Permeation of Naproxen from Saturated Solutions and Commercial Formulations Through Synthetic Membranes

Abstract

The release of naproxen through synthetic membranes, mounted in modified Franz-type diffusion cells, was evaluated, either from saturated solutions or from commercially available topical formulations containing 10% naproxen. The results obtained showed that the porous type synthetic membranes chosen (cellulose acetate and polyethersulphone) can be used for assessing product performance in quality control procedures. The formulations interacted with the solid membranes (silicone and EVA) to change their diffusional characteristics. However, transfer in the membrane, and not the formulation was rate controlling. These membranes could not therefore be used in assessing product release performance for quality control.     

Permeation of naproxen from saturated solutions and commercial formulations through synthetic membranes

The release of naproxen through synthetic membranes, mounted in modified Franz-type diffusion cells, was evaluated, either from saturated solutions or from commercially available topical formulations containing 10% naproxen. The results obtained showed that the porous type synthetic membranes chosen (cellulose acetate and polyethersulphone) can be used for assessing product performance in quality control procedures. The formulations interacted with the solid membranes (silicone and EVA) to change their diffusional characteristics. However, transfer in the membrane, and not the formulation was rate controlling. These membranes could not therefore be used in assessing product release performance for quality control.     

阿斯匹林配体与萘普生在水溶液中形成常数的研究

通过紫外分光光度法测定了阿斯匹林配体与萘普生在水溶液中,能够形成分子复合物,该复合物在25℃常压下的形成常数K11＝117．55,从而说明了阿斯匹林对萘普生在水溶液中的增溶作用的本质原因。     

2－芳基丙酸类消炎药合成中的重排反应

通过讨论缩酮结构、离去基活性和芳基迁移活性对重排反应的影响，总结了经重排反应合成２－芳基丙酸的一些规律，介绍了一条值得借鉴的不对称重排法合成萘普生的工艺路线     

Ozonation of NSAID: A Biodegradability and Toxicity Study

This work deals with the biodegradability and toxicity of three non-steroidal anti-inflammatory drugs (NSAID) (diclofenac, ibuprofen and naproxen) treated by ozonation. The results show that the total removal of 200 mg L^?1 of diclofenac and 100 mg L^?1 of naproxen is possible using an ozone dose of 0.20 and 0.04 g L^?1, respectively. For 200 mg L^?1 of ibuprofen, 90% removal is achieved using an ozone dose of 2.3 g L^?1. The BOD₅/COD ratio, the Zahn-Wallens test and EC₅₀ toxicity test (Microtox) are chosen as biological and toxicity indicators of NSAID intermediates. The evolution of BOD₅/COD ratio during 1 hour of treatment is evaluated and the results show that ozonation improves the biodegradability for the three NSAID treated solution. The Zahn-Wellens test for diclofenac and ibuprofen solutions shows that biological mineralization, after 28 days, is higher for diclofenac than for ibuprofen solution. According to the Microtox test, the treatment with ozone removes the toxicity of the naproxen solution. Taking into account the results obtained with the biocompatibility tests it could be assumed that ozonation is an adequate treatment for removal NSAID in aquatic medium, and the ozonated effluents could be post-treated in a biological wastewater facility.     

Wet nanomilling of naproxen using a novel stabilization mechanism via zirconium complexation

Using a novel electrostatic stabilization mechanism that utilizes complexation of Zr(IV) species by carboxylic acid groups at the particle surface, the true grinding limit of monocrystalline naproxen nanoparticles was identified at 30 nm under an optimized naproxen/Zr(IV)-salt formulation. In a stirred media mill, we studied the influence of stress energy and number of stress events by varying the milling bead diameter. Small milling beads provide a compromise between sufficiently high stress energy and stress number and are beneficial for nanomilling of naproxen in terms of grinding kinetics. It is shown that the product particle size can be controlled by adjusting the colloidal stability via the Zr(IV) concentration. Regardless of formulation properties, particle fracture propagates along the grain boundaries as revealed by crystallite size analysis. Investigations of the solvent phase and the particle geometry reveal that mechanical stress leads to enhanced solubility of the drug, which in return promotes recrystallization and thus particle growth. The solubility can be reduced by lowering the process temperature and stabilizer concentration. In contrast to inorganic nanoparticles, which are almost free of lattice imperfections at the true grinding limit, we find a clear indication of lattice strain in the stressed naproxen nanoparticles. Since the nanoparticle yield is still limited to 40% due to particle ripening, fast removal of the nanoparticles from the mill must be a further next step to be solved in nanoparticle processing.     

