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Anisotropic Surface Energetics and Wettability of Macroscopic Form I Paracetamol Crystals Jerry Y. Y. Heng,† Alexander Bismarck,† Adam F. Lee,‡ Karen Wilson,‡ and Daryl R. Williams*,† Department of Chemical Engineering, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom, and Department of Chemistry, UniVersity of York, York YO10 5DD, United Kingdom. ReceiVed NoVember 30, 2005. In Final Form: January 24, 2006 Advancing (θA) and receding (θR) contact angles were measured with several probe liquids on the external facets (201), (001), (011), and (110) of macroscopic form I paracetamol crystals as well as the cleaved (internal) facet (010). For the external crystal facets, dispersive surface energies γd calculated from the contact angles were found to be similar (34 ( 1 mJ/m2), while the polar components varied significantly. Cleaving the crystals exposed a more apolar (010) surface with very different surface properties, including γd ) 45 ( 1 mJ/m2. The relative surface polarity (γp/γ) of the facets in decreasing order was (001) > (011) > (201) > (110) > (010), which agreed with the fraction of exposed polar hydroxyl groups as determined from C and O 1s X-ray photoelectron spectroscopy (XPS) spectra, and could be correlated with the number of non-hydrogen-bonded hydroxyl groups per unit area present for each crystal facet, based on the known crystal structures. In conclusion, all facets of form I paracetamol crystals examined exhibited anisotropic wetting behavior and surface energetics that correlated to the presence of surface hydroxyl groups.
Introduction The wetting properties of solid-state materials are of both fundamental and practical importance in the performance of particulate materials such as pharmaceutical and fine chemicals. The final delivery of the majority of drugs is in solid-state dosage forms such as tablets and capsules.1 A detailed knowledge of particulate surface properties will help to predict processing stability, surfactant adsorption, adhesion, solubility, colloid stability, toughness, powder flow, mixing performances, and product performance, including the rate of drug release.2-6 Traditional methods of characterizing the wettability of particulate solid pharmaceuticals have relied on powder bed techniques, which can be inaccurate and complicated. Currently used methods to characterize powders include sessile droplet on powder compacts,7,8 Wilhelmy plate,9 capillary rise or wicking,10,11 and vapor sorption techniques.12-14 While these ap* To whom correspondence should be addressed. Tel.: +44 (0) 207 594 5611. Fax: +44 (0) 207 5945604. E-mail:
[email protected]. † Imperial College London. ‡ University of York. (1) Carstensen, J. T. Pharmaceutical Principles of Solid Dosage Formsp; Technomic Publishing Company: Lancaster, PA, 1993. (2) Duncan-Hewitt, W.; Nisman, R. Investigation of the surface free energy of pharmaceutical materials from contact angle, sedimentation, and adhesion measurements. In Contact Angle, Wettability and Adhesion; Mittal, K. L., Ed.; VSP: Utrecht, The Netherlands, 1993; p 791-811. (3) Zhang, D.; Flory, J. H.; Panmai, S.; Batra, U.; Kaufman, M. J. Colloids Surf., A 2002, 206, 547-554. (4) Buckton, G. Assessment of the wettability of pharmaceutical powders. In Contact Angle, Wettability and Adhesion; Mittal, K. L., Ed.; VSP: Ultrecht, The Netherlands, 1993; p 437-451. (5) Ahfat, N. M.; Buckton, G.; Burrows, R.; Ticehurst, M. D. Int. J. Pharm. 1997, 156, 89-95. (6) Adams, M. J.; Briscoe, B. J.; Law, J. Y. C.; Luckham, P. F.; Williams, D. R. Langmuir 2001, 17, 6953-6963. (7) Muster, T. H.; Prestidge, C. A. Int. J. Pharm. 2002, 234, 43-54. (8) Kiang, Y. H.; Shi, H. G.; Mathre, D. J.; Xu, W.; Zhang, D.; Panmai, S. Int. J. Pharm. 2004, 280, 17-26. (9) Planinsek, O.; Trojak, A.; Srcic, S. Int. J. Pharm. 2001, 221, 211-217. (10) Prestidge, C. A.; Tsatouhas, G. Int. J. Pharm. 2000, 198, 201-212. (11) Chibowski, E.; Holysz, L. Langmuir 1992, 8, 710-716. (12) Ambarkhane, A. V.; Pincott, K.; Buckton, G. Int. J. Pharm. 2005, 294, 129-135.
proaches might be valid for low-energy flat surfaces such as polymers, their applicability is more problematic for complex crystalline organic materials, such as pharmaceutical solids. Specific concerns about these types of solids include the scope for nonequilibrium interactions between the solid and the liquid, such as dissolution, swelling, hydration, and solvent-mediated morphological transformations. Despite these potential risks, traditional approaches are still commonly used for complex organic solids such as pharmaceuticals.15,16 A number of workers have reported problematic wettability data for sessile drop measurement on pharmaceutical powder compacts. Problems encountered include liquid penetration into the tablet bulk4,7,17 as well as plastic deformation in the tablets during sample preparation.18 Prestidge and Tsatouhas10 used the capillary rise technique to determine the wettability of morphine sulfate powders; however, contact angles derived via the Washburn equation incorporate numerous assumptions and may not be well suited to pharmaceutical or porous solids.19-21 Dove et al.22 determined θ for compressed theophylline and caffeine powder disks as well as for glass plates on which powder had been coated and subsequently characterized using the Wilhelmy plate approach. They found that surface energy values obtained from the powder-coated plates were more realistic compared to the sessile drop results obtained from compressed powder disks. (13) Grimsey, I. M.; Osborn, J. C.; Doughty, S. W.; York, P.; Rowe, R. C. J. Chromatogr., A 2002, 969, 49-57. (14) Newell, H. E.; Buckton, G.; Butler, D. A.; Thielmann, F.; Williams, D. R. Pharm. Res. 2001, 18, 662-666. (15) Hapgood, K. P.; Litster, J. D.; Biggs, S. R.; Howes, T. J. Colloid Interface Sci. 2002, 253, 353-366. (16) Vargha-Butler, E. I.; Moy, E.; Neumann, A. W. Colloids Surf. 1987, 24, 315-324. (17) Clarke, A.; Blake, T. D.; Carruthers, K.; Woodward, A. Langmuir 2002, 18, 2980-2984. (18) Buckton, G.; Newton, J. M. Powder Technol. 1986, 46, 201-208. (19) Washburn, E. W. Phys. ReV. 1921, 17, 273-283. (20) Lockington, D. A.; Parlange, J.-Y. J. Colloid Interface Sci. 2004, 278, 404-409. (21) Martic, G.; Coninck, J. D.; Blake, T. D. J. Colloid Interface Sci. 2003, 263, 213-216. (22) Dove, J. W.; Buckton, G.; Doherty, C. Int. J. Pharm. 1996, 138, 199206.
