Article pubs.acs.org/crystal
“Predicting” Crystal Forms of Pharmaceuticals Using Hydrogen Bond Propensities: Two Test Cases Published as part of the Crystal Growth & Design Mikhail Antipin Memorial virtual special issue Elisa Nauha† and Joel Bernstein*,†,‡ †
New York University Abu Dhabi, Center for Science and Engineering, P.O. Box 129188, Abu Dhabi, United Arab Emirates Ben-Gurion University of the Negev, Department of Chemistry (Emeritus), Beer Sheva, Israel 84105
‡
S Supporting Information *
ABSTRACT: The Cambridge Structural Database incorporates an algorithm, based on data mining and statistical analysis of the structures in the database, for evaluating the “risk of polymorphism” in any compound. We have applied that algorithm to a number of pharmaceutically important compounds from the European Pharmacopoeia for which multiple crystal forms have not been reported. The survey suggested the possibility of polymorphism in at least two compounds, bufexamac and meglumine. The statistical analysis and the subsequent experimental search for polymorphism are reported here. While polymorphism was detected and characterized in both cases, the structural results were not necessarily compatible with the basis for the measure of the “risk of polymorphism”.
■
INTRODUCTION
any still unknown crystal forms, or (3) what their properties might be. Thus, any tool to reduce the role of chance in this search is welcome, and the Cambridge Crystallographic Data Centre (CCDC) software noted above provides such a tool. While there are no “predictors”, the CCDC has developed an algorithm to assess the likelihood of a compound to exhibit polymorphism, and this tool is available in the solid form module of its Mercury2 package. The algorithm of the guideline is based on the hydrogen bonding propensity3−5 of a molecule as determined for various chemical functionalities by data mining of the >600000 entries in the database. In the analysis, structures with the same functional groups are found from the CSD and used in a statistical survey of the most likely hydrogen bonds. To the survey of the possible hydrogen bonding pairs, parameters for the functional group, bonding competition, steric density, and aromaticity are applied to obtain the propensities for the hydrogen bonds for the specific molecule. The analysis can be performed on a single molecule to assess the “risk” of polymorphs6 or on a combination of molecules to determine the likelihood of the formation of multicomponent crystal forms. The algorithm assigns to each donor and acceptor pair a propensity index for the formation of the hydrogen bondthe
Recent releases of the Cambridge Structural Database (CSD) include an algorithm for assessing the “risk” of polymorphism for any particular entry in the database.1−6 Webster’s New Unabridged Dictionary defines “risk” as “the chance of injury, damage, or loss; a dangerous chance; a hazard”. Examples of synonyms are “danger, peril, jeopardy, hazard”. Thus, the choice of the term “risk” reflects a common, but in our opinion, mistaken view of polymorphism in quite a negative context. In the pharmaceutical industry the appearance of polymorphsin the current context “multiple crystal forms”, including solvates and hydrates would be more appropriate especially in a late stage of development or even after launch, may indeed be a risk, as one cannot guarantee whether a new crystal form will exhibit improved or deleterious properties compared to the earlier form(s) of a marketed drug or threaten the intellectual property of the marketing company. Thus, it is of considerable interest to acquire as much detailed knowledge as possible on the crystal form landscape of a compound in the course of research and development from a lead compound to a marketed product. Crystal form screening is an important component of that R&D process and often continues well beyond the launch of a product. Even after considerable research activity recently in this area, for any specific compound there is still no means of predicting, simply from the structural formula, (1) how many crystal forms a compound might exhibit, (2) how to prepare © 2014 American Chemical Society
Received: April 9, 2014 Revised: June 30, 2014 Published: July 28, 2014 4364
dx.doi.org/10.1021/cg500478p | Cryst. Growth Des. 2014, 14, 4364−4370
Crystal Growth & Design
Article
high risk of contact allergies.7 No polymorphs and no previous crystal structures have been reported for this compound. Meglumine ((2R,3R,4R,5S)-6-(methylamino)hexane1,2,3,4,5-pentol, Figure 1b) is an amino sugar used as a stabilizing agent in pharmaceutical formulations and also as a basic salt former with other active pharmaceutical ingredients. A crystal structure (CSD code NUYJEW) has been reported for meglumine.8 It is clear that both of these small, flexible molecules have a considerable potential for a variety of hydrogen bonding possibilities.
