Solid-State Properties and Dehydration Behavior of the Active

Article pubs.acs.org/crystal

Solid-State Properties and Dehydration Behavior of the Active Pharmaceutical Ingredient Potassium Guaiacol-4-sulfonate Nathalie Mahé,† Béatrice Nicolaï,† Maria Barrio,‡ Marc-Antoine Perrin,† Bernard Do,§ Josep-Lluis Tamarit,‡ René Céolin,† and Ivo B. Rietveld*,† †

EAD Physico-chimie Industrielle du Médicament (EA4066), Université Paris Descartes, 4, Avenue de l’Observatoire, 75006 Paris, France ‡ Grup de Caracterització de Materials (GCM), Departament de Física i Enginyeria Nuclear, Universitat Politècnica de Catalunya, ETSEIB, Diagonal 647, 08028 Barcelona, Spain § Etablissement Pharmaceutique de l'Assistance Publique-Hôpitaux de Paris, Agence Générale des Equipements et Produits de Santé, 7, rue du Fer à Moulin, 75005 Paris, France S Supporting Information *

ABSTRACT: Potassium guaiacolsulfonate is an active pharmaceutical ingredient that has been in use for more than a century, and it is still widely used in cough syrups. Nonetheless, no crystal structure has ever been determined to facilitate quality control. This is all the more surprising because two isomers are known to exist. A commercial sample has been studied by X-ray diffraction and thermogravimetric methods. It consists of potassium guaiacol-4-sulfonate, and it crystallizes in the monoclinic space group C2/c as a hemihydrate. The crystals exhibit uniaxial negative thermal expansion, and the electrostatic forces between the ions appear to be the major driving force of the observed displacements. Dehydration of the hemihydrate was observed above 380 K. The anhydrate has a structure similar to the hemihydrate with almost the same unit cell parameters. The dehydration kinetics points to a displacive mechanism; water molecules are located in channels, through which they leave the crystal. The structural readjustments that occur to accommodate the loss of water are driven by electrostatic interactions between the ions similar to the displacements observed for thermal expansion. Under ambient conditions (and humidity), the anhydrate is not stable and transforms into the hemihydrate.

1. INTRODUCTION Potassium guaiacolsulfonate (PGS) or potassium sulfoguaiacolate (Figure 1) has been used for years as an expectorant to

commercially available PGS consists predominantly of potassium guaiacol-4-sulfonate.2 They also established that the commercial form was a hydrate with at most 2/3 mol of water per mol of PGS.2 An anhydrous form was obtained by drying the hydrate for 2 h at 443 K under a vacuum. The anhydrate transforms back into the hydrate overnight at 298 K and 45% relative humidity.2 Even though X-ray diffraction patterns had been used to differentiate the hydrate from the anhydrate, no crystal structure has been published for PGS. Considering that PGS is an old active pharmaceutical ingredient, the absence of a crystal structure is unexpected, not in the least because crystal structures are necessary for quality control. In the present paper, the crystal structures of the hydrate and the anhydrate are presented. In addition, thermal expansion of the hydrate has been studied as well as its dehydration kinetics to obtain a better understanding of the interactions in the crystal.

Figure 1. Potassium guaiacol-4-sulfonate.

help loosen and clear mucus.1,2 PGS has been derived from guaiacol, which was used prior to PGS. To reduce bad taste and irritation of the mucous membrane, guaiacol was sulfonated.3,4 The salt potassium guaiacolsulfonate is still used in cough syrups and cold remedies.5 The synthesis has been known to yield two isomers:4 potassium guaiacol-4-sulfonate and potassium guaiacol-5-sulfonate, ever since it was first reported, and it is not clear which of the two isomers is produced commercially.3,5 According to Kawamura et al. in 1987, © XXXX American Chemical Society

Received: March 22, 2013 Revised: May 17, 2013

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dx.doi.org/10.1021/cg400427v | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