10.1021/la0532407 CCC: $33.50 © 2006 American Chemical Society Published on Web 02/18/2006
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Figure 1. Equilibrium contact angles on (a) a clean surface and (b) a surface with adsorbed vapor molecules.
Duncan-Hewitt and Nisman2 examined the wettability of paracetamol and adipic acid powders using a range of experimental techniques, including the Washburn capillary rise method and sedimentation volume methods, as well as sessile drop determinations on compacts, films, and single crystals. It was concluded that these powder characterization techniques have problems, including sample preparation, data interpretation, and methodology imprecision. They recommended that work be undertaken on films or single crystals, and the latter forms the basis of the work reported here. Wettability of a solid is governed by its surface free energy, but this surface property cannot be easily measured directly for rigid solid surfaces. However, the surface free energy may be estimated by measuring the contact angles of a series of known reference liquids on the surface (as shown in Figure 1) and analyzing the contact angle data using Young’s equation (eq. 1):23
where γoSV is the solid surface energy, γLV is the liquid-vapor surface tension, γSL is the solid-liquid surface energy, and θY is the Young contact angle. Young’s equation was originally derived on the basis of a mechanical equilibrium for forces acting at the three-phase contact line. Dupre (1869) included the work of adhesion, defined as the reversible work per unit area to separate two surfaces initially sharing a common interface, into the Young equation to obtain the Young-Dupre equation:
During the past 30 years, two main schools of thought have developed for analyzing contact angle data for determining a solid’s surface free energy. The equation of state approaches championed by Neumann and co-workers stipulates that interfacial interactions are independent of specific intermolecular forces,26 and that the surface energetics of the solid may be deduced via a mean field-based analysis. This approach has, however, attracted only limited support in the literature, and it is unclear whether this approach would be applicable,27 including for our study of highly ordered organic crystalline solids, having previously been applied to primarily amorphous polymeric materials. A second, more widespread school of thought has resulted in a range of semiempirical analyses, which have been developed for determining the surface energetics of solid-state materials, as well as the intrinsic chemical components that make up the surface free energy. Surface energy component approaches, such as the Fowkes,28 Owens-Wendt,29 Wu,30 Fowkes and Mostafa,31 van Oss et al.,32 and Chen-Chang33 acid-base analyses, have been used to evaluate the surface free energy components of many solid materials, but most commonly, polymer surfaces. All of these models are based on the assumption that the surface free energy of a solid or a liquid can be treated as consisting of a number independent or partially independent components, each of which represents a distinctly different type of intermolecular interaction. Initially, Fowkes proposed that a solid’s surface free energy, γS, could be considered to consist of a dispersive and a polar component such that
γLV (1 + cos θ) ) γoSV + γLV - γSL
γS ) γdS + γpS
γoSV ) γSL + γLV‚cos θY
(1)
(2)
The Young equation is derived assuming the liquid and solid surface in contact are in equilibrium at a saturated vapor pressure. Therefore, it is likely that the saturated vapor will adsorb onto the solid surface. The equilibrium spreading pressure, πe is defined as an adsorption vapor layer that results in a change (decrease) in the solid surface’s free energy.24 Thus,
γLV (1 + cos θ) ) (γSV + πe) + γLV - γSL
(3)
In the case of low surface energy solids such as polymers and pharmaceuticals, the surface free energy of a solid in vacuum is presumed to be equal or similar to the surface free energy of a solid with an adsorbed vapor film present. For liquids that exhibit finite θA > 10°, it is assumed that the spreading pressure is negligible (πe = 0).25 (23) Young, T. Philos. Trans. R. Soc. London 1805, 95, 65-87. (24) Adamson, A. W. Physical Chemistry of Surfaces, 5th ed.; John Wiley & Sons: New York, 1990. (25) Good, R. J. Contact angles and the surface free energy of solids. In Surface and Colloid Science; Good, R. J., Stromberg, R. R., Eds.; Plenum Press: New York, 1979.
(4)
This type of formalism has since been extended, and shortrange chemical interactions previously described as polar forces are now considered to be better represented as acid-base interactions, γSAB, while the longer-range forces are described as Lifshitz van der Waals forces, γSLW. Fowkes was the first to introduce this reinterpretation of short-range forces with an associated analysis for the specific heat of adsorption based on Drago’s E&C acid-base model.34 This model has since been succeeded by a simpler model proposed by van Oss et al.32 (26) Li, D.; Neumann, A. W. AdV. Colloid Interface Sci. 1992, 39, 299-345. (27) Graf, K.; Riegler, H. Langmuir 2000, 16, 5187-5191. (28) Fowkes, F. M. Ind. Eng. Chem. 1964, 56, 40-52. (29) Owens, D. K.; Wendt, R. C. J. Appl. Polym. Sci. 1969, 13, 1741-1747. (30) Wu, S. Polymer Interface and Adhesion; Marcel Dekker: New York, 1982. (31) Fowkes, F. M.; Mostafa, M. A. Ind. Eng. Chem. Prod. Res. DeV. 1978, 17, 3-7. (32) vanOss, C. J.; Good, R. J.; Chaudhury, M. K. Langmuir 1988, 4, 884891. (33) Chen, F.; Chang, W. V. Langmuir 1991, 7, 2401-2404. (34) Drago, R. S.; Vogel, G. C.; Needham, T. E. J. Am. Chem. Soc. 1971, 93, 6014-6026.
