Designing Co-Crystals of Pharmaceutically Relevant Compounds That

This result is used to design a 1:1 co-crystal using a molecule crystallizing with Z′ = 3 in its pure form, as well as to predict and engineer two s...
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Designing Co-Crystals of Pharmaceutically Relevant Compounds That Crystallize with Z′ > 1 Kirsty M. Anderson, Michael R. Probert, Christopher N. Whiteley, Adrian M. Rowland, Andre´s E. Goeta, and Jonathan W. Steed*

CRYSTAL GROWTH & DESIGN 2009 VOL. 9, NO. 2 1082–1087

Department of Chemistry, Durham UniVersity, South Road, Durham DH1 3LE, U.K. ReceiVed August 19, 2008; ReVised Manuscript ReceiVed NoVember 11, 2008

ABSTRACT: Molecules which crystallize with Z′ > 1 show a markedly stronger tendency to form co-crystals than compounds that crystallize in the pure form with Z′ ) 1. The proportion of bioactive compounds with Z′ ) 1 which form co-crystals is 4.8% as opposed to 7.1% for compounds crystallizing with Z′ > 1 in the pure state. Moreover, the Z′ > 1 percentage of the distinct set of molecules in the entire Cambridge Structural Database (CSD) that form co-crystals is 17.7% compared to the CSD average for organic molecules of 11.5%. This tendency is demonstrated experimentally by the design and preparation of a new 1:1 co-crystal of Ornidazole (Z′ ) 3 in pure form) with 3,5-dinitrobenzoic acid. Two new pure structures with Z′ > 1 are also predicted and prepared from molecules known to form co-crystals, namely, 2,3,4-trihydroxybenzophenone and 6-phenyl-3(2H)-pyridazinone. These compounds crystallize in their pure form with Z′ ) 2 and 3, respectively. Introduction 1

Co-crystals which contain at least one active pharmaceutical ingredient (API) are becoming an increasingly important new direction in drug formulation.2-4 In their recent review on cocrystals, Almarsson and Zaworotko5 stated, “strategies of rational design of co-crystal experimentation are viable”. Most studies on the design and prediction of co-crystals adopt synthon type strategies using molecules with complementary hydrogen bonding groups;6,7 however, some more general approaches have also been explored.8-10 Polymorphic compounds have been suggested5 to be a good source of co-crystals as it can be argued that the degree of “self-complementarity” in these systems is less than that for non-polymorphic systems. By “self-complementary” in this context we mean molecules of a single type that can pack together efficiently in terms of size and shape, as well as possess complementary binding sites in the same molecule (e.g., a hydrogen bond donor and a hydrogen bond acceptor). It has also been suggested that co-crystals resulting from polymorphic species may be less prone to exhibiting polymorphism themselves.5 The self-complementarity argument is also relevant to structures which crystallize with Z′ > 1 (i.e., have more than one molecule in the crystallographic asymmetric unit). Around 8.8% of molecular solids crystallize with Z′ > 1, and although the reasons for this phenomenon are complex,11-15 non-self complementary shape and/or functionalities have been cited as possible contributors.16 We therefore suggest that the evidence is so far consistent with the hypothesis that molecules which crystallize in their pure form with Z′ > 1 may show an increased tendency to form co-crystals than molecules that crystallize with Z′ ) 1 in their pure form, an idea also suggested by Brock.17 This postulate can be explored by using the Cambridge Structural Database (CSD)18,19 to seek out the number of compounds crystallizing with Z′ ) 1 and Z′ > 1 that also form co-crystals. Results and Discussion As our interest lies mostly in APIs, the CSD was initially searched for entries containing the keyword “bioactivity”. * To whom correspondence should be addressed. E-mail: jon.steed@ durham.ac.uk. Fax: +44 (0)191 384 4737. Phone: +44 (0)191 334 2085.

