DOI: 10.1021/cg1012846
Published as part of a virtual special issue on Structural Chemistry in India: Emerging Themes.
2011, Vol. 11 278–286
Water Bridged Assembly and Dimer Formation in Co-Crystals of Caffeine or Theophylline with Polycarboxylic Acids Babulal Das and Jubaraj B. Baruah* Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781 039 Assam, India Received September 30, 2010; Revised Manuscript Received November 15, 2010
ABSTRACT: Caffeine (caf) forms co-crystals caf 3 dpa (1), caf 3 pzca (2) and 2caf 3 trimel (3) with dipicolinic acid (dpa), 3,5pyrazole dicarboxylic acid (pzca), and trimellitic acid (trimel), respectively, whereas theophylline formed co-crystals theo 3 2dpa (4) and 2theo 3 2pzca (5) with the first two acids. These co-crystals are characterized by X-ray diffraction and conventional spectroscopic techniques. Co-crystal 1 forms a hydrogen-bonded assembly through one of the carboxylic acids with the imidazole moiety of caffeine, whereas the other carboxylic acid group is involved in strong hydrogen bonding with the crystallized water molecule. Thus, water-assisted assemblies are formed in which the water molecules are held by the nitrogen atom and also by the two carboxylic acid groups of dpa. In the case of co-crystal 2, pzca exhibits a hydrogen-bonded dimer through N-H 3 3 3 O and O-H 3 3 3 O interactions. A three component 2:1 co-crystal 3 of caffeine and trimellitic acid possesses acid-imidazole as well as O-H 3 3 3 OdC interactions. Similar to 1, theophylline co-crystal with dpa, 4, also exhibits an aqua bridged assembly, whereas a 2:2 co-crystal with pzca, 5, resulted in a dimer through an R22(8) homosynthon in the presence of a heterosynthon.
Introduction The synthon approach1,2 is of great importance to generalize a synthetic approach in “crystal engineering”.3 At present, the subject of crystal engineering has been directed toward the design of self-assemblies and co-crystals to develop new organic semiconductors,4 template-directed solid-state synthesis,5-7 and various functional materials.8-12 Co-crystals, or multicomponent molecular crystals,13 which are solid at ambient temperatures, have recently found many applications as pharmaceuticals,14 electronic materials, or in synthetic organic chemistry.15 Co-crystals containing pharmaceutical agents with appropriate partners exhibit a significant impact on pharmaceutical formulations such as improvement of solubility, dissolution, bioavailability, hygroscopicity, stability, and compatibility.16-18 Among such pharmaceutical compounds, caffeine and theophylline are naturally occurring drug molecules with very simple structure as illustrated in Figure 1a,b. They are widely known to form various types of co-crystals, salts,19 and polymorphs.20,21 Co-crystals of caffeine with oxalic, maleic, malonic, and glutaric acid are well studied.22 The structural studies of co-crystals of caffeine with hydroxy benzoic acids,23-25 hydroxy naphthoic acid,26 succinic acid,27 adipic acid,28 citric acid29 have led to various heterosynthons. Some of such commonly observed heterosynthons are illustrated in Figure 1c-e. Recently, rationalization of structures of different co-crystals in different stoichiometries derived from maleic acid/caffeine and glutaric acid-caffeine-acetonitrile, at low temperature through various phase equilibria have been studied.30,31 Similarly, theophylline, another active pharmaceutical ingredient, is used *To whom correspondence should be addressed. E-mail:
[email protected]. pubs.acs.org/crystal
Published on Web 11/29/2010
in the treatment of acute asthma, tremor therapy, and as a diuretic, and is also known to form various pharmaceutical cocrystals with carboxylic acids,29,32 nicotinamide,33 etc. Caffeine and theophylline were chosen as crystal partners because their co-crystals with carboxylic acids are considered as valuable materials due to their ability to improve physical properties and structural effects associated with pharmaceutical cocrystals. Systematic introduction of di/tricarboxylic acid groups in an aromatic periphery with or without a heteroatom was done with an anticipation to observe structural changes, availability of a high active pharmaceutical ingredients (API)to-co-crystal ratio, identification of new heterosynthons and changes in properties