A Comparison of Cocrystal Structure Solutions from Powder and

Sep 9, 2010 - †Department of Physics and Astronomy, Stony Brook University, Stony Brook, ... University of South Florida, 4202 East Fowler Avenue, T...
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DOI: 10.1021/cg1009237

A Comparison of Cocrystal Structure Solutions from Powder and Single Crystal Techniques

2010, Vol. 10 4630–4637

Saul H. Lapidus,*,† Peter W. Stephens,† Kapildev K. Arora,‡ Tanise R. Shattock,‡ and Michael J. Zaworotko‡ †

Department of Physics and Astronomy, Stony Brook University, Stony Brook, New York 11794, and Department of Chemistry, University of South Florida, 4202 East Fowler Avenue, Tampa, Florida 33620

‡

Received July 12, 2010; Revised Manuscript Received August 20, 2010

ABSTRACT: We demonstrate the effectiveness and accuracy of high resolution powder diffraction for determination of cocrystal structures through a double-blind study. Structures of 10 cocrystals of varying complexity were determined independently using single crystal and powder techniques. The two methodologies give identical molecular packing and hydrogen bond topology, and an rms difference in covalent bond lengths of 0.035 A˚. Powder techniques are clearly sufficient to establish a complete characterization of cocrystal geometry.

Introduction Single crystal X-ray diffraction is a powerful and widely used technique and the basis for the enormous growth in knowledge of structural chemistry that has occurred in the past generation.1 However, there are circumstances for which suitable single crystals are not routinely available. In particular, solvates and polymorphs are frequently unavailable as single crystals because of the nonequilibrium nature of their preparation. Growth of suitable single crystals may also be difficult with low solubility compounds, which might not be amenable to controlled crystal growth of single crystals from solution. Advances in instrumentation and software have facilitated crystal structure determination from powder diffraction data to the point where it is widely used and accepted.2-4 Nevertheless, it appears to be a niche technique, insofar as many workers synthesizing new materials do not presently avail themselves of the fact that structures may be obtained from powder data. Consequently, there is value in the presentation of crystal structures determined independently from powder and single crystal techniques. Particularly valuable are cases in which the structure from powder data is solved and refined without any prior knowledge of the results of the single crystal measurement, such as guaifenesin.5 One of the strengths of single crystal diffraction is the overwhelmingly large ratio of measured data to unknown parameters. This enables routine application of techniques such as direct methods6 and leads to widely adopted standards for what constitutes an acceptable solution, for example, threshold values of agreement parameters such as R factors.7 A powder pattern contains much less information than a single crystal data set because of the random orientation of the powder which causes the three-dimensional (3D) reciprocal lattice to collapse onto a single dimension. Consequently, multiple Bragg peaks can overlap in a powder pattern and thus cannot be measured independently. Additionally, the signal-to-noise ratio in a powder pattern is generally less than *To whom correspondence should be addressed E-mail: slapidus@ gmail.com. pubs.acs.org/crystal

Published on Web 09/09/2010

that of a single crystal data set. These limitations may be overcome in a variety of ways. In the case of small molecules, it is possible to achieve this by the introduction of the additional prior information of molecular geometry. The molecular geometry reduces the parameters necessary to model from three per atom to in general six per molecule (three for position and three for orientation of the molecule) plus any torsion angles for bonds that allow rotations. However, the use of this prior information does not come without difficulties. If this prior information is incorrect, for example, a chemical reaction changing the starting materials, it may make a solution unattainable. For this reason, additional measurements, such as solid-state NMR, are frequently valuable in confirming a complicated structure determined from powder data. Independent of its source, the information in a crystal structure may be regarded in successive levels of detail. The most basic description would be the lattice parameters, space group, and molecular content of the unit cell. The minimum additional information embodied in a crystal structure would be the locations of non-hydrogen atoms, covalent bonds between them, and noncovalent interactions such as apparent hydrogen bonds and nonbonding contacts. The most complete description of a structure would generally include thermal ellipsoids of all non-hydrogen atoms and measured positions of all hydrogen atoms. Only in the most favorable cases can all of this information be truly determined by the diffraction data; for example, even in determinations from single crystals, hydrogen atoms are often attached to heavier atoms by geometric constraints during refinements. A structure determined from powder data will therefore generally contain less detailed information than that which would be available from a single crystal of the same material. Nevertheless, in many cases, the information from a powder diffraction experiment is sufficient to address most if not all issues of interest to a structural chemist. Structure determination is particularly relevant to the pharmaceutical industry as active pharmaceutical ingredients (APIs) are typically delivered orally through crystal forms of the API that are formulated with pharmaceutically approved r 2010 American Chemical Society

