Surface Characterizations of Spin-Coated Films of Ethylcellulose and

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Surface Characterizations of Spin-Coated Films of Ethylcellulose and Hydroxypropyl Methylcellulose Blends Yit-Yian Lua, Xiaoping Cao,* Brian R. Rohrs, and D. Scott Aldrich Pfizer Global Research and DeVelopment, Eastern Point Road, Groton, Connecticut 06340 ReceiVed October 9, 2006. In Final Form: December 8, 2006 Films of pure ethylcellulose (EC) and hydroxypropyl methylcellulose (HPMC) polymers and EC/HPMC blends were prepared from solutions by spin coating where isopropyl alcohol (IPA), water, and IPA/water cosolvent were used as solvents. Surface structures of the films were investigated using optical microscopy, atomic force microscopy (AFM), and Raman mapping and spectroscopy. For the films prepared from EC/HPMC blend solutions using the IPA/water cosolvent, different domain structures such as islands or pits and phase separation between EC and HPMC were observed by optical microscopy and AFM. The nature of the polymer components on the surface of the films was identified by Raman mapping and spectroscopy. Experimental results also indicated that polymer composition, solvent, and temperature during spin coating had significant impacts on surface structures of the films.

Introduction Film coatings of ethylcellulose (EC) and hydroxypropyl methylcellulose (HPMC) blends are widely used in solid pharmaceutical dosage forms to control drug release.1,2 In the EC/HPMC film coatings, EC is water insoluble and is usually a major component in the composition of the blends. It is believed that EC serves as a matrix on the surface, whereas the minor component, water-soluble HPMC, dissolves in water and creates a pore structure on the surface.3 The release of drug through the pores can be manipulated by changing the composition and concentration of polymers used in the film coating. Previous studies on the interactions and the leaching/retention of EC/ HPMC blends have shown that phase separation between EC and HPMC can be observed throughout a wide polymer composition range and the leaching of HPMC from the film is dependent on both the water solubility of HPMC and the phase morphology of the blend.3-5 Further study on the surface structure of EC/HPMC blends can provide important information on surface properties of the blends and help in designing formulations with desired drug release profiles. Since atomic force microscopy (AFM) was introduced in 1986, it has played an important role in studying the surface morphology of polymers,6-10 including a variety of polymer blends such as * Corresponding author. Telephone: (860) 686-1260. Fax: (860) 4413972. E-mail: [email protected]. (1) Shah, N. B.; Sheth, B. B. A Method for Study of Timed-Release films. J. Pharm. Sci. 1972, 61 (3), 412-416. (2) Rowe, R. C. Film-CoatingsThe Ideal Process for the Production of Modified-Release Oral Dosage Forms. Pharm. Int. 1985, 6, 14-17. (3) Sakellariou, P.; Rowe, R. C. The Morphology of Blends of Ethylcellulose with Hydroxypropyl methylcellulose as Used in Film Coating. Int. J. Pharm. 1995, 125, 289-296. (4) Sakellariou, P.; Rowe, R. C.; White, E. F. T. Polymer/polymer Interaction in Blends of Ethylcellulose with both Cellulose Derivatives and Polyethylene glycol 6000. Int. J. Pharm. 1986, 34, 93-103. (5) Sakellariou, P.; Rowe, R. C.; White, E. F. T. A Study of the Leaching. Retention of Water-Soluble Polymers in Blends with Ethylcellulose Using Torsional Braid Analysis. J. Controlled Release 1988, 7, 147-157. (6) Li, X.; Han, Y.; An, L. Surface Morphology Control of Immiscible PolymerBlend Thin Films. Polymer 2003, 44, 8155-8165. (7) Li, X.; Han, Y.; An, L. Annealing Effects on the Surface Morphologies of Thin PS/PMMA blend films with different film thickness. Appl. Surf. Sci. 2004, 230, 115-124. (8) Luo, S.-C.; Craciun, V.; Douglas, E. P. Instabilities during the Formation of Electroactive Polymer Thin Films. Langmuir 2005, 21, 2881-2886. (9) Strawhecker, K. E.; Kumer, S. K.; Douglas, J. F.; Karim, A. The Critical Role of Solvent Evaporation on the Roughness of Spin-Cast Polymer Films. Macromolecules 2001, 34, 4669-4672.

