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.
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.
Purpose. To recover polymer-stabilized amorphous nanoparticles from aqueous dispersions efficiently by salt flocculation and to show that the particles redisperse and dissolve rapidly to produce highly supersaturated solutions. Methods. Nanoparticle dispersions of itraconazole stabilized by nonionic polymers were formed by antisolvent precipitation and immediately flocculated with sodium sulfate, filtered and dried. The size after redispersion in water, crystallinity, and morphology were compared with those for particles produced by spray drying and rapid freezing. Results. Particle drug loading increased to similar to 90% after salt flocculation and removal of excess polymer with the filtrate. The formation of the flocs at constant particle volume fraction led to low fractal dimensions (open flocs), which facilitated redispersion in water to the original primary particle size of similar to 300 nm. Amorphous particles, which were preserved throughout the flocculation-filtration-drying process, dissolved to supersaturation levels of up to 14 in pH 6.8 media. In contrast, both spray dried and rapidly frozen nanoparticle dispersions crystallized and did not produce submicron particle dispersions upon addition to water, nor high supersaturation values. Conclusions. Salt flocculation produces large yields of high surface area amorphous nanoparticle powders that de-aggregate and dissolve rapidly upon redispersion in pH 6.8 media, for supersaturation levels up to 14.
Purpose. Highly stable, submicron lactate dehydrogenase (LDH) and lysozyme particles may be produced by thin film freezing (TFF) of aqueous solutions followed by lyophilization. Methods. The LDH activity was determined by measuring the decrease in absorbance of NADH over time for the reaction of pyruvate to lactate. For lysozyme the particle morphology was determined by scanning electron microscopy (SEM) and compared with the specific surface area (BET) and the particle size, as measured by laser light scattering, Results. Protein particles with an average diameter of 300 nm and 100% enzyme activity upon reconstitution (for LDH) were formed by TFF. Droplets of protein solutions, 3.6 mm in diameter, spread upon impact with 223 and 133 K metal surfaces to form cylindrical disks with thicknesses of 200-300 mu m. Calculated cooling rates of the disks of 10(2) K/s were confirmed experimentally with infrared measurements. Conclusions. The cooling rates of 10(2) K/s, intermediate to those in lyophilization (1 K/min) and spray freeze-drying (SFD) (10(6) K/s), were sufficiently fast to produce sub-micron protein particles with surface areas of 31-73 m(2)/g, an order of magnitude higher than in lyophilization. In addition, the low surface area/volume ratio (32-45 cm(-1)) of the gas-liquid interface led to minimal protein adsorption and denaturation relative to SFD.
Purpose. Solid dispersions containing various stabilizers and tacrolimus (TAC) prepared by an Ultra-rapid Freezing (URF) process were investigated to determine the effect on their ability to form supersaturated solutions in aqueous media and on enhancing transport across biological membranes. Materials and Methods. The stabilizers included poly(vinyl alcohol; PVA), poloxamer 407 (P407), and sodium dodecyl sulfate (SDS). In vivo absorption enhancement in rats was also investigated. Dissolution studies were conducted at supersaturated conditions in both acidic media for 24 h and at delayed release (enteric) conditions to simulate intestinal transit. Results. The rank order of C/Ceq(max) in the dissolution studies at acidic conditions was URF-P407 > URF-SDS > Prograf((R)) (PRO)> URF-PVA:P407. For C/Ceq(max) under enteric conditions, the order was URF-SDS > PRO > URF-PVA:P407 > URF-P407, and for the extent of supersaturation (AUC) in acidic and pH shift conditions it was URF-SDS > PRO > URF-PVA:P407 > URF-P407. The pharmacokinetic data suggests URF-P407 had the greatest absorption having higher C(max) with a 1.5-fold increase in AUC compared to PRO. All URF compositions had a shorter T(max) compared to PRO. Conclusions. The nanostructured powders containing various stabilizing polymers formed by the URF process offer enhanced supersaturation characteristics leading to increased oral absorption of TAC.
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.
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.
