Monoclinic Paracetamol vs. Paracetamol-4,4 ... https://www.researchgate.net/.../322587241_Monoclinic_Paracetamol_vs_Paracetamol-4...

crystals Article

Monoclinic Paracetamol vs. Paracetamol-4,40-Bipyridine Co-Crystal; What Is the Difference? A Charge Density Study

Jonathan J. Du 1 , Felcia Lai 1 , Linda Váradi 1 ID , Peter A. Williams 1,2 , Paul W. Groundwater 1 James A. Platts 3 ID , David E. Hibbs 1, * and Jacob Overgaard 4, * ID 1

2 3 4

*

ID

,

Faculty of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia; [email protected] (J.J.D.); [email protected] (F.L.); [email protected] (L.V.); [email protected] (P.A.W.); [email protected] (P.W.G.) School of Science and Health, Western Sydney University, Locked Bag 1797, Penrith, NSW 2751, Australia School of Chemistry, Cardiff University, Cardiff CF10 3AT, UK; [email protected] Department of Chemistry, Center for Materials Crystallography, Aarhus University, Langelandsgade 140, DK-8000 Aarhus C, Denmark Correspondence: [email protected] (D.E.H.); [email protected] (J.O.)

Received: 22 December 2017; Accepted: 15 January 2018; Published: 18 January 2018

Abstract: Paracetamol (PCM) has two well-documented polymorphic forms at room temperature; monoclinic Form I is more stable than the other orthorhombic Form II. Form II exhibits improved tabletting properties compared to Form I due to low shearing forces; however, difficulties in its manufacture have limited its use in industrial manufacture. Previous studies have found that the introduction of a co-former to form co-crystals would allow the PCM molecule to exist in a conformation similar to that of the orthorhombic form while being more stable at room temperature. Experimental charge density analysis of the paracetamol-4,40 -bipyridine (PCM-44BP) co-crystal system, and its constituent molecules, has been carried out to examine the forces that drive the formation and stabilisation of the co-crystal, while allowing PCM to maintain a packing motif similar to that found in Form II. It is hoped studies on this well-known compound will help apply the knowledge gained to other drug molecules that are less successful. The PCM molecules in the co-crystal were found to exhibit similar packing motifs to that found in Form I, however, intercalation of the 44BP molecule between the PCM layers resulted in a shallower angle between molecular planes, which could result in the required lateral shear. Topological analysis identified more weak interactions in the co-crystal compared to the individual molecules, thus allowing for greater stability as evidenced by the lattice energies. Weak interactions in the PCM-44BP co-crystal were found to range in strength from 4.08–84.33 kJ mol−1 , and this variety allowed the PCM-44BP planes to be held together, while a weak π–π interaction (15.14 kJ mol−1 ) allowed lateral shear to occur, thus mimicking the planes found in Form II PCM and offering the possibility of improved tabletting properties. A comparison of integrated atomic charges between partitions of the PCM molecules in the single and co-crystal found that the hydroxyl and amide groups were involved in greater hydrogen bonding in the co-crystal, resulting in a charge redistribution across the molecule evidenced by a larger molecular dipole moment (µ = 12.34D). These findings, in addition to the co-crystal having the largest lattice energy, form a potential basis with which to predict that the co-crystal exhibits improved solubility and stability profiles. It is anticipated that these findings will contribute to improvements in the formulation and other physical properties of PCM and other pharmaceutical compounds. Keywords: paracetamol; charge density study; tableting performance; co-crystals

Crystals 2018, 8, 46; doi:10.3390/cryst8010046

www.mdpi.com/journal/crystals

Crystals 2018, 8, 46

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1. Introduction Crystal engineering refers to the rational design of solids by inducing the reproducible formation of weak interactions between pairs of functional groups [1]. This field has recently undergone a resurgence because of increased interest from pharmaceutical companies and research institutions. This coincides with a recent reduction in the number of novel drugs approved by the FDA and other global regulatory agencies relative to the early 1990s [2]. Due to the excessive costs associated with bringing a new drug from the design stage through to the market, many pharmaceutical companies have opted to revisit older drug candidates that did not make it to market and to seek to improve their physicochemical properties. This approach encompasses a very large number of drugs as over 90% of drug candidates fail due to poor physicochemical properties, resulting in sub-optimal in vivo performance or a requirement for the development of inconvenient dosage forms [3]. Incorporating these drugs into co-crystal systems has emerged as an innovative and effective means of improving the physicochemical properties of these agents without any requirements for covalent modifications [4]. This is especially relevant in cases where salt formation is not a viable option (i.e., in cases where there is no ionisable group on the drug). There continues to be much debate regarding the definition of co-crystals, including whether solvates and hydrates are included in the same definition: the FDA has defined co-crystals as “solids that are crystalline materials composed of two or more molecules in the same crystal lattice” with the interactions between them governed by “non-ionic interactions” [5]. The use of co-crystals to modulate the physicochemical properties of an active pharmaceutical ingredient (API) has seen some success in the form of dapagliflozin, the sodium/glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes (T2D) [6]. However, the approach is still in its infancy with current approaches giving unpredictable results. Paracetamol (PCM) has been extensively studied both individually and as part of co-crystal systems; it is known that PCM exists in three forms with the monoclinic Form I being the most thermodynamically stable. Two other, orthorhombic, metastable forms require more sophisticated growth conditions including melting and anhydrous nitrogen conditions for Form III [7–9]. Although PCM is well known, the stable monoclinic Form I is known to have very poor compressibility and tabletability properties, while the orthorhombic metastable Form II exhibits improved tabletability [10,11]. Commercial production of PCM tablets currently utilizes Form I PCM in combination with gelatine or starch derivatives to improve its tableting properties [7]. The commercial success of PCM Form I has rendered the poor tabletability a non-issue. However, it is hoped studies on such a well-known drug molecule, resulting in increased understanding of the relationship between different polymorphic forms and their physical properties may lay the fundamentals for applying this knowledge to less successful drugs. Different packing motifs in the PCM polymorphs are believed to be one of the reasons why they exhibit different physical properties with Form I forming zig-zag shapes via O–H···O=C hydrogen bonds and Form II being organised into parallel sheets and slip planes, which make it easier to form into tablets via N–H···O and O–H···O intermolecular hydrogen bonds [12]. It has been established that Form II can only be produced reliably from the melt, and many research groups have thus tried to co-crystallise PCM in attempts to replicate the sheet packing motif and slip planes present in Form II. This has been achieved with limited success; a variety of co-formers have been used, with only three forming the desired motif [12,13]. As epitomised by this example alone, the brute force approach to developing co-crystals with the desired physical properties is no longer feasible, and a more targeted approach is required. Greater insights into the driving forces behind the formation of weak interactions, such as hydrogen bonds, van der Waals and π–π interactions, are required to develop a more streamlined and information-driven approach to developing pharmaceutically-desirable co-crystals, as well as to help develop the field of crystal engineering. High resolution X-ray diffraction can be used to determine the electron density distribution (EDD) in crystalline systems. Here, we present a comparative analysis of the EDD between PCM Form I (1), 4,40 -bipyridine (44BP) (2) and the PCM-44BP co-crystal (3) with the aim of examining the weak

Crystals 2018, 8, 46 Crystals 2018, 8, 46

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the tabletability of different forms of PCM. Structures of the constituent molecules can be foundthe in interactions present and rationalising the observations reported in other publications regarding Figure 1. of different forms of PCM. Structures of the constituent molecules can be found in Figure 1. tabletability

0 -bipyridine (44BP) (PCM) (1) (1) and and 4,4 4,4′-bipyridine (44BP) (2). (2). Figure 1. Chemical structures of paracetamol (PCM)