upon interacting with the simple biomolecules under consideration. With this background, we have studied the structural features of co-crystals of caffeine/theophylline with three different carboxylic acids (Figure 1f,g), namely, dipicolinic acid (dpa), 3,5-pyrazole dicarboxylic acid (pzca), and trimellitic acid (trimel). Experimental Section Materials. Caffeine (Merck), theophyliine (Loba), dipicolinic acid (99%), 3,5-pyrazole dicarboxylic acid monohydrate (97%), and trimellitic acid (97%) were purchased from Sigma-Aldrich and were used as such. Ethanol (Bengal chemicals) and Millipore Direct Q water was used both as solvent and for crystallization purposes. Single Crystal Preparation. Single crystals of caf 3 dpa (1), caf 3 pzca (2), 2caf 3 trimel (3) (caf = caffeine, dpa = dipicolinic acid, pzca = 3,5-pyrazole dicarboxylic acid and trimel = trimellitic acid) were obtained by slow evaporation from corresponding solutions of an equimolar amount of caffeine and corresponding carboxylic acid. For such crystallizations, caffeine (0.5 mmol, 5 mL of water) was mixed independently with dipicolinic acid (0.5 mmol, 5 mL of ethanol), 3,5-pyrazole dicarboxylic acid monohydrate (0.5 mmol, r 2010 American Chemical Society
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Figure 1. Structure of (a) caffeine, (b) theophylline, (c-e) commonly observed hydrogen-bonded synthons, (f) dipicolinic acid, (g) 3,5-pyrazole dicarboxylic acid, and (h) trimellitic acid.
Figure 2. Optical micrograph of the co-crystals 1-5. 5 mL of ethanol), and trimellitic acid (0.25 mmol, 2 mL of ethanol) respectively. For co-crystals theo 3 2dpa (4) and 2theo 3 2pzca (5), theophylline (theo) (0.5 mmol in 5 mL of water) was mixed separately with dipicolinic acid (0.5 mmol, 5 mL of ethanol) and 3,5-pyrazole dicarboxylic acid monohydrate (0.5 mmol in 5 mL of ethanol), respectively. The resulting solution was left stirred for 2 h at ambient temperature. The colorless solution obtained in each case after filtration was left to evaporate slowly at room temperature. Needle and block types of single crystals suitable for X-ray diffraction study were obtained after two/three days. The crystal morphologies of the co-crystals obtained from caffeine/theophylline with different carboxylic acids 1-5 are shown in Figure 2. Physical Measurements. Infrared spectra (KBr pellets) of the solids were recorded with a Perkin-Elmer Spectrum One FT-IR spectrophotometer in the region 4000-400 cm-1 spectral region. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were performed on a TA Instruments Q20 differential scanning calorimeter and SDT Q600 analyzer under nitrogen atmosphere from 35 to 350 C with a heating rate of 5 C. Powder X-ray diffraction (XRD) diffractograms were carried out on a Bruker D8 Advance (Germany) diffractometer with Cu KR (1.542 A˚) radiations operated at 40 kV and 40 mA. An optical microscope (BX-51, Olympus, Japan) equipped with a CCD camera (XC10) was used to take images of the crystal morphology. X-ray Crystallographic Studies. The co-crystals 1-5 were individually mounted on quartz fibers. X-ray intensity data were collected at 296 K with Mo KR radiation (λ = 0.71073 A˚) using a Bruker Nonius SMART CCD diffractometer equipped with graphite monochromator and Apex CD camera. The SMART software was used for data collection and for indexing the reflections and determining the unit cell parameters; the collected data were integrated using
SAINT software.34 The structures were solved by direct methods and refined by full-matrix least-squares calculations using SHELXTL software. All the non-H atoms were refined in the anisotropic approximation against F2 of all reflections. The H-atoms attached to nitrogen and oxygen molecules in these co-crystals were located in the difference Fourier synthesis maps, and refined with isotropic displacement coefficients. The locations of acidic protons were justified by difference Fourier synthesis map, and in the refinement these were allowed for as riding atoms in 3. The H-atom (H10o) in co-crystal 4 was observed as disordered, and the H-atoms in one of the water molecules (O12w) could not be located. Absorption was found to be negligible in each crystal. Crystal parameters and details of the final refinement parameters are summarized in Table 1.
