Dominic
Cheuk
a,
Michael
Svärd
ab,
Colin
Seaton
c,
Patrick
McArdle
d and
Åke C.
Rasmuson
*ab
aSynthesis and Solid State Pharmaceutical Centre, Materials and Surface Science Institute, Department of Chemical and Environmental Sciences, University of Limerick, Limerick, Ireland. E-mail: ake.rasmuson@ul.ie
bDepartment of Chemical Engineering and Technology, KTH Royal Institute of Technology, Stockholm, Sweden
cChemistry and Forensic Science, University of Bradford, Bradford, UK
dSchool of Chemistry, National University of Ireland Galway, University Road, Galway, Ireland
First published on 21st April 2015
Polymorphism, crystal shape and solubility of 1,4-dihydroxyanthraquinone (quinizarin) have been investigated in acetic acid, acetone, acetonitrile, n-butanol and toluene. The solubility of FI and FII from 20 °C to 45 °C has been determined by a gravimetric method. By slow evaporation, pure FI was obtained from n-butanol and toluene, pure FII was obtained from acetone, while either a mixture of the two forms or pure FI was obtained from acetic acid and acetonitrile. Slurry conversion experiments have established an enantiotropic relationship between the two polymorphs and that the commercially available FI is actually a metastable polymorph of quinizarin under ambient conditions. However, in the absence of FII, FI is kinetically stable for many days over the temperature range and in the solvents investigated. FI and FII have been characterized by infrared spectroscopy (IR), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), transmission and ordinary powder X-ray diffraction (PXRD) at different temperatures. The crystal structure of FII has been determined by single-crystal XRD. DSC and high-temperature PXRD have shown that both FI and FII will transform into a not previously reported high-temperature form (FIII) around 185 °C before this form melts at 200–202 °C. By indexing FIII PXRD data, a triclinic P cell was assigned to FIII. The solubility of quinizarin FI and FII in the pure organic solvents used in the present work is below 2.5% by weight and decreases in the order: toluene, acetone, acetic acid, acetonitrile and n-butanol. The crystal shapes obtained in different solvents range from thin rods to flat plates or very flat leaves, with no clear principal difference observed between FI and FII.
Anthraquinones are the most important quinone derivatives of anthracene5 which are known to be present in many plant families such as Leguminosae, Liliaceae, Polygonaceae, Rubiaceae, and Rhamnaceae.6 Anthraquinone derivatives have been widely used as dyes for many years since they can provide a wide range of colours covering the entire visible spectrum.7 Anthraquinone derivatives exert a wide range of biological activities including laxative,8 diuretic,9 antioxidant,10 antifungal,11 antimicrobial and antiviral activities.12 They have also been used as anticancer agents, e.g. Ametantrone [64862-96-0] and Mitoxantrone (also known as Novantrone) [65271-80-9], to treat breast cancer and acute leukemia. Recently, more and more derivatives have been found to possess abilities as listed above, especially in the search of novel or second-generation anti-cancer drugs.13,14
Among the anthraquinones, dihydroxyanthraquinones constitute the most important group and are largely used as dyes and in the manufacture of dye intermediates.15,16 They also form the building blocks of many medicinal drugs.17 1,4-Dihydroxyanthraquinone (quinizarin) (Fig. 1) is used as a fungicide and pesticide chemical18 and has shown the ability to inhibit tumour cell growth.19
Two polymorphs of quinizarin (FI and FII) are known, and FI has been reported as the stable form in the literature.20 Unit cells of both FI and FII have been reported.21 The full crystal structure of FI has been solved22 (CSD refcode DHXANT10) and it crystallizes in the monoclinic system, space group number 14 with one molecule per asymmetric unit. To date, to the best of our knowledge, no single crystal data for FII have been reported, and there are no published solubility data for quinizarin in organic solvents.
In this study, the solubility of both polymorphs in several pure organic solvents at different temperatures was measured using a gravimetric method. In crystallization experiments, different crystal shapes and polymorphic forms were investigated. In slurry conversion experiments, we show that there is, in fact, an enantiotropic relationship between FI and FII. In order to gain an understanding of the relationship between crystal structure and crystal growth, the crystal structure of FI was re-determined and the structure of FII has been solved, and in addition, crystals of each polymorph have been face indexed.