2. Methods Methods 2. Raw materials materials of of (1) (1) and and (2) (2) were were purchased purchased from from Sigma Sigma Aldrich Aldrich and and used used without without further further Raw purification. Crystals for (1) were grown via slow evaporation from ethanol. Crystals for (2) were as purification. Crystals for (1) were grown via slow evaporation from ethanol. Crystals for (2) were as received from from Sigma Sigma Aldrich. Aldrich. The The co-crystal co-crystal (3) was grown grown by by dissolving dissolving equimolar equimolar amounts received (3) was amounts of of (1) (1) and (2) individually, in ethanol, before mixing, and the solution was allowed to evaporate. and (2) individually, in ethanol, before mixing, and the solution was allowed to evaporate. Computational Computational Methods Methods Gas phase, single point (SP) calculations were were performed performed on on (1), (2) and (3) with geometry taken from the high-order high-order experimental experimental coordinates. coordinates. All theoretical calculations were performed with the Gaussian 09 suite [14] [14] at at the the 6-311++G** 6-311++G** level of theory for all all structures. structures. All calculations used the three-parameter hybrid exchange function developed by Becke [15] in conjunction conjunction (vide supra) with the exchange correlation potential, corrected via gradient developed by Lee et al. [16] together together with the long-range correction proposed by Tawada et al. [17,18] (CAM-B3LYP). (CAM-B3LYP). Analysis of the topology of electron density from the experimental model was performed via the properties module of XD, XDPROP XDPROP [19], [19], while while analysis analysis of the electron density for the theoretical densities was performed using the AIMALL [20] package. package. Details collection, integration and reduction of data of candata be found in the Supporting Detailson onthe the collection, integration and reduction can be found in the Information. Supporting The multipole refinement procedure used has procedure been reported in previous publications [21–23]. Refer to Information. The multipole refinement used has been reported in previous Table 1 for selected crystallographic information from the independent atom model (IAM) and multipole publications [21–23]. Refer to Table 1 for selected crystallographic information from the independent (EXP) refinements. atom model (IAM) and multipole (EXP) refinements. Table Table 1. 1. Selected crystallographic crystallographic information information for for (1), (1), (2) (2) and and (3). (3). IAM, IAM, independent independent atom atom model. model.

1 89H CC N91N O21O2 8H 151.16 151.16 0.1 × 0.25 × 0.15 0.1 ×150 0.25 × 0.15 Monoclinic 150 P21 /n Monoclinic 7.093(1) 9.241(1) P21/n 11.635(1) 7.093(1) 9.241(1) 97.75(1) 11.635(1) 1

Formula Formula Molecular Mass Molecular Mass Crystal Size (mm) Crystal Size(K) (mm) Temperature Crystal System (K) Temperature Space Group Crystal a (Å)System b Space(Å)Group c (Å) a (Å) α (o ) o) b β ((Å) o) γc ((Å) Volume (Å3 ) αZ (o) Refinement β (oMethod ) No. of Reflections collected o) γ ( No. Unique Rint (Å3) Volume Z Refinement Method

755.67(1) 4 Full-matrix least-squares 97.75(1) on F2 325,928 12,351 0.0344 755.67(1)

4 Full-matrix leastsquares on F2

22 CC HH NN 2020 16 16 4 4 312.37 312.37 0.1 × 0.2 × 0.5 0.1 ×150 0.2 × 0.5 Triclinic 150 P1 Triclinic 8.693(2) 8.735(2) P1 10.982(2) 8.693(2) 85.14(2) 8.735(2) 85.37(2) 98.95(2) 10.982(2) 813.80(3) 85.14(2) 2 Full-matrix 85.37(2) least-squares on F2 55,114 98.95(2) 13,284 0.0162 813.80(3)


33

C 36H H3434NN6 O 6O C36 4 4 614.69 614.69 0.3 × 0.25 × 0.3 0.3 × 0.25 150 × 0.3 Monoclinic 150 P21 /c Monoclinic 11.307(1) 24.118(2) P21/c 11.566(1) 11.307(1) 24.118(2) 96.21(1) 11.566(1)

3135.72 4 Full-matrix96.21(1) least-squares on F2 410,446 35,389 0.0518 3135.72



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Table 1. Cont.

Completeness (%) No. Reflections Used ρc (g·cm−1 ) F(000) µ (mm−1 ) sin θ/λmax θ Range for Data Collection (◦ ) Index Ranges IAM Refinement Final R1, wR2 Goodness of Fit Residual Density (eÅ−3 ) Multipole Refinement Nobs /Nvar R(F), R(F2 ), all data R(F), R(F2 ) > 2σ(F) Goodness of Fit Residual Density (eÅ−3 )

1

2

3

99.9 10,0164 1.329 320 0.096 1.25 3.534–62.673 −17 ≤ h ≤ 17 −23 ≤ k ≤ 23 −29 ≤ l ≤ 29

99.1 19,186 1.275 328 0.078 1.00 2.920–45.294 −17 ≤ h ≤ 17 −17 ≤ k ≤ 17 −21 ≤ l ≤ 21

99.0 170,540 1.336 1316 0.102 1.11 3.379–52.222 −24 ≤ h ≤ 25 −53 ≤ k ≤ 53 −25 ≤ l ≤ 25

0.0329, 0.118 0.983 −0.31, 0.5

0.0470, 0.150 1.018 −0.27, 0.49

0.0612, 0.195 1.012 0.26, 0.56

31.13 0.0388, 0.0377 0.0221, 0.0370 2.8370 −0.256, 0.107

16.76 0.0435, 0.0305 0.0271, 0.0298 1.4609 −0.126, 0.116

15.29 0.1027, 0.0439 0.0408, 0.0350 1.5576 −0.130, 0.130

3. Results 3.1. Geometry Bond lengths and angles for all experimental structures were obtained from the multipole model (MM) refinement output. For all of the structures, the X-ray structure was in excellent agreement with results reported in the literature with mean differences in bond lengths of 0.002, 0.044 and 0.001 Å for (1), (2) and (3), respectively. Similarly, the mean differences in angles were 0.086, 0.039 and 0.043◦ . Refer to Tables S4–S21 (ESI) for a full list of bond lengths and angles. The crystal structure of (1) contained one molecule of PCM in the asymmetric unit. The asymmetric units of (2) and (3) both contained more than one molecule with (2) containing two 44BP molecules in a T-shaped arrangement and (3) 2018, containing two molecules each of PCM and 44BP in an alternating pattern. Refer to Figures5 of 2–4 Crystals 8, 46 18 for ORTEP diagrams and labelling schemes.

Figure 2. ORTEP diagram of PCM (1). Thermal ellipsoids are shown at the 50% probability level [24]. Figure 2. ORTEP diagram of PCM (1). Thermal ellipsoids are shown at the 50% probability level [24].


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Figure 2. ORTEP diagram of PCM (1). Thermal ellipsoids are shown at the 50% probability level [24].


Figure Figure3. 3. ORTEP ORTEPdiagram diagram of of 44BP 44BP (2). (2). Thermal Thermalellipsoids ellipsoidsare are shown shown at at the the 50% 50% probability probability level level [24]. [24].

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Figure 4. ORTEP diagram of the PCM-44BP co-crystal (3).(3). Thermal ellipsoids areare shown at the 50% Figure 4. ORTEP diagram of the PCM-44BP co-crystal Thermal ellipsoids shown at the 50% probability level [24]. probability level [24].

