Anionic Diclofenac Research Articles

Sorption of structurally different ionized pharmaceutical and illicit drugs to a mixed-mode coated microsampler

The mixed-mode (C18/strong cation exchange-SCX) solid-phase microextraction (SPME) fiber has recently been shown to have increased sensitivity for ionic compounds compared to more conventional sampler coatings such as polyacrylate and polydimethylsiloxane (PDMS). However, data for structurally diverse compounds to this (prototype) sampler coating are too limited to define its structural limitations. We determined C18/SCX fiber partitioning coefficients of nineteen cationic structures without hydrogen bonding capacity besides the charged group, stretching over a wide hydrophobicity range (including amphetamine, amitriptyline, promazine, chlorpromazine, triflupromazine, difenzoquat), and eight basic pharmaceutical and illicit drugs (pKa>8.86) with additional hydrogen bonding moieties (MDMA, atenolol, alprenolol, metoprolol, morphine, nicotine, tramadol, verapamil). In addition, sorption data for three neutral benzodiazepines (diazepam, temazepam, and oxazepam) and the anionic NSAID diclofenac were collected to determine the efficiency to sample non-basic drugs. All tested compounds showed nonlinear isotherms above 1mmol/L coating, and linear isotherms below 1mmol/L. The affinity for C18/SCX-SPME for tested organic cations without Hbond capacities increased with longer alkyl chains, ranging from logarithmic fiber-water distribution coefficients (log Dfw) of 1.8 (benzylamine) to 5.8 (triflupromazine). Amines smaller than benzylamine may thus have limited detection levels, while cationic surfactants with alkyl chain lengths >12 carbon atoms may sorb too strong to the C18/SCX sampler which hampers calibration of the fiber-water relationship in the linear range. The log Dfw for these simple cation structures closely correlates with the octanol-water partition coefficient of the neutral form (Kow,N), and decreases with increased branching and presence of multiple aromatic rings. Oxygen moieties in organic cations decreased the affinity for C18/SCX-SPME. Log Dfw values of neutral benzodiazepines were an order of magnitude higher than their log Kow,N. Results for anionic diclofenac species (logKow,N 4.5, pKa 4.0, log Dfw 2.9) indicate that the C18-SCX fiber might also be useful for sampling of organic anions. This data supports our theory that C18-based coatings are able to sorb ionized compounds through adsorption and demonstrates the applicability of C18-based SPME in the measurement of freely dissolved concentrations of a wide range of ionizable compounds.

Intercalation of diclofenac in modified Zn/Al hydrotalcite-like preparation

The intercalation of a pharmaceutically active material diclofenac into modified Zn/Al Hydrotalcite-like (Zn/Al HTlc) preparation has been investigated by the coprecipitation and ion exchange method, respectively. The synthetic materials were characterized using X- Ray Diffraction (XRD); Fourier transforms infrared spectroscopy (FTIR); Scanning Electron Microscope (SEM); X-Ray Fluorescence (XRF) and surface area analyzer. The results show that the basal spacing of the product was expanded to 11.03 A for direct synthesis and 10.68 A for indirect synthesis, suggesting that diclofenac anion was intercalated into Zn/Al HTlc and arranged in a tilted bilayer fashion and the specific surface area of material increased after the intercalation of diclofenac.

Conductometric study of diclofenac salts in water at different temperatures

The conductivity of diclofenac alkali metal salts in water in the temperature range between 293.15 and 318.15K has been obtained experimentally. The values of the limiting molar conductivity of salts were calculated using the Lee–Wheaton equation in the version, introduced by Pethybridge. The limiting molar conductivity of the diclofenac anion was estimated, and the hydration number of diclofenac was calculated based on its values. The analysis of the activation energy of conductivity shows that the ion transport process in the systems under study is carried out mainly by the ion migration mechanism.

