Virtual Screening Identifies New Cocrystals of Nalidixic Acid

Article pubs.acs.org/crystal

Virtual Screening Identifies New Cocrystals of Nalidixic Acid Tudor Grecu,† Harry Adams,† Christopher A. Hunter,*,† James F. McCabe,‡ Anna Portell,§ and Rafel Prohens§ †

Department of Chemistry, University of Sheffield, Sheffield S3 7HF, U.K. AstraZeneca, Silk Road Business Park, Macclesfield, Cheshire SK10 2NA, U.K. § Unitat de Polimorfisme i Calorimetria, Centres Cientı ́fics i Tecnològics, Universitat de Barcelona, 08028 Barcelona, Spain ‡

S Supporting Information *

ABSTRACT: Formulation of solids as cocrystals offers an opportunity to modulate physical properties, so identification of cocrystal formers (CCFs) for an active pharmaceutical ingredient is an area of significant interest. Exhaustive experimental screening would be time-consuming, but we have developed a computational method for identifying CCFs that have a high chance of success based on calculated functional group interaction energies. This virtual screening tool has been applied to nalidixic acid cocrystals. Calculations on a library of 310 compounds identified the 44 most promising CCFs for formation of nalidixic acid cocrystals. Six of these compounds were already known to form cocrystals, and experimental work was undertaken on the remaining 38 compounds. X-ray powder diffraction (XRPD) of mixtures obtained from grinding experiments identified seven CCFs that form new solid phases with nalidixic acid. Infrared spectroscopy and differential scanning calorimetry confirm that these new solid phases are different from the pure components. Further structural characterization was not possible for the skatole, 2,4-dihydroxybenzoic acid, and 3,4-dihydroxybenzoic acid cocrystals, but X-ray crystal structures were obtained from single crystals of the 1:1 tert-butylhydroquinone cocrystal and of the 1:1 propyl gallate cocrystal and from the XRPD pattern for the 1:1 2-phenylphenol cocrystal and for the 1:2 indole cocrystal. The results suggest that success rates in cocrystal screening can be significantly improved by application of computational filters to select the most appropriate CCFs for experimental study.

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INTRODUCTION Active pharmaceutical ingredients (APIs) can be developed in a variety of solid forms: polymorphs, solvates, hydrates, salts, and cocrystals.1 Formulation as a cocrystal provides a potential method for improving biopharmaceutical properties such as solubility, dissolution rate, stability, and hydroscopicity.2,3 Cocrystal development therefore has important implications in the pharmaceutical intellectual property landscape.4 The Center for Drug Evaluation and Research of the Food and Drug Administration (FDA) has recently released the latest regulatory classification of pharmaceutical cocrystals: a cocrystal is a dissociable API-excipient complex classified as a drug product intermediate that can improve drug performance.5 The huge number of potential cocrystal formers (CCFs) that could be used to develop pharmaceutically acceptable cocrystals means that predictive tools for identifying the most likely cocrystallization candidates for a given API are valuable in focusing experimental cocrystal screens. Methods for cocrystal design are structure-based or energy-based. One structurebased approach uses design strategies based on supramolecular synthons identified from analyses of the Cambridge Structural Database (CSD).6 For example, carboxylic acids show a strong preference for interactions with nitrogen H-bond acceptors (heterosynthon) as opposed to formation of the carboxylic acid dimer (homosynthon).7 An alternative approach is based on statistical analysis of the properties of molecules that are © 2014 American Chemical Society

observed to form cocrystals in the CSD, and a complementarity measure based on a range of different molecular descriptors has been developed for prediction of cocrystal formation.8,9 First-principles calculation of the lattice energies of solids has been used to investigate cocrystal formation based on the energy difference between the cocrystal and the two pure solid forms.10 Such calculations are challenging, because they require prediction of the crystal structure, the energy differences between cocrystal and components are usually small, and significant computational resources would be required for implementation in high-throughput screening.11 In a recent blind test, only two groups out of the participating 14 correctly predicted the experimental structure of a cocrystal.12 Nevertheless, the crystal structure prediction approach has been used to rationalize the results of an experimental screen for cocrystals of succinic acid and 4-aminobenzoic acid.13 If the solid state is treated as a supercooled liquid, the need for crystal structure prediction is avoided, and the probability of cocrystal formation can be calculated on the basis of the difference in excess enthalpy between the cocrystal and the pure components.14 A better high-throughput method is based on Hansen solubility parameters, which can be used to predict the miscibility of two Received: December 18, 2013 Revised: February 24, 2014 Published: March 13, 2014 1749