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The normal approach to obtaining sample surfaces large enough for using the sessile drop technique is to grow large macroscopic single crystals. As crystals are a rigid lattice assembly of molecules with a regular internal structure, resulting in smooth surfaces of a characteristic shape,35 their smooth and flat crystal facets are ideal surfaces for the sessile drop contact angle determination. Very little work has been reported on the anisotropic surface energetics and wettability of crystalline solids based on contact angle data. Anisotropic wetting behavior has been observed for the wetting of liquid pure metals on diamond36 and MgO single crystals37 by Nogi and co-workers. In the first case, the wettability of (100), (110), and (111) facets of diamond were characterized using sessile drops of Sn, Bi, Ag, and Pb between 773 K and 1773 K.36 Small differences in θ were observed, which were indicative of anisotropic surface properties. In the case of MgO crystals, larger anisotropic variations in θ of up to 40° were reported for liquid Sn, Pb, and Bi. However, the authors were unable to establish any clear relationship between crystal structure and anisotropic wettability.37 Muster and Prestidge investigated the wettability of N,n-octylD-gluconamide and sulfathiazole crystals.38 They reported facespecific contact angles for water for both systems, as well as a correlation between surface hydrophobicity and the presence of alkyl surface groups, as detected using time-of-flight secondaryion mass spectrometry (TOF-SIMS). The same group also reported that morphine sulfate crystals exhibit facet-dependent θ’s.10 However, the surface energetics were not determined, as only a single contact angle liquid was utilized.10,38 These trends in anisotropic surface properties are fully consistent with Wulff’s Theorem, which describes the relationship between equilibrium crystal shape and the surface energy of the component facets:
γn γ1 γ 2 γ 3 ) ) ) ... ) l1 l2 l3 ln
(5)
where γi (i ) 1, 2, 3...n) is the surface energy, and li is the physical distance from the center of mass of the crystal to the ith facet measured along a normal.39 Following Wulff, Bravais, Freidle, Donnay, and Harker introduced the BFDH theory, postulating that the facet growth rate was inversely proportionate to the interplanar spacing, dhkl.40 Intermolecular forces, rather than geometric considerations, were taken into account by Hartman and Perdok,41-43 proposing that growth rates were proportional to the attachment energies of crystalline facets. Of these two theories, neither makes any specific predictions on crystal surface energetics. In real systems, however, the crystal shapes may be at variance with the Wulff Theorem because of kinetic or nonequilibrium effects. This can manifest itself as crystal facet surface roughness, which can facilitate the multiplecrystal habits existing for the one-crystal form. A number of researchers have established the important effect of surface roughness on the real and apparent contact angles (35) Mullin, J. W. Crystallization, 3rd ed.; Butterworth-Heinemann Ltd.: Oxford, 1993. (36) Nogi, K.; Nishikawa, M.; Fujii, H.; Hara, S. Acta Mater. 1998, 46, 23052311. (37) Nogi, K.; Tsujimoto, M.; Ogino, K.; Iwamoto, N. Acta Metall. Mater. 1992, 40, 1045-1050. (38) Muster, T. H.; Prestidge, C. A. J. Pharm. Sci. 2002, 91, 1432-1444. (39) Adamson, A. W.; Gast, A. P. Physical Chemistry of Surfaces, 6th ed.; Wiley-Interscience: New York, 1997. (40) Winn, D.; Doherty, M. F. AIChE J. 2000, 46, 1348-1367. (41) Hartman, P.; Perdok, W. G. Acta Crystallogr. 1955, 8, 525-529. (42) Hartman, P.; Perdok, W. G. Acta Crystallogr. 1955, 8, 521-524. (43) Hartman, P.; Perdok, W. G. Acta Crystallogr. 1955, 8, 49-52.
Figure 2. Molecular structure of paracetamol with the (1) hydroxyl, (2) amine, and (3) carbonyl functional groups.
measured in sessile drop wettability studies of solids. The effects of surface roughness on contact angles were first described by Wenzel,44 while the effects of chemical heterogeneities were addressed by Cassie.45 Surface roughness, along with surface heterogeneity, and swelling are three of the primary factors that result in contact angle hysteresis, the measured difference between the advancing (θA) and receding (θR) contact angles. Morra et al.46 reviewed contact angle measurements and confirm that it is generally accepted that surface roughness has a negligible effect on the measured contact angle when the surface roughness, or asperity height, is about 100 nm or less. In the current work, paracetamol crystals have been produced. Three polymorphs of paracetamol have been reported in the literature:47 a thermodynamically stable monoclinic form I, a metastable orthorhombic form II, and a very unstable form III. The monoclinic form I is the commercially used form, due to its thermodynamic stability at room temperature, and is the subject of this current work. Paracetamol (H3C-C(O)-NH-phenyl-OH) contains functional hydroxyl, carbonyl, amine, and a benzene ring groups, with its molecular structure shown in Figure 2. With the aid of crystallographic graphical imaging software (Mercury, CCDC, Cambridge, UK), molecular structure diagrams have been generated for the monoclinic (I) and orthorhombic (II) forms. Form I has pleated sheets stacked along the b axis, making a relatively rigid structure. Since the molecular structure of form I lacks a crystallographic slip plane, it displays poor powder compaction behavior. However, form II has parallel hydrogenbonded sheets along the c axis, resulting in slip planes that accommodate mechanical deformations during compaction. Consequently, chemicals are added to form I powders prior to tabletting to facilitate compaction. Such an additional process is both time-consuming and costly.48 The hydroxyl, carbonyl, and amine functional groups found within paracetamol molecules are capable of forming inter- and intramolecular hydrogen bonds. This leads to a crystal structure in which the paracetamol molecules align themselves into hydrogen-bonded chains of molecules packed in a criss-cross configuration. The crystallographic structure of a typical external face, facet (001) of the macroscopic crystal, and a cleaved internal facet (010) are shown in Figure 3. Experimental Section Materials. Paracetamol (4-acetamidophenol) (98%, SigmaAldrich) and methyl alcohol (>99.9%, Sigma-Aldrich) were used (44) Wenzel, R. N. Ind. Eng. Chem. 1936, 28, 988-994. (45) Cassie, A. B. D. Discuss. Faraday Soc. 1948, 3, 11-16. (46) Morra, M.; Occhiello, E.; Garbassi, F. AdV. Colloid Interface Sci. 1990, 32, 79-116. (47) DiMartino, P.; Conflant, P.; Drache, M.; Huvenne, J.-P.; Guyot-Hermann, A.-M. J. Therm. Anal. Calorim. 1997, 48, 447-458. (48) Beyer, T.; Day, G. M.; Price, S. L. J. Am. Chem. Soc. 2001, 123, 50865094.