Refcodes are allocated this keyword if the author has indicated that the compound (or a near relative) is of biological interest. There are 12586 entries with this keyword in the CSD.20 This subset of the CSD was further restricted to contain only nonionic, non-polymeric structures of organic compounds with no disorder or errors. Refcodes where the 3D coordinates are not included were also rejected. This combination of searches gives 6903 hits in total. To screen the “parent” molecules from the co-crystals initially this subset was examined for structures containing one type of chemical residue. It is important to note that the number of types of chemical residue (subsequently defined as Z r) is distinct from the parameter Z ′′ which represents the total number of crystallographically non-equivalent molecules of whatever type in the asymmetric unit.21 For example, an asymmetric unit consisting of 6 molecules of A, 4 molecules of B, 8 molecules of C, and 2 molecules of D would have Z ′ ) 2 (the “formula unit” is 3A 2B 4C 1D), Z′′ ) 20, and Z r ) 4. A total of 1150 refcodes containing more than one residue (Z r > 1) were removed, leaving 5753 hits corresponding to possible “parents”. These were then further separated into two data sets, 4846 refcodes with Z′ ) 1 and 757 with Z ′ > 1. The 150 refcodes with Z′ < 1 were disregarded. Extracting the number of these 5603 “parent” hits from the CSD for which there is also a co-crystal is not a trivial problem as each compound needs to be searched for independently, requiring a separate input file and search for each compound. A similar approach to ours has been utilized in the SOLVATES program developed by the Cambridge Crystallographic Data Centre (CCDC);22 however, it was not suitable for our needs as the software searches for one co-crystallizing agent (“solvate”) at a time and hence a new methodology was required. We therefore developed an in-house program (mol2man)23 to generate the input coordinate files from ConQuest24 and then search the CSD in “batch mode”, which allows many searches to run sequentially. A full description of the search procedures carried out can be found in the Supporting Information; the final results are shown in Table 1. From the results obtained from the database search, we see that a total of 288 compounds out of the initial data set of 5603 molecules form co-crystals (5.1%). This can be compared with

10.1021/cg8009089 CCC: $40.75  2009 American Chemical Society Published on Web 12/24/2008

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Table 1. Percentage of Structures of “Bioactive Compounds” in the CSD with Co-Crystals

all Z′ g 1 Z′ ) 1 Z′ > 1

total

“co-crystals”

%

5603 4846 757

288 234 54

5.1 4.8 7.1

values for the Z′ ) 1 data set where co-crystals are formed 4.8% of the time and the Z′ > 1 data set where co-crystals are formed 7.1% of the time. This difference is significant at the 99.99% level (χ2 ) 6.67). These results are completely in line with our initial prediction and show that the subset of bioactive molecules which crystallize with Z′ > 1 show a greater tendency to form co-crystals than those with Z′ ) 1. However, this data set studied is comparatively small (less than 2% of the CSD as a whole); therefore, a method of applying this approach to the whole CSD is required. Extending the current search method to the whole CSD would involve over 90,000 searches and thus is prohibitive because of time constraints. A new approach was therefore developed. So far we have used the CSD to extract information about the number of co-crystals formed by molecules which crystallize with Z′ ) 1 and Z′ > 1, respectively. The alternative approach considered was to construct a subset of molecules (“parents”) which form co-crystals (“children”) and then look at the percentage of these molecules which crystallize with Z′ > 1. If our hypothesis is correct then the “parent” structures should contain a higher than average percentage of molecules which crystallize with Z′ > 1 in their pure form, that is, greater than the 8.8% of structures with Z′ > 1 in the database as a whole. The basic methodology for the whole database investigation was first to search for compounds with Zr > 1 (i.e., possible co-crystals) using the same restricted search parameters as the previous search (i.e., structures must have 3D coordinates, no disorder, no errors, not polymeric, no ions, and organic molecules only), this gave 15075 hits. Each of these 15075 hits was then run through the mol2man program as before to extract a single query file for each structure containing just the coordinates of the largest molecule (i.e., the molecule with the greatest number of atoms chosen to be the “parent”) within each formula unit. In each case this query file was then used as the basis for a CSD search to determine whether the “parent” structure was known. To remove multiple redeterminations of the same structure or polymorph which may bias the data, a previously derived “best representative polymorph” data set25 was used for the search. Any “parent” structures found were collated and were then subjected to some checks, first to ensure that the relevant part of the “child” formula matched the “parent” formula exactly to eliminate any potential problems with the query generation, with coordination to alkali metals, and so forth. The second check carried out concerned the problem of racemic versus chiral structures. As the search is necessarily based on a 2D structure diagram, no information concerning the stereochemistry is carried forward from the child to the subsequent parent search; therefore, in theory a co-crystal containing a particular enantiomer of a chiral molecule could match a racemic parent structure during the search. This possibility was dealt with by classifying the parent and child depending on whether they crystallized in a chiral space group. Any mismatched pairs (e.g., a child in a non-chiral space group with a parent in a chiral space group or vice versa) were removed from the search. While this eliminates the more obvious cases of configurational mismatching, it is possible that there are some further cases that remain, for example, a left-handed molecule in a co-crystal could match the same right-handed molecule in a parent