dx.doi.org/10.1021/cg401889h | Cryst. Growth Des. 2014, 14, 1749−1755

Crystal Growth & Design

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for each CCF−nalidixic acid combination using eqs 1 and 2, and the CCFs were ranked in order of decreasing ΔE. Materials. Nalidixic acid and the 38 CCFs selected for experimental screening were purchased from Sigma-Aldrich and used without further purification. Analytical grade solvents were used for crystallization experiments: chloroform, dichloromethane, chlorobenzene, acetonitrile, acetone, toluene, ethanol, methanol, n-hexane, and n-heptane. Grinding Experiments. A weighed amount of nalidixic acid (20− 30 mg) and either 0.5, 1.0, or 2.0 equiv of the CCF were combined in a 5 mL stainless steel grinding jar containing a 7 mm diameter grinding ball. In liquid-assisted grinding experiments, 30 μL of ethanol or nheptane was also added. The mixtures were ground on a Retsch MM 200 mixer mill for 45 min at 25 Hz. X-ray Powder Diffraction (XRPD) Measurements. Powder samples were mounted on a silicon wafer mount. These were analyzed on a PANalytical CubiX PRO diffractometer with a copper long-fine focus tube running at 45 kV and 40 mA (λ = 1.5418 Å). Samples were measured in reflection geometry in the θ−2θ configuration over a scan range from 2° to 40° 2θ with 1.9 s exposure per 0.0025° increment. Infrared Spectroscopy (IR). IR spectra were recorded with a universal ATR sampling accessory on a Perkin-Elmer Spectrum 100 Fourier transform spectrophotometer over a range from 400 to 4000 cm−1 with a resolution of 1 cm−1 (eight scans). The spectra were processed with the Spectrum v 10.03.07 software. Differential Scanning Calorimetry (DSC). DSC measurements were performed using a TA Instruments model Q 1000 version 5.4.0 calorimeter. A 1−3 mg portion of the mixtures obtained from the grinding experiments was weighed and loaded into an aluminum sample pan fitted with a lid. Samples were equilibrated at 25 °C and then heated to 240 °C at a rate of 10 °C min−1. Single Crystal Structure Determination. Slow evaporation experiments were attempted using a range of solvents and binary solvent mixtures (chloroform, dichloromethane, chlorobenzene, acetonitrile, acetone, toluene, ethanol, methanol). A weighed amount of nalidixic acid (10−20 mg) was dissolved in the solvent, and the corresponding amount of CCF required to give a 1:1, 1:2, or 2:1 stoichiometry was added. The solution was filtered through cotton wool into a clean glass vial. The vial was covered with a perforated lid, and the solvent was allowed to evaporate under ambient conditions or in a refrigerator at 2 °C. Seeded crystallizations were performed in the same way, except that a seed of the cocrystal obtained from the grinding experiments was added to the crystallization vial. High-quality single crystals of nalidixic acid cocrystals of tert-butylhydroquinone and propyl gallate were obtained in this way. Crystals suitable for X-ray crystallography were selected using an optical microscope and examined at 100 K on a Bruker SMART APEX-II CCD diffractometer operating with a Mo Kα sealed tube Xray source. The structures were solved using SHELXL-97 and refined using WinGX V1.64.05.23,24 All non-hydrogen atoms were refined anisotropically. Hydrogen atoms were found on the Fourier difference map and were included in the refinement process. Simulated powder diffraction patterns were calculated from the final crystal structures using Mercury. XRPD Structure Determination. A Panalytical X’Pert PRO MPD instrument was used in the capillary configuration and transmission geometry with an elliptic mirror and PIXcel detector working at a maximum detector active length of 3.347° 2θ. Cu Kα1+2 radiation (λ = 1.5418 Å, operating at 45 kV and 40 mA) was selected with 0.01 and 0.02 rad Soller slits. Samples were placed in 0.5 or 0.7 mm diameter Lindemman capillaries and were measured from 2° to 70° 2θ with a step size of 0.013° and a data collection time of 16 h. The XRPD pattern was indexed using DICVOL04 to determine the unit cell and space group.25 A Le Bail fit of the data using FullProf was used to confirm the space group, refine the unit cell and determine the shape parameters.26 The background was set by manually selecting a set of points across the XRPD pattern. For each component of the cocrystal, the structure was drawn in Spartan, energy-minimized using molecular mechanics, and exported as a pdb file.27 The pdb files were converted to Fenske−Hall Z matrices using OpenBabel.28 The