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Figure 2. Left-hand side: commercial sample. Center: Crystal obtained after partial recrystallization from water and mounted on a glass rod for single-crystal data collection. Right-hand side: pyramidal crystals from complete dissolution experiments. capillary to obtain a high signal over noise diffraction pattern for structure solution. 2.4. Structure Solution from X-ray Powder Diffraction. For structure solution, the program DASH11 was employed, and the powder pattern was truncated to 34.8° in 2θ (Cu Kα1), corresponding to a real-space resolution of 2.6 Å. The background was subtracted with a Bayesian high-pass filter.12 Peak positions for indexing were obtained by fitting with an asymmetry-corrected pseudo-Voigt function.13,14 Twenty peaks were indexed with the program DICVOL91.15 An orthorhombic unit cell was obtained. The figures of merit given by DICVOL were M(20) = 10.4 and F(20) = 21 (0.0113, 84). Pawley refinement was used to extract integrated intensities and their correlations, from which the space group was determined using Bayesian statistical analysis.16 The extinction symbol Cc was returned, which led to C2/c as the most probable space group. It was the space group with the highest symmetry, and it is the same space group as the hemihydrate (see section 2.2). It resulted in a Pawley χ2 of 11.04. The high value for the Pawley χ2 was caused by the presence of some hemihydrate peaks visible in the background of the diffraction pattern; apparently either the hemihydrate had not been removed completely or it had been formed during the 15 h of measurement. Simulated annealing was used to solve the crystal structure from the powder pattern in direct space. The starting molecular geometry was taken from the hemihydrate. In 30 simulated annealing runs, the same crystal structure was found 15 times. The profile χ2 of the best solution was 26.52, which is less than three times the Pawley χ2; this is a good indication that the correct solution has been found. For the Rietveld refinement, data out to 68.5° 2θ were used, which corresponds to 1.37 Å real-space resolution. The Rietveld refinement was carried out with TOPAS-Academic.17 The anhydrate was first refined separately and for the final steps combined with a Pawley fit for the hemihydrate peaks. Bond lengths, bond angles, and planar groups were subjected to suitable restraints, including bonds to H atoms; the values for the restraints were taken from the hemihydrate structure. A global Biso was refined for all non-hydrogen atoms, with the Biso of the hydrogen atoms constrained at 1.2 times the value of the global Biso. The inclusion of a preferred-orientation correction with the MarchDollase formula18 was tried for directions (100), (010), and (001). No significant effect on the Rwp value could be observed. The molecular geometry was checked with Mogul,19 which compares each bond length and bond angle to corresponding distributions from singlecrystal data. Supplementary crystallographic data for the hemihydrate and the anhydrate can be found in the CCDC, deposit numbers 928396 and 928397, respectively, and obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/ cif/. 2.5. Thermogravimetric Analysis and Differential Scanning Calorimetry. TGA was carried out with a Mettler Toledo TGA/ DSC1 SF/177 containing a SF SDTA FRS2 heat sensor and an MX 1 microbalance with a sensitivity of 0.001 mg. The TG was equipped with a Huber Ministat CC1. The heating rate for the TG measurements was 10 and 1 K min−1.