structure, but both would be in chiral space groups; therefore, the mismatch would be impossible to spot using space group matching. There may also be cases where there is more than one chiral center in the molecule (for example in sugars where the orientation of the -OH groups is of importance and there are many possible distinct configurations arising from the same 2D representation); however, the numbers of both of these examples is thought to be comparatively low based on a preliminary search of the data and hence no pruning of the data set was thought necessary. Taking out any structures which fail the formula and spacegroup chirality tests leaves 4473 parent structures. Many of the original 15075 structures contain the same parent molecule with different co-crystallizing agents (i.e., the same parent can have several children); therefore, any duplicate parents were removed leaving a unique list of 1608 parents. The number of structures with Z′ > 1 within this set is 285, giving an overall Z′ > 1 percentage of 17.7%, more than double the overall CSD average (8.8%) and nearly 1.5 times the overall average for organic structures (11.5%). It is clear from both of the database studies above that molecules which crystallize with Z′ > 1 show a markedly greater tendency to form co-crystals than those with Z′ ) 1. It should therefore be possible to form an unknown co-crystal from an API with Z′ > 1 experimentally. Synthetic Approach. Nitroimidazoles such as Azomycin (2nitroimidazole) (1) are known to be excellent antimicrobial drugs. The 5-nitroimidazole derivative 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole (Ornidazole or Tiberal) (2) is an antiprotozoal agent which works by targeting and killing anaerobic bacteria or amoeba present in the body and is used to treat a variety of infections including bacterial vaginosis and amoebic dysentery.26 The (R)-enantiomer of Ornidazole crystallizes in P212121 with Z′ ) 127 but the racemic form crystallizes in P1j with three molecules in the asymmetric unit (Z′ ) 3).28 Both racemic and chiral packing motifs are dominated by O-H · · · N hydrogen bonds which form a 1D chain structure in the (R)-enantiomer and discrete hexamers held together by O-H · · · N and O-H · · · O hydrogen bonds (Figure 1, Scheme 1) in the racemic form. The Z′ ) 3 racemic form is therefore a good candidate “parent” to test for co-crystal formation. Attempts were made to co-crystallize 2 with a range of cocrystallizing agents with a variety of functionality; triphenylphosphine, triphenylphosphine oxide, nicotinamide, isonicotinamide, 2-iodobenzoic acid, 3-iodobenzoic acid, aniline, phenyl ether, urea, and caffeine, but all crystalline samples were shown by single crystal X-ray diffraction to be pure Ornidazole (with the co-crystallizing agent presumably remaining in solution) and no co-crystals were forthcoming, possibly because the molecule is highly self-complementary with the hydroxyl donor and imidazole acceptor representing a well-matched hydrogen bond donor-acceptor pair. Therefore when considering further co-crystallizing agents, we concentrated on molecules possessing functional groups which could compete favorably with the O-H · · · N and O-H · · · O hydrogen bonds present in the structure of 2. Aakero¨y et al. have shown that carboxylic acids repeatedly form strong hydrogen bonds with imidazole and benzimidazole type nitrogen atoms;29 therefore, 4-nitrobenzoic acid (3) and 3,5-dinitrobenzoic acid (4) were chosen as possible co-crystal formers as we anticipated that the carboxylic acid hydrogen would be a better hydrogen bond donor than the secondary alcohol in 2 and is also more acidic than the iodobenzoic acids attempted previously. Attempts to co-crystallize 2 with 3 in chloroform led to crystals of pure 3; however,

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Figure 1. Discrete hydrogen bonded hexamer in racemic 2. The asymmetric unit consists of one molecule of each color. Disorder in the CH2Cl group has been omitted.

