Novel Synthons in Sulfamethizole Cocrystals: StructureâProperty

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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 Cryst. Growth Des., Just Accepted Manuscript • Publication Date (Web): 12 Jun 2015 Downloaded from http://pubs.acs.org on June 12, 2015

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Crystal Growth & Design

Novel Synthons in Sulfamethizole Cocrystals: Structure−Property Relations and Solubility Kuthuru Suresh,a Vasily S. Minkov,b,c Kranthi Kumar Namila,aElizaveta Derevyannikova,b,c Evgeniy Losev,b,c Ashwini Nangia,*,a and Elena V. Boldyreva*,b,c E-mail: [email protected], [email protected] a

School of Chemistry, University of Hyderabad, Central University P.O., Prof. C. R. Rao Road, Hyderabad 500 046, India

b

Novosibirsk State University, 2 Pirogov str., 630090 Novosibirsk, Russian Federation

c

Institute of Solid State Chemistry and Mechanochemistry SB RAS, 18 Kutateladze, 630128 Novosibirsk, Russian Federation 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.paminobenzoic 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 H-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 lower intrinsic dissolution rate (IDR) and equilibrium solubility compared to SMT in 0.1N 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 (0.1N HCl), whereas in neutral medium (phosphate buffer) no SMT-OA salt formation was observed.

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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 as 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 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 short half-life (2.1 h) due to rapid metabolism and systematic elimination.20 To improve the concentration of SMT in blood level, an extended release of Lipase-SMT granule system is reported,21 withSMT 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 particles. In another case, Zaworotko’s group reported that cocrystals of Epigallocatechin gallate (EGCG) exhibited lower solubility compared to the parent drug resulting in 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 towards higher or lower levels by 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) makes 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 non-GRAS 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.


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Experimental Section SMT and coformers (purity > 99.8%) were purchased from Sigma-Aldrich (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. Table 1 Preparation of SMT cocrystals and salts. Solid form SMT-ADP

SMT(mg, mmol) 270.3, 0.1

Coformer(mg, mmol) 73.0, 0.05

SMT-PABA

270.3, 0.1

137.1, 0.1

SMT-VLA

270.3, 0.1

168.1, 0.1

SMT-ABA

270.3, 0.1

136.1, 0.1

SMT-BIP

270.3, 0.1

156.1, 0.1

SMT-SBA

270.3, 0.1

87.0, 0.05

SMT-OA

270.3, 0.1

90.0, 0.1

Method, Solvent Mortar-pestle grinding, CH3CN (1 mL) Mortar-pestle grinding, CH3CN (1 mL) Mortar-pestle grinding, CH3CN (1 mL)) Mortar-pestle grinding, CH3CN (1 mL) Mortar-pestle grinding, CH3CN (1 mL) Mortar-pestle grinding, CH3CN (1 mL) Mortar-pestle grinding, CH3CN (1 mL)

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

Table 2 ∆pKa values of dicarboxylic acid coformers and SMT drug. 1st, 2ndpKa in water ∆pKa Molecular complex SMT 1.95 for aromatic ----aminea OA 1.36, 4.11 0.59, 2.16 1:1 salt ADP 4.70, 3.92 2.75, 1.97 1:0.5cocrystal SBA 4.90, 4.15 2.95, 2.20 1:0.5 cocrystal a The pKa(1.95) of 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 3 ACS Paragon Plus Environment


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b

pKa’s were calculated using Marvin 5.10.1, 2012, ChemAxon, http://www.chemaxon.com, e.g. see ref. 27). c These values are closely matching with pKa values compiled by R. Williams.28 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 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 Mettler Toledo DSC 822e module (Mettler Toledo, Columbus, Ohio). Samples were placed in crimped but vented aluminum sample pans. The typical sample size is 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 (BrukerAXS, 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 Xray diffraction experiments were performed at 100 K. All crystals were covered by low viscosity CryoOil (MiTeGen) to protect them additionally from 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,29and the structures were refined using SHELXL30-32implemented 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 restrains, Uiso(H) = 1.5 Ueq(C) for terminal methyl H atoms, and 1.2 Ueq (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. 4 ACS Paragon Plus Environment