2. EXPERIMENTAL SECTION 2.1. Sample Preparation. Potassium guaiacolsulfonate (4hydroxy-3-methoxybenzenesulfonic acid potassium) of medicinal grade was obtained from Bouchara-Recordati (Levallois-Perret, France). The sample contained crystals with irregular shapes, which were partially dissolved in water and recrystallized by slow evaporation. It resulted in polyhedral crystals (Figure 2). In addition, part of the sample was dissolved completely in pure water and recrystallized by slow evaporation. In the latter case, pyramidal crystals (Figure 2) were obtained. X-ray powder diffraction of the polyhedral crystals and of the pyramidal crystals demonstrated that they were identical. The water content of the commercial sample was investigated by volumetric Karl Fischer titration. 0.1144 g of sample was dissolved in methanol and titrated using a Mettler Toledo DL 38 titrator. The sample was found to contain 3.69% m/m of water. 2.2. Single Crystal X-ray Diffraction and Structure Solution. The diffraction of a single crystal (Figure 2) was obtained at 298 K using a Bruker AXS Smart-Apex CCD platform 3-circle diffractometer with monochromatic (by graphite) Mo Kα radiation (λ = 0.71073 Å) from a sealed tube operated at 50 kV/40 mA. The structure was solved in a monoclinic unit cell with space group C2/c (No. 15). The heavy atoms were located using direct methods with the program SIR976 available in the WinGX software package.7,8 The remaining non-H atoms and H atoms were localized by successive difference Fourier maps with SHELXL-97.9 All atoms were included in the final leastsquares refinement, in which the following restraints were applied: an O−H distance in the guaiacolsulfonate moiety of 0.82(2) Å, in the methyl group a C−H distance of 0.96(2) Å and distances among the three H atoms of 1.55(3) Å each, and in the water molecule an O−H distance of 0.96(2) Å and a distance between the two hydrogen atoms of 1.52(3) Å. The program SOLV included in the software PLATON10 indicated the absence of voids accessible to residual solvent. 2.3. High Resolution X-ray Powder Diffraction as a Function of Temperature. X-ray powder diffraction (XRPD) was performed on a transmission mode diffractometer using Debye−Scherrer geometry equipped with cylindrical position-sensitive detectors (CPS120) from INEL (France) containing 4096 channels (0.029° 2θ angular step) with monochromatic Cu Kα1 (λ = 1.54061 Å) radiation. To control the temperature of the sample, a liquid nitrogen 700 series Cryostream Cooler from Oxford Cryosystems (UK) was used. Ground specimens were introduced in a Lindemann capillary (0.5 mm diameter) rotating perpendicularly to the X-ray beam during the experiments to improve the average over the crystallite orientations. The temperature range for the measurements ran from 100 K up to 500 K. The sample temperature was allowed to equilibrate for about 10 min followed by an acquisition time of ca. 1 h. The heating rate in between data collection was 1.33 K/min. 8.05 mg of PGS hemihydrate was heated in a thermogravimetric analysis (TGA) apparatus under a nitrogen atmosphere at 433 K until no further weight loss was observed. This presumably anhydrous sample was measured for 15 h at 293 K by X-ray diffraction in a sealed B



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Differential scanning calorimetry (DSC) was carried out with a Mettler-Toledo (Switzerland) 822e thermal analyzer equipped with a Huber (Germany) TC100 cooling device. Indium (Tfus = 156.60 °C, ΔfusH = 3267 J mol−1) and zinc (Tfus = 419.53 °C, ΔfusH = 7320 J mol−1) were used for calibration of temperature and enthalpy. Specimens were weighed with a microbalance sensitive to 0.01 mg and sealed in aluminum pans. DSC runs were carried out at 10 K min−1. 2.6. Isobaric Thermal Expansion Tensor. The intermolecular interactions were investigated with the isobaric thermal expansion tensor, obtained from X-ray powder diffraction data as a function of temperature from 100 K up to 340 K. The tensor was calculated with the lattice parameters as a function of temperature by the program DEFORM.20 Details of the procedure for the calculation of the tensor have been published elsewhere.21−23 Decomposition of the tensor matrix yields the magnitude (eigenvalue) and orientation (eigenvector) of the thermal expansion along three principal axes, e1, e2, and e3. The tensor provides the direction of the weakest and strongest deformation as a function of temperature, and these directions are commonly referred to as hard and soft directions, respectively. The anisotropy of the thermal behavior of the intermolecular interactions can be summarized using the aspherism coefficient.24