The conformational geometry of PCM was found to vary between individual and co-crystal The conformational geometry of PCM was found to vary between thethe individual and co-crystal forms. The C(05)-C(04)-N(01)-C(07) torsion angle highlighting orientation acetamide group forms. The C(05)-C(04)-N(01)-C(07) torsion angle highlighting thethe orientation of of thethe acetamide group ◦ relative aromatic ring was foundtotobebe22.69 22.69°. Theanalogous analogousangles angles in in (3) (3) were found to relative to to thethe aromatic ring inin (1)(1) was found . The to be 10.28 and 14.49° 14.49◦ for for the the two two crystallographically crystallographicallyindependent independentPCM PCMmolecules. molecules.Figure Figure55shows showsthe PCM in both (1) and (3). Figure 6 shows the differing conformation of the PCM molecules thepacking packingofof PCM in both (1) and (3). Figure 6 shows the differing conformation of the PCM in (1) and differing torsion angles. The zig-zag packing previously described by molecules in(3) (1)due andto(3)the due to the differing torsion angles. The zig-zagshape packing shape previously Ahmed et al. [25] in the monoclinic form of PCM is clearly present in both (1) and (3) and explains why (3) exhibits worse tabletting properties than other PCM co-crystals [13]. However, further analysis of the angle between PCM planes reveals a much larger angle between PCM packing planes (116.91 vs. 149.81° for (1) in the C(04)-C(07)-C(02) plane and (3) in the C(07′)-C(08′)-N(01) plane). These differences in PCM packing can be attributed to the conformation of the 44BP molecules


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described by Ahmed et al. [25] in the monoclinic form of PCM is clearly present in both (1) and (3) and explains why (3) exhibits worse tabletting properties than other PCM co-crystals [13]. However, further analysis of the angle between PCM planes reveals a much larger angle between PCM packing planes (116.91 vs. 149.81◦ for (1) in the C(04)-C(07)-C(02) plane and (3) in the C(070 )-C(080 )-N(01) plane). These differences in PCM packing can be attributed to the conformation of the 44BP molecules in (3). There are no major differences between the conformations of the 44BP molecules in (2) and (3) with the dihedral angles (C(4)-C(5)-C(6)-C(7)) being 16.6 and −34.6◦ in (2) and 32.4 and 19.9◦ in (3). Previous studies have shown that the minimum conformation energy structure of 44BP corresponds to a dihedral angle of 38.6◦ [26]. The conformation of the second 44BP molecule in both (1) and (3) resulting in a higher energy state is in accordance with previous observations that 44BP molecules are highly influenced by surrounding interactions such as crystal packing effects [27]. Based on the previous discussion, it can be said that the intercalation of the 44BP molecules into the PCM packing structure in (3) causes the increased angle between PCM packing planes when compared to (1) and Crystals2018, 2018,8, 8,46 46 of18 18 Crystals 77of results in improved tableting performance over the single constituent crystal.

(a) (a)

(b) (b) Figure5. 5.Diagram Diagramshowing showingthe thepacking packingmotif motifof ofthe thePCM PCMmolecule moleculein in(a) (a)(1) (1)and and(b) (b)(3) (3)[28]. [28]. Figure 5. packing motif of the PCM molecule in (a) (1) and (b) (3) [28]. Figure

Figure 6. Structural overlays of PCM in (1) (red) and (3) blue and green. The 44BP molecule has been Figure 6. 6. Structural overlays of of PCM PCM in in (1) (1) (red) (red) and and (3) (3) blue blue and and green. green. The The 44BP 44BP molecule molecule has has been been Figure Structural overlays omitted for clarity [29]. omitted for clarity [29]. omitted for clarity [29].

3.2. Topological Topological Analysis Analysis 3.2. Topological analysis analysis based based on on Bader’s Bader’s Atoms Atoms in in Molecules Molecules (AIM) (AIM) [30] [30] theory theory were were carried carried out out Topological on both the EXP and SP models. Completeness of analysis was ensured by ensuring satisfaction of on both the EXP and SP models. Completeness of analysis was ensured by ensuring satisfaction of


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3.2. Topological Analysis Topological analysis based on Bader’s Atoms in Molecules (AIM) [30] theory were carried out on both the EXP and SP models. Completeness of analysis was ensured by ensuring satisfaction of the Poincaré–Hopf or its crystalline equivalent, the Morse relationship [31]. There was very little difference in the topological parameters obtained from the EXP and SP models as seen through the small differences in ρbcp and ∇2 ρbcp. Refer to Tables S22–S27 (ESI) for a full list of BCP and ring critical points (RCPs) found in our analysis. For (1), mean differences of 0.044 eÅ−3 and 4.26 eÅ−5 were found for ρbcp and ∇2 ρbcp , respectively. For (2) and (3), mean differences of 0.053 and 0.020 e Å−3 and 1.68 and 3.76 eÅ−5 were found for ρbcp and ∇2 ρbcp , respectively. For (1), the largest discrepancies between EXP and SP were in ∇2 ρbcp for the O(01)-H(01), N(01)-H(01A) and O(02)-C(07) bonds. For the first two bonds, the EXP ∇2 ρbcp was greater than the SP value, while the converse was true for the third bond. In all cases, both models report open shell interactions as expected of covalent bonds; however, the differences in magnitude can be attributed to the first two bonds being hydrogen bond donors, while the third is a hydrogen bond acceptor. Similar trends can also be seen in the analogous bonds in (3), which reiterates the findings discussed above that the 44BP molecules seem to intercalate between the PCM molecules and do not interfere with the intermolecular bonding between those molecules. There were no significant differences between the EXP and SP models for (2). 3.3. Hydrogen Bonds There were no clear trends present in the hydrogen bonds found for all systems from a geometrical perspective. One and two intramolecular bonds were found in (1) and (3), respectively. In each case, the bond was located in the PCM molecule between the carbonyl oxygen and aromatic hydrogen (C(05)–H(05)···O(02)). The hydrogen bond acceptor atoms involved in intramolecular bonding in (2) were also involved in similar hydrogen bonding arrangements in (3). Estimations of bond strength were obtained via a method developed by Abramov [32] and Espinosa [33], which used ρbcp and ∇2 ρbcp values to calculate the total (H), kinetic (G) and potential (V) energy density of the hydrogen bonds found. The topology of all hydrogen bonds found was in accordance with suggestions by Koch et al. that these bonds could be characterised by having relatively low ρbcp and positive ∇2 ρbcp values, indicating closed shell interactions. H-bonds can be separated into three groups by their strengths: weak H-bonds (EHB < 20 kJ·mol−1 ), moderate strength H-bonds (EHB = 20–40 kJ mol−1 ) and strong H-bonds (EHB > 60 kJ mol−1 ) [34]. Details of the hydrogen bonds as determined by topological analysis are reported in Table 2 for (3). Similar details for (1) and (2) are in the Supplementary Information in Tables S31 and S32, respectively. Table 2. Topological analysis of hydrogen bonding in (3). Standard uncertainties have been omitted from the table for clarity. They are closely scattered around 0.02 eÅ−3 (ρbcp ) and 0.05 eÅ−5 (∇2 ρbcp ). Bond Intramolecular C(050 )–H(050 )···O(020 ) C(05)–H(05)···O(02) Intermolecular N(01)–H(01)···N(2) N(010 )–H(010 )···N(20 ) C(02)–H(02)···N(10 ) a C(030 )–H(030 )···N(1) b C(30 )–H(30 )···O(010 ) c C(4)–H(4)···O(020 ) d C(80 )–H(80 )···O(01) e C(08)–H(08A)···O(010 ) f C(9)–H(9)···O(02) g O(01)–H(01A)···O(020 ) h Short Contacts H(9)···H(03)

ρ (eÅ−3 )

∇2 ρ (eÅ−5 )

ε

dH···bcp (Å)

dA···bcp (Å)

G/Eh (eÅ−3 )

V/Eh (eÅ−3 )

H/Eh (eÅ−3 )

G/ρ

EHB (kJ mol−1 )

0.129 0.135

1.7 1.8

0.21 0.15

0.911 0.918

1.307 1.303

0.11 0.11

−0.09 −0.1

0.01 0.01

0.83

36.18 38.4

0.14 0.172 0.051 0.050 0.030 0.033 0.01 0.011 0.036 0.203

2.5 2.8 0.6 0.6 0.5 0.5 0.4 0.5 0.6 4.5

0.06 0.05 0.30 0.09 0.41 0.11 5.05 4.47 0.24 0.02

0.698 0.668 1.187 1.136 1.102 1.061 1.048 1.041 1.096 0.575

1.316 1.267 1.576 1.516 1.562 1.531 1.716 1.656 1.503 1.161

0.15 0.17 0.03 0.04 0.03 0.03 0.02 0.02 0.03 0.26

−0.12 −0.15 −0.03 −0.03 −0.02 −0.02 −0.01 −0.01 −0.02 −0.22

0.03 0.02 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.05

1.06 1.02 0.68 0.71 0.87 0.85 1.98 1.95 0.81 1.3

46.45 58.97 10.02 10.09 6.44 7.04 4.08 4.44 7.53 84.33

0.041

0.6

0.91

1.301

1.105

0.03

−0.02

0.01

0.73

8.07

Symmetry operators: a –x + 1, y − 1/2, −z + 1/2; b –x + 1, y + 1/2, −z + 1/2; c x, −y + 3/2, z−1/2; d –x + 2, −y + 1, −z + 1; e x + 1, −y + 3/2, z + 1/2; f –x + 2, −y + 1, −z + 1; g –x + 1, −y + 1, −z + 1; h x − 1, y, z − 1.