Scheme 1. Molecular Structures Of Azomycin (1), Ornidazole (2), 4-Nitrobenzoic acid (3), and 3,5-Dinitrobenzoic acid (4)

a solution of 2 and 4 in chloroform gave rise to small colorless crystals which were shown by crystal structure determination to be a 1:1 co-crystal (2 · 4) (Figure 2). Salt formation,30 where the hydrogen is transferred to the imidazole nitrogen atom from the carboxylic acid oxygen atom, was ruled out by first being able to locate the relevant hydrogen atom in the Fourier difference map and also by examination of the IR spectrum of 2 · 4 which showed the typical CdO carboxylic acid stretch at 1715 cm-1,31 as well as a broad peak at 2500 cm-1 assigned to the carboxylic acid OH stretch. As we predicted, there is a carboxylic acid · · · imidazole hydrogen bond between the two molecules. In addition the secondary alcohol in 2 forms an O-H · · · O hydrogen bond with an oxygen atom from a nitro group of 4, a nice example of strength matching of hydrogen bonds7,32-34 with the strong carboxylic acid donor pairing with the strong imidazole nitrogen acceptor and the weaker OH donor now pairing with the weaker nitro acceptor. This change in hydrogen bonding of the ornidazole OH group can also be followed by IR spectroscopy as the peak assigned to the ornidazole O-H stretch shifts to higher frequency from 3174 cm-1 in the spectrum of pure ornidazole to 3512 cm-1 in the IR spectrum of the co-crystal, corresponding to a weaker hydrogen bond. Overall the two synthons combine to form an infinite hydrogen bonded chain (Figure 3). The chains are held together by unusual CdO · · · NO2 interactions between adjacent chains. These interactions are a surprising feature of the structure with very little precedent in the CSD. During the preparation of this manuscript the hemihydrate of 2 (2.0.5H2O) was also published;35 this coupled with our

3,5-dinitrobenzoic acid example shows that under the correct conditions a variety of Ornidazole co-crystals may be possible, consistent with its Z′ ) 3 structure in the pure compound. Having shown that it was possible to form co-crystals from a parent molecule which crystallizes with Z′ > 1, we then sought to test the theory in reverse, namely, to take a molecule which is known only in a Zr > 1 form and crystallize out the parent Zr ) 1 structure, which we predict would be likely to have Z′ > 1. We refer to such parentless structures as “orphans”. Using the CSD, we selected two such orphans, 2,3,4trihydroxybenzophenone (5) and 6-phenyl-3(2H)-pyridazinone (6) (Scheme 2). Both compounds were recrystallized from a variety of solvents in an attempt to form crystals containing just the pure parent structures. 2,3,4-Trihydroxybenzophenone (5) is a model compound of exifone (3,4,5,2′,3′,4′-hexahydroxybenzophenone)36 which has previously been used to treat cognitive disorders in elderly patients. The hydrate structure is known37 (5) · H2O and crystallizes in a 1:1 ratio with Z′ ) 1. The water molecule takes part in a number of hydrogen bonds involving the carbonyl oxygen and two of the three -OH groups, and the remaining hydroxyl group forms an intermolecular hydrogen bond with the carbonyl oxygen. Upon recrystallization from chloroform, crystals of the pure parent molecule were obtained, crystallizing with Z′ ) 2 (Figure 4). The two independent molecules have slightly different conformations with approximately 10° difference in the torsion angle around the carbonyl. The analogous torsion angle in the original co-crystal structure (11.6°) lies in the middle of these two values. With no water molecule to link the molecules together the two independent molecules present in the asymmetric unit now interact with each other via a series of hydrogen bonds, as well as the internal O-H · · · O hydrogen bonds present in the molecules. The second molecule chosen was 6-phenyl-3(2H)-pyridazinone (6). Pyridazinone derivatives are widely used in the pharmaceutical industry as anti-inflammatory and antihypertensive agents and in the agricultural industry as herbicides. The 1:1 co-crystal of 6 with acetic acid (6 · CH3COOH) is known38 and crystallizes with Z′ ) 1 (Figure 5). The acetic acid forms hydrogen bonds with the pyridazinone hydrogen and carboxyl oxygen of the pyridazinone giving rise to a onedimensional chain. Recrystallization of 6 from acetonitrile forms

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Figure 2. Asymmetric unit of co-crystal formed between Ornidazole (2) and 3,5-dinitrobenzoic acid (4). Red dotted lines indicate hydrogen bonds.