Sorption of amitriptyline and amphetamine to mixed-mode solid-phase microextraction in different test conditions

A solid-phase microextraction (SPME) method based on a sampler coating that includes strong cation groups (C18/SCX) is explored as a rapid direct sampling tool to detect and quantify freely dissolved basic drugs. Sampling kinetics, sorption isotherms and competitive effects on extraction yields in mixtures were tested for amphetamine and the relatively large/hydrophobic tricyclic antidepressant amitriptyline. Both compounds are >99% ionized at pH 7.4 but their affinity for the C18/SCX fiber is markedly different with distribution coefficients (Dfw values) of 2.49±0.02 for amphetamine and 4.72±0.10 for amitriptyline. Typical changes in electrolyte homeostasis that may occur in biomedical samples were simulated by altering pH and ionic composition (Na+ and K+ concentrations). These changes were shown to affect C18/SCX sorption affinities of the tested drugs with less than 0.2log units. At relatively low fiber loadings (<10mmol/L coating) and at all tested exposure times, linear sorption isotherms were obtained for both compounds but at aqueous concentrations of the individual drugs corresponding to concentrations in blood that are lethal, sorption isotherms became strongly nonlinear. Competition effects within binary mixtures occurred only if combinations of aqueous concentrations resulted in total fiber loadings that were in the nonlinear range of the SPME sorption isotherm for the individual compounds. We also compared sorption to the (prototype) C18/SCX SPME coating with analogue (biocompatible) C18 coated SPME fibers. C18/SCX fibers show increased sorption affinity for cationic compounds compared to C18 fibers, as tested using amitriptyline, amphetamine and trimethoprim. Surprisingly, sorption affinity of these ionized compounds for the C18 SPME fibers were within 1log unit of the C18/SCX SPME fibers. This shows that the strong cation exchange groups within the C18/SCX coating only has a relatively small contribution to the total sorption affinity of cationic compounds. Also the role of negatively charged silanol groups in both the C18 and C18/SCX coating seems small, as anionic diclofenac species sorbed strongly to the C18 fiber. Ionized organic species seem to be substantially adsorbed to the high surface area of C18 in SPME types using porous silica based coatings.

Controlled release of Diclofenac, an anti-inflammatory drug by nanocompositing with layered zinc hydroxide

The anti-inflammatory drug, Diclofenac (DIC) anion, was intercalated into the layered zinc hydroxide (LZH) by ion-exchange method. Then, the DIC–LZH/Chitosan nanocomposite was prepared by coating of Chitosan on DIC–LZH. LZH intercalated with DIC was successfully encapsulated into Chitosan by precipitation method. The structures of the obtained products were studied by powder X-ray diffraction, FT-IR spectroscopy, scanning electron microscopy, and thermal analysis. The XRD patterns and FTIR analyses showed that the DIC was successfully intercalated into the LZH interlayer space with an average basal spacing of 29.42 A. Thermal analysis studies confirmed that the thermal stability of DIC was enhanced after intercalation into LZH. In addition, drug release behaviors in vitro of DIC from DIC–LZH and DIC–LZH/Chitosan nanocomposites were observed in phosphate buffer solution under the conditions of pH 4.8 and 7.4, respectively.

Ruthenium(II) Complexes Containing Anti-Inflammatory Drugs as Ligands: Synthesis, Characterization andin vitroCytotoxicity Activities on Cancer Cell Lines

The synthesis, characterization and cytotoxic activity of cis-[Ru(dicl)(dppm)2]PF6 and cis-[Ru(ibu)(dppm)2]PF6, (dppm = 1,1-bis(diphenylphosphine)methane; dicl = diclofenac anion and ibu = ibuprofen anion), are described in this work. Complexes were characterized by elemental analysis, Fourier transform infrared spectroscopy (FTIR), UV-Vis, 31P{1H} nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRESIMS). X-ray structure of cis-[Ru(ibu)(dppm)2]PF6 is also described. Preliminary calf thymus DNA (ct-DNA) binding studies were carried out by UV-Vis and viscosity experiments, with results suggesting the existence of electrostatic interactions between ruthenium complexes and ct-DNA. Cytotoxicity assays were carried out on a panel of human cancer cell lines and a human normal cell line. Complexes displayed a high to moderate cytotoxicity with IC50 ranging from 5 to 47 µmol L-1. cis-[Ru(ibu) (dppm)2]PF6 was found to be the most active, with IC50 values lower than cisplatin. The degree of cytotoxicity was maintained for the normal cell line, although cis-[Ru(ibu)(dppm)2]PF6 exhibited a similar selectivity to that of cisplatin but with a higher activity for at least two tumor cell lines which evidences a promising anticancer candidate and selects this complex for further experiments.

