Effect of O-acylmenthol and salt formation on the skin permeation of diclofenac acid

Purpose: To enhance the transdermal delivery of diclofenac acid (DA) by using O-acylmenthol as a penetration enhancer and complexing with amines, or by a combination of the two methods. Methods: The skin permeability of diclofenac was tested in vitro across rat skin with each of the evaluated permeants in a saturated isopropyl myristate (IPM) donor solution. Results: A 4.5-fold increase in the flux of diclofenac was observed by ion-pair formation with diethylamine; however, the cations with hydroxyl groups had negative effects on the transdermal delivery of diclofenac. 2-isopropyl-5-methylcyclohexyl 2-hydroxypanoate and 2-isopropyl-5-methylcyclohexyl heptanoate produced significant increase in the permeation of diclofenac potassium (D-K); however, both of them were ineffective for the other diclofenac salts, including diclofenac diethylamine (D-DETA), diclofenac ethanolamine (D-EA), diclofenac diethanolamine (D-DEA), diclofenac triethanolamine, and diclofenac N-(hydroxylethyl) piperidine. 2-isopropyl-5-methylcyclohexyl tetradecanoate was effective on the penetration of D-K, D-DETA, D-EA, and D-DEA. Also, it is exciting to note that the combined use of diethylamine with 2-isopropyl-5-methylcyclohexyl tetradecanoate produced a 9.74-fold increase in accumulation amount of diclofenac compared with DA in IPM. Conclusions: The use of ion pair in combination with O-acylmenthol is necessary to further increase the diclofenac flux to provide better compliance for the patients undergoing clinical therapy.     

Stability-indicating spectrophotometric and densitometric methods for determination of aceclofenac

Three methods were developed for the determination of aceclofenac in the presence of its degradation product, diclofenac. In the first method, third-derivative spectrophotometry (D₃) is used. The D₃ absorbance is measured at 283 nm where its hydrolytic degradation product diclofenac does not interfere. The suggested method shows a linear relationship in the range of 4-24 µg mL^-1 with mean percentage accuracy of 100.05±0.88. This method determines the intact drug in the presence of up to 70% degradation product with mean percentage recovery of 100.42±0.94. The second method depends on ratio-spectra first-derivative (RSD₁) spectrophotometry at 252 nm for aceclofenac and at 248 nm for determination of degradation product over concentration ranges of 4-32 µg mL^-1 for both aceclofenac and diclofenac with mean percentage accuracy of 99.81±0.84 and 100.19±0.72 for pure drugs and 100.17±0.94 and 99.73±0.74 for laboratory-prepared mixtures, respectively. The third method depends on the quantitative evaluation of thin-layer chromatography of aceclofenac using chloroform:methanol: ammonia (48:11.5:0.5 v/v/v) as a mobile phase. Chromatograms were scanned at 274 and 283 nm for aceclofenac and diclofenac, respectively. The method determined aceclofenac and diclofenac in concentration ranges of 2-10 and 1-9 µg spot^-1 with mean percentage accuracy of 100.20±1.03 and 100.14±0.98 for pure drugs and 99.77±0.74 and 100.07±0.78 for laboratory-prepared mixtures, respectively. This method retains its accuracy in the presence of up to 80% degradation product for the studied drug.

The suggested procedures were checked using laboratory-prepared mixtures and were successfully applied for the analysis of their pharmaceutical preparation. The validity of the proposed methods was further assessed by applying a standard addition technique. The obtained results agreed statistically with those obtained by the reported method.     