Results and Discussion Co-crystal 1 (caf 3 dpa) was obtained as colorless thin needles crystallizing in P1 space group. The asymmetric unit constitutes of one unit each of caffeine and dipicolinic acid (dpa) molecules along with a crystallized water molecule (Figure 3a). Caffeine and dpa form a two-component 1:1 assembly based on a well-established acid-imidazole heterosynthon. The key structural feature of 1 is that the crystallized water molecule is involved in simultaneous hydrogen bonding with carbonyl oxygen, the hydroxyl group of carboxylic acid, and the neighboring dpa molecule leading to a four component hydrogen bonded assembly (Figure 3b). The water molecule acts as a donor with carbonyl oxygen in the assembly and as acceptor with the hydroxyl moiety of the carboxylic acid
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Table 1. Crystal Structure and Refinement Parameters of 1-5 co-crystal molecular formula Mr crystal size (mm3) crystal system space group a (A˚) b (A˚) c (A˚) R (deg) β (deg) γ (deg) V (A˚3) Z Fcalc (g cm-3) μ (M0 KR) (mm-1) F(000) T (K) range of indices no. of reflections collected unique reflections Rint goodness-of-fit R1 [I g 2σ(I)] wR2 [I g 2σ(I)] R1 (all data) wR2 (all data) Δr (max, min) e A˚-3
1 (C8H10N4O2) 3 (C7H5NO4) 3 H2O 379.34 0.34 0.18 0.10 triclinic P1 7.0067(3) 8.5496(4) 14.8640(7) 81.218(2) 76.958(2) 76.769(2) 839.62(7) 2 1.500 0.121 396 296 -8, 8; -9, 9; -17, 17 9621 2706 0.0556 0.947 0.0421 0.1129 0.0743 0.1279 0.203, -0.154
2 (C8H10N4O2) 3 (C5H4N2O4) 350.30 0.28 0.18 0.12 triclinic P1 7.5311(7) 7.8947(6) 14.2199(12) 78.166(6) 75.128(6) 66.750(6) 745.63(11) 2 1.560 0.126 364 296 -8, 8; -9, 9; -16, 16 8120 2544 0.0517 0.953 0.0407 0.0937 0.0620 0.1007 0.189, -0.239
3 2(C8H10N4O2) 3 (C9H6O6) 598.54 0.25 0.16 0.12 triclinic P1 9.6071(4) 10.3730(4) 15.3939(7) 76.390(3) 81.941(3) 66.586(3) 1366.35(10) 2 1.455 0.115 624 296 -11, 11; -12, 12; -18, 17 15143 4733 0.0492 1.086 0.0720 0.2149 0.1018 0.2461 0.542, -0.510
4 (C7H8N4O2) 3 2(C7H5NO4) 3 2H2O 550.45 0.26 0.18 0.08 triclinic P1 7.0692(4) 8.0877(4) 20.8190(10) 90.126(3) 94.010(3) 98.789(3) 1173.34(10) 2 1.558 0.130 572 296 -8, 8; -9, 9; -23, 24 14951 3825 0.0273 1.195 0.0490 0.1565 0.0564 0.1635 0.256, -0.530
5 2(C7H8N4O2) 3 2(C5H4N2O4) 3 2H2O 708.58 0.28 0.18 0.12 triclinic P1 8.1862(5) 9.7027(5) 20.4351(11) 97.385(4) 95.162(3) 107.772(3) 1518.43(15) 2 1.550 0.130 736 296 -9, 7; -11, 11; -23, 23 19359 4806 0.0365 0.819 0.0453 0.1159 0.0746 0.1418 0.241, -0.243
Figure 3. (a) ORTEP view of 1 (drawn with 50% thermal ellipsoids). (b) A perspective view of hydrogen bonded crystallized water bridged assembly. (c) π-π stacking and C-H...O interactions. (d) A space filling model of the crystal packing of stacked assemblies along the crystallographic a axis (green = caffeine, yellow = dpa, red = water).
