Publications

2008
M. E. Matteucci, Miller, M. A., Williams, R. O., and Johnston, K. P., “Highly Supersaturated Solutions of Amorphous Drugs Approaching Predictions from Configurational Thermodynamic Properties,” Journal of Physical Chemistry B, vol. 112, pp. 16675-16681, 2008. Publisher's VersionAbstract
Dissolution of pure solid itraconazole in metastable amorphous states was used to produce high supersaturation in low pH media. For a prewet dispersion of particles on the order of 1 mu m produced by antisolvent precipitation, an experimental supersaturation of 63 times the crystalline solubility was achieved. This experimental value approached the calculated value of 95 from the configurational free energy, G(conf), which was determined from modulated differential scanning calorimetry measurements. A high fragility, quantitatively determined by the fragility parameter, gamma(cp), is dependent on the configurational heat capacity, C(pconf), favoring a high G(conf) and thus high supersaturation. However, high fragility also increases the driving force for crystallization of the solid during dissolution. The relatively fragile prewet dispersions dissolved rapidly and produced high supersaturation without crystallizing, in contrast with much lower supersaturation values for slowly dissolving particles with low wetted-surface areas formed by spray drying or lyophilization of aqueous dispersions.
K. P. Johnston, Engstrom, J., Tam, J., Matteucci, M., Mazuski, A., Ma, L., Williams, R., Milner, T., and Feldman, M., “I&EC 19-Design of pharmaceutical nanoparticles for drug delivery,” Abstracts of Papers of the American Chemical Society, vol. 236, 2008. Publisher's VersionAbstract
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P. Sinswat, Overhoff, K. A., McConville, J. T., Johnston, K. P., and Williams, R. O., “Nebulization of nanoparticulate amorphous or crystalline tacrolimus - Single-dose pharmacokinetics study in mice,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 69, pp. 1057-1066, 2008. Publisher's VersionAbstract
Developing a pulmonary composition of tacrolimus (TAC) provides direct access to the graft in lung transplant offering the possibility of high drug levels. The objective of this study was to investigate the physicochemical and pharrnacokinetic characteristics of the nanostructured aggregates containing amorphous or crystalline nanoparticles of TAC produced by ultra-rapid freezing (URF). TAC and lactose (1:1 ratio; URF-TAC:LAC) and TAC alone (URF-TAC) were investigated for pulmonary delivery and compared to unprocessed TAC. X-ray diffraction (XRD) results indicated that URF-TAC was crystalline, whereas URF-TACLAC was amorphous. In vitro results revealed the superior physiochemical characteristics of both URF formulations cornpared to unprocessed TAC. The Surface area of URF processed TAC was higher (25-29 m(2)/g) than that of the unprocessed TAC (0.53 m(2)/g) and subsequently enhanced dissolution rates. In addition, URF- TAC:LAC displayed the ability to supersaturate in the dissolution media to about I I times the crystalline equilibrium solubility. Similar aerodynamic particle sizes of 2-3 mu m, and fine particle fraction between 70% and 75% were found in both formulations. The local and systemic pharmacokmetic studies in mice showed similar AUC((0-24)), higher C(max), and lower T(max), for the URF-TACLAC compared to the URF-TAC. Nanostructured aggregates containing amorphous or crystalline nanoparticles of TAC were demonstrated to be effectively delivered via nebulization, with similar in vitro and in vivo performances. (C) 2008 Elsevier B.V. All rights reserved.