Permanganate oxidation of diclofenac: The pH-dependent reaction kinetics and a ring-opening mechanism

In this work, the fate of diclofenac (DCF) during permanganate (Mn(VII)) oxidation was investigated at environmentally relevant pH conditions (from 5 to 9). The batch experiments showed that the kinetics of the Mn(VII)/DCF reaction follows a second-order rate law with an apparent rate constant of 1.57±0.02M−1s−1 at pH 7 and 20°C. The half-value of DCF was calculated to be 37.5min, when the concentration of Mn(VII) (0.4mM) was 20-fold excess of DCF. The pH-dependence of the reaction kinetics was investigated, and the DCF reactivity with Mn(VII) was found to decrease with increasing pH. The second-order rate constants were then quantitatively described by incorporating the species distribution of DCF. A lower reactivity of the anionic DCF (DCF−) in comparison with its neutral counterpart (DCF0) was most likely attributable to the interaction between the ionized carboxylate group and amine nitrogen position, which can reduce the nucleophilicity of amine nitrogen by inductive and resonance effects. Moreover, a range of degradation products and the corresponding structures were proposed on the basis of the LC–Q–TOF–MS analysis. A detailed ring-opening reaction mechanism was proposed as follows: Mn(VII) acts as an electrophile to attack the amine moiety, leading to the formation of the primary intermediate products 2,6-dichloroaniline and 5-hydroxy-diclofenac, which can be further transformed. The further degradation proceeded through a multistep process including ring-opening, decarboxylation, hydroxylation, and cyclation reactions.

New shell crosslinked micelles from dextran with hydrophobic end groups and their interaction with bioactive molecules.

Micelles formed in aqueous solution by dextran with hydrophobic (alkyl) end-groups were stabilized through divinyl sulfone crosslinking of the dextran shell. The efficacy of the crosslinking reaction was influenced by the divinyl sulfone amount, the pH and micelle concentration. Crosslinked micelles with a moderate crosslinking degree were further functionalized by attachment of 10 and 17 moles% N-(2-hydroxypropyl)-N,N-dimethyl-N-benzylammonium chloride groups along the dextran chain. The size and shape of both crosslinked micelles and their cationic derivatives were analyzed by DLS and TEM. The prepared micelles were able to bind anionic diclofenac (60-370 mg/g), hydrophobic anionic indometacin (70-120 mg/g), and hydrophobic alpha-tocopherol (170-220 mg/g) or ergocalciferol (90-110 mg/g) by hydrophobic or/and electrostatic forces. The release experiments and the antioxidant activity of bound alpha-tocopherol highlighted the potential of the new nano-sized micelles mainly as carriers for prolonged and controlled delivery of hydrophobic drugs.

Encapsulation of Diclofenac Molecules into Poly(ε‐Caprolactone) Electrospun Fibers for Delivery Protection

Mg‐Al Hydrotalcite‐like clay (LDH) intercalated with diclofenac anions (HTlc‐DIC) was introduced into poly(ε‐caprolactone) (PCL) in different concentrations by the electrospinning technique, and mats of nonwoven fibers were obtained and compared to the pristine pure electrospun PCL. The fibers, characterized by X‐ray diffraction, thermogravimetric analysis, and differential scanning calorimetry, show an exfoliated clay structure up to 3 wt%, a good thermal stability of the diclofenac molecules and a crystallinity of PCL comparable to the pure polymer. The scanning electron microscopy revealed electrospun PCL and PCL composite fibers diameters ranging between 500 nm to 3.0 μm and a generally uniform thickness along the fibers. As the results suggested the in vitro drug release from the composite fibers is remarkably slower than the release from the corresponding control spun solutions of PCL and diclofenac sodium salt. Thus, HTlc‐DIC/PCL fibrous membranes can be used as an antinflammatory scaffold for tissue engineering.