styrene-block-ethylene/butylenes-block-styrene,11 polystyrene/ polymethacrylate,12 poly(n-butyl methacrylate)/polystyrene,13 polystyrene/poly(methyl methacrylate),14 and polystyrene/poly(tert-butyl acrylate).15 In this study, the EC/HPMC blend was investigated. Although the surface morphology of the EC/HPMC films has been previously investigated using optical microscopy,3 it was conducted in a large scale of ∼2500 µm × 2500 µm and the films were prepared using a dip-coating method with 50% methanol/50% methylene chloride as solvent.3 The EC/HPMC films investigated in this study were prepared through a spincoating process with isopropyl alcohol/water as the solvent. In addition to optical microscopy, more importantly AFM was employed to closely examine the surface structure of the EC/ HPMC films at small scales, and it revealed detailed surface features of the EC/HPMC films with a nanometer resolution. Furthermore, Raman mapping and spectroscopy were used to identify the nature of surface features on the polymer films. The effects of polymer composition, solvent, and temperature were investigated to understand their impacts on surface morphology of the EC/HPMC films. As a film preparation process, spin coating has been commonly used in preparing various thin films such as polymers, polymer blends, and metal oxides, and it has been well studied.8,9,11,16-19 (10) Ton-That, C.; Shard, A. G.; Teare, D. O. H.; Bradley, R. H. XPS and AFM Surface Studies of Solvent-Cast PS/PMMA blends. Polymer 2001, 42, 1121-1129. (11) Li, X.; Han, Y.; An, L. Surface Morphology Evolution of Thin Triblock Copolymer Films during Spin Coating. Langmuir 2002, 18, 5293-5298. (12) Woodcock, S. E.; Chen, C.; Chen, Z. Surface Restructuring of Polystyrene/ Polymethacrylate Blends in Water Studied by Atomic Force Microscopy. Langmuir 2004, 20, 1928-1933. (13) Chen, C.; Wang, J.; Woodcock, S. E.; Chen, Z. Surface Morphology and Molecular Chemical Structure of Poly(n-butyl methacrylate)/Polystyrene Blend Studied by Atomic Force Microscopy (AFM) and Sum Frequency Generation (SFG) Vibrational Spectroscopy. Langmuir 2002, 18, 1302-1309. (14) Ton-That, C.; Shard, A. G.; Daley, R.; Bradley, R. H. Effects of Annealing on the Surface Composition and Morphology of PS/PMMA Blend. Macromolecules 2000, 33, 8453-8459. (15) Wang, P.; Koberstein, J. T. Morphology of Immiscible Polymer Blend Thin Films Prepared by Spin-Coating. Macromolecules 2004, 37, 5671-5681. (16) Emslie, A. G.; Bonner, F. T.; Peck, L. G. Flow of a viscous liquid on a rotating disk. J. Appl. Phys. 1958, 29, 858-862. (17) Flack, W. W.; Soong, D. S.; Bell, A. T.; Hess, D. W. A mathematical model for spin coating of polymer resists. J. Appl. Phys. 1984, 56, 1199-1206. (18) Cao, X.; Cao, L.; Yao, W.; Ye, X. Structural characterization of Pd-doped SnO2 thin films using XPS. Surf. Interface Anal. 1996, 24 (9), 662-666. (19) Cao, X.; Cao, L.; Yao, W.; Ye, X. Influences of dopants on the electronic structure of SnO2 thin films. Thin Solid Films 1998, 317 (1,2), 443-445.