group of dpa, thus enhancing the stability of the assembly. It also displays hydrogen contact with the nitrogen atom of dpa. Alternatively, it can be described as a dimeric assembly of two dpa molecules held by two intervening water molecules further linked to caffeine molecules through -O-H 3 3 3 N hydrogen bonds. It is also observed that the crystallized water moleculedpa occurring in a pair in the assembly are not in one plane and are separated by a distance of 1.96 A˚. Fourier difference
synthesis map analyses revealed the location of the hydrogen atoms in the carboxylic acid group and crystallized water. Selected H-bond parameters are listed in Table 2. The other weak interactions stabilizing co-crystal 1 are the π-π stacking between the pyrimidine ring of caffeine and the pyridine ring of dpa (Figure 3c). The plane-to-plane distance between two such rings is measured as 3.38 A˚. Caffeine and dpa assemblies stack in a parallel and offset manner and
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Table 2. Selected H-Bond Parameters for 1-5a co-crystal
bond (symmetry)
dD-H (A˚)
dH 3 3 3 3 A (A˚)
dD 3 3 3 3 A (A˚)
1
O(4)-H(4O) 3 3 3 O(7) O(4)-H(4O) 3 3 3 N(5) [intra] O(6)-H(6O) 3 3 3 N(3)i O(7)-H(7A) 3 3 3 O(5) O(7)-H(7A) 3 3 3 N(5) O(7)-H(7B) 3 3 3 O(5)ii O(4)-H(4O) 3 3 3 N(3)iii N(6)-H(6N) 3 3 3 O(3)iv O(6)-H(6O) 3 3 3 O(1)v O(6)-H(6) 3 3 3 N(7)vi O(7)-H(7) 3 3 3 O(2)vii O(9)-H(9) 3 3 3 N(3)viii N(4)-H(4N) 3 3 3 O(11)vi O(4)-H(4O) 3 3 3 N(3)iii O(6)-H(6O) 3 3 3 O(11) O(8)-H(8O) 3 3 3 O(2)xii O(10)-H(10O) 3 3 3 O(10)v O(11)-H(11A) 3 3 3 O(7) O(11)-H(11B) 3 3 3 O(9) N(4)-H(4N) 3 3 3 O(8)vii O(6)-H(6O) 3 3 3 N(7)viii O(7)-H(7O) 3 3 3 O(2)ix N(8)-H(8N) 3 3 3 N(11) O(9)-H(9O) 3 3 3 N(3)x N(10)-H(10N) 3 3 3 O(13)viii N(12)-H(12N) 3 3 3 O(4) O(12)-H(12O) 3 3 3 O(11)xi O(13)-H(13A) 3 3 3 N(9)vi O(13)-H(13B) 3 3 3 O(14) O(14)-H(14A) 3 3 3 O(3)x O(14)-H(14B) 3 3 3 O(5)viii
1.00(3) 1.00(3) 1.04(4) 0.90(6) 0.90(6) 0.94(5) 1.03(3) 0.92(2) 0.84(3) 0.82 0.82 0.82 0.94(3) 0.85(3) 0.96(3) 0.93(2) 1.04(9) 0.90(3) 0.94(6) 0.92(3) 0.90(4) 0.88(4) 0.92(3) 0.94(5) 0.96(4) 0.85(3) 1.10(5) 0.93(6) 0.87(5) 0.96(9) 0.90(5)
1.75(3) 2.15(3) 1.60(4) 2.11(6) 2.48(6) 1.96(5) 1.64(3) 1.90(2) 1.84(3) 1.87 1.92 1.86 2.12(3) 1.84(3) 1.79(3) 1.77(3) 1.88(10) 2.07(4) 1.94(6) 1.87(3) 1.77(4) 1.73(4) 1.97(3) 1.86(5) 1.73(4) 1.90(3) 1.58(5) 1.87(6) 2.03(5) 2.05(9) 2.00(5)
2.644(3) 2.729(3) 2.628(3) 2.975(3) 2.941(3) 2.902(3) 2.662(2) 2.787(2) 2.646(2) 2.686 2.712 2.662 2.947(3) 2.659(3) 2.721(2) 2.640(2) 2.702(2) 2.937(3) 2.719(3) 2.787(3) 2.675(3) 2.603(3) 2.842(3) 2.785(3) 2.682(3) 2.727(3) 2.681(3) 2.801(3) 2.843(4) 2.950(4) 2.876(4)
2 3 4
5
— D-H 3 3 3 3 A () 148(3) 115(2) 171(3) 163(6) 112(4) 175(4) 170(3) 162(2) 159(3) 174 163 168 147(2) 177(3) 163(4) 154(3) 133(7) 160(4) 138(6) 173(3) 179(5) 170(4) 157(3) 171(5) 176(4) 163(3) 180(6) 176(4) 158(4) 155(6) 167(5)