A nebulized dispersion of amorphous, high surface area, nanostructured aggregates of itraconazole (ITZ): mannitol: lecithin (1:0.5:0.2, w/w) yielded improved bioavailability in mice. The ultra-rapid freezing (URF) technique used to produce the nanoparticles was found to molecularly disperse the ITZ with the excipients as a solid solution. Upon addition to water, ITZ formed a colloidal dispersion suitable for nebulization, which demonstrated optimal aerodynamic properties for deep lung delivery and high lung and systemic levels when dosed to mice. The ITZ nanoparticles produced supersaturation levels 27 times the crystalline solubility upon dissolution in simulated lung fluid. A dissolution/permeation model indicated that the absorption of 3 mu m ITZ particles is limited by the dissolution rate (BCS Class II behavior), while absorption is permeation-limited for more rapidly dissolving 230 nm particles. The predicted absorption half-life for 230 turn amorphous ITZ particles was only 15 min, as a result of the small particle size and high supersaturation, in general agreement with the in vivo results. Thus, bioavailability may be enhanced, by decreasing the particle size to accelerate dissolution and increasing permeation with (I) an amorphous morphology to raise the drug solubility, and (2) permeability enhancers. (C) 2008 Elsevier B.V. All rights reserved.
A novel synthetic route to prepare polystyrene/SiO(2) composite microparticles in supercritical carbon dioxide (scCO(2)) is presented. Silica particles with the size of 130 nm which were surface-modified with 3-(trimethoxysilyl) propyl methacrylate were used as seeds in the dispersion polymerization of styrene in the presence of a polymeric stabilizer, poly(1,1-dihydroheptafluorobutyl methacrylate-co-diisopropylaminoethyl methacrylate) to produce dry composite particles. The transmission electron microscopy analysis revealed that the composite microspheres contained several silica particles.
Au nanocrystals stabilized by dodecanethiol were deposited into 100-150 run thick TiO2, films with evenly spaced perpendicular nanopillars and mesochannels oil the order of 10 nm supported oil conducting ITO/glass electrodes. Electrophoretic deposition was used to enhance nanocrystal deposition within the mesoporous TiO2 film. X-ray photoelectron spectroscopy (XPS), scanning electron microscopy with energy dispersive X-ray (EDX), UV-vis spectroscopy, variable-angle spectroscopic ellipsometry (VASE). and scanning Surface potential microscopy (SSPM) were used to characterize the resulting Au nanocrystal/ TiO, composites. Au nanocrystal loadings reached 21 wt % and were not kinetically limited at 10 min, relative to depositions performed for 20 h. Both VASE Measurements of the anisotropy of the imaginary refractive index, k, and X-ray photoelectron spectroscopy (XPS) depth profiling Studies indicate that Au nanocrystals are dispersed within the vertically aligned mesopores and distributed throughout the film. The mean penetration depth of a single nanocrystal penetrating inside the film is described with I model in terms of the electric field and a local deposition rate constant, which is influenced by ligand binding and architecture oil the nanocrystal surface.
Aqueous colloidal dispersions of amorphous cyclosporin A (CsA) nanoparticles, intended for pulmonary delivery, were formed by antisolvent precipitation and stabilized with 10% polysorbate 80. Dissolution of the dispersion of CsA nanoparticles produced supersaturation values 18 times the aqueous equilibrium solubility. Nebulization of the dispersion to mice produced therapeutic lung levels and systemic concentrations below toxic limits. The sizes of the aerosolized aqueous droplets are optimal for deep lung deposition, whereas the amorphous drug nanoparticles facilitate rapid dissolution. A dissolution/permeation model was developed to characterize the effects of particle size, solubility, and drug dose on the absorption half-lives of poorly water soluble drugs in the alveolar epithelium. For crystalline 3 mu m particles with a solubility of 1 mu g/mL, the half-life for absorption was estimated to be 500 min. The half-life may be reduced to less than I min by increasing the solubility by a factor of 100 with an amorphous form as well as by decreasing the particle size 10-fold. The in vitro and in vivo data, as well as the dissolution/permeation model, indicate that nebulization of amorphous nanoparticle suspensions has the potential to enhance lung epithelial absorption markedly for poorly water soluble drugs, relative to respiratory delivery of crystalline, micron-sized particles. (C) 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:4915-4933, 2008