Effect of formulation composition on the properties of controlled release tablets prepared by roller compaction

This study discusses the effect of formulation composition on the physical characteristics and drug release behavior of controlled-release formulations made by roller compaction. The authors used mixture experimental design to study the effect of formulation components using diclofenac sodium as the model drug substance and varying relative amounts of microcrystalline cellulose (Avicel), hydroxypropyl methylcellulose (HPMC), and glyceryl behenate (Compritol). Dissolution studies revealed very little variability in drug release. The t₇₀ values for the 13 formulations were found to vary between 260 and 550 min. A reduced cubic model was found to best fit the t₇₀ data and gave an adjusted r-square of 0.9406. Each of the linear terms, the interaction terms between Compritol and Avicel and between all three of the tested factors were found to be significant. The longest release times were observed for formulations having higher concentrations of HPMC or Compritol. Tablets with higher concentrations of Avicel showed reduced ability to retard the release of the drug from the tablet matrix. Crushing strength showed systematic dependence on the formulation factors and could be modeled using a reduced quadratic model. The crushing strength values were highest at high concentrations of Avicel, while tablets with a high level of Compritol showed the lowest values. A predicted optimum formulation was derived by a numerical, multiresponse optimization technique. The validity of the model for predicting physical attributes of the product was also verified by experiment. The observed responses from the calculated optimum formulation were in very close agreement with values predicted by the model. The utility of a mixture experimental design for selecting formulation components of a roller compacted product was demonstrated. These simple statistical tools can allow a formulator to rationally select levels of various components in a formulation, improve the quality of products, and develop more robust processes.     

Physicochemical characterization of diclofenac sodium-loaded poloxamer gel as a rectal delivery system with fast absorption

Rectal poloxamer gel systems composed of poloxamers and bioadhesive polymers were easy to administer to the anus and were mucoadhesive to the rectal tissues without leakage after the dose. However, a poloxamer gel containing diclofenac sodium could not be developed using bioadhesive polymers, since the drug was precipitated in this preparation. To develop a poloxamer gel using sodium chloride instead of bioadhesive polymers, the physicochemical properties such as gelation temperature, gel strength, and bioadhesive force of various formulations composed of diclofenac sodium, poloxamers, and sodium chloride were investigated. Furthermore, the pharmacokinetic study of diclofenac sodium delivered by the poloxamer gel was performed. Diclofenac sodium significantly increased the gelation temperature and weakened the gel strength and bioadhesive force, while sodium chloride did the opposite. The poloxamer gels with less than 1.0% sodium chloride, in which the drug was not precipitated, were inserted into the rectum without difficulty and leakage, and were retained in the rectum of rats for at least 6 hr. Furthermore, poloxamer gel gave significantly higher initial plasma concentrations and faster T_max of diclofenac sodium than did solid suppository, indicating that drug from poloxamer gel could be absorbed faster than that from the solid one in rats. Our results suggested that a rectal poloxamer gel system with sodium chloride and poloxamers was a more physically stable, convenient, and effective rectal dosage form for diclofenac sodium.     

Electrocatalytic oxidation of some anti-inflammatory drugs on a nickel hydroxide-modified nickel electrode

The electrocatalytic oxidation of several anti-inflammatory drugs (mefenamic acid, diclofenac and indomethacin) was investigated on a nickel hydroxide-modified nickel (NHMN) electrode in alkaline solution. This oxidation process and its kinetics were studied using cyclic voltammetry, chronoamperometry, and electrochemical impedance spectroscopy techniques. Voltammetric studies indicated that in the presence of drugs, the anodic peak current of low-valence nickel species increases, followed by a decrease in the corresponding cathodic current. This pattern indicates that drugs were oxidized on the redox mediator immobilized on the electrode surface via an electrocatalytic mechanism. A mechanism based on the electrochemical generation of Ni(III) active sites and their subsequent consumption by drugs was also investigated. The corresponding rate law under the control of charge transfer was developed and kinetic parameters were derived. In this context, the charge-transfer resistance accessible both theoretically and through impedancemetry was used as a criterion. The rate constants of the catalytic oxidation of drugs and the electron-transfer coefficients are reported. A sensitive, simple and time-saving amperometric procedure was developed for the analysis of these drugs in bulk form and for the direct assay of tablets, using the NHMN electrode.     

