Article pubs.acs.org/crystal
Evidence of Weak Halogen Bonding: New Insights on Itraconazole and its Succinic Acid Cocrystal Nonappa,*,†,∥ Manu Lahtinen,*,‡ Erkki Kolehmainen,† Jorma Haarala,§ and Anna Shevchenko§ †
University of Jyväskylä, Department of Chemistry, Laboratory of Organic Chemistry, P.O. Box 35, FI-40014, Finland University of Jyväskylä, Department of Chemistry, Laboratory of Inorganic and Analytical Chemistry, P.O. Box 35, FI-40014, Finland § Orion Corporation, Orionintie 1A, 02200 Espoo, P.O. Box 65, FI-02101 Espoo, Finland ‡
S Supporting Information *
ABSTRACT: Exact knowledge of the crystal structure of drugs and lead compounds plays a significant role in the fields of crystal engineering, docking, computational modeling (drug−receptor interactions), and rational design of potent drugs in pharmaceutical chemistry. The succinic acid cocrystal of the systemic antifungal drug, itraconazole, reported by Remenar et al. (J. Am. Chem. Soc. 2003, 125, 8456−8457) (CSD: IKEQEU), represents one of the classical examples displaying a molecular fitting mechanism in the solid state. In this work, we disclose the X-ray single-crystal structure of the cis-itraconazole−succinic acid (2:1) cocrystal and found that it differs slightly from the previously reported structure by the location of the elements (C, H, and N) in the 1,2,4-triazol-5-one ring. By making use of the new solid-state structure, we have also applied an enhanced disorder model, which, in turn, uncovered the intriguing halogen bond (XB) interactions (0.86 × van der Waals distance of C−Cl···N), which were previously unnoticed. Furthermore, the crystal structure of cis-itraconazole reported by Peeters et al. (Acta Crystallogr. 1996, C52, 2225−2229) (CSD: TEHZIP) is also revisited. For the structure of neat cis-itraconazole, new low-temperature as well as a revised ambient temperature (0 °C) X-ray single crystal structures with new disorder models are described. More importantly, a weak halogen bonding interaction (0.9 × van der Waals distance of C− Cl···O) has now been perceived in this structure. The XB contacts remained without consideration in the original report primarily due to the lack of its recognition, at that time. In addition to these new findings, solid-state NMR and the thermoanalytical properties were examined by thermogravimetric analysis and differential scanning calorimetry.
1. INTRODUCTION Cocrystals of active pharmaceutical ingredients (API) have emerged as an attractive area of crystal engineering. 1 Pharmaceutical cocrystals owing to their unique ability to alter physical and chemical properties have been shown to increase the bioavailability of poorly water-soluble drugs.2 This single-crystalline homogeneous phase with two or more components has gained tremendous attention lately as an alternative in drug formulation. The components of a cocrystal are neutral compared to salts and are present in a definite stoichiometric ratio that is self-assembled via noncovalent interactions, such as H-bonding, π-stacking, van der Waals interactions, and, more recently found, halogen bonding interactions.3 By utilizing the knowledge and principle of complementarity in building suitable host−guest materials, several cocrystals of APIs have been reported in the literature and are shown to possess superior properties compared to the native crystalline form.4 Itraconazole 1 (Figure 1), on the other hand, is an antifungal drug invented by Janssen Pharmaceutica in 1984 and has the commercial name Sporanox.5 Very recently, it has been demonstrated that itraconazole acts as a potent antagonist of the hedgehog (Hh) signaling pathway and prevents the cancer growth.6 In their work, Rudin et al. © 2012 American Chemical Society
successfully demonstrated the unique antiangiogenesis properties of itraconazole and inhibition of tumor growth in nonsmall lung cancer cells.7 In another related work, Liu and co-workers have shown that itraconazole inhibits vascular endothelial growth factor receptor 2 (VEGFR2) glycosylation, trafficking, and signaling in endothelial cells.8 These properties of itraconazole prompted researchers from various fields to study structure property relationships, such as the impact of side chain structure and absolute stereochemistry on its biological activities.9 The first crystal structure of this prominent drug molecule (cis-itraconazole) was reported in 1996 by Peeters et al.10 In 2003, Remenar et al. prepared its cocrystals with a number of dicarboxylic acids and successfully demonstrated the improved water solubility of cocrystals.5,11 The supramolecular trimer of the itraconazole-succinic acid 2 (Figure 1) has been considered as an excellent example for a molecular fitting mechanism in crystal engineering and displayed significantly enhanced water solubility compared to that of the parent drug.11 However, during the course of our Received: October 18, 2012 Revised: November 19, 2012 Published: December 5, 2012 346
dx.doi.org/10.1021/cg3015282 | Cryst. Growth Des. 2013, 13, 346−351
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studies, including a combined single-crystal and powder X-ray diffraction, thermoanalytical methods (DSC, TGA), and solidstate NMR of cis-itraconazole 1 and the itraconazole−succinic acid cocrystal 2 (Figure 1). The new structure models were determined for both compounds, which unambiguously show the existence of halogen bonding between C−Cl···O and C− Cl···N in itraconazole 1 and the cocrystal 2, respectively. In this respect, this work provides useful new insights into an everincreasing prominent pharmaceutical.