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Figure 4. (a) Macroscopically large single crystal (scale in centimeters) and (b) habit of form I paracetamol.
Figure 3. Molecular structure of form I paracetamol: (a) facet (001), and (b) facet (010). Insets are water droplets saturated with paracetamol on the crystalline facets showing large variations in droplet profiles. Table 1. Properties of the Liquid Probes Used liquids
purity (%)
density (kg/m3)
γLV (mJ/m2)
γd (mJ/m2)
γp (mJ/m2)
diiodomethane water ethylene glycol formamide
>99 deionized >99 >99.5
3325 998 1109 1139
50.8 72.8 48.0 58.0
50.8 21.8 29.0 39.0
0.0 51.0 19.0 19.0
for the preparation of paracetamol crystals without further purification. Deionized water, diiodomethane (>99%, Acros Organics), formamide (>99.5%, Acros Organics), and ethylene glycol (>99%, SigmaAldrich) were used as probe liquids for the contact angle measurements. The liquid properties are shown in Table 1. Diiodomethane was purified by passing it through chromatographic columns packed with silica (Merck) and basic alumina (Sigma-Aldrich).
Macroscopic Crystal Preparation. Macroscopic crystals were prepared by slow solvent evaporation from a saturated methanol solution of paracetamol at 20 °C over a period of 20-30 days. These solutions were stirred constantly until the solubility limit was reached. Heating of the solutions was avoided, as paracetamol is reported to oxidize readily in warm alcohol solutions, yielding a pink solution.49 It was observed that these solutions may turn a pinkish color after exposure to light, so care was taken to avoid exposure to daylight. Fresh saturated solutions were prepared and replaced any saturated solutions that turned slightly pink. A single-seed paracetamol crystal was suspended using a single aramid fiber (diameter ) 10 µm) in the saturated solution without stirring. The solvent was allowed to evaporate slowly, resulting in crystal growth, which ultimately culminated in macroscopically large crystals (length > 1 cm). The macroscopic single crystals obtained along with their habit is shown in Figure 4,panels a and b, respectively. This crystal habit corresponds to those reported in the literature,50 with major facets of (201), (001), (011), and (110). The crystals were dried under ambient conditions before conducting contact angle measurements. Facet (010) has been reported as being the preferred cleavage plane of paracetamol, as the attachment energy of the crystal face is the lowest.51,52 This facet will be the dominant face present in milled samples. Facet (010) was exposed by cleaving the macroscopic crystal perpendicular to the b axis using a razor blade. Contact angles reported were obtained on freshly cleaved surfaces. Contact Angle Measurements. Sessile-drop contact angles were obtained with a Kru¨ss drop shape analyzer (DSA 10, Kru¨ss GmbH, Hamburg, Germany). Initial drops of about 5 µL were dispensed (49) Politov, A. A.; Kostrovskii, V. G.; Boldyrev, V. V. Russ. J. Phys. Chem. 2001, 75, 1903-1911. (50) Ristic, R. I.; Finnie, S.; Sheen, D. B.; Sherwood, J. N. J. Phys. Chem. B 2001, 105, 9057-9066. (51) Duncan-Hewitt, W. C.; Mount, D. L.; Yu, A. Pharm. Res. 1994, 11, 616-623. (52) Prasad, K. V. R.; Sheen, D. B.; Sherwood, J. N. Pharm. Res. 2001, 18, 867-872.
2764 Langmuir, Vol. 22, No. 6, 2006 onto the solid surface. By use of a motor-driven syringe, the test liquid was added onto the droplet, allowing the advancing contact angles to be obtained, and then liquid was removed to obtain the receding contact angles. The needle remained immersed within the top half of the droplet, and the advancing contact angles were determined with a slowly advancing wetting line. The droplet was monitored with a CCD camera and analyzed by the Drop Shape Analysis software (DSA version 1.0, Kru¨ss). The droplet contour was fitted by the tangent method (function f(x) ) a + bx + cx0.5 + d/ln x + e/x2) at both the left and right sides of the drop. The function is differentiated, and the slope at the threephase contact point gives the contact angle. At least eight (typically between 8 and 20) contact angle measurements were taken for each liquid on each facet, which were obtained from numerous single crystals. Measurements were obtained in the open air at ambient conditions (T ) 20 ( 2 °C). Although slip/stick behavior is often reported for contact angle measurements with diiodomethane, this behavior was not significant in this study. In cases when it was observed, these data were not included in the analysis reported. To address any concerns of the effects of dissolution, contact angles of saturated aqueous solutions of paracetamol on the various facets were also obtained. The paracetamol-saturated water solutions were prepared at 20 °C. X-ray Photoelectron Spectroscopy (XPS). XP spectra were recorded on facets sliced from the macroscopic paracetamol crystal using a high-vacuum XPS instrument (Kratos AXIS HSi, England) equipped with a charge neutralizer and a Mg KR X-ray source. C, N, and O 1s spectra were acquired at a 40 eV pass energy with two-point energy referencing employed using adventitious carbon at 285 eV and the valence band. All spectra were Shirley backgroundsubtracted and fitted using a Duniach-Sunjic profile convoluted with a Gaussian/Lorentzian (4:1) mix. Similar line shapes were employed for all C, N, and O 1s components, with respective fwhm of 1.65, 1.69, and 1.76 eV, unless otherwise stated. Fitting was performed using CasaXPS Version 2.0.35 using the minimum number of peaks required to minimize the R-factor. Form I Identification. Differential scanning calorimetry (DSC) measurements were performed using a Pyris 1 (Perkin-Elmer Cooperation, Boston, USA) differential scanning calorimeter. Samples masses of not more than 10 mg were sealed in aluminum pans with a similar empty pan used as the reference. DSC curves were obtained under nitrogen purge of 20 mL/min at a heating rate of 10 °C/min from 30 to 200 °C to determine the crystal-melting endotherm. Curves were analyzed by the Perkin-Elmer Thermal Analysis software. Fourier transform infrared (FTIR) spectra were obtained using an Equinox 55 (Bruker Optics, England) spectrometer with a liquidnitrogen-cooled mercury cadmium telluride (MCT) detector and a KBr beam splitter. The background measurements for all spectra were collected for a clean dry attenuated total reflection (ATR) crystal with air at the measured interface. A total of 32 individual scans were signal-averaged using an optical resolution of 4 cm-1. The sample crystal was in good contact with the spectroscopic ATR diamond crystal, so as to obtain strong absorbance. The incident angle was 45°, and a spectral range from 4000 to 600 cm-1 was recorded. DSC curves reveal a melting point onset of 169.7 °C and an enthalpy of fusion of 187.5 J/g. ATR-FTIR spectra obtained for both commercial paracetamol and recrystallized samples were similar. These results are comparable and in agreement with DSC53 and FTIR54 published data for the stable monoclinic form I of paracetamol. No evidence of sample oxidation could be detected by these thermal and spectroscopic experiments. Surface Roughness Determination. The surface roughness of crystal facets was determined using noncontact optical laser surface profilometry. The purpose-built instrument utilizes a Rodenstock RM 300 noncontact laser system with a height resolution of 5 nm, incorporated into an xyz motion control system with a position (53) Sacchetti, M. J. Therm. Anal. Calorim. 2001, 63, 345-350. (54) Moynihan, H. A.; O’Hare, I. P. Int. J. Pharm. 2002, 247, 179-185.