10.1021/la0629680 CCC: $37.00 © 2007 American Chemical Society Published on Web 03/09/2007

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The good uniformity of thin films, well-controlled film thickness, and easy operation are the primary reasons that spin coating is often chosen as a convenient way to prepare polymer thin films for the study of polymer surface morphology.6,7,10,11,13-15,20-23 Experimental Section Materials. Both EC (Ethocel Standard 10 premium) and HPMC (Methocel E5 premium) used in this study were manufactured by Dow Chemical Company (Grove City, OH). The degree of substitution of ethoxyl for EC was 48-49.5% (w/w). The degrees of substitution of methoxyl and hydroxypropoxyl for HPMC were 28-30% (w/w) and 7-12% (w/w), respectively. Both polymers were used as received. Sample Preparation. Since EC dissolves in isopropyl alcohol (IPA) but not water, and HPMC dissolves in water but not IPA, the preparation of polymer blend solutions for EC and HPMC in IPA/ water cosolvent system was more complicated than usual solution preparations. EC was first dispersed in a 97% IPA/3% water (volume percent) cosolvent system, while HPMC was dispersed in a 50% IPA/50% water cosolvent system. Both polymer solutions were either stirred overnight or stirred until polymer dissolved, and then EC solution was added to HPMC solution with stirring for at least 15 min. The final solution was clear and consisted of 73.5% IPA and 26.5% water. The cosolvent system used for all the polymer blend solutions in this study was 73.5% IPA/26.5% water unless otherwise stated specifically. The 2 wt % polymer solutions were prepared for spin coating. A spin coater from Cookson Electronics Equipment, Model G3P8, was used for film preparations. All the polymer films were prepared at 3000 rpm for 30 s using glass coverslips (round, Ted Pella, Inc., Redding, CA) as the substrates. The substrates were cleaned with ethanol prior to spin coating. The samples without heating were prepared at room temperature (∼23 °C). A heat gun was used to heat the substrates if a temperature higher than room temperature was applied during spin coating, and an infrared thermometer was used to monitor the temperature of the substrates. Optical Microscopy. A computer-video-enhanced microscope (Model Axioplan 2, Zeiss) was used for all photomicrographs to observe large-scale surface features. Plane-polarized light was used for imaging, and digital images were captured using the imaging software SPOT (Diagnostic Instruments, Inc.). All the samples were analyzed directly using a transmission mode without using silicone oil. Atomic Force Microscopy (AFM). A NanoScope IV Multimode AFM (Digital Instruments, Santa Barbara, CA) was employed to characterize the polymer films. A JV-type scanner was used in the experiments. Prior to experiments, the scanner was calibrated using the standard procedures provided by Digital Instruments. All the experiments were performed in air at ambient conditions. All images were acquired using a tapping mode. Silicon probes (Digital Instruments) with a cantilever length of 125 µm, a nominal tip radius of curvature of 5-10 nm, and resonant frequency of 280-380 kHz were used. Both height and phase images were collected and analyzed with Nanoscope software (Digital Instruments). All images were collected with a resolution of 256 × 256 pixels and a scan rate of 1 Hz for the 5 µm × 5 µm images or 0.2 Hz for the 20 µm × 20 µm images. The set point for the feedback control was between 1.2 and 1.5 V. AFM force measurements were performed on the polymer surface by measuring the cantilever deflection as the sample moved (20) Affrossman, S.; Henn, G.; O’Neill, S. A.; Pethrick, R. A.; Stamm, M. Surface Topography and Composition of Deuterated Polystyrene-Poly(bromostyrene) Blends. Macromolecules 1996, 29, 5010-5016. (21) Dalnoki-Veress, K.; Forrest, J. A.; Dutcher, J. R. Mechanical Confinement Effects on the Phase Separation Morphology of Polymer Blend Thin Films. Phys. ReV. E 1998, 57 (5), 5811-5817. (22) Dalnoki-Veress, K.; Forrest, J. A.; Stevens, J. R.; Dutcher, J. R. Phase Separation Morphology of Spin-Coated Polymer Blend Thin Films. Physica A 1997, 239, 87-94. (23) Dalnoki-Veress, K.; Forrest, J. A.; Stevens, J. R.; Dutcher, J. R. Phase Separation Morphology of Thin Films of Polystyrene/Polyisoprene Blends. J. Polym. Sci., Part B: Polym. Phys. 1996, 34, 3017-3024.