compounds. Calculations on the miscibility of indomethacin and 33 potential CCFs correctly identified two new indomethacin cocrystals.15 We have developed a virtual cocrystal screening tool to predict the probability of cocrystal formation,16 and this method has been validated using data on 18 experimental cocrystal screens from the literature. The difference between the energy of the cocrystal and that of the pure components was used to rank CCFs, and CCFs that were found to form cocrystals experimentally were significantly enriched at the top of the ranked list in most cases.17 This approach uses surface site interaction points (SSIPs) calculated from the ab initio molecular electrostatic potential surface (MEPS) of the isolated molecule in the gas phase.18 The interaction of a molecule with its environment is described by a discrete set of SSIPs, each represented by an interaction parameter, εi, which is positive for a H-bond-donor site (or positive region on the MEPS) and negative for a H-bond-acceptor site (or negative region on the MEPS). The energy of interaction between two SSIPs, i and j, is given by the product εiεj. We assume that pairwise interactions between SSIPs are optimized in a solid, and this provides a method for evaluating the interaction site pairing energy of a solid without knowledge of the crystal structure.19 The most positive SSIP is paired with the most negative SSIP, the next most positive SSIP with the next most negative, and so on, giving a hierarchical list of interactions.20 This interaction site pairing strategy provides a straightforward method for estimating the energy of a solid, E (eq 1). The same approach can be used to estimate the energy of a cocrystal, and the difference between the interaction site pairing energies of the cocrystal and the pure components, ΔE, can be used to estimate the probability of cocrystal formation (eq 2) E=

∑ εiεj

ΔE = −(Ecc − E1 − E2)

(1) (2)

where E1, E2, and Ecc are the interaction site pairing energies of the pure solids, 1 and 2, and a cocrystal, respectively. Note that this definition means that ΔE is always positive, and a large value indicates a high probability of cocrystal formation. To date, this approach has only been used to reproduce experimental observations, but here we apply the method predictively to obtain new cocrystals. In our previous work, the cocrystal prediction tool performed extremely well on nalidixic acid: the six CCFs that were found to form cocrystals with nalidixic acid in an experimental screen were the top six CCFs when the compounds were ranked on the basis of calculated ΔE values. On the basis of these results, nalidixic acid was chosen as a promising candidate for application of the cocrystal prediction tool to identify new cocrystals, and in this paper, we describe successful characterization of four new nalidixic acid cocrystals.

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EXPERIMENTAL SECTION

Virtual Cocrystal Screen. For each compound, the molecule was drawn in an extended conformation and energy-minimized using the molecular mechanics methods implemented in TorchLite.21 Gaussian 09 was used to optimize the geometry and calculate the MEPS on the 0.002 Bohr Å−3 electron density isosurface using DFT and a B3LYP/631G* basis set.22 The MEPS was converted into SSIPs using in-house software.18b The difference between the interaction site pairing energies of the 1:1 cocrystal and the pure components was calculated 1750



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Figure 1. (a) The chemical structure of nalidixic acid. (b) The DFT MEPS (red is negative and blue is positive). (c) The SSIP representation (red is negative and blue is positive, and the size of the sphere is proportional to εi). structure of the cocrystal was solved using the parallel tempering algorithm implemented in FOX with the aromatic rings constrained to be rigid.29 Several runs, each of 10−20 million trials, were performed, and the best resulting structure was used as the basis for subsequent Rietveld refinement with Fullprof. For the nalidixic acid−2-phenylphenol cocrystal, the Le Bail fit gave Rwp = 6.57%, Rp = 1.09%, and the Rietveld refinement (2θ range 2.02°−69.98°, 5229 profile points) gave Rwp = 10.42%, Rp = 1.74%. For the nalidixic acid−indole cocrystal, the Le Bail fit gave Rwp = 7.51%, Rp = 1.08%, and the Rietveld refinement (2θ range 2.02°− 69.98°, 5229 profile points) gave Rwp = 12.4%, Rp = 1.79%.

