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Langmuir 2007, 23, 5148-5153
Inhibiting Surface Crystallization of Amorphous Indomethacin by Nanocoating Tian Wu, Ye Sun, Ning Li, Melgardt M. de Villiers, and Lian Yu* School of Pharmacy, UniVersity of Wisconsin-Madison, 777 Highland AVenue, Madison, Wisconsin 53705-2222 ReceiVed January 8, 2007. In Final Form: February 9, 2007 An amorphous solid (glass) may crystallize faster at the surface than through the bulk, making surface crystallization a mechanism of failure for amorphous pharmaceuticals and other materials. An ultrathin coating of gold or polyelectrolytes inhibited the surface crystallization of amorphous indomethacin (IMC), an anti-inflammatory drug and model organic glass. The gold coating (10 nm) was deposited by sputtering, and the polyelectrolyte coating (3-20 nm) was deposited by an electrostatic layer-by-layer assembly of cationic poly(dimethyldiallyl ammonium chloride) (PDDA) and anionic sodium poly(styrenesulfonate) (PSS) in aqueous solution. The coating also inhibited the growth of existing crystals. The inhibition was strong even with one layer of PDDA. The polyelectrolyte coating still permitted fast dissolution of amorphous IMC and improved its wetting and flow. The finding supports the view that the surface crystallization of amorphous IMC is enabled by the mobility of a thin layer of surface molecules, and this mobility can be suppressed by a coating of only a few nanometers. This technique may be used to stabilize amorphous drugs prone to surface crystallization, with the aqueous coating process especially suitable for drugs of low aqueous solubility.
Introduction Amorphous solids (glasses) are advantageous over their crystalline counterparts for many applications.1 Amorphous drugs, for example, are more soluble than their crystalline forms, a property useful for delivering drugs whose bioavailability is limited by their poor solubility.2-4 For any amorphous material, the stability against crystallization is essential because crystallization negates its advantages. Of special interest in this context is the role of surface crystallization in relation to bulk crystallization. Recent studies found that the surface not only can initiate heterogeneous nucleation5-7 but also can accelerate crystal growth.8 For amorphous indomethacin (IMC), a nonsteroid antiinflammatory drug and model organic glass,9-11 the rate of crystal growth at the free surface is at least 2 orders of magnitude faster than that through the bulk below the glass transition temperature Tg.8 Our previous study of amorphous IMC8 found that its surface crystallization could be inhibited if the material remained in contact with a silicate glass (microscope cover glass). This result suggests that the surface crystallization might be linked to the higher molecular mobility at the free surface and might be preventable by a coating. The existence of a mobile surface layer over an amorphous solid has been suggested. For example, gold clusters deposited on the surface of amorphous polystyrene * Corresponding author. Telephone: (608) 263-2263. Fax: (608) 2625345. E-mail:
[email protected]. (1) Zallen, R. The Physics of Amorphous Solids; John Wiley & Sons: New York, 1983. (2) Kaushal, A. M.; Gupta, P.; Bansal, A. K. Crit. ReV. Ther. Drug Carrier Syst. 2004, 21, 133-193. (3) Hancock, B. C.; Zografi, G. J. Pharm. Sci. 1997, 86, 1-12. (4) Yu, L. AdV. Drug DeliVery ReV. 2001, 48, 27-42. (5) Zanotto, E. D. Ceram. Trans. 1993, 30, 65-74. (6) Diaz-Mora, N.; Zanotto, E. D.; Hergt, R.; Muller, R. J. Non-Cryst. Solids 2000, 273, 81-93. (7) Wittman, E.; Zanotto, E. D. J. Non-Cryst. Solids 2000, 271, 94-99. (8) Wu, T.; Yu, L. Pharm. Res. 2006, 23, 2350-2355. (9) Imaizumi, H.; Nambu, N.; Nagai, T. Chem. Pharm. Bull. 1980, 28, 25652569. (10) Yoshioka, M.; Hancock, B. C.; Zografi, G. J. Pharm. Sci. 1994, 83, 1700-5. (11) Wu, T.; Yu, L. J. Phys. Chem. B 2006, 110, 15694-15699.
