Partial-solubility Parameters of Naproxen and Sodium Diclofenac

The expanded Hansen method was tested for determination of the solubility parameters of two non-steroidal anti-inflammatory drugs, naproxen and sodium diclofenac. This work describes for the first time the application of the method to the sodium salt of a drug. The original dependent variable of the expanded Hansen method, involving the activity coefficient of the drug, was compared with the direct use of the logarithm of the mole fraction solubility lnX₂ in the solubility models. The solubility of both drugs was measured in pure solvents of several chemical classes and the activity coefficient was obtained from the molar heat and the temperature of fusion. Differential scanning calorimetry was performed on the original powder and on the solid phase after equilibration with the pure solvents, enabling detection of possible changes of the thermal properties of the solid phase that might change the value of the activity coefficient. The molar heat and temperature of fusion of sodium diclofenac could not be determined because this drug decomposed near the fusion temperature. The best results for both drugs were obtained with the dependent variable lnX₂ in association with the four-parameter model which includes the acidic and basic partial-solubility parameters δ_a and δ_b instead of the Hansen hydrogen bonding parameter δ_h. Because the dispersion parameter does not vary greatly from one drug to another, the variation of solubility among solvents is largely a result of the dipolar and hydrogen-bonding parameters, a fact that is being consistently found for other drugs of small molecular weight. These results support earlier findings with citric acid and paracetamol that the expanded Hansen approach is suitable for determining partial-solubility parameters. The modification introduced in the expanded Hansen method, i.e. the use of lnX₂ as the dependent variable, provides better results than the activity coefficient used in the original method. This is advantageous for drugs such as sodium diclofenac for which the ideal solubility cannot be estimated. This paper shows for the first time that the method is suitable for determination of the partial-solubility parameters of a sodium salt of a drug, sodium diclofenac.     

In-vitro protein binding interaction between a metabolite of triflusal, 2-hydroxy-4-trifluoromethylbenzoic acid and other drugs.

2-Hydroxy-4-trifluoromethylbenzoic acid (HTB) is the main active metabolite of triflusal, an antiplatelet drug. The in-vitro binding of HTB to human serum was studied in the presence of different drugs. The results indicate that no statistically significant changes are observed in the HTB binding in the presence of caffeine, theophylline, glisentide, enalapril, cimetidine or warfarin. The free fraction of HTB increases significantly in the presence of the non-steroidal anti-inflammatory drugs studied: diclofenac, ibuprofen, indomethacin, naproxen, piroxicam and salicylic acid. At high concentrations, HTB displaces these anti-inflammatory drugs and also glisentide and warfarin from their protein binding sites.     

In-process crystallization of acidic drugs in acrylic microparticle systems: influence of physical factors and drug-polymer interactions

Emulsion-solvent evaporation is an established method to fabricate amorphous drug-loaded microparticles. In some cases, however, the encapsulated drug is present in its crystalline form, which can affect drug release and negatively impact on other characteristics of the final product. This work aimed to investigate the factors that are responsible for the formation (and inhibition) of drug crystals in modified-release microparticles. Five acidic drugs were encapsulated into Eudragit S or Eudragit L microparticles. Drug crystallinity was observed when indometacin and naproxen were encapsulated, while crystallization was not observed in the case of ketoprofen, salicylic acid, or paracetamol (acetaminophen). All drug-loaded microparticles had single glass transition temperature (T(g) ) intermediate between the T(g) of the drug and that of the polymer. The drop in T(g) in the case of the paracetamol-loaded particles was higher than predicted from the Gordon-Taylor equation, indicating that paracetamol was acting as a plasticizer in this system. After melt quenching in the presence of the Eudragit polymers, the crystallization of paracetamol was inhibited. The ratio of drug to polymer in the microparticles was the major determinant of drug crystallization, as was the solubility of the drug in the processing solvent. This work confirms that drug crystallization is a complex phenomenon, and that drug-polymer molecular interactions play a role in the inhibition of drug crystallization.     

Placebo granules as cores for timed release drug delivery systems

A drug delivery system is proposed constituted of spherical placebo granules as cores with polymeric surface films containing drug. This timed release dosage form has been prepared by means of a fluidized bed coating technique using ethyl cellulose as the polymeric film and caffeine and salicylic acid as model drugs. The release of the drugs from the dosage form (a) at different drug concentrations and (b) into solutions of different pH showed that drug release was linearly related to the square root of time. Good agreement was found between the theoretical release rate of caffeine, calculated according to Higuchi's equation for a homogenous matrix using membrane permