Co-Crystallization of the Anti-Cholesterol Drug Bezafibrate: Molecular

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Co-crystallization of the Anti-Cholesterol Drug Bezafibrate: Molecular Recognition of a Pharmaceutical Contaminant in the Solid State and Solution via Hydrogen Bonding Jesus Daniel Loya, Jinchun Qiu, Daniel K. Unruh, Anthony Frank Cozzolino, and Kristin M. Hutchins Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b00812 • Publication Date (Web): 13 Aug 2018 Downloaded from http://pubs.acs.org on August 15, 2018

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Crystal Growth & Design

Co-crystallization of the Anti-Cholesterol Drug Bezafibrate: Molecular Recognition of a Pharmaceutical Contaminant in the Solid State and Solution via Hydrogen Bonding Jesus Daniel Loya, Jinchun Qiu, Daniel K. Unruh, Anthony F. Cozzolino* and Kristin M. Hutchins* Department of Chemistry & Biochemistry, Texas Tech University, 1204 Boston Avenue, Lubbock, TX 79409, USA.

ABSTRACT Pharmaceuticals have been found as contaminants in wastewater, causing concern for health of aquatic life and humans. The anti-cholesterol medication bezafibrate is one such contaminant and is difficult to remove from wastewater. The lack of studies investigating the bonding behaviour of bezafibrate with potential acceptor motifs prompted us to determine the types of molecules that would engage in intermolecular bonds with the drug. Although cocrystallization of bezafibrate has been previously attempted, we altered the approach by utilizing molecules containing only hydrogen-bond acceptor sites. Here, we discuss the first successful co-crystallizations of bezafibrate, intermolecular bonding behaviour, and solution-state binding studies with potential acceptor molecules. One acceptor, 4-dimethylaminopyridine, exhibits a

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stronger bond in the solid state, and a solution-state binding constant over 18 times higher than any other drug-acceptor pair studied here. These studies should aid in designing contaminantremoval materials that will effectively bond with the drug.

The presence of pharmaceuticals and other organic compounds in wastewater has raised concerns due to potential negative risks for aquatic species, plants, and human health.1-3 For example, endocrine-disrupting compounds and other pharmaceuticals have been demonstrated to cause adverse effects such as reproductive disruption and organ impairment in aquatic life.4,5 Wastewater treatment plants do not typically remove many of these contaminants.6 Polar compounds, in particular, are difficult to remove,7 which has spurred increased efforts to find methods for removing such contaminants from wastewater.8 Understanding the specific intermolecular interactions between the treatment material and the contaminant will aid in designing materials that are more effective at removal. For many pharmaceutical contaminants, minimal studies investigating the intermolecular bonding and supramolecular behavior9,10 are available. For example, the anti-cholesterol and blood pressure medications bezafibrate, atenolol, eprosartan, gemfibrozil, and pravastatin have been found as persistent contaminants in wastewater treatment plants;11 however, to our knowledge, there are no reported co-crystals involving these drugs.12-17 Co-crystallization, the process of combining two or more neutral molecules,18-20 has found use in constructing multicomponent solids involving pharmaceuticals.21-24 The components in the co-crystal typically associate with each other via non-covalent interactions. Quantifying such intermolecular bonding behavior of contaminants with potential receptor candidates could provide useful metrics for determining what functional group motifs to incorporate into contaminant-removing materials (e.g. polymers, membranes).


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Scheme 1. BEZA: (a) chemical structure of drug and supramolecular synthon in single component crystal and (b) co-crystallization strategy and results using different acceptor motifs.

The drug bezafibrate (BEZA) (Scheme 1a) is a lipid-regulating agent that lowers the amounts of low-density lipoprotein (LDL) and triglycerides and raises high-density lipoprotein (HDL), which reduces the risk of heart disease.25,26 BEZA was first introduced in the 1970s,27,28 and the drug has been shown to crystallize in two polymorphic forms (α and β).9,29 BEZA contains a carboxylic acid and amide functional group, both of which can act as complementary hydrogenbond donor/acceptor moieties. The single-crystal structures of both BEZA polymorphs are dominated by O-H···O and N-H···O hydrogen bonds between the acid and amide functional groups to generate a four-component supramolecular synthon (Scheme 1a, Figure S1). Each BEZA molecule participates in two supramolecular synthons, forming a 2D sheet, which largely contributes to the stabilization of both structures in the solid and solution states.30 Cocrystallization of BEZA has been previously attempted; however, only single crystals of BEZA have ever been isolated.30 BEZA has also been found as a wastewater contaminant in effluents31,32 at concentrations higher than the predicted no-effect concentration.11 Thus, we sought to synthesize co-crystals of