become embedded at as low as Tg -50 °C.12,13 Surface mobility in amorphous 3-methylpentane is detected at as low as Tg -50 °C.14 A mobile surface layer is responsible for the preparation of the exceptionally stable glass of IMC by vapor deposition.15 These findings suggest that an amorphous drug, whose Tg is typically below 60 °C, has a solid-like interior but a liquid-like surface at normal storage temperatures. The high surface mobility may be a general source of instability for amorphous drugs. There is evidence that the highly mobile surface layer is only a few nanometers. Only the top few nanometers of a 3-methyl pentane glass has significantly lower viscosity than the bulk.14 A nanometer-thick mobile surface layer over amorphous 1,3bis(1-naphthyl)-5-(2-naphthyl)benzene is inferred from the interfacial sharpness of isotope-labeled multilayers prepared by vapor deposition.15 The small thickness of the mobile surface layer suggests that it could be immobilized by contact with a substrate or coating, which converts liquid-like molecules at the free surface to solid-like molecules in the bulk. Indeed, if amorphous 3-methylpentane contacts a solid substrate [Pt(111)14 or porous silica16], the molecular mobility at the interface becomes lower than that in the bulk. The embedding temperature of gold clusters into amorphous polystyrene rises sharply with the amount of gold deposited, indicating that even nanometer-size gold clusters (not enough to make a continuous film) can substantially reduce the surface mobility.12,13 The small thickness of the mobile surface layer suggests that it could be immobilized by an ultrathin coating. This way of stabilizing an amorphous drug would complement the method of uniformly dispersing the drug in a polymer17,18 and might require only a small amount of the coating (12) Weber, R.; Zimmermann, K.-M.; Tolan, M.; Stettner, J.; Press, W.; Seeck, O. H.; Erichsen, J.; Zaporojtchenko, V.; Strunskus, T.; Faupel, F. Phys. ReV. E 2001, 64, 061508-1-5. (13) Weber, R.; Grotkopp, I.; Stettner, J.; Tolan, M.; Press, W. Macromolecules 2003, 36, 9100-9106 (14) Bell, R. C.; Wang, H.; Iedema, M. J.; Cowin, J. P. J. Am. Chem. Soc. 2003, 125, 5176-5185. (15) Swallen, S.; Kearns, K.; Mapes, M.; McMahon, R.; Kim, S.; Ediger, M.; Yu, L.; Wu, T.; Satija, S. Science 2007, 315, 353-356. (16) Richert, R.; Yang, M. J. Phys. Chem. B 2003, 107, 895-898. (17) Imaizumi, H.; Nambu, N.; Nagai, T. Chem. Pharm. Bull. 1983, 31, 25102512.
10.1021/la070050i CCC: $37.00 © 2007 American Chemical Society Published on Web 03/31/2007
Inhibiting Surface Crystallization by Nanocoating
Figure 1. Molecular structures of IMC, PDDA, and PSS.
material. Herein, we demonstrate that a 10 nm gold coating or 3-20 nm polyelectrolyte coating inhibits the surface crystallization of amorphous IMC and improves its wetting and flow. The polymer coating of this study was formed by a layerby-layer (LbL) assembly of oppositely charged polyelectrolytes through electrostatic attraction.19 Anionic and cationic polyelectrolytes can be alternatingly adsorbed onto the surface of a material, forming a multilayer with molecular precision. Such coating has been applied to drugs,20-22 enzymes,23 paper fibers,24 and in principle any material that bears a net charge and is not exceedingly soluble in coating solutions. The method has been used to coat crystalline IMC for controlled release,25,26 but has not been used to coat amorphous IMC to improve its stability against crystallization. Materials and Methods Indomethacin [1-(p-chlorobenzoyl)-5-methoxy-2-methylindole3-acetic acid, 99+%, IMC, γ polymorph] was obtained from Sigma (St. Louis, MO) and used as received. Amorphous IMC was prepared by melting IMC at 175 °C for 5 min and quenching to 22 °C. Poly(dimethyldiallyl ammonium chloride) (PDDA, MW 100 000200 000, 20 wt % in water) was obtained from Sigma (St. Louis, MO), and sodium poly(styrenesulfonate) (PSS, MW 70 000) was from Alfa Aesar (Ward Hill, MA). Unused solutions of PDDA or PSS might be stored at 4 °C for up to a week. Figure 1 shows the molecular structures of IMC, PDDA, and PSS. A Denton Vacuum Desk II (Denton Vacuum, Moorestown, NJ) was used to deposit a gold coating on amorphous IMC. The condition used was 50 mTorr pressure, 45 mA current, and 30 s deposition time. Under this condition, the deposition rate was ca. 10 nm/30 s, and we estimate the thickness of the gold coating to be 10 nm. The gold coating was applied to a 15 µm thick amorphous IMC film (18) Crowley, K. J.; Zografi, G. Pharm. Res. 2003, 20, 1417-1422. (19) Lvov, Y.; Decher, G.; Moehwald, H. Langmuir 1993, 9, 481-6. (20) Ai, H.; Jones, S.; de Villiers, M. M.; Lvov, Y. M. J. Controlled Release 2003, 86, 59-68. (21) Pargaonkar, N.; Lvov, Y. M.; Li, N.; Steenekamp, J. H.; de Villiers, M. M. Pharm. Res. 2005, 22, 826-835. (22) Zahr, A. S.; de Villiers, M. M.; Pishko, M. V. Langmuir 2005, 21, 403410. (23) Shutava, T. G.; Kommireddy, D. S.; Lvov, Y. M. J. Am. Chem. Soc. 2006, 128, 9926-9934. (24) Zheng, Z.; McDonald, J.; Khillan, R.; Su, Y.; Shutava, T.; Grozdits, G.; Lvov, Y. M. J. Nanosci. Nanotechnol. 2006, 6, 624-32. (25) Ye, S.; Wang, C.; Liu, X.; Tong, Z. J. Controlled Release 2005, 106, 319-328. (26) Chen, Y.; Lin, X. J. Microencapsulation 2005, 22, 47-55.
