21/c 100(2) 7.9915(4) 21.6918(8) 8.5756(4) 90 95.737(4) 90 4 1479.13(11) 1.542 17542 3665 0.0291 0.0714 1.016 STOE 1060516

SMT−PABA (C9 H10 N4 O2 S2)·(C7 H7 N O2) 407.47 monoclinic P21/n 100(2) 9.2097(3) 10.8241(5) 18.2910(7) 90 101.645(3) 90 4 1785.84(12) 1.516 21883 4427 0.0294 0.0748 1.022 STOE 1060513

SMT−VLA

SMT−ABA

(C9 H10 N4 O2 S2)·(C8 H8 O4) 490.61 monoclinic P21/c 100(2) 8.1263(5) 19.7763(7) 12.0584(7) 90 109.396(4) 90 4 1827.90 1.593 27232 4527 0.0292 0.0707 1.059 STOE 1060511

(C9H10 N4 O2 S2)·(C7 H8 N2 O) 406.48 triclinic P1̅ 100(2) 13.5102(6) 15.2418(6) 18.3238(7) 99.534(3) 98.720(3) 90.086(3) 8 3676.7(3) 1.469 59096 16205 0.0943 0.2400 1.116 STOE 1060517

SMT−BIP (C9 H10 N4 O2 S2) ·(C10 H 8 N2) 426.51 monoclinic P21/n 100(2) 8.1754(7) 18.6120(10) 13.1690(11) 90 93.048(7) 90 4 2001.0(3) 1.416 12415 3412 0.0560 0.1160 1.047 STOE 1060515

SMT−SBA

SMT−OA

2(C9 H10 N4 O2 S2)·(C8 H14 O4)

(C9 H11 N4 O2 S2)·(C2 H O4)

714.85 orthorhombic Pca21 100(2) 10.4481(3) 19.2259(5) 16.5666(7) 90 90 90 4 3327.80(19) 1.427 26795 7643 0.0440 0.0865 1.040 STOE 1060512

360.37 monoclinic P21/c 100(2) 8.0559(3) Å 20.6543(6) 8.5539(4) 90 99.903(3) 90 4 1402.07(9) 1.707 12515 3479 0.0324 0.0789 1.034 STOE 1060514

method34 in pH 1.2 HCl medium at 30 °C. First, the absorbance of a known concentration of the all these forms was measured at the given λmax 268 nm in pH 1.2 HCl medium on Thermo Scientific Evolution 300 UV−vis spectrometer (Thermo Scientific, Waltham, MA). These absorbance values were plotted against several known concentrations to prepare the concentration vs intensity calibration curve. From the slope of the calibration curves, molar extinction coefficients for SMT, SMT−ADP, SMT−SBA, and SMT−OA were calculated. The molar extinction coefficients (for that compound as calculated above) were used to determine the intrinsic dissolution rate (IDR) values and equilibrium solubility values. An excess amount of the sample was added to 5 mL of pH 1.2 HCl medium. The supersaturated solution was stirred at 800 rpm using a magnetic stirrer at 30 °C. After 24 h, the suspension was filtered through Whatman 0.45 μm syringe filter. Intrinsic dissolution rate experiments were carried out on a USP certified Electrolab TDT-08L dissolution tester (Electrolab, Mumbai, MH). Dissolution experiments were performed for 240 min in pH 1.2, 0.1 N HCl medium at 37 °C. For IDR measurements, 250 mg of the compound was taken in the intrinsic attachment and compressed to a 0.5 cm2 disc using a hydraulic press at a pressure of 4.0 ton/inch2 for 5 min. The intrinsic attachment was placed in a jar of 500 mL pH 1.2, 0.1 N HCl medium preheated to 37 °C and rotated at 100 rpm. Five milliliter aliquots were collected at specific time intervals, and concentrations of the aliquots were determined with appropriate dilutions from the predetermined standard curves of the respective compounds. The identity of the undissolved material after the dissolution experiment was ascertained by powder X-ray diffraction (PXRD) (Figures S6 and S7). The stability of the solid samples upon disc compression and solubility conditions was confirmed by PXRD.