Symmetry codes: (i) 2 - x, -y, -z; (ii) 1 - x, 1 - y, -z; (iii) 1 - x, -y, 1 - z; (iv) -x, 1 - y, 1 - z; (v) 2 - x, 1 - y, -z; (vi) x, -1 þ y, z; (vii) 1 þ x, y, z; (viii) 1 - x, 1 - y, 1 - z; (ix) -1 þ x, y, z; (x) -1 þ x, -1 þ y, z; (xi) -x, 2 - y, -z. (xii) -1 þ x, 1 þ y, z. a
sustained by various C-H 3 3 3 O interactions between the carbonyl oxygen and methyl hydrogen/ring hydrogen (Figure 3d). The co-crystal structure may thus be described in terms of consecutive layers of caffeine and layers of dpa with water. A strong hydrogen-bonded bridged assembly between two acid molecules with interstitial water enhances the stability of the co-crystal. This may also be considered as complementing criteria for the formation of the crystalline product that is similar to intramolecular O-H 3 3 3 O hydrogen bonds that functions in the co-crystal of caffeine with hydroxy benzoic/ hydroxy naphthoic acids.23,26 Crystals of anhydrous co-crystal 2 (caf 3 pzca) obtained from ethanol/water crystallizes in P1 space group. The asymmetric unit contains one molecule each of caffeine and 3,5pyrazole dicarboxylic acid (pzca) (Figure 4a). They form a twocomponent assembly through intermolecular -O-H(carboxy) 3 3 3 N(imidazole) and -O-H(carboxy) 3 3 3 O(amide) hydrogen bonds. In addition, surprisingly one of the acid group and -NH moieties of pzca interacts with each other forming a dimer that is based on R22 (10) homosynthon. This dimeric assembly thus produced now leads to an infinite one-dimensional molecular tape along with the caffeine molecules via an N6-H 3 3 3 O3 hydrogen bond [d = 1.90(2) A˚, D = 2.787(2) A˚, — DH 3 3 3 A = 162(2)] in an ABAB manner (Figure 4b). It is to be mentioned that although the self-assembly process in carboxylic acid is very often observed, the coexistence of a carboxylic acid dimer in the presence of an acid-imidazole heterosynthon is rare.35,36 The hydrogen bond parameters of the dimer and caffeine are summarized in Table 2. Co-crystal 2 also forms hydrogen bonded assemblies based on acid-imidazole followed by CdO 3 3 3 O-H heterosynthon. The other prominent weak interactions stabilizing the co-crystal are the π-π stacking and C-H 3 3 3 O interactions. The centroid-
to-centroid π-π distance between the pyrimidine ring of caffeine and the pyrazole ring of the acid is measured as 3.40 A˚ (Figure 4c). In packing, the assemblies of molecular tapes stack in a parallel and offset manner as shown in Figure 4d, being held together by weak van der Waals forces and other interactions mentioned above. The asymmetric unit of co-crystal 3 (2caf 3 trimel) contains two symmetry-independent caffeine molecules and one molecule of trimellitic acid (Figure 5a). Within the co-crystal, both molecules adopt a conformation similar to that found in their pure form. The locations of acidic protons were justified by difference Fourier synthesis map, and in the refinement these were allowed for as riding atoms with O-H bond distances as 0.82 A˚. The difference in C-O and CdO bond distances in the acid group indicates a lack of delocalization, confirming no salt formation through proton transfer