Fig. 2 (a) Asymmetric unit of the FI structure (labelled atoms) and its hydrogen bond ribbon motif and (b) π-stacking in the FI structure. |
The crystal structure of FII was determined using a needle-shaped crystal grown from acetic acid solution. The asymmetric unit containing 8 molecules is shown in Fig. 3(a). As in the FI structure, the molecules form intra- and intermolecular hydrogen bonds leading to the formation of ribbons which are stacked along the b axis (Fig. 3(b)).
The structures of FI and FII contain essentially the same bonding motifs, and the difference between the two crystal structures is in the packing of the 1-D chains of quinizarin molecules. FI forms a herringbone packing with alternating stacks (Fig. 4(a)). In contrast, FII forms a stack of molecules in alternating layers (Fig. 4(b)). The transformation from FI to FII involves a reduction in the symmetry of FI in which eight symmetry-related molecules become independent to accommodate tiny changes in conformation which allow the FII structure to pack better and give a small increase in density. Crystal structure data and hydrogen bond distances of both structures are provided in the ESI.†
Fig. 4 (a) View of the herringbone packing of FI, viewed along the b-axis and (b) view of the packing of layers in FII. |
Fig. 5 shows DSC thermograms from two consecutive heating–cooling cycles with a ramp rate of 10 K·min−1, starting with FII and FI, respectively. The cycles have been repeated several times in order to isolate and identify the polymorphic form at different transformation stages using PXRD. It can be seen that both FI and FII transformed with an endothermic peak into a previously unreported high-temperature stable polymorph (FIII) at 185.8 °C and 189.3 °C, respectively. FIII started to melt at approximately 200 °C. Upon cooling, the melt recrystallized around 190 °C followed by a further transformation into FI below 175 °C. Attempts made to isolate this high temperature form using different cooling rates and quenching the DSC pans containing the melt or FIII in liquid nitrogen have been unsuccessful, resulting in FI. The determined enthalpy, extrapolated onset and peak temperature of the observed thermal events, averaged over 6 scans, are given in Table 1.
Fig. 5 DSC heating–cooling cycles (10 K min−1) using quinizarin FII as starting material, indicating the transformations into high-temperature FIII and the melting of FIII. |
FI to FIII transformation | FII to FIII transformation | Melting of FIII | |
---|---|---|---|
T (onset)/°C | 185.79 ± 0.57 | 189.32 ± 0.30 | 200.00 ± 0.67 |
T (peak)/°C | 187.62 ± 0.29 | 191.64 ± 0.35 | 202.97 ± 0.19 |
ΔH/kJ·mol−1 | 6.65 ± 0.058 | 6.81 ± 0.074 | 19.41 ± 0.14 |
Transmission PXRD patterns of quinizarin, as shown in Fig. 6, demonstrate the commercial quinizarin to be pure FI, with an XRD pattern identical to the theoretical pattern of FI obtained from the structure DHXANT10. Prominent peak positions (2θ values) for FI are at 15.65, 17.12, 18.21, 20.97, 23.60, 25.70 and 28.71°, and for FII, they are at 6.0, 15.43, 18.02, 21.47, 23.83, 25.97 and 29.00°.
Fig. 6 Theoretical PXRD pattern of FI (DHXANT10) along with experimental PXRD patterns of FI, FII and a mechanical mixture of FI and FII. |
The endothermic transformation of FI into FIII was confirmed to be solid–solid phase transformation by applying different heating rates (0.2, 2, 10 and 50 K min−1) using DSC. This transformation was further validated by HT-PXRD, equipped with a hot stage accessory that was calibrated with indium. Visual comparison of the HT-PXRD data (Fig. 7) indicates that a new phase appeared at about 176 °C, with complete conversion by 186 °C. Reduction of diffraction angles can be observed as the temperature increases, due to the temperature dependence of lattice constants.