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BEZA to determine what types of functional groups would form intermolecular bonds with BEZA and could act as potential receptor motifs for removal applications. Here, we report the first successful co-crystallizations of the pharmaceutical contaminant BEZA. The second molecule in each co-crystal comprises only hydrogen-bond acceptor sites, which fundamentally differs from molecules used in previous co-crystallization attempts (Scheme 1, 2). We demonstrate one co-crystal that exhibits ca. 0.1 Å shorter hydrogen bond between the drug and acceptor molecule in the crystalline state, and a solution-state binding constant over 18 times higher than any other drug-acceptor pair. Scheme 2. Hydrogen-bond-acceptor molecules used in co-crystals with BEZA. acceptor

BEZA

R

R=

BPE

4,4’-AP

BPEth

BIPY

DMAP

Prior co-crystallization attempts of BEZA utilized molecules containing both a pyridine and amide group (Scheme 1b). This motif would favor 1D chain formation instead of a 2D sheet. Using one of the two hydrogen-bonding groups already present in BEZA as the second component could favor crystallization of BEZA alone because of the stability30 of the amideacid tetramer interactions. Indeed, when we attempted co-crystallization of BEZA with molecules containing a pyridine and carboxylic acid (4-pyridinecarboxylic acid) or two carboxylic acids (phthalic acid), only crystals of BEZA were isolated.


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We then hypothesized that molecules containing only hydrogen-bond acceptor sites would favor co-crystallization of BEZA and overcome tetramer formation. Ditopic bipyridyl molecules 1,2-bis(4-pyridyl)ethylene (BPE), 4,4'-azopyridine (4,4'-AP), 1,2-bis(4-pyridyl)ethane (BPEth), and 4,4’-bipyridine (BIPY) (Scheme 2), which can be expected to aid in the formation of supramolecular chains in the solid state,33,34 were used in co-crystallization experiments. Co-crystals were synthesized by dissolving BEZA and the bipyridine acceptor in a 2:1 molar ratio in ethanol or acetonitrile (see Supplementary Information (SI)). The solutions were allowed to evaporate slowly, and single crystals suitable for X-ray diffraction formed within 2-3 days. The formulas of the co-crystals were confirmed by single-crystal X-ray diffraction and 1H NMR spectroscopy (Figures S8-S12). Single-crystal

X-ray

diffraction

studies

revealed

the

co-crystals

2(BEZA)·BPE,

2(BEZA)·4,4'-AP, and 2(BEZA)·BPEth to be isostructural, crystallizing in the monoclinic, centrosymmetric space group P21/c. The components crystallized in a 2:1 ratio, with one crystallographically unique BEZA molecule and one-half of a bipyridine molecule in the asymmetric unit. The co-crystal 2(BEZA)·BIPY·CH3CN is nearly isostructural to the previous three co-crystals, but the asymmetric unit contains two crystallographically unique BEZA molecules, one BIPY, and one molecule of acetonitrile. A portion of one BEZA molecule is also disordered over two sites [site occupancies 0.50(1) and 0.50(1)]. The acetonitrile molecule interacts with BEZA via C-H···O (3.37 Å) and C···O contacts (3.13 Å).


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Figure 1. X-ray crystal structures of: (a) 2(BEZA)·BPE, (b) 2(BEZA)·4,4'-AP, and (c) 2(BEZA)·BIPY·CH3CN. Disorder in the BEZA molecule in part (c) is omitted for clarity. Hydrogen bonds shown with green dashes lines. All four structures are viewed in the ab plane. The assembly of BEZA and the bipyridines in all four co-crystals is directed by COO-H···N hydrogen bonds between the carboxylic acid of BEZA and the pyridyl nitrogen atoms of the bipyridines [O···N separations (Å): BPE: 2.658(2); 4,4'-AP: 2.692(2); BPEth: 2.612(2); BIPY: 2.632(4) and 2.671(4)] (Figure 1, Figures S2-S6). The carboxylic acid groups of BEZA lie in the syn conformation in all four co-crystals, akin to the α polymorph geometry of pure BEZA (Figure S1).9