1:1 mixtures of nalidixic acid and each of the CCFs. Four of the CCFs (2-phenylphenol, indole, skatole, and xylenol) were too soluble for LAG, so neat grinding was used for these systems. In all cases, the resulting solids were analyzed using powder X-ray diffraction (XRPD), which readily distinguishes physical mixtures from new solid phases.34 A difference between the XRPD patterns of a 1:1 mixture and the two pure components indicates formation of a new solid phase. Figure 2 shows an example of the XRPD data for nalidixic acid and tertbutylhydroquinone. The XRPD peaks observed for the two pure components are not present in the XRPD pattern of the 1:1 mixture following LAG. Although the new XRPD pattern is good evidence for formation of a nalidixic acid−tertbutylhydroquinone cocrystal, a solvate or polymorph would also produce a new XRPD pattern. There are three known polymorphs of nalidixic acid. The XRPD patterns obtained for the pure nalidixic samples correspond to form I, which is the most stable polymorph.32 XRPD patterns obtained for the nalidixic acid−CCF mixtures showed no signs of the other two nalidixic acid polymorphs. To eliminate solvates, the pure components were also subjected to LAG, but no evidence of solvate formation was detected in the resulting XRPD patterns. We conclude, therefore, that differences in the XRPD patterns, as illustrated in Figure 2, indicate cocrystal formation. The 1:1 grinding experiments identified seven CCFs that formed a new solid phase with nalidixic acid: tertbutylhydroquinone, propyl gallate, 2-phenylphenol, indole, skatole, 2,4-dihydroxybenzoic acid, and 3,4-dihydroxybenzoic acid (Figure 3). The 1:1 mixtures of nalidixic acid and tertbutylhydroquinone, propyl gallate, 2-phenylphenol, and 3,4dihydroxybenzoic acid all gave XRPD patterns of a new solid phase, and peaks corresponding to the pure components were absent. The other three nalidixic acid−CCF mixtures gave XRPD patterns that contained peaks from the pure components as well as peaks from the new solid phase. In an effort to obtain samples that contained only the new solid phase, the LAG experiments were repeated using 1:2 and 2:1 nalidixic acid−CCF mixtures. This was successful for 1:2 nalidixic acid−indole and 1:2 nalidixic acid−skatole mixtures, but the XRPD data for the nalidixic acid−2,4-dihydroxybenzoic acid system still showed peaks from the pure components. Cocrystal Characterization. The seven new cocrystal samples were analyzed by solid-state infrared spectroscopy (IR). A difference between the IR spectrum of a cocrystal and the IR spectra of the two pure components provides further evidence for cocrystal formation, and changes in the frequency of the signals can be diagnostic of the formation of new Hbonding interactions. Figure 4 shows an example of the IR spectra of nalidixic acid (blue), tert-butylhydroquinone (red), and the cocrystal (green). The carbonyl stretch at 1710 cm−1 in