Scientific, Waltham, Massachusetts). ATR IR spectra (attenuated total reflection mode) were recorded on a Digilab Excalibur 3100 spectrometer equipped with MIRacle ATR (Pike) accessory in the frequency range 4500 to 600 cm−1 and a resolution of 2 cm−1. The sample was prepared without any grinding to avoid possible phase transformations during sample preparation grinding. Differential Scanning Calorimetry. DSC was performed on a Mettler Toledo DSC 822e module (Mettler Toledo, Columbus, Ohio). Samples were placed in crimped but vented aluminum sample pans. The typical sample size was 4−6 mg; temperature range was 30− 250 °C @ 5 °C/min. Samples were purged by a stream of nitrogen flowing at 150 mL/min. Powder X-ray Diffraction. Powder X-ray diffraction was recorded on a Bruker D8 Advance diffractometer (Bruker-AXS, Karlsruhe, Germany) using Cu−Kα radiation (λ = 1.5406 Å) at 40 kV and 30 mA power. X-ray diffraction patterns were collected over the 2θ range 5− 50° at a scan rate of 5°/min. Single Crystal X-ray Diffraction. Single crystal X-ray diffraction experiments were carried out using a Stoe IPDS-II diffractometer (STOE, Darmstadt, Germany) equipped with a molybdenum X-ray tube (λ = 0.71073 Å), an image plate detector, a flat graphite monochromatic and an Oxford Cryostream cooling device (stability of gas flow temperature is ±0.1 K). All single-crystal X-ray diffraction experiments were performed at 100 K. All crystals were covered by low viscosity CryoOil (MiTeGen) to protect them additionally from the environment during data collection. The data collection, indexing, and integration of the reflections were performed using Stoe X-Area software package, data reduction was performed using Stoe X-Red software,29 and the structures were refined using SHELXL30−32 implemented in the X-Step32 shell.33 Hydrogen atoms were experimentally located through the Fourier difference electron density maps in all crystal structures. All H atoms were found in difference Fourier electron density maps, and their positions were refined using the appropriate restraints, Uiso(H) = 1.5Ueq(C) for terminal methyl H atoms, and 1.2Ueq (parent atom) for internal chain H atoms. The parameters characterizing data collection and refinement are summarized in Table 3. The structural data for different Sulfamethizole cocrystals are deposited as CIFs at the Cambridge Crystallographic Database (CCDC Nos.: 1060511−1060517) and can be downloaded freely from http://www.ccdc.cam.ac.uk. Dissolution and Solubility. The solubility curves of SMT, two cocrystals, and one salt were measured using the Higuchi and Connor

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RESULTS AND DISCUSSION Selection of Coformers. A solid form screening of SMT with several GRAS24 molecules with different functional groups was performed (Scheme 1). A few non-GRAS model compounds, such as p-amino benzamide and 4,4′-bipyridine, were also included to better understand structural correlations in this family. The cocrystals were produced by cogrinding35−37 as a first choice method. The bulk phase composition of adducts were tested by PXRD, DSC, and IR. The powder samples were used 3500



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as seeds in evaporative crystallization (see Experimental Section)38,39 to obtain single crystals for X-ray diffraction. Cocrystals with adipic acid (ADP), p-aminobenzoic acid (PABA), vanillic acid (VLA), p-aminobenzamide (ABA), suberic acid (SBA), 4,4′-bipyridine (BIP), and a salt with oxalic acid (OA) were crystallized. The crystal structures were solved and refined (ORTEP diagrams are shown in Figure S1, Supporting Information). Selected crystal data, data collection, and refinement parameters are summarized in Table 3. Comparison of the experimental X-ray diffraction pattern of the powder samples with those calculated from the single crystal diffraction data confirmed the phase purity of each crystalline sample (Figures S2 and S3) together with DSC thermograms. Crystal Structure Analysis. In the X-ray crystal structure of SMT16 the conformationally flexible molecule exists as the imidine tautomer (Scheme 1). The sulfaimidine nitrogen and amine nitrogen atoms form a dimeric N−H···N (N1−H1···N, 3.242 Å, 148.6°) hydrogen bond synthon in a R22(8) ring motif (Figure 1). These dimeric motifs are associated through

Scheme 2. Schematic Representations of Supramolecular Synthons in SMT Cocrystals Observed in This Study

Figure 2. Type I and Type II geometry of sulfur···heteroatom (S···X) nonbonded interactions classified based on the S···X directional preference to the Y−S−Z plane.41

Figure 1. Linear chains of SMT molecule are bridged by N−H···N (N4−H9···N, , 2.226 Å, 163.2°) hydrogen bond interaction in a 2D network16 (CSD refcode FOLHAP).