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In each co-crystal, the amide moieties of neighboring BEZA molecules engage in N-H···O hydrogen bonds, generating 1D hydrogen-bonded chains [N···O separations (Å): BPE: 2.958(2); 4,4'-AP: 2.964(2); BPEth: 3.012(1); BIPY: 2.965(4) and 3.19(1)]. The amide-amide interactions extend along the crystallographic b-axis with neighboring BEZA molecules lying parallel and rotated 180° relative to each other, assembling in an ABAB fashion (Figure 1). The 1D hydrogen-bonded chains pack into corrugated layers. The pyridine molecules in neighboring layers stack offset and exhibit long π-π interactions between the aromatic rings [π centroid···π centroid (Å): BPE 5.72; 4,4'-AP 5.73; BPEth 5.95; BIPY 5.60]. In order to determine the strength of the molecular recognition between BEZA and the pyridine acceptors, we performed solution-state binding studies (Table 1). In combination with the crystallographic studies, binding experiments provide insight into molecular recognition events in solution and may reflect the mechanism of contaminant removal from wastewater. Two of the pyridines utilized in the co-crystals (BPE and 4,4'-AP) were subjected to solution-state binding experiments with BEZA. As BIPY and BPEth are structurally and electronically similar to BPE, we expected similar binding behavior; thus, BPE was used as a bipyridyl representative. Pyridine was used as a model system, and 2-acetamidopyridine was used based on its ability to bond with carboxylic acids through two points.35 The binding studies were performed by titrating solutions of the pyridine acceptor into a solution of BEZA and monitoring changes in the UV/Vis absorption spectra. To quantify the binding between BEZA and the pyridine acceptor, the data were initially fitted with a 1:1 binding model (eq. 1). The binding constant, K1, was varied to minimize the sum of the square of the differences between the modeled and experimental UV/Vis absorbance values (see SI). The residuals were analyzed to determine if the model was appropriate.36 Although 2:1


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binding is possible with some of the pyridine acceptors, the 1:1 binding model provided the best fit for the data. The binding constants and Gibbs free energies are provided in Table 1. BEZA + Pyr ⇌ BEZA·Pyr

(1)

K1

Table 1. Solution-state binding studies with BEZA and pyridine acceptor molecules. Pyridine acceptor

K1 (mol–1)

∆G (kJ/mol)

σpa

4,4'-AP

400 ± 200

-14.9 ± 1.0

0.39

2-acetamidopyridine

700 ± 100

-16.2 ± 0.5

–

pyridine

830 ± 80

-16.6 ± 0.2

0

BPE

1400 ± 300

-18.0 ± 0.6

-0.07

DMAPb, c

26000 ± 4000

-25.2 ± 0.4

-0.83

a

Hammett parameter for the para position. bDMAP also exhibited a second binding constant (K2) of 180 with an error of 80. cReported binding constants (in parentheses) for DMAP with other acceptors: thiourea (170 M-1),37 2,6-dimethoxyphenol (64 M-1),38 1-hydroxy-2,2,6,6tetramethylpiperidine (2.66 M-1),39 and 1,1,1,3,3,3-hexafluoropropan-2-ol (33,000 dm3 mol-1).40 In an effort to aid in the design of a superior system, the binding constants were correlated with Hammett parameters (σ).41 A strong correlation with the Hammett parameters was observed, with more negative Hammett parameters favoring tighter binding. With this in mind, the dimethylamino group (σp = –0.83)41 was incorporated para to the pyridyl nitrogen, and 4dimethylaminopyridine (DMAP) was tested as the acceptor for BEZA in solution. The 1:1 model showed a systematic variation in the residuals (Figure S18),36,42 so other composite models were investigated. Ultimately, a model that also includes a second molecule of DMAP binding to BEZA was found to fit the data (eq. 1 and 2, Figures 2, S19). The second molecule of DMAP likely binds with the amide hydrogen of BEZA. Consistent with extrapolation from the Hammett plot (Figure S20), DMAP exhibited the largest binding constant of all the pyridines


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studied. Notably, the binding constant (K1) between DMAP and BEZA is over 18 times higher than the other drug-acceptor pairs.