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Dissolution and solubility The solubility curves of SMT, two cocrystals and one salt were measured using the Higuchi and Connor method34 in pH1.2 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 pH1.2 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 IDR values and equilibrium solubility values.An excess amount of the sample was added to 5 mL of pH1.2 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 Whatmann 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 pH1.2 0.1NHCl medium at 37 ºC. 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 pressure of 4.0 ton/inch2 for 5 min. The intrinsic attachment was placed in a jar of 500 mL pH1.2 0.1NHCl medium preheated to 37 °C and rotated at 100 rpm. 5 mL aliquots were collected at specific time intervals and concentration 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 PXRD (Figure S6 and Figure S7). The stability of the solid samples upon disc compression and solubility conditions was confirmed by powder X-ray diffraction. Results and Discussion Selection of coformers A solid form screening of SMT with several GRAS (Generally Regarded as Safe)24 molecules different functional groups was performed (Scheme 1). A few non-GRAS model compounds, such as p-amino benzamide and4,4'-bipyridine, were also included to better understand structural correlations in this family.



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H O

N

N

O

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O

O CH3

S

CH3

S

S

N

N

N

S

N H

H2N

H2N SMT Tautomer II

SMT Tautomer I

O

O HO

O

HO

HO

OH

OH O

OH O

OA O

OH

O

ADP

O

OH

O

SBA

NH2

N

OCH3 NH2 PABA

OH

NH2 ABA

VLA

N BIP

Scheme 1 Molecular structures and acronyms of sulfamethizole and coformers. The cocrystals were produced by co-grinding35-37 as a first choice method. The bulk phase composition of adducts were tested by powder X-ray diffraction, DSC and IR. The powder samples were used as seeds in evaporative crystallization (see Experimental Section)38,39 to obtain single crystals for X-ray diffraction. Cocrystals with adipic acid (ADP), paminobenzoic acid (PABA), vanillic acid (VLA), p-aminobenzamide (ABA), suberic acid (SBA), 4,4'-bipyridine (BIP), and a salt with oxalic acid (OA) was 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 (Figure S2 and S3) together with DSC thermograms.


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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···N32.42 Å, 148.6º) hydrogen bond synthon in aR22(8) ring motif (Figure 1). These dimeric motifs are associated through bifurcated type II inter chalcogenchalcogen S···O (S1···O2, 3.22 Å, 157º) interactions of R22(10) rings as a 1D chain, which are in turn connected via N–H···N (N1–H1A···0 2.19 Å, 163º) hydrogen bonds.

Figure 1 Linear chains of SMT molecule are bridged by N–H···N (N4–H9···N22.26 Å, 163.2º) hydrogen bond interaction in 2D network 16(CSD refcode FOLHAP). In the cocrystal structures, however, the hydrogen bonds motifs of SMT (Figure 1) are replaced by new synthons (Scheme 2).



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H N

H H

N

H

O

H

O

O

O

S synthon 2

synthon 1

N H N

H

N

S

H H

O N

H

O

N synthon 4

synthon 3

OH N O

S

N

H

N

HN

N

H H

N

S N

synthon 5

H

synthon 6

Scheme 2 Schematic representations of supramolecular synthons in SMT cocrystals observed in this study. 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 SMTSBA, whereas equilibrium solubility varies as SMT > 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 is 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 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 melting point of SMT cocrystals and salt, the high melting of SMT-OA (217-220 °C, Table 6) showed least solubility compared to the lower melting cocrystals (SMT-SBA and SMT-ADP). Intrinsic dissolution rate curves are displayed in Figure 11, and dissolution rates, equilibrium solubility and molar extinction coefficient are listed in Table 7. All solids forms were stable during the dissolution and equilibrium solubility experiments as confirmed by PXRD (Figure S6 and S7). Thus, the cocrystals and salt of SMT provide a slow release form SMT drug.



