Evaporative Precipitation Into Aqueous Solution Research Articles

Effects of nanosuspension and inclusion complex techniques on the in vitro protease inhibitory activity of naproxen

This study investigated the effects of nanosuspension and inclusion complex techniques on in vitro trypsin inhibitory activity of naproxen—a member of the propionic acid derivatives, which are a group of antipyretic, analgesic, and non-steroidal anti-inflammatory drugs. Nanosuspension and inclusion complex techniques were used to increase the solubility and anti-inflammatory efficacy of naproxen. The evaporative precipitation into aqueous solution (EPAS) technique and the kneading methods were used to prepare the nanosuspension and inclusion complex of naproxen, respectively. We also used an in vitro protease inhibitory assay to investigate the anti-inflammatory effect of modified naproxen formulations. Physiochemical properties of modified naproxen formulations were analyzed using UV, IR spectra, and solubility studies. Beta-cyclodextrin inclusion complex of naproxen was found to have a lower percentage of antitryptic activity than a pure nanosuspension of naproxen did. In conclusion, nanosuspension of naproxen has a greater anti-inflammatory effect than the other two tested formulations. This is because the nanosuspension formulation reduces the particle size of naproxen. Based on these results, the antitryptic activity of naproxen nanosuspension was noteworthy; therefore, this formulation can be used for the management of inflammatory disorders.

Paclitaxel nanosuspensions coated with P-gp inhibitory surfactants: I. Acute toxicity and pharmacokinetics studies

PurposeThe aim of the present study was to evaluate the acute toxicity and pharmacokinetics of paclitaxel nanosuspensions stabilized with TPGS in mice. MethodThe paclitaxel nanosuspensions were prepared by evaporative precipitation into aqueous solution (EPAS) method, and freeze-dried powders of the nanosuspensions were obtained through lyophilization process. The morphology and particle size of nanosuspensions were determined by transmission electron microscope and Zetasizer, respectively. The acute toxicity and pharmacokinetics of paclitaxel nanosuspensions after intravenous administration to Kunming mice were studied. A marketed paclitaxel injectable solution was studied parallelly. ResultsThe paclitaxel nanoparticles were in rod shape under transmission electron microscope, and their mean particle size was 135.4±5.7nm. Results of acute toxicity showed the LD50 of paclitaxel nanosuspensions was 98.63mg/kg, twice more than that of the marketed injection (41.46mg/kg). After intravenous injection paclitaxel nanosuspensions displayed different pharmacokinetic properties in comparison with the marketed injectable solution, including a decreased initial drug concentration, increased plasma half-life, AUC and MRT. ConclusionsThe paclitaxel nanosuspensions prepared in this study could markedly enhance the tolerance dosage in mice, and manifest different pharmacokinetic properties compared with the solution.

Comparison of different methods for preparation of a stable riccardin D formulation via nano-technology

Riccardin D is a new compound extracted from liverwort Marchantia polymorpha L. It has been proved to be useful in antifungal therapy and reversing the resistance of Candida albicans against fluconazole. However, the poor solubility leads to the poor bioavailability and limits its development. In this study, nanocrystals were prepared in the evaporative precipitation into aqueous solution (EPAS) and the microfluidisation process. The characterizations of nanocrystals were compared by transmission electron microscope, size distribution, and zeta potential. In the EPAS method, the drug was dissolved in the organic phase and F68, HPMC, PVP K30 were dissolved in water with the mass ratio of 2:1:2:1. In the microfluidisation process, two key factors – pressure and number of cycles were screened and 8 cycles at 2000 bar was the most efficient parameter. The nanocrystals made in EPAS process were smaller, more uniform and had a narrower distribution than the microfluidisation nanocrystals. Differential scanning calorimetry (DSC) and X-ray diffraction confirmed the crystalline states that were both reserved. The solubility was greatly improved by the two methods and the EPAS nanocrystals were more soluble due to the smaller size. An enhanced dissolution was obvious in vitro. And the stable nanocrystals were successfully achieved by the two methods.