Applying Le Bail analysis using the program GSAS30 on the FIII PXRD data at 180 °C, it was found that none of the known unit cells (FI, FII from CSD and our determined structures) give a satisfactory fit to the experimental data. Therefore the obtained peak positions were used as the basis of indexing attempt using the range of indexing programs available in the CMPR program.31 Only the ITO indexing program32 located a suitable cell (a = 4.2846 Å, b = 10.1957 Å, c = 15.3383 Å, α = 88.6360°, β = 83.2210°, γ = 78.3660°, V = 651.69 Å3). While this displays a figure of merit lower than those normally considered correct (M20 = 5.4), it does match all the peaks in the pattern, and the cell parameters and volume are consistent with a molecule of this size (2 molecules in the unit cell assuming 18 Å3 for each non-H atom). Therefore a Le Bail analysis was attempted in P for this cell to confirm the match of the cell to experimental data. This was successfully carried out (Rwp = 7.75%, Rp = 5.60%, χ2 = 8.727, Fig. 8). A comparison of the three structures is shown in Table 2. The metric values of the unit cell are similar to the FII cell reported in the CSD (a = 14.80 Å, b = 9.49 Å, c = 3.77 Å, α = 90°, β = 93.0°, γ = 90°); however, this cell cannot be refined to fit the data as well as the indexed triclinic cell and so we believe the triclinic cell to be the correct high-temperature cell. This phase, reported as FII in the previous work by Borgen in 1966 (ref. 21), was different from our experimental FII and was obtained from slow cooling of the melt in which some crystals reverted to FI at room temperature. Thus this cell may refer to another high-temperature polymorph of quinizarin.
FI | FII | Predicted FIII | |
---|---|---|---|
Crystal system | Monoclinic | Monoclinic | Triclinic |
Space group | P21/n | Cc | P |
Unit cell dimensions | a = 10.2390(8) Å | a = 20.0099(12) Å | a = 4.2846 Å |
b = 6.0429(4) Å | b = 24.6219(9) Å | b = 10.1957 Å | |
c = 16.454(2) Å | c = 18.3201(11) Å | c = 15.3383 Å | |
α = 90° | α = 90° | α = 88.6360° | |
β = 95.999(8)°. | β = 116.274(8)° | β = 83.221° | |
γ = 90° | γ = 90° | γ = 78.366° | |
Unit cell volume | 1012.51(17) Å3 | 8093.4(9) Å3 | 651.69 Å3 |
Z | 4 | 32 | 2 |
Z′ | 1 | 8 | 1 |
Density (calculated) | 1.576 Mg m−3 | 1.577 Mg m−3 | 1.22 Mg m−3 |
Some of the crystal habits observed by SEM are shown in Fig. 9–11. By slow evaporation, thin plates were obtained from acetic acid and acetonitrile solutions, rods from acetone and toluene solutions, while a leaf-shaped habit was obtained from n-butanol (Fig. 9). In cooling crystallization (ΔT = 5 °C), quinizarin mainly crystallizes as plates or prisms (Fig. 10) but as needles in toluene solution when no agitation was used (Fig. 10(f)). Moreover, with a higher driving force (ΔT = 35 °C) in acetone (Fig. 11), quinizarin crystallizes as very thin plates and the morphology is undistinguishable between the two forms. From observation, quinizarin generally crystallizes as plates and needles and often seen mixed together without any tendency of the solvent effects. However, we can see that the needle growth is favoured without agitation and a high driving force will yield very thin plate crystals.