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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. Table 7 Intrinsic dissolution rates of SMT and its cocrystal and salt. The ratio of IDR/ solubility with SMT is given in parenthesis. Compound

Coformer Solubility in (mg mL-1)

Molar Extinction coefficient (mM-1 cm-1)

SMT SMT-ADP SMT-SBA SMT-OA

10.5 23.0 11.9 143.0

14.2 15.5 13.7 14.6

Equilibrium Solubility in pH 1.2, 0.1N HCl medium (mg mL-1) 3.7 3.5 (x0.94) 3.4 (x0.91) 3.0 (x0.81)

Intrinsic dissolution rate, IDR (mg cm-2/min) 1.36 0.83 (x0.61) 0.62 (x0.45) 0.67 (x0.49)

Cumulative amount dissolved per unit area (mg/500 mL) 190.8 169.5 (x0.86) 113.1 (x0.59) 144.4 (x0.75)

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 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 one hour (analyzed by PXRD of the residue, Figure 12). In neutral medium (phosphate buffer), however, the components remained as separate species. The formation of SMT-OA salt in strongly acidic medium is driven by the HSAB principle62,63 The preferred hard acidhard base and soft acid-soft base pairing will give 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 multi-point ammonium···oxalate R12(5) ring 18 ACS Paragon Plus Environment

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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 towards 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 SMTADP partially converted to the parent components and SMT-SBA was completely dissociated (Figure S7 and Figure S8).

Figure 12 Equimolar SMT and OA physical mixture kept in slurry for 1h gave SMT-OA salt in acidic medium(0.1 N HCl) but the components are separate in neutral medium(phosphate buffer) (by PXRD pattern analysis). Conclusions A solid form screening of sulfamethizole for multi-component crystalline solids afforded six cocrystals and one salt. In the crystal structures, three aliphatic dicarboxylic acid coformers interact with different hydrogen bonding synthons. SMT-ADP has strong acid-amine synthon, 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 19 ACS Paragon Plus Environment


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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 salt could be useful in 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.

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. This material is available free of charge via the Internet at http://pubs.acs.org. Corresponding authors *E mail: [email protected], [email protected]

Notes The authors declare no competing financial interest. Acknowledgements K. S. and K. K. N. thank UGC and DST for 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 20 ACS Paragon Plus Environment

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Sciences were used for X-ray diffraction, vibrational spectroscopy and thermal analysis studies.

References 1. Desiraju, G. R. Crystal Engineering: The Design of Organic Solids, Elesevier, Amsterdam, 1989. 2. Desiraju, G. R.; Steiner, T.; The Weak Hydrogen Bond in Structural Chemistry and Biology, IUCr Monographs in Crystallography, 1999. 3. Etter, M. C.; Macdonald, J. C.; Bernstein, J. Acta Crystallogr. 1990, B46, 256-262. 4. Etter, M. C.; Reutzel, S. M. J. Am. Chem. Soc. 1991, 113, 2586–2598. 5. Almarsson, Ö, Zaworotko, M. J. Chem. Commun. 2004, 17, 18891896. 6. Desiraju, G. R. J. Am. Chem. Soc.2013, 135, 9952−9967. 7. Schulthesiss, N.; Newman, A. Cryst. Growth Des. 2009, 9, 2950–2967. 8. Babu, N. J.; Nangia, A. Cryst. Growth Des. 2011, 11, 2662–2679. 9. Remenar, J. F.; Morissette, S. L.; Peterson, M. L.; Moulton, B.; MacPhee, J. M.; Guzman, H. R.; Almarsson, O. J. Am. Chem. Soc.2003, 125, 8456−8457. 10. Karki, S.; Friščić, T.; Fábián, L.; Laity, P.R.; Day, G.M.; Jones, W.; Adv. Mater. 2009, 21, 3905–3909. 11. Suresh, K.; Goud, N. R.; Nangia, A. Chem. Asian J. 2013, 8, 3032–3041. 12. Wang, J. -R.; Zhou, C.; Yu, X.; Mei, X. Chem. Commun.2014, 50, 855–858. 13. Sravani, E.; Mannava, M. M. C.; Kaur, D.; Annapurna, B. R.; Khan, R.A.; Suresh, K.; Mittapalli, S.; Nangia, A.; Kumar, B. D.; Curr. Sci. 2015, 108, 1097-1106. 14. Hickey, M. B.; Peterson, M. L.; Scoppettuolo, L. A.; Morrisette, S. L.; Vetter, A.; Guzman, H.; Remenar, J. F.; Zhang, Z.; Tawa, M. D.; Haley, S.; Zaworotko, M. J.; Almarsson, O. Eur. J. Pharm. Biopharm.2007, 67, 112–119. 15. Kerrn, M. B.; Frimodt-Møller, N.; Espersen, F. Antimicrob. Agents Chemother. 2003, 47, 1002–1009. 16. Fuglp, V.; Kalman, A. J. Mol. Struct.1987,159, 303–310. 17. Vilarnovo, B.; Perdomo-López, I.; Echezarreta-López, M.; Schroth-Pardo, P.; Estrada, E.; Torres-Labandeira, J. J. Eur. J. Pharm.2001, 13, 325–331. 18. Lemke, T.L.; Williams, D.A. Foye's Principles of Medicinal Chemistry,2008, 1– 1377. 19. Sulfamethizole solubility http://www.drugbank.ca/drugs/DB01015. 20. Shear, N. H.; Spielberg, S. P.; Grant, D. M.; Tang, B. K.; Kalow, W. Ann Intern. Med. 1986, 105, 179–184. 21. Javaid, K.A.; Hartman, C. W. J. Pharm. Sci. 1972, 61, 900–902. 22. Smith, A. J.; Kavuru, P.; Arora, K. K.; Kesani, S.; Tan, J.; Zaworotko, M. J.; Shytle, R. D. Mol. Pharmaceutics 2013, 10, 2948–2961. 23. Goud, N. R.; Khan, R. A.; Nangia, A. CrystEngComm 2014, 16, 5859–5869. 24. Generally Regarded as Safe chemicals by the U.S. FDA. http://www.fda.gov/Food/IngredientsPackagingLabeling/FoodAdditivesIngredients/uc m091048.htm (Accessed 14 Feb. 2015) 21 ACS Paragon Plus Environment