Heng et al. Table 2. Advancing Contact Angles (degrees) facet
diiodomethane
water
ethylene glycol
(201) (001) (011) (110) (010)
48.8 ( 2.2 49.8 ( 3.2 50.7 ( 2.9 50.2 ( 2.4 27.8 ( 2.5
38.1 ( 4.6 15.9 ( 3.1 29.8 ( 5.7 50.8 ( 4.9 67.7 ( 2.5
formamide 13.3 ( 1.2
10.9 ( 2.5 15.7 ( 2.2 42.5 ( 3.2
14.5 ( 2.5 17.6 ( 3.0 46.9 ( 2.4
Table 3. Advancing and Receding Contact Angles Data (degrees) diiodomethane
water
facet
θA
θR
∆θ
θA
θR
∆θ
(201) (001) (011) (110) (010)
48.8 ( 2.2 49.8 ( 3.2 50.7 ( 2.9 50.2 ( 2.4 27.8 ( 2.5
26.9 ( 5.7 26.4 ( 5.3 30.4 ( 4.3 23.8 ( 3.0 13.4 ( 2.0
22 23 20 26 14
38.1 ( 4.6 15.9 ( 3.1 29.8 ( 5.7 50.8 ( 4.9 67.7 ( 2.5
22.6 ( 3.6 0 23.7 ( 6.0 17.5 ( 3.0 26.4 ( 4.5
16 16 6 33 41
resolution of 100 nm. Surface topography maps based on a scan area of typically 100 × 100 µm were reported for all facets with a 256 × 256 raster scan. In addition, selected crystals were sputter-coated with a gold coating of approximately 100 nm thickness. These coated surfaces were then subject to contact angle analysis with water and diiodomethane in the same manner as the uncoated crystals. This method allows the effects of surface roughness and surface heterogeneity to be differentiated with respect to contact angle hysteresis.
Results and Discussion Contact Angle Analysis. The contact angle is defined as the angle between the solid surface and the tangent of the liquid drop surface, through the liquid phase at the three-phase contact point, as shown in Figure 1. By continuously adding liquid to, or removing liquid from, the droplet, the θA and θR were respectively obtained. The relationship between θA and θR to θY is not straightforward, and a number of interpretations have been proposed, such as the use of an arithmetic mean of θA and θR. It is common practice that θA, which is commonly observed to be the most reproducible contact angle, is approximated to θY for the purpose of surface characterization.55 This methodology is supported by the work of Li and Neumann, who observed that θA approaches the minimum free energy state, and hence the equilibrium Young state, for model patterned heterogeneous surfaces.56 Therefore, θA is commonly used in the surface energetic determination of solid surfaces, as in this study. θA for four probe liquids, and θR for water and diiodomethane, were measured on the major facets and on the cleaved facet (010) of the macroscopic single crystals. The θA and θR data are summarized in Tables 2 and 3. There are several well established phenomena that can contribute to contact angles hysteresis. They are surface roughness, chemical heterogeneity, material swelling, dissolution, and surface restructuring, as well as other nonequilibrium effects. It is, however, the first two phenomena that are the most commonly encountered for crystalline solids. In this work, specific experiments were performed to establish the significance of surface roughness, crystal dissolution, nonequilibrium effects, and local surface chemistry to the contact angle data obtained. To establish the importance of surface roughness, crystal facets were splutter-coated with 100 nm thick films of gold, and θA was measured for water and diiodomethane on both coated and uncoated facets (Table 4). This thin gold coating will mask any (55) Good, R. J. Contact angle, wetting and adhesion: A critical review. In Contact Angle, Wettability and Adhesion; Mittal, K. L., Ed.; VSP: Utrecht, The Netherlands, 1993; p 3-36. (56) Li, D.; Neumann, A. W. Colloids Polym. Sci. 1992, 270, 498.