Fig. 9 Crystals recrystallized by slow evaporation in (a) acetic acid (mix of FI and FII), (b) acetone (FII), (c) acetonitrile (mix of FI and FII), (d) n-butanol (FI) and (e) toluene (FI). |
Fig. 10 FI recrystallized by cooling (ΔT = 5 °C) in (a) acetic acid, (b) acetone, (c) acetonitrile, (d) n-butanol, (e) toluene with agitation and (f) toluene without agitation. |
A prediction of the crystal morphology of FI in vacuo was obtained using the attachment energy method.33 These calculations assume that the growth rates of different faces are based only on the energy released in forming the lattice and that kinetic factors including solvent effects make no contribution. Calculations were carried out using the Morphology module of Materials Studio 7.0 (Accelrys), with the pcff force field34 and force field-specific point charges. Fig. 12 shows the resulting crystal shape, with Miller indices of visible faces. FI is predicted to favour a plate-like habit, elongated in the b-direction, dominated by the two {002} faces with the lowest attachment energy, followed by the two {101} faces. The predicted habit is more prismatic than observed experimentally, which emphasizes that kinetic factors can dominate crystal growth from solution.
Fig. 12 Predicted vacuum crystal morphology of FI, with unit cell representation and tabulated data for dominant faces. |
Using single-crystal XRD, the main visible faces of a needle-shaped crystal of FI grown from toluene solution were indexed (Fig. 13). The needle growth direction in the FI crystal structure is along the b axis, as predicted, coinciding with the direction of π-stacking of ribbons. The planes defined by the ribbons are 3.35 Å apart with the atoms of adjacent ribbons in van der Waals contact and this is typical of slipped π-stacked systems and similar to the packing in β-phthalocyanine and benzoic acid.35 The high growth rate in the needle direction of β-phthalocyanine has been associated with the low activation energy required to generate a new step in the stacking direction.36 The importance of the crystallization driving force in controlling needle growth in the gas phase for flat molecule stacked systems has also been demonstrated.37
Notably, in the present case, when agitation was suspended upon nucleation needles were observed (Fig. 10(f)), whereas if agitation continued after nucleation the crystals became more blocky. The possibility of this being the result of crystal breakage due to agitation was ruled out based on visual observation. Without agitation, the effective supersaturation is expected to decrease locally and thus result in a reduced crystallization driving force close to the growing crystal surface, favouring needle growth.35 It might appear surprising that this system in solution mimics the behaviour of other flat molecule systems in the gas phase. However, toluene is not a hydrogen bonding solvent and would not be expected to exert a direct influence on the crystal growth.
Face-indexed crystals of FII grown from acetic acid without agitation are shown in Fig. 14. The crystals are initially needle-like (Fig. 14(a)) but with time gradually take on a more isotropic shape (Fig. 14(b)). The needles show extended growth in directions normal to the {101} faces. In the more prismatic crystals which develop after some time the {10−1} faces are dominant. It is clear that unlike FI growth in toluene, FII growth in acetic acid solution is not controlled by stacking effects. Here solvent hydrogen bonding to growing crystal faces seems to be more important.
Fig. 14 Face indexed crystals of FII from acetic acid solution: (a) initially observed needle and (b) later developed, more prismatic crystal. |
If the packing at the {101}, {010} and {10−1} faces are compared (Fig. 15), it is clear that the hydrogen bonding solvent will bind more strongly to the latter faces which have a higher concentration of exposed O atoms and OH groups. The solvent molecules would be expected to bind least strongly to the {101} faces as they are dominated by surface CH groups and it is reasonable that its growth is initially faster. It is also reasonable that the {10−1} faces are the ones which eventually become dominant as they provide the greatest surface concentration of O atoms and OH groups and thus are likely to give the lowest interfacial energy.