during crystallization. In the co-crystal, caffeine and trimellitic acid builds a three-component caffeineacid-caffeine adduct linked by strong O6-H 3 3 3 N7, O9-H 3 3 3 N3, and O7-H 3 3 3 O2 hydrogen bonds (Figure 5b). This trimeric three-component adduct is assembled with another similar trimer resulting in a six component discrete hexa-molecular assembly in the solid state. It is to be mentioned that two of the three carboxylic acid groups of trimellitic acid interact with caffeine through the imidazole-acid heterosynthon, whereas the third acid group interacts via a rare CdO 3 3 3 O-H heterosynthon. Thus, the introduction of an aromatic tricarboxylic acid resulted in a three-component 2:1 co-crystal based on OH 3 3 3 N and CdO 3 3 3 O-H interactions. Similar to co-crystals 1 and 2, the symmetrically independent caffeine molecules and trimellitic acid exhibit consecutive layers stacked in a parallel and offset manner (Figure 5c,d). The stacks are further held by weak van der Waals forces and various C-H 3 3 3 O interactions. Selected hydrogen bond parameters are included in Table 2.
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Figure 4. (a) ORTEP view of 2 (drawn with 50% thermal ellipsoids). (b) A perspective view of 1:1 co-crystal of 2 showing the H-bonded dimer of pzca in a one-dimensional tape. (c) A part of the structure showing π-π interactions. (d) A space filling model of the crystal packing of stacked assemblies along the crystallographic a axis (green = caffeine, yellow = pzca).
Figure 5. (a) Structure of 3 (ORTEP drawn with 50% thermal ellipsoids). (b) H-bonded interaction of caffeine with trimellitic acid. (c) Packing in space filling mode along the crystallographic a axis, (d) along the crystallographic b axis (green/light green = caffeine, yellow = trimel).
The 1:2 co-crystal 4 of theophylline and dpa in P1 space group has one molecule of theophylline and two molecules of dpa along with two water molecules of crystallization in its asymmetric unit (Figure 6a). The interaction of theophylline with two crystallographically independent dpa molecules take place through O-H 3 3 3 OdC as well as O-H 3 3 3 N heterosynthons. Similar to co-crystal 1, one of the dpa molecules
forms a four-component assembly with crystallized water molecule (O12w), which is further hydrogen bonded to theophylline and the other crystallized water molecule (O11w) (Figure 6b). In addition, the other crystallized water molecule (O11w) is strongly hydrogen bonded to both the carbonyl oxygen atoms of the dpa molecule as donor and with the neighboring dpa and theophylline molecule as acceptor in a
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Figure 6. (a) ORTEP view of 4 (drawn with 50% thermal ellipsoids). (b) A perspective view of hydrogen bonded water bridged assembly. (c) Tetrahedral H-bonding of crystallized water molecule with the components. (d) Packing in space filling mode along the crystallographic a axis (green = theophylline, yellow/blue = dpa).