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Table 4. θA and Ra Data for Native and Gold-Coated Single-Crystal Facets θA for water (°)
θA for diiodomethane (°)
Ra(µm)
facet
single crystals
gold-coated crystals
paracetamol-saturated water
single crystals
gold-coated crystals
single crystals 50 × 50 µm scan
(201) (001) (011) (110) (010)
38.1 ( 4.6 15.9 ( 3.1 29.8 ( 5.7 50.8 ( 4.9 67.7 ( 2.5
78.7 ( 4.1 68.6 ( 5.8 72.8 ( 3.2 69.8 ( 4.2 73.1 ( 3.6
37.3 ( 3.7 18.4 ( 4.3 31.0 ( 3.7 49.6 ( 5.8 72.7 ( 2.5
48.8 ( 2.2 49.8 ( 3.2 50.7 ( 2.9 50.2 ( 2.4 27.8 ( 2.5
40.8 ( 2.5 34.7 ( 2.5 38.7 ( 3.7 39.0 ( 4.4 38.0 ( 2.5
0.16 0.19 0.32 0.29 0.20
effects of facet surface chemistry, while retaining the gross surface topographical features that might contribute to surface roughness. For both water and diiodomethane, all coated facets exhibited the same θA, within an experimental error of typically 4°. This contrasts with the θA variations reported for the uncoated facets, which were greater than 50° for water droplets. These data clearly confirm that the surface roughness has a negligible role on the θA differences reported in this study. In addition, the measured Ra’s for all sample facets were very similar at about 0.2 µm, close to accepted estimates of 0.1 µm, whereupon roughness is known to have a negligible impact on θA measurements.46 To establish the significance of crystal dissolution, θA was measured for both water and paracetamol solutions (Figure 5). Although paracetamol has low solubility with water (solubility at 20 °C, CS ) 12.78 ( 0.05 g/kg H2O),57 the potential effects of the presence of dissolved paracetamol on the measured contact angles were unknown and could be significant. Specifically, it is known that impurities present in the contact angle fluids can effect the results by adsorbing at either the solid-liquid interface and/or the liquid-vapor surface.58 However, measured values of θA were found, within experimental error, to be same for both water and paracetamol-saturated solutions (Table 4). It was thus concluded that any dissolution of paracetamol that might occur during the measurements with water was inconsequential with respect to measured θA’s. Different workers have reported on a range of nonequilibrium effects that can effect contact angle determinations. In this study, no swelling of the solids was observed with any liquids used in this study. Furthermore, no time-dependent contact angle phenomena were observed. It is therefore concluded that timedependent nonequilibrium effects did not make a significant contribution to the measured contact angles. It is therefore inferred that variations in contact angles reported in this study must be a consequence of surface chemical heterogeneities present on the specific crystal facets. The solid-liquid interactions between diiodomethane, a purely dispersive van der Waals liquid, and the surfaces examined will consist of purely dispersive, nonspecific van der Waals interactions. However, water (H2O), ethylene glycol (HO-CH2CH2-OH), and formamide (HCONH2) liquid probe molecules are postulated to interact with the solid surfaces via both nonspecific and specific intermolecular interactions. The interfacial interaction of these liquid probes will vary depending on the nature of each surface characterized and, more specifically, their local surface chemistry, orientation of molecules, and density of end-groups exposed at the surface. The θA of polar probes (water, ethylene glycol, and formamide) vary significantly for the different external facets, with the water data exhibiting the largest variation: 16-51°. Ethylene glycol drops spread on facets (201) and (001), and formamide drops spread on the (001) facet. On all other facets, ethylene glycol (57) Granberg, R. A.; Rasmuson, A. C. J. Chem. Eng. Data 1999, 44, 13911395. (58) Ebril, H. Y. Surface Tension of Polymers. In Surface and Colloid Chemistry; Birdi, K. S., Ed.; CRC Press: New York, 1997; p 265-312.
and formamide gave low, but finite θA. The wetting behavior of both ethylene glycol and formamide on facet (001) would indicate that this surface interacts strongly with these polar probes, while facet (201) interacts slightly less strongly, as only ethylene glycol wets this surface. No other significant differences were observed in the measurable contact angles of both ethylene glycol and formamide. Table 3 shows that θA and θR for diiodomethane on the four major external crystal facets were very similar: between 49 and 51° and 23-31°, respectively. These results indicated similar long-range dispersive interactions for these four facets. The θA for diiodomethane on internal facet (010) is 27.8 ( 2.5°, which is about half the observed θA for any of the external facets. This result is indicative of stronger van der Waals dispersive interactions on the cleaved facet and thus a higher value of γd. On the other hand, the θA of all polar probe liquids on facet (010) was much higher than those observed for the external facets, signifying less significant specific interactions for this facet and thus greater hydrophobicity. The θA for water on the internal facet (010) is 67.7 ( 2.5°. It is well-known that facet (010) is the preferred cleavage plane due to its low attachment energy,51,52 and this is fully consistent with the hydrophobic surface observed here. Surfaces that exhibit a high θA for water were defined as being hydrophobic, while those that exhibited a low value of θA for water were defined as being hydrophilic. On the basis of these results, a hydrophilicity order for paracetamol form I facets can be proposed:
(001) > (011) > (201) > (110) > (010) From the contact angle data for diiodomethane, we can prepare an order of the van der Waals type of interactions for the paracetamol facets which is
(010) > (001) ) (011) ) (201) ) (110) The effects of milling on single paracetamol crystals will lead to fracture, predominantly exposing the lowest attachment energy facet, (010). As particle size reduces, the prevalence of this facet is expected to increase, resulting in an increasing hydrophobic nature of the milled paracetamol powders. Such surface chemical behavior may have a significant bearing on the performance of the subsequent powder granulation of milled powders, which is common practice in industry and is the subject of a separate study.59 Calculation of Solid Surface Energy. In this study, the wetting data was analyzed using a simple Owens-Wendt methodology for dispersive and polar component analysis using the θA data for water and diiodomethane. Other analyses were evaluated, including the Wu and van Oss analyses. All three componentbased analyses gave similar trends in facet-dependent surface energies, but slightly different quantitative results. The theoretical basis of these analyses and other semiempirical relations for the (59) Heng, J. Y. Y.; Thielmann, F.; Williams, D. R. Pharm. Res., submitted for publication, 2005.