Figure 1. Photomicrographs of spin-coated films of 50% EC/50% HPMC blend prepared from 2 wt % polymer solution on glass coverslip substrates with 73.5% IPA/26.5% water solvent system. (a) No heating applied, (b) heated at a temperature of 50 °C for 15 min after spin coating, and (c) heated at a temperature of 100 °C for 15 min after spin coating. toward the tip. When a force curve was acquired, the lateral (X and Y) movement of the scanner was stopped, and the scanner was extended and retracted in the vertical direction (Z). As the purpose of these experiments was relative comparison of adhesion forces between tip and different polymer components, the exact value of the spring constant was not required. Raman Spectroscopy and Mapping. Raman spectra of EC/ HPMC polymer films were collected on a Nicolet Almega Raman Spectrometer. An excitation laser (532 nm, 25 mW) focused on the sample through a microscope optic (100×), and scattered light was collected by the same optics. A 25 µm pinhole spectrometer aperture and a 672 lines/mm blaze grating were used in providing spectral resolution of 6.4-10.5 cm-1 and spatial resolution of 1 µm. The maps were collected at a scale of ∼200 µm × ∼150 µm with 1 µm spacing and 20 s collection time at each point. During the experiments using the optical microscope, AFM, and Raman spectrometer, the center of the sample was analyzed.

Results and Discussion Optical Micrographs. The 50% EC/50% HPMC polymer films were prepared on glass coverslip substrates using a 2 wt % polymer solution. Parts a, b, and c, respectively, of Figure 1show photomicrographs of the films prepared without heating throughout the sample preparation, with heating at 50 °C for 15 min after spin coating, and with heating at 100 °C for 15 min after spin coating. Similar surface morphology with a cellular

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structure was observed for all three samples. A striation structure was also observed when the photomicrographs were taken from the center area (photomicrographs are not shown). The cellular and striation surface structures were probably caused by Marangoni convection. During the spin-coating process, the evaporation of the solvent induces the composition and temperature gradients in the thin solution film, leaving the solution layer with a higher polymer concentration near the surface. In addition, the evaporation can also induce cooling near the surface. Because surface tension is a function of solution concentration and temperature, the concentration and temperature gradients will change the surface tension during the spin-coating process, inducing flow near the surface of the thin solution film. The high surface tension area pulls the solution from the low surface tension area, leading to Marangoni convection.8,24 Applied heating after spin coating appeared to have no significant effect on the film structure. More details about temperature effect are discussed below. AFM Characterizations. Figure 2 shows AFM images of 50% EC/50% HPMC polymer film on glass coverslips with heating at 50 °C for 15 min after spin coating (the same sample as in Figure 1b). The scan size of the images was 5 µm × 5 µm, and the Z-range was 500 nm. Apparently, phase separation was observed from the AFM height image (Figure 2a), phase image (Figure 2b), and three-dimensional surface plot (Figure 2c). The diameter of the island features on surface ranged between 300 and 500 nm. The height of the island features was about 100300 nm. AFM images (not shown) of the other three samples, which were the same as in Figure 1a,c,d, showed similar surface structures in both size and shape. Therefore, the size and shape of the island features were independent of the substrates such as glass coverslip and mica and were not affected by the heating after spin coating, consistent with what was observed by optical microscopy. AFM phase images (Figure 2b) clearly showed the phase separation of EC and HPMC on the surface. AFM force measurements (not shown) indicated that the island features and low-lying areas had different adhesion forces from those of the AFM probe. Similar AFM force measurements were conducted for pure EC and HPMC films. The results suggested that the island features had an adhesion force similar to that of HPMC while the low-lying areas had an adhesion force similar to that of EC. Raman Mapping and Spectroscopy. To confirm the phase identification, a more characteristic technique is required to provide further information on the polymer films. Figure 3 shows the Raman mapping and spectra of the 50% EC/50% HPMC polymer film on a glass coverslip with heating at 50 °C for 15 min after spin coating (same sample as in Figure 1b and Figure 2). Figure 3a shows the video image of the area over which Raman mapping was conducted. The island features are darker in color in the video image. A straightforward approach for Raman mapping would be to plot the intensity of a unique and distinctive peak. Theoretically, a peak area analysis would be a more accurate indicator of sample concentration, but it could not be performed due to complicated peak shape and extensive peak convolution. Instead, a peak height analysis was used for the Raman mapping. Moreover, since there was no unique peak free from interference from another for EC and HPMC, a peak height ratio strategy was used to create the profile. The Raman map in Figure 3b was created using the peak height ratio of the peak at 2975 cm-1 (a more distinctive peak for EC as shown in Figure 3c) to the one at 2838 cm-1 (a more distinctive peak for HPMC as shown in (24) Scriven, L. E.; Sternling, C. V. The Marangoni Effects. Nature 1960, 187, 186-188.