Synthesis and Evaluation of a Nonsteroidal Anti-inflammatory Polymeric Prodrug for Sustained and Site-Specific Delivery

A new polymerizable drug derivative of diclofenac sodium was synthesized and characterized in terms of melting point, elemental analysis, and infrared spectroscopy. It was then polymerized to obtain a new polymeric prodrug. The prodrug was evaluated for its viscosity, drug content, and in vitro drug release behavior at pH 1.2 and 7.2. The in vitro studies showed that the drug release takes place predominantly at the higher pH and in a sustained manner, as hypothesized. Stability at room temperature, bioavailability, and ulcer-inducing effect of the polymeric prodrug were also studied. The investigations showed complete drug absorption from the polymeric prodrug with a statistically significant decrease in ulcer scoring effect, thus showing its potential for site-specific and sustained drug delivery.     

Computer-Assisted Determination of Reaction Parameters for the Simulation of Micropollutant Abatement in Wastewater Ozonation

For the purpose of the simulation of the kinetics of the reaction of ozone with wastewater in a bubble column, the kinetics can be adequately described by two components and their respective rate constants. Ozone uptake and ozone steady states along a bubble column have been determined. A modeling procedure has been developed that allows us to describe this behavior and to simulate the degradation of micropollutants. For fast (diclofenac) and moderately fast (bezafibrate) reacting micropollutants this model describes their measured elimination well.     

Solar radiation influence on the decomposition process of diclofenac in surface waters

Diclofenac can be detected in surface water of many rivers with human impacts worldwide. The observed decrease of the diclofenac concentration in waters and the formation of its photochemical transformation products under the impact of natural irradiation during one to 16 days are explained in this article. In semi-natural laboratory tests and in a field experiment it could be shown, that sunlight stimulates the decomposition of diclofenac in surface waters. During one day intensive solar radiation in middle European summer diclofenac decomposes in the surface layer of the water (0 to 5 cm) up to 83%, determined in laboratory exposition experiments. After two weeks in a field experiment, the diclofenac was not detectable anymore in the water surface layer (limit of quantification: 5 ng/L). At a water depth of 50 cm, within two weeks 96% of the initial concentration was degraded, while in 100 cm depth 2/3 of the initial diclofenac concentration remained. With the decomposition, stable and meta-stable photolysis products were formed and observed by UV detection. Beyond that the chemical structure of these products were determined. Three transformation products, that were not described in the literature so far, were identified and quantified with GC-MS.     

Heterogenous photocatalytic degradation kinetics and detoxification of an urban wastewater treatment plant effluent contaminated with pharmaceuticals

Degradation kinetics and mineralization of an urban wastewater treatment plant effluent contaminated with a mixture of pharmaceutical compounds composed of amoxicillin (10 mg L⁻¹), carbamazepine (5 mg L⁻¹) and diclofenac (2.5 mg L⁻¹) by TiO₂ photocatalysis were investigated. The photocatalytic effect was investigated using both spiked distilled water and actual wastewater solutions. The process efficiency was evaluated through UV absorbance and TOC measurements. A set of bioassays (Daphnia magna, Pseudokirchneriella subcapitata and Lepidium sativum) was performed to evaluate the potential toxicity of the oxidation intermediates. A pseudo-first order kinetic model was found to fit well the experimental data. The mineralization rate (TOC) of the wastewater contaminated with the pharmaceuticals was found to be really slow (t_1/2 = 86.6 min) compared to that of the same pharmaceuticals spiked in distilled water (t_1/2 = 46.5 min). The results from the toxicity tests of single pharmaceuticals, their mixture and the wastewater matrix spiked with the pharmaceuticals displayed a general accordance between the responses of the freshwater aquatic species (P. subscapitata > D. magna). In general the photocatalytic treatment did not completely reduce the toxicity under the investigated conditions (maximum catalyst loading and irradiation time 0.8 g TiO₂ L⁻¹ and 120 min respectively).