G. Gupta, Patel, M. N., Ferrer, D., Heitsch, A. T., Korgel, B. A., Jose-Yacaman, M., and Johnston, K. P., “Stable ordered FePt mesoporous silica catalysts with high loadings,” Chemistry of Materials, vol. 20, pp. 5005-5015, 2008. Publisher's VersionAbstract
A new concept is presented to form catalysts by infusion of presynthesized bimetallic nanocrystals into ordered mesoporous supports. For presynthesized FePt nanocrystals (<4 nm) coated with oleic acid and oleylamine ligands in toluene, high loadings above 10 wt .% were achieved in 10 min. The strong metal-support interactions were favored by the low coverage of the weakly bound ligands. The nanocrystals were highly dispersed within the pores as indicated by HAADF-STEM and X-ray diffraction (XRD) and stable against sintering at 700 degrees C and desorption into polar and nonpolar solvents at room temperature. A phase transformation from a disordered phase (FCC) to ordered phase (FCT) was observed upon thermal annealing at 700 degrees C without sintering, as confirmed by convergent beam electron diffraction and XRD. The calcined FePt catalyst exhibited 6-fold higher catalyst activity (TOF = 30 s(-1)) than that of a commercial Pd-alumina catalyst for liquid I-decene hydrogenation and was stable for multiple reactions. The decoupling of nanocrystal synthesis and infusion provides exquisite control of the nanocrystal size, alloy structure, binding to the support and dispersibility within the pores, offering broad opportunities for enhanced catalyst activities, selectivities, and stabilities.
K. P. Johnston, Tam, J., Matteucci, M., Mazuski, A., and Williams, R. O., “I&EC 44-Design of pharmaceutical nanoparticles for enhanced therapeutics,” Abstracts of Papers of the American Chemical Society, vol. 235, 2008. Publisher's VersionAbstract
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S. S. Adkins, Hobbs, H. R., Benaissi, K., Johnston, K. P., Poliakoff, M., and Thomas, N. R., “Stable colloidal dispersions of a lipase-perfluoropolyether complex in liquid and Supercritical carbon dioxide,” Journal of Physical Chemistry B, vol. 112, pp. 4760-4769, 2008. Publisher's VersionAbstract
The technique of hydrophobic ion pairing was used to solubilize the lipase from Candida rugosa in a fluorinated solvent, perfluoromethylcyclohexane (PFMC), in complex with a perfluoropolyether (PFPE) surfactant, KDP 4606. The enzyme-surfactant complex was determined to have a hydrodynamic diameter of 6.5 nm at atmospheric pressure by dynamic light scattering (DLS), indicating that a single lipase molecule is stabilized by surrounding surfactant molecules. The complex formed a highly stable colloidal dispersion in both liquid and supercritical carbon dioxide at high CO(2) densities (>0.92 and 0.847 g/mL, respectively), with 4% by volume PFMC as a cosolvent, yielding a fluid that was orange, optically translucent, and very nearly transparent. DLS demonstrated aggregation of the enzyme-surfactant complexes in CO(2) at 25 and 40 degrees C and various pressures (2000-5000 psia) with hydrodynamic diameters ranging from 50 to 200 nm. The mechanism by which the enzyme-surfactant particles aggregate was shown to be via condensation due to very low polydispersities as characterized by the size distribution moments. Interparticle interactions were investigated with respect to density and temperature, and it was shown that on decreasing the CO? density, the particle size increased, and the stability against settling decreased. Particle size also decreased as the temperature was increased to 40 degrees C, at constant CO(2) density. Nanoparticle aggregates of an enzyme-surfactant complex in CO(2), which are nearly optically transparent and stable to settling, are a promising new alternative to previous types of dispersions of proteins in CO(2) that either required water/CO(2) microemulsions or were composed of large particles unstable to settling.
2007
M. E. Matteucci, Brettmann, B. K., Rogers, T. L., Elder, E. J., Williams, R. O., and Johnston, K. P., “Design of potent amorphous drug nanoparticles for rapid generation of highly supersaturated media,” Molecular Pharmaceutics, vol. 4, pp. 782-793, 2007. Publisher's VersionAbstract
Controlled precipitation produced aqueous nanoparticle suspensions of a poorly water soluble drug, itraconazole (ITZ), in an amorphous state, despite unusually high potencies (drug weight/ total weight) of up to 94%. Adsorption of the amphiphilic stabilizer hydroxypropylmethylcellulose (HPMC) at the particle-aqueous solution interface arrested particle growth, producing surface areas from 13 to 51 m(2)/g. Dissolution of the particles in acidic media yielded high plateau levels in supersaturation up to 90 times the equilibrium solubility. The degree of supersaturation increased with particle curvature, as characterized by the surface area and described qualitatively by the Kelvin equation. A thermodynamic analysis indicated HPMC maintained amorphous ITZ in the solid phase with a fugacity 90 times the crystalline value, while it did not influence the fugacity of ITZ in the aqueous phase. High surface areas led to more rapid and levels of supersaturation higher than those seen for low-surface area solid dispersions, which undergo crystallization during slow dissolution. The rapid generation of high levels of supersaturation with potent amorphous nanoparticles, containing small amounts of stabilizers oriented at the particle surface, offers new opportunities for improving bioavailability of poorly water soluble drugs.
