Solid Forms, Crystal Habits, and Solubility of Danthron - Journal of

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Solid Forms, Crystal Habits, and Solubility of Danthron Dominic Cheuk,† Dikshitkumar Khamar,† Patrick McArdle,‡ and Åke C. Rasmuson*,† †

Synthesis and Solid State Pharmaceutical Centre, Materials and Surface Science Institute, Department of Chemical and Environmental Sciences, University of Limerick, Limerick, Ireland ‡ School of Chemistry, National University of Ireland Galway, University Road, Galway, Ireland S Supporting Information *

ABSTRACT: The polymorphism, crystal habits, and solubility of 1,8-dihydroxyanthraquinone (danthron) were investigated in acetic acid, acetone, acetonitrile, nbutanol, and toluene. The solubility was determined for the commercially available form (FI) from 293.15 K to 318.15 K by the gravimetric method. The influence of solvents on crystal habit and polymorphic form has been investigated. Three different crystal habits of danthron were obtained from slow evaporation and cooling experiments. By evaporation, thin squares of FI were obtained from nbutanol and toluene solutions while both FI and fine needles of FII were obtained from acetone and acetonitrile solutions. In addition, needle-shaped solvate crystals were obtained from acetic acid solutions and the structure of the solvate was solved by single crystal X-ray diffraction. From cooling crystallization experiments, mixtures of FI and FII were often obtained from various solvents, but FI and FII possess distinct habits which can be easily distinguished by visual comparison. Slurry conversion experiments have established that FI is the thermodynamically stable polymorph of danthron at ambient conditions. Differntial scanning calorimetry (DSC) and high-temperature powder X-ray diffraction (PXRD) have shown that both FI and FII will transform into a high-temperature form (FIV) around 435 K to 439 K before this form melts at 468.5 K. FI, FII, and FIV have been characterized by transmission and high-temperature PXRD, scanning electron microscopy, infrared spectrometry, Raman spectrometry, thermogravimetric analysis, and DSC. The solubility of danthron FI in the pure organic solvents of the present work and in the temperature range investigated is below 4.3 % by weight and decreases in the order toluene, acetone, acetonitrile, and n-butanol.

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INTRODUCTION Crystallization from solution continues to be an important separation and purification process in the pharmaceutical industry. The knowledge of the polymorphism, crystal habit, and solubility of an active pharmaceutical ingredient (API) plays crucial roles in the development, manufacturing, and formulation processes.1 The solubility of an API in solvents has an influence on the choice of solvents and the design of the crystallization process. 2 The polymorphism of an API determines its thermodynamic, spectroscopic, kinetic, surface, packing, and mechanical properties in the solid state.3 The crystal habit of an API also has profound effects on the rate at which the API can be processed and the success of the API in the downstream process.4 Solubility, polymorphism and crystal habit are all solvent dependent; therefore, a deep understanding is necessary for designing the crystallization process. Anthraquinone derivatives represent the largest and the most important group of natural quinones which are known to be presented in many plant families such as Leguminosae, Liliaceae, Polygonaceae, Rubiaceae, and Rhamnaceae.5 Both naturally occurring and synthetic anthraquinones have been widely used as colorants in foods, cosmetics, hair dyes, and textiles for many years since they can provide a wide range of colors covering the entire visible spectrum.6 The hydroxyderivatives of anthraquinone have important applications as a © XXXX American Chemical Society

prominent family of pharmaceutically active and biologically relevant chromophores. In particular 1,8-dihydroxyanthraquinone (danthron) and its derivatives, such as emodin, aloeemodin, chrysophanol, physcion, and rhein are the most studied compounds for their known pharmacological activity. Danthron, Figure 1, is a naturally occurring anthraquinone derivative which has been widely used as a laxative since the beginning of last century.7 Moreover, danthron and its derivatives have also been found to exhibit antifungal8 and anticancer ability.9−12 However, due to its danger as a possible

Figure 1. Chemical structure of danthron. Received: March 2, 2015 Accepted: June 16, 2015

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DOI: 10.1021/acs.jced.5b00192 J. Chem. Eng. Data XXXX, XXX, XXX−XXX