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The four hydrogen bonds in (1) all have EHB > 20 kJ mol−1 . The intramolecular bond is the weakest of the four, while the remaining bonds are all above 50 kJ mol−1 . The three intermolecular hydrogen bonds spread out in opposite directions to stabilise the two PCM molecules perpendicular to the original. An approximate binding energy of 190 kJ mol−1 in this area resulting in the formation of a perpendicular plane of PCM is responsible for the zig-zag packing motif and poor compressibility of the monoclinic form of PCM, confirming the observations reported previously [13]. Figure 7 shows the Laplacian of the intermolecular hydrogen bonds, which bond the PCM molecules in (1) together into the zig-zag packing shape. Crystals 2018, 8, 46

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(a) Figure 7. -∇ ρ

2 bcp

(b)

maps showing intermolecular hydrogen bonds that form the primary bonding motifs

2ρ Figure in 7. (1) -∇in maps showing intermolecular hydrogen bonds that form the primary bonding motifs bcp(a) the C(01)-O(01)-H(01) plane and (b) H(03)–N(01)-H(01A) plane. Contour lines are plotted in (1) inonthe (a)scale. C(01)-O(01)-H(01) plane andcontours, (b) H(03)–N(01)-H(01A) plane. Contour lines are plotted a log Solid lines indicate positive and dashed lines indicate negative contours. on a log scale. Solid lines indicate positive contours, and dashed lines indicate negative contours.

The crystal structure of (2) is held together by weak interactions with all hydrogen bonds being less than 20 kJ mol−1 in strength. The hydrogen bonds between N(2′) and H(10′) and H(1′) help the The crystal structure of (2) is held together by weak interactions with all hydrogen bonds being structure to maintain the T-shaped arrangement in the asymmetric unit. The two bonds however are −1 in strength. The hydrogen bonds between N(20 ) and H(100 ) and H(10 ) help the less than molstrength, not20 of kJ equal with the N(2)···H(10′) being stronger than the N(2)···H(1′) bond (18.8 kJ mol−1 structure maintain T-shaped arrangement in the asymmetric unit. are vs. to 8.36 kJ mol−1).the Previous studies [35,36] have examined the concept of loneThe pairtwo (LP) bonds positionhowever as a 0 ) bond predictor of hydrogen bondN(2) directionality and have found than that the theH(1 value of the(18.8 DHAkJ mol−1 not of equal strength, with the ···H(100 ) being stronger thecloser N(2)··· and DH-LP angles, the pair more (LP) likelyposition a vs. 8.36(donor-hydrogen-acceptor) kJ mol−1 ). Previous studies [35,36](donor-hydrogen-lone have examined the pair) concept of lone as hydrogen bond is to form. Furthermore, the DH-LP angle may also be reflective of the direction of a predictor of hydrogen bond directionality and have found that the closer the value of the DHA polarisation of the valence shell of the acceptor atom and may have a direct effect on bond strength. (donor-hydrogen-acceptor) DH-LP (donor-hydrogen-lone pair) angles, likely a hydrogen The DH-LP angles for and the C(10′)–H(10′)···N(2) and C(1′)–H(1′)···N(2) bonds the are more 150.8 and 143.4° bond isdegrees, to form.respectively. Furthermore, DH-LP may bethe reflective thepair direction of polarisation of This the is also seen inangle Figure 8a,calso where nitrogenof lone is in a more linear alignment H(10′). The difference in DH-LP may be the the disparity bond angles the valence shell towards of the acceptor atom and may have aangle direct effect oncause bondofstrength. TheinDH-LP 0 )···N(2) in 0 )··· The difference strength between these stabilising interactions may◦contribute the for the strength. C(100 )–H(10 and C(10 )–H(1 N(2)two bonds are 150.8 and 143.4 degrees,torespectively. presence of two 44BP molecules in the asymmetric unit with differing geometries. This is also seen in Figure 8a,c where the nitrogen lone pair is in a more linear alignment towards H(100 ). Although the intermolecular bonds present in (2) were not conserved in (3), the nitrogen atoms The difference in DH-LP angle may be the cause of the disparity in bond strength. The difference play a similar role and form very similar bonding motifs. This can be seen in Figure 8b,e, where in strength between these two stabilising may to the presence two 44BP analogous nitrogen atoms (N(2) in (2) and interactions N(2′) in (3) both formcontribute bifurcated hydrogen bonds andofcan molecules in the asymmetric unit with differing geometries. be seen both EXP and SP models. Figure 8e shows a third hydrogen bond between N(2′) and H(03′) in the SP the model for (3). This bond waspresent not found in the topological analysisin of(3), the the EXPnitrogen model. atoms Although intermolecular bonds in (2) were not conserved Interestingly, the DH-LP angles for the N(2′)···H(03′) and N(2′)···H(08E) bonds are very similar play a similar role and form very similar bonding motifs. This can be seen in Figure with 8b,e, where values of 128.6 and 132.8°, respectively. Visual analysis of the polarisation of the N(2′) atom in analogous nitrogen atoms (N(2) in (2) and N(20 ) in (3) both form bifurcated hydrogen bonds and can be Figure 8d shows that for the EXP model, the lone pair is almost directly facing H(01′) with a slight seen both EXP and SP models. Figure 8e shows a third hydrogen bond between N(20 ) and H(030 ) in the deviation towards H(08E), whereas in Figure 8e, the polarization of the same atom appears to have SP model forspread (3). This bond was This not difference found in in the topological analysis of in the model. some towards H(03′). polarisation is also reflected theEXP difference in Interestingly, bond 0 )···H(030 ) and N(20 )···H(08E) bonds are very similar with values of 128.6 the DH-LP angles for the N(2 strengths. In the EXP model, both N(2′)···H(08E) and N(2′)···H(01) bonds have a strength of −1, ◦ , respectively. 58.97 kJ mol−1, whileVisual the same bonds in model have of strengths 62.43 kJ8d mol and 132.8 analysis of the theSP polarisation the N(2of0 ) 10.23 atomand in Figure shows that 0 respectively. Crystal packing effects present only in the EXP model in combination with the relatively for the EXP model, the lone pair is almost directly facing H(01 ) with a slight deviation towards H(08E), weak bond strength of 10.34 kJ mol−1 for the N(2′)···H(03′) bond may explain its absence from the EXP model even though the DH-LP angles were similar.


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whereas in Figure 8e, the polarization of the same atom appears to have some spread towards H(030 ). This difference in polarisation is also reflected in the difference in bond strengths. In the EXP model, both N(20 )···H(08E) and N(20 )···H(01) bonds have a strength of 58.97 kJ mol−1 , while the same bonds in the SP model have strengths of 10.23 and 62.43 kJ mol−1 , respectively. Crystal packing effects present only in the EXP model in combination with the relatively weak bond strength of 10.34 kJ mol−1 for the N(20 )···H(030 ) bond may explain its absence from the EXP model even though the DH-LP angles were similar. Crystals 2018, 8, 46

10 of 18

(a)

(b)

(c)

(d)

(e) Figure 8. Topological maps pf hydrogen bonding involving analogous nitrogen atoms in (2) (a–c) and

Figure 8.(3)Topological pf(b) hydrogen bonding involving analogous nitrogen (2) (a–c) and (d,e). (a) N(2)maps in EXP N(2) single point (SP), (c) deformation density map of atoms N(2), (d)inN(2′) in 0 (3) (d,e). EXP (a) N(2) N(2) singlelines pointare(SP), (c) deformation map of N(2), (d) N(2 ) in EXP and and in (e)EXP N(2′)(b) in SP. Contour plotted on a log scale.density Solid lines indicate positive contours, (e) N(20 ) and in SP. Contour arenegative plottedcontours. on a log scale. Solid lines indicate positive contours, and dashed dashed lines lines indicate lines indicate negative contours.