Solubility of quinizarin FI (standard deviation over three samples) (g per 100 g of solvent) | |||||
---|---|---|---|---|---|
T/°C | Acetic acid | Acetone | Acetonitrile | n-Butanol | Toluene |
20 | 0.3036 (0.0004) | 0.3986 (0.0045) | 0.1924 (0.0033) | 0.0768 (0.0046) | 1.0968 (0.0044) |
25 | 0.3417 (0.0007) | 0.4601 (0.0045) | 0.2198 (0.0005) | 0.0833 (0.0035) | 1.2769 (0.0143) |
30 | 0.4208 (0.0038) | 0.5713 (0.0031) | 0.2836 (0.0046) | 0.1012 (0.0032) | 1.4951 (0.0011) |
35 | 0.4912 (0.0044) | 0.6865 (0.0045) | 0.3433 (0.0063) | 0.1169 (0.0054) | 1.7583 (0.0049) |
40 | 0.5730 (0.0051) | 0.8101 (0.0086) | 0.4144 (0.0015) | 0.1416 (0.0033) | 2.0879 (0.0154) |
45 | 0.6573 (0.0123) | 0.9555 (0.0177) | 0.4915 (0.0060) | 0.1702 (0.0019) | 2.4204 (0.0224) |
Solubility of quinizarin FII (standard deviation over three samples) (g per 100 g of solvent) | |||||
T/°C | Acetic acid | Acetone | Acetonitrile | n-Butanol | Toluene |
20 | 0.2790 (0.0008) | 0.3677 (0.0007) | 0.1745 (0.0022) | 0.0503 (0.0005) | 1.0394 (0.0025) |
25 | 0.3287 (0.0007) | 0.4440 (0.0027) | 0.2122 (0.0004) | 0.0615 (0.0012) | 1.2296 (0.0119) |
30 | 0.3854 (0.0068) | 0.5350 (0.0003) | 0.2638 (0.0015) | 0.0776 (0.0005) | 1.4601 (0.0084) |
35 | 0.4649 (0.0027) | 0.6447 (0.0022) | 0.3188 (0.0010) | 0.0974 (0.0011) | 1.7004 (0.0095) |
40 | 0.5526 (0.0007) | 0.7826 (0.0042) | 0.3897 (0.0017) | 0.1270 (0.0013) | 1.9837 (0.0018) |
45 | 0.6540 (0.0011) | 0.9341 (0.0023) | 0.4752 (0.0008) | 0.1580 (0.0005) | 2.3399 (0.0115) |
Fig. 16 Solubility of quinizarin FI (solid symbols) and FII (hollow symbols) in: ■, toluene; ▲, acetone; ●, acetic acid; ◆, acetonitrile; and ▼, n-butanol. |
Fig. 17 lnxeq of quinizarin FI (solid symbols) and FII (hollow symbols) vs. 1/T in: ■, toluene; ▲, acetone; ●, acetic acid; ◆, acetonitrile; and ▼, n-butanol. |
The mole fraction solubility obtained at different temperatures in each solvent was correlated using eqn (1):
lnxeq = A + B/T | (1) |
Solvent | FI | FII | ||
---|---|---|---|---|
A | B | A | B | |
Acetic acid | 2.9110 | −2964.6 | 3.6166 | −3195.7 |
Acetone | 4.3868 | −3327.4 | 4.8512 | −3484.5 |
Acetonitrile | 4.2780 | −3613.4 | 4.6314 | −3740.3 |
n-Butanol | 1.9620 | −3037.6 | 5.9597 | −4327.7 |
Toluene | 4.6154 | −2961.9 | 4.6699 | −2990.4 |
The apparent or van't Hoff enthalpy of solution38 is essentially constant over the temperature range studied:
(2) |
Solvent | ΔvHsolnH (kJ mol−1) | |
---|---|---|
FI | FII | |
Acetic acid | 24.6 | 26.6 |
Acetone | 27.7 | 29.0 |
Acetonitrile | 30.0 | 31.1 |
n-Butanol | 25.3 | 36.0 |
Toluene | 24.6 | 24.9 |
Overall, mainly as a consequence of the high stability of the solid phase over the investigated temperature interval, the solubility is quite low. The highest solubility, expressed both as mole and mass fractions, is found in toluene, followed by acetone, acetic acid, acetonitrile and n-butanol. The solubility of FII is lower than FI, reaffirming the higher stability of FII over this temperature range. However, careful examination of the data for the two forms in each solvent indicates that a transition in thermodynamic stability will occur not far above the experimental T-range. If eqn (1) and the coefficients in Table 4 are used for extrapolation of the solubility data, on average over four solvents, acetic acid, acetone, acetonitrile and n-butanol, the estimated transition temperature is 64 °C. However, the value obtained from toluene (249 °C) is quite different from the others, which may be attributed partly to an increased uncertainty due to the relatively close, parallel solubility curves of FI and FII in this solvent.