Journal of Chemical & Engineering Data

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Table 1. Crystallographic Parameters of Danthron−Acetic Acid Solvate (Other Polymorphs Included for Comparison, Taken from Rohl et al.19) crystal system space group [no.] description a, Å. b, Å. c, Å. α, deg β, deg γ, deg volume, Å3 Z Dcalcd, g cm−3 T, K

FI

FII

FIII

FIV

FV

solvate

tetragonal P41 [76] orange, plate 5.746 (3) 5.746 (3) 31.39 (5) 90 90 90 1036.39 4 1.539 295 (2)

orthorhombic Pca21 [29] orange, needle 21.578 (2) 3.766 (1) 24.683 (2) 90 90 90 2005.8 (9) 8 1.591 130 (2)

triclinic P1̅ [2] orange, prism 10.211 (2) 10.308 (2) 19.776 (3) 78.058 (8) 83.905 (9) 88.995 (5) 2024.9 (5) 8 1.576 130 (2)

monoclinic P21/n [14] orange, prism 7.2930 (5) 9.5001 (7) 14.7208 (11) 90 91.634 (2) 90 1019.5 (1) 4 1.565 110 (2)

tetragonal P41212 [92] red, block 5.7440 (6) 5.7440 (6) 31.393 (3) 90 90 90 1035.8 (2) 4 1.540 295 (2)

monoclinic P21/c [14] orange, needle 19.7826(11) 11.0872(5) 30.0405(17) 90 95.850 (6) 90 6554.6(6) 32 1.582 151.0 (1)

human carcinogen,13−16 the U.S. Food and Drug Administration (FDA) ordered the withdrawal of danthron-containing products from the U.S. market for use as laxative17 and it is restricted to patients who have already been diagnosed as having terminal cancer in U.K.18 Danthron has five previously reported polymorphs in the Cambridge Structural Database (CSD), refcode: DHANQU. The crystallographic parameters for the reported forms of danthron along with an acetic acid solvate from this work are presented in Table 1 as an aid in clarifying the name of the different polymorphic forms. The FI crystal was found to be orange with a squared shape and was reported to grow simultaneous with FII upon evaporation from acetone and acetonitrile mixtures in which FI was often overlaid by fine orange needles of FII.19 Smulevich and Marzocchi had observed a phase transition of FI at 418 K and showed that this high-temperature phase was equivalent to the room temperature needle FII.20 FIII appeared to be an odd-looking polyhedron distinct from the FI thin plates and FII fine needles but was only rarely found in the work of Rohl et al.19 FIV was obtained by sublimation at 393 K to 398 K under a vacuum (3−5 Torr)19 and FV was reported by Zain and Ng, obtained by evaporation from a pyridine solution.21 Despite many reported polymorphs, only three polymorphs (FI, FII, and FIV) were reproduced using our methods and solvents of choice. FI is shown to be the most thermodynamically stable form among of these structures, followed by FII and FIV.19 In the present manuscript, these three polymorphs along with the danthron-acetic acid solvate have been characterized by thermal, crystallographic, spectroscopic, and microscopic techniques. In addition, the solubility of FI in five organic solvents from 293.15 K to 318.15 K has been investigated, and is reported for acetone, acetonitrile, n-butanol, and toluene. In acetic acid the formation of the solvate prevented determination of the solubility of FI.

microscopy (SEM), and the structure of the acetic acid solvate was determined by single crystal X-ray diffraction. Materials. 1,8-Dihydroxyanthraquinone (CAS registry number 117-10-2) was purchased from Aldrich, purity > 99.9 %, and was used without further purification. This commercial form was verified to be the pure FI by transmission PXRD. Organic solvents were purchased from Sigma-Aldrich and used as received: acetic acid (Puriss grade, ≥ 99.8 %), acetone (Chromasolv, ≥ 99.8 %), acetonitrile (Chromasolv plus, ≥ 99.9 %), n-butanol (Chromasolv plus, ≥ 99.7 %) and toluene (Chromasolv, 99.9 %). Solubility of FI in Organic Solvents. The experimental setup for the solubility measurements consisted of a thermostatic water bath (Grant S26 stainless steel water bath, 26 L, 505 mm × 300 mm × 200 mm; equipped with a Grant C2G cooling unit and a Grant GR150 control unit; @ 310 K, stability ± 0.005 K and uniformity ± 0.02 K) with a serial submersible 60 points magnetic stirrer plate (2Mag) placed on the base and a submersible water pump (1400 L/h) to enhance circulation in the bath. The set temperature was validated by a digital thermometer (D750 PT, Dostmann electronic, Wertheim, Germany, uncertainty of ± 0.01 K). Solutions with excess FI were prepared in 30 mL glass vials with PTFE-coated magnetic stirrers. The vials were placed on the magnetic stirrer plate with an agitation of 600 rpm in the water bath for at least 18 h at each temperature to allow equilibrium to be reached. Stirring was then turned off and excess solids were allowed to settle for 2 h. Clear solution was sampled using syringes (5 mL) and filtered through syringe filters (PTFE or Nylon, 25 mm, pore size 0.2 μm, VWR) into preweighed glass vials. Syringes and filters were preheated to 5 K above the saturation temperature to prevent nucleation inside the syringes during sampling. The weight of the vials with solution was recorded immediately. The samples were completely dried in a ventilated laboratory hood at room temperature, and the weight of each sample was recorded repeatedly throughout the drying process in order to ensure complete dryness. Finally, the samples were dried in an oven at 313 K for 6 h to ensure all solvent had evaporated. At each temperature, the solids in equilibrium with the solution were sampled by filtration and quickly analyzed by transmission PXRD in order to ensure that no transformation of the original solid structure had occurred.

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EXPERIMENTAL SECTION The solubility of FI danthron in four different pure solvents (acetone, acetonitrile, n-butanol, and toluene) has been determined gravimetrically between 293.15 K and 318.15 K, in 5 K increments. Various solid-state forms of danthron have been characterized by differntial scanning calorimetry (DSC), thermogravimetric analysis (TGA), powder X-ray diffraction (PXRD), IR, Raman spectrometry, and scanning electron B



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Crystal Habits and Polymorph Stability. Slow evaporation crystallization experiments were performed in 5 mL scale at room temperature in a ventilated laboratory hood. The solvent was allowed to evaporate through small holes in an aluminum foil cover over a week, during which the crystals were isolated before it reached complete dryness. Cooling crystallization experiments were conducted in 30 mL vials filled with approximately 20 mL of solution saturated at 313 K. Solutions were cooled at a rate of 10 K/h under agitation of 600 rpm using magnetic stirrers. The crystals were sampled by filtration immediately after nucleation had occurred. The structural composition and the shape of the crystals were examined by ex-situ PXRD and SEM. Mechanical mixtures of solid FI and FII were slurried in different solvents for 3 days to investigate the stability between the two forms at room temperature. Solid samples were collected and analyzed by transmission PXRD after transformation had completed. Complete transformation can be visibly identified as the habit of the two forms is significantly different.

SEM was performed using a JEOL CarryScope scanning electron microscope JCM-5700. Crystal samples were mounted onto aluminum stubs with carbon tabs and coated by an ultrathin gold layer prior to analysis.

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RESULTS AND DISCUSSION Solid State Characterization of Danthron. PXRD and Single Crystal-XRD of the Acetic Acid Solvate. PXRD patterns

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Figure 2. Experimental transmission PXRD patterns of FI, FII, FIV, and danthron−acetic acid solvate.