Y. Li, Pham, J. Q., Johnston, K. P., and Green, P. F., “Contact angle of water on polystyrene thin films: Effects of CO2 environment and film thickness,” Langmuir, vol. 23, pp. 9785-9793, 2007. Publisher's VersionAbstract
We examine the contact angle of water droplets on polystyrene (PS) thin films of varying thicknesses supported by silicon wafers under both air and pressurized carbon dioxide (CO2) environments. At 23 degrees C, the contact angle is found to increase upon increasing CO2 pressure in the vapor regime and then levels off in the liquid CO2 regime. A macroscopic model based on Young’s equation and the geometric-mean method for interfacial tensions, and long-range van der Waals interactions, correctly predicts the trends and the magnitude of the contact angle dependence on pressure, although deviations occur at high CO2 activities. The contact angle was also found to depend on film thickness, h, when h was comparable to or smaller than 50 nm. Specifically, the contact angle decreases with decreasing PS film thickness. This behavior could be accounted for with the use of a model that incorporates the effects of film thickness, CO2 pressure, and the long-range van der Waals potential.
L. Meli, Li, Y., Lim, K. T., Johnston, K. P., and Green, P. F., “Templating of gold nanocrystals in micellar cores of block copolymer films,” Macromolecules, vol. 40, pp. 6713-6720, 2007. Publisher's VersionAbstract
Thin film functional hybrid materials composed of inorganic nanocrystals sequestered within a self-assembled template are important for a diverse range of applications, from sensors to device electronics. The properties of these materials can be "tailored" by control of composition over various length scales; the major processing challenges are associated with understanding and controlling external factors, such as confinement and interfacial interactions, that affect the self-organization process. Spin-cast polystyrene-b-poly(1,1’,2,2’-tetrahydroperflurooctyl methacrylate) (PS-b-PFOMA) diblock copolymer films can form a micellar structure, with a PFOMA core (PS corona), and are induced to undergo a transition by annealing in supercritical CO2; consequently, the PS segments form the core with a PFOMA corona. We show that functionalized Au nanocrystals, initially dispersed within the corona (the PS phase) of the micelles, follow the morphological inversion and become sequestered within the core, now composed of PS chains; the nanoparticles segregate primarily at the PS/PFOMA interface within the core. These inversion experiments were performed on nanocomposite films with thicknesses h <= 150 nm. Therefore, only one or two layers of micelles spanned the entire film. The nanoparticles were not distributed uniformly throughout the films but remained primarily near the substrate. Several competing factors determine the overall distribution of nanoparticles: the van der Waals interaction between nanoparticles and interfaces, favorable ligand-block enthalpic interactions, and the conformational entropy of the host chains.