higher the index, the greater the propensity. The analysis then produces a landscape of possible structures with combinations of these hydrogen bonds. When there is only one combination with high propensity bonds and all donors and acceptors being used (denoted as “high coordination”), the risk of polymorphism is ranked as low. On the other hand, when there are many combinations with similar propensity and coordination the risk of polymorphism is considered high. The algorithm says nothing, of course, about which strategies might be employed to search for the multiple crystal forms and nothing about the properties of the crystal forms that might be formed. Nevertheless, applying the propensity algorithm to a particular compound is, in principle, preferable to operating in a total vacuum. Given our continuing occupation with multiple crystal forms, we were interested in testing the utility of the hydrogen bonding propensity tool on pharmaceutically important compounds. We learned that Prof. Ulrich Griesser of the University of Innsbruck had recently surveyed the European Pharmacopaeia for pharmaceutically important compounds for which only one solid form had been reported in the open literature. He identified some 300 compounds that fell into that category. We randomly selected a subset of about 60 of those compounds to which we applied the propensity analysis and based on the survey (and ease of acquisition, lack of toxicity, etc.) selected seven commercially available compounds in the “high-risk” category for polymorphism or hydrate formation for further study. At this stage in the process we were not aware of earlier reports of any additional crystal forms of any of the compounds surveyed. The results of our search for polymorphs on two of those compounds, bufexamac and meglumine, are reported here, since these studies shed considerable light on the utility of this propensity tool. Bufexamac (2-(4-butoxyphenyl)-N-hydroxyacetamide, Figure 1a) is an anti-inflammatory drug for topical use as ointments and lotions. It was taken off EU markets in 2010 because of a
■
HYDROGEN BONDING PROPENSITY The hydrogen bonding propensity analysis was done for the pure molecule as well as for the molecule with a molecule of water to assess the propensity for both polymorphism and monohydrate formation. Database studies were carried out using CSD Version 5.34 (May 2013) with CSD Mercury version 3.1.1. Bufexamac. In the structure search for the hydrogen bonding propensity analysis, the ether oxygen was taken as one group and the CONHOH as another group. A total of 723 structures were used for the model with 611 structures containing the ether O and 115 the CONHOH group, which is a relatively uncommon functional group. The area under the receiver operating characteristics (ROC) curve serves as a measure of the goodness of fit of the mode. Values above 0.5 indicate predictions to be better than random, and a value of 1 indicates a perfect model (3). For bufexamac, the value is 0.926 signifying excellent discrimination. The propensities for the N−H and O−H donors to hydrogen bond to the strong acceptors O−H and CO are quite similar (Table 1) so competition is expected. The ether Table 1. Predicted and Realized Intermolecular Hydrogen Bond Propensities for Bufexamac donor
acceptor
propensity
observed inter-?
O1−H N1−H O1−H N1−H O1−H N1−H
O1−H O1−H CO2 CO2 O3 ether O3 ether
0.99 0.99 0.93 0.92 0.05 0.04
yes yes
oxygen is an unlikely acceptor. The putative structure landscape (Figure 2) shows that there are three sets of structures that could be nearly equally viable suggesting the possible existence of three polymorphic structures. At the time of the hydrogen bonding propensity analysis, no crystal structure of bufexamac had been reported. Meglumine. In the structure search for the hydrogen bonding propensity analysis, the O−H groups of meglumine (Figure 1b) were described as two different types, the terminal O1 and the O2−O5 in the chain. The amino group was described as a C−CH2−NH−CH3 group. A total of 1519 structures were used for the model with 668 structures containing each one of the donor/acceptor groups. The area under the ROC curve was 0.815 signifying good discrimination. The propensities for the possible intermolecular hydrogen bonds are in Table 2. The best hydrogen bond, with the highest propensity, is predicted to be from N1−H to O2. This seems to be because of a lower steric density around the group when
Figure 1. (a) Bufexamac and (b) meglumine molecules with atomic numbering. 4365
dx.doi.org/10.1021/cg500478p | Cryst. Growth Des. 2014, 14, 4364−4370
Crystal Growth & Design
Article
Figure 2. Putative structure landscape for bufexamac; the experimental structure is in pink. The more likely structures lie to the bottom right of the landscape.