The heteroatom interactions in pure SMT are of Type II. In the structures of SMT−ADP and SMT-BIP, the S atom acts as an electrophile (Sδ+) to the oxygen (Oδ−) and nitrogen (Nδ−) acceptor atoms, and the interaction may be termed Type II. SMT−ADP (1:0.5) Cocrystal. ADP binds to two SMT molecules through a single amine−acid H bond (synthon 1, Scheme 2) (O4−H4A···N1, 1.76 Å, 168°). The acid group of ADP binds to the lone pair of NH2 group of SMT. The sinusoidal wave is extended in a 1D motif through type II chalcogen−oxygen S···O (S2···O4, 3.176 Å, 164°) intermolecular interaction between the thiazolidine S and sulfonyl O of SMT molecules (Figure 3). The more electronegative oxygen acts as a nucleophile (Oδ−), and the sulfur acts as an electrophile (Sδ+) in a R22(10) ring motif. The nonbonded heteroatom interactions S···O and Se···O electrostatic interactions have been studied computationally.42,43 The molecular chains are sustained by strong N−H···OS (N3−H3A···O3 1.96 Å, 173°) hydrogen bonds in a 2D network. SMT−PABA (1:1) Cocrystal. PABA interacts with SMT through amine−sulfonyl synthon (synthon 2, Scheme 2) (N5− H5A···O2:2.41 Å, 122°). The N−H···N dimer R22(10) ring motif of SMT(N3−H3A···N2 2.00 Å, 170°) and acid dimer

bifurcated type II inter chalcogen−chalcogen S···O (S1···O2, 3.22 Å, 157°) interactions of R22(10) rings as a 1D chain, which are in turn connected via N−H···N (N1−H1A···0, 2.19 Å, 163°) hydrogen bonds. In the cocrystal structures, however, the hydrogen bonds motifs of SMT (Figure 1) are replaced by new synthons (Scheme 2). Generally, sulfur is an ambivalent atom and acts either as an electrophile or a nucleophile, depending on the partner heteroatom. While coordinating to metal complexes (X = H+, Na+, Cu+), S acts as a nucleophile and approaches them along the lone pair direction, while nonbonded interactions with halogens or electronegative atoms (Cl, Br, I, N, O, F, X−), when S acts as an electrophile, the approach is in the Y−S−Z plane. The two main types of nonbonded contacts of divalent sulfur are defined as Type I and Type II (Figure 2). In Type I interactions, S···X directionality is SMT−ADP > SMT−SBA > SMT−OA. The decreases for both solubility and IDR in cocrystals is due to the tighter close packing and strong homomeric and heteromeric N−H···N and N−H···O interactions in the crystal lattice. Interestingly, in SMT−OA salt case, even though it is an ionic compound and in addition OA is a highly soluble coformer, the IDR and equilibrium solubility are lower than that of the pure drug. In the crystal structure of SMT−OA, one carboxyl group is deprotonated, and the other carboxyl group is engaged in the O−H···O hydrogen bond R22 (10) ring motif with the carboxylate anion. The crystal density of SMT−OA is high (1.7 g cm−3, Table 3). Furthermore, when correlating with the melting point of SMT cocrystals and salt, the high melting of SMT−OA (217−220 °C, Table 6) showed the lowest solubility compared to the lower melting cocrystals (SMT−SBA and SMT−ADP). IDR curves are displayed in Figure 11, and

salt that is contrary to the rule because the pKa difference should be large (>3) for salt formation. The formation of a carboxylate anion for OA further stabilized by the proximal CO group seems to favor deprotonation despite the pKa’s of acid and base being so close. Thus, the bifurcated ammonium··· diketo hydrogen bond motif in the SMT−OA structure appears to drive deprotonation even though ΔpKa is negligible. This point that the special positioning of functional groups will favor salt formation has been discussed by Sarma et al.57 The ammonium···oxalate R12(5) ring motif present on SMT−OA salt (Figure 8) is quite frequent, being observed in 68 crystal structures out of 87 which contain a primary amine and the oxalic acid functional groups (data extracted from the Cambridge Structure Database). The carbonyl stretching bands in FT-IR are consistent with a free carboxylic acid group in SMT−ADP, SMT−SBA (about 1740 cm−1), and a carboxylate for SMT−OA (1550 cm−1, Table 5). Melting Point by DSC. DSC can confirm the purity and monitor phase transformations.58,59 The melting point of the cocrystals was found to be lower than that of SMT except that for SMT−OA, which is higher because it is a salt (Table 6). Table 6. Melting Point of SMT Cocrystals/Salt and Conformersa

a

s. no.

cocrystal/salt

m.p. (°C)

coformer

m.p. (°C)

1 2 3 4 5 6 7

SMT−ABA SMT−BIP SMT−PABA SMT−VLA SMT−SBA SMT−ADP SMT−OA

174−176 185−187 187−189 199−201 173−175 177−179 217−220

ABA BIP PABA VLA SBA ADP OA

181−183 109−112 187−189 210−213 141−144 151−154 102−104

Melting point of SMT 209−210 °C.

