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ABSTRACT: Aqueous suspensions of crystalline naproxen nanoparticles, formed by antisolvent precipitation, were flocculated with sodium sulfate, filtered, and dried to form redispersible powders for oral delivery. The particles were stabilized with polyvinylpyrrolidone (PVP K-15) and/or poly(ethylene oxide-b-propylene oxide-b-ethylene oxide) (poloxamer 407). The yield of the drug in the powder was typically 92-99%, and the drug loading was reproducible to within 1-2%. The filtration process increased the drug loading by up to 61% relative to the initial value, as unbound surfactant was removed with the filtrate. Upon redispersion of the dried powder, the average particle size measured by light scattering was comparable to the original value in the aqueous suspension prior to flocculation, and consistent with primary particle sizes observed by scanning electron microscopy (SEM). For 300-nm particles, up to 95% of the drug dissolved in 2 min. The dissolution rate was correlated linearly with the specific surface area calculated from the average particle diameter after redispersion. The redispersion of dried powders was examined as a function of the salt concentration used for flocculation and the surfactant composition and concentration. Flocculation followed by filtration and drying is an efficient and highly reproducible process for the rapid recovery of drug nanoparticles to produce wettable powders with high drug loading and rapid dissolution.
Drug Development and Industrial Pharmacy 10/2008; 35(3):283-96. · 1.49 Impact Factor
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ABSTRACT: The biopharmaceutical classification system (BCS) is used to group pharmaceutical actives depending upon the solubility and permeability characteristics of the drug. BCS class II compounds are poorly soluble but highly permeable, exhibiting bioavailability that is limited by dissolution. The dissolution rate of BCS class II drug substances may be accelerated by enhancing the wetting of the bulk powder and by reducing the primary particle size of the drug to increase the surface area. These goals may be achieved by nucleating drug particles from solution in the presence of stabilizing excipients. In the spray freezing into liquid (SFL) process, a drug containing solution is atomized and frozen rapidly to engineer porous amorphous drug/excipient particles with high surface areas and dissolution rates. Aqueous suspensions of nanostructured particles may be produced from organic solutions by evaporative precipitation into aqueous solution (EPAS). The suspensions may be dried by lyophilization. The particle size and morphology may be controlled by the type and level of stabilizers. In vivo studies have shown increased bioavailability of a wide variety of drugs particles formed by SFL or EPAS. For both processes, increased serum levels of danazol (DAN) were observed in mice relative to bulk DAN and the commercial product, Danocrine. Orally dosed itraconazole (ITZ) compositions, formed by SFL, produce higher serum levels of the drug compared to the commercial product, Sporanox oral solution. Additionally, nebulized SFL processed ITZ particles suspended in normal saline have been dosed via the pulmonary route and led to extended survival times for mice inoculated with Aspergillis flavus. SFL and EPAS processes produce amorphous drug particles with increased wetting and dissolution rates, which will subsequently supersaturate biological fluids in vivo, resulting in increased drug bioavailability and efficacy.
International Journal of Pharmaceutics 11/2006; 324(1):43-50. · 3.35 Impact Factor
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ABSTRACT: Aqueous nanoparticle gels of a poorly-water soluble drug, ketoprofen, were produced by evaporative precipitation into aqueous solution (EPAS). Liquid droplets of surfactant stabilized ketoprofen containing residual solvent were dispersed in water from 60 to 90°C below the melting point of pure ketoprofen. The carboxylic acid group in ketoprofen dissociates in pure water, providing electrostatic stabilization of the droplets to complement steric stabilization. Stable amorphous ketoprofen particles with a mean size of 135 nm, measured by dynamic light scattering, were formed with only 0.1% w/v poloxamer 407, resulting in an exceptionally high drug-to-surfactant ratio of 10:1. For 5% w/v poloxamer 407, interactions with ketoprofen produced a bluish, transparent gel composed of ∼50 nm particles. In 2 min, 98% of the ketoprofen in the gel nanoparticles dissolved. The favorable interactions between the ketoprofen and poloxamer 407, along with the electrostatic and steric stabilization, lead to gelation, which further stabilizes the unusually small particles. The rapidly dissolving wet gels with extremely small particle sizes, one month stability, and relatively low viscosities, are of interest in transdermal and parenteral delivery; furthermore, the gels may be dried for oral delivery. © 2006 American Institute of Chemical Engineers AIChE J, 2006
AIChE Journal 04/2006; 52(7):2428 - 2435. · 2.26 Impact Factor
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ABSTRACT: High-potency danazol particles with high dissolution rates were produced by evaporative precipitation into aqueous solution (EPAS). Aqueous suspensions formed by EPAS were centrifuged to remove the nonadsorbed surfactant. The resulting surfactant-coated drug particles had extremely high drug-to-surfactant ratios greater than 5, corresponding to potencies (wt drug/wt drug + wt surfactant) as high as 93%. The mechanism of the high dissolution rates was characterized as a function of surfactant adsorption, particle size and surface area, drug crystallinity, and the contact angle for water on the drug surface. For danazol stabilized by polyvinyl pyrrolidone (PVP) alone or with sodium lauryl sulfate (SLS), small particle diameter and high surface area led to high dissolution rates with approximately 90% drug dissolved in 2 min. The crystallinity of the danazol was typically 80%. The properties of the particles and the dissolution rates were mostly unchanged under a 2-week thermal cycling stress test.
Journal of Pharmaceutical Sciences 08/2004; 93(7):1867-78. · 3.06 Impact Factor
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ABSTRACT: A new process, evaporative precipitation into aqueous solution (EPAS) has been developed to coat poorly water soluble drugs, in this case carbamazepine, with hydrophilic stabilizers to enhance dissolution rates. A heated organic solution of the drug in dichloromethane is sprayed though a fine nozzle into a heated aqueous solution. The rapid evaporation of the organic solvent produces high supersaturation and rapid precipitation of the drug in the form of a colloidal suspension that is stabilized by a variety of low molecular weight and polymeric surfactants. The stabilizer adsorbs to the drug surface and prevents particle growth and crystallization during the spray process. The suspensions are dried by spray drying or ultra-rapid freezing. The high dissolution rates are a consequence of the following advantages of the EPAS process: a small primary particle size, a hydrophilic coating on the particles that enhances wetting, and low crystallinity.
International Journal of Pharmaceutics 09/2002; 243(1-2):17-31. · 3.35 Impact Factor
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ABSTRACT: Amorphous nanoparticle suspensions of a poorly water-soluble drug, cyclosporine A, are produced by a new process, evaporative precipitation into aqueous solution (EPAS). The rapid evaporation of a heated organic solution of the drug, which is atomized into an aqueous solution, results in fast nucleation leading to nanoparticles suspensions. Hydrophilic stabilizers, introduced in the organic or aqueous phases, limit particle growth and inhibit crystallization for drug concentrations as high as 35 mg/ml, and drug/surfactant ratios up to 1.0. The suspensions may be used in parenteral formulations to enhance bioavailability or may be dried to produce oral dosage forms with the potential for high dissolution rates due to the low crystallinity, small particle size and hydrophilic stabilizer that enhances wetting.
International Journal of Pharmaceutics 09/2002; 242(1-2):3-14. · 3.35 Impact Factor