2. RESULTS AND DISCUSSION In the course of our investigations on cis-itraconazole and its cocrystals, we noticed small discrepancies between the experimental X-ray powder diffraction patterns (Supporting Information, Figure S1) and the simulated powder pattern (from the CSD database), in addition to a wrong definition of atoms on the triazolone ring of 2, as mentioned above. This prompted us to undertake a detailed investigation of the structure properties of both compounds. Accordingly, the racemic cis-itraconazole 1 was recrystallized from dimethyl sulfoxide, and the quality single crystals obtained were used for single-crystal X-ray analysis. Similarly, the itraconazole−succinic acid cocrystal 2 was prepared by dissolving in a 2:1 molar ratio (itraconazole-succinic acid) in 10/2/1 (v/v/v) of 1,2-dichloroethane/ethyl acetate/1,4-dioxane. The single crystals of the cocrystals were obtained within 8 h, and several of them were subjected for the single-crystal X-ray analysis. The same crystallization batch was used for solid-state 13C and 15N CPMAS NMR as well as X-ray powder diffraction studies. On the basis of the literature, the previously reported crystal structures of 1 and 2 were obtained at 20 and −173 °C, respectively.10,11 In general, both structure models in the original reports are reasonable, with sufficient quality indicators (although cocrystal 2 has a slightly high R value; R1 = 0.0925), correct unit cell and space group settings, which are also consistent with that obtained for now reported structure revisions. However, for neat itraconazole 1, it can be assumed that, due to limitations in the instrumentation performance, generally accessible in the mid 90s (e.g., no cooling used) along with typically ungrateful crystal shapes of itraconazole (thin plates), a somewhat limited data range had been achieved (sin θ/λ = 0.54), in contrast to nowadays routines (typically, sin θ/λ > 0.59). A careful inspection of the crystal structure of 2 (CSD: IKEQEU) revealed chemical inconsistencies, due to unfortunate misplacing or a wrong definition of the elements (C−H, N) in the 2,4-dihydro-3H-1,2,4-triazol-5-one ring, which, in turn, generated a few artificial/false interactions (Figure 2c; see the Supporting Information for the structure at 0 °C). Moreover, the disorder model described in the literature handled only the sec-butyl groups without considering the tilt of triazolone ring as part of the disorder model (Supporting Information, Figure S2c,d). Therefore, the existence of weak intermolecular XB (C−Cl···N and C−Cl···O) contacts remained undisclosed in the original reports. To match up to the correct chemical composition of the triazolone ring in cocrystal 2, the element types have now been properly defined in the new structure model. Second, the enhanced disorder model is suggested for both compounds along with a proper interpretation of the intermolecular interactions resulting from it (Figure 2; the Supporting Information for structures at 0 °C, Figure S2). The crystallographic data reported in this work, as well as the selected
Figure 1. Chemical structure of itraconazole (1) and itraconazole− succinic acid cocrystal (2).