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RESULTS AND DISCUSSION Virtual Cocrystal Screen. A total of 310 potential CCFs were chosen from the GRAS (Generally Regarded as Safe) and EAFUS (Everything Added to Food in the United States) lists (see the Supporting Information).30,31 SSIPs were calculated for nalidixic acid and each of the 310 CCFs using methods described previously.18b The procedure is illustrated for nalidixic acid in Figure 1. The molecular structure was drawn and energy-minimized using molecular mechanics, and the MEPS was calculated using quantum mechanics (Figure 1b). This surface was footprinted to give the set of SSIPs shown in Figure 1c. The intermolecular interaction properties of nalidixic acid are dominated by the strong H-bond-acceptor sites around the carbonyl groups (large red spheres). In the conformation shown (which is the same as the conformation in the CSD), the carboxylic acid H-bond donor is not accessible, because it is involved in an intramolecular H-bond with the neighboring carbonyl oxygen. Similarly, the pyridine H-bond acceptor is not accessible due to the steric hindrance of the flanking alkyl groups. Figure 1 suggests that CCFs that are complementary to nalidixic acid are likely to feature strong H-bond donor sites. Equations 1 and 2 were used to calculate the difference between the interaction site pairing energies of the cocrystal and the pure components, ΔE, for all combinations of the 310 CCFs and nalidixic acid. The CCFs were ranked in decreasing order of ΔE values, so that compounds predicted to be most likely to form cocrystals were at the top of the list. Table 1 shows the top 44 CCFs and the corresponding values of ΔE. As expected, these compounds all contain strong H-bond donors, and most of the 44 CCFs are either carboxylic acids or phenols. Nalidixic acid cocrystals have already been reported for six of the CCFs in Table 1: resorcinol, catechol, hydroquinone, pyrogallol, orcinol, and phloroglucinol.32 We describe below an experimental investigation of cocrystal formation for the remaining 38 potential CCFs in Table 1. Experimental Cocrystal Screen. Mechanochemistry is one of the most useful experimental methods for cocrystal screening.33 Liquid-assisted grinding (LAG), using catalytic amounts of ethanol or n-heptane, was therefore carried out on 1751



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The seven new cocrystal systems were also analyzed by differential scanning calorimetry (DSC). The DSC traces of the two pure components were compared with the traces of the mixtures obtained from the grinding experiments. Figure 5 shows an example of the DSC data for nalidixic acid and tertbutylhydroquinone. The 1:1 mixture melts at 139 °C, which is quite different from the melting points of the pure components (129 and 229 °C).35 The broad endotherm around 190 °C in the tert-butylhydroquinone DSC suggests that this material decomposes, and a similar broad peak is observed in the DSC of the mixture. The endotherm observed at 229 °C for the cocrystal is due to melting of pure nalidixic acid, which crystallized out of the melt. The DSC traces for all seven CCFs showed well-defined melting points that were different from those of either of the two pure components (see the Supporting Information). Structure Determination. For each of the seven new cocrystal systems, a variety of crystallization methods were used in an attempt to obtain single crystals suitable for structure determination (see the Supporting Information), but only two systems gave high-quality single crystals. Needle-shaped crystals of the nalidixic acid−tert-butylhydroquinone cocrystal were obtained by slow evaporation from chloroform at room temperature, and needle-shaped crystals of the nalidixic acid− propyl gallate cocrystal were obtained by cooling crystallization from chloroform at 2 °C. For the remaining five cocrystal systems, attempts to grow crystals using a variety of different solvents, solvent mixtures, stoichiometries, and seeding with material from the grinding experiments were all unsuccessful. However, pure phases of the 1:1 nalidixic acid−2-phenylphenol cocrystal and the 1:2 nalidixic acid−indole cocrystal were obtained by neat grinding, and the structures of these cocrystals were solved by powder diffraction. Neat grinding of a 1:2 mixture of nalidixic acid and skatole gave a cocrystal phase that contained minor impurities of nalidixic acid. By excluding the nalidixic acid peaks in the indexing procedure, pattern matching of the XRPD pattern was successful, and it was possible to determine the space group and unit cell of this cocrystal. The XRPD data for the 2,4-dihydroxybenzoic acid− and 3,4dihydroxybenzoic acid−nalidixic acid mixtures were not of sufficient quality for structure determination. Figure 6 shows the crystal structures of the four new cocrystals, and Table 2 summarizes the crystallographic parameters. The 1:1 nalidixic acid−tert-butylhydroquinone system crystallized in the triclinic space group P1̅ with one molecule of each component in the asymmetric unit (Figure 6a). H-bonds between the tert-butylhydroquinone hydroxyl groups form linear chains of these molecules. These chains constitute the frames of a molecular ladder with nalidixic acid molecules as the rungs. The nalidixic acid molecules are stacked in an alternate face-to-face orientation up the middle of the ladder and interact with the tert-butylhydroquinone chains via a H-bond between the nalidixic acid carboxylic acid H-bond acceptor and the hydroxyl H-bond donor of tert-butylhydroquinone. The crystal structure of the 2:1 nalidixic acid− hydroquinone cocrystal has been reported previously, but the interactions in the 1:1 nalidixic acid−tert-butylhydroquinone cocrystal reported here are quite different, despite the similarity in the structures of the CCFs.32 The crystal structure was used to simulate the XRPD pattern of the nalidixic acid−tertbutylhydroquinone cocrystal, and the results agree well with the experimental XRPD pattern obtained from the LAG experiments (see the Supporting Information).