Figure 2. Speciation diagram from titration of BEZA with DMAP fitted to a 1:1 and 1:2 composite binding model, monitored at 304 nm. Hashed line is BEZA, solid line is 1:1 complex, dotted line is 1:2 complex. BEZA·Pyr + Pyr ⇌ BEZA·Pyr2

K2

(2)

To determine if this tighter binding of BEZA to DMAP translated into measurable differences in the solid state, single crystals were grown. Slow evaporation of a nitromethane solution of the two components (2:1 BEZA:DMAP) yielded single crystals suitable for X-ray diffraction within three days. Single-crystal X-ray diffraction and 1H NMR spectroscopy revealed the components in the co-crystal BEZA·DMAP to be present in a 1:1 ratio. Similar to the other four co-crystals, COO-H···N hydrogen bonds between the acid and pyridine were also used to direct the assembly of BEZA·DMAP, as well as N-H···O hydrogen bonds between the amide groups [O···N and N···O separations, respectively (Å): 2.529(2), 2.809(2)] (Figure 3a, b). The syn conformation of the acid group is also observed in the BEZA·DMAP co-crystal. The solution state 1H NMR spectrum of the co-crystal indicated slight


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shifts in the peaks for the hydrogen atoms nearest to the COO-H···N hydrogen bond interaction (Figures S8, S13), consistent with the solution binding observed by UV/Vis spectroscopy. Importantly, the hydrogen bond between the acid of BEZA and pyridyl nitrogen of DMAP is noticeably shorter (ca 0.1 Å) than in the other four co-crystals. The amide chain within the BEZA·DMAP co-crystal is similar to the other four co-crystals, but adjacent BEZA molecules lie slightly slanted, and the chains extend along the crystallographic c-axis (Figure 3b). Due to the unsymmetrical nature of DMAP and 1:1 binding with BEZA, neighboring DMAP molecules stack in offset, face-to-face pairs. This stacking motif is similar to other hydrogen-bonded co-crystals involving DMAP.43,44 The π-π stacking distance between DMAP molecules in the BEZA·DMAP co-crystal is over 1.1 Å shorter than any bipyridine co-crystals [π centroid-π centroid: 4.47 Å] (Figure 3c). The bonding between BEZA and DMAP in both the solution and solid state is stronger than any other donor-acceptor pair. In addition to the Hammett parameter correlation discussed above, DMAP has been demonstrated to exhibit stronger binding when compared to pyridine and its derivatives.37,39,45 Moreover, the higher basicity of DMAP (pKa = 9.2) compared to the pyridines used here (pKa values ~ 4.2-5.4) also supports our observation of stronger bonding.


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Figure 3. X-ray crystal structure of BEZA·DMAP highlighting: (a) asymmetric unit, (b) hydrogen-bonded chain, and (c) π-π stacking. Hydrogen bonds shown with green dashed lines. In summary, we have synthesized the first co-crystals of BEZA using molecules containing only hydrogen-bond acceptor motifs. Solution-state binding studies were used to provide insight into the extent of molecular recognition between the drug and acceptor in solution. From both the crystallographic and solution-state studies, it is apparent that DMAP engages in stronger hydrogen-bonding interactions with BEZA than any of the other pyridyl acceptors that were utilized. Incorporation of DMAP-type motifs into contaminant-removing materials (e.g. membranes) may result in successful bonding; however, use of stronger intermolecular interactions (i.e. ionic)23,46 will likely increase removal efficiency. We are currently investigating alternative motifs that can engage in intermolecular bonds with pharmaceutical contaminants.


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ASSOCIATED CONTENT Supporting Information Materials and co-crystallization experiments, single-crystal X-ray diffraction data and structures, 1

H NMR data, and solution-state binding data. (PDF)

Accession Codes CCDC 1842557−1842561 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. AUTHOR INFORMATION Corresponding Author Email: [email protected] Email: [email protected] Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes ACKNOWLEDGMENT AFC and KMH gratefully acknowledge financial support from Texas Tech University.