Langmuir, Vol. 23, No. 9, 2007 5149 prepared on a round microscope cover glass attached to a metal stub. Once coated, the film was golden and reflective. Zeta potentials were measured with a ZetaSizer 3000HSA (Malvern Instruments, USA). Sample particles (ca. 5 mg) were dispersed in 0.01 M NaCl. The measurement was used to determine the surface charge of IMC and follow its reversal as a result of coating with polyelectrolytes of alternating charges. Each reported result was the average of three measurements. LbL Polyelectrolyte Coating. Zeta potential measurement showed that amorphous IMC bears negative charges in pure water, in accord with its pKa (4.5). Amorphous IMC is poorly soluble in water (25 µg/mL27), making aqueous medium suitable for coating. 2 mg/mL aqueous solution of PDDA was prepared by dissolving the polymer in Milli-Q water; the solution pH was 6.1. At this pH, PDDA (isoelectric point ) 12) is positively charged.21 2 mg/mL aqueous solution of PSS was prepared by dissolving the polymer in Milli-Q water; the solution pH was 6.4. At this pH, PSS (isoelectric point ) 1) is negatively charged. One set of experiments was performed with 15 µm thick amorphous IMC films on microscope cover glasses. Each film was prepared by melting 5 mg of γ IMC at 175 °C for 5 min between two microscope cover glasses, cooling the sample to 22 °C (Tg -20 °C), and gently removing one cover glass. To coat several films at once, they were loaded into a Teflon rack and immersed into the PDDA solution for 15 min. The samples were washed twice in Milli-Q water to remove the excess PDDA and immersed in the PSS solution. This procedure was repeated until the desired number of polymer layers was reached. The coated samples were left on a Whatman filter paper to remove the excess liquid on the slide and dried in vacuum (0.4 mTorr) at 22 °C for 3 h. To coat amorphous IMC particles, 100 mg of amorphous IMC (prepared by melt-quenching) was ground in a mortar with a pestle in the presence of 6 mL of the PDDA solution for 2 min. The suspension was transferred to a 1.5 mL Eppendorf tube and, 15 min later, centrifuged at 5000 rpm for 30 s (model 5145D, Eppendorf, Westbury, NY). The supernatant was removed, and the particles were washed twice with Milli-Q water. The PSS solution was then added to the sample to coat the second layer (coating time ) 5 min). The procedure was repeated until the desired number of layers was reached. To coat amorphous IMC particles with one layer of PDDA at a larger scale, 2 g of amorphous IMC was loaded into a cryogenic impact mill (model 6750, SPEX CertiPrep, Metuchen, NJ) and ground with an impact frequency of 10 Hz for 2 min with subsequent cooling provided by liquid nitrogen. The particles were sieved through to a 75 µm screen, transferred to a 200 mL beaker containing 100 mL of the PDDA solution, and kept in contact with the solution for 15 min. The suspension was filtered through #2 Whatman filter paper to remove the supernatant and washed with Milli-Q water. Vacuum was then applied to dry the particles for at least 3 h. TGA showed that, on heating to 150 °C, the weight loss of the resulting material was about 0.2%. X-ray powder diffraction (XRPD) was performed with a Bruker D8 Advance X-ray diffractometer, which was equipped with a Cu KR source (λ ) 1.54056 Å) operating at a tube load of 40 kV and 40 mA. The divergence slit size was 1 mm, the receiving slit was 1 mm, and the detector slit was 0.1 mm. Data were collected by a high-resolution Sol-X detector. Each sample was scanned between 2° and 40° (2θ) with a step size of 0.02° and a maximum scan rate of 3 s/step. The NIST standard SRM 1976 was used to check the instrument’s calibration and performance. Samples of small quantity were analyzed on a Si(510) zero-background holder. Polarized light microscopy (PLM) was performed with a Nikon Optiphot Pol 2 microscope equipped with an Olympus video camera. The video image was calibrated against a 1 mm stage micrometer (100 divisions). Differential scanning calorimetry (DSC) was conducted in crimped Al pans using a TA Instruments Q1000 unit under 50 mL/min N2 purge. (27) Hancock, B. C.; Parks, M. Pharm. Res. 2000, 17, 397-404.