Table 1. Top Ranked CCFs Based on the Difference between the Interaction Site Pairing Energies of the Nalidixic Acid Cocrystal and the Pure Components, ΔE CCF a

phloroglucinol resorcinola 3,4-dihydroxybenzoic acid sulfamic acid orcinola etidronic acid hydroquinonea pyrogallola propyl gallate methyl gallate tert-butylhydroquinone tartaric acid citric acid fumaric acid 4-hydroxybenzoic acid 3-hydroxybenzoic acid malic acid 2,5-dihydroxybenzoic acid 2,4-dihydroxybenzoic acid catechola succinic acid thiodipropionic acid ascorbic acid L-tyrosine thymol 2-phenylphenol sucrose L-rhamnose L-glutamic acid adipic acid inositol 4-tert-butylphenol 2,5-xylenol indole 3,4-xylenol oxalic acid skatole taurine 2-tert-butyl-4-hydroxyanisole D-isoascorbic acid pyridoxine 2,6-xylenol methionine 2,5-dihydroxy-1,4-dithiane

ΔE/kJ mol−1 31.7 31.1 30.4 30.3 28.8 28.4 28.1 25.2 23.7 23.5 22.8 22.8 22.2 22.1 21.8 21.4 20.9 20.1 20.1 19.4 18.1 18.0 17.8 17.7 17.2 17.2 16.8 16.4 16.3 16.2 16.2 15.7 15.5 15.3 14.9 14.9 14.7 14.7 14.4 13.9 13.5 13.0 12.4 11.4

a

Cocrystals of nalidixic acid and these CCFs were reported previously.32

the nalidixic acid spectrum moves to 1694 cm−1 in the cocrystal, which is characteristic of the formation of a new Hbond to this functional group in the cocrystal. Similar differences between the IR spectra of the mixtures and those of the pure solids were observed for six of seven CCFs (see the Supporting Information). The IR spectrum of the 1:1 mixture of nalidixic acid and 2,4-dihydroxybenzoic acid obtained by LAG appears to be a superimposition of the IR spectra of the two pure components, which implies that this sample is a physical mixture rather than a cocrystal. 1752



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Figure 2. XRPD patterns of nalidixic acid (blue), tert-butylhydroquinone (red) and a 1:1 mixture after LAG (green).

Figure 3. Chemical structures of the CCFs that form cocrystals with nalidixic acid as judged by XRPD.

Figure 5. DSC traces of nalidixic acid (blue), tert-butylhydroquinone (red), and the cocrystal (green).

simulate the XRPD pattern of the nalidixic acid−propyl gallate cocrystal. Although there are some slight shifts in the peaks at higher 2θ angles, the results agree reasonably well with the experimental XRPD pattern obtained from the LAG experiments (see the Supporting Information). The structure of the 1:1 nalidixic acid−2-phenylphenol cocrystal shown in Figure 6c was solved using the XRPD data (see the Supporting Information for details). The nalidixic acid

The 1:1 nalidixic acid−propyl gallate system crystallized in the triclinic space group P1̅ with one molecule of each component in the asymmetric unit (Figure 6b). The cocrystal is composed of alternating stacks of nalidixic acid and propyl gallate molecules. The stacks are held together by multiple Hbonds between propyl gallate molecules and a H-bond between one of the propyl gallate phenol groups and the nalidixic acid carboxylic acid group. The crystal structure was used to

Figure 4. IR spectra of nalidixic acid (blue), tert-butylhydroquinone (red), and the cocrystal (green) (arbitrary vertical scale). The carbonyl stretch at 1710 cm−1 in pure nalidixic acid (*) is shifted to 1694 cm−1 in the cocrystal (**). 1753