SOLID STATE CHARACTERIZATION The thermal behavior of solid samples was monitored using DSC (PerkinElmer instruments Pyris 1 DSC), from 303 K to 483 K, at a rate of 10 K·min−1, under 50 mL·min−1 N2 purge. Approximately 5 mg of sample (masses controlled to ± 0.005 mg using Ohaus Analytical Plus electronic balance) was weighed into Al-Pans without pinholes (40 μL) which were hermetically sealed by crimper press. The instrument was calibrated with indium (429.75 K, 28.45 J·g−1) and lead (600.62 K, 23.01 J·g−1). TGA measurements were performed using a DSC−TGA thermobalance (SDT Q600, T.A. Instruments) with a ramping rate of 10 K·min−1 from 303 K to 773 K. Sample crystals were weighted into open alumina crucibles (50 μL), and the weights were approximately 5 mg. Nitrogen purging was set at a rate of 50 mL·min−1. IR spectra of the solid samples were collected using PerkinElmer Spectrum 100 FT-IR spectrometer equipped with a Universal ATR sampling accessory (single reflection and diamond/zinc selenide material). Spectra were recorded at room temperature as the average of 32 scans with a spectral resolution of 4 cm−1 in the spectral region 4000 cm−1 to 650 cm−1. Raman spectra were collected using a Kaiser Raman Rxn2 analyzer with an Invictus 785 nm excitation laser and a CCD camera-based detector. A noncontact probe was used for solid samples and each spectrum was collected for a minimum of 10 s exposure time and five accumulations in the region of 3400 cm−1 to 200 cm−1 using Mettler Toledo iC Raman software version 4.1. Transmission PXRD was performed using an Empyrean diffractometer (PANalytical, Phillips) with Cu Kα radiation (λ = 1.5406 Å) at room temperature. Data were recorded at a tube voltage of 40 kV and a tube current of 40 mA, applying a step size of 0.0066° (2θ) and a scan speed of 0.082° (2θ·s−1) in the angular range of 4° to 35° in 2θ with 4 rpm. Single crystal XRD for the danthron−acetic acid solvate was performed using an Oxford Diffraction Xcalibur diffractometer with Mo Kα radiation (λ = 0.71073 Å, θmax = 25.320°) at 150 K. A needle shaped crystal of 0.2 mm × 0.4 mm × 0.5 mm used for the measurement was grown by slow evaporation and was selected from the solution.

of the three anhydrous forms of danthron and the danthron− acetic acid solvate are presented in Figure 2. Comparison of the diffractograms shows that all forms possess characteristic diffraction peaks between 5° and 35° (2θ) and their major peak positions are provided as Supporting Information. Rohl et al. provided the crystallographic data for FI to FV along with the illustration of the differences between structures.19 The present study evidenced the differences between polymorphs using transmission PXRD. The commercial danthron was found to be pure FI and the PXRD pattern of the solvate shows that it is significantly different from all other reported polymorphs. The needle-shaped danthron−acetic acid solvate grown by slow evaporation was further examined by single crystal X-ray diffraction for structure determination. This solvate crystallizes in monoclinic symmetry in the P21/c space group. The asymmetric unit is shown in Figure 3a and it contains six danthron molecules and two acetic acid molecules. The structure is provided as Supporting Information, and its crystallographic parameters are summarized in Table 1 along with those of previously reported polymorphs. The only intermolecular hydrogen bonds in the solvate structure are in the centro-symmetric acetic acid dimers. The centroids of the central rings are all in contact with distances in the range 3.673 Å to 3.715 Å. The π-stacking is in the b direction, and this is clear from the unit cell packing which is shown in Figure 3b. It is believed that the energy of generating a new step in that direction is much lower due to the flat nature of the molecules which causes the stacking direction to be the same as the needle growth direction in Figure 4. DSC, HT-PXRD, and TGA. The DSC curves in Figure 5 show two consecutive heating and cooling cycles with a ramp rate of 10 K·min−1, starting with FII and FIV, respectively. It can be seen that in the second heating cycle, the high temperature stable polymorph (FIV) transformed back to FI with an exothermic peak and both FI and FII transformed with an endothermic peak into FIV at 435.4 K and 438.9 K, respectively. This FIV was brought down to room temperature by quenching the DSC sample pan into liquid nitrogen and the C



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Figure 3. (a) Asymmetric unit showing atoms with 40 % probability ellipsoids, and (b) view down b-axis in the danthron−acetic acid solvate unit cell.

Table 2. Thermal Properties of Danthron with 95 % Confidence Intervala

T (onset)/K T (peak)/K ΔH/(kJ·mol−1)

FI to FIV endothermic transformation

FII to FIV endothermic transformation

melting of FIV

435.39 ± 0.39 437.16 ± 0.48 4.96 ± 0.055

438.84 ± 0.70 440.58 ± 0.80 5.00 ± 0.079

468.53 ± 0.75 471.23 ± 1.19 20.06 ± 0.31

a The standard uncertainty for the temperatures u(T) are 0.2 K, and the standard uncertainty of the enthalpy determination u(ΔH) is 0.5 kJ·mol−1.

Figure 4. Face indexed crystal of danthron−acetic acid solvate showing the direction of needle growth. Figure 6. PXRD of danthron at different temperatures, showing the high-temperature transformation of FI into FIV.

Figure 5. DSC thermograms consisting of two heating−cooling cycles using danthron FII as starting material, indicating the transformation into and melting of FIV.