Table 2. Predicted Intermolecular Hydrogen Bond Propensities and Realized Hydrogen Bonds with Distances for Meglumine donor
acceptor
propensity
N1−H N1−H N1−H N1−H N1−H N1−H O2−H O5−H O3−H O4−H O2−H O2−H O2−H O5−H O3−H O5−H O3−H O4−H O4−H O2−H O5−H O3−H O1−H O4−H O5−H O3−H O4−H O2−H O1−H O1−H O5−H O3−H O4−H O1−H O1−H O1−H
O2−H O5−H O3−H O4−H O1−H N1−H O2−H O2−H O2−H O2−H O5−H O3−H O4−H O5−H O5−H O3−H O3−H O5−H O3−H O1−H O4−H O4−H O2−H O4−H O1−H O1−H O1−H N1−H O5−H O3−H N1−H N1−H N1−H O4−H O1−H N1−H
0.82 0.78 0.78 0.76 0.75 0.71 0.62 0.59 0.59 0.58 0.57 0.57 0.54 0.54 0.54 0.54 0.54 0.53 0.52 0.52 0.51 0.51 0.51 0.50 0.49 0.49 0.48 0.47 0.45 0.45 0.45 0.44 0.43 0.43 0.41 0.36
form I d(D···A)
Form II d(D···A)
3.309(5)
3.367(4)
2.857(4)
Figure 3. Putative structure landscape of meglumine with the structures with all donors in use highlighted, and a zoom-in of only those structures. The lower part of the figure suggests that a number of polymorphic structures are likely for this compound.
2.735(3)
optimal, especially when taking into account the coordination score that describes now many hydrogen bonds each donor/ acceptor forms. Generally one would expect each donor to bond at least once. If the group is cut down to only those that have bonds to each donor, the group of structures is much smaller with around 40 combinations (Figure 3).
2.730(4)
2.722(3)
2.720(4)
2.692(3)
■
EXPERIMENTAL SEARCH FOR POLYMORPHS Bufexamac and meglumine were purchased from Sigma and used without further purification. Experimental polymorph screening was performed via evaporation crystallization from 16 solvents (acetone, methanol, ethanol, water, acetonitrile, 2propanol, cyclohexane, toluene, benzene, chlorobenzene, DCM, chloroform, pyridine, THF, DMF, and DMSO). The crystallization products were characterized with powder and single crystal X-ray diffraction, depending on the crystallite size. Bufexamac. Room temperature studies of the crystallization products did not lead to polymorphic structures. A combination of hot/cold stage microscopy, differential scanning calorimetry (DSC) measurements and variable temperature Xray powder diffraction did reveal polymorphic behavior. A polymorphic change at around −40 °C can be seen in a DSC (Figure 4) and on the thermomicroscope under polarized light. During the change the crystals move, but the change in the polarization colors is not markedly visible (Figure 5), making the change best noticeable when viewed in a video (Supporting Information). The transformation is also visible in a variable temperature X-ray powder diffraction (XRPD) experiment (Figure 4).
2.877(4) 2.811(5)
2.767(3) 2.867(3)
compared to the other similar O−H groups (O3, O4, and O5) as acceptors. Not surprisingly, there are over 130000 unique combinations of hydrogen bonds (Figure 3). Many of these of course are not 4366
dx.doi.org/10.1021/cg500478p | Cryst. Growth Des. 2014, 14, 4364−4370
Crystal Growth & Design
Article
Bufexamac. Crystal structures for the low temperature (LT, 200 K) and high temperature (HT, 250 K) forms were measured with Cu-Kα radiation (Table 3). Both forms Table 3. Structure and Refinement Parameters for Bufexamac LT Form and HT form formula formula weight crystal system space group a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) volume (Å3) Z density μ (mm−1) crystal size mm3 description refl collected indp refl R(int) GOF on F2 R1 [I > 2σ(I)] wR2 [I > 2σ(I)]
LT form 200 K
HT form 250 K
C12H17NO3 223.27 monoclinic C2/c 47.0072(17) 5.4802(2) 9.5037(4) 90 101.488(2) 90 2399.19(16) 8 1.236 0.725 0.10 × 0.10 × 0.02 colorless, plate 6896 1503 0.0226 1.060 0.0329 0.0772
C12H17NO3 223.27 monoclinic C2/c 47.646(5) 5.5179(5) 9.5052(9) 90 98.313(6) 90 2472.7(4) 8 1.199 0.704 0.10 × 0.10 × 0.02 colorless, plate 6363 1548 0.0232 1.072 0.0420 0.1121
crystallize in space group C2/c. The cell parameters are similar with the biggest differences in the a-axis and the β-angle. In the HT form the butyl tail of the molecule is disordered over two positions with an occupancy of 0.65 for the conformation found in the LT form. Meglumine. The data for the two structures were measured at 100 K with Mo-Kα radiation (Table 4). Form I crystallized from acetone in space group P212121 and form II from ethanol in space group P1. The CSD structure NUYJEW, form I, is reported to be crystallized from ethanol, so the solvent is not the decisive factor in the crystallization of the polymorphs. Attempts to crystallize more form II after the initial determination for further experiments have so far failed, producing microcrystalline or syrupy material.
