Inter­molecular inter­actions and disorder in six isostructural cele­coxib solvates

Six isostructural crystalline solvates of cele­coxib are reported and the inter­molecular inter­actions involving the solvent mol­ecules are described.

Abstract

Six isostructural crystalline solvates of the active pharmaceutical ingredient cele­coxib {4-[5-(4-methyl­phen­yl)-3-(tri­fluoro­meth­yl)pyrazol-1-yl]benzene­sul­fon­amide; C₁₇H₁₄F₃N₃O₂S} are described, containing di­methyl­formamide (DMF, C₃H₇NO, 1), di­methyl­acetamide (DMA, C₄H₉NO, 2), N-methylpyrrolidin-2-one (NMP, C₅H₉NO, 3), tetra­methyl­urea (TMU, C₅H₁₂N₂O, 4), 1,3-dimethyl-3,4,5,6-tetra­hydro­pyrimidin-2(1H)-one (DMPU, C₆H₁₂N₂O, 5) or dimethyl sulfoxide (DMSO, C₂H₆OS, 6). The host cele­coxib structure contains one-dimensional channel voids accommodating the solvent mol­ecules, which accept hydrogen bonds from the NH₂ groups of two cele­coxib mol­ecules. The solvent binding sites have local twofold rotation symmetry, which is consistent with the point symmetry of the solvent mol­ecule in 4 and 5, but introduces orientational disorder for the solvent mol­ecules in 1, 2, 3 and 6. Despite the isostructurality of 1–6, the unit-cell volume and solvent-accessible void space show significant variation. In particular, 4 and 5 show an enlarged and skewed unit cell, which can be attributed to a specific inter­action between an N—CH₃ group in the solvent mol­ecule and the toluene group of cele­coxib. Inter­molecular inter­action energies calculated using the PIXEL method show that the total inter­action energy between the cele­coxib and solvent mol­ecules is broadly correlated with the mol­ecular volume of the solvent, except in 6, where the increased polarity of the S=O bond leads to greater overall stabilization com­pared to the similarly-sized DMF mol­ecule in 1. In the structures showing disorder, the most stable orientations of the solvent mol­ecules make C—H⋯O contacts to the S=O groups of cele­coxib.

Introduction  

Understanding the structures and properties of crystalline solids can be of significant importance for active pharmaceutical ingredients (APIs) (Sun, 2009 ▸). Solid-form screening is an integral part of most pre-formulation activities (Morissette et al., 2004 ▸), with an aim to establish the range of solid forms that can exist for a given API. These generally include both polymorphs and multicom­ponent forms, which may variously be described as salts, cocrystals, solvates, etc. (Aitipamula et al., 2012 ▸).

The API of inter­est in this work is the anti-inflammatory drug cele­coxib (see Scheme 1). To date, there is only one polymorph (Form III) of cele­coxib for which a single-crystal X-ray structure has been reported (Dev et al., 1999 ▸; Wang et al., 2019 ▸) in the Cambridge Structural Database (CSD; Groom et al., 2016 ▸), although several polymorphs are established in the literature (Dev et al., 1999 ▸; Lu et al., 2006 ▸; Wang & Sun, 2019 ▸). Crystal structures are known for numerous multicom­ponent forms, including with pyrrolidin-2-one, caprolactam, valerolactam (Bolla et al., 2014 ▸), pyridin-2(1H)-one (Bolla & Nangia, 2019 ▸), nicotinamide (Zhang et al., 2017 ▸) and bis­(proline) (as a zwitterion; Li et al., 2018 ▸). Some cele­coxib cocrystals with 4,4′-bi­pyridine and 1,2-bis­(pyridin-4-yl)ethyl­ene have also been reported to form isostructural solvates (i.e. isostructural three-com­ponent crystals) when combined with acetone, THF or 1,4-dioxane (Wang et al., 2014 ▸).