tetrahedral fashion (Figure 6c). Further to this, two equivalent dpa molecules form hydrogen bonded (O10 3 3 3 H10o 3 3 3 O10) self-assembly through disordered hydrogen atom (H10o) in the solid state. The disorder assisted dpa self-assemblies are perpendicular to the theophylline and other set of dpa molecules which are stacked parallel with interstitial water molecules along the b axis and sustained by various π-π stacking, C-H 3 3 3 O and weak van der Waals interactions in a threedimensional (3D) structure (Figure 6d). It is to be mentioned that, although both the theophylline and dpa molecule possess multiple hydrogen bonding sites, a low theophylline to dpa cocrystal ratio might be due to the formation of self-assembly and crystallized water-dpa assembly, which leaves a limited site to interact with the theophylline molecule. Theophylline forms a 2:2 co-crystal 5 (2theo 3 2pzca) with 3,5-pyrazole dicarboxylic acid monohydrate. The asymmetric unit contains two symmetry independent molecules of theophylline and pzca respectively along with two water molecules of crystallization (Figure 7a). In addition to the commonly observed acid-imidazole heterosynthon, theophylline interacts either through an R22(8) or R22(9) heterosynthon with two different pzca. The hydrogen bonded interactions involved are N8-H8N 3 3 3 N11, N12-H12N 3 3 3 O4 for R22(8) and O7-H7 3 3 3 O2, N4-H4N 3 3 3 O8 for R22(9) heterosynthon. Similar to co-crystal 2, the identical carboxylic acid group of the two acids interact with each other, forming a dimer which is based on R22(8) homosynthon (Figure 7b). It is to be mentioned that the coexistence of a similar dimer of 6hydroxy naphthoic acid with caffeine co-crystal is known.26
The interstitial water molecules present as solvent of crystallization act as a donor-acceptor bridge between the two acids and also shows hydrogen contact with the carbonyl group of theophylline molecule (Figure 7c). The hydrogen-bonded assembly thus produced makes a one-dimensional (1D) array along with the interstitial water molecules in the solid state. Thus, there are two types of environments of carboxylic acid in terms of association with theophylline molecules. This causes two independent environments and the symmetry nonequivalence among the host molecules in the crystal lattice. The consecutive layers of pzca and theophylline are stacked in a parallel and offset manner similar to previous co-crystals, sustained further by various π-π stackings between the components, C-H 3 3 3 O and weak van der Waals interactions (Figure 7d). The prominent C-H 3 3 3 O interactions observed between the theophylline and pzca molecule is based on R22(10) heterosynthons. With the absence of an N-methyl group in the imidazole moiety, theophylline possesses multiple hydrogen bonding sites, which might be responsible for the high API-to-co-crystal ratio in 5. Selected hydrogen bond parameters are shown in Table 2. We have carried out some other conventional spectroscopic techniques for further characterization of these compounds. X-ray powder diffraction (XRPD) patterns of the three caffeine co-crystals were compared with those simulated from the single-crystal structures. The measured XRPD patterns of each crystalline solid exhibits good agreement with the simulated one avoiding reflections belonging to the starting materials, confirming the homogeneity of the bulk samples (Figure 8).
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Figure 7. (a) Structure of 5 (ORTEP drawn with 50% thermal ellipsoids). (b) A perspective view of 5 showing the H-bonded dimer of pzca. (c) A view of interstitial water bridged assembly and discrete pzca (d) packing in space filling mode along the crystallographic a axis (green/light green = theophylline, yellow/orange = pzca).
Figure 8. XRPD patterns of the caffeine co-crystals 1-3 (a) experimental and (b) simulated.