Aromatic acids and amide group containing coformers, e.g., SMT−PABA, SMT−VLA, and SMT−ABA, gave a lower melting endotherm compared to the starting materials. Cocrystals with aliphatic acids and aromatic bipyridine, such as SMT−ADP, SMT−SBA, and SMT−BIP, have an intermediate temperature melting endotherm. Solubility and Dissolution. Solubility is a measure of “how much” a drug is soluble in the medium, while dissolution rate is “how fast” the drug reaches that equilibrium value. The former is a thermodynamic quantity, while the latter is influenced by kinetic factors, which gives an idea of the peak concentration and amount of drug dissolved in a short time. Solubility and dissolution are determined mainly by two factors: strength of crystal lattice and solvation of components in cocrystals. These two factors can modulate (increase/ decrease) the cocrystal solubility. An objective of the present SMT cocrystals is to address the extended release by decreasing solubility of SMT to avoid the rapid absorption rate in kinetic profile. This decreasing solubility profile could be altered through hydrogen bonding interactions of SMT as cocrystals via strong homomeric and heteromeric N−H···N and N−H···O interactions. In this regard, the present IDR and equilibrium solubility experiments on SMT, SMT−ADP, SMT−SBA, and SMT−OA were carried out in 0.1 N HCl (pH 1.2) medium. The IDR measurements were performed for 4 h by rotating disk intrinsic dissolution rate (DIDR) method60 at 37 °C. However, it was not possible to measure IDR and solubility for SMT−VLA and SMT−PABA cocrystals (aromatic ring

Figure 11. Intrinsic dissolution rate curves of SMT, SMT−ADP, SMT−SBA, and SMT−OA in pH 1.2 HCl medium. Measurement time is 4 h.

dissolution rates, equilibrium solubility and molar extinction coefficients are listed in Table 7. All solids forms were stable during the dissolution and equilibrium solubility experiments as confirmed by PXRD (Figures S6 and S7). Thus, the cocrystals and salt of SMT provide a slow release form SMT drug. Phase Stability in Acidic and Neutral Media. Next we studied the phase transformation of cocrystal/salt in acidic and neutral media by dissolving the parent components in a 1:1 molar ratio in 5 mL of the medium for SMT−ADP, SMT− SBA, and SMT−OA. Generally salt formation is driven by the acidity and basicity of the components.61 Here we observed that there is no cocrystal formation in the slurry medium (both acidic and neutral) after 24 h for SMT−SBA and SMT−ADP. In the case of SMT and OA, the physical mixture mixed in acidic slurry medium (0.1 N HCl) gave SMT−OA salt after 1 h (analyzed by PXRD of the residue, Figure 12). In neutral medium (phosphate buffer), however, the components 3507



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Table 7. Intrinsic Dissolution Rates of SMT and Its Cocrystal and Salta

a

compound

coformer solubility in (mg mL−1)

molar extinction coefficient (mM−1 cm−1)

equilibrium solubility in pH 1.2, 0.1 N HCl medium (mg mL−1)

intrinsic dissolution rate, IDR (mg cm−2/min)

cumulative amount dissolved per unit area (mg/500 mL)

SMT SMT−ADP SMT−SBA SMT−OA

10.5 23.0 11.9 143.0

14.2 15.5 13.7 14.6

3.7 3.5 (x0.94) 3.4 (x0.91) 3.0 (x0.81)

1.36 0.83 (x0.61) 0.62 (x0.45) 0.67 (x0.49)

190.8 169.5 (x0.86) 113.1 (x0.59) 144.4 (x0.75)

The ratio of IDR/solubility with SMT is given in parentheses.