investigations on itraconazole and its succinic acid cocrystal, we have noticed that the crystal structure model of 2 reported in the literature (CSD:12 IKEQEU),11 has its carbon, hydrogen, and nitrogen atoms wrongly placed in the 1,2,4-triazol-5-one ring. Furthermore, structural inspection of the neat itraconazole 1 itself (CSD entry: TEHZIP)10 revealed that the structure has been determined at room temperature (RT) with limited resolution for today's needs. In addition, the disorder model describing sec-butyl groups seemed a bit unusual. All of these aspects prompted us to undertake a detailed investigation of the neat itraconazole and the cocrystal forms particularly, as, in general, an erroneous crystal structure of a compound may lead to false interpretations due to artificial interactions, unusual bond distances, and/or impossible intra- and intermolecular nonbonded contacts.13 In turn, the real interactions present in a crystal system may remain undiscovered without proper knowledge of the correct crystal structure. All of these ambiguities may, in later stages, be costly and lead to a number of problems in drug discovery as eventually the solid-state structures of the lead compounds are used for crystal engineering and docking studies, wherein the incorrect definition of an atom will induce incorrect donor and acceptor properties of heteroatoms and may lead to serious docking errors.14 For example, in the work of Watson and Crick, wrong tautomeric forms (enol forms) were originally assigned for the nucleic acid bases, and thus a helical model with purine−pyrimidine hydrogen-bonded base pairs failed to build. Later, with the proper tautomeric structures (keto forms) of the bases, all the important features of the three-dimensional structure of double-helical DNA were readily determined.15 Halogen bonding, on the other hand, gained considerable interest in the field of crystal engineering and supramolecular chemistry over the last two decades.3 The new understanding and potential applications of halogen bonding in molecular recognition, separation science, and nonlinear optical materials (NLO) continued to evolve rapidly.16 According to a provisional recommendation released by the International Union of Pure and Applied Chemistry (IUPAC), “halogen bond R-X···Y-Z occurs when there is evidence of a net attractive interaction between an electrophilic region of a halogen atom X belonging to a molecular f ragment (R-X) and a nucleophilic region of another molecule or f ragment (Y-Z)”.16 Herein, we present our 347
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Figure 2. (a) Asymmetric unit of 1 showing two crystallographically distinct conformations of the itraconazole molecules. (b) Overlay of two nonequivalent molecules in an asymmetric unit and (c) trimeric packing (2 times asymmetric unit) of 2. For 1 and 2, pivotally tilted disorder through N38 and C39 atoms of 1,2,4-triazol-5-one and the sec-butyl group is shown with yellow color. Thermal ellipsoids are shown at the 50% probability level.
ketone (PTK), 2-(4-chlorophenyl)-5-fluoro-3-methylsulfinyl-1benzofuran, and 2-chloro-5-nitropyrimidine.19 The crystallographic inspection of the racemic cis-itraconazole 1 revealed that it crystallizes in the triclinic crystal system showing two conformationally distinct molecules in the asymmetric unit (Figure 2b). The main difference between the conformations A and B lies on their methoxyphenylpiperazine moiety that is tilted in the B conformation nearly 90°, in contrast to the phenyl ring adjacent to a piperazine. It can also be noted that the geometries of various homo- and heterocyclic rings in the structure are consistent with that reported earlier (folded dioxolane, chairlike piperazine). The presence of two nonequivalent molecules in an asymmetric unit is also evident
parameters of the previously reported structures, are gathered in Table S1 (Supporting Information). New interpretations of intermolecular interactions are also constructed for the neat itraconazole 1. Most importantly, the existence of weak halogen bond contacts (C−Cl···O) are now evidenced, which otherwise remained without consideration in the original report, mainly due to lack of its recognition at that time. To evaluate the frequency of chlorine-based halogen bonding with either oxygen or nitrogen as XB acceptors, the CSD searches were made.17,18 The C−Cl···O contacts were found to be far more frequent (>1200 hits) in contrast to the C−Cl···N (