Preparation of a chemically stable quercetin formulation using nanosuspension technology

In the present study the evaporative precipitation into aqueous solution (EPAS) process and the high homogenization press (HPH) process were compared to evaluate their feasibility to form a chemically stable quercetin nanosuspension. The particle size and Zeta potential of the EPAS nanosuspension were similar to those of the HPH nanosuspension. Differences in results of differential scanning calorimetery and X-ray measures were observed between the two processes. The crystalline-to-amorphous phase transition was shown in the profile of EPAS dried powder. On the contrary the initial crystalline state of drug was maintained throughout the HPH process. Dissolution test results indicated that the EPAS process showed a higher improvement in the drug solubility and dissolution rate than the HPH process. At last the High performance liquid chromatography (HPLC) analysis proved the superiority of both nanosuspensions over QCT solution formulation for the chemical and photo-stability. As a result, it can be concluded that the EPAS and HPH techniques were feasible to prepare a chemically stable QCT nanosuspension with significantly enhanced dissolution rate.

Cryogenic liquids, nanoparticles, and microencapsulation

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.

Ketoprofen nanoparticle gels formed by evaporative precipitation into aqueous solution

AbstractAqueous 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

Supersaturation Produces High Bioavailability of Amorphous Danazol Particles Formed by Evaporative Precipitation into Aqueous Solution and Spray Freezing into Liquid Technologies

ABSTRACTThe bioavailability of high surface area danazol formulations was evaluated in a mouse model to determine what effect high supersaturation, as measured in vitro, has on the absorption of a poorly water soluble drug. Danazol, a biopharmaceutics classification system II (BCS II) compound, was used as the model drug. Evaporative precipitation into aqueous solution (EPAS) and spray freezing into liquid (SFL) technologies were used to prepare powders of danazol/PVP K-15 in a 1:1 ratio. The evaporative precipitation into aqueous solution (EPAS) and SFL compositions, physical mixture and commercial product were dosed by oral gavage to 28 male Swiss/ICR mice for each arm of the study. Samples were taken at time points ranging from 0.5 to 24 h. Pooled mouse serum was analyzed for danazol by high performance liquid chromatography (HPLC). Powders were analyzed for their ability to form supersaturated solutions through dissolution at concentrations of 1 mg/mL which was the dose delivered to the mouse models. Spray freezing into liquid (SFL) and EPAS compositions displayed higher Cmax at 392.5 ng/mL and 430.1 ng/mL, respectively, compared to the physical mixture (204.4 ng/mL) and commercially available danazol (199.3 ng/mL). The Tmax for all compositions studied was near the 1 h time point. The area under the curve (AUC) for the SFL composition was 2558 ng.h/mL compared to EPAS composition at 1534 ng.h/mL. The area under the curve (AUC) for the physical mixture and commercially available danazol were 672 ng.h/mL and 1519 ng.h/mL, respectively. The elimination rate constants for the EPAS composition, SFL composition, and physical mixture were similar at ∼0.15 h−1 where as the commercially available danazol capsules displayed an elimination rate constant of 0.103 h−1. The extent of danazol absorption in the mouse model was higher for SFL composition compared to the less amorphous EPAS composition, physical mixture, and commercially available danazol powders. Both EPAS and SFL compositions were able to form supersaturated solutions. However, the SFL composition displayed a supersaturation of 33% above control and was able to maintain supersaturation for 90 min compared to the EPAS composition (27% supersaturation above control for 60 min). Through the use of a testing method for supersaturation, it was found that EPAS and SFL compositions achieve higher apparent solubilities when compared to the physical mixture and commercially available danazol capsules. Because of the greater extent of dissolution of the SFL composition, the bioavailability was enhanced in a mouse model.