The hydrogen bonds in (3) are of varying strength. The moderate strength intramolecular bonds within the PCM molecules C(05)–H(05)···O(02) and C(05′)–H(05′)···O(02′) help PCM to maintain its Therelatively hydrogen bonds in (3) are of varying strength. Thebonds moderate strength intramolecular planar conformation, with the slightly stronger in (3) compared to (1) due to the bonds 0 0 0 within the PCM molecules C(05)–H(05) ···O(02) andacetamide C(05 )–H(05 ···discussed O(02 ) help PCM to maintain its larger torsion angle between the aromatic ring and group)as above. Examination of the packing motifs in (3) show that the 44BP molecules stack on top of each other and form a bridge between two PCM molecules as seen in Figure 9. The O(01)–H(01A)···O(02′) bond (84.33 kJ mol−1) is


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relatively planar conformation, with the slightly stronger bonds in (3) compared to (1) due to the larger torsion angle between the aromatic ring and acetamide group as discussed above. Examination of the packing motifs in (3) show that the 44BP molecules stack on top of each other and form a bridge Crystals 2018, 8, 46 11 of 18 between two PCM molecules as seen in Figure 9. The O(01)–H(01A)···O(020 ) bond (84.33 kJ mol−1 ) is the strongest hydrogen bond andlinks linksthe thedifferent differentpacking packingmotifs motifstogether togetherby byjoining joining the the the strongest hydrogen bond in in (3)(3) and hydroxyl group group of of one one PCM PCM molecule molecule to to the theacetamide acetamidegroup group of ofanother. another. One One nitrogen nitrogen on on each each of ofthe the hydroxyl 0 ) forms moderate strength bonds (approximately 45 and 60 kJ mol−1 , 44BP molecules (N(2) and N(2 44BP molecules (N(2) and N(2′) forms moderate strength bonds (approximately 45 and 60 kJ mol−1, 0 ) forms two hydrogen bonds to its respectively), while while the respectively), the remaining remainingnitrogen nitrogenforms formsweak weakbonds. bonds.N(2 N(2′) forms two hydrogen bonds to 0 closest PCM neighbour. The two bonds formed by N(2 ) along with the bond by N(10 )by result in its closest PCM neighbour. The two bonds formed by N(2′) along with theformed bond formed N(1′) 0 0 ◦ a twist in the C(5 )–C(6 ) axis to a dihedral angle of 19.88 , while previous literature has found that result in a twist in the C(5′)–C(6′) axis to a dihedral angle of 19.88°, while previous literature has ◦ [26]. The second 44BP the minimum stateenergy of 44BP corresponds to a dihedraltoangle of 38.6angle found that the energy minimum state of 44BP corresponds a dihedral of 38.6° [26]. The molecule, which is notwhich as involved in involved hydrogeninbonding, has a conformation closer to the energy second 44BP molecule, is not as hydrogen bonding, has a conformation closer to ◦ . The π–π interactions are present between the stacked 44BP minimum with a dihedral angle of 32.4 the energy minimum with a dihedral angle of 32.4°. The π–π interactions are present between the −1 molecules shown in Figure 9, and the interaction was found to befound 15.14 to kJ be mol the −1 stacked 44BP molecules shown in Figure 9, and the strength interaction strength was 15.14using kJ mol method developed by Waller et al. [37] on the SP model. This interaction can be considered weak. using the method developed by Waller et al. [37] on the SP model. This interaction can be considered Overall, the hydrogen bonds discussed above ensure that the planes and of 44BP molecules are weak. Overall, the hydrogen bonds discussed above ensure that of thePCM planes PCM and 44BP held together to maintain physical stability; however, the weak interaction between 44BP molecules molecules are held together to maintain physical stability; however, the weak interaction between allows lateral shear to occur, resulting in improved compressibility and tabletability ofand the 44BP molecules allows lateralpotentially shear to occur, potentially resulting in improved compressibility co-crystal like reported for form IIreported PCM. for form II PCM. tabletability of the the properties co-crystal like the properties An inverse relationship is known to exist between bond strength and length [38].length This relationship An inverse relationship is known to exist between bond strength and [38]. This was also investigated, thespecifically distances between the hydrogen and acceptor atoms of acceptor the bond relationship was also specifically investigated, the distances between the hydrogen and and the bond critical point (bcp) (d and d ). The relationship was found to be true for the H ··· bcp A ··· bcp atoms of the bond and the bond critical point (bcp) (dH···bcp and dA···bcp). The relationship was found to hydrogen bonds found across all systems. be true for the hydrogen bonds found across all systems.

Figure Figure9. 9.Packing Packingdiagram diagramof ofthe thebonding bondingmotif motiffound foundin in(3) (3)[28]. [28].

3.4. 3.4. Hirshfeld HirshfeldSurfaces SurfacesAnalysis Analysis Three-dimensional Hirshfeldsurfaces surfacesand and corresponding two-dimensional fingerprint Three-dimensional Hirshfeld corresponding two-dimensional fingerprint plotsplots were were generated using the CrystalExplorer program [39]. Hirshfeld surfaces provide a visual generated using the CrystalExplorer program [39]. Hirshfeld surfaces provide a visual representation representation the electron density aroundillustrating a molecule,the illustrating extent which the of the electronof density around a molecule, extent to the which theto electrons in electrons the space in the space surrounding the molecules can be attributed to the molecule. Hirshfeld surfaces surrounding the molecules can be attributed to the molecule. Hirshfeld surfaces for (1), (2) for and(1), (3) (2) and (3) can be found in the Supplementary Information in Figures S4–S6, while Figure 10 shows can be found in the Supplementary Information in Figures S4–S6, while Figure 10 shows selected selected fingerprint for (3). These plots are an of extension of thesurface Hirshfeld provide fingerprint plots for plots (3). These plots are an extension the Hirshfeld andsurface provideand information information on the distance of thenuclei interacting nuclei fromValues the surface. Values de and as di are on the distance of the interacting from the surface. of de and di areofdefined the defined distance as the distance from the Hirshfeld surface to the nearest external and internal nucleus, respectively. from the Hirshfeld surface to the nearest external and internal nucleus, respectively. The parameter The parameter dnorm is defined as thecontact normalised contact with reference to de, di and van der dnorm is defined as the normalised distance withdistance reference to d e , di and van der Waals radii Waals radii of the atoms [40]. Unsurprisingly, analysis of the fingerprint plots for systems of the atoms [40]. Unsurprisingly, analysis of the fingerprint plots for all systemsall shows thatshows H···H that H···H and C···C bonds contribute the most towards the Hirshfeld surface in the form of van der and C···C bonds contribute the most towards the Hirshfeld surface in the form of van der Waals Waals interactions. The remainder the fingerprint are composed of weak the weak interactions in interactions. The remainder of theoffingerprint plotsplots are composed of the interactions in the the system. The O···H and N···H interactions also play a role in maintaining the structure of (1) and system. The O···H and N···H interactions also play a role in maintaining the structure of (1) and (2), (2), accounting accounting for for 26.2% 26.2% and and 20.7% 20.7% of of the the fingerprint fingerprint plot, plot, respectively. respectively. Both Both of of these these interactions interactions contribute evenly to the fingerprint plot of (3), with 11.9% and 9.5%, respectively. Similar plots for (1) and (2) can be found in the Supplementary Information in Figures S7 and S8, respectively.


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contribute evenly to the fingerprint plot of (3), with 11.9% and 9.5%, respectively. Similar plots for (1) and (2) 2018, can be found in the Supplementary Information in Figures S7 and S8, respectively. Crystals 8, 46 12 of 18

(a)

(b)

(c) Figure10. 10.Two-dimensional Two-dimensionalfingerprint fingerprintplots plotsofof(a) (a)all allinteractions interactionsinin(3), (3),(b) (b)NN···H interactionsin in(3) (3) Figure ···H interactions and (c) O···H interactions in (3) [39]. and (c) O···H interactions in (3) [39].