2; the observed crystals are pyramidal with polyhedral faces and polyhedral with triangular faces. In both morphologies the [111] faces are dominant. 3.2. Crystal Structure of the Hemihydrate. Single-crystal X-ray analysis reveals that the crystals obtained by recrystallization from aqueous solution belong to the monoclinic space group C2/c. Details on the crystallographic data and the refinement data can be found in Table 1. The asymmetric unit consists of one potassium cation (K+ ion), one guaiacol-4sulfonate (GS) anion, and half a molecule of water, which coincides with 3.69% m/m found by Karl Fischer titration. The molecular structure of PGS is shown in Figure 4. The bond lengths and bond angles of the hemihydrate are compiled in Table S1, Supporting Information. They are similar to those reported for other benzenesulfonate compounds.31−35 The methoxy group of the benzenesulfonate anion is coplanar with the benzene ring. The coordination shell of the potassium cation, which forms a polyhedron with eight oxygen atoms, is shown in Figure 5. Interatomic distances between the oxygen atoms in the polyhedron are compiled in Table 2. The KO8 polyhedron is composed of two bidentate sulfonate groups, one monodentate sulfonate group, one bidentate guaiacol moiety by its oxygen atom of the hydroxyl group and one oxygen of the ester group, and finally one monodentate water molecule (Figure 5). Thus, each K+ ion is linked to four GS anions and one H2O molecule. The average distances in the KO8 polyhedron are in good agreement with previously reported values for compounds containing 8-fold coordinated K+ ions, e.g., InK(C2O4)2·4H2O and ScK(C2O4)2(H2O)2.36,37 Moreover, the mean K−O distance of 2.9(1) Å agrees well with the theoretical value of 2.901 Å calculated with the bond valence method.36 Each K+ ion has three other K+ ions in its direct vicinity. Oxygen atoms O3, O5, and Ow form so-called μ2-bridges linking them together. This type of bridge has been observed previously for benzenesulfonate.31 The K···K distances are relatively small, 4.532(1), 4.788(1), and 4.769(1) Å, and the K−O−K angles are 108.06(5)°, 108.61(5)°, and 111.5(1)°, respectively. The μ2-bridged K+ ions form a semihexagonal arrangement in planes perpendicular to the a axis (Figure 6). The distance between subsequent planes is a/2, and they are interconnected by GS anions along the a axis (Figure 7). This type of arrangement is also found in the recently published structure of potassium tetrazole.38 The water molecules are found in channels parallel to the b axis (Figure 7). They prevent a direct cation−cation interaction between neighboring K+ ions. The distance between two water molecules (O···O) in a channel is 6.345(3) Å. Most hydrogen bonds are present close to or in the plane formed by the K+ ions (Figure 8). They strengthen the interactions in this plane, and they contribute to the interactions between the interchanging anion−cation layers along the a axis (Figure 8). The H2O molecule and the hydroxyl group of the GS anion are the only two hydrogen bond donors. Two oxygen atoms (O4 and O5) belonging to the sulfonate group are hydrogen bond acceptors. O4 is involved in two hydrogen bonds, one with the H2O molecule and one with the OH group of a neighboring GS anion. The O1−H1···O4 hydrogen bond is strong (Table 3). The oxygen atom of the H2O molecule, Ow, is involved in two hydrogen bonds with two different O4 atoms. This pattern has been observed previously for potassium benzene sulfonate.32 In conclusion, the hydrogen bond network in combination with

3. RESULTS 3.1. Crystal Morphology of the Hydrate. The crystals obtained by (partially) dissolving the commercial sample in water and recrystallization can be seen in Figure 2. On the right-hand side, the drop of solution visible underneath or in the crystal is reminiscent of the inclusions observed in benzoyl lusitanicol.25 Two different crystal morphologies can be observed in Figure 2. Crystal morphologies can be calculated with the Bravais− Friedel−Donnay−Harker (BFDH) method, which is based on dhkl spacings of the crystal planes coinciding with the crystal faces.26−28 The lowest growth rate is attributed to the largest interplanar spacings dhkl; however, this method does not take detailed molecular structure or intermolecular forces into account. Three different growth rates, Rhkl, have been formulated:28 R hkl = 1/(Cdhkl)

(1)

R hkl = exp( −Cdhkl)

(2)

R hkl = dhkl exp( −Cdhkl)

(3)

C is a rate constant. The morphologies obtained with KrystalShaper29 using the room temperature lattice parameters presented below are shown in Figure 3. The morphology obtained with eq 1 (Figure 3a) has not been observed. However, those obtained with growth rates given by eqs 2 and 3 (Figure 3, panels b and c, respectively) compare well with the experimentally observed habits in Figure

Figure 3. Morphology predicted with the BFDH theory; (a) growth rate eq 1, C = 0.5, (b) eq 2, C = 0.5, (c) eq 3, C = 0.5. Panel b compares well with the crystal on the right-hand side of Figure 2 and panel c with the crystal in the center of Figure 2. The crystal morphologies been drawn with WinXMorph.30 C