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ABBREVIATIONS BEZA, bezafibrate; BPEth, 1,2-bis(4-pyridyl)ethane; DMAP, 4-dimethylaminopyridine; BPE, 1,2-bis(4-pyridyl)ethylene; 4,4′-AP, 4,4′-azopyridine; BIPY, 4,4′-bipyridine; UV/Vis, ultraviolet-visible spectroscopy. REFERENCES (1) Arnnok, P.; Singh, R. R.; Burakham, R.; Pérez-Fuentetaja, A.; Aga, D. S. Selective Uptake and Bioaccumulation of Antidepressants in Fish from Effluent-Impacted Niagara River. Environ. Sci. Technol. 2017, 51, 10652-10662. (2) Richardson, S. D.; Kimura, S. Y. Water Analysis: Emerging Contaminants and Current Issues. Anal. Chem. 2016, 88, 546-582. (3) Reemtsma, T.; Berger, U.; Arp, H. P. H.; Gallard, H.; Knepper, T. P.; Neumann, M.; Quintana, J. B.; de Voogt, P. Mind the Gap: Persistent and Mobile Organic Compounds Water Contaminants That Slip Through. Environ. Sci. Technol. 2016, 50, 10308-10315. (4) Bizarro, C.; Ros, O.; Vallejo, A.; Prieto, A.; Etxebarria, N.; Cajaraville, M. P.; OrtizZarragoitia, M. Intersex condition and molecular markers of endocrine disruption in relation with burdens of emerging pollutants in thicklip grey mullets (Chelon labrosus) from Basque estuaries (South-East Bay of Biscay). Mar. Environ. Res. 2014, 96, 19-28. (5) Vajda, A. M.; Barber, L. B.; Gray, J. L.; Lopez, E. M.; Woodling, J. D.; Norris, D. O. Reproductive Disruption in Fish Downstream from an Estrogenic Wastewater Effluent. Environ. Sci. Technol. 2008, 42, 3407-3414. (6) Bui, X. T.; Vo, T. P. T.; Ngo, H. H.; Guo, W. S.; Nguyen, T. T. Multicriteria assessment of advanced treatment technologies for micropollutants removal at large-scale applications. Sci. Total Environ. 2016, 563-564, 1050-1067. (7) Benner, J.; Helbling, D. E.; Kohler, H.-P. E.; Wittebol, J.; Kaiser, E.; Prasse, C.; Ternes, T. A.; Albers, C. N.; Aamand, J.; Horemans, B.; Springael, D.; Walravens, E.; Boon, N. Is biological treatment a viable alternative for micropollutant removal in drinking water treatment processes? Water Res. 2013, 47, 5955-5976. (8) Ling, Y. H.; Klemes, M. J.; Xiao, L. L.; Alsbaiee, A.; Dichtel, W. R.; Helbling, D. E. Benchmarking Micropollutant Removal by Activated Carbon and Porous (beta-Cyclodextrin Polymers under Environmentally Relevant Scenarios. Environ. Sci. Technol. 2017, 51, 75907598. (9) Djinovic, K.; Glokar, M.; Zupet, P. Structure of Bezafibrate (2-{p-[2-(pChlorobenzamide)ethyl]phenoxy}-2-methylpropanoic Acid). Acta Crystallogr. Sect. C: Cryst. Struct. Commun. 1989, 45, 772-775. (10) Ardila-Fierro, K. J.; André, V.; Tan, D.; Duarte, M. T.; Lancaster, R. W.; Karamertzanis, P. G.; Friščić, T. Molecular Recognition of Steroid Hormones in the Solid State: Stark Differences in Cocrystallization of β-Estradiol and Estrone. Cryst. Growth Des. 2015, 15, 1492-1501. (11) Margot, J.; Rossi, L.; Barry, D. A.; Holliger, C. A review of the fate of micropollutants in wastewater treamtent plants. WIREs, Water. 2015, 2, 457-487.