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excipients. Crystal forms are preferred because, among other things, they tend to be pure, stable, processable by bulk crystallization and patentable.8 However, the very nature of APIs, that is, small or medium organic molecules with peripheral hydrogen bonding groups, makes them promiscuous in terms of crystal forms as they are prone to form polymorphs, hydrates, or solvates.9 The understanding of the arrangement of molecules within the crystal structure is important as it is the crystal packing as well as the molecular structure that determine the physicochemical properties of the API.10 APIs with poor physicochemical properties such as low solubility and poor stability can hinder or even stop further development of an API into a drug. In this context, salt formation has been a method used to diversify the number of crystal forms of an API, and conversion to a salt can optimize both the solubility and stability of an API.11,12 However, according to a recent review of the “orange book” database more than half of APIs are weakly or nonionizable,13 and even though salt screening is a long established part of drug development, a limited number of pharmaceutically acceptable salt formers exist.14 In such a situation, processing the API into an amorphous form is an alternate approach to improve physicochemical properties; however, amorphous forms tend to be metastable, might crystallize over time, and have a greater tendency to react in the solid state in comparison to their crystalline counterparts.15 Pharmaceutical cocrystals represent a more recently developed approach to optimizing the physicochemical properties of an API. Cocrystals are multicomponent crystals consisting of two or more compounds where at least one component is molecular and a solid at room temperature (the cocrystal former). This cocrystal former generates a supramolecular synthon, typically a hydrogen bond, with a molecular or ionic API.16 Cocrystallization provides an alternative strategy for the modification of the physicochemical properties of the API, and there are several recent studies that demonstrate how cocrystals of APIs can enhance the physicochemical properties in comparison to the pure API.17 Cocrystals are therefore of topical interest, and they are also particularly suitable for powder diffraction measurements since mechanochemical techniques have been found to be efficient methods for discovery of new cocrystals.18 Such techniques do not lead directly to single crystals and the information available from a low resolution powder pattern is often sufficient to confirm the existence of a new cocrystal form. This study illustrates the level and accuracy available from fairly routine application of high resolution powder diffraction techniques on a collection of small molecule cocrystals. The unit cells and hydrogen bond topology are unambiguously given by the powder diffraction data, and the intramolecular geometry is reliable at the level of a few hundredths of an angstrom.19

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Table 1. Compounds code

name

1 2 3 4 5 6 7 8 9 10

4-hydroxybenzoic acid and 4-phenylpyridine (1:1) 3-hydroxybenzoic acid and 4-phenylpyridine (1:2) 3-hydroxybenzoic acid and tetramethylpyrazine (2:3) 3-hydroxybenzoic acid and 4,40 -bipyridine (1:1) 3-hydroxybenzoic acid and 1,2-bis(4-pyridyl)ethane (1:1) 4-hydroxybenzoic acid and 1,2-bis(4-pyridyl)ethene (1:1) 3-hydroxybenzoic acid and trans-1,2-bis(4-pyridyl)ethene (1:1) 4-hydroxybenzoic acid and 1,2-bis(4-pyridine)ethane (2:1) 3-hydroxypyridine and isophthalic acid (1:1) L-ascorbic acid and nicotinic acid (1:1)