interact with different hydrogen bonding synthons. SMT−ADP has a strong acid−amine synthon, the SMT−SBA cocrystal has weak C−H···O hydrogen bonds together with homomeric interactions, and in SMT−OA structure the proton is transformed from OA to SMT. The uncommon chalcogen− oxygen (S···O) interaction was observed in SMT−ADP and S··· N interaction in SMT−BIP. These chalcogenic interactions are important in the tubular structures of peptides and in superconducting tetrathiafulvalene (TTF) and tetracyanoquinodimethane (TCNQ).64 Furthermore, in vitro solubility and dissolution experiments for SMT−ADP, SMT−SBA, and SMT−OA showed that the IDR and equilibrium solubility of adducts were reduced compared to SMT, which is ascribed to efficient molecular packing and stronger interactions through strong homomeric and heteromeric N−H···N and N−H···O hydrogen bonds in the crystal lattice of salt/cocrystal. Thus, SMT cocrystals and salts could be useful in the controlled/ extended release of drug to improve its short residence time by reducing the absorption rate in modified crystal forms. Interestingly, we noted salt formation of SMT−OA in acidic slurry medium as well due to the soft acid−soft base rule. Phase stability studies in neutral and acidic media showed that SMT− ADP, SMT−SBA, and SMT−OA are stable in acidic medium, whereas in neutral medium these solid forms dissociated to the components. Our structural and solubility and stability studies on sulfamethizole provide novel and practical leads for further improvements on the physicochemical properties of sulfonamide drugs.

Figure 12. Equimolar SMT and OA physical mixture kept in slurry for 1 h gave the SMT−OA salt in acidic medium (0.1 N HCl), but the components are separate in neutral medium (phosphate buffer) (by PXRD pattern analysis).

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remained as separate species. The formation of SMT−OA salt in strongly acidic medium is driven by the HSAB principle.62,63 The preferred hard acid-hard base and soft acid-soft base pairing will give the SMT−OA salt (both are organic species with dispersed charges). In acidic media, the weak base SMT will form a salt with OA due to soft acid−soft base interactions. The strength of multipoint ammonium···oxalate R12(5) ring motif is another factor to favor SMT−OA salt formation over SMT−HCl which will have a single hydrogen bond. In neutral media, there is no drive toward acid−base pairing, and hence no salt formation was observed. For cocrystals, no adduct formation was noted in either acidic or neutral medium due to solubility mismatch of coformer and SMT in the solvent. A phase stability study was performed for 24 h in the slurry medium. The cocrystals and salt were stable for up to 24 h in acidic medium, whereas in neutral medium SMT−OA and SMT−ADP partially converted to the parent components and SMT−SBA was completely dissociated (Figures S7 and S8).

ASSOCIATED CONTENT

S Supporting Information *

Crystallographic information files: CCDC Nos. 1060511− 1060517; Figure S1a−g: ORTEP diagrams of cocrystals and salt of SMT. Figure S2: Overlay of the experimental PXRD pattern (black) and calculated diffraction line pattern from the X-ray crystal structure (red). Figure S3: DSC thermogram of SMT cocrystals and salts. Figure S4a−g: Overlay of cocrystals and salt of SMT FT-IR spectra with its starting components (KBr dispersion sample pellet). Figure S5: ATR IR spectra of SMT cocrystals and salt (attenuated total reflection mode). Figure S6a−d: Comparison of powder XRD patterns of cocrystals and salt of SMT after IDR experiment with the calculated powder pattern from the crystal structure. Figure S7a−d: Comparison of powder XRD pattern of cocrystals and salt of SMT at the end of equilibrium solubility experiment with the calculated powder XRD pattern from the crystal structure. Figure S8a−d: PXRD of SMT cocrystals and salt at the end of equilibrium solubility/phase stability experiment (24 h) matches with the calculated powder pattern of the crystal structure. Table S1: Torsion angles in SMT molecule in different crystal structures. The Supporting Information is

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CONCLUSIONS A solid form screening of sulfamethizole for multicomponent crystalline solids afforded six cocrystals and one salt. In the crystal structures, three aliphatic dicarboxylic acid coformers 3508



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available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.5b00587.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS K.S. and K.K.N. thank UGC and DST for a fellowship. We thank Indo-Russia DST-RFBR scheme (Projects INT/RUS/ RFBR/P-150 and 13-03-92704) for funding. DST (IRPHA and PURSE) and UGC (UPE grant) are thanked for providing instrumentation and infrastructure facilities at University of Hyderabad (UOH). Instruments of the Novosibirsk State University and Institute of Solid State Chemistry and Mechanochemistry SB Russian Academy of Sciences were used for X-ray diffraction, vibrational spectroscopy and thermal analysis studies. E.D. acknowledges partial support from Project 1828 Russian Ministry of Science and Education.

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