Contrasting the Surface and Bulk Properties of Anhydrate and

Jan 19, 2011 - Engineering, Purdue University 225 South University Street, West Lafayette, Indiana 47907,. United States. Received August 21, 2010; Re...
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DOI: 10.1021/cg101098v

Contrasting the Surface and Bulk Properties of Anhydrate and Dehydrated Hydrate Materials

2011, Vol. 11 692–698

Masahiro Yamauchi,†,‡ Eun Hee Lee,† Andrew Otte,† Stephen R. Byrn,† and M. Teresa Carvajal*,†,§ †

Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United States, ‡Pharmaceutical Research Center, Kyowa Hakko Kogyo Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan, and §Agricultural and Biological Engineering, Purdue University 225 South University Street, West Lafayette, Indiana 47907, United States Received August 21, 2010; Revised Manuscript Received December 13, 2010

ABSTRACT: Surface and bulk characterization of niclosamide and naproxen sodium between anhydrate and dehydrated hydrate were investigated. A comprehensive solid-state characterization was conducted using X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), and scanning electron microscopy (SEM) for the identification and determination of physical properties of the materials. Surface properties were addressed by evaluating the various forms: by inverse gas chromatography (IGC) and water sorption tendency (dynamic vapor sorption, VTI). The XRPD, DSC, and TGA data show slight or no differences between anhydrate and dehydrated hydrate. However, the SEM, IGC, and water vapor sorption isotherms results provided evidence of the heterogeneity of surface for both compounds. The SEM microphotographs clearly showed the rugosity of the powders. Niclosamide dehydrated hydrate showed a higher dispersive surface energy and higher rate of moisture sorption than the correspondent anhydrate, whereas the opposite was observed for naproxen sodium. The dispersive surface energy is a complementary approach to the existing and traditional robust characterization techniques. This study has provided an insight of the bulk and surface properties of the anhydrate and the dehydrated hydrate forms of niclosamide and naproxen sodium.

Introduction Drug substances with both anhydrate and hydrate forms are sometimes chosen for drug development in the pharmaceutical industry.1-5 During processing and storage, these drugs may undergo certain physical changes such as hydration-dehydration in response to processing or environmental conditions such as temperature and relative humidity. Physical changes can affect physicochemical and mechanical properties of the drug, resulting in significant differences on stability, hygroscopicity, dissolution rate, and bioavailability of the drug formulation.6-9 Therefore, it is important to evaluate the hydration and dehydration phenomena of the materials as well as the impact on the behavior, performance, and stability during processing. The hydration of an anhydrate form and the dehydration of a hydrated form are always of a concern during drug development. The issues related to the behavior of phase evolution phenomena of the dehydration-rehydration of solids have been considered in a large number of studies.1,2,5,10-14 Some hydrates tend to suffer phase transformations after dehydration.1,2,11-15 The solubility of a hydrate in water is usually lower than that of an anhydrous form.10,16-19 Ono et al.20,21 observed that the dehydrated hydrates of theophylline and carbamazepine exhibited different rehydration behavior20,21 and hygroscopic tendencies even though both forms showed crystallinity when analyzed by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). This difference in sorption rates have been attributed to the porosity of the material20,21 or diffusion through the crystal *To whom correspondence should be addressed. Phone: (765) 496-6438. E-mail: [email protected]. pubs.acs.org/crystal

Published on Web 01/19/2011

lattice due to certain amount of void spaces in the crystal structure.22 However, to the best of our knowledge, there are no reports on the surface energetics of the dehydrated materials. Pharmaceutical material science has gained recent interest on the surface properties of materials.23-26 Surface analysis by inverse gas chromatography (IGC) has been able to detect changes on the surface of powders such as defects caused by milling.23,24 The objective of this work is to probe the surface characteristics and evaluate the differences in the physicochemical solid-state properties between the anhydrate and dehydrated hydrate forms of niclosamide and naproxen sodium and anticipate the impact on stability and performance. Niclosamide and naproxen sodium have been chosen as model compounds; to have diversity on properties, these compounds offer hydrophobic and hydrophilic nature and in addition that both undergo transformation to crystalline anhydrate forms upon dehydration and have significant different solubilities in water.16-20 Materials and Methods Materials. Niclosamide and naproxen sodium are used as model drugs (Figure 1). Niclosamide and naproxen sodium were obtained from Sigma-Aldrich (St. Louis, MO). Ethanol was purchased from Pharmco (Brookfield, CT) and 2-propanol from Mallinckrodt (Phillipsburg, NJ). Methods. Sample Preparation. Several reports have indicated that the history of crystallization has an effect on the properties of solids.27-29 Therefore, all of the crystals were recrystallized in our laboratory in order to clear any history of crystallization and to reduce the effects of potential batch-to-batch variability that may accompany the materials acquired from the supplier. Anhydrate niclosamide was prepared by crystallization from a supersaturated solution of niclosamide in 2-propanol at 70 °C. The solution was allowed to cool at room temperature (25 °C) for 6 h. r 2011 American Chemical Society