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Table 1. Crystallographic and Structure Refinement Data for Potassium Guaiacolsulfonate Hemihydrate and Anhydrate hemihydrate molecular formula formula weight (g mol−1) CCDC no. crystal system space group unit cell dimensions

volume (Å3) Z T (K) calculated density (g/cm3) absorption coefficient (mm−1) F(000) color, habit crystal size (mm) 2θ range for data collection (deg) index ranges reflections collected/unique data/parameters/restraints goodness-of-fit on F2 final R indices [I > 2σ(I)] largest diff peak and hole (e/Å3)

anhydrate

C14O11H16K2S2 502.61

C7O5H7KS 242.3

monoclinic C2/c (No. 15) a = 19.4360(16) Å b = 6.3452(5) Å c = 16.2640(14) Å α = 90° β = 97.1560(10)° γ = 90° 1990.1(3) 4 298(2) 1.677 0.742 1032 colorless, prism 0.60/0.40/0.10 2.11−23.24 −21 < h < 21; −7 < k < 7; −18 < l < 18 5862/1427 1427/164/9 1.076 0.0262 0.275 and −0.281

monoclinic C2/c (No. 15) a = 18.888(2) Å b = 6.4079(8) Å c = 16.508(2) Å α = 90° β = 96.885(6)° γ = 90° 1983.6(4) 8 293(2) 1.623 0.66 (calc.) 992 (calc.) white powder n.a. 8.01−68.47 n.a. n.a. −/176/106 1.776 0.01303 n.a.

Table 2. Interatomic Distances (Å) and Their Standard Deviations for the Oxygen Atoms in the KO8 Polyhedron Present in the Hemihydratea O4···O1(i) O5···O3(ii) O5···O5(ii) O4···O5(ii) O3···O5 O4···O5 O1···O2 Ow···O4 O5···O3(iii)

Figure 4. ORTEP (20% probability level) of potassium guaiacol-4sulfonate in the hydrate. The structure contains one water molecule for every two PGS moieties, and it is thus a hemihydrate.

3.871(2) 3.954(2) 3.439(2) 4.372(3) 2.405(2) 2.407(2) 2.590(2) 4.463(3) 4.198(2)

Ow···O3(iii) O5···O3(iv) O3···O3(v) O3···O5(v) O1···O5(vi) O2···O3(vi) O2···Ow(vii) O1···Ow(vii) O2···O3(viii)

3.323(1) 4.198(2) 3.292(2) 4.888(2) 3.800(2) 3.423(3) 3.560(2) 3.473(1) 4.143(2)

a Symmetry codes: (i) 0.5 + x, −0.5 + y, z; (ii) 1 − x, −y, 2 − z; (iii) x, −1 + y, z; (iv) x, 1 + y, z; (v) 1 − x, 1 − y, 2 − z; (vi) 0.5 − x, 0.5 − y, 2 − z; (vii) −0.5 + x, 0.5 + y, z; (viii) −0.5 + x, −0.5 + y, z.

Figure 5. Coordination shell of the potassium cation in the crystal structure of the hemihydrate.

Figure 6. Potassium cation planes perpendicular to the a axis exhibiting a semihexagonal arrangement in the hemihydrate crystal structure.

the ionic interactions forms a solid 3D network, wherein the hydrogen bonds are concentrated in planes parallel to the ac plane. Along the c axis, π−π interactions exist between the benzene rings exhibiting alternatingly T-shaped and parallel-displaced configurations.39 The distance between the centers of mass, Cg,

of two benzene rings [0.24863(4), 0.19663(12), 0.14349(5)] is 4.7232(11) Å for parallel-displaced and 4.6931(12) Å for Tshaped π−π interactions. D



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Figure 7. Projection of the hemihydrate crystal structure along [010]. The coordination of the K+ ions with eight oxygen atoms can be observed. The planes formed by K+ ions are perpendicular to the ac plane and have a frequency of a/2; GS anions lie in between the K+ planes. Water molecules are present between the K+ ions in channels that run along the b axis.