J. A. Keagy, Li, Y., Green, P. F., Johnston, K. P., Weber, F., Rhoad, J. T., Busch, E. L., and Wolf, P. J., “CO2 promotes penetration and removal of aqueous hydrocarbon surfactant cleaning solutions and silylation in low-k dielectrics with 3 nm pores,” Journal of Supercritical Fluids, vol. 42, pp. 398-409, 2007. Publisher's VersionAbstract
CO2 promotes penetration and removal of aqueous surfactant cleaning solutions in methylsilsesquioxane (MSQ) low dielectric constant (k) films with 3 nm hydrophobic open pores. The films were characterized by mercury probe dielectric constant (k value) measurements and FTIR spectroscopy. Penetration of a solution of 2 wt.% polyoxyethylene 2,6,8-trimethyl-4-nonyl ether, 5b-C12E8, in H2O at ambient pressure increased the k value of etched and N-2/H-2 ashed JSR 5109 pMSQ from 2.5 to 7.6, indicating 68% of the total pore volume was filled with the solution. This level of penetration was corroborated by the OH peak at 3150-3560 cm(-1) and the CH3 peak (surfactant) at 2800-3000 cm(-1). Rapid removal of the surfactant solution was achieved by rinsing and drying with 10 mL/min supercritical carbon dioxide (scCO(2)) at 45 degrees C and 10 MPa for 2 min. Both water and surfactant are dissolved and emulsified into CO2. Nearly complete removal of the surfactant and water was observed in the k value, which dropped to 2.5, and in the OH and CH3 peak areas. In addition, the cleaning and drying steps may be integrated with silylation in CO2 to remove silanol groups and to add carbon to further reduce the k value. After rinsing and drying with CO2, silylation with 1 wt.% hexamethyldisilazane (HMDS) in CO2 at 45 degrees C and 10 MPa followed by annealing at 380 degrees C for 60 min led to a k value of 2.3, near the original value of 2.15. The ability of CO2 to lower the magnitude of the capillary pressure well below the total pressure facilitates removal of the surfactant solution during rinsing and drying. These results suggest that aqueous surfactant solutions, mixed with CO2, may offer significant advantages for cleaning and drying patterned low-k dielectric insulators, particularly as the feature size shrinks below 50nm and capillary forces become significant. (c) 2007 Elsevier B.V All rights reserved.
K. A. Overhoff, Moreno, A., Miller, D. A., Johnston, K. P., and Williams, R. O., “Solid dispersions of itraconazole and enteric polymers made by ultra-rapid freezing,” International Journal of Pharmaceutics, vol. 336, pp. 122-132, 2007. Publisher's VersionAbstract
The primary objective of the study is to investigate the influence of composition parameters including drug:polymer ratio and polymer type, and particle structure of enteric solid dispersions on the release of ITZ under sink and supersaturated dissolution conditions. Modulated differential scanning calorimetry (MDSC) was utilized to define the level of ITZ miscibility with each polymer. The compositions were completely miscible at 60% ITZ for both polymers and as high as 70% in HP-55. High potency composition glass transition temperatures (Tg) correlated with predicted Tg’s from the Gordon-Taylor equation, however, recrystallization exotherms revealed pure amorphous regions indicating that phase separation occurred during particle formation. Furthermore, in vitro studies including X-ray powder diffraction (XRD), scanning electron microscopy (SEM), surface area analysis (BET), and dissolution were performed to determine differences between low potency (completely miscible) and high potency (partially miscible) compositions. Dissolution studies on low potency ITZ compositions revealed that miscibility plays an active role in ITZ release under sink conditions, and square root diffusion through the enteric polymer is observed. Supersaturated dissolution profiles revealed high potency compositions had maximum saturation levels (C/C-eqmax) between 10.6- and 8-times equilibrium solubility, but had higher cumulative extents of supersaturation, compared to low potency compositions which had C/C-eqmax values of 15-19.6. However, these low potency compositions rapidly precipitated leading to significantly lower AUCs (p < 0.05). The change in the miscibility of the solid dispersion had a pronounced effect of drug release (sink) while differences in potency influenced supersaturated dissolution profiles. (C) 2006 Elsevier B.V. All rights reserved.