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Figure 2. AFM images of 50% EC/50% HPMC film on glass coverslip with heating at 50 °C for 15 min after spin coating. Height and phase images were taken simultaneously with tapping mode. Scan area 5 µm × 5 µm. Z-range 500 nm. (a) Height image, (b) phase image, and (c) surface plot.

Figure 3c). Note that a higher response (blue, as shown in the map) would be expected where EC was present because the denominator (peak height at 2838 cm-1) was smaller. Similarly, a lower response (orange, as shown in the map) would be expected where HPMC was present. The two circles in Figure 3a were the same spots as the two circles in Figure 3b. The circle on the left was an island feature, and the circle on the right was a low-lying area on the surface. The Raman map showed that the island feature had a higher response in EC, but the low-lying area showed a higher response in HPMC. To further confirm the identification, four Raman spectra are shown in Figure 3c: from top to bottom, they are pure EC reference, the island feature corresponding to the left circled area in Figure 3b, the low-lying spot corresponding to the right circled area in Figure 3b, and pure HPMC reference. The spectrum of the island feature is similar to that of the EC reference, while the spectrum of the low-lying spot on the surface is similar to that of HPMC. Since the resolution of the Raman mapping was

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Figure 4. Photomicrographs of EC/HPMC films prepared from different polymer compositions. The polymer films were prepared without heating, and the concentration of the polymer solutions was 2 wt %. (a) 100% HPMC, (b) 20% EC/80% HPMC, (c) 35% EC/ 65% HPMC, (d) 50% EC/50% HPMC, (e) 65% EC/35% HPMC, (f) 80% EC/20% HPMC, and (g) 100% EC. Figure 3. Raman mapping and spectra of 50% EC/50% HPMC film on glass coverslip prepared with heating at 50 °C for 15 min after spin coating. (a) Video image of the mapping area, (b) Raman map, and (c) Raman spectra of pure EC, domain structure, low-lying area, and pure HPMC. Mapping area of 200 µm × 150 µm.

1 µm and most EC and HPMC features were smaller than 1 µm, many areas of EC and HPMC combination were observed, as shown in the Raman map as the green and yellow areas. The results from Raman mapping and spectroscopy were consistent with the results from AFM force measurements. Therefore, Raman mapping and spectroscopy confirmed that the island features on the spin-coated polymer film were EC and the low-lying areas were HPMC. Effect of Polymer Composition. To study the effects of polymer composition on the surface structure, film samples were prepared from solutions with different polymer compositions. The films were prepared at room temperature (without heating during or after the spin coating) and the concentration of the polymer solutions was 2 wt % with 73.5% IPA/26.5% water as the solvent. Figure 4 shows the photomicrographs of various EC/HPMC polymer films. Differences in surface structure were observed from the films prepared from different polymer compositions. More domain structures on the surface were observed for the samples with higher EC composition. Polymer film of 100% HPMC (Figure 4a) was smooth, continuous, and