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Figure 1. Molecular structures of (a) niclosamide and (b) naproxen sodium. The resulting crystals were collected in a filter, following by drying at 70 °C for 2 h. Monohydrate (Ha) niclosamide was obtained by heating a 95% 2-propanol solution at 70 °C. The solution was allowed to cool at room temperature (25 °C) for 6 h. Crystals were collected and dried at 40 °C for 1.5 h. Dehydrated hydrate of niclosamide was prepared by heating the monohydrate form at 70 °C for 4 h. Anhydrate naproxen sodium was recrystallized from 2-propanol at 70 °C. The solution was cooled at 25 °C. Crystals were obtained and collected and followed by drying at 70 °C. Monohydrate naproxen sodium was recrystallized in 99% of ethanol from a supersaturated solution at 70 °C. A similar condition as in the entire sample recrystallization in this study, the solution was cooled at 25 °C. Crystals were collected and dried at 25 °C. Dehydrated hydrate was prepared from the monohydrate by heating at 70 °C for 3 h. The anhydrate and dehydrated hydrate were stored in desiccators under low relative humidity (RH) until analyzed. Typical solid-state characterization was carried out to verify, identify, and compare the crystal materials obtained; analysis of the respective surfaces was performed as well. Moisture Sorption Measurement. Dynamic vapor sorption analysis was carried out using a symmetric vapor sorption analyzer SGA-100 (VTI Corporation, Hialeah, FL) in order to probe the isothermal moisture sorption profiles of niclosamide and naproxen sodium. Sorption data were collected under 90% and 60% relative humidity for niclosamide and naproxen sodium, respectively. Samples were dried at 25 °C for up to 60 min prior to analysis. The weight changes of the samples were monitored for 24 h. Sieve samples with narrow and similar size distribution (∼100-200 μm) were used for the measurements in order to minimize any effects of surface area. Powder X-ray Diffraction (PXRD). Powder X-ray diffraction patterns were taken for each of the samples using a Siemens D5000 (Munich, Germany) over the range of 4-40° 2θ at a scanning rate of 4°/min with a Cu KR radiation. Calculated powder patterns of the single crystal were obtained utilizing Mercury 1.4 (The Cambridge Crystallographic Data Centre, Cambridge, UK). Thermogravimetric Analysis (TGA). The weight loss upon heating was measured using a TGA2050 thermogravimetric analyzer TA Instruments (New Castle, Delaware). Samples were heated from 25 to 180 °C at 10 °C/min under nitrogen atmosphere in open aluminum pans. Differential Scanning Calorimetry (DSC). Differential scanning calorimetry was performed on a DSC 2920 (TA Instruments, New Castle, Delaware). The instrument was calibrated with indium (melting point 156.6 °C) and tin (melting point 231.9 °C). Samples were measured from 25 to 300 °C at a scanning rate of 10 °C/min under nitrogen atmosphere. A sample size of about 2 mg was measured into aluminum pans with or without the pinhole in the lid, with for the hydrate and without for the anhydrate and dehydrated hydrate samples. Scanning Electron Microscopy (SEM). The samples were sputtercoated in a Hummer II sputter coater (Technics, Inc., Alexandria, VA) for 3 min at 100 mTorr and 10 mA with gold:palladium. SEM images were taken with a FEI NOVA nanoSEM200 field emission scanning electron microscope (FEI Company, Hillsboro, Oregon) at 3 kV. Inverse Gas Chromatography (IGC). The IGC experiments were conducted using a commercial IGC system (iGC, Surface Measurements System Ltd., London, UK). Approximately 500 mg of the

Figure 2. Isothermal water vapor adsorption profiles at 90% RH and 25 °C for niclosamide: (a) dehydrated hydrate and (b) anhydrate. sample were packed in silinized glass columns using a standardized packing method under controlled environmental conditions. Samples were equilibrated with dry helium at 303 K for 4 h prior to the measurements. Helium was used as the carrier gas and methane was used to correct for dead volume. The vapor probes used included a linear hydrocarbon series (hexane, heptane, octane, nonane, decane), ethanol, 2-propanol, acetonitrile, and ethyl acetate at infinite dilution conditions. Calculation of the dispersive and specific surface energy were performed according to that of Schultz et al.30 Data presented is an average of triplicates. Crystal Face Indexing and Morphology Prediction. Crystal structure was geometrically optimized using the Compass force field in the Forcite module of Materials Studio 4.0 (Accelrys Software Inc., San Diego). Morphology with face indexing of naproxen sodium anhydrate was calculated based on the attachment energy model (all default options in the morphology module were used: CSD refcode naproxen sodium anhydrate, ASUBUL; naproxen sodium monohydrate, IVIDEW)