K. P. Johnston, Adkins, S., Chen, X., Dickson, J., Gupta, G., Patel, M., Milner, T., and Rossky, P. J., “Tuning liquid-llquid and liquid-solid interfaces with carbon dioxide,” Abstracts of Papers of the American Chemical Society, vol. 233, 2007. Publisher's VersionAbstract
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J. M. Vaughn, Wiederhold, N. P., McConville, J. T., Coalson, J. J., Talbert, R. L., Burgess, D. S., Johnston, K. P., Williams, R. O., and Peters, J. I., “Murine airway histology and intracellular uptake of inhaled amorphous itraconazole,” International Journal of Pharmaceutics, vol. 338, pp. 219-224, 2007. Publisher's VersionAbstract
Aerosolization of amorphous itraconazole may be a safe and effective method of pulmonary delivery. Our objective was to evaluate the histologic effects, immunogenic potential, and cellular uptake of aerosolized amorphous itraconazole. Mice received amorphous itraconazole (30 mg/kg), excipient placebo, or saline control by nebulization every 12 h for up to 12 days. Broncho-alveolar lavage (BAL) and formalin fixation of both lungs were conducted. BAL supernatant was assayed for IL-12 by ELISA, and cellular components were analyzed by high performance liquid chromatography-mass spectroscopy. Coronal sections of the entire lung were stained, viewed by light microscopy, and the Cimolai histopathologic inflammatory score was obtained for each lobe. No evidence of bronchiolar, peribronchiolar or perivascular inflammation was found in any treatment group, nor were epithelial ulceration or repair observed. The Cimolai histopathologic scores for amorphous itraconazole, excipient, and saline control on days 3 and 8 did not differ between groups. ELISA analysis showed no cytokine induction of IL-12. ltraconazole was detected within cells collected from BAL fluid on days 1, 3, 8 and 12. Aerosolized administration of amorphous itraconazole or excipients does not cause inflammation or changes in pulmonary histology and are not associated with pro-inflammatory cytokine production. (c) 2007 Elsevier B.V. All rights reserved.
Y. Li, Park, E. J., Lim, K. T. L., Johnston, K. P., and Green, P. F., “Role of interfacial interactions on the anomalous swelling of polymer thin films in supercritical carbon dioxide,” Journal of Polymer Science Part B-Polymer Physics, vol. 45, pp. 1313-1324, 2007. Publisher's VersionAbstract
It has recently been shown that thin polymer films in the nanometer thickness range exhibit anomalous swelling maxima in supercritical CO2 (Sc-Co-2) in the vicinity of the critical point of CO2. The adsorption isotherm of CO2 on carbon black, silica surfaces, porous zeolites, and other surfaces, is known to exhibit anomalous maxima under similar CO2 conditions. It is believed that because CO2 possesses a low cohesive energy density, there would be an excess amount of CO2 at the surfaces of these materials and hence the CO2/Polymer interface. This might cause excess CO2 in the polymer films near the free surface, and hence the swelling anomaly. In addition, an excess of CO2 would reside at the polymer/substrate and polymer/CO2 interfaces for entropic reasons. These interfacial effects, as have been suggested, should account for an overall excess of CO2 in a thin polymer film compared to the bulk, and would be responsible for the anomalous swelling. In this study, we use in situ spectroscopic ellipsometry to investigate the role of interfaces on the anomalous swelling of polymer thin films of varying initial thicknesses, h(o), exposed to Sc-CO2. We examined three homopolymers, poly(1,1’-dihydroperflurooctyl methacrylate) (PFOMA), polystyrene (PS), poly(ethylene oxide) (PEO), that exhibit very different interactions with SC-CO2, and the diblock copolymer of PS-b-PFOMA. We show that the anomalous swelling cannot be solely explained by the excess adsorption of CO2 at interfaces. (C) 2007 Wiley Periodicals, Inc.
C. A. Alvarez, Wiederhold, N. P., McConville, J. T., Peters, J. I., Najvar, L. K., Graybill, J. R., Coalson, J. J., Talbert, R. L., Burgess, D. S., Bocanegra, R., Johnston, K. P., and Williams, R. O., “Aerosolized nanostructured itraconazole as prophylaxis against invasive pulmonary aspergillosis,” Journal of Infection, vol. 55, pp. 68-74, 2007. Publisher's VersionAbstract
Objective: Prophylactic strategies against invasive pulmonary aspergillosis are often limited by drug interactions and toxicities. Targeted airway delivery of antifungals to the lungs may avoid these pitfalls. We evaluated the effectiveness of an aerosolized nanostructured formulation of itraconazole produced by spray freezing into liquid (SFL) as prophylaxis against invasive pulmonary aspergillosis caused by A. fumigatus. Methods: Immunocompromised Balb/C mice received either itraconazole by oral gavage (Sporanox Oral Liquid [SOL] 30 mg/kg TID) or by aerosolization (SFL 30 mg/kg via 20 min aerosolizations, or control, BID). Dosing began 2 days prior to pulmonary inoculation with A. fumigatus and continued for 7 days post-inoculation. Changes in lung histopathology were also assessed. In the survival arm, mice were monitored over a 5 day period following discontinuation of therapy and survival was assessed by Kaplan-Meier analysis. Results: SFL survival (35%) was greater compared to control (10%; p = 0.03) and SOL (10%; p = 0.02). Histopathology demonstrated severe invasive disease involving vessels and small airways in control and SOL animals. SFL animals demonstrated colonization with some invasion predominately of large airways. Conclusions: Prophylactic aerosolization of nanostructured SFL significantly improved survival and limited invasive disease of small airways due to A. fumigatus. (c) 2007 The British Infection Society. Published by Elsevier Ltd. All rights reserved.