5150 Langmuir, Vol. 23, No. 9, 2007 Contact angle measurement was performed at 22 °C and 70% RH using a method similar to that of Zografi and Tam.28 Ten microliters of Milli-Q water was deposited on the surface of an amorphous IMC film prepared on a microscope slide. The water droplet thus formed was about 3 mm in diameter. A side view of the droplet was recorded with a digital camera, and the contact angle was measured from the image (Image J 1.34 S). Each amorphous film was measured three times at different sites. Three samples were measured for each coating condition. To measure the angle of repose, an indicator of flowability,29 1.5 g of IMC powder (sieved through to a 75 µm screen) was poured through a funnel with a 9 mm inside diameter and with the outlet 1” above the receiving surface. To determine tapped density and compressibility, ca. 1.5 g of powder was poured into a 10 mL cylinder. The initial volume (V0) yielded the initial bulk density D0 (“fluff or poured bulk density”). The powder was then tapped for 5 min to obtain the final bulk volume (Vf) and the final bulk density Df (“equilibrium, tapped, or consolidated bulk density”). The % compressibility (Carr’s Index) was calculated from (Df - D0)/Df × 100, which is another measure of powder flowability (% compressibility higher than 40% is thought to indicate a non-flowing, cohesive powder; % compressibility lower than 28% is thought to indicate a fluid to free-flowing powder). The intrinsic dissolution rate (IDR) was measured using a USP Dissolution Apparatus II (rotating paddle, model RC-8D, Vanguard, Spring, TX) following standard procedures.30,31 250 mg of IMC powder was loaded into a 13 mm diameter steel shaft and compressed into a tablet under a force of 5500 lb for 30 s with a single-punch press (model 3890.1D10A00, Carver, Wabash, IN). Tablets without visible chipping or surface imperfection were used for dissolution measurement. Each tablet used for IDR measurement was coated on one side and around the rim with water-impervious shellac (clear nail polish) that contained as the primary ingredient tosylamide epoxy resin. Conditions of the IDR measurement: 500 mL of 0.1 M phosphate buffer (pH 7.2), 50 pm of paddle speed, 1 in. between the tablet and the paddle, and 37 °C. The sampling was every 2.5 min up to 15 min, every 5 min up to 30 min, and every 10 min up to 60 min. Each sample (2 mL) of the solution was drawn with a syringe and filtered through a 0.22 µm filter needle. Its concentration was determined via UV-visible spectrometry at 318 nm. The analyzed solution was returned to the dissolution vessel to maintain the constant volume. For each amorphous IMC material studied (with and without coating, with and without aging), the IDR measurement was performed six times with three independently prepared materials as described above. The standard curve for UVvisible spectrometry was obtained by measuring IMC solutions of known concentrations in 0.1 M PBS buffers (pH 7.2). The solubility of γ IMC at 37 °C in the same buffer was determined by measuring the concentration of a 2 mL solution equilibrated with excess γ IMC (shaken for 24-48 h until no change of absorbance).