Results and Discussion Moisture Sorption Measurement. The water sorption profiles at 90% RH and 25 °C for the anhydrate and dehydrated hydrate forms of niclosamide are shown in Figure 2. The water sorption rate of niclosamide dehydrated hydrate (Figure 2a) is clearly different from that of the anhydrate (Figure 2b). The dehydrated hydrate sorbed water in a faster manner to approximately 0.7% in 24 h, whereas in the anhydrate configuration, no sorption of water was observed within the same period of time of 24 h. The isothermal hydration profiles at 60% RH and 25 °C for the anhydrate and dehydrated hydrate forms of naproxen sodium are displayed in Figure 3. Both samples exhibited weight gain of about 14% in 14 h, and the calculations indicated that the hydration corresponded to the stoichiometric value of 1.97 water molecules, representing the formation of the dihydrated form. This form was obtained after 14 h when subjecting either form, anhydrous or dehydrated, to high RH. This was confirmed by the X-ray powder diffraction patterns (not shown). The hydration of the anhydrate was completed within 9 h, while the dehydrated hydrate needed 14 h to be completely hydrated and transformed as per the experimental conditions used for this work. The results for both compounds are consistent with previous reports.1,5 XRPD. Powder X-ray diffraction patterns of the anhydrate, dehydrated hydrate, and hydrate of niclosamide are

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Figure 3. Isothermal water vapor adsorption profiles at 60% RH and 25 °C for naproxen sodium: (a) anhydrate and (b) dehydrated hydrate.

Figure 4. X-ray powder diffraction patterns of niclosamide: (a) anhydrate, (b) dehydrated hydrate, and (c) monohydrate.

shown in Figure 4. The three samples showed XRPD patterns characteristic of crystalline materials. A slight difference was observed at the diffraction angle of 2θ = 31° between the anhydrate and dehydrated hydrate. The anhydrate had a large peak at that angle, but there was almost no peak in the dehydrated hydrate. It was confirmed that there was a small peak at the angle in the dehydrated hydrate when the PXRD measurement was done with a longer acquisition time. This strategy was followed after confirming that preferred orientation was not responsible of the peak resolution. It was also noticeable that some peaks in the dehydrated hydrate were broader than those of the anhydrate, and except for those, there was no significant difference between anhydrate and dehydrated hydrate. The calculated patterns for niclosamide anhydrate and monohydrate are unavailable from the crystal structure database (CSD). The monohydrate pattern shows a slight hump between 15° and 27° 2θ, but this is not a concern because the patterns are consistent with those reported in the literature for this compound,1 and in addition, the lack of transition temperature followed by recystallization on the DSC thermograms led us to believe that there is no or insignificant amorphous content that will be disturbing this study. Powder X-ray diffraction patterns of the anhydrate, dehydrated hydrate, and monohydrate of naproxen sodium are shown in Figure 5 as well as the dihydrate form in Figure 6.

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Figure 5. X-ray powder diffraction patterns of naproxen sodium anhydrate: (a) anhydrate, (b) dehydrated hydrate, (c) calculated from crystal structure of anhydrate.

Figure 6. X-ray powder diffraction patterns of naproxen sodium hydrate: (a) dihydrate and (b) calculated from crystal structure of dihydrate.

All of the samples showed crystallinity on the PXRD patterns, and diffraction angles were consistent with those calculated from CSD for the anhydrate and monohydrate forms. There was no significant difference between the anhydrate and dehydrated hydrate. The peak positions and intensities present in the X-ray patterns for both compounds are clear differences among the structures, confirming that these compounds are distinct. It is apparent that the differences are the result from the water content in the crystal structure. DSC/TGA. DSC and TGA curves of the anhydrate, dehydrated hydrate, and hydrate forms of niclosamide are shown in Figure 7. The niclosamide monohydrate showed a broad endothermic peak around 110 °C and a sharp endothermic at 229 °C in DSC curve. The first endothermic peak coincided with weight loss of 5.25 ( 0.03% (mean ( SD, n = 3) from approximately 70 to 120 °C observed on the TGA curve, and this is characteristic of niclosamide monohydrate dehydration.18 The stoichiometric value calculated from the TGA analysis for the monohydrate dehydration was 5.22%. The second endothermic peak was due to the melting point of the anhydrate.16 In contrast, the anhydrate and dehydrated hydrate showed only one endothermic peak at 229 °C due to the melting point, and no weight loss was observed on the TGA analysis. The DSC and TGA analyses