Co-crystals 1, 4, and 5 can be considered as hydrated cocrystals due to the presence of crystallized water molecules, whereas the left two as anhydrous co-crystals resulted under similar reaction conditions. Formation of co-crystals (i.e., neutral molecular complexes) has been confirmed by FTIR data as well as by assignment of the acidic protons from the difference Fourier synthesis maps. The carbonyl stretching frequency for all the solids is above 1600 cm-1 in the infrared spectra confirming the presence of un-ionized carboxylic acids. A typical carboxylic acid salt would be expected to have IR absorptions around 1592 cm-1 (Figure 9). The carboxylic acid absorption bands are shifted toward a lower frequency range 1658-1667 cm-1 from 1694 to 1704 cm-1 depending on the strength of hydrogen bonds. In contrast, the carbonyl bands of free caffeine appearing at 1698 cm-1 and 1659 cm-1 are shifted toward higher frequencies in the range 1726-1739 cm-1 and
1702-1707 cm-1, respectively, because of the said hydrogen bond interactions that disturb the electron distribution throughout the ring system. Similarly, the carbonyl bands of anhydrous theophylline that appear at 1667 cm-1 and 1717 cm-1 are also shifted toward the higher frequency range in the cocrystals (Figures S2 and S3, Supporting Information). The DSC of these crystalline solids display flat baseline and sharp melting peaks for the respective components (Figure 10). This is also consistent with the high purity of the powders suggested by the PXRD pattern. Co-crystal 1 shows the presence of three endothermal peaks, which are at peak temperatures 134.8 C, corresponding to the loss of crystallized water. A sharp endothermal peak at 193.5 C followed by a broad peak at 223.9 C shows the melting of the co-crystal (the melting point for caffeine37 and dpa are 236.0 and 250.0 C, respectively). Loss of crystallized water molecule at a relatively
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Figure 9. FTIR spectra of (1) (a) caffeine (b) dpa (c) co-crystal 1; (2) (a) caffeine, (b) pzca (c) co-crystal 2; (3) (a) caffeine (b) trimel (c) co-crystal 3.
atom on the heterocyclic nitrogen with the carbonyl oxygen atom of acid group in 2 or through the conventional cyclic hydrogen bond between two acid groups in 5. Introduction of aromatic tricarboxylic acid resulted in a discrete hexa-molecular assembly in 3, whereas in co-crystal 5 theophylline are placed in two independent environments caused by discrete and self-assembled pairs of 3,5-pyrazole dicarboxylic acid molecules in the lattice. This is reflected in the symmetry nonequivalence between two theophylline molecules. Acknowledgment. The authors thank Department of Science and Technology (New-Delhi) India for financial support.
Figure 10. DSC thermograms of the caffeine co-crystals 1-3.
higher temperature also suggests the stability of the hydrogenbonded assembly in the crystal. A sharp peak at 276.3 C followed by a medium endothermal peak at 285.6 C observed for co-crystal 2 explains the formation of the dimer of pzca in a 1D hexa-molecular assembly (the melting point of pzca is 290.0 C). The co-crystal 3 shows two sharp endothermal peaks (peak temp. 177.4 and 181.1 C) followed by two broad peaks (the melting temperature of trimellitic acid is 231.0 C). These may be attributed to weak hydrogen bonded interactions in the packing in comparison to co-crystals 1 and 2. Theophylline co-crystals 4 and 5 exhibit loss of encapsulated water molecules at peak temperatures 112.8 and 144.5 C, respectively, followed by sharp endothermal peaks at 224.5 and 271.1 C, respectively, for the loss of co-crystals (the melting temperature of theophylline 271-272 C) (Figure S4, Supporting Information). Thus, DSC thermograms disclosed a significant drop in melting temperature of caffeine/theophylline in co-crystals 1, 3, and 4; whereas co-crystals 2 and 5 melt at a temperature close to their parent counterparts. In conclusion, the water molecule present as solvent of crystallization in 1 and 4 resulted stable assembly of dipicolinic acid having water bridges. The π-π stacking and CH 3 3 3 O interactions in the lattice led to stabilization of sheetlike structures. Although it was not possible to incorporate a new type of heterosynthon, it has been observed that the stabilization of the co-crystal via supporting intermolecular forces between the layers is also important. The 3,5-pyrazole dicarboxylic acids are self-assembled either through the hydrogen
Supporting Information Available: CIF files of all the compounds reported; these files are deposited with the CCDC (Nos. 792939, 792940, 792941, 800580, and 794250). Thermogravimetry plots for 1-5; FTIR and DSC plots of 4 and 5. This material is available free of charge via the Internet at http://pubs.acs.org.
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