Figure 9. X-ray powder diffraction patterns as a function of temperature. Around 380 K, additional Bragg peaks can be observed (marked with arrows), indicating the formation of another structure.

thermal expansion is anisotropic over the entire measured temperature range. It is even negative along the e3 axis (Figure 10), although smaller in absolute value than the expansion along e1 and e2; therefore the unit cell volume increases with temperature (Figure 10). It is given by Vhemihydrate(Å3) = 1954.7 + 0.1505T (K)

(4)

As a result, the specific volume at room temperature (298 K) is 0.599 cm3 g−1. The maximum expansion is along e1 parallel to the b axis and parallel to the channels with water molecules (Figure 10, see also Figure S1). The thermal expansion along e2 is parallel to c (Figure 10 and Figure S1). Thus, thermal expansion occurs along the directions defined by the planes formed by the K+ ions. Along the a axis, the crystal contracts with increasing temperature (uniaxial negative thermal expansion: red lobe along e3 in Figure 10). This direction coincides with the cation−anion chain. The cation−anion interaction apparently promotes a small contraction, while the overall volume experiences expansion. A similar phenomenon has been observed for 3,4-diaminopyridine dihydrogen phosphate.41 3.4. Dehydration of the Hemihydrate. Kawamura et al. found that the powder diffraction pattern of PGS hemihydrate changed considerably after 2 h at 443 K under vacuum.2 This was interpreted as formation of an anhydrate form; however, they did not quantify how much of the sample had converted.2 In the present study, the formation of a structure different from the hemihydrate can be observed in Figure 9; additional Bragg peaks can be observed in the X-ray diffraction patterns from 430 K on indicating that the initial crystalline phase is changing. The high-temperature pattern corresponds to the pattern for the anhydrate found by Kawamura et al. (Figure 11).2

Figure 8. Hydrogen bonds parallel to the ac plane in the hemihydrate crystal structure. The hydrogen bonds extend across the cation planes and interconnect GS anions in different layers via water molecules.

3.3. Thermal Expansion of the Hemihydrate. Le Bail fits of the XRPD data were used to determine the unit cell parameters from 100 K up to 340 K (Figure 9 and Table S2 in Supporting Information). Up to 340 K, all the observed Bragg reflections are accounted for by the C2/c monoclinic unit, implying that no phase transition occurs below 340 K. This result is confirmed by data obtained by DSC and by TGA. Above 380 K, additional peaks can be observed in the diffraction patterns. This will be discussed in the next section. The unit cell parameters as a function of temperature are presented in Figure 10 (see also Tables S2 and S3 in Supporting Information). The aspherism coefficient (Table S3) remains constant with a value of 0.6, indicating that the

Table 3. Hydrogen Bonds of Potassium Guaiacolsulfonate Hemihydrate and the Anhydratea D−H···A hemihydrate O1−H1···O4(x) Ow−Hw···O4(iii) Ow−Hw···O4(ix) anhydrate O1−H1···O4(x) a

d(D−H) (Å)

d(H···A) (Å)

d(D···A) (Å)

angle (D−H···A) (deg)

0.81(3) 0.94(5) 0.94(5)

1.89(3) 2.25(5) 2.25(5)

2.672(2) 3.02(3) 3.02(3)

165(3) 140(5) 140(5)

0.83(4)

1.82(4)

2.65(2)

170(4)

Symmetry codes: (iii) x, −1 + y, z; (ix) 1 − x, y, 1.5 − z; (x) 0.5 − x, 0.5 + y, 1.5 − z. E



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Figure 10. Evolution of unit cell volume and parameters of potassium guaiacolsulfonate hemihydrate as a function of temperature and graphical representation of the thermal expansion tensor at 300 K.40

Figure 11. Left-hand side: Comparison between the pattern of the current hemihydrate at 340 K (top) and the diffraction profile of the hydrate crystallized from an aqueous solution by Kawamura et al. (bottom) Right-hand side: Comparison between the pattern of the current hightemperature form measured at 500 K (top) and the diffraction profile of the anhydrate obtained by drying at 443 K for 2 h under vacuum (bottom).

