Cocrystallization of adamantane-1,3-dicarboxylic acid and 4,4'-bipyridine

The cocrystallization of adamantane-1,3-dicarboxylic acid (adc) and 4,4'-bipyridine (4,4'-bpy) yields a unique 1:1 cocrystal, C₁₂H₁₆O₄·C₁₀H₈N₂, in the C2/c space group, with half of each mol­ecule in the asymmetric unit. The mid-point of the central C-C bond of the 4,4'-bpy mol­ecule rests on a center of inversion, while the adc mol­ecule straddles a twofold rotation axis that passes through two of the adamantyl C atoms. The constituents of this cocrystal are joined by hydrogen bonds, the stronger of which are O-H...N hydrogen bonds [O...N = 2.6801 (17) Å] and the weaker of which are C-H...O hydrogen bonds [C...O = 3.367 (2) Å]. Alternate adc and 4,4'-bpy mol­ecules engage in these hydrogen bonds to form zigzag chains. In turn, these chains are linked through [pi]-[pi] inter­actions along the c axis to generate two-dimensional layers. These layers are neatly packed into a stable crystalline three-dimensional form via weak C-H...O hydrogen bonds [C...O = 3.2744 (19) Å] and van der Waals attractions.

S1. Comment

As awareness of the importance of pharmaceutical cocrystallization grows, it becomes imperative to fully understand and investigate the intermolecular relationships in a cocrystal. Cocrystals are, by definition, a crystalline material that consists of different molecular species held together by noncovalent forces (Aakeröy, 1997). Cocrystallization may change the physical properties of active pharmaceutical ingredients (APIs), including their stability, hygroscopicity, dissolution rate, solubility and bioavailability (Thayer, 2007). It may be possible to use cocrystallization to solve the problem that most pharmaceutical developers are now facing; the most stable crystalline forms of drugs are, often, the most insoluble ones. Moreover, some expensive drugs are not optimally absorbed into the blood stream, an economically unfavorable situation. A great way to circumvent this problem is to combine an API with an API-former, a molecule that weakly bonds with the API, usually via a pyridine or amine group (Thayer, 2007). The cocrystal formed will very likely exhibit solubility similar to that of an amorphous phase while also retaining the stability of crystalline salts. For example, the insoluble drug itraconazole is actually very stable and quite soluble as a cocrystal with various 1,4-dicarboxylic acids (Remenar et al., 2003).

The title cocrystal, (I), is formed by adamantane-1,3-dicarboxylic acid (adc) with 4,4'-bipyridine (4,4'-bpy). Because adc contains the carboxyl functional group prevalent among APIs, it is possible to further delve into the complexity of pharmaceutical cocrystals through analysis of intermolecular relationships in this particular cocrystal. The dicarboxylic acid adc has been previously explored as a component of cocrystals with several different pyridine ligands, such as 1,2-di(4-pyridyl)ethylene (dipy-ete) and 1,2-bis(4-pyridyl)ethane (Zeng et al., 2006). The rigid base 4,4'-bipyridine was chosen as the cocrystal former in the present study because it readily participates in hydrogen bonds with organic molecules with attached carboxyl groups (Du et al., 2005). It is a weak bidentate base commonly used in crystal engineering on account of its bridging abilities (Cowan et al., 2001).

There are several types of packing interactions in (I). The most dominant is the O—H···N hydrogen bond formed between a carboxylic acid group and a pyridine N atom. The length of this hydrogen bond [O···N = 2.6801 (17) Å] is very close to that of O—H···N bonds found in similar cocrystals [2.6323 (15) Å in the adduct of 2,5-dihydroxy-1,4-benzoquinone and 4,4'-bipyridine (Cowan et al., 2001), and 2.625 (2) Å in 4,4'-bipyridyl– N,N'-dioxide-3-hydroxy-2-naphthoic acid (1/2) (Lou & Huang, 2007), respectively]. The refined position of the carboxylic acid H atom clearly shows that the acid retains the H atom rather than transferring it to the adjoining pyridine N atom (Fig. 1 and Table 1). Because the adc molecule is V-shaped with two flexible carboxylic acid arms, a series of interchanging adc and 4,4'-bpy molecules results in a zigzag chain, thus forming a one-dimensional structure (Fig. 2). To comply with the general packing pattern, the angle of the hydrogen bond formed between the adc and 4,4'-bpy molecules is 168 (2)°.