Stabilizer choice for rapid dissolving high potency itraconazole particles formed by evaporative precipitation into aqueous solution

The objective of this study was to investigate the influence of stabilizer type on the physicochemical properties, including dissolution, of ultra-high potency powders containing itraconazole (ITZ) formed by evaporative precipitation into aqueous solution (EPAS). ITZ was dissolved in dichloromethane, which was then atomized through a heated coil at 80 °C into an aqueous solution over precise periods of time. Stabilizers were present in either the aqueous, organic or both phases. The dispersions were centrifuged and the supernatant was removed. Three hydrophilic stabilizers were investigated, including polysorbate 80, polyvinyl pyrrolidone and poloxamer 407. Rapid dissolving ultra-high potency of ITZ powders was successfully produced. Greater than 80% of ITZ was dissolved in 5 min compared to only 13% of ITZ bulk powders. The resulting stabilizer-coated drug particles had high drug-to-stabilizer ratios greater than 12, corresponding to potencies (wt drug/wt drug + wt surfactant) as high as 93%. An increase in dissolution rate was correlated with the amount of stabilizer adsorbed and the wettability. The combination of polysorbate 80 and poloxamer 407 present in the aqueous and organic phases, respectively, was superior in achieving high wetting and rapid dissolving ITZ powders. The ability to control the adsorption behavior of stabilizers by using synergistic combinations affords the opportunity to achieve high dissolution rates with higher potencies compared to previously reported values.

Comparison of powder produced by evaporative precipitation into aqueous solution (EPAS) and spray freezing into liquid (SFL) technologies using novel Z-contrast STEM and complimentary techniques

The objective of this study was to compare the properties of particles formed by nucleation and polymer stabilization (e.g. evaporative precipitation into aqueous solution (EPAS)) versus rapid freezing (e.g. spray freezing into liquid (SFL)). Powders formed by EPAS and SFL, composed of danazol and PVP K-15 in a 1:1 ratio, were characterized using X-ray powder diffraction, modulated differential scanning calorimetry (MDSC), contact angle determination, dissolution, scanning electron microscopy (SEM), environmental scanning electron microscopy (ESEM), BET specific surface area, and Z-contrast scanning transmission electron microscopy (STEM). Large differences in particle morphologies and properties were observed and explained in terms of the particle formation mechanisms. Both techniques produced amorphous powders with high T g and low contact angle values. However, STEM analysis showed highly porous bicontinuous nanostructured 30 nm particles connected by narrow bridges for SFL versus aggregated 500 nm primary particles for EPAS. The combination of STEM and other characterization techniques indicates solid solutions were formed for the SFL powders consistent with rapid freezing. In contrast, the EPAS particle cores are enriched in hydrophobic API and the outer surface is enriched in the hydrophilic polymer, with less miscibility than in the SFL powders. Consequently, dissolution rates are faster for the SFL particles, although both techniques enhanced dissolution rates of the API.

Rapid Dissolution of High‐Potency Danazol Particles Produced by Evaporative Precipitation into Aqueous Solution

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 ∼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. © 2004 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1867–1878, 2004

Rapid dissolution of high potency itraconazole particles produced by evaporative precipitation into aqueous solution

High potency itraconazole crystalline particles with high dissolution rates were produced by evaporative precipitation into aqueous solution (EPAS). Aqueous suspensions formed by EPAS were centrifuged and the free non-adsorbed surfactant was removed with the supernatant to raise the active pharmaceutical ingredient (API)-to-surfactant ratio. The API-to-surfactant ratios of the resulting surfactant-stabilized API particles ranged from 0.9:1 to 3.7:1, corresponding to potencies from 47 to 79%. A conical nozzle was found to produce PVP K-15 and Pluronic F127- stabilized itraconazole particles with high surface areas up to 9 m 2 /g. The high surface areas along with the wettability due to PVP and Pluronic F127 led to high dissolution rates with ~ 90% API dissolved in 10 min.

Preparation of cyclosporine A nanoparticles by evaporative precipitation into aqueous solution.

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.

Enhanced drug dissolution using evaporative precipitation into aqueous solution.

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.