experimental conditions: the sample temperature temporarily returned to 293 K, because of technical reasons. After approximately 42 h (disregarding the time that the dehydration was interrupted; thus in the graph (Figure 12) this is at approximately 60 h), the dehydration started to level off to a mass fraction of about 0.24. Apparently, 393 K is not high enough to fully dehydrate the hemihydrate against the partial pressure of atmospheric water vapor, at least not at the time scale of this experiment. 3.5. Crystal Structure of the Anhydrate. Because it appeared to be impossible to obtain single crystals of the anhydrate, 8.05 mg of PGS hemihydrate was heated in the TGA apparatus under a nitrogen atmosphere at 433 K until no further weight loss was observed. After 4 h, the total weight loss equaled 0.219 mg. Taking into account the molar mass of PGS hemihydrate, 0.288 mg of water should be present in 8.05 mg of hemihydrate, from which it can be concluded that 0.24 weight fraction of hemihydrate remained in the sample after

Furthermore, the diffraction pattern of the hemihydrate corresponds to that of the hydrate found by Kawamura et al. (Figure 11). Thermogravimetric analysis carried out at 10 K min−1 under a nitrogen atmosphere points to a gradual weight loss starting at approximately 383 K; however at the melting point of approximately 513 K, only 15% water has left the compound (Figure S2). Thus, water is obviously tightly bound to the K+ ions. A similar observation was made by Kawamura et al.2 To study the dehydration kinetics, a sample of hemihydrate powder was placed in the X-ray diffraction apparatus and kept at 393 K. At regular time intervals, X-ray diffraction patterns were registered. The resulting patterns were analyzed by TOPAS Academic17 using Rietveld refinement for both crystalline phases. The respective mass fractions were determined from the fitted intensities relative to the measurement time. The resulting graph can be seen in Figure 12. The plateau that can be observed from 10 to 30 h is due to F



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the differences in the unit cell parameters are not due to temperature differences. The arrangement of the molecules in the anhydrate structure is effectively the same as that in the hemihydrate except that the water molecules are absent. The single obvious difference in the molecular structure is a rotation of the sulfonate group as can be seen in Figure 13. This rotation

Figure 12. The mass fractions of hemihydrate (open circles) and anhydrate (filled squares) of potassium guaiacol-4-sulfonate maintained at 393 K as a function of time. The mass fractions have been determined by Rietveld refinement of the two structures. The experimental standard deviation is about 5% for the mass fractions.

Figure 13. The molecular configuration of the guaiacol-4-sulfonate moiety in the hemihydrate (left) and the anhydrate (right). The only significant change in the configuration is the rotation of the sulfonate group.

drying. This predominantly anhydrous sample was measured for 15 h at 293 K by X-ray diffraction in a sealed capillary to obtain a high signal over noise diffraction pattern for structure solution. The Rietveld refinement progressed smoothly and produced a good fit with χ2 = 1.776, R′p = 10.104, R′wp = 10.040 (values after background correction), Rp = 1.753 and Rwp = 2.313 (values before background subtraction). The anhydrate and the hemihydrate refined to weight fractions of 0.77 and 0.23, respectively, which coincides very well with the value found by TGA. The cell parameters of the anhydrate, determined with powder diffraction, can be found in Table 1. The structure is monoclinic, space group C2/c, and a unit cell volume of 1983.61(42) Å3. The fit to the diffraction data resulting from the Rietveld refinement can be seen in Figure S3. Selected bond lengths and angles are compiled in Table S1. Details on the single hydrogen bond are listed in Table 3.

probably accommodates for the 7-coordination around the K+ ion, in the absence of water. The absence increases most likely the repulsion felt between the K+ ions, which explains the expansion parallel to the bc plane. Simultaneously, the absence of water increases the interaction between the K+ ions and the remaining oxygen atoms surrounding the cation, as can be seen by the decrease in interatomic distances between them (Table S1). This explains the observed decrease in the a axis of the unit cell. Thus, for PGS, the electrostatic charges drive the displacement in the crystal lattice induced by temperature or by removal of water. The dehydration process leads to a very similar crystal structure with only small inter- and intramolecular adjustments. Therefore, it must be possible for the water molecules to diffuse through the channels without disrupting the main structure. This is confirmed by the experiment on the dehydration behavior (Figure 12). The mass fractions of anhydrate and hemihydrate cross each other at exactly 50%. This indicates that there is no transitional (amorphous) phase and that the hemihydrate transforms directly into the anhydrate, once the water molecules have left. The process is therefore expected to be mainly displacive. The dehydration process is very slow. None of the methods applied in the present study seem to have led to pure anhydrate crystals. Obviously, the water molecules are tightly bound to the K+ ions. The Gibbs free energy gained by the evaporation of the water molecules is counteracted by the strong interactions between the K+ ions and the water molecules in the crystal structure. It is therefore possible that the anhydrate obtained by Kawamura et al. by 2 h at 443 K under vacuum is also only partially dehydrated, because they only compared the powder diffraction patterns of the anhydrate and the hemihydrate, which are obviously very closely related (Figure 11).2 In addition, it seems that the number of water molecules that leaves the crystal depends on the temperature controlling the thermal agitation for the breakup of the K+−water bond and on the partial vapor pressure of water in the atmosphere. It is therefore not possible to pinpoint a single “transition temperature”; one will have to define the transition by temperature and partial water pressure ranges.