We were initially inter­ested in studying solvates of cele­coxib as part of a broader structure–property correlation exercise to understand and address its pharmaceutical deficiencies, e.g. high punch sticking propensity (Wang et al., 2020 ▸; Paul et al., 2017 ▸, 2020 ▸), amorphous phase stability (Wang & Sun, 2019 ▸), poor flowability (Chen et al., 2020 ▸) and high elastic flexibility (Wang et al., 2019 ▸). In the course of this work, we identified a group of six solvates (see Scheme 1) that form an isostructural group, different from any of the multicom­ponent cele­coxib crystal structures in the CSD. We describe the new structure type in this paper and explore aspects of the isostructurality, including variation of the unit-cell parameters, disorder of the solvent mol­ecules, and the inter­molecular inter­actions between the solvent and cele­coxib mol­ecules.

Experimental  

Synthesis and crystallization  

Single crystals suitable for X-ray analysis were obtained by slow cooling of a warm solution of cele­coxib in either di­methyl­formamide (DMF, 1), di­methyl­acetamide (DMA, 2), N-methylpyrrolidin-2-one (NMP, 3), tetra­methyl­urea (TMU, 4), 1,3-dimethyl-3,4,5,6-tetra­hydropyrimidin-2(1H)-one (DMPU, 5) or dimethyl sulfoxide (DMSO, 6). The DMF (1) and DMA (2) solvates have been prepared previously (Chawla et al., 2003 ▸), but structural details were not provided. A powder X-ray diffraction pattern published by Chawla et al. (2003 ▸) clearly matches that simulated from the crystal structure of 2. The match to 1 is less clear, but additional thermal analysis is broadly consistent with our observations, so it seems probable that the structures described herein are consistent with the previously studied material.

Refinement of 1–6  

H atoms bound to C atoms were placed in idealized positions and refined using a riding model, with U _iso(H) = 1.2 or 1.5U _eq(C). For the methyl group (C11) in cele­coxib, the H atoms were allowed to rotate around the local threefold axis. H atoms of the NH₂ groups were located in difference Fourier maps, then refined with isotropic displacement parameters, with the N—H and H⋯H distances restrained to 0.86 (1) and 1.50 (1) Å, respectively. All of the structures display rotational disorder of the CF₃ group. This was modelled in each case as two sets of three F atoms, with site-occupancy factors constrained to sum to unity. To ensure a regular geometry, the C—F distances were restrained to a common refined value and the F⋯F distances were restrained to 1.633 times that value. All F atoms were refined with anisotropic ADPs. This produces highly distorted (prolate) ellipsoids in several cases, despite the inclusion of two sets of atomic sites, indicating that the rotational disorder is extensive. Given this rotational disorder, the distorted ellipsoids were considered to be an acceptable com­promise to model the electron density in this region. For the disordered solvent mol­ecules in 1, 2, 3 and 6, two sets of atoms were refined, with site-occupancy factors summing to unity, and with appropriate geometrical restraints. Anisotropic ADPs were applied to all non-H atoms and H atoms were placed in idealized positions and refined as riding. The structure and refinement details are presented in Table 1 ▸.

Table 1. Experimental details.

For all structures: monoclinic, P2₁/c, Z = 4. Experiments were carried out at 298 K with Cu Kα radiation using a Bruker D8-QUEST PHOTON-100 diffractometer. Absorption was corrected for by multi-scan methods (SADABS; Bruker, 2016 ▸). H atoms were treated by a mixture of independent and constrained refinement.

	1	2	3
Crystal data
Chemical formula	C17H14F3N3O2S·C3H7NO	C17H14F3N3O2S·C4H9NO	C17H14F3N3O2S·C5H9NO
M r	454.47	468.49	480.50
a, b, c (Å)	11.8973 (4), 8.8360 (3), 21.8286 (7)	11.9584 (3), 9.2028 (2), 21.2811 (6)	11.9978 (4), 9.0896 (3), 21.9732 (8)
β (°)	103.4537 (13)	103.3826 (12)	101.358 (2)
V (Å3)	2231.75 (13)	2278.41 (10)	2349.36 (14)
μ (mm−1)	1.77	1.75	1.71
Crystal size (mm)	0.16 × 0.16 × 0.14	0.20 × 0.18 × 0.18	0.20 × 0.18 × 0.18
Data collection
T min, T max	0.440, 0.753	0.608, 0.753	0.593, 0.753
No. of measured, independent and observed [I > 2σ(I)] reflections	16627, 3940, 3362	38939, 4032, 3394	24378, 4146, 3112
R int	0.053	0.041	0.047
(sin θ/λ)max (Å−1)	0.596	0.597	0.596
Refinement
R[F 2 > 2σ(F 2)], wR(F 2), S	0.056, 0.149, 1.08	0.047, 0.129, 1.03	0.048, 0.136, 1.03
No. of reflections	3940	4032	4146
No. of parameters	346	345	389
No. of restraints	35	26	103
Δρmax, Δρmin (e Å−3)	0.25, −0.37	0.22, −0.29	0.22, −0.24

	4	5	6
Crystal data
Chemical formula	C17H14F3N3O2S·C5H12N2O	C17H14F3N3O2S·C6H12N2O	C17H14F3N3O2S·C2H6OS
M r	497.54	509.55	459.50
a, b, c (Å)	12.4050 (3), 8.9351 (2), 22.5727 (6)	12.4495 (17), 8.7822 (13), 22.656 (3)	11.9884 (3), 9.0230 (3), 20.8537 (6)
β (°)	98.6702 (13)	97.861 (5)	100.3908 (9)
V (Å3)	2473.36 (11)	2453.9 (6)	2218.78 (11)
μ (mm−1)	1.66	1.68	2.63
Crystal size (mm)	0.16 × 0.14 × 0.14	0.20 × 0.20 × 0.18	0.14 × 0.12 × 0.12
Data collection
T min, T max	0.657, 0.753	0.526, 0.753	0.476, 0.753
No. of measured, independent and observed [I > 2σ(I)] reflections	27591, 4397, 3339	25201, 4318, 3733	22464, 3916, 3520
R int	0.034	0.031	0.042
(sin θ/λ)max (Å−1)	0.597	0.597	0.596
Refinement
R[F 2 > 2σ(F 2)], wR(F 2), S	0.046, 0.142, 1.04	0.040, 0.118, 1.02	0.044, 0.126, 1.04
No. of reflections	4397	4318	3916
No. of parameters	349	364	318
No. of restraints	15	29	15
Δρmax, Δρmin (e Å−3)	0.42, −0.20	0.25, −0.21	0.29, −0.28

Computer programs: APEX3 (Bruker, 2018 ▸), SAINT (Bruker, 2018 ▸), SHELXT (Sheldrick, 2015a ▸), SHELXL2018 (Sheldrick, 2015b ▸) and Mercury (Macrae et al., 2020 ▸).

Computational details  

The crystal structures were energy-minimized with dispersion-corrected density functional theory (DFT-D) using the CASTEP module (Clark et al., 2005 ▸) in Materials Studio (Accelrys, 2011 ▸). The PBE functional (Perdew et al., 1996 ▸) was applied with a plane-wave cut-off energy of 520 eV, in combination with the Grimme semi-empirical dispersion correction (Grimme, 2006 ▸). The unit-cell parameters were constrained to the experimental values and the space group P2₁/c was imposed. Only one com­ponent of the rotationally-disordered CF₃ group was included (arbitrarily). For the structures with disordered solvent mol­ecules, separate models were minimized for each disorder com­ponent. In each case, minimization produced only small geometrical deviations from the starting structure, as expected for high-quality single-crystal structures (van de Streek & Neumann, 2010 ▸). The purpose of the optimization step is to place the structures on a common basis for com­parison, particularly for the disordered structures, where the results of the crystallographic refinement are generally less precise. The DFT-D-optimized structures were then used as input for the PIXEL module of the CSP package (Gavezzotti, 2002 ▸, 2003 ▸, 2011 ▸). The calculated pairwise inter­action energies are estimated to have an accuracy within a range of ca ±3 kJ mol⁻¹.