the starting components in an appropriate HPLC reagent grade solvent. Powder samples were created by grinding the resulting material in a mortar and pestle. The compounds were characterized by single X-ray crystallography, powder X-ray diffraction, and FT-IR spectroscopy, but these details were not made available in advance of the structure solution studies described herein. The specific cocrystals studied are listed in Table 1. Chronologically, the single crystal data were measured, solved, and refined before the powder data were collected. However, that information was not shared with the investigators who collected and analyzed the powder data until the powder refinements were finalized. Single Crystal Measurements Single crystal X-ray diffraction data of 1-10 were collected on a Bruker-AXS SMART APEX CCD diffractometer with monochromatized Mo KR radiation (λ = 0.71073 A˚) connected to a KRYO-FLEX low-temperature device. Data for 1-10 were collected at 100 K. Lattice parameters were determined from least-squares analysis, and reflection data were integrated using the program SAINT.22 Lorentz and polarization corrections were applied for diffracted reflections. In addition, the data were corrected for absorption using SADABS.23 Structures were solved by direct methods and refined by full matrix least-squares based on F2 using SHELXTL.24 Non-hydrogen atoms were refined with anisotropic displacement parameters. All H-atoms bonded to carbon atoms, except methyl groups, were placed geometrically and refined with an isotropic displacement parameter fixed at 1.2 times Uq of the atoms to which they are attached. N or O bonded protons and H-atoms of methyl groups were located from difference Fourier map inspection and refined isotropically with thermal parameters based upon the corresponding N, O, or C atom (U(H) = 1.2Uq(N, O)). Full details of the crystal structures are presented elsewhere,20,21 and compounds 1-9 have been archived in the Cambridge Structural Database under the following refcodes: HONTAG, HONTOU, HONVIQ, HONVAI, HONTUA, HONVUC, HONWAJ, HONSUZ, and RIBXAC01 respectively.

Preparation of Samples

Powder Diffraction Measurements and Analysis

The cocrystals studied herein were generated as part of studies on crystal engineering of cocrystals and their structures have been published elsewhere.20,21 Compounds 1-9 were prepared in the context of a study of the hierarchy of the supramolecular heterosynthons between cocrystal formers containing COOH, OH, and Narom moieties.20 Compound 10 was prepared as part of a study of weakly acidic OH groups crystallized in the presence of carboxylate moieties.21 Single crystals of compounds 1-10 were obtained via slow evaporation of stoichiometric amounts of

High resolution synchrotron X-ray powder diffraction patterns were collected at the X16C beamline at the National Synchrotron Light Source at Brookhaven National Laboratory. X-rays of wavelength 0.6984 A˚ were selected using a Si(111) channel cut monochromator. After the sample, the diffracted beam was analyzed with a Ge(111) crystal and detected by a NaI scintillation counter. Wavelength and diffractometer zero were calibrated using a sample of NIST Standard Reference Material 1976, a sintered plate of Al2O3.

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Figure 1. Rietveld refinement of (A) Sample 1, (B) Sample 4, (C) Sample 8, and (D) Sample 10. The points are the data, the solid line is the calculated pattern from the refinement, and the difference between the two is shown below the main plot.

Samples were flame-sealed in thin walled glass capillaries of nominal diameter 1.5 mm and spun during data collection for improved powder averaging. The use of capillaries tends to reduce the role of preferred orientation, although it may be a concern at the stage of refinement. All powder measurements were performed at ambient temperature, nominally 295 K. Typical time of data collection was approximately 12 h per sample with an increasing count time with higher angle. Typical patterns are shown in Figure 1A-D. We discuss three stages of solution and refinement: lattice and space group, topology, and atomic structure. Several techniques for determining lattice parameters from powder

measurements have been described and are in general use. For the present work, the indexing module of Topas Academic was used.25 With this quality of data, the correct lattice is often unambiguously determined, subject to confirmation by successful structure solution and refinement. For the 10 samples discussed here, there were no unindexed peaks leading to the conclusion that there was no crystalline impurity phase. Unlike single crystal X-ray diffraction, systematic absences are less clear in powder diffraction because of overlapping peaks; frequently a space group must be postulated based on the absence of only a few peaks at low angles. The space group assignment is ultimately confirmed by a successful structure

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Table 2. Comparison of Lattice Parameters from Powder Measurements at Room Temperature with Lattice Parameters from Single Crystal at 100 K sample

technique

a (A˚)

b (A˚)

c (A˚)

R

β

γ

powder single crystal powder single crystal powder single crystal powder single crystal powder single crystal powder single crystal powder single crystal powder single crystal powder single crystal powder single crystal

27.243 26.780 9.3537 9.2032 9.4644 9.4609 8.2326 8.1965 8.0446 7.9810 6.2043 6.1928 8.129 7.901 7.5869 7.3666 10.060 10.218 5.394 5.408

7.5516 7.4445 21.117 20.819 17.734 17.807 9.0509 8.8828 9.0984 8.9312 7.106 6.957 10.359 10.310 23.943 23.716 10.954 11.001 8.173 8.040

19.480 19.471 11.907 11.827 10.9533 11.0809 10.4682 10.3613 11.307 11.209 18.615 18.499 10.916 10.863 12.5825 12.5523 10.371 10.412 28.390 28.370

90 90 90 90 90 90 71.730 72.213 97.187 97.585 92.987 95.046 114.450 114.081 90 90 90 90 90 90

131.101 131.101 92.808 93.487 91.783 92.184 72.438 72.678 91.531 90.745 94.266 94.058 104.452 103.883 103.786 103.033 99.279 99.983 90 90

90 90 90 90 90 90 87.088 86.773 91.106 90.665 103.892 103.928 93.167 93.041 90 90 90 90 90 90

space group

1

C2/c

2

P21/n

3

P21/c

4

P1

5

P1

6

P1

7

P1

8

P21/c

9

P21/n

10

P212121

determination. Lattice parameters and space groups of all samples determined from the powder diffraction data are listed in Table 2. In all cases, the single crystal and powder lattices were compatible, differing only by thermal contraction. The technique used to accomplish the structure determination from powder data was simulated annealing, implemented in Topas Academic26 and DASH.27 Simulated annealing takes advantage of the prior information of molecular geometry. During simulated annealing, it is important to keep the size of the search space manageable, so parameters such as bond lengths, lattice parameters, etc. are held constant. Under such a calculation, the molecules are placed at a random position, orientation, and torsion angle of the rotatable bonds, which form a configuration space for the search. From this, a powder pattern is calculated and a comparison is made with the experimental pattern with a corresponding goodness of fit, with the goal of minimizing this fit parameter. The two programs, Topas Academic and DASH, use different goodness of fit parameters for their simulated annealing. DASH uses a comparison P based on the integrated intensities defined as χ2DASH = h,k(Ih - c|Fh|2)(V-1)hk(Ik - c|Fk|2), where h and k run over all reflections in the pattern, Ih are the Lorentzpolarization corrected, extracted integrated intensities from a Pawley refinement of the diffraction pattern, V is the covariance matrix from the Pawley refinement, c is the scale factor, and Fh are the structure factor magnitudes of the trial model.27 Topas Academic uses the weighted pattern R-factor vffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi uP u wm ðYo, m - Yc, m Þ2 um RWP ¼ u P t wm Yo, m 2 m

where m indexes the 2θ values in the powder diffraction pattern, and Yom, Ycm, and wm are the observed data, calculated model data, and statistical weight of the mth point in the pattern.26 A random step is then taken in this configuration space and a new goodness of fit is calculated. Depending on the complexity of the problem, there may be a number of local minima. If only steps that improved the goodness of fit were taken, it would be very likely to get stuck in a local minimum corresponding to an incorrect solution. Thus, it is necessary to sometimes take a step that may degrade the goodness of fit. The strategy of accepting or rejecting steps is as follows: if the

new goodness of fit is better, then the step is accepted; if not, the step is taken with a probability equal to e-ΔE/TSA, where ΔE is the change in the goodness of fit parameter and TSA is the effective temperature, a parameter of the simulated annealing. With a sufficient effective temperature, the trial solution will be kicked out of local minima and thus be more likely to approach the global minima corresponding to the correct structure solution. Successful computer programs, such as Topas and DASH, embody heuristics for variation of TSA during the search for a solution. In order to use simulated annealing, the configuration space has to be determined. From the indexing a volume has been determined and with the fact that a typical molecular crystal has a volume of approximately 17 A˚3 per non-hydrogen atom, it is possible to make a hypothesis about the molecular contents of the unit cell. It is important to recognize if any of the molecules have a symmetry such as an inversion center, which is also in the space group that is being considered. If there is such a correspondence, it may be necessary to place the molecule on that special position during simulated annealing. When placed on the special position, the molecule has fewer degrees of freedom, and thus the configuration space is quite different. Such a situation occurs in a number of the samples considered; for example, in Sample 3, one of the tetramethylpyrazine molecules is on an inversion center. Simulated annealing in an incorrect configuration space will not achieve a correct structure, and there is frequently some trial and error in the process. A candidate solution can be confirmed by a reasonable and stable refinement. By reasonable, we mean that the refinement is in line with chemical knowledge, for example, bond lengths do not get very small or very large. Each molecule is defined by a z-matrix, which defines every atom by a length, angle, and torsion angle from other atoms in the molecule. These parameters of the z-matrix are then refined in order to achieve the final structure. Because of the random orientation powder, there is less information than with single crystals. This lack of information makes it necessary to put constraints on the refinement. In most molecules, there are a number of bonds which will have comparable lengths, that is, aromatic bonds have approximately the same length. Thus, each bond length is not refined by itself but similar bond lengths are refined as a group. Examples of such groupings are aromatic, N-C bonds, C-O bonds, etc. Similar constraints are made for