4. DISCUSSION The present PGS sample contains guaiacol-4-sulfonate and not guaiacol-5-sulfonate or a mixture similar to the findings of Kawamura et al. The obtained crystal structure demonstrates clearly that potassium guaiacol-4-sulfonate exists as a hemihydrate under ambient conditions. The mole fraction of water in the sample falls within the range given by Kawamura et al., who stated that PGS contains at most 2/3 mol of water per mol of PGS. The similarity of the two powder diffraction patterns (Figure 11) demonstrates that the crystal structure of Kawamura et al. for the hemihydrate was identical to the one obtained in this paper. When heated, the hemihydrate expands along the planes formed by the K+ ions, but contracts slightly along the a axis equivalent to the direction of the anion−cation chain. Apparently, the increase in thermal energy allows for a slight relaxation in the anion−cation attraction within the crystal. The crystal structures of the anhydrate and the hemihydrate are strikingly similar, and the differences between the unit cells appear to reflect the behavior observed for thermal expansion. The b and c axes of the anhydrate are slightly larger than those of the hemihydrate, whereas the a axis of the anhydrate is considerably shorter than that of the hemihydrate. Both structures have been obtained at room temperature; hence G



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5. CONCLUSIONS The crystalline structure of potassium guaiacolsulfonate has been solved. Besides the potassium cation, the sample in this study consists of a guaiacol-4-sulfonate anion, and no evidence of the presence of guaiacol-5-sulfonate could be found. The stable solid form is a hemihydrate. Two types of crystal habit were found experimentally, both characterized by [111] faces, which experience the slowest growth rates in water. Thermal expansion is observed for the hemihydrate PGS crystal along the b and c axes of the unit cell coinciding with an increase in the distances between neighboring cations. Uniaxial negative thermal expansion, or contraction, is observed along the a axis, coinciding with a decrease in distance between the anions and cations. The crystal of the anhydrate has a very similar structure to that of the hemihydrate. Water can escape through channels, and the structure immediately readjusts for its absence, as can be judged from the dehydration kinetics; the transition can therefore be considered displacive. Nonetheless, water is tightly bound and does not start leaving below 380 K under ordinary conditions.

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ASSOCIATED CONTENT

S Supporting Information *

Table S1: Bond lengths and angles for potassium guaiacolsulfonate hemihydrate and anhydrate. Table S2: Cell parameters of the hemihydrate as a function of temperature. Table S3: Eigenvalues of the thermal expansion tensor and aspherism coefficient. Table S4: Coordinates of the eigenvectors e1, e2, e3 in the a, b, c space. Figure S1: Projections of the thermal expansion tensor in relation to the unit cell of the hemihydrate structure. Figure S2: TGA curve, demonstrating the dehydration of the hemihydrate at 10 K min−1. Figure S3: the Rietveld fit to the powder diffraction pattern of the anhydrate. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank E. Moreau (Bouchara-Recordati, France) for providing a commercial sample of potassium guaiacolsulfonate and C. Ribot and S. Illouli (AGEPS, AP-HP, France) for the Karl Fischer titrations. M.B. and J.-Ll.T. were supported by the Spanish Ministry of Science and Innovation (Grant FIS201124439) and the Catalan Government (Grant 2009SGR-1251).

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REFERENCES

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