Results and Discussion Our previous study found that an amorphous IMC film prepared between two microscope cover glasses does not crystallize for months below Tg (42 °C). Even in the presence of crystal seeds (introduced by partial melting of crystals and quenching), crystals grow slowly, at ca. 10-11.3 m/s at 40 °C (Tg -2 °C).8 In contrast, if one of the cover glasses is removed to expose a free surface, crystals appear in days at 40 °C, growing at 10-8.9 m/s in the γ polymorph and 10-9.8 m/s in the R polymorph during the first week.8 The crystals were found to be several micrometers thick by cross-sectioning. This result was repeated in this work. Figure 2a shows a typical film after 90 h at 40 °C; the round opaque (28) Zografi, G.; Tam, S. S. J. Pharm. Sci. 1976, 65, 1145-9. (29) Aulton, M. E. Pharmaceutics: The Science of Dosage Form Design; Churchil Livingstone: London, 2002. (30) Viegas, T. X.; Curatella, R. U.; Van Winkle, L. L.; Brinker, G. Pharm. Technol. North America 2001, 25, 44-53. (31) Mauger, J.; Ballard, J.; Brockson, R.; De, S.; Gray, V.; Robinson, D. Dissolution Technol. 2003, 10, 6-15.
Wu et al.
Figure 2. Effect of 10 nm gold coating on the surface crystallization of amorphous IMC. (a) Uncoated amorphous IMC on a 15 mm diameter microscope cover glass after 90 h at 40 °C. (b) Same as (a), but 7 days later. Gold-coated samples showed no crystals under the same conditions. (c) Crystals of γ IMC in a partially crystallized sample (as in (a)) coated with gold. (d) Same as (c), after 7 days at 40 °C. (e) Crystals of R IMC in a partially crystallized sample coated with gold. (f) Same as (c), after 7 days at 40 °C.
spots are IMC crystals on an otherwise transparent glass film. The crystals were birefringent. Figure 2b shows the same film after 11 days (7 days after Figure 2a); by then the crystals had grown larger. After 2 or 3 weeks, the surface was fully covered with crystals. In this study, we also confirmed that the surface crystallization is unlikely a result of moisture adsorption by repeating selected experiments in vacuum, which were previous done in desiccators.8 At 0.4 mTorr and 22 °C, the surface crystallization of amorphous IMC occurred similarly to that in the desiccated ambient air,8 showing the same rate of crystal growth. Figure 2c-f shows how 10 nm gold coating affected the surface crystallization of amorphous IMC. All samples were tested at 40 °C in a desiccator. A gold-coated surface of amorphous IMC showed no crystals in 3 weeks (the longest time of observation). Moreover, coating a partially crystallized sample with gold inhibited further crystallization. Figure 2c shows a region of γ IMC crystals in a sample that had been stored for 90 h (as the one in Figure 2a) and then coated with gold. After another 7 days, the crystals showed no observable growth (Figure 2d). Figure 2e shows a region of R IMC crystals in a sample that had been stored for 90 h (as the one in Figure 2a) and then coated with gold. After another 7 days, the crystals showed no observable growth (Figure 2f). Using 1 µm as the limit of optical resolution, we estimate the growth rate of crystals coated with gold to be 40%) to one easy-flowing. Figure 8 shows how a polyelectrolyte coating affected the intrinsic dissolution rate (IDR) of amorphous IMC. Because one layer of PDDA was nearly as effective as several layers of PDDA and PSS for inhibiting surface crystallization (Figure 4), our dissolution study was limited to materials coated with only one layer of PDDA. With the same protection against surface crystallization, thinner coatings are preferred to maximize the rate of dissolution. For this measurement, the IMC powder was compressed into 13 mm diameter tablets about 1.8 mm thick. For comparison, we also measured the IDR of γ IMC. Each data point in Figure 8 is the average of six measurements. For each sample of amorphous IMC (uncoated or coated), the six measurements were performed with three independently prepared materials (including melting, grinding, coating, and tableting). The solubility of γ IMC in 0.1 M PBS buffer pH 7.2 was determined to be 1.5 mg/mL, which far exceeds the IMC concentration reached during dissolution testing (Figure 8) and which ensured a sink condition for the IDR measurement. Similarly, we assume the IDR of amorphous IMC was measured under a sink condition. The tablet of amorphous IMC began crystallizing to R IMC in ca. 20 min in the dissolution medium. Consequently, each IDR reported (Table 2) was measured within the first 15 min of dissolution. Table 2 shows that the freshly made, uncoated amorphous IMC had an IDR 8.0 times that of the crystalline γ IMC (8.0
Table 2. Intrinsic Dissolution Rate (IDR) of Amorphous IMC without and with Nanocoating
IDR (mg/cm2/min)
uncoated
uncoated 2d
coated
coated 20 d
γ IMC
0.56 ( 0.12
0.10 ( 0.02
0.33 ( 0.09
0.29 ( 0.04
0.07 ( 0.02
Inhibiting Surface Crystallization by Nanocoating