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Figure 7. DSC and TGA curves of niclosamide: (a) TGA curve of anhydrate, (b) TGA curve of dehydrated hydrate, (c) TGA curve of monohydrate, (d) DSC curve of anhydrate, (e) DSC curve of dehydrated hydrate, and (f) DSC curve of monohydrated hydrate.

indicated no difference between the anhydrate and dehydrated hydrate. DSC and TGA curves of the anhydrate, dehydrated hydrate, and monohydrate of naproxen sodium are shown in Figure 8. The monohydrate showed a broad endothermic peak around 100 °C and a sharp endothermic at 257 °C in the DSC curve. The first endothermic peak on the TGA was due to the dehydration and weight loss of 6.75 ( 0.09% (mean ( SD, n = 3) from approximately 40 to 120 °C. This result agreed with the theoretical stoichiometric water content of 6.66% w/w. The small peak at about 80 °C corresponded to an endotherm associated with a slight over hydration of the monohydrate sample, as described in the literature.5,12,13 The second endothermic peak was due to the melting point of the anhydrate. In contrast, the anhydrate and dehydrated hydrate showed only one endothermic peak at 257 °C due to the melting point, and no weight loss was observed. The thermograms of the various forms for both compounds showed practically no difference between the anhydrous and dehydrate forms. SEM. The morphology of the niclosamide anhydrate and dehydrate samples is shown in the SEM microphotographs (Figure 9) where the particles of the anhydrate form consisted of flat and rectangular crystals with smooth surfaces, whereas the dehydrated hydrate consisted of small needles. The morphology (shape, size and texture) changed upon dehydration. Figure 10 reveals the crystal habit of naproxen sodium. The particles of anhydrate consisted of rectangular crystals that often appeared to be attached at one end and radiated out from this location, somewhat like flower petals. The dehydrated hydrate appeared to have some flatter and bigger crystals. With the SEM, it seems that the surface area of anhydrate was larger than that of the counterpart dehydrated hydrate. In both situations, the compounds have different crystal habits for the anhydrate and the dehydrate hydrate partners; therefore, it is reasonable to believe that the water sorption could depend on the surface area. IGC. The dispersive surface energies of the anhydrate and dehydrated hydrate of niclosamide and naproxen sodium are presented in Table 1. The dispersive surface energy is based on the calculations from IGC measurements. The dispersive surface energies (γD) of niclosamide anhydrate

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Figure 8. DSC and TGA curves of naproxen sodium: (a) TGA curve of anhydrate, (b) TGA curve of dehydrated hydrate, (c) TGA curve of monohydrate, (d) DSC curve of anhydrate, (e) DSC curve of dehydrated hydrate, and (f) DSC curve of monohydrated hydrate.

and dehydrated hydrate were 48.6 and 72.4 mJ/m2, respectively. The data showed that the dehydrated hydrate has a higher specific surface energy than the anhydrate, likely due to the difference in the crystal habit, which suggests that the functional groups exposed at the surface for each habit are dissimilar. It could be hypothesized based on the polar probes used in IGC measurements that the crystal of the dehydrated hydrate exposes more hydrophilic groups on the surface than that of the anhydrate upon dehydration. The effect of particle size and most importantly surface area play a significant role in the observed dispersive surface energy difference between the niclosamide anhydrate and dehydrated hydrate. Particle size has been previously shown to have an effect of the dispersive surface energy of milled paracetamol crystals24 due to milling exposing a more hydrophobic surface, which in turn becomes increasingly more dominant with decreasing particle size.24,25 In this case, the different crystalline habits will result in different surface areas, which may result in a greater surface area of dispersive facets.23,24 While it can be difficult to delineate the effects of crystal habit, particle size, and surface area on IGC measurements when all may contribute to the calculated surface energy, it is apparent the existing difference between the two forms. Because particle size distribution for both forms were comparable during the water sorption experiments and surface energetic assessment, the different crystalline habits will result in different surface areas,31 which may result in a greater surface area of dispersive facets leading to a greater calculated dispersive surface area. Hence the differences in the surface energetics and crystal habit suggest being responsible for the observed water uptake variation. The mean dispersive energies of anhydrate and dehydrated hydrate of naproxen sodium were 75.6 and 67.1 mJ/ m2, respectively. The dispersive energy of dehydrated hydrate was smaller than that of the anhydrate. It is clearly just by looking at the morphology of these compounds (Figure 10) that the surface area is again responsible for the distinct water sorption. The effect of the dehydration process had an apparent impact on the behavior. The result of the simulation suggests that the hydrophilic part of naproxen sodium is located in the (001) and (001) planes of the anhydrate crystal (Figure 11). Naproxen

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Figure 9. SEM photographs of niclosamide: (a,b) anhydrate and (c,d) dehydrated hydrate.