Figure 7. Thermogravimetric analysis of danthron−acetic acid solvate, showing a two-stage decomposition.

D



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Figure 8. Selected bands in (a) IR and (b) Raman spectra for the three anhydrous forms and the acetic acid solvate of danthron.

In the graph shown, FIV remained unchanged after the first cycle, and it transformed into FI in the second heating cycle between 333 K to 363 K. FI was further transformed into the high temperature FIV upon heating but the transformation temperature (435 K) was slightly lower than that of the FII, indicating FII is more stable than FI at a higher temperature which supports the transformation of FI into FII found by Smulevich and Marzocchi in 1985.20 The enthalpy, onset, and peak temperature of the two transformations and melting events are given in Table 2. The endothermic solid−solid phase transformation of FI into FIV observed with DSC was validated using HT-PXRD. Visual comparison of the HT-PXRD data (Figure 6) indicates that the transformation of FI into FIV completed below 439 K. The hot stage accessory was calibrated against indium, 429.75 K. Reduction of diffraction angles can be observed as the temperature increases, due to the temperature dependence of lattice constants. Thermogravimetric analysis (TGA) of the danthron crystals obtained from different solvents all show a one-step decomposition process except for the crystals from acetic acid. The acetic acid solvate shows a two-step decomposition (Figure 7) in which 7.144 weight % is lost during the first step, and the onset temperature was found to be 337.75 ± 0.22 K by DSC with 95 % confidence interval. Hence, the molar ratio of the solvent to solute can simply be calculated as 1:3.25. The

Table 3. Comparison of Selected Bands in the Raman Spectra of Different Forms of Danthron Raman (cm−1)a vibration modes22

FI

FII

FIV

v(−CO) v(CC) δ(CH) v(CC), δ(CO) v(C−O)

1675(s) 1569(s) 1446(m) 1353(m) 1304(m) and 1292(m) 1164(w) 1060(m) 976(m) 583(m) 488(s)

1669(s) 1558(s) 1441(m) 1359(m) 1289(m) and 1270(m) 1165(sh) 1062(m) 980(m) 581(m) 482(s)

1671(s, b) 1565(s) 1444(m) 1357(m) 1294(b)

δ(CH) v(CC) v(CC) γ(C−O) ring deformation

1161(b) 1060(m) 980(m) 582(m) 483(s)

acetic acid solvate 1674(s) 1559(s) 1444(m) 1357(m) 1293(m) and 1271(m) 1172(w) 1060(m) 980(m) 581(m) 480(b)

Notation: v, stretching mode; δ, in-plane bending; γ, out-of-plane bending; s, strong; m, medium; w, weak; sh, shoulder; b, broad.

a

powder spectra was determined by ex-situ PXRD. FIV began to melt approximately at 468 K. Upon cooling, the melt recrystallized as FIV at (463.2 ± 1.5) K, and it could be cooled to room temperature without transformation but it often transformed to FI between 393 K and 373 K on cooling.

Figure 9. Raman spectra of (a) FIV collected over a period of time showing solid state transformation of FIV into FI (b) FIV (green) at the start of the experiment, FI (blue) left at the end of the experiment, and comparison with pure FI (red). E



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Table 4. Solubility of Danthron (FI) in Four Organic Solvents from 293.15 K to 318.15 K Solubility of danthron FIa (standard deviation over three samples) (g per 100 g of solvent) T/K 293.15 298.15 303.15 308.15 313.15 318.15 a

acetone 0.6535 0.7676 0.9269 1.1077 1.3053 1.5382

acetonitrile

(0.0015) (0.0017) (0.0015) (0.0029) (0.0030) (0.0053)

0.3075 0.3703 0.4589 0.5574 0.6812 0.8081

(0.0021) (0.0006) (0.0015) (0.0010) (0.0066) (0.0108)

n-butanol 0.0821 0.0943 0.1254 0.1451 0.1926 0.2432

(0.0016) (0.0007) (0.0022) (0.0032) (0.0038) (0.0020)

toluene 2.0571 2.3402 2.7387 3.2007 3.7043 4.2727

(0.0016) (0.0114) (0.0194) (0.0085) (0.0132) (0.0223)

The standard uncertainty for the temperatures u(T) is 0.05 K and the relative standard uncertainty in solubility ur(x) is 0.015.