In Vivo Transdermal Delivery of Diclofenac by Ion-Exchange Iontophoresis with Geraniol

A novel iontophoretic system utilizing ion-exchange membranes is effective for selective transdermal delivery of ionized drugs. In the present study, we examined in vivo availability and safety of ion-exchange iontophoresis in the transdermal delivery of anionic diclofenac, a well known anti-inflammatory medication, to rat dorsal skin. While iontophoresis increased the plasma concentration of diclofenac sodium and skin injury was not observed, no anti-inflammatory effect was exerted. To enhance the efficiency of transdermal delivery of diclofenac sodium, iontophoresis was combined with topical application of one of three terpenes (menthol, nerolidol or geraniol) as chemical enhancers. By combining iontophoresis with geraniol, the plasma concentration of diclofenac sodium increased over 20-fold, and suppression of inflammation was achieved. Skin irritation was not seen even after 1.5 h iontophoresis. The enhancing effect of geraniol is attributed to increased penetration of the drug into the stratum corneum as well as enhanced transport across the anion-exchange membrane. Ion-exchange iontophoresis combined with geraniol is a highly effective transdermal delivery system.

Diclofenac Solubility: Independent Determination of the Intrinsic Solubility of Three Crystal Forms

The solubility in water of diclofenac ({2-[(2,6-dichlorophenyl)amino]phenyl}acetic acid), a potent nonsteroidal anti-inflammatory drug, has been investigated. The various solid forms have been characterized by thermogravimetric analysis, differential scanning calorimetry, and X-ray diffraction. The commercially available form of diclofenac is the anhydrous sodium salt. This was recrystallized from ethanol and precipitated as a hydrate containing four diclofenac anions, four sodium cations, and nineteen water molecules per unit cell. This crystal structure is similar to but different from an earlier report of the structure. Crystals of the acid form of diclofenac were anhydrous and corresponded to an earlier crystal structure. Separate solubility measurements on all three of these solid forms of diclofenac gave consistent results for the intrinsic solubility. The aqueous solubility values reported in the literature for diclofenac are spread over a large range, with a factor of 100 separating the largest and the smallest. Our value is at the smaller end of this range. It is the only one supported by three independent procedures and rigorous characterization of the solid forms. The experimental conditions were precisely controlled.

Enhanced Skin Permeation of Diclofenac by Ion-Pair Formation and Further Enhancement by Microemulsion

Enhancement of skin permeability of anionic diclofenac from non-aqueous vehicle isopropyl myristate (IPM) by ion-pair formation with either alkylamines or benzylamine as model cationic ions was examined in guinea pig dorsal skin. Diclofenac ion flux increased in the presence of these amines due to an increase in solubility. Maximum flux was observed in the presence of n-hexylamine, which induced 7.3-fold increase accompanied by a 45-fold increase in solubility. Permeability coefficients of the ionic form of diclofenac in the presence of benzylamine, n-hexylamine and iso-octylamine as counter ions in IPM were larger than those of the non-ionic form of diclofenac. Since the solubility of diclofenac was still limited, to obtain further enhancement of skin permeation, the effects of microemulsions as a vehicle consisting of phosphate buffered saline (PBS), isopropyl myristate (IPM), polyoxyethylene sorbitan monooleate (Tween 80) and ethanol were examined for transport of diclofenac-benzylamine ion-pairs. All microemulsion formulations tested increased diclofenac flux 4.9-fold to 10.7-fold over the value without a microemulsion accompanied by a 217-fold to 302-fold improvement in the solubility of diclofenac-benzylamine ion-pairs, but permeability coefficients were decreased 28-44 fold. Maximum enhancement was observed for a microemulsion with a ratio of PBS, IPM, ethanol and Tween 80 of 25 : 8 : 47 : 20 (w/w). The present findings suggest the usefulness of combined use of ion-pairs with microemulsions for enhancement of skin permeation of ionic drugs.