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Figure 2. Illustration of the pattern of hydrogen bonding.

bond angles. Another constraint necessary is fixing torsions so that sections of the molecule remain planar. Another effect of this lack of information is the inability to independently determine the position of the hydrogen atoms. Hydrogen atoms are placed by geometric constraints in relationship to heavier atoms. More information may be available from single crystal to confirm hypotheses about placement of hydrogen atoms, for example, proton transfer. A comparison of the calculated pattern of this refined structure and the measured pattern can be seen in Figure 1A-D. These four were chosen to represent the whole collection because of the different dimensionality of their hydrogen bonded networks. All of the pairs of molecules discussed here contain groups that can act as donors and/or acceptors of hydrogen bonds, and so it is not surprising that all of the structures exhibit

hydrogen bonding. In fact, the powder X-ray diffraction measurements presented here do not reliably locate individual hydrogen atoms, but they can be confidently inferred from geometric relations. The next level of description of a molecular crystal is the topology formed by the hydrogen bonds of the solution. Topology refers to the basic structure and dimensionality of the solution, whether the hydrogen bonded network forms dimers, chains, planes, etc. and the orientation of the molecules in such an organization. In this study, there are hydrogen bond networks of zero dimension (finite clusters), one dimension (infinite chains), two dimensions (planes), and three dimensions. In the case of all but the 3D structure, it is possible to show a two-dimensional representation of the main repeating pattern with unique hydrogen bonds labeled (Figure 2).

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Graph sets can provide a detailed description of the topology in a hydrogen-bonded system. This technique was introduced by Etter28 and is a useful way of classifying crystal Table 3. Graph Sets of Sample 1: 4-Hydroxybenzoic Acid and 4-Phenylpyridine (1:1), a Zero-Dimensional Topology a b

a

b

D D33(19)

R22(8)

Table 4. Graph Sets of Sample 4: 3-Hydroxybenzoic Acid and 4,40 -Bipyridine (1:1), a One-Dimensional Topology a b

a

b

D C22(16)

D

Table 5. Graph Sets of Sample 8: 4-Hydroxybenzoic Acid and 1,2-Bis(4-pyridine)ethane (2:1), a Two-Dimensional Topology a b c d

a

b

c

d

D D22(6) 2 C2(16) D22(10)

D D22(11) D22(12)

D D22(6)

D

Table 6. Graph Sets of Sample 10: L-Ascorbic Acid and Nicotinic Acid (1:2), a Two-Dimensional Topology a a b c d e

C(5) D33(18) D33(16) C22(8)

b

c

d

D R22(9) D33(16) D32(9)

D D33(12) 3 D3(11)

C(7)

e

C(6)