IDRγ), but the IDR dropped to 1.4 IDRγ after 2 days of storage at 40 °C due to crystallization. The IDR of coated amorphous IMC was 4.7 IDRγ and decreased to 4.1 IDRγ after 20 days at 40 °C. Thus, the polymer coating decreased the IDR significantly, but the reduced IDR still greatly exceeded that of γ IMC. More importantly, the decrease of IDR due to crystallization was significantly slower for the coated material. For the material studied, the rate at which the IDR decreased due to crystallization was ca. 100-fold slower with coating than without coating. The decrease of IDR by one layer of PDDA, although expected, seems larger than the reported decrease of drug dissolution rate by LbL polyelectrolyte coatings. For example, coating crystalline particles of IMC with five layers of sodium alginate and chitosan reduced the fraction released from 100% to 80% in 20 min.25 Furosemide coated with 4-10 PSS/PDDA bilayers did not show significant slowdown of dissolution.20 These results suggest that an LbL polyelectrolyte coating of a few layers is unlikely to slow down dissolution so much to negate the solubility advantage of amorphous IMC over crystalline IMC. We note that our dissolution study differs from the previous studies in that we used compressed tablets (to measure the IDR), whereas the previous studies used loose powders. It is possible that the polymer coating on the drug particles not only served as a barrier to dissolution but also a binder of particles, which slowed dissolution. Further studies are needed to test this hypothesis. While both inhibited the surface crystallization of amorphous IMC, the gold coating (10 nm) was more effective than the LbL polyelectrolyte coatings (3-20 nm), as judged by testing at 40 °C. By the same test, the gold coating was as effective as the microscope cover glass (silicate glass) in direct contact with amorphous IMC for suppressing surface crystallization. Not enough is known about how the chemical composition of the coating or substrate affects its effectiveness to reduce surface mobility and crystallization, although the first effect to note is that contact with any of these materials suppressed the surface crystallization of amorphous IMC. With the inert metal gold, even isolated gold clusters on amorphous polystyrene (not enough to make a continuous film) substantially reduce the surface mobility.12,13 As a pharmaceutical coating, an LbL polyelectrolyte coating seems more appropriate than a gold coating. A gold coating is easily applied to flat surfaces but not around particles, the common form of pharmaceutical solids. The LbL process is
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suitable for coating particles because it is performed in solution. The use of aqueous coating solutions, moreover, is compatible with drugs of poor aqueous solubility. A possible disadvantage of the LbL process is the potential crystallization during processing (recall that crystallization occurred during the dissolution testing of amorphous IMC after 20 min). We are studying how to minimize the crystallization during processing.
Conclusions The surface crystallization of amorphous IMC was inhibited by contact with a 10 nm coating of gold, a 3-20 nm coating of polyelectrolytes PDDA and PSS prepared by the layer-by-layer method, or, as found earlier,8 a silicate glass (microscope cover glass). With the polyelectrolyte coating, one layer of PDDA was almost as effective as several layers of PDDA and PSS. The coating also suppressed the growth of existing crystals. The effect is consistent with the view that the surface crystallization of amorphous IMC results from the enhanced molecular mobility at the surface. This study suggests that the molecular mobility at the surface can be reduced with a coating only a few nanometers thick, which agrees with the conclusion that the mobile surface layer over an amorphous solid has comparable thickness.14,15 How this thin mobile layer of molecules enables the mass transport necessary to grow crystals to visible sizes and thickness, while bulk molecules are effectively frozen, deserves attention. With one layer of PDDA, the intrinsic dissolution rate of amorphous IMC was ca. 5 times that of the crystalline IMC, and the decrease of the intrinsic dissolution rate due to crystallization was ca. 100 times slower than that of uncoated amorphous IMC. The polyelectrolyte coating also improved the wetting and flow of amorphous IMC. The ultrathin polymer coating may be a general method to stabilize amorphous drugs prone to surface crystallization, with the aqueous coating process especially suitable for drugs of low aqueous solubility. Acknowledgment. We thank the University of WisconsinMadison, USDA, NSF (#0210298 “Nanoengineered Shells”), and NSF MRSEC for supporting this work, Walter Zeltner from Water Science and Engineering Technology at UW-Madison for his assistance in the zeta potential measurements, and Mark Ediger and George Zografi for helpful discussions. LA070050I