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(12) There are reported X-ray structures of salts involving some of the drugs (e.g. chloride, bromide) and salt-hydrate/solvate complexes, but no neutral co-crystals. See references 13-17 for examples. To our knowledge, there are no reported X-ray structures of bezafibrate salts. (13) Lou, B. Y.; Bostrom, D.; Velaga, S. P. Hydrogen-bonding interactions in the 4aminobenzoic acid salt of atenolol monohydrate. Acta Crystallogr. Sect. C: Cryst. Struct. Commun. 2007, 63, O714-O716. (14) Khare, S. G.; Jena, S. K.; Sangamwar, A. T.; Khullar, S.; Mandal, S. K. Multicomponent Pharmaceutical Adducts of α-Eprosartan: Physicochemical Properties and Pharmacokinetic Study. Cryst. Growth Des. 2017, 17, 1589-1599. (15) Yang, Q.; Ren, T.; Yang, S.; Li, X.; Chi, Y.; Yang, Y.; Gu, J.; Hu, C. Synthesis and Pharmacokinetic Study of Three Gemfibrozil Salts: An Exploration of the Structure–Property Relationship. Cryst. Growth Des. 2016, 16, 6060-6068. (16) Cheung, E. Y.; David, S. E.; Harris, K. D. M.; Conway, B. R.; Timmins, P. Structural properties of a family of hydrogen-bonded co-crystals formed between gemfibrozil and hydroxy derivatives of t-butylamine, determined directly from powder X-ray diffraction data. J. Solid State Chem. 2007, 180, 1068-1075. (17) Ramirez, M.; David, S. E.; Schwalbe, C. H.; Asare-Addo, K.; Conway, B. R.; Timmins, P. Crystal Packing Arrangement, Chain Conformation, and Physicochemical Properties of Gemfibrozil Amine Salts. Cryst. Growth Des. 2017, 17, 3743-3750. (18) Desiraju, G. R. Crystal engineering: A brief overview. J. Chem. Sci. 2010, 122, 667-675. (19) Aakeröy, C. B.; Salmon, D. J. Building co-crystals with molecular sense and supramolecular sensibility. CrystEngComm 2005, 7, 439-448. (20) Koch, E. S.; McKenna, K. A.; Kim, H. J.; Young, V. G.; Swift, J. A. Thymine cocrystals based on DNA-inspired binding motifs. CrystEngComm 2017, 19, 5679-5685. (21) Eddleston, M. D.; Arhangelskis, M.; Fabian, L.; Tizzard, G. J.; Coles, S. J.; Jones, W. Investigation of an Amide-Pseudo Amide Hydrogen Bonding Motif within a Series of Theophylline:Amide Cocrystals. Cryst. Growth Des. 2016, 16, 51-58. (22) Allu, S.; Bolla, G.; Tothadi, S.; Nangia, A. Supramolecular Synthons in Bumetanide Cocrystals and Ternary Products. Cryst. Growth Des. 2017, 17, 4225-4236. (23) Duggirala, N. K.; Perry, M. L.; Almarsson, O.; Zaworotko, M. J. Pharmaceutical cocrystals: along the path to improved medicines. Chem. Commun. 2016, 52, 640-655. (24) Oburn, S. M.; Ray, O. A.; MacGillivray, L. R. Elusive Nonsolvated Cocrystals of Aspirin: Two Polymorphs with Bipyridine Discovered with the Assistance of Mechanochemistry. Cryst. Growth Des. 2018, 18, 2495-2501. (25) Staels, B.; Dallongeville, J.; Auwerx, J.; Schoonjans, K.; Leitersdorf, E.; Fruchart, J.-C. Mechanism of Action of Fibrates on Lipid and Lipoprotein Metabolism. Circulation 1998, 98, 2088-2093. (26) Lalloyer, F.; Staels, B. Fibrates, Glitazones, and Peroxisome Proliferator-Activated Receptors. Arterioscler., Thromb., Vasc. Biol. 2010, 30, 894-899. (27) Witte, E. C.; Stach, K.; Thiel, M.; Schmidt, F.; Stork, H.; Office, G. P. a. T. M., Ed.; Boehringer Mannheim G.m.b.H.: Germany, 1973; Vol. DE 2149070. (28) Beyer, P.; Office, G. B. P., Ed.; Boehringer Mannheim G.m.b.H., Fed. Rep. Ger.: Great Britain, 1979; Vol. GB 2021575. (29) Moersdorf, P.; Maier, P.; Schmitt, J.; Ahrens, K. H.; Organization, E. P., Ed.; Heumann Pharma G.m.b.H., Germany: 1994; Vol. EP 625504.