Investigation on influence of Wurster coating process parameters for the development of delayed release minitablets of Naproxen

The present work aims at studying process parameters affecting coating of minitablets (3?mm in diameter) through Wurster coating process. Minitablets of Naproxen with high drug loading were manufactured using 3?mm multi-tip punches. The release profile of core pellets (published) and minitablets was compared with that of marketed formulation. The core formulation of minitablets was found to show similarity in dissolution profile with marketed formulation and hence was further carried forward for functional coating over it. Wurster processing was implemented to pursue functional coating over core formulation. Different process parameters were screened and control strategy was applied for factors significantly affecting the process. Modified Plackett Burman Design was applied for studying important factors. Based on the significant factors and minimum level of coating required for functionalization, optimized process was executed. Final coated batch was evaluated for coating thickness, surface morphology, and drug release study.     

Modeling aspirin and naproxen ternary solubility in supercritical CO2/alcohol with a new Peng–Robinson EOS plus association model

A new version of the Peng–Robinson equation of state (PR EOS) is developed through the use of Wertheim's thermodynamic perturbation theory of associating fluids and statistical associating fluid theory (SAFT). The new equation is characterized by two temperature-independent parameters, namely, association strength and association volume, which account for the association interactions between associating molecules. In this work, we employed the equation to model aspirin and naproxen solubility enhancement obtained in the ternary supercritical CO₂/alcohol systems, where the original PR EOS has resulted in large and negative binary interaction parameters between the polar solute and polar cosolvent. Calculated results show that the Peng–Robinson EOS plus association model gives better performance to correlate these ternary solubility data over the ranges of temperature, pressure and cosolvent concentration investigated than its conventional form that uses temperature-dependent parameters.     

Adsorption characteristics of selected pharmaceuticals and an endocrine disrupting compound-Naproxen, carbamazepine and nonylphenol-on activated carbon

The adsorption of two representative pharmaceutically active compounds (PhACs) (naproxen and carbamazepine) and one endocrine disrupting compound (nonylphenol) were evaluated on two types of activated carbon. When determining their isotherms at environmentally relevant concentration levels, it was found that at this low concentration range (10-800 ng/L), removals of the target compounds were contrary to expectations based on their hydrophobicity. Nonylphenol (log K(ow) 5.8) was most poorly adsorbed, whereas carbamazepine (log K(ow) 2.45) was most adsorbable. Nonylphenol Freundlich isotherms at this very low concentration range had a much higher 1/n compared to isotherms at much higher concentrations. This indicates that extrapolation from an isotherm obtained at a high concentration range to predict the adsorption of nonylphenol at a concentration well below the range of the original isotherm, leads to a substantial overestimation of its removals. Comparison of isotherms for the target compounds to those for other conventional micropollutants suggested that naproxen and carbamazepine could be effectively removed by applying the same dosage utilized to remove odorous compounds (geosmin and MIB) at very low concentrations. The impact of competitive adsorption by background natural organic matter (NOM) on the adsorption of the target compounds was quantified by using the ideal adsorbed solution theory (IAST) in combination with the equivalent background compound (EBC) approach. The fulfilment of the requirements for applying the simplified IAST-EBC model, which leads to the conclusion that the percentage removal of the target compounds at a given carbon dosage is independent of the initial contaminant concentration, was confirmed for the situation examined in the paper. On this basis it is suggested that the estimated minimum carbon usage rates (CURs) to achieve 90% removal of these emerging contaminants would be valid at concentrations of less than 500 ng/L in natural water.     

Molecular dynamics simulation of the formation of pharmaceutical particles by rapid expansion of a supercritical solution

The formation of pharmaceutical particles by the rapid expansion of a supercritical solution is investigated by molecular dynamics simulation. As a pharmaceutical model substance naproxen, a pain reliever and anti-inflammatory drug, is used. The expansion process is modeled in the simulation method by stepwise increasing the size of the simulation box. Comparison with an accurate reference equation of state for the pure solvent carbon dioxide shows that the simulation system follows an adiabatic expansion path. The expansion of a solution of naproxen in supercritical carbon dioxide leads to a highly supersaturated system that starts to form particles. The nucleation and growth kinetics of this particle formation process is investigated and the effect on the particle structure is analyzed.