Results and discussion  

Description of the crystal structures  

The mol­ecular structures of 1–6 are shown in Figs. 1 ▸–6 ▸ ▸ ▸ ▸ ▸. In the crystal structures, the cele­coxib mol­ecules are arranged into pairs around inversion centres with two solvent mol­ecules accepting N—H⋯O hydrogen bonds (Fig. 7 ▸). The local symmetry of this unit is effectively 2/m (C _2h), where the C=O (or S=O) group of each solvent mol­ecule is approximately aligned along the local twofold rotation axis. For the TMU and DMPU mol­ecules in 4 and 5, which themselves show twofold rotational point symmetry, this produces an ordered crystallographic result. The DMPU mol­ecule displays minor conformational disorder of its six-membered ring (atoms C3S/C3SA in Fig. 5 ▸), but the parts of the mol­ecule involved in binding to cele­coxib are ordered and consistent for TMU and DMPU. For DMF (1), DMA (2), NMP (3) and DMSO (6), which do not possess twofold rotational symmetry, the crystal structure is disordered, with the mol­ecules adopting two alternative orientations related by the local twofold axis. However, the full crystallographic environment of each solvent mol­ecule is not twofold symmetric. Hence, the two orientations of the disordered solvent mol­ecules have different total inter­action energies (§3.3). With the solvent mol­ecules removed from the structures, the void space between the cele­coxib mol­ecules defines one-dimensional (1D) channels along the b axis (Fig. 8 ▸). The solvent-accessible volume spans a considerable range for 1–6 (Table 2 ▸), constituting approximately 21–28% of the unit-cell volume.

Figure 1.

The mol­ecular structure of 1, with displacement ellipsoids at the 50% probability level. H atoms have been omitted. The second disorder com­ponent of the DMF mol­ecule [site-occupancy factor = 0.221 (7)] is shown in outline only. Atoms O1S and C3S are common to both DMF com­ponents.

Figure 2.

The mol­ecular structure of 2, with displacement ellipsoids at the 50% probability level. H atoms have been omitted. The second disorder com­ponent of the DMA mol­ecule [site-occupancy factor = 0.464 (8)] is shown in outline only. Atoms O1S, C2S, C3S and C4S are common to both DMA com­ponents.

Figure 3.

The mol­ecular structure of 3, with displacement ellipsoids at the 50% probability level. H atoms have been omitted. The second disorder com­ponent of the NMP mol­ecule [site-occupancy factor = 0.321 (8)] is shown in outline only. Atoms C2SA and C5SA are not labelled, C2SA is directly below C5S and C5SA is hidden behind C2S.

Figure 4.

The mol­ecular structure of 4, with displacement ellipsoids at the 50% probability level. H atoms have been omitted. Disorder is not evident for the TMU mol­ecule.

Figure 5.

The mol­ecular structure of 5, with displacement ellipsoids at the 50% probability level. H atoms have been omitted. The alternative positions C3S and C3SA [site-occupancy factors = 0.584 (16):0.416 (16)] are shown for the DMPU mol­ecule.

Figure 6.

The mol­ecular structure of 6, with displacement ellipsoids at the 50% probability level. H atoms have been omitted. Atoms C1S and C2S are common to both disorder com­ponents for the DMSO mol­ecule. The relatively large displacement ellipsoid of atom C2S was retained in preference to multiple atom sites for simplicity of the model.

Figure 7.

Hydrogen-bonded motif with two solvent mol­ecules (TMU is shown) accepting N—H⋯O hydrogen bonds from two cele­coxib mol­ecules across a crystallographic inversion centre (indicated by the open circle). H atoms not involved in hydrogen bonding have been omitted. The atoms shown in ball-and-stick style conform to local 2/m (C _2h) point symmetry.

Figure 8.

Views of the 1D voids running along the b axis in the cele­coxib framework structure, after removing the solvent mol­ecules. Structure 6 is shown. The voids are generated using Mercury (contact surface, probe radius 1.2 Å; Macrae et al., 2020 ▸).

Table 2. Inter­molecular inter­action energies between the cele­coxib and solvent mol­ecules [E(tot)_cel–solv] and between the solvent mol­ecules [E(tot)_solv–solv], calculated using the PIXEL method, together with the unit-cell volume (V _cell), void volume (V _void) and solvent mol­ecular volume (V _solv).