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1 2 3 4 5 6Table 3 Summary of crystal structure parameters. 7 8 SMT-ADP SMT-PABA SMT-VLA 9 10 11 (C912H10 N4 O2 S2). (C9 H10 N4 O2 (C9 H10 N4 O2 0.513 (C6 H10 O4) S2). (C7 H7 N O2) S2).(C8 H8 O4) 14 343.40 407.47 490.61 15 16 17 Monoclinic Monoclinic Monoclinic 18 19 P220 P21/n P21/c 1/c 21 100(2) 100(2) 100(2) 22 7.9915(4) 9.2097(3) 8.1263(5) 23 24 21.6918(8) 10.8241(5) 19.7763(7) 25 8.5756(4) 18.2910(7) 12.0584(7) 26 9027 90 90 28 95.737(4) 101.645(3) 109.396(4) 29 9030 90 90 4 31 4 4 32 1479.13(11) 1785.84(12) 1827.90 33 34 1.542 1.516 1.593 35 17542 21883 27232 36 37 38 3665 4427 4527 39 40 41 0.0291 0.0294 0.0292 42 0.0714 0.0748 0.0707 43 1.016 1.022 1.059 44 45 46 STOE STOE STOE 47 48 49 1060516 1060513 1060511 50 51 52 53 54 55 56 57 58 59 60

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SMT-ABA

SMT-BIP

(C9H10 N4 O2 S2).(C7 H8 N2 O)

(C9 H10 N4 O2 S2) 2(C9 H10 N4 O2 (C9 H11 S2). (C8 H14 O4) H O4) .(C10 H8 N2)

406.48

426.51

714.85

360.37

Triclinic

Monoclinic

Orthorhombic

Monoc

P1 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

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

Pca21 100(2) 10.4481(3) 19.2259(5) 16.5666(7) 90 90 90 4 3327.80(19) 1.427 26795

P21/c 100(2) 8.0559 20.654 8.5539 90 99.903 90 4 1402.0 1.707 12515

16205

3412

7643

3479

0.0943 0.2400 1.116

0.0560 0.1160 1.047

0.0440 0.0865 1.040

0.0324 0.0789 1.034

STOE

STOE

STOE

STOE

1060517

1060515

1060512

106051

ACS Paragon Plus Environment

24

SMT-SBA

SMT-O

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Table 4 Selected geometric parameters characterizing hydrogen bonds in SMT cocrystals. D−H···A