featureless. Figure 5 shows the AFM height images of the same samples in Figure 4 with a scan are of 5 µm × 5 µm. Phase images (not shown) were acquired simultaneously, and the same surface morphologies were observed. Again, the island features were observed for the EC/HPMC and 100% EC films. They were identified to be EC by Raman mapping and spectroscopy as discussed above. The island features appeared to be larger in the samples with higher EC composition, suggesting more aggregation with more EC present in the film. The diameter range of the island features on the EC/HPMC polymer films was estimated using AFM, as shown in Table 1. The measurements were obtained only for isolated island features, and aggregated domain structures were not included. As the EC content increased in composition from 20% to 100%, the diameter of the island features increased from ∼150-215 nm to ∼400-760 nm. The film thickness was also roughly estimated using AFM: the edges of the polymer films were imaged using tapping mode AFM, and analyses were conducted on the image to estimate the vertical distances between the films and the substrates (film thickness). Table 2 shows the estimation results. The thickness range was the results of three measurements at different spots of the same sample. For 100% HPMC, 50% EC/50% HPMC, and 100% EC films, the film thickness was ∼118-123, ∼220480, and ∼500-1000 nm, respectively. The thickness of polymer films increased with the EC percentage of polymer composition.

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Figure 5. AFM height images of EC/HPMC films prepared from different polymer compositions. (a) 20% EC/80% HPMC, (b) 35% EC/65% HPMC, (c) 50% EC/50% HPMC, (d) 65% EC/35% HPMC, (e) 80% EC/20% HPMC, and (f) 100% EC. The polymer films were prepared without heating, and the concentration of the polymer solutions was 2 wt %. Scan area 5 µm × 5 µm. The Z-ranges for the images are (a) 400, (b) 400, (c) 600, (d) 600, (e) 1000, and (f) 1000 nm. Table 1. Size Range of Island Features on HPMC, EC, and EC/HPMC Polymer Films Measured by AFM Section Analysis polymer composition

size range (nm)

100% HPMC 20% EC/80% HPMC 35% EC/65% HPMC 50% EC/50% HPMC 65% EC/35% HPMC 80% EC/20% HPMC 100% EC

no island features observed ∼150-215 ∼200-310 ∼250-560 ∼250-600 ∼390-720 ∼400-760

Table 2. Thickness of Polymer Films Prepared from 2 wt % Polymer Solution Measured by AFM polymer composition

thickness range (nm)

100% HPMC 50% EC/50% HPMC 100% EC

∼118-123 ∼220-480 ∼500-1000

This is probably because a polymer solution with a higher EC percentage is more viscous and spin coating produces thicker films for a more viscous solution. Solvent Effect. It is well recognized that solvent has a significant influence on the surface morphology of polymer films.9,25-28 Polymer films prepared from pure polymer solutions (25) To, T.; Wang, H.; Djurisic, A. B.; Xie, M. H.; Chan, W. K.; Xie, Z.; Wu, C.; Tong, S. Y. Solvent Dependence of the Evolution of the Surface Mophology of thin asymmetric diblock copolymer films. Thin Solid Films 2004, 467, 59-65.

Figure 6. Photomicrographs of EC/HPMC films prepared from different polymer compositions. The polymer films were spin-coated on the substrates at a temperature of ∼45 °C, and the concentration of the polymer solutions was 2 wt %. (a) 100% HPMC, (b) 20% EC/80% HPMC, (c) 35% EC/65% HPMC, (d) 50% EC/50% HPMC, (e) 65% EC/35% HPMC, (f) 80% EC/20% HPMC, and (g) 100% EC.