	Solvent	V cell (Å3)	V void (Å3)a	V solv (Å3)b	Disorder com­ponent	E(tot)cel–solv (kJ mol−1)	E(tot)solv–solv (kJ mol−1)
1	DMF	2231.8	485.4 (21.7%)	76.7	A	−144.0	+3.8
					B	−132.2	+5.1
2	DMA	2278.4	481.8 (21.1%)	93.2	A	−160.5	+2.4
					B	−162.1	+3.3
3	NMP	2349.4	617.5 (25.0%)	100.1	A	−170.7	+1.9
					B	−160.1	+1.5
4	TMU	2473.4	572.3 (24.4%)	121.8	–	−155.1	+0.7
5	DMPU	2453.9	692.1 (28.2%)	127.9	A	−180.5	−1.9
					B	−187.1	−3.0
6	DMSO	2218.8	466.5 (21.0%)	71.7	A	−168.9	+4.6
					B	−164.3	+4.5

Notes: (a) the voids were generated using Mercury (Macrae et al., 2020 ▸) as a contact surface with probe radius of 1.2 Å and (b) mol­ecular volumes are derived from van der Waals surfaces, calculated in Materials Studio (Accelrys, 2011 ▸) as a Connolly surface generated with zero probe radius.

Variation of the unit-cell parameters  

Despite the isostructural nature of the solvates, the unit-cell parameters differ quite significantly, with a difference of ca 250 ų between the smallest (6) and largest (4) volumes. Plotting the b or c axis of 1–6 by ascending length (see supporting information) shows an approximately linear change in each case, but plotting the a axis in a similar manner shows a clear discontinuity, with the a axis in 4 and 5 being approximately 0.5 Å longer than in 1, 2, 3 and 6. A similar pattern is seen for the β angle, indicating a relative skewing of the ac plane in 4 and 5. Comparing representative structures in projection along the b axis (Fig. 9 ▸) indicates a reason for this observation. Common to structures 4 and 5, but not present in 1, 2, 3 or 6, is an N—CH₃ group in the solvent mol­ecule that points approximately along the a axis and is directed towards a neighbouring toluene ring of cele­coxib. The inter­action pushes the toluene ring away from the position seen in the structures that do not have this N—CH₃ group. The cele­coxib mol­ecules are ‘anchored’ by their hydrogen-bonding NH₂ groups, which retain essentially identical positions in all structures, so the effect of pushing away the toluene ring is a relative rotation of the cele­coxib mol­ecules (Fig. 9 ▸). This serves to elongate both the a and the c axes, and to skew the unit cell. The other CH₃ groups in TMU (4) or DMPU (5) adopt positions that are seen in one or more of the other structures, and they do not make any clearly com­parable inter­molecular contacts to cele­coxib.

Figure 9.

Projection of the structures of 4 (standard colour) and 6 (green) along the b axis. The highlighted N—CH₃⋯π inter­action in 4 [C2S⋯centroid(C5–C10) = 3.825 Å] causes the cele­coxib mol­ecules to rotate outwards relative to each other, as indicated by the thick arrows, causing expansion and skewing of the unit cell com­pared to 6.

Inter­actions between the solvent mol­ecules and cele­coxib  

On account of the isostructurality, the pairwise inter­molecular inter­actions in each structure can be directly matched. Table 2 ▸ lists the total inter­action energy between the cele­coxib and solvent mol­ecules, based on an equivalent set of inter­actions in each structure. For 1–5, the total cele­coxib–solvent inter­action energy broadly increases with the mol­ecular volume of the solvent, with 2 (DMA) and 3 (NMP) being closely com­parable. The DMSO mol­ecule in 6 has a significantly more stabilizing total inter­action with cele­coxib, com­pared to the similarly-sized DMF mol­ecule in 1, due to the increased polarity of the S=O bond. For example, the two independent pairwise inter­actions including the hydrogen bonds to cele­coxib are both approximately −50 kJ mol⁻¹ in 1 (varying slightly for the two disorder com­ponents), but approximately −57 and −68 kJ mol⁻¹ in 6. The N—CH₃⋯π inter­action highlighted in Fig. 9 ▸ belongs to the cele­coxib–solvent pair within the asymmetric unit (as shown in Figs. 4 ▸ and 5 ▸). Since PIXEL energies refer to total pairwise inter­molecular inter­actions, any specific features of the N—CH₃⋯π inter­action are masked by the total inter­action energy. Table 2 ▸ also lists the total inter­action energy between solvent mol­ecules, based on three equivalent significant inter­actions in each structure. The inter­action between the two solvent mol­ecules involved in the hydrogen-bonded motif (Fig. 7 ▸) is repulsive, due to the destabilizing Coulombic O⋯O inter­action. The only other significant inter­actions between solvent mol­ecules are along the 2₁ screw axis parallel to b, which are slightly stabilizing. The extent to which these inter­actions mitigate the destabilizing O⋯O inter­action increases with the mol­ecular volume of the solvent, and the overall solvent–solvent inter­action is slightly stabilizing for the largest mol­ecule, i.e. DMPU (5).