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Table 5. Results of a Surface Energy Analysis Using the Owens-Wendt Analysis facet
γd
γp
γ
γp/γ
(201) (001) (011) (110) (010)
34.9 34.4 33.9 34.2 45.1
27.5 38.0 32.7 20.2 7.0
62.4 72.4 66.5 54.4 52.1
0.44 0.53 0.49 0.37 0.13
Table 6. Unit Cell Information for Form I Paracetamol and Predicted Free Hydroxyl Group Surface Concentrations
facet (201) (001) (011) (110) (010)
unit cell unit cell unit cell unit cell no. of OH group depth angle area length free OH density (Å) (Å) (°) (Å2) groups (Å-2) 14.44 12.93 11.78 15.99 12.93
9.4 9.4 12.93 7.1 7.1
90 90 74.74 69.31 64.1
135.7 121.5 146.9 106.0 82.59
2 2 2 1 0
0.0147 0.0165 0.0136 0.0094 0.0000
determination of surface energies has been recently reviewed in detail.60 The data obtained is summarized in Table 5. γd was marginally different on each of the external crystal facets, but γp varied significantly. Both the γd and γp results for the cleaved facet (010) were at variance with those obtained for the external surfaces. It was established in a separate study that the above trend in γd and γp actually depends on whether the facet examined is the lowest energy attachment plane or not, and is independent of the facet being external or internal.61 Surface polarities (γp/γ) were determined from the ratio of the polar surface energy component, γp, to the total surface energy, γ. For the monoclinic form of paracetamol, the hydroxyl group accepts hydrogen bonds from the amine and donates them to the carbonyl of an adjacent molecule and forms a criss-cross sheet along the a-c plane. These sheets are held weakly together by van der Waals intermolecular forces along the b axis. Various facets are formed by planes that slice through the crystal at different angles, resulting in an exposure of dissimilar proportions and availability of chemical groups. These differences are clearly illustrated in Figure 3, showing significant hydrogen bonding potential for facet (001) but negligible potential at facet (010). The concentration of “free” or non-hydrogen-bonded hydroxyl groups has been estimated by examining molecular configurations for the individual crystal facets using Mercury software, and estimating the number of free hydroxyl groups per unit area for each facet. Table 6 shows gives information on the form I unit cell for paracetamol, as well as estimated free surface group concentrations for the hydroxyl groups. Each hydroxyl group was examined and a decision was made as to whether the group was free and thus sufficiently labile to interact with a liquid for example. In the case of a hydroxyl group fully engaged in hydrogen bonding, that is, behaving as both an electron donor (O) and an electron acceptor (H), the hydroxyl group was considered to be not labile and was not counted in the free hydroxyl group concentration. In the case where it was free to act as either a hydrogen bond donor or acceptor or both, it was considered to be labile, and such groups were counted as a part of the free hydroxyl group concentration. Although this classification is rudimentary, it does provide a first-order estimation of potential contributions of hydroxyl groups to the surface chemistry of paracetamol facets. Table 6 shows that the number of hydroxyl (60) Etzler, F. M. Characterization of surface free energies and surface chemistry of solids. In Contact Angle, Wettability and Adhesion; Mittal, K. L., Ed.; VSP: Ultrecht, The Netherlands, 2003; p 1-46. (61) Heng, J. Y. Y. Anisotropic Surface Properties of Crystalline Pharmaceutical Solids. Ph.D. Thesis, University of London, London, 2006.
groups free to interact with an external media such as a liquid varies significantly from facet to facet, with a minimum of 0 groups and a maximum of 2 groups per unit cell area. In Figure 6 we can see a good correlation between the surface polarity as given by the contact-angle-based surface energy analysis, and the predicted free OH surface-group concentrations. Thus, we may conclude the wettability of these crystal faces is directly linked to the number of hydroxyl groups present on the crystal surface. This result, though intuitive, has not been previously reported for organic crystalline solids. This analysis does have limitations. The surface chemical contributions of the amide and carbonyl groups are considered to be much less significant than those of the hydroxyl groups, due to both the relatively high acidity and basicity of the hydroxyl groups compared to amide groups, as well as their amphoteric nature. The orientation of the hydroxyl groups at the crystal surface and their molecular accessibility are also not considered in this calculation. Facet (010) exposes the hydrophobic methyl groups together with the amine and carbonyl functionalities. The phenolic OH groups appear to form hydrogen bonds with neighboring amine and carbonyl functionalities, leaving negligible residual hydrogenbonding potential available for interacting with a contact angle fluid (Figure 3b). The paracetamol molecules form a corrugated hydrogen bond sheet held by van der Waals interactions; this surface chemistry yields an overall apolar surface. The slight polarity of this surface could be due to the weak donor ability of the π electrons within the phenyl rings. At the surface of facet (010), the lack of polar groups and dependence on only the dispersive forces is reflected in the low attachment energy of this facet, with (010) being the preferred cleavage plane. Facets (201), (001), and (011) have similar functional group contributions and the slight differences may be due to the differences in densities of the functional groups and their orientation at the surface. The polarity on facet (110) was lower than all other external facets, although amine, carbonyl, and hydroxyl functionalities are present but may not be free to interact with external molecules. These differences may give rise to different interactions. This trend was further confirmed by dissolution kinetics experiments by Prasad et al.,62 with similar dissolution rates observed for facets (201), (001), and (011), but different rates for facet (110). This indicates that dissolution is thermodynamically controlled, and that surface energies may determine the solubility from the wettability of a solid surface. Surface energies calculated from θA with the component approaches indicated relatively high polar component contributions on facets (201), (001), and (011). The polar component on facet (110) was lower, indicating that the specific interactions of the probe liquids with the surface were limited. The surface energy of the cleaved facet (010) confirms that the surface is hydrophobic and possesses minimal potential for hydrogen-bond interactions. XPS Analysis. The surface atomic composition of each facet was determined by XPS and is presented in Table 7. In all cases the surface compositions were comparable to the theoretical values for bulk pure paracetamol of ∼73% C, 9% N, and 18% O. The nitrogen content showed the greatest deviations and was reduced relative to the bulk paracetamol composition for every facet examined. This trend was previously observed in the XPS of amide compounds.63 The (010) facet most closely mirrored the (62) Prasad, K. V. R.; Ristic, R. I.; Sheen, D. B.; Sheerwood, J. N. Int. J. Pharm. 2002, 238, 29-41. (63) Chappell, P. J. C.; Williams, D. R.; George, G. A. J. Colloid Interface Sci. 1990, 134, 385-397.
Anisotropic Wettability of Paracetamol Crystals
Langmuir, Vol. 22, No. 6, 2006 2767
Figure 5. Droplet of water saturated with paracetamol at 20 °C on (a) facet (010) and (b) facet (011).