Figure 10. SEM photographs of naproxen sodium: (a,b) anhydrate and (c,d) dehydrated hydrate.

sodium is a channel hydrate,15 and the crystal structure does not collapse upon dehydration, an indicator of this is the preservation of molecular order confirmed by the XRPD. We would speculate that on the crystal faces where the water

molecules are lost during dehydration, a greater exposure of the carboxyl groups may be present due to the loss of water and reorganization of these surface molecules postdehydration. This in turn gives a greater dispersive surface energy

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Table 1. Dispersive and Specific Surface Energy of Naproxen Sodium (Hydrophilic Compound) and Niclosamide (Hydrophobic Compound) dispersive surface energy 2-propanol (dG) acetonitrile (dG) ethanol (dG) ethyl acetate (dG)

naproxen sodium anhydrate

naproxen sodium dehydrate hydrate

75.58 (0.80) 9.56 (0.12) 13.85 (0.10) 11.58 (0.11) 11.54 (0.05)

67.06 (3.81) 9.13 (0.70) 13.30 (0.43) 11.20 (0.90) 10.90 (0.36)

[mJ/m2] [kJ/mol] [kJ/mol] [kJ/mol] [kJ/mol] [mJ/m2] [kJ/mol] [kJ/mol] [kJ/mol] [kJ/mol]

dispersive surface energy 2-propanol (dG) acetonitrile (dG) ethanol (dG) ethyl acetate (dG)

niclosamide anhydrate

niclosamide dehydrate hydrate

48.60 (2.71) 6.20 (0.32) 11.49 (0.53) 8.38 (0.41) 9.31 (0.48)

72.42 (0.64) 12.00 (0.04) 14.36 (0.06) 12.46 (0.09) 13.65 (0.04)

Figure 11. Crystal structure of naproxen sodium with unit cell. The (001) lattice plane is emphasized above the unit cell.

compared to the dehydrated crystal, where most of the hydrophilic groups seem to be contained in the channel where the water molecules are not on the surface. Conclusion The physicochemical differences with emphasis on the surface properties of niclosamide and naproxen sodium and their respective anhydrate and dehydrated hydrate forms were investigated. Assessment of bulk and surface characteristic of powders was conducted by XRPD, DSC, TGA, and by SEM, VTI, and IGC. Bulk properties of the anhydrate and dehydrate forms were practically similar to the eye of the DSC and TGA and little distinction by XRPD. However, the surface analyses showed differences between the dehydratedhydrate and anhydrate forms for both compounds. The difference in surface energy between dehydrated hydrate and hydrate forms shown by IGC was manifested as differences in the hydration behavior. The dehydration of the hydrophilic compound, naproxen sodium, decreased the surface energy, resulting in slower water sorption than that of the original anhydrate form. The dehydration of the hydrophobic compound, niclosamide, increased the specific free energies and thus, faster water vapor sorption occurred than that of the original anhydrate form. This response in water uptake seems reasonable to attribute it to the surface energy and surface area, as observed by the IGC and SEM photographs.

This study is succinct, hitting the importance of surface properties for immediate interaction with other materials or water, while bulk properties are important for long-term behavior such as stability upon storage. This study stresses the importance of understanding, knowing, and characterizing the physicochemical properties of raw materials, including the susceptibility to physical changes during processing specifically during wet granulation and drying and subsequent development. Emphasis is given to surface energy profiles and water sorption isotherms and together offer thermodynamic and kinetic information respectively that can lead to better control of formulations that exhibit greater stability and performance. Acknowledgment. We acknowledge the financial support provided by Kyowa Hakko Kogyo Co., Ltd. (Tokyo, Japan) and funding by NSF IUCRC 0003064-EEC Dane O. Kildsig Center for Pharmaceutical Processing Research (CPPR). The assistance of Dr. D. M. Sherman for SEM measurements and of Dr. N. Khalef, Mr. T. Irasi, and Dr. K. Kobayashi for discussions is greatly appreciated.

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