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structures.29 Graph sets describe the connectivity formed by a particular group of unique hydrogen bonds; as such there are multiple levels of graph sets. The first level is the connectivity that a single hydrogen bond makes with its symmetry equivalents, while the second level is the connectivity that two different hydrogen bonds form and so forth. The general descriptor of a graph set is Gda(n), where a is the number of hydrogen bond acceptors, d is the number of hydrogen bond donors, and n is the total number of atoms in the connectivity. G designates the type of connectivity formed: chains (C), rings (R), or finite patterns (D). The convention for finite patterns is to count from the hydrogen of the first donor to the last acceptor. The first level of a graph set is a single symbol for each inequivalent hydrogen bond. For example, in 1, bond a connects a single donor and a single acceptor, and according the scheme for finite patterns, two atoms are involved so the symbol is D11(2). General convention is that, unless otherwise specified, a and d are both one and for finite patterns n = 2. Thus, the graph set can be written as just D. Bond b is associated with a pair of carboxyls in which two O atoms are regarded as donors and two as acceptors, so the symbol is R22(8). The second level graph set in 1 is between the two types of bonds and leads to a finite pattern: D33(19). The first two levels of the graph set may be given as a symmetric matrix. Tables 3-6 give these graph set matrices for examples of zero-, one-, two-, and three-dimensional connectivity. The structures determined from powder and single crystal measurements all agree on proximate donors and acceptors, and therefore yield the same graph sets (Tables 3-6). Having established that powder and single crystal methods give the same hydrogen bond topologies, closer comparison

Figure 3. Overlays of (A) Sample 1, (B) Sample 4, (C) Sample 8, and (D) Sample 10. Overlays of the powder structure solution and single crystal solution. The blue outlines correspond to the solution from powder data, whereas the red outlines come from the solution of single crystal data sets.

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common bond length is allowed to refine freely. Likewise, in benzoic acids, the sp2 C-C bond length is refined separately from the two C-O bonds, which are set equal. On the other hand, all internal coordinates of non-H atoms have been independently refined in the single crystal structure determinations. Figures 4 and 5 show histograms of the differences of all non-hydrogen interatomic distances and angles between the two determinations. The majority of powder-derived bond lengths are within 0.03 A˚ of the correct (single crystal) values, with an rms difference in bond lengths of 0.035 A˚. A majority of the powder-derived bond angles are within one degree of the correct values, although that result is strongly affected by the fact that a majority of the aromatic bond angles are essentially 120 degrees. The rms difference of bond angles, 2.04 degrees is significantly larger than the average, due to presence of a number of significant outliers. These outliers may be caused by thermal effects or the choice to enforce sections of molecules to be planar in the powder diffraction refinements. Figure 4. Histogram of difference between refined bond distances from powder and single crystal data sets.

Figure 5. Histogram of the difference between refined bond angles from powder and single crystal data sets.

between the two is complicated by the fact that the powder measurements described here were performed at different temperatures than the reference single crystal data sets. One cannot compare fractional coordinates of two solutions because the lattice dimensions are not identical. At the simplest level of comparison, overlaying the two solutions for each given cocrystal yields excellent agreement. Several illustrations are provided in Figure 3A-D. The small differences seen are more likely due to thermal expansion of the lattice rather than a discrepancy between the two techniques. One can also ask how accurately the powder diffraction measurements can determine the intramolecular structural details. In the powder refinements in this work, we have generally imposed restraints on individual bond lengths, angles, and torsions to improve the stability of the refinements without significant loss of information. For example, aromatic rings are forced to be planar, regular hexagons, whose

Conclusion The work described herein has compared the crystal structures of 10 cocrystal samples determined by both powder and single crystal techniques. The level of effort required of structure solution from powder diffraction is significantly greater than that from single crystal X-ray diffraction and the precision obtained (bond lengths and angles) is somewhat less. However, for cases in which the desired information is composition of matter and intermolecular bonding geometry, powder diffraction is seen to be a reliable technique. The samples considered here are somewhat unusual insofar as there were independent structure determinations from powder and single crystal data. Before this work, many authors have established the validity of powder diffraction in crystal structure analysis. This work is partly intended to bring awareness that the lack of single crystals should not impede analysis of cocrystals at the level of complexity encountered in most research. Acknowledgment. We are grateful for useful discussions with Joel Bernstein. This work was partially supported by Transform Pharma, by the US-Israel Binational Science Foundation under Grant 2004118, and by National Science Foundation grant CHE-0911089. Use of the National Synchrotron Light Source, Brookhaven National Laboratory, was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-98CH10886. Supporting Information Available: Figures of Rietvield refinement and overlays for structures 2, 3, 5, 6, 7, and 9; crystallographic information (.cif files) for all of the structures. This information is available free of charge via the Internet at http://pubs.acs.org/

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(18) (19)

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