D···A (Å)

N1−H1A···N2 N1−H1B···O1 N3−H3A···O3 O4−H4A···N1 C2 −H2···O2 C3−H3···N2

3.306(17) 2.930(17) 2.748(16) 2.705(16) 2.928(16) 3.451(17)

N1−H1B···N5 N3 −H3A···N2 O3−H3B···O4 N5−H5A···O2 N5−H5B···O1 C11−H1···O3

3.393(2) 2.895(15) 2.616(14) 2.968(15) 3.115(16) 2.743(16)

N1−H1A···O1 N3−H3A···O5 N3−H3A···O6 O4−H4A···O3 O5−H5A···N1 C9−H9B···O1

3.247(3) 2.769(5) 3.155(4) 2.621(2) 2.760(1) 3.337(9)

N1−H1A···O2 N1−H2A···O1 N1−H3A···N6 C3−H3···O2 C6−H6···O2 C13−H13···O1 C19−H19···O1

2.971(4) 3.025(4) 2.739(4) 3.320(4) 2.919(4) 3.447(5) 3.447(4)

N1−H1A···O1 N1−H1B···O2 N3−H3A···N6 N5−H5A···O3 N5−H5B···O4 O6−H6A···O7 N7−H7A···N2

2.937(4) 2.894(4) 2.851(3) 2.961(3) 2.888(3) 2.640(3) 2.845(3)

H···A (Å) SMT-ADP 2.48 2.29 1.96 1.76 2.57 2.61 SMT-PABA 2.52 2.00 1.80 2.41 2.29 2.37 SMT-VLA 2.52 2.18 2.38 1.80 1.91 2.44 SMT-BIP 2.17 2.12 1.84 2.56 2.51 2.53 2.41 SMT-SBA 2.05 2.07 1.94 2.00 2.08 1.81 2.02

D−H···A (°)

Symmetry code

160 130 173 168 102 147

-1+x,y,z -1+x,1/2-y,-1/2+z x,y,-1+z 1+x,y,1+z intramolecular -1+x,y,z

175 173 173 122 162 102

3/2-x,1/2+y,1/2-z 2-x,1-y,1-z 1-x,1-y,1-z -1+x,-1+y,z 1/2-x,-1/2+y,1/2-z Intramolecular

146 130 161 177 166 155

-1+x,1/2-y,-1/2+z x,1/2-y,1/2+z x,1/2-y,1/2+z -x,-y,1-z -x,-y,-z 1-x,1/2+y,1/2-z

159 165 170 136 107 151 177

1/2+x,1/2-y,-1/2+z 1+x,y,z -3/2+x,1/2-y,-1/2+z 1/2+x,1/2-y,-1/2+z Intramolecular 1+x,y,z 1+x,y,z

164 166 174 164 150 172 167

-3/2-x,y,-1/2+z 1-x,-y,-1/2+z x,y,z 1/2-x,y,-1/2+z 1-x,1-y,-1/2+z 1+x,y,z x,y,z



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

O8−H8A···O5 C9−H9B···O2 C18−H18A···N4 C9−H9A···O6

2.670(3) 3.400(4) 3.489(4) 3.321(4)

1.88 2.60 2.56 2.65

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167 139 158 126

-1+x,y,z -1/2+x,-y,z 1+x,y,z 1/2-x,y,-1/2+z

SMT-OA N1−H1A···N2 N1−H1B···O1 N1−H1B···O5 N1−H1C···O4 N1−H1C···O5

2.9837(19) 2.7853(19) 3.1302(19) 2.8815(19) 2.8360(18)

2.08 2.25 2.40 2.35 2.00

173 116 137 118 154

-1+x,y,z -1+x,1/2-y,-1/2+z -1+x,1/2-y,-1/2+z -1+x,y,-1+z -1+x,y,-1+z

N3−H3A···O4 O6−H6A···O3 O6−H6A···O3 C2−H2···O2 C3−H3···O6 C6−H6···O1

2.6642(17) 2.6658(17) 2.7017(17) 2.9307(19) 3.0872(18) 2.9470(2)