Figure 3. Part of the hydrogen bond network in 2 · 4. Red dotted lines indicate hydrogen bonds, black dotted lines indicate CdO · · · NO2 interactions (O(4) · · · N(4) 2.762(9) Å, CdO(4) · · · N(4) 159.1°). Selected hydrogen bonds: O(1) · · · H(1)-O(8)#1 2.08 Å, 2.919(8) Å, 173°, O(5) · · · H(5)-N(1) 1.78 Å, 2.610(9) Å, 172° where #1 ) -1 + x, 3/2 - y, 1/2 + z.

Scheme 2. Molecular Formulae of 2,3,4-Trihydroxybenzophenone (5) and 6-Phenyl-3(2H)-pyridazinone (6)

the database search, it is nonetheless a pleasing result showing that it is possible to engineer structures with Z′ > 1 by considering how the parent molecule interacts with other species.

Conclusions

a pure parent crystal with three molecules in the asymmetric unit (Z′ ) 3). In this parent structure the molecules form hydrogen bonded dimers with one unique dimer and one-half of a symmetry-related dimer present in the asymmetric unit (Figure 5). The three independent molecules again differ slightly in conformation with the angle between the two rings ranging from -1.6(3) to 26.0(3)°, and again the value for the Z′ ) 1 cocrystal in 6 · CH3COOH (-17.0°) lies between the observed values in 6. The two examples above show that is it possible to predict and prepare crystal structures with Z′ > 1 by choosing compounds known to form co-crystals. While this is obviously not proof of concept as crystallization with Z′ > 1 would only be expected in roughly 1 in 5 cases according to the results of

In summary we have shown that molecules which crystallize with Z′ > 1 show a greater tendency to form co-crystals than those with Z′ ) 1. We first compared the number of molecules with Z′ ) 1 and Z′ > 1 which form co-crystals (4.8 vs 7.1%) and second looked at the Z′ percentage of the distinct set of molecules which form co-crystals (17.7% compared to the CSD average for organic molecules of 11.5%). We have also tested this premise synthetically and shown that even in cases where the molecule is relatively self-complementary, as in 2 where a robust hydrogen bonded hexamer is found in the parent crystal structure, careful choice of co-crystallizing agent can still lead to formation of co-crystals. Finally we have synthesized two structures with Z′ > 1 by choosing molecules known to form co-crystals. We therefore suggest that compounds which crystallize with more than one molecule in the asymmetric unit are likely to be good candidates for co-crystal formation because

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Figure 4. Asymmetric unit of 5 showing hydrogen bonding between the two independent molecules. Selected torsion angles C(9)-C(8)-C(7)-C(1) -7.8(6)° and C(14)-C(20)-C(21)-C(22) -18.4(6)°. Selected hydrogen bonds: O(2)-H(2O) · · · O(1) 1.90(6) Å, 2.529(4) Å, 129(6)°, O(8)-H(8O) · · · O(2) 1.96(4) Å, 2.670(4) Å, 136(3)°, O(3)-H(5O) · · · O(7) 2.07(4) Å, 2.863(4) Å, 139(3)°, O(6)-H(6O) · · · O(5) 1.60(6) Å, 2.571(4) Å, 149(4)°. Ornidazole:3,5-dinitrobenzoic acid, 2 · 4. Ornidazole (0.10 g, 0.037mmol) and 3,5-dinitrobenzoic acid (0.10 g, 0.047mmol) were dissolved in 5 mL of chloroform. Small colorless crystals formed after 3 days of slow evaporation of the solvent. Anal. Calcd for C14H14ClN5O9: C, 38.95; H, 3.27; N, 16.43. Found: C, 38.93; H, 3.21; N, 16.43. Crystal data: C14H14ClN5O9, M ) 431.75, colorless plate, 0.30 × 0.30 × 0.05 mm3, monoclinic, space group P21/c (No. 14), a ) 6.497(3), b ) 9.728(5), c ) 28.105(15) Å, β ) 92.645(11)°, V ) 1774.5(16) Å3, Z ) 4, Dc ) 1.616 g/cm3, F000 ) 888, SMART 6k, Mo KR radiation, λ ) 0.71073 Å, T ) 120(2) K, 2θmax ) 58.4°, 25709 reflections collected, 4807 unique (Rint ) 0.0573). Final GOF ) 2.237, R1 ) 0.1492, wR2 ) 0.4779, R indices based on 4073 reflections with I >2σ(I) (refinement on F2), 265 parameters, 0 restraints. Lp and absorption corrections applied, µ ) 0.279 mm-1.