Y. Li, Wang, X. C., Sanchez, I. C., Johnston, K. P., and Green, P. F., “Ordering in asymmetric block copolymer films by a compressible fluid,” Journal of Physical Chemistry B, vol. 111, pp. 16-25, 2007. Publisher's VersionAbstract
We examine the morphological structures of asymmetric poly(ethylene oxide)-b-poly(1,1’-dihydroperflurooctyl methacrylate) (PEO-b-PFOMA) thin films upon annealing in a compressible fluid, supercritical CO2 (Sc-CO2). The strong affinity between PFOMA and CO2 is found to induce phase segregation when annealing PEO-b-PFOMA films at the same temperature as compared with vacuum. In vacuum, PEO-b-PFOMA films remain disordered from 80 to 180 degrees C, whereas, in Sc-CO2 at 13.9 MPa, an upper order-disorder transition (UODT) between 116 and 145 degrees C is found. In Sc-CO2, the observed ordered structure is layers of PEO spheres embedded in the matrix of PFOMA, followed by a brush layer, in which PEO wets the substrate. The swelling isotherms of PFOMA and PEO in CO2 are correlated with the Sanchez-Lacombe equation of state (SLEOS) to estimate the interaction parameters, chi(PFOMA-CO2) and chi(PEO-CO2). The phase segregation (order) induced by CO2 relative to vacuum at a given temperature is explained in terms of two factors: (1) copolymer volume fraction upon dilution with CO2, phi, and (2) the relative interaction parameter, Delta chi = chi(PEO-CO2) - chi(PFOMA-CO2). The latter factor favors order and is dominant at low temperatures over the phi factor, which always favors disorder. At high temperatures (above the T-ODT), the preferential swelling of PFOMA by CO2 is less pronounced (Delta chi decreases), and the copolymer is disordered.
X. G. Zhang and Johnston, K. P., “Supercritical CO2-based solvents in next generation microelectronics processing,” Chinese Science Bulletin, vol. 52, pp. 27-33, 2007. Publisher's VersionAbstract
Large amount of chemicals and highly purified-water are needed in microelectronic manufacture. The ability of solutions to penetrate tiny spaces will become significantly more challenging as the feature size of semiconductor devices decreases to nanoscale dimensions and the functional complexity of integrated circuitries (ICs) ever increases. Supercritical fluids (SCFs) possess a unique combination of properties (no surface tension and gas-like viscosity) that can potentially be exploited for application in microelectronics manufacturing and processing in response to needs for material-compatible cleaning systems, small-dimension developing solvents, and low chemical-use processes. Recent microelectronics processes for cleaning and rinsing of patterned porous low-k dielectrics and drying of photoresist in CO2-based solvents are the main focus of this review. Additional topics in supercritical fluid processing include spin coating of photoresists, development with nanoscale dimensions, metal deposition and silylation.