The difference between the total inter­action energies with the cele­coxib framework for the two disorder com­ponents of the solvent mol­ecules in each structure is also shown in Table 2 ▸. The most significant difference within a single structure is seen for DMF (1), where the two orientations exchange the positions of the C—H and N—CH₃ groups (Fig. 1 ▸). Approximately two thirds of the energy difference arises from the inter­actions of the DMF mol­ecule with the two cele­coxib mol­ecules in the hydrogen-bonding motif (Fig. 7 ▸), where the more stable DMF orientation brings the CH₃ group of atom C2S into close proximity to O1 in one of the S=O bonds (Fig. 10 ▸). For DMA (2), the disorder com­ponents have essentially the same mol­ecular footprint (the positions of atoms O1S, C2S, C3S and C4S are common to both DMA com­ponents; Fig. 2 ▸), and the total inter­action energies of the two com­ponents with the cele­coxib framework are the same within the expected precision of the calculations. For NMP (3), the two solvent orientations are geometrically com­parable, except for the positions of C3S/C3SA (Fig. 3 ▸). However, one orientation is noticeably more stable than the other. A significant energy difference also exists for the two orientations of the DMPU mol­ecule in 5, for which the principal geometrical difference is the position of one CH₂ group (C3S/C3SA), with accom­panying differences in the positions of the H atoms on the neighbouring CH₂ groups. Comparing the most stable disorder com­ponents for 3 and 5, they share a common position for one CH₂ group (C3S in 3 and C2S in 5) that is not seen in the other disorder com­ponents. This introduces a short C—H⋯O contact to an S=O group of the neighbouring cele­coxib mol­ecule (Fig. 11 ▸). The PIXEL energies confirm that the inter­action with this cele­coxib mol­ecule is significantly more stabilizing when this contact is present than when it is not. For the DMSO mol­ecules in 6, the difference between the two solvent orientations involves only the position of the S atom, and the inter­action energies with the cele­coxib framework are com­parable.

Figure 10.

The most stable orientation of the disordered DMF mol­ecule in 1, high­lighting the C—H⋯O contact to an S=O group of cele­coxib [symmetry code: (i) −x + 1, −y + 1, −z + 1]. The less stable DMF orientation is shown as semi-transparent.

Figure 11.

The most stable orientation of the disordered NMP mol­ecule in 3. A short C—H⋯O contact is made to an S=O group of the neighbouring cele­coxib mol­ecule [symmetry code: (ii) x, −y + , z − ]. The less stable NMP orientation for 3 is shown as semi-transparent. A com­parable C—H⋯O contact is seen for the most stable disorder com­ponent of DMPU in 5.

Conclusion  

This set of six isostructural cele­coxib solvates includes small solvent mol­ecules that can accept hydrogen bonds. The host cele­coxib framework is consistent within the set, but it shows quite substantial flexibility in its unit-cell parameters and solvent-accessible void space, and can therefore accommodate solvent mol­ecules of varying size and shape. The crystallographic disorder in several of the structures is understandable on the basis of the local twofold symmetry of the solvent binding site, com­pared to the point symmetry of the solvent mol­ecules. In the absence of any additional hydrogen-bond donors in the solvent mol­ecules, the next most stabilizing inter­actions between the solvent mol­ecules and the cele­coxib framework are C—H⋯O contacts to the S=O groups. The consideration of PIXEL inter­action energies, in combination with geometrical analysis of the crystal structures, is helpful in drawing these conclusions.

Supplementary Material

CCDC references: 2011633, 2011634, 2011635, 2011636, 2011637, 2011638

Funding Statement

This work was funded by The Lundbeck Foundation (Denmark) grant R143-2014-25. Danish Council for Independent Research | Natural Sciences grant DFF-1323-00122.