Figure 5. Asymmetric unit of 6 including symmetry-related O(3) and H(3N) to show hydrogen bonding [1: 1 - x, -y, 2 - z]. Selected torsion angles: N(2)-C(4)-C(5)-C(10) -1.6(3)°, N(4)-C(14)-C(15)-C(20) -24.6(3)°, N(6)-C(24)-C(25)-C(30) 26.0(3)°. Selected hydrogen bond parameters: O(1) · · · H(2N)-N(3) 1.77(2) Å, 2.766(3) Å, 174(2)°, O(2) · · · H(1N)-N1(2)1.77(2)Å,2.766(3)Å,174(2)°,O(3) · · · H(3N)-N(3) 1 1.83(2) Å, 2.826(3) Å, 171(2)°.

they are, in general, less self-complementary than compounds with Z′ ) 1. Experimental Section Crystals of commercially available Ornidazole (2) were grown from toluene. As the original data was only collected at room temperature and hydrogen atoms were not included in the model, we have repeated the experiment and recollected data at 120 K. Crystal data: C7H10ClN3O3, M ) 219.63, colorless block, 0.20 × 0.20 × 0.10 mm3, triclinic, space group P1j (No. 2), a ) 8.8046(5), b ) 13.4844(8), c ) 13.9866(9) Å, R ) 65.057(2), β ) 71.754(2), γ ) 78.800(2)°, V ) 1426.23(15) Å3, Z ) 6, Dc ) 1.534 g/cm3, F000 ) 684, SMART 6k, Mo KR radiation, λ ) 0.71073 Å, T ) 120(2) K, 2θmax ) 58.3°, 24290 reflections collected, 7673 unique (Rint ) 0.0710). Final GOF ) 1.003, R1 ) 0.0516, wR2 ) 0.0958, R indices based on 4584 reflections with I >2σ(I) (refinement on F2), 408 parameters, 0 restraints. Lp and absorption corrections applied, µ ) 0.387 mm-1.

Crystals of commercially available 2,3,4-trihydroxybenzophenone (5) were grown from chloroform. Crystal data: C13H10O4, M ) 230.21, yellow needle, 0.20 × 0.10 × 0.05 mm3, monoclinic, space group P21/c (No. 14), a ) 18.769(5), b ) 5.1302(14), c ) 21.989(6) Å, β ) 103.547(8)°, V ) 2058.4(9) Å3, Z ) 8, Dc ) 1.486 g/cm3, F000 ) 960, SMART 6k, Mo KR radiation, λ ) 0.71073 Å, T ) 120(2) K, 2θmax ) 58.5°, 27581 reflections collected, 5546 unique (Rint ) 0.2776). Final GOF ) 0.768, R1 ) 0.0623, wR2 ) 0.1314, R indices based on 1695 reflections with I >2σ(I) (refinement on F2), 332 parameters, 0 restraints. Lp and absorption corrections applied, µ ) 0.111 mm-1. Crystals of commercially available 6-phenyl-3(2H)-pyridazinone (6) were grown from acetonitrile. Crystal data: C10H8N2O, M ) 172.18, colorless block, 0.10 × 0.10 × 0.10 mm3, monoclinic, space group P21/n (No. 14), a ) 7.2950(9), b ) 28.918(4), c ) 11.9149(16) Å, β ) 99.914(6)°, V ) 2476.0(6) Å3, Z ) 12, Dc ) 1.386 g/cm3, F000 ) 1080, SMART 6k, Mo KR radiation, λ ) 0.71073 Å, T ) 120(2) K, 2θmax ) 58.6°, 28930 reflections collected, 6718 unique (Rint ) 0.1239). Final GOF ) 0.674, R1 ) 0.0482, wR2 ) 0.0806, R indices based on 1985 reflections with I >2σ(I) (refinement on F2), 364 parameters, 0 restraints. Lp and absorption corrections applied, µ ) 0.093 mm-1.

Acknowledgment. We are very grateful for the assistance of the Cambridge Crystallographic Data Centre for their help and advice with the searches used in this work. We would also like to thank the EPSRC for funding. Supporting Information Available: Details of exact CSD searches carried out. This material is available free of charge via the Internet at http://pubs.acs.org.

Co-Crystals of Pharmaceutically Relevant Compounds

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