Figure 6. Comparison between contact angle polarity and predicted free OH surface group concentration for various facets of form I paracetamol. Table 7. Atomic Composition of C, N, and O on Various Crystalline Paracetamol Facets facet
C atomic %
N atomic %
O atomic %
theoretical (201) (001) (011) (110) (010)
72.7 75.7 78.9 80.0 79.8 77.2
9.1 5.6 2.8 2.4 3.5 6.4
18.2 18.7 18.3 17.6 16.7 11.1
composition of pure paracetamol, while the (001) was the most nitrogen-deficient and, correspondingly, carbon-enriched. Highresolution scans of the C and O 1s XP spectra for each facet are shown in Figures 7 and 8. A single nitrogen environment was observed at 400 eV binding energy (BE) for all surfaces, in good accordance with literature values for NHR2 groups and consistent with the single amine group present in paracetamol. In contrast, both the C and O 1s spectra reveal multiple chemical environments. The carbon region contains contributions from methyl/ aromatic moieties around 285 eV together with C-OH and -CdO functions at 286.8 and 288.8 eV, respectively, in good agreement with the literature. The oxygen region likewise contains contributions from both carbonyl (531.3 eV) and hydroxyl (532.8/ 534.6 eV) groups. A detailed analysis of the relative contributions of these surface functions provides greater insight into the chemical properties of these facets. The relative intensity ratio of (CdO + C-OH)/ CHx groups determined from the C 1s spectra varies greatly, being highest for the (001) facet and an order of magnitude lower for the (010) facet (Figure 9). This directly correlates with the measured polarities based on the wettability of these surfaces and demonstrates that there are strong differences in the distribution of surface groups over the different facets of paracetamol crystals. The (011), (201), and (110) facets likewise contain a relatively high number of CdO and C-OH groups;
Figure 7. C 1s XP spectra for various facets of form I paracetamol crystal.
Figure 8. O 1s XP spectra for various facets of form I paracetamol crystal.
although, the concentration of such moieties on the (110) surface is only ∼35% of that of the most polar (001) facet (Figure 10). The order of polarity is therefore in excellent agreement with the contact angle measurements (Figure 6). Note that it was not possible to fit the weak, high BE CO(H) component in the (010)
2768 Langmuir, Vol. 22, No. 6, 2006
Figure 9. Deconvoluted C 1s XP spectra for the (001) and (010) facets of form I paracetamol crystal. Note that the 288.1 eV component of (010) required fitting with fwhm ) 0.82 eV.
Figure 10. Variation in surface composition of polar groups for different facets of form I paracetamol crystal as determined from C 1s and O 1s XP peak-fitting. Surface H2O (-OH) intensities taken from the 534.6 eV component in Figure 11.
facet using the same parameters as those used for the welldefined carbonyl/hydroxyl species in the (001) facet, presumably reflecting differing intermolecular interactions and associated carbon environments. All the O 1s spectra contained two principal components that can be readily associated with the unique carbonyl (531.3 eV) and alcohol (532.8) environments within paracetamol. The ratio of these states exhibited only a weak dependence on the crystallographic orientation, varying between 0.5 and 0.8. In view of the long inelastic mean free path of O 1s photoelectrons (∼1.5-2 nm), the predominance of these two low BE features (accounting for >90% of detected oxygen in all cases) and their relative facet invariance suggests they are associated with subsurface (bulklike) paracetamol. The (001), (011), and (110) surfaces also exhibit a third, weak, high BE component at 534.6 eV (Figure 11). This latter state was strongest for the most polar (001) facet, and may be associated with either surface hydroxyl groups (illustrated in Figure 3a), or more likely, water molecules adsorbed at polar centers; the BE of chemisorbed water is ∼1.3
Heng et al.
Figure 11. Deconvoluted O 1s XP spectra for the (001) and (010) facets of form I paracetamol crystal.
eV higher than that of -OH groups, consistent with our deconvoluted spectra in Figure 11.64 In contrast, this high BE component was absent from the nonpolar (010) facet, consistent with the methyl-terminated surface structure proposed in Figure 3b. The correspondence between the C and O 1s-derived surface functionality is clear from Figure 10, wherein the intensity of the O 1s 534.6 eV (adsorbed H2O) state clearly tracks that of the combined (CdO + C-OH) C 1s intensity. This correlation both confirms our peak assignments and provides direct, unambiguous confirmation for anisotropic surface termination of form I paracetamol crystals. The surface polarity of paracetamol facets determined by XPS is therefore predicted to decrease in the order (001) > (011) > (110) > (010). The dominant role of surface hydroxyls in regulating surface polarity is also confirmed in accordance with our contact-angle-based surface energy analysis. It is thus concluded that, although examination of the crystal structure allows for a first-order estimation of the probable presence of functional groups at the surface, the more subtle features of molecular location and orientation also play a role that cannot be described by simple inspection of the crystal lattice structure.
Conclusions Contact angle measurements on macroscopic single crystals demonstrated that the wettability of paracetamol crystals is anisotropic. These differences are attributed to the presence of different functional groups, their surface concentrations, and the molecular orientation and location of the groups on the crystal surface. Facets (201), (001), (011), and (110) had very similar values for γd, although values for (010) were much higher. Values for γp varied significantly for all faces, although the values for (010) were very low. The lowest attachment energy facet, (010), will be preferentially exposed following crystal fracture. This facet is found to be the most hydrophobic surface based on the surface energy computed from θA for water. The hydrophilicity order, as determined from the θA with water is (001) > (011) > (201) > (110) > (010). XPS identified strong variations in (64) McCafferty, E.; Wightman, J. P. Surf. Interface Anal. 1998, 26, 549564.
Anisotropic Wettability of Paracetamol Crystals
the surface termination of each facet and the concentration of exposed polar groups correlated well with the predicted surface hydroxyl group density based on crystallographic data and contact angle measurements. The wettability of paracetamol was found to be facet-specific and significantly determined by the number of hydroxyl groups present on the surface. It is concluded that
Langmuir, Vol. 22, No. 6, 2006 2769
the surface chemistry and surface energetics of paracetamol crystal facets are highly anisotropic. Acknowledgment. J.Y.Y.H. acknowledges the financial support of an ORS scholarship. LA0532407