In addition to the strong O—H···N hydrogen bond, a weaker C—H···O hydrogen bond also exists between the adc and 4,4'-bpy molecules (C8—H8···O2). The length of this bond [C···O = 3.367 (2) Å] is comparable to that of most C—H···O hydrogen bonds found in crystals with similar structures, for example the adduct of 2,5-dihydroxy-1,4-benzoquinone and 4,4'-bipyridine [C···O = 3.2082 (17) Å; Cowan et al., 2001]. The combination of these two hydrogen bonds between the adc and 4,4'-bpy molecules is denoted as R₂²(7) using graph-set notation (Bernstein et al., 1995).

Because 4,4'-bpy is characterized by two aromatic rings, electrostatic forces of attraction occur between face-to-face rings (Lou & Huang, 2007). Thus, π–π stacking is established between infinite stacks of 4,4'-bpy molecules along the c axis. Although each 4,4'-bpy molecule is parallel to an adjacent one, the position of each is shifted so that one is not directly over the other. The perpendicular distance between two parallel molecules is 3.46 Å. This weak interaction holds the hydrogen-bonded chains together, supporting a two-dimensional framework. Similar π–π interactions between interlocking chains also control the crystal packing of the adc–dipy-ete cocrystal (Zeng et al., 2006). In addition, one C—H bond of the pyridyl ring is involved in a C—H···O interaction (C11—H11···O1ⁱⁱⁱ) with the carboxylic acid group of the adc moelcule at (-x + 1/2, y + 1/2, -z + 1/2). These weak hydrogen bonds further join the two-dimensional layers into a three-dimensional network.

Thermogravimetric analysis (TGA) confirms that adamantane-1,3-dicarboxylic acid and 4,4'-bipyridine are in a 1:1 ratio in the cocrystal. According to the molar weights of adc and 4,4'-bpy, the mass of adc to that of 4,4'-bpy should be 1.44. The TGA results show that the first weight loss is caused by the departure of 4,4'-bpy from the crystal, starting at around 398 K, which accounts for about 41% of the total mass. It is then followed by a mass loss of about 59% representing loss of adc, beginning at about 453 K. This test gives rise to an adc-to-bpy mass ratio of 1.43.

Related literature

For related literature, see: Aakeröy (1997); Cowan et al. (2001); Du et al. (2005); Lou & Huang (2007); Remenar et al. (2003); Thayer (2007); Zeng et al. (2006).

S2. Experimental

Adamantane-1,3-dicarboxylic acid (3 mmol, 67.4 mg) was mixed with 4,4'-bipyridine (3 mmol, 46.8 mg) in a 1:1 stoichiometry and immersed in an aqueous solution (10 ml). The resulting mixture was placed in a Teflon-lined stainless steel vessel, which was heated to 424 K for two days. Two types of colorless crystals were engendered, viz. the desired cocrystal, which is block-like, mixed with unreacted sheet-like crystals of adc.

S3. Refinement

All H atoms were found in intermediate difference Fourier maps and were refined fully with isotropic displacement parameters [C—H = 0.94 (2)–1.019 (18) Å].

Computing details

Data collection: SMART (Bruker, 2001); cell refinement: SAINT (Bruker, 2001); data reduction: SAINT (Bruker, 2001); program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL (Bruker, 2001); software used to prepare material for publication: SHELXTL (Bruker, 2001).