in a single solvent system, including 100% EC in IPA and 100% HPMC in water, were smooth and continuous without noticeable surface features (images not shown). Smooth and continuous films were also observed for 100% HPMC in the IPA/water cosolvent system (73.5% IPA/26.5% water), as shown in Figure 4g. However, the polymer films prepared from the 100% EC solution in the same cosolvent system showed domain structures and polymer aggregation (Figures 4a and 5a). In the IPA/water cosolvent system, EC dissolves in IPA but not in water, while HPMC dissolves in water but not in IPA. Since the boiling point of IPA (82.3 °C) is lower than that of water (100 °C), IPA has a faster evaporation rate than water during the spin-coating process. For the 100% EC polymer solution in the IPA/water cosolvent system, the faster evaporation of IPA resulted in EC aggregation because EC was insoluble in the remaining water solvent, forming the taller domain structures on surface. Similarly, (26) Muller-Buschbaum, P.; Gutmann, J. S.; Wolkenhauer, M.; Kraus, J.; Stamm, M.; Smilgies, D.; Petry, W. Solvent-Induced Surface Morphology of Thin Polymer Films. Macromolecules 2001, 34, 1369-1375. (27) Muller-Buschbaum, P.; Stamm, M. Correlated Roughness, Long-Range Correlations, and Dewetting of Thin Polymer Films. Macromolecules 1998, 31, 3686-3692. (28) Birnie, D. P. Rational solvent selection strategies to combat striation formation during spin coating of thin films. J. Mater. Res. 2001, 16 (4), 11451154.

Spin-Coated Films of EC and HPMC Blends

Figure 7. AFM surface plots of 65% EC/35% HPMC films prepared from 2 wt % solutions: (a) without heating (∼23 °C), scan area 5 µm × 5 µm; and (b) substrate heated at ∼45 °C during spin coating, scan area 20 µm × 20 µm.

for the EC/HPMC blend solutions in the IPA/water cosolvent system, during the spin coating, EC aggregation was observed because not only EC was insoluble in the remaining water but also EC was incompatible with HPMC.3 For the 100% HPMC polymer solution in a cosolvent system, HPMC was soluble in the remaining water as IPA evaporated prior to water. As a result, smooth and continuous HPMC films were formed. For single solvent systems such as 100% EC in IPA and 100% HPMC in water, no solubility issue was involved during the spin-coating process; thus smooth and continuous films were observed. Temperature Effect. As shown in Figure 1, similar surface morphology was observed for the samples prepared without heating and with heating applied after spin coating, suggesting that the surface morphology was fixed and not affected by applied temperatures such as 50 and 100 °C after spin coating. Since the applied temperatures were below the glass transition temperatures of both polymers (131.5 °C for EC and 153.5 °C for HPMC),29 it was not a surprise that no surface structure change was observed. However, a previous study3 showed that the essential morphological features of the EC/HPMC films remained unaltered even if a temperature of 200 °C that was well above the glass transition temperatures of both polymers was applied after the films were prepared. This confirmed that the morphologies obtained after film preparation were near-equilibrium ones and polymer incompatibility was due to thermodynamic incompatibility of the two polymers.3 The effect of temperature during spin coating on the surface structure was also investigated. Figure 6 shows the photomicrographs of EC/HPMC films prepared from 2 wt % solutions with different polymer compositions at a temperature of ∼45 °C during spin coating. The surface structure of the films was compared with those in Figure 4 that were prepared at room (29) Sakellariou, P.; Rowe, R. C.; White, E. F. T. The solubility parameters of some cellulose derivatives and polyethylene glycols used in tablet film coating. Int. J. Pharm. 1986, 31, 175-177.