P. G. Smith, Patel, M. N., Kim, J., Milner, T. E., and Johnston, K. P., “Effect of surface hydrophilicity on charging mechanism of colloids in low-permittivity solvents,” Journal of Physical Chemistry C, vol. 111, pp. 840-848, 2007. Publisher's VersionAbstract
Electrophoretic mobilities of TiO2 colloids in an apolar solvent, toluene, were measured by differential-phase optical coherence tomography (DP-OCT). An electrode spacing of 0.18 mm, made possible by optical coherence tomography with transparent electrodes, enables measurement of the electrophoretic mobility with small samples (20 mu L) of highly turbid colloids at low applied electric potential to avoid electrohydrodynamic instability and electrochemical reactions. In the presence of Aerosol-OT reverse micelles, which stabilized the countercharges, the zeta potential was positive for hydrophilic TiO2 (13 mV at 90 mM AOT) and negative for hydrophobic TiO2. The magnitudes of the zeta potentials were very similar for these two types of TiO2 and decreased at the same rate with AOT concentration. For both hydrophilic and hydrophobic TiO2, a general mechanism is presented to describe the zeta potential in terms of preferential partitioning of cations and sulfosuccinate anions between the particle surface and reverse micelle cores in bulk. This preferential partitioning is governed by the hydrophilicities and extents of the particle surfaces and reverse micelle cores, as a function of surfactant and water concentration. The emerging understanding of the complex charging and stabilization mechanisms for colloids in apolar solvents will be highly beneficial for the design of novel materials.
K. A. Overhoff, Engstrom, J. D., Chen, B., Scherzer, B. D., Milner, T. E., Johnston, K. P., and Williams, R. O., “Novel ultra-rapid freezing particle engineering process for enhancement of dissolution rates of poorly water-soluble drugs,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 65, pp. 57-67, 2007. Publisher's VersionAbstract
An ultra-rapid freezing (URF) technology has been developed to produce high surface area powders composed of solid solutions of an active pharmaceutical ingredient (API) and a polymer stabilizer. A solution of API and polymer excipient(s) is spread on a cold solid surface to form a thin film that freezes in 50 ms to 1 s. This study provides an understanding of how the solvent’s physical properties and the thin film geometry influence the freezing rate and consequently the final physico-chemical properties of URF-processed powders. Theoretical calculations of heat transfer rates are shown to be in agreement with infrared images with 10 ms resolution. Danazol (DAN)/polyvinylpyrrolidone (PVP) powders, produced from both acetonitrile (ACN) and tert-butanol (T-BUT) as the solvent, were amorphous with high surface areas (similar to 28-30 m(2)/g) and enhanced dissolution rates. However, differences in surface morphology were observed and attributed to the cooling rate (film thickness) as predicted by the model. Relative to spray-freezing processes that use liquid nitrogen, URF also offers fast heat transfer rates as a result of the intimate contact between the solution and cold solid surface, but without the complexity of cryogen evaporation (Leidenfrost effect). The ability to produce amorphous high surface area powders with submicron primary particles with a simple ultra-rapid freezing process is of practical interest in particle engineering to increase dissolution rates, and ultimately bioavailability. (c) 2006 Elsevier B.V. All rights reserved.
P. G. Smith, Patel, M. N., Kim, J., Johnston, K. P., and Milner, T. E., “Electrophoretic mobility measurement by differential-phase optical coherence tomography,” Journal of Physical Chemistry C, vol. 111, pp. 2614-2622, 2007. Publisher's VersionAbstract
We report the use of differential-phase optical coherence tomography (DP-OCT) for measurement of electrophoretic mobility in low-conductivity solvents. Weakly charged particles are common in low-permittivity solvents, particularly in practical applications that contain water as a result of ambient humidity. Use of DP-OCT with transparent electrodes enables close electrode spacing (0.18 mm) and thus high electric fields despite low applied electric potential, to avoid electrohydrodynamic instability and electrochemical interference. Further advantages include small sample volume requirement (20 mu L), the ability to analyze highly turbid colloids, and avoidance of electro-osmosis. This phase-sensitive method is demonstrated on weakly charged TiO2 particles dispersed in toluene with Aerosol-OT surfactant at a relatively high water content (50 mM), with small mobility of 2.8-3.0 x 10(-10) m(2)/V S ( potential 11-13 mV). Mobility is independent of applied field strength (28-56 kV/m). Measurement reproducibility is comparable to that by phase analysis light scattering (PALS) for dispersions in low-permittivity media. Capabilities of DP-OCT, including high sensitivity, high spatial resolution, and small detection volume, offer potential for significant expansion of the field of charged colloids in low-permittivity media.

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