Figures

	Fig. 1. A displacement ellipsoid plot of the title compound, with 30% probability. Hydrogen bonds are shown as dashed lines [Symmetry codes: (i) -x, y, -z + 1/2; (ii) -x + 1/2, -y + 5/2, -z + 1.]
	Fig. 2. Zigzag chains of adc and 4,4'-bpy along the a axis. Hydrogen bonds and π–π interactions are shown as dashed lines.

adamantane-1,3-dicarboxylic acid–4,4'-bipyridine (1/1)

Crystal data

C12H16O4·C10H8N2	F(000) = 808
Mr = 380.43	Dx = 1.334 Mg m^−3
Monoclinic, C2/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -C 2yc	Cell parameters from 5290 reflections
a = 21.5610 (16) Å	θ = 3.0–30.5°
b = 7.2378 (5) Å	µ = 0.09 mm^−1
c = 12.1520 (9) Å	T = 295 K
β = 92.580 (1)°	Block, colourless
V = 1894.5 (2) Å^3	0.38 × 0.31 × 0.22 mm
Z = 4

Data collection

Bruker SMART CCD area-detector diffractometer	2360 independent reflections
Radiation source: fine-focus sealed tube	2005 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.021
phi and ω scans	θmax = 28.3°, θmin = 1.9°
Absorption correction: multi-scan (SADABS; Bruker, 2001)	h = −28→28
Tmin = 0.966, Tmax = 0.980	k = −9→9
9381 measured reflections	l = −16→16

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.048	Hydrogen site location: difference Fourier map
wR(F^2) = 0.121	All H-atom parameters refined
S = 1.00	w = 1/[σ^2(Fo^2) + (0.050P)^2 + 1.350P] where P = (Fo^2 + 2Fc^2)/3
2360 reflections	(Δ/σ)max < 0.001
176 parameters	Δρmax = 0.27 e Å^−3
0 restraints	Δρmin = −0.23 e Å^−3

Special details

Experimental. Thermogravimetric analyses (TGA) were recorded under N2 at a scan rate of 15 K per minute on a TA Instrument TGA50 system.