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temperature (∼23 °C, no heating throughout sample preparation). Both heated and nonheated 100% HPMC films showed a smooth continuous surface without noticeable surface features (Figures 4a and 6a). For polymer films that prepared from solutions with 20% and 35% EC, no significant differences were observed from optical microscopy between heated (Figure 6b,c) and nonheated samples (Figure 4b,c), probably due to a low degree of phase separation and low resolution of the images. However, for films prepared from polymer solutions with more than 50% EC, substantial differences in surface morphology were observed between heated (Figure 6d-g) and nonheated samples (Figure 4d-g). In addition, although phase separation was observed for both heated and nonheated samples, different extents and patterns of phase separation were observed. The surface structure of the heated and nonheated films was also examined and compared using AFM to show the temperature effect during spin coating. Figure 7a shows the AFM surface plot of 65% EC/35% HPMC polymer films prepared without heating (∼23 °C). As discussed in previous sections (Figures 2-5), the island features in Figure 7a were identified to be EC and the low-lying areas were identified to be HPMC. Figure 7b shows the AFM surface plot of 65% EC/35% HPMC polymer films prepared at ∼45 °C, and a pitted surface structure was observed. The diameters of the pits ranged between 2 and 6 µm, and the depth of the pits varied between 400 and 600 nm. Again, Raman spectroscopy was employed to identify the nature of the different surface structures. The Raman spectra of polymer films in Figure 7b are shown in Figure 8. The red cross-hairs in the video images (Figure 8a,b) indicate the exact spots where Raman

Figure 8. Raman spectra of 65% EC/35% HPMC film spin-coated on glass coverslip at ∼45 °C. (a) Video image of the spot focused on a pit on the surface, (b) video image of the spot focused on taller continuous matrix structure, and (c) Raman spectra of (from top to bottom) pure EC, continuous matrix structure, pitted structure, and pure HPMC.

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spectra were collected. The Raman spectra in Figure 8c from top to bottom are pure EC reference, taller continuous matrix structure, pitted structure, and pure HPMC reference, respectively. Figure 8c shows that the spectrum of the pit was similar to that of pure HPMC reference, while the spectrum of the taller continuous matrix structure was similar to that of pure EC reference, indicating that the taller continuous matrix structures on the surface were EC and pitted structures were HPMC. AFM images (not shown) were also obtained for other films shown in Figure 6. For the films prepared from 100% EC, the heated film showed a much more continuous EC layer on the surface with less substrate exposure than the nonheated films. The pitted structure was also observed in the heated 80% EC/20% HPMC film. However, AFM images for 35% EC/65% HPMC and 20% EC/80% HPMC films showed no significant differences between heated and nonheated samples. In general, for both heated and nonheated samples, the EC components in the EC/HPMC films were taller features than the HPMC components. With or without heating, IPA has a faster evaporate rate than water. It is expected that aggregation happens first for EC to form taller structures because EC is insoluble in water and incompatible with HPMC. When heating was applied during the spin coating, with the presence of IPA and enough EC (e.g., 65% or higher) on the surface, the migration of EC on the surface might be enhanced to form a continuous structure, resulting a pitted surface structure. As shown above, different preparation conditions such as polymer composition, solvent, and temperature have significant impact on the surface structure of the EC/HPMC films. When the films are used as coatings for controlled solid dosage forms, the drug release profile is directly related to the surface structure of the films (e.g., phase separation and different domain features). Therefore, controlling the preparation conditions enables us to

Lua et al.

control the surface structure of the films, and thus allows us to control the drug release profile. For example, as a tablet coating, the HPMC component of an EC/HPMC film will be leached away when the tablet is exposed to water, creating open holes for the drug to release to the media. How much HPMC has and how HPMC distributes in the film directly affect the film structure after exposure. This work provides basic understanding of how the surface structure of the EC/HPMC films is correlated with the preparation conditions. Future work may include how the films change their structures when exposed to different media and how drug release profiles are related to the structures.

Conclusions The surface structures of the EC/HPMC films prepared by spin coating at various conditions were characterized. Different domain structures such as islands or pits and phase separation between EC and HPMC were observed for the EC/HPMC films by optical microscopy and AFM. The nature of different polymers on the surface was identified by Raman mapping and spectroscopy. The polymer composition and solvent showed significant effects on the surface morphology. Although heating showed no effect on the surface structure after spin coating, it had a significant impact on the surface structure when it was applied during spin coating. Acknowledgment. The authors thank Mark A. Smith and Thomas J. Thamann for their assistance with the optical microscope and Raman spectrometer. We also thank Diane Goll for providing EC and HPMC samples and instructions on sample preparations. Review of the manuscript by Bruno C. Hancock is also appreciated. LA0629680