Figure 4. Cycling DSC of bufexamac showing a reversible phase change at ca. −40 °C and a variable temperature XRPD showing the same change.
■
Figure 5. Very slight change in the polarization of bufexamac crystal during the phase transition when cooling at −38 °C (left) and −46 °C (right).
DISCUSSION
Bufexamac. The conformation of the molecules is the same in the two structures, other than disorder in the high temperature form (Figure 6). The occupancy of the same conformation as in the LT form is 0.65 in the HT form. Contrary to what might be expected from the polymorph propensity algorithm, the observed polymorphic change does not involve any changes in the hydrogen bonding. Hydrogen bonded molecules build up sheets that stack up differently in the two forms (Figure 7). The CO acts as a bifurcated acceptor for both the N−H and O−H donor. The N−H···O C hydrogen bonds build up C(4) chains, and the O−H···OC bonds make up a R22(10) motif that connects the chains. There is one set of predictions that is propensity and coordination wise better than the experimental structure. In this structure, the O−H would also act as an acceptor for a hydrogen bond. However, if weak C−H donors are taken into
Meglumine. Crystallizing meglumine is inherently difficult, as it tends to produce a syrupy material in crystallizations. The screen yielded two polymorphs, which were identified by single crystal diffraction.
■
CRYSTAL STRUCTURE DETERMINATIONS Single crystal XRD measurements were done on a Bruker APEX Duo equipped with an Oxford Cryosystems Cobra cryosystem. The structures were measured with Cu- or Mo-Kα radiation at 100, 200, or 250 K. Structures were solved with direct methods using Shelxs and refined against |F2|, with Shelxl.9 The O−H and N−H hydrogen atoms were found from the difference electron density map; all other hydrogen atoms were fixed. 4367
dx.doi.org/10.1021/cg500478p | Cryst. Growth Des. 2014, 14, 4364−4370
Crystal Growth & Design
Article
Table 4. Structure and Refinement Parameters for Meglumine Form I and Form II formula formula weight crystal system space group a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) volume (Å3) Z density μ (mm−1) crystal size mm3 description refl collected indp refl R(int) GOF on F2 R1 [I > 2σ(I)] wR2 [I > 2σ(I)]
Form I
Form II
C7H17NO5 195.22 orthorhombic P212121 4.571(4) 10.174(8) 19.653(16) 90 90 90 914.0(13) 4 1.419 0.120 0.16 × 0.08 × 0.02 colorless, plate 5318 1698 0.0492 1.096 0.0549 0.1176
C7H17NO5 195.22 triclinic P1 4.819(6) 5.131(6) 9.627(11) 104.662(13) 93.985(14) 92.586(14) 229.2(5) 1 1.414 0.119 0.18 × 0.12 × 0.06 colorless, plate 3423 1762 0.0294 1.105 0.0345 0.092
Figure 7. Comparison of the structures of the two polymorphs of bufexamac. The reference molecules of the two structures are overlapped in the upper left-hand corner, and the dispersion from that overlap can be viewed with increasing distance from the origin molecules. Disorder in HT form removed for clarity. LT blue and HT red.
obtain a better comparison. The great similarity in the overall structures in spite of clear evidence for a phase change in the DSC and XRPD is consistent with the lack of a dramatic change in the cold stage microscopic image. Meglumine. The previously reported form I crystallizes in the space group P212121, and the new form II crystallizes in space group P1, both with one molecule in the asymmetric unit. P1 is a polar space group, but P212121 is only chiral. Because of this, the molecules always point in the same direction in form II, but they alternate directions in form I. The conformations of the molecules in the two structures are almost identical with a molecule overlay root-mean-square deviation of 0.14 (2). Both structures have the same number of hydrogen bonds, although the details are slightly different. The N1−H···O2−H bond having the biggest propensity does not occur in either of the two polymorphs even though both do have a N−H···O hydrogen bond. In both forms, there are chains connected with three hydrogen bonds from O5−H to N1 (propensity 0.45), from O3−H to O4 (0.51), and from O2−H to O1 (0.52). These chains propagate in the direction of the crystallographic a-axis in both forms. There are further hydrogen bond connections to adjacent chains (Figure 8). An O4−H···O2 (0.58) bond is present in both structures, but the bond comes from differing directions. There is another bond to the same adjacent molecule from O1−H to O5 (0.45) in the case of form I and to O3 (0.45) in
Figure 6. Bufexamac conformations at 200 K and at 250 K, and fingerprint plots of the two forms with HT form disorder removed for a better comparison.
account, the O−H does function as a donor for a CH2 group in the known structures. The differences between the fingerprint plots10 (Figure 6) of the two forms are very small, confirming the visual impression in Figure 7 that the molecular environment is similar in the two structures. The disorder in the HT structure was removed to 4368
dx.doi.org/10.1021/cg500478p | Cryst. Growth Des. 2014, 14, 4364−4370
Crystal Growth & Design
Article
Figure 9. Powder diffraction pattern of the original sample and the calculated patterns of the two forms of meglumine.
“propensity” is meant to give an indication of the possibility of multiple crystal forms; in that sense it can provide some guidance on the amount of “time and money”11 that might be expended in experimentally searching for multiple crystal forms. Nevertheless it is a statistical tool, and there is no guarantee that any particular compound will adhere to the statistics. The two cases presented here demonstrate the dichotomy in the use of the tool. For bufexamac the propensity tool suggests the possible existence of three crystal forms. We have found and characterized two. However, they were not discovered by a conventional solution screen but rather by a low temperature variable temperature microscope experiment and confirmed by variable temperature X-ray powder and single crystal diffraction. Since the hydrogen bonding is the same for the two crystal structures, they would not generate different points on the propensity graph, and no guidance would be given by the algorithm to search for additional crystal forms. In meglumine the hydrogen bonding is slightly different for the two forms, which should have led to two different points on the propensity plot. The actual structures of Form I and Form II, however, are not calculated into the putative structure landscape of the prediction, since the propensity for an OH group to act as a bifurcated acceptor is calculated at nearly zero.12 It is of interest to note that in our hands Form I crystallized from acetone and Form II from ethanol. The structure reported in the CSD NUYJEW, identical to Form I reported here, was also crystallized from ethanol, indicating that the solvent is not the decisive factor in the crystallization of the polymorphs. Thus, under certain conditions the two forms may appear either exclusively or concomitantly from ethanol. We have not determined those conditions. In spite of some of the apparent weakness and even failures, we believe that the propensity tool can be useful in suggesting the possibility of multiple crystal forms. Indeed we chose to work on these compounds because there was an indication that they might prove to exhibit multiple forms. While those indications were realized, they were not always for the reasons that led to those indications. The example of bufexamac indicates that it may be necessary to employ somewhat unconventional techniques to obtain new crystal forms. Nevertheless, in the absence of any other information we believe that the propensity tool can provide some usefulbut
Figure 8. Meglumine forms I and II looking down the crystallographic a-axis, showing the hydrogen bonds that connect adjacent chains, and fingerprint plots of the two forms.
the case of form II. This makes an adjacent chain run in a different direction in form I contrary to it running in the same direction in form II. Connection to another adjacent chain is through the N1−H, which in the case of form I bonds to an O5 (0.78) and in the case of form II to an O1 (0.75). Propensitywise the only bond that differs is the one with N1−H as a donor. Notably, the actual structures of form I and form II are not calculated into the putative structure landscape of the prediction, likely as the propensity for an OH group to act as a bifurcated acceptor is calculated as very close to zero and there being a number of combinations, at least 130000, with a better combined propensity. The fingerprint plots of the Hirshfeld surfaces of the two forms (Figure 8) are quite different in shape other than regarding the strong hydrogen bonding interactions. The O− H···O contacts are the inner spikes and the O−H···N contacts the outer spikes. Form I appears to be less densely packed than form II according to the fingerprint plots; however, the calculated densities of the two forms are very similar (form I 1.419 Mg/m3, form II 1.414 Mg/m3), and if anything, indicate that Form I is more dense. The calculated powder patterns (Figure 9) of the two forms are clearly distinguishable. The original purchased sample was of form I.
■
CONCLUSIONS The object of this research was essentially a proof of concept test of the hydrogen bonding propensity tool of the Cambridge Crystallographic Data Centre. At the outset of this discussion, it is important to note that the propensity tool is not claimed to be a means for predicting polymorphism. The choice of the term 4369
dx.doi.org/10.1021/cg500478p | Cryst. Growth Des. 2014, 14, 4364−4370
Crystal Growth & Design
Article
not absolute−guidelines in the initial stages of searching for solid forms of a compound.
■
ASSOCIATED CONTENT
* Supporting Information S
Video of bufexamac transition on the thermomicroscope; crystallographic information file. This material is available free of charge via the Internet at http://pubs.acs.org.
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS We are indeed grateful to Prof. Ulrich Griesser of the University of Innsbruck for providing the list of pharmaceuticals from the European Pharmacopoeia for which multiple crystal forms had not been previously reported.
■ ■
DEDICATION Dedicated to the memory of Mikhail (Misha) Antipin who made so many contributions to this field. ABBREVIATIONS CCDC, Cambridge Crystallographic Data Centre; CSD, Cambridge Structural Database; DSC, differential scanning calorimetry; XRPD, X-ray powder diffraction
■
REFERENCES
(1) Allen, F. H. Acta Crystallogr. 2002, B58, 380−388. (2) Macrae, F.; Bruno, I. J.; Chisholm, J. A.; Edgington, P. R.; McCabe, P.; Pidcock, E.; Rodriguez-Monge, L.; Taylor, R.; van de Streek, J.; Wood, P. A. J. Appl. Crystallogr. 2008, 41, 466−470. (3) Galek, P. T. A.; Fábián, L.; Motherwell, W. D. S.; Allen, F. H.; Feeder, N. Acta Crystallogr. 2007, B63, 768−782. (4) Galek, P. T. A.; Allen, F. H.; Fábián, L.; Feeder, N. CrystEngComm 2009, 11, 2634−2639. (5) Galek, P. T. A.; Fábián, L.; Allen, F. H. CrystEngComm 2010, 12, 2091−2099. (6) Mercury User Guide and Tutorials, Appendix C: Tutorials, Assessing the Risk of Polymorphism via H-Bonding Propensities. (7) EMA/246395/2010, 22 April 2010. European Medicines Agency, 7 Westferry Circus, Canary Wharf, London E14 4HB, United Kingdom. http://www.ema.europa.eu/docs/en_GB/document_ library/Press_release/2010/04/WC500089623.pdf. (8) Kraudelt, H.; Schilde, U.; Uhlemann, E.; Kristallogr, Z. New Cryst. Struct. 1998, 213, 177. (9) Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112−122. (10) Spackman, M. A.; McKinnon, J. J. CrystEngComm 2002, 4, 378− 392. (11) McCrone, W. C. In Physics and Chemistry of the Organic Solid State; Fox, D.; Labes, M. M.; Weissberger, A., Eds.; Interscience Publishers: London, 1965; Vol. 2, pp 725−767. (12) In the new 2014 Mercury CSD version 3.3.1, both experimental structures can be seen in the putative structure landscape (now “possible polymorphs”) chart, though they are nevertheless not calculated in as possible structures when the structures are not used in the propensity calculation. Part of the problem is likely the huge number of possible combinations available for meglumine. It seems a maximum of “only” 150 000 possible structures are calculated for the chart, and the experimental structures happen to not be in these.
4370
dx.doi.org/10.1021/cg500478p | Cryst. Growth Des. 2014, 14, 4364−4370