166 118 139 102 114 103

x,y,-1+z Intramolecular 2-x,-y,1-z Intramolecular -1+x,y,z Intramolecular

N1−H1A···N14 N1−H1B···O14 N3−H3A···O4 N4 −H4A···N11 N4 −H4B···N21 N5−H5A···N24 N5−H5B···N12 N6−H6A···O2 N6 −H6B···N23 N8 −H8B···O13 N10−H10···O2 N12−H12A···O8 N12−H12B···O9 N13−H13A···O8 N13 −H13B···O9 N15−H15···O13 N18−H18···O14 N20−H20A···O5 N20−H20B···O11 N21−H21B···O5 N22−H22···O4 N25−H25A···N16

3.277(8) 2.926(7) 2.967(7) 3.068(8) 3.070(8) 3.033(8) 3.061(8) 2.971(7) 3.335(8) 2.973(7) 2.654(6) 3.546(7) 3.030(7) 3.030(7) 3.440(7) 2.710(6) 2.668(7) 3.448(7) 3.039(7) 3.030(7) 2.667(6) 2.964(7)

1.78 2.13 1.96 2.59 2.55 2.55 SMT-ABA 2.27 1.89 1.95 2.08 2.22 2.03 2.19 2.01 2.26 1.93 1.77 2.51 1.96 2.07 2.50 1.83 1.79 2.41 1.98 1.96 1.79 1.96

154 160 156 150 134 153 136 146 173 160 177 161 169 146 145 175 177 161 166 170 179 153

1-x,-y,-z -1+x,y,z 1+x,y,z x,y,z x,y,z -1+x,y,z x,y,z x,y,z 1-x,1-y,-z x,y,z x,y,z -1+x,y,z x,y,z x,y,z 1+x,y,z x,y,z -1+x,y,z x,y,z x,-1+y,z x,1+y,z 1+x,y,z x,y,z


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N25−H25B···N20 N26−H26A···N19 N26−H26B···N13 C31−H31···O12 C34−H34···O7 C40−H40···O6 C43−H43···O10 C49−H49···O7 C52−H52···O12 C61−H61···O10 C64−H64···O6

3.066(8) 2.991(6) 3.057(7) 3.395(7) 3.276(8) 3.316(7) 3.413(8) 3.397(7) 3.285(7) 3.304(7) 3.413(8)

2.17 2.00 2.18 2.46 2.57 2.58 2.47 2.46 2.57 2.57 2.47

139 151 137 168 131 134 171 167 132 134 170


x,y,z 1+x,y,z x,y,z x,-1+y,z x,y,z -1+x,1+y,z x,y,z x,y,z 1+x,-1+y,z x,y,z x,1+y,z


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Table of Contents Novel Synthons in Sulfamethizole Cocrystals: Structure−Property Relations and Solubility Kuthuru Suresh,a Vasily S. Minkov,b,c Kranthi Kumar Namila,a Elizaveta Derevyannikova,b,c Evgeniy Losev,b,c Ashwini Nangia,*,a and Elena V. Boldyreva*,b,c E-mail: [email protected], [email protected] a

School of Chemistry, University of Hyderabad, Central University P.O., Prof. C. R. Rao Road, Hyderabad 500 046, India

b

Novosibirsk State University, 2 Pirogov str., 630090 Novosibirsk, Russian Federation

c

Institute of Solid State Chemistry and Mechanochemistry SB RAS, 18 Kutateladze, 630128 Novosibirsk, Russian Federation

Sulfamethizole is a conformationally flexible drug molecule with multiple hydrogen bond functionalities (donors: amine NH2 and imine NH; acceptors: sulfonyl O atoms, thiazolidine N and S, and imidine N). Six novel N–H···O and O–H···N synthons as well as weaker hydrogen bonds and chalcogen interactions are analyzed in cocrystals of this drug. The remarkably high stability of sulfamethizole oxalate salt is presented. Key words Cocrystal, Conformation, Differential scanning calorimetry, Solubility, Vibrational spectroscopy, X-ray diffraction.


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Novel Synthons in Sulfamethizole Cocrystals: StructureâProperty

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