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
O1	0.13609 (6)	0.52680 (19)	0.30675 (10)	0.0712 (4)
H1	0.1589 (11)	0.613 (4)	0.3422 (19)	0.095 (7)*
O2	0.09343 (6)	0.4964 (2)	0.46669 (10)	0.0767 (4)
C1	0.09471 (6)	0.4576 (2)	0.37100 (11)	0.0433 (3)
C2	0.04885 (5)	0.32848 (17)	0.31155 (10)	0.0355 (3)
C3	0.01594 (7)	0.2066 (2)	0.39395 (11)	0.0440 (3)
H3A	−0.0041 (8)	0.283 (2)	0.4495 (14)	0.056 (5)*
H3B	0.0482 (8)	0.127 (2)	0.4331 (14)	0.057 (5)*
C4	0.0000	0.4511 (2)	0.2500	0.0354 (4)
H4	−0.0208 (7)	0.528 (2)	0.3058 (12)	0.042 (4)*
C5	0.08076 (6)	0.20706 (19)	0.22707 (12)	0.0415 (3)
H5A	0.1022 (7)	0.284 (2)	0.1737 (13)	0.047 (4)*
H6B	0.1137 (7)	0.129 (2)	0.2641 (13)	0.051 (4)*
C6	0.03203 (7)	0.08481 (19)	0.16736 (12)	0.0465 (3)
H6	0.0538 (8)	0.007 (2)	0.1136 (14)	0.057 (5)*
C7	0.0000	−0.0376 (3)	0.2500	0.0552 (5)
H7	−0.0319 (8)	−0.121 (3)	0.2107 (14)	0.066 (5)*
N1	0.19746 (5)	0.81941 (17)	0.39186 (10)	0.0473 (3)
C8	0.16828 (7)	0.9049 (2)	0.47075 (14)	0.0536 (4)
H8	0.1330 (9)	0.843 (3)	0.4995 (15)	0.070 (5)*
C9	0.18683 (7)	1.0727 (2)	0.51509 (14)	0.0539 (4)
H9	0.1631 (9)	1.127 (3)	0.5690 (16)	0.070 (5)*
C10	0.23917 (6)	1.15934 (18)	0.47739 (10)	0.0383 (3)
C11	0.26991 (7)	1.0692 (2)	0.39601 (13)	0.0507 (4)
H11	0.3066 (9)	1.117 (3)	0.3668 (15)	0.066 (5)*
C12	0.24781 (7)	0.9022 (2)	0.35584 (14)	0.0550 (4)
H12	0.2692 (8)	0.840 (3)	0.3002 (15)	0.067 (5)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0742 (8)	0.0822 (9)	0.0587 (7)	−0.0411 (7)	0.0210 (6)	−0.0264 (6)
O2	0.0751 (8)	0.1074 (11)	0.0478 (6)	−0.0293 (8)	0.0063 (6)	−0.0257 (7)
C1	0.0393 (6)	0.0476 (7)	0.0429 (7)	0.0018 (5)	0.0013 (5)	−0.0090 (6)
C2	0.0366 (6)	0.0357 (6)	0.0344 (6)	0.0010 (5)	0.0047 (5)	−0.0026 (5)
C3	0.0457 (7)	0.0485 (8)	0.0381 (6)	0.0050 (6)	0.0045 (5)	0.0097 (6)
C4	0.0396 (9)	0.0302 (8)	0.0367 (8)	0.000	0.0056 (7)	0.000
C5	0.0388 (6)	0.0407 (7)	0.0454 (7)	0.0039 (5)	0.0069 (5)	−0.0075 (5)
C6	0.0480 (7)	0.0384 (7)	0.0538 (8)	0.0025 (6)	0.0079 (6)	−0.0155 (6)
C7	0.0576 (12)	0.0309 (9)	0.0770 (15)	0.000	0.0020 (11)	0.000
N1	0.0439 (6)	0.0446 (6)	0.0532 (7)	−0.0056 (5)	0.0003 (5)	−0.0057 (5)
C8	0.0476 (8)	0.0504 (8)	0.0637 (9)	−0.0141 (7)	0.0128 (7)	−0.0062 (7)
C9	0.0490 (8)	0.0519 (8)	0.0624 (9)	−0.0108 (7)	0.0198 (7)	−0.0126 (7)
C10	0.0343 (6)	0.0403 (6)	0.0402 (6)	−0.0023 (5)	0.0005 (5)	0.0000 (5)
C11	0.0449 (7)	0.0541 (8)	0.0542 (8)	−0.0126 (6)	0.0146 (6)	−0.0104 (7)
C12	0.0514 (8)	0.0564 (9)	0.0581 (9)	−0.0097 (7)	0.0128 (7)	−0.0176 (7)

Geometric parameters (Å, º)