Figure 10. Solubility of danthron FI in ■, toluene; acetonitrile; ●, n-butanol.

▲,

acetone;

IR and Raman Spectrometry. IR spectra of the three anhydrous forms of danthron (FI, FII, and FIV) and the acetic acid solvate are shown in Figure 8a and the data are compared in Table 3. The unique regions of these forms appear below 1700 cm−1. IR spectra for the three forms look quite similar besides some differences apparent in the −CO region, 1400−1500 cm−1 and 750−900 cm−1. The high similarity in IR spectra was expected considering the small difference in terms of hydrogen bonding between different anhydrous forms. The acetic acid solvate spectrum is essentially the same as for FI besides a characteristic peak at 1711 cm−1 corresponding to carbonyl stretching in the acetic acid molecules. This supports the fact that FI appears upon desolvation of acetic acid from the solvated form at heating. The Raman spectrum is more useful in distinguishing different forms of danthron (Figure 8b). The three forms show differences mainly in −CO and −C−O stretching and in the region of different ring vibration modes. The stable form, FI, shows −CO peak at 1675 cm−1 in both IR and Raman spectra. The broadness of this peak increases in both FII and FIV. The shape of the carbonyl peak in the three forms, particularly from IR spectra, suggests that it can be deconvoluted into two peaks. This is mainly due to the different environment for the two −CO groups in the danthron molecule arising from the presence of both −O−H groups at one side. Both FI and FII transform into FIV at higher temperature and FIV is the stable form above 439 K. Thus, FIV is metastable at room temperature but it could be brought down to room temperature by quenching the DSC sample pan in the liquid nitrogen. By continuously collecting Raman spectra of this metastable FIV at ambient conditions over a period of time, it was observed that FIV started converting into the thermodynamically stable form (FI) after 3 h. Figure 9 panel a shows the collection of spectra over a 7 h period, and panel b shows the individual spectra at the start (green) and at the end of the experiment (blue) in comparison with that of pure FI (red). Only a small region of spectra is shown where the transformation can be clearly traced. Stability of FII and Solubility of FI in Organic Solvents. Samples from the cooling crystallization experiments, along with mechanical mixtures of pure FI and FII in acetone, acetonitrile, n-butanol, and toluene were placed in water baths with stirring in order to determine the stability between the two forms at room temperature. Over the course of 2 days, only FI remained in all samples by visual observation. Solid samples were taken for PXRD examination and FI was confirmed in all samples collected. Table 4 presents mean values and standard deviations of the triplicate measurements of the solubility of FI in four pure solvents at temperatures between 293.15 K and 318.15 K. The

⧫,

Figure 11. ln xeq of danthron FI vs 1/T in ■, toluene; ▲, acetone; ⧫, acetonitrile; ●, n-butanol.

Table 5. Solubility Regression Coefficients (eq 1) for FI in Four Solvents in the T-Range (293 to 318) K equation: ln(x) = A + B/T solvent

A

B

acetone acetonitrile n-butanol toluene

4.5113 4.8903 5.6718 4.4563

−3216.9 −3650.3 −4105.2 −2732.6

actual ratio will be slightly lower as PXRD analysis showed that some portion of acetic acid molecules had escaped when the solvates were left dried at ambient conditions, and this matches the result from the crystal structure determination. After desolvation above this temperature, the structure reassembles into FI, confirmed by PXRD and IR spectrometry. F



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Figure 12. Crystal habits of FI, FII, and acetic acid solvate (left to right).

Figure 13. Mixtures of FI and FII from cooling crystallization experiments in acetonitrile solutions.

Figure 14. Predicted crystal morphology of danthron FI and FII using BFDF method, with Miller indices of the visible faces.

standard deviations are relatively small (less than 2.23·10−2 g/ 100 g of solvent in all cases) indicating good reproducibility. The data are represented graphically in Figure 10, with linear axis scales, and as a van’t Hoff plot in Figure 11, in which the logarithm mole fraction solubility, ln xeq, is plotted against the reciprocal of the absolute temperature. The mole fraction solubility obtained at different temperatures in each solvent was correlated using eq 1:

ln xeq = A + B /T

The apparent, or van’t Hoff enthalpy of solution:23 vH Δsoln H = −R

d ln xeq d(1/T )