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Figure 6. Crystal structures of (a) the 1:1 nalidixic acid−tert-butylhydroquinone cocrystal [d(O1−O3) = 2.53 Å, d(O4−O5) = 2.69 Å, d(O5−O2) = 2.65 Å], (b) the 1:1 nalidixic acid−propyl gallate cocrystal [d(O2−O3) = 2.54 Å, d(O6−O2) = 2.88 Å, d(O8−O5) = 2.70 Å, d(O7−O8) = 2.69 Å], (c) the 1:1 nalidixic acid−2-phenylphenol cocrystal [d(O2−O4) = 2.65 Å], and (d) the 1:2 nalidixic acid−indole cocrystal [d(O2−N2) = 2.84 Å, d(O1−N1) = 2.94 Å]. The black dotted lines represent H-bonds, and CH hydrogens are omitted for clarity.

Table 2. Crystallographic Data for Nalidixic Acid Cocrystals CCF nalidixic acid−CCF stoichiometry crystal system space group a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) Z unit cell volume (Å3) R1 goodness of fit

tert-butyl-hydroquinone 1:1 triclinic P1̅ 6.9991(14) 12.106(2) 13.199(3) 96.07(3) 103.76(3) 106.11(3) 2 1025.8(4) 0.0374 1.054

propyl gallate 1:1 triclinic P1̅ 7.3792(8) 9.4077(10) 14.9887(16) 79.440(4) 81.526(4) 88.573(4) 2 1011.74(19) 0.0423 1.041

indole 1:2 triclinic P1̅ 13.2492(2) 10.8238(14) 8.3799(10) 96.0718(8) 93.5031(11) 91.5041(10) 2 1192.12(3) 0.1240 3.740

skatole 1:2 monoclinic P21/n 14.8802 12.5321 14.7177 90 107.2209 90 4 2620.91 0.1710 8.814

assess the probability of cocrystal formation for 310 different CCFs. The CCFs were ranked in order of decreasing probability of cocrystal formation, and the six known cocrystals of nalidixic acid were all found near the top of this list. The other 38 CCFs at the top of the ranked list were investigated experimentally. XRPD patterns of the products of grinding experiments indicated that seven of the CCFs form new solid phases with nalidixic acid. IR spectra and DSC measurements support the assignment of these new phases as cocrystals. X-ray crystal structures of the cocrystals of nalidixic acid and four of the CCFs (tert-butylhydroquinone, propyl gallate, 2-phenylphenol, and indole) confirm these conclusions. The results indicate that virtual screening provides a powerful tool for focusing experimental cocrystal screens on a limited number of CCFs that have a high chance of success.

molecules are stacked in an alternate face-to-face orientation, and there is a H-bond between the nalidixic acid carboxylic acid group and the 2-phenylphenol hydroxyl group. The structure of the 1:2 nalidixic acid−indole cocrystal shown in Figure 6d was also solved using the XRPD data (see the Supporting Information for details). The cocrystal is composed of alternating stacks of nalidixic acid and indole molecules. The stacks are held together by H-bonds between the two different nalidixic acid carbonyl groups and indole NH donors.

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2-phenylphenol 1:1 monoclinic P21/c 19.3675(2) 13.8554(12) 7.7264(6) 90 95.0300(9) 90 4 2065.35(4) 0.1042 5.988

CONCLUSIONS

A virtual screening method has been used to identify potential cocrystal coformers (CCFs) for nalidixic acid. The difference between calculated interaction site pairing energies of a potential cocrystal and the two pure components was used to 1754



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ASSOCIATED CONTENT

S Supporting Information *

List of the 310 CCFs used in this work. XRPD patterns, IR spectra, and DSC traces of nalidixic acid, the CCFs, and cocrystals. Methods attempted to obtain single crystals. Comparison of the experimental XRPD data for cocrystals with the patterns simulated using the crystal structures. This material is available free of charge via the Internet at http:// pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: c.hunter@sheffield.ac.uk. Notes

The authors declare no competing financial interest.

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REFERENCES

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NOTE ADDED AFTER ASAP PUBLICATION This paper was published ASAP on March 13, 2014, with changes to the Supporting Information. The corrected version was reposted on March 21, 2014.

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Virtual Screening Identifies New Cocrystals of Nalidixic Acid

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