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(30) Lemmerer, A.; Bathori, N. B.; Esterhuysen, C.; Bourne, S. A.; Cairs, M. R. Concomitant Polymorphs of the Antihypoproteinemic Bezafibrate. Cryst. Growth Des. 2009, 9, 2646-2655. (31) Liu, J.; Dan, X.; Lu, G.; Shen, J.; Wu, D.; Yan, Z. Investigation of pharmaceutically active compounds in an urban receiving water: Occurrence, fate and environmental risk assessment. Ecotoxicol. Environ. Saf. 2018, 154, 214-220. (32) Ternes, T. A. Occurrence of drugs in German sewage treatment plants and rivers. Water Res. 1998, 32, 3245-3260. (33) Krueger, E. L.; Sinha, A. S.; Desper, J.; Aakeröy, C. B. Exploring binding preferences in co-crystals of conformationally flexible multitopic ligands. CrystEngComm 2017, 19, 46054614. (34) Patil, R. S.; Zhang, C.; Barnes, C. L.; Atwood, J. L. Construction of Supramolecular Organic Frameworks Based on Noria and Bipyridine Type Spacers. Cryst. Growth Des. 2017, 17, 7-10. (35) Ghosh, K.; Masanta, G. Anthracene-appended Pyridine Amide: A Simple Sensor for Monocarboxylic Acids. Supramol. Chem. 2005, 17, 331-334. (36) Ulatowski, F.; Dąbrowa, K.; Bałakier, T.; Jurczak, J. Recognizing the Limited Applicability of Job Plots in Studying Host–Guest Interactions in Supramolecular Chemistry. J. Org. Chem. 2016, 81, 1746-1756. (37) Kazakov, O. I.; Datta, P. P.; Isajani, M.; Kiesewetter, E. T.; Kiesewetter, M. K. Cooperative Hydrogen-Bond Pairing in Organocatalytic Ring-Opening Polymerization. Macromolecules 2014, 47, 7463-7468. (38) Kumar, P. H.; Venkatesh, Y.; Prashanthi, S.; Siva, D.; Ramakrishna, B.; Bangal, P. R. Diffusive and non-diffusive photo-induced proton coupled electron transfer from hydrogen bonded phenols to meso-tetrakis-5,10,15,20-pentafluorophenyl porphyrin. Phys. Chem. Chem. Phys. 2014, 16, 23173-23181. (39) Morris, W. D.; Mayer, J. M. Separating Proton and Electron Transfer Effects in ThreeComponent Concerted Proton-Coupled Electron Transfer Reactions. J. Am. Chem. Soc. 2017, 139, 10312-10319. (40) Demeter, A.; Mile, V.; Bérces, T. Hydrogen Bond Formation between 4(Dimethylamino)pyridine and Aliphatic Alcohols. J. Phys. Chem. A 2007, 111, 8942-8949. (41) Laurence, C.; Brameld, K. A.; Graton, J.; Le Questel, J.-Y.; Renault, E. The pKBHX Database: Toward a Better Understanding of Hydrogen-Bond Basicity for Medicinal Chemists. J. Med. Chem. 2009, 52, 4073-4086. (42) Thordarson, P. Determining association constants from titration experiments in supramolecular chemistry. Chem. Soc. Rev. 2011, 40, 1305-1323. (43) Mukherjee, A.; Grobelny, P.; Thakur, T. S.; Desiraju, G. R. Polymorphs, Pseudopolymorphs, and Co-Crystals of Orcinol: Exploring the Structural Landscape with High Throughput Crystallography. Cryst. Growth Des. 2011, 11, 2637-2653. (44) Mir, N. A.; Dubey, R.; Tothadi, S.; Desiraju, G. R. Combinatorial crystal synthesis of ternary solids based on 2-methylresorcinol. CrystEngComm 2015, 17, 7866-7869. (45) Zhao, H.; Reibenspies, J. H.; Gabbaï, F. P. Lewis acidic behavior of B(C6Cl5)3. Dalton Trans. 2013, 42, 608-610. (46) Duggirala, N. K.; Wood, G. P. F.; Fischer, A.; Wojtas, Ł.; Perry, M. L.; Zaworotko, M. J. Hydrogen Bond Hierarchy: Persistent Phenol···Chloride Hydrogen Bonds in the Presence of Carboxylic Acid Moieties. Cryst. Growth Des. 2015, 15, 4341-4354.


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For Table of Contents Use Only Co-crystallization of the Anti-Cholesterol Drug Bezafibrate: Molecular Recognition of a Pharmaceutical Contaminant in the Solid State and Solution via Hydrogen Bonding Jesus Daniel Loya, Jinchun Qiu, Daniel K. Unruh, Anthony F. Cozzolino* and Kristin M. Hutchins*

The first successful co-crystallizations of the anti-cholesterol medication and wastewater contaminant, bezafibrate, are described. Solution-state binding studies with potential acceptor molecules are also performed. Once drug-acceptor pair exhibits a shorter intermolecular bond in the crystalline state and a solution-state binding constant over 18 times higher than any other pair studied.


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Co-Crystallization of the Anti-Cholesterol Drug Bezafibrate: Molecular

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