(2)

is essentially constant over the temperature range studied. The vH values of Δsoln H calculated for danthron FI in acetone, acetonitrile, n-butanol, and toluene are 26.7, 30.3, 34.1, and 22.7 kJ·mol−1, respectively. Crystal Habits. Danthron crystals obtained from the five organic solvents by slow evaporation at room temperature exhibit three different crystal habits, and their SEM images are provided in Figure 12. FI crystallizes as thin plates, FII with a hair-like needle habit, and the acetic acid solvate as needles. In the case of a mixture of the two polymorphs, squared-shaped crystals of FI often lay on or between a bed of FII fine needles,

(1)

where T is in units of K, and A and B are the regression coefficients valid within the temperature range (293 to 318) K. The coefficients of eq 1 obtained for each solvent by leastsquares fitting to the mole fraction solubility data are displayed in Table 5. R2 values for all systems exceed 0.99. G



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and sometimes they will stick onto relatively large needles of FII (Figure 13). From slow evaporation, FII was obtained from the vapor−liquid interface of the solution, often forming a network structure at the surface, leaving FI to be found at the bottom of the vials. FI appeared as orange squared plates in solution and often observed with what appears to be twinning. There is no apparent influence of the solvent on the shape of the crystals of each of the two polymorphs, and the shape is not found to be strongly influenced by whether the process is slow evaporation or fast cooling. Hence, the shape should be primarily governed by the crystal lattice. Prediction of the crystal morphology of FI and FII, respectively, using the Bravais−Friedel−Donnay−Harker (BFDH) method24 implemented in the Morphology module of Mercury 3.5, provides the shapes given in Figure 14. For FI a blocky square-like shaped crystal is predicted with two large {004} faces in principal resembling the shape of the experimental crystals however not at all as thin. For FII, a rod-like shape is predicted, elongated in the b-direction and dominated by the two {002} faces, followed by the {200} and {201} faces. Again the shape is not at all as extreme as that experimentally found but of similar principal character. From slow evaporation experiments in toluene and nbutanol, pure FI is obtained. From acetone and acetonitrile, a mixture of FI and FII is obtained. From cooling crystallization experiments, FII is often crystallized out with trace of FI from various solvents unless pure FI is obtained. No significant influence of the solvent on the polymorphic outcome is observed in the cooling crystallizations. For the evaporation experiments we note that because of the higher volatility of acetone and acetonitrile we expect the evaporation rate to be higher than in toluene and n-butanol, potentially leading to a higher rate of supersaturation generation. In the cooling crystallizations there is an even faster rate of generation of supersaturation. Accordingly, in agreement with many observations in the literature, there is a tendency to get more of FII, the metastable form, in experiments of higher supersaturation.

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ASSOCIATED CONTENT

S Supporting Information *

Crystallographic data of danthron−acetic acid solvate, X-ray diffraction peak positions, and relative intensity of FI, FII, FIV and danthron−acetic acid solvate. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jced.5b00192.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Funding

The financial support of the Science Foundation Ireland (10/ IN.1/B3038) is gratefully acknowledged. Notes

The authors declare no competing financial interest.

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REFERENCES

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CONCLUSIONS Three anhydrous forms and an acetic acid solvate of danthron have been characterized by various solid-state techniques, and the structure of the solvate has been solved by single crystal Xray diffraction. The solubility of danthron FI in organic solvents decreases in the order toluene, acetone, acetonitrile, and nbutanol but is overall low in the range of conditions of this work: below 4.3% by weight. The van’t Hoff curves are quite linear in the investigated temperature interval. The influence of solvents on crystal habit and polymorphic form has been investigated. Three different crystal habits of danthron were obtained from slow evaporation and cooling experiments. By evaporation, thin squares of FI were obtained from n-butanol and toluene solutions while both FI and fine needles of FII were obtained from acetone and acetonitrile solutions. In addition, needle-shaped solvate crystals were obtained from acetic acid solutions. From cooling crystallization experiments, mixtures of FI and FII are often obtained from various solvents but FI and FII possess distinct habits which can be easily distinguished by visual comparison. Slurry conversion experiments have established that FI is the thermodynamically stable polymorph of danthron at ambient conditions. H



Article

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Solid Forms, Crystal Habits, and Solubility of Danthron - Journal of

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