In slurry conversion experiments performed between 30 °C and 80 °C in the five chosen solvents, the enantiotropic transition temperature was established to be between 50 °C and 60 °C, below which FII is the stable form. The rate of transformation is low in the vicinity of the transition temperature, but it could be established that over a period of three weeks a mixture of FI and FII transformed into FII at 50 °C and into FI at 60 °C. However, in the absence of FII crystals, the commercial FI exhibited sufficient kinetic stability to retain its structure over ten days in each of the five evaluated solvents at three temperatures (25 °C, 35 °C and 50 °C).
Unfortunately, solubility data above the estimated transition temperature could not be collected. However, assuming that the linear relationship between solubility and temperature can be extrapolated up to the transition point, an estimate of the enthalpy and entropy of transition can be obtained, e.g. according to the method outlined by Svärd et al.,39 by neglecting the influence of the activity coefficient on the ratio of solid state activities. The entropy of transformation can be expressed as:
(3) |
(4) |
Eqn (4) shows that the entropy of transformation is independent of temperature over the range where solubility curves form linear van't Hoff plots. At the transition temperature, the Gibbs energy difference between the polymorphs is zero. With the calculated entropy values, the enthalpy difference can be estimated using eqn (5). The resulting data obtained in four solvents, using the transition temperatures obtained by extrapolation in each solvent, are presented in Table 6. Toluene was excluded from the analysis for previously outlined reasons.
ΔHII→I(Ttr) = TtrΔSII→I = RTtr(AII − AI) | (5) |
Solvent | T tr (°C) | ΔHII→I (kJ mol−1) | ΔSII→I (J mol−1 K−1) |
---|---|---|---|
Acetic acid | 55 | 1.92 | 5.87 |
Acetone | 65 | 1.31 | 3.86 |
Acetonitrile | 87 | 1.06 | 2.94 |
n-Butanol | 49 | 10.70 | 33.24 |
The calculations assume that the solubility ratio can approximate the corresponding activity ratio in all the solvents and that the temperature derivative of the saturated solution activity coefficients can likewise be neglected. The lack of consistency in the data obtained in the five solvents suggests that these assumptions are not well met, especially not in butanol.
The quinizarin molecule contains the fully conjugated cyclic dione structure embedded as in the 9,10-anthraquinone structure. The two ketone groups are, in principle, hydrogen bond accepting. In quinizarin, there are, in addition to the anthraquinone structure, two alcohol groups in para-position, and these have hydrogen bond accepting as well as donating functionality. However, the proximity of each ketone group with each respective alcohol group leads to intra-molecular hydrogen bonding, reducing the inter-molecular hydrogen bond accepting functionality of the ketone groups and the hydrogen bond donating capability of the alcohol groups. Obviously, solvation of the hydrophobic parts of the molecule plays an important role for the solubility and should explain why the solubility is highest in toluene. The results further show that the hydrogen bonding of acetone and acetonitrile to the alcohol groups of quinizarin does not sufficiently compensate for the lower capability of these solvents of solvating the hydrophobic part. n-Butanol is able to hydrogen bond to the ketones as well as to the alcohol groups, but in spite of this, the solubility in this solvent is the lowest. The acetic acid solubility is at first surprising. Of course, acetic acid has the capability to hydrogen bond to both the ketone groups and the alcohol groups, but in fact the strongest bonding is expected to occur as dimerization of two acetic acid molecules. Perhaps this dimerization actually provides acetic acid with a greater capability to solvate the hydrophobic parts of the quinizarin molecule. Single acetic acid molecules can hydrogen bond to the polar parts of the molecule, while dimers can solvate the hydrophobic parts.
Footnote |
† Electronic supplementary information (ESI) available: IR spectra of FI and FII, crystallographic data of quinizarin FI and FII, hydrogen-bond geometry in the crystal structures of quinizarin FI and FII. CCDC 1044980 and 1044981. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ce00147a |
This journal is © The Royal Society of Chemistry 2015 |