O1—C1	1.3111 (18)	C6—C7	1.5275 (19)
O1—H1	0.90 (3)	C6—H6	0.995 (18)
O2—C1	1.1977 (17)	C7—C6^i	1.5275 (19)
C1—C2	1.5196 (18)	C7—H7	1.019 (18)
C2—C3	1.5322 (17)	N1—C8	1.324 (2)
C2—C5	1.5372 (17)	N1—C12	1.3309 (19)
C2—C4	1.5445 (15)	C8—C9	1.381 (2)
C3—C6^i	1.527 (2)	C8—H8	0.964 (19)
C3—H3A	0.988 (17)	C9—C10	1.3868 (19)
C3—H3B	1.007 (17)	C9—H9	0.94 (2)
C4—C2^i	1.5445 (15)	C10—C11	1.3792 (19)
C4—H4	1.000 (15)	C10—C10^ii	1.490 (3)
C5—C6	1.5311 (19)	C11—C12	1.381 (2)
C5—H5A	0.985 (16)	C11—H11	0.946 (19)
C5—H6B	0.998 (16)	C12—H12	0.950 (19)
C6—C3^i	1.527 (2)
C1—O1—H1	110.8 (15)	C3^i—C6—C7	109.83 (11)
O2—C1—O1	122.33 (14)	C3^i—C6—C5	109.43 (12)
O2—C1—C2	124.25 (13)	C7—C6—C5	110.16 (11)
O1—C1—C2	113.42 (11)	C3^i—C6—H6	109.5 (10)
C1—C2—C3	110.73 (11)	C7—C6—H6	110.2 (10)
C1—C2—C5	111.59 (10)	C5—C6—H6	107.6 (10)
C3—C2—C5	109.98 (11)	C6^i—C7—C6	109.08 (16)
C1—C2—C4	106.96 (10)	C6^i—C7—H7	109.7 (10)
C3—C2—C4	108.76 (9)	C6—C7—H7	110.6 (10)
C5—C2—C4	108.73 (9)	C8—N1—C12	116.70 (12)
C6^i—C3—C2	109.68 (11)	N1—C8—C9	123.70 (14)
C6^i—C3—H3A	110.6 (10)	N1—C8—H8	116.9 (12)
C2—C3—H3A	110.6 (10)	C9—C8—H8	119.3 (12)
C6^i—C3—H3B	109.7 (10)	C8—C9—C10	119.66 (14)
C2—C3—H3B	107.9 (9)	C8—C9—H9	119.1 (12)
H3A—C3—H3B	108.3 (13)	C10—C9—H9	121.2 (12)
C2^i—C4—C2	109.85 (14)	C11—C10—C9	116.57 (13)
C2^i—C4—H4	109.4 (8)	C11—C10—C10^ii	121.91 (14)
C2—C4—H4	108.0 (8)	C9—C10—C10^ii	121.52 (15)
C6—C5—C2	109.19 (10)	C10—C11—C12	119.89 (13)
C6—C5—H5A	110.2 (9)	C10—C11—H11	122.2 (12)
C2—C5—H5A	110.8 (9)	C12—C11—H11	117.9 (12)
C6—C5—H6B	110.2 (9)	N1—C12—C11	123.47 (14)
C2—C5—H6B	110.6 (9)	N1—C12—H12	116.6 (11)
H5A—C5—H6B	105.7 (13)	C11—C12—H12	119.9 (11)
O2—C1—C2—C3	−19.1 (2)	C4—C2—C5—C6	−60.44 (14)
O1—C1—C2—C3	161.91 (13)	C2—C5—C6—C3^i	61.34 (15)
O2—C1—C2—C5	−142.01 (16)	C2—C5—C6—C7	−59.51 (15)
O1—C1—C2—C5	39.05 (17)	C3^i—C6—C7—C6^i	−60.23 (8)
O2—C1—C2—C4	99.20 (17)	C5—C6—C7—C6^i	60.37 (8)
O1—C1—C2—C4	−79.74 (14)	C12—N1—C8—C9	0.8 (3)
C1—C2—C3—C6^i	177.32 (11)	N1—C8—C9—C10	−0.7 (3)
C5—C2—C3—C6^i	−58.89 (14)	C8—C9—C10—C11	−0.1 (2)
C4—C2—C3—C6^i	60.07 (14)	C8—C9—C10—C10^ii	179.85 (16)
C1—C2—C4—C2^i	−179.34 (10)	C9—C10—C11—C12	0.5 (2)
C3—C2—C4—C2^i	−59.72 (8)	C10^ii—C10—C11—C12	−179.39 (16)
C5—C2—C4—C2^i	60.03 (8)	C8—N1—C12—C11	−0.3 (3)
C1—C2—C5—C6	−178.17 (11)	C10—C11—C12—N1	−0.3 (3)
C3—C2—C5—C6	58.54 (14)

Symmetry codes: (i) −x, y, −z+1/2; (ii) −x+1/2, −y+5/2, −z+1.

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O1—H1···N1	0.90 (3)	1.80 (3)	2.6801 (17)	168 (2)
C11—H11···O1^iii	0.946 (19)	2.576 (19)	3.2744 (19)	130.9 (15)
C8—H8···O2	0.964 (19)	2.67 (2)	3.367 (2)	129.6 (14)

Symmetry code: (iii) −x+1/2, y+1/2, −z+1/2.