3.5. Atomic Charges 3.5. Atomic Charges Integrated atomic basin charges were also determined from topological analysis of (1), (2) and Integrated atomic basin charges were also determined from topological analysis of (1), (2) and (3). (3). There was excellent agreement between the charges obtained from the EXP and SP models. There was excellent agreement between the charges obtained from the EXP and SP models. Across Across all systems, the largest differences were seen in the nitrogen atoms in the 44BP molecules in all systems, the largest differences were seen in the nitrogen atoms in the 44BP molecules in (2) and (2) and (3). The EXP model consistently underestimates the charge on these atoms by approximately (3). The EXP model consistently underestimates the charge on these atoms by approximately 0.3e. 0.3e. This can be attributed to their involvement in intermolecular hydrogen bonding often as This can be attributed to their involvement in intermolecular hydrogen bonding often as acceptors as acceptors as previously discussed. The gas phase nature of the SP calculations along with only the previously discussed. The gas phase nature of the SP calculations along with only the asymmetric unit asymmetric unit being evaluated removing supramolecular effects such as crystal packing may also being evaluated removing supramolecular effects such as crystal packing may also affect the charge affect the charge distribution. This is especially relevant in the case of the 44BP molecule, as it is well distribution. This is especially relevant in the case of the 44BP molecule, as it is well known that the known that the conformation is heavily influenced by its supramolecular environment [27,41]. conformation is heavily influenced by its supramolecular environment [27,41]. Similar analysis of the Similar analysis of the atomic charges between atoms in (1) and (2) and their analogous atoms in (3) atomic charges between atoms in (1) and (2) and their analogous atoms in (3) was insignificant, and no was insignificant, and no differences of note were found. differences of note were found. The PCM and 44BP molecules in all structures were partitioned into distinct chemical groups to The PCM and 44BP molecules in all structures were partitioned into distinct chemical groups to examine the changes in charge across each part of the molecule. PCM was separated into three examine the changes in charge across each part of the molecule. PCM was separated into three sections; sections; the -OH, aromatic ring and -CONH2CH3 groups. The -CONH2CH3 groups underwent the the -OH, aromatic ring and -CONH2 CH3 groups. The -CONH2 CH3 groups underwent the largest largest change going from having a net charge of −0.39e in (1) to −0.13 and −0.17e in (3). This is due to the group being significantly more involved in the hydrogen bond in the co-crystal where it contributes as a hydrogen bond acceptor four times and five times as a donor. The hydroxyl group also follows this trend, being involved in four hydrogen bonds including the O(01)-H(01A)···O(02′) bond, which was the strongest in (3) with a strength of 84.33 kJ mol−1. As required, the aromatic ring


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change going from having a net charge of −0.39e in (1) to −0.13 and −0.17e in (3). This is due to the group being significantly more involved in the hydrogen bond in the co-crystal where it contributes as Crystals 2018, 8, 46acceptor four times and five times as a donor. The hydroxyl group also follows this 13 of 18 a hydrogen bond 0 trend, being involved in four hydrogen bonds including the O(01)-H(01A)···O(02 ) bond, which Crystals 2018, 8,2018, 46 13 of 18was Crystals 2018,8,8,46 46 13ofof18 18 Crystals 13 PCM became morea strength positive to compensate. molecule was separated its axis of 1 . As44BP thein strongest in (3) with of 84.33 kJ mol−The required, the aromatic ring in along PCM became symmetry. Due to the 44BP molecules being involved in similar motifs in its (2)Due andto (3), is in PCM became more positive to compensate. Thewas 44BP molecule wasbonding separated along axis more positive to compensate. The 44BP molecule separated along its axisseparated of symmetry. theitof inPCM PCMbecame became morepositive positive tocompensate. compensate. The 44BPmolecule molecule was separated along itsofaxis axis of in more to The 44BP was along its unsurprising that there was very little difference in charge with the largest difference being 0.11e. symmetry. Due to the 44BP molecules being involved in similar bonding motifs in (2) and (3), it is 44BP molecules being involved in similar bonding motifs in (2) and (3), it is unsurprising that there symmetry.Due Duetotothe the44BP 44BPmolecules moleculesbeing beinginvolved involvedin insimilar similarbonding bondingmotifs motifsin in(2) (2)and and(3), (3),ititisis symmetry. Details of each moiety and their respective charges can be found in Details Table 3.ofThe complete list of unsurprising that there was difference in charge with the largest difference being 0.11e. was very little difference invery charge with thedifference largest difference being 0.11e. each moiety unsurprising thatthere there waslittle very little difference incharge charge with thelargest largest difference beingand 0.11e. unsurprising that was very little in with the difference being 0.11e. atomic charges can becan found in Tables S33–S35 in the Supplementary Information. Details of each moiety and their respective charges can be found in Table 3. The complete list of their respective charges be found in Table 3. The complete list of atomic charges can be found in of Detailsof ofeach eachmoiety moietyand andtheir theirrespective respectivecharges chargescan canbe befound foundin inTable Table3.3.The Thecomplete completelist list of Details atomic charges can be found in Tables S33–S35 in the Supplementary Information. Tables S33–S35 in the Supplementary Information. atomiccharges chargescan canbe befound foundin inTables TablesS33–S35 S33–S35in inthe theSupplementary SupplementaryInformation. Information. atomic Table 3. Atomic charges (e) from multipole refinement.

Table 3.Table Atomic charges (e) from multipole refinement. Table 3. Atomic charges (e) (e) from multipole refinement. Atomic charges (e) from multipole refinement. Table 3.3.Atomic charges from multipole refinement.

Paracetamol

Paracetamol Paracetamol Paracetamol Paracetamol

Ω(1)

Ω(1)

−0.52

−0.52

0.97

Ω(3) Molecule 1 −0.52 −0.71 Ω(1) Ω(3)Ω(1) Molecule 1 −0.71 Ω(1) −0.52 −0.52 Ω(3) Molecule 2 2−0.71 −0.63 Ω(3) Molecule −0.63 Ω(3) Molecule 1 Ω(3) Molecule 1 −0.71 Ω(3) Molecule 1 −0.71

0.97 0.86 0.97 0.86 0.97 0.97 0.78 0.86 0.78 0.86

Ω(3) Molecule 2 Ω(3)Molecule Molecule −0.63 Ω(3) 22 −0.63 −0.63

0.78

0.86

0.78 0.78

−0.39

−0.39 −0.13 −0.39 −0.13−0.39 −0.39 −0.17 −0.17 −0.13 −0.13

−0.13 −0.17 −0.17 −0.17

4,4-bipyridine 4,4-bipyridine 4,4-bipyridine 4,4-bipyridine 4,4-bipyridine

Ω(2)Molecule Molecule Ω(2) 1 1

−0.03 −0.03 Ω(2) Molecule 2 0.08 Ω(2) Molecule 2 0.08 Ω(2) Molecule 1 Ω(2)Molecule Molecule −0.03 Ω(3) Molecule 0.03 Ω(2) 11 1−0.03 −0.03 Ω(3) Molecule 1 20.08 0.03 Molecule 0.02 Ω(3) Ω(2) Molecule 2 Ω(2) Molecule 2 0.08 Ω(2) Molecule 2 Ω(3) Molecule 2 Ω(3) Molecule 1 Ω(3)Molecule Molecule Ω(3) 11 0.03