Studies on the encapsulation of diclofenac in small unilamellar liposomes of soya phosphatidylcholine

The encapsulation of acid (AD) and sodium diclofenac (SD) in small unilamellar liposomes (SUV) as well as the interactions of the drug with the bilayer was studied. SUV was prepared by sonication from multilamellar liposomes containing soya phosphatidylcholine and diclofenac at various proportions. The size distribution obtained from dynamic light scattering showed that the incorporation of SD decreases significantly the size of the liposomes suggesting that the drug interacts with the bilayer of the liposomes. This size decrease is related with the phase transition of liposomes to mixed micelar solution. The encapsulation of the hydrophilic dye indocyanine green in the aqueous compartment of liposomes showed that the rate of captured dye decreases with SD concentration suggesting the transition of liposomes to mixed micelles. The 31P NMR analysis indicates that SD interacts with the phosphate of phosphatidylcholine head groups. A schematic model for interaction of SD with phosphatidylcholine of the liposomes in which the diclofenac anion interacts with the ammonium group of the phospholipid and the dichlorophenyl ring occupies a more internal site of bilayer near phosphate group was proposed.

Diclofenac salts. I. fractal and thermal analysis of sodium and potassium diclofenac salts

Sodium and potassium diclofenac salts form hydrates when crystallized from water; the sodium salt contains four crystallization water molecules, while the potassium salt precipitates as a dihydrate. Crystallization from organic solvents occurs with a change of the crystal habit. The fractal dimension of the particle surface of both salts obtained from water is low and is in agreement with the formation of smooth and regular surfaces during crystallization. The fractal dimension for dissolution is relatively high and comparable for hydrate and anhydrate forms of both salts, and the result was interpreted as being due to the surfactant behavior of diclofenac anions. Thermograms of both salts show a couple of endotherms in the range 30–100°C, which disappear when the salts have been previously heated at 100°C, but slowly reappear when the anhydrate forms are stored in a humid environment. Both salts present a complex exotherm of decomposition at 284 and 314°C, respectively. The results are briefly discussed with regard to the formulations of the anti‐inflammatory agent diclofenac. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:2049–2057, 2001

Formation of ion-pairs in aqueous solutions of diclofenac salts

In this work we studied the ability of the diclofenac anion to form ion-pairs in aqueous solution in the presence of organic and inorganic cations: ion-pairs have a polarity and hydrophobicity more suitable to the partition than each ion considered separately and can be extracted by a lipid phase. The cations considered were those of the organic bases diethylamine, diethanolamine, pyrrolidine, N-(2-hydroxyethyl) pyrrolidine and N-(2-hydroxyethyl) piperidine; the inorganic cations studied were Li +, Na +, K +, Rb +, Cs +. Related to each cation we determined the equilibrium constant ( K XD) for the ion-pair formation with the diclofenac anion in aqueous solution and the water/ n-octanol partition coefficient ( P XD) for each type of ion-pair formed. Among the alkali metal cations, only Li + shows some interaction with the diclofenac anion, in agreement with its physiological behaviour of increasing clearance during the administration of diclofenac. The influence of the ionic radius and desolvation enthalpy of the alkali metal cations on the ion-pair formation and partition was briefly discussed. Organic cations promote the formation of ion-pairs with the diclofenac anion better than the inorganic ones, and improve the partition of the ion-pair according to their hydrophobicity. The values of the equilibrium parameters for the formation and partition of ion-pairs are not high enough to allow the direct detection of their presence in the aqueous solution. Their formation can be appreciated in the presence of a lipid phase that continuously extracts the ion-pair. Extraction constants ( E XD= P XD· K XD) increase passing from inorganic to organic cations. This study could help to clarify the mechanism of the percutaneous absorption of diclofenac in the form of a salt, a route where the formation of ion-pairs appears to play an important role.

Plastic membrane electrode for selective determination of diclofenac (voltaren) in pharmaceutical preparations

A novel plastic membrane ion-selective electrode for determining the diclofenac anion is described. The sensing membrane of the electrode consists of diclofenac-nickel(II) bathophenanthroline as an ion-exchanger site in a poly(vinyl chloride) matrix plasticized with o–nitrophenyl phenyl ether. In borate buffer solutions of pH 8–12, the electrode exhibits a fast, stable and linear response for 1 × 10–2–5 × 10–5 mol dm–3 diclofenac with an anionic slope of 55.1 ± 0.2 mV decade–1 at 25 °C. Potentiometric selectivity measurements revealed negligible interferences from 14 different anions including aromatic and aliphatic carboxylic acid salts. The electrode displays useful analytical characteristics for the direct determination of diclofenac in various pharmaceutical preparations. Results with an average recovery of 98 ± 0.6% of the nominal value were obtained.