0.08 0.02 0.03 0.03

0.05 0.05 −0.05 −0.05 0.05 0.03 0.05 0.05 0.03 −0.05 0.06 −0.05 −0.05 0.03

0.06 0.03 0.03

3.6. Electrostatic Potential Ω(3) Molecule 2 0.06 0.06 Ω(3)Molecule Molecule 0.02 0.06 Ω(3) 22 0.02 0.02 3.6. Electrostatic Potential The molecular electrostatic potential (MEP) is an integral part in linking the results found in EDD 3.6.studies Electrostatic Potential The molecular electrostatic potential such (MEP) is an reactivities integral part inhow linking the results 3.6.Electrostatic Electrostatic Potential 3.6. such as thisPotential to real physical outcomes as atom and electrons move found when in EDD studies such as this to real physical outcomes such as atom reactivities and how electrons weak are formed. The MEP maps(MEP) in 11–13 arelinking athe visualisation of found these The interactions molecular electrostatic potential (MEP) isshown an integral part in linking results found in move Themolecular molecular electrostatic potential anFigures integral part in theresults results in The electrostatic potential (MEP) isisan integral part in linking the found in when weak interactions are formed. The for MEP maps shown intheir Figures 11–13 are aco-crystalline visualisation of properties, and a comparison of these maps the molecules in individual and EDD studies such as this to real physical outcomes such as atom reactivities and how electrons move EDDstudies studiessuch suchas asthis thistotoreal realphysical physicaloutcomes outcomessuch suchas asatom atomreactivities reactivitiesand andhow howelectrons electronsmove move EDD these properties, and a comparison of maps these maps in for the molecules ina visualisation their individual states provides insights which groups involved the formation weak interactions when weak interactions areinto formed. The MEP shown in Figures 11–13of are ofandand when weakinteractions interactions are formed. Theare MEP mapsshown shown inFigures Figures 11–13 are visualisation of when weak are formed. The MEP maps in 11–13 are aavisualisation of co-crystalline states provides insights intomaps which are involved inisosurface the formation of weak thethese impetus behind them to The been mapped onto of ρ,and which these properties, and aand comparison of MEP these forgroups the in an their individual these properties, and comparison ofmaps thesehave maps formolecules the molecules molecules in their their individual individual and properties, aa form. comparison of these maps for the in and interactions impetus behind them to form.Visual Theinvolved MEP maps have been for mapped onto an have been plotted onthe the same scale for comparability. inspection the maps (1),weak (2) co-crystalline statesand provides insights into which groups are in of the formation of co-crystalline states provides insights into which which groups are involved involved in the formation formation ofand weak co-crystalline states provides insights into groups are in the of weak isosurface of ρ, which have been plotted on the same scale for comparability. Visual inspection of the (3)interactions did notand yield any unusual features. The most regions located the hetero interactions the impetus behind them to form. The maps have been mapped onto an interactions and the impetus behind them toelectronegative form.MEP The MEP MEP mapsare have beennear mapped onto an an and the impetus behind them to form. The maps have been mapped onto maps for (1), (2) and (3) did not yield any unusual features. The most electronegative regions are atoms, and the most electropositive regions were found near the hydrogen atoms. This is expected as isosurface of ρ, which have been plotted on the same scale for comparability. Visual inspection of the isosurface of ρ, which have been plotted on the same scale for comparability. Visual inspection of the isosurface of ρ, which have been plotted on the same scale for comparability. Visual inspection of the located near the(3) hetero atoms, and theunusual most electropositive regions were found near the hydrogen most weak interactions found were traditional bonds, these areas correspond toregions regions maps for (1),for (2) and did not yield any features. The and most electronegative regions are are maps for (1), (2)and and (3) did not yield anyhydrogen unusual features. The most electronegative regions are maps (1), (2) (3) did not yield any unusual features. The most electronegative atoms. This is expected as most weak interactions found were traditional hydrogen bonds, and these where much of the intermolecular bonding occurs in the form of hydrogen bonds. Further analysis of located near the hetero atoms, and the most electropositive regions were found near the hydrogen locatednear nearthe thehetero heteroatoms, atoms,and andthe themost mostelectropositive electropositiveregions regionswere werefound foundnear nearthe thehydrogen hydrogen located areas correspond tomost regions where much found of thewere intermolecular bonding occurs inthem the form of theatoms. map (3) shows excellent complementarity between bond donors and acceptors with being atoms. This of is expected as interactions traditional hydrogen bonds, and these atoms. This expected asweak most weakinteractions interactions found were traditional hydrogen bonds, and these This isisexpected as most weak found were traditional hydrogen bonds, and these hydrogen bonds. Further analysis of the map of (3) shows excellent complementarity between bond more electropositive and electronegative, It was also found that larger differences in of areas correspond to regions wherewhere much much ofrespectively. theof intermolecular bonding occurs in the form of areas correspond to regions regions where much of the intermolecular intermolecular bonding occurs in the form form of areas correspond to the bonding occurs in the donors and acceptors with them being more and electronegative, respectively. It was electrostatic potential between bond donor/acceptor pairs corresponded to strongerbetween hydrogen bonds, hydrogen bonds. Further analysis of the map (3)electropositive shows excellent complementarity bond hydrogen bonds. Further analysis ofthe theof map of(3) (3) shows excellent complementarity between bond hydrogen bonds. Further analysis of map of shows excellent complementarity between bond also thatwith larger differences in electropositive electrostatic potential between bond donor/acceptor as donors discussed above. Additionally, atoms onelectropositive the periphery of the asymmetric unit withIt notable donors andfound acceptors them more and electronegative, respectively. wasItItpairs donors and acceptors withbeing themthe being more electropositive and electronegative, respectively. was and acceptors with them being more and electronegative, respectively. was corresponded to stronger hydrogen bonds, as discussed above. Additionally, the atoms the charges were same atoms involved in intermolecular bonding as discussed alsoelectrostatic found thatpotential larger differences in the electrostatic potential between bond bond donor/acceptor pairson also found found that larger larger differences in electrostatic electrostatic potential between bond donor/acceptor pairs also that differences in potential between donor/acceptor pairs periphery the asymmetric unit withofnotable electrostatic potential charges theon same atoms previously. The findings from the analysis MEP maps in Figures 11–13 validate the use ofthe corresponded toofstronger hydrogen bonds, asthe discussed above. Additionally, thewere atoms the corresponded to stronger stronger hydrogen bonds, as discussed discussed above. Additionally, thefuture atoms on the corresponded to hydrogen bonds, as above. Additionally, the atoms on involved in intermolecular bonding as discussed previously. The findings from the analysis of the periphery of the asymmetric unit with notable electrostatic potential charges were the same atoms peripheryof ofthe theasymmetric asymmetricunit unitwith withnotable notableelectrostatic electrostaticpotential potentialcharges chargeswere werethe thesame sameatoms atoms periphery MEP in Figures 11–13 as validate the previously. future use of potential as a predictor of involved in maps intermolecular bonding discussed Theelectrostatic findings from the analysis of theof involved inintermolecular intermolecular bonding asdiscussed discussedpreviously. previously. Thefindings findings from theanalysis analysis ofthe the involved in bonding as The from the hydrogen bonds and weakthe interactions opposed to thepotential current as geometrical definitions MEP MEP maps in Figures 11–13other validate future useasofuse electrostatic a predictor of MEP maps maps in Figures Figures 11–13 validate the future future use of electrostatic electrostatic potential as aa predictor predictor of in 11–13 validate the of potential as of used today. hydrogen bonds and other weak interactions as opposed to the current geometrical definitions hydrogen bonds bonds and and other other weak weak interactions interactions as as opposed opposed to to the the current current geometrical geometrical definitions definitions hydrogen used today. usedtoday. today. used


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electrostatic as a predictor of hydrogen bonds and other weak interactions as opposed to14the Crystals 2018,potential 8, 46 of 18 Crystals geometrical 2018, 8, 46 14 of 18 current definitions used today. Crystals 2018, 8, 46 14 of 18

Figure 11. Molecular electrostatic potential maps of (1) mapped on an isosurface of ρ. Figure Molecular electrostatic potential maps mapped isosurface Figure 11.11. electrostatic potential maps ofof (1)(1) mapped onon anan isosurface ofof ρ. ρ. Figure 11.Molecular Molecular electrostatic potential maps of (1) mapped on an isosurface of ρ.

Figure 12. Molecular electrostatic potential maps of (2) mapped on an isosurface of ρ. Figure 12. Molecular electrostatic potential maps ofof (2) mapped on anan isosurface ofof ρ. Figure Figure 12. 12. Molecular Molecular electrostatic electrostatic potential potential maps maps of (2) (2) mapped mapped on on an isosurface isosurface of ρ. ρ.

Figure 13.13. Molecular electrostatic potential maps of of (4)(4) mapped onon anan isosurface of of ρ. ρ. Figure Molecular electrostatic potential maps mapped isosurface Figure 13. Molecular electrostatic potential maps of (4) mapped on an isosurface of Figure 13. Molecular electrostatic potential maps of (4) mapped on an isosurface of ρ. ρ.

3.7. Lattice Energies 3.7. Energies 3.7. Lattice Lattice Energies The lattice energies of (1), (2) and (3) were determined for the EXP model to assess the effect of The of (3) EXP to the of the changes in energies charge distribution during the determined co-crystallisation as described on the The lattice lattice energies of (1), (1), (2) (2) and and (3) were were determined for for the theprocess EXP model model to assess assessabove the effect effect of the changes in the process as above overall stability of thedistribution system. Thisduring has connections to real-world physical outcomes such on as the the the changes in charge charge distribution during the co-crystallisation co-crystallisation process as described described above on the overall overall stability stability of of the the system. system. This This has has connections connections to to real-world real-world physical physical outcomes outcomes such such as as the the


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3.7. Lattice Energies The lattice energies of (1), (2) and (3) were determined for the EXP model to assess the effect of the changes in charge distribution during the co-crystallisation process as described above on the overall stability of the system. This has connections to real-world physical outcomes such as the solubility of the co-crystal complex in solution compared to its individual counterparts. Two methods were used to calculate the lattice energy; the LATEN option in XD2006 [19] based on the method for calculating total interaction energies suggested by Volkov et al. [42,43] and the PIXEL method developed by Gavezzotti [44], which partitions the electron density into ‘pixels’, which are then used for the calculation. The PIXEL method utilises a theoretical approach where the electron density of the asymmetric unit is calculated and its neighbours generated by symmetry. Thus, changes resulting from intermolecular bonding such as charge redistribution may not be reflected in its results. Refer to Table 4 for the lattice energies calculated for all structures using both methods. The PIXEL calculation for (3) was split into three different pairs: two pairs of the PCM-44BP complex and the two PCM molecules in the middle. The value reported in Table 4 is the sum of the three separate calculations. The LATEN method consistently reports values considerably higher than that of the PIXEL method. This phenomenon has previously been attributed by Spackman [45] to certain intermolecular BCPs not being found even though the Morse equation has been satisfied. This is thought to be due to the extremely flat nature of these critical points. Our results are in accordance with these conclusions with the lattice energies of (1) differing by the smallest amount (10 kJ mol−1 ) as there is only one molecule in the asymmetric unit, while (2) and (3) both differ by at least 40 kJ mol−1 and have two and four molecules in the asymmetric unit, respectively. Table 4. Table of lattice energies for (1), (2) and (3) predicted by the LATEN option in the XD package and the PIXEL program developed by Gavezzotti. Energies are given in kJ mol−1 .

LATEN PIXEL

PCM

44BP

PCM-44BP

−188.5 −170.7

−311.2 −110.5

−271.3 −228.9 *

* PIXEL energies for the PCM-44BP complex were obtained by taking the sum of three separate PIXEL calculations; two involving each of the PCM-44BP pairs and one involving the two PCM molecules in the middle of the asymmetric unit.

In both methods, the co-crystal was found to be more stable than PCM by approximately 90 kJ mol−1 . Considering enthalpic and entropic factors associated with solvation, it would be plausible to conclude that a larger net lattice energy also indicates a greater net solubility. The molecular dipole moment (MDM) is an indicator of the spread of charge across a molecule and may also provide insights into the likelihood of solvation of the system. The co-crystal was found to have the largest MDM (12.34D), across the asymmetric unit, while the value for PCM was slightly smaller (10.29D). The large value of the MDM for PCM can be attributed to the strong intermolecular hydrogen bonds it forms, which causes charge to accumulate at the ends of the molecule and depletion in the middle. The value for the SP model (4.52D) lends credence to this conclusion and is in accordance with findings reported by Coppens et al. [46]. The MDM value for (3) is only marginally larger than that of (1). This difference can be attributed to a number of factors including more numerous hydrogen bonds, the nature of the 44BP molecule and the arrangement of the molecules inside the asymmetric unit of (3). The 44BP molecule inherently has a low MDM (3.18D for the asymmetric unit and 2.20 and 2.01D for the individual molecules) due to the inherent symmetry and as a result does not contribute significantly to the MDM. The lack of change in polarisation between the 44BP molecules in (2) and (3) also means it does not contribute significantly to the MDM of (3). Further analysis of the arrangement of molecules in the asymmetric unit of (3) shows that for both PCM and 44BP, the molecules are perpendicular to each other, resulting in a negation of the charge separation due to intermolecular bonding. Evaluation of the MDM of the two PCM-44BP pairs in (3) yielded MDM values of 9.49 and


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5.75D, highlighting that each pair individually has some charge separation; however, they seem to negate each other. All the above factors contribute to (3) only having a marginally larger MDM than (1). Evaluation of the MDM for the SP models of (1) and (3) yielded different results with values of 4.52 and 17.22D, respectively. The gas phase nature of the SP calculations does not account for electron density redistribution from intermolecular hydrogen bonding and explains the significantly different MDM values. 4. Conclusions Here, we present an EDD study of PCM (1), 44BP (2) and the PCM-44BP (3) co-crystal with the aim of exploring a potential contributing factor towards the poor tableting properties exhibited by Form I PCM, which is currently overcome by co-formulation with gelatine or starch, while co-crystallised complexes perform relatively better. PCM has not been hindered by this limitation as seen through its commercial success; however, it is hoped that the insights gained from studying the weak interactions in the PCM and co-crystal system can be applied to other drugs to improve their physical properties. High resolution X-ray crystallography was used to examine these systems at the electronic level. Topological analysis revealed a total of 4, 8 and 13 hydrogen bonds for (1), (2) and (3), respectively, with π–π interactions also present. Many of the weak interactions found in (1) were also found in (3) and, in both cases, were responsible for the zig-zag packing motif in their structures. 44BP was found to intercalate between the PCM molecules in (3), resulting in a shallower zig-zag packing shape potentially translating into (3), exhibiting better tableting properties, allowing the sheets of PCM and 44BP in the co-crystal to exhibit lateral shear similar to Form II PCM. The weak interactions present in all structures were also reflected visually in the MEP diagrams and the MDM. A larger number of weak interactions was found in (3) compared to (1) and (2), and these interactions ranged in strength from 4.08–84.33 kJ mol−1 . These interactions allowed the PCM-44BP planes in (3) to be stable; however, the weak π-stack interaction between 44BP molecules allows lateral shear to occur, which potentially gives rise to desirable tabletting properties as described for Form II PCM. When comparing the integrated atomic basin charges of partitions of the PCM molecule, we found that the more numerous weak interactions in (3) resulted in a charge redistribution with the hydroxyl and amide group becoming more negative and the aromatic region of PCM more positive. This resulted in a larger MDM in (3) (µ = 12.34D), indicating an increased polar surface area, and along with the largest lattice energy, provided a good basis to predict how the co-crystal may exhibit more desirable solubility and stability profiles compared to (1). Supplementary Materials: The following are available online at www.mdpi.com/2073-4352/8/1/46/s1. Acknowledgments: David E. Hibbs and Paul W. Groundwater would like to thank The University of Sydney Bridging Support Scheme for funding. Jonathan J. Du and Felcia Lai would like to thank the University of Sydney for an Australian Postgraduate Award (APA) scholarship, the Faculty of Pharmacy for research funding and the Sydney Informatics Hub at the University of Sydney for providing access to the High Performance Computer Artemis. The work was supported by the Danish National Research Foundation (Center for Materials Crystallography, DNRF-93). Author Contributions: Jonathan J. Du and David E. Hibbs conceived and designed the experiments. Jonathan J. Du and Felcia Lai crystallised all the samples used in the study with materials and reagents provided by Paul W. Groundwater and David E. Hibbs, Peter A. Williams and David E. Hibbs collected and analysed the data in conjunction with Jonathan J. Du. James A. Platts and Jacob Overgaard provided assistance with the computational and experimental analyses respectively. Jonathan J. Du wrote the paper with aid from Linda Váradi. Conflicts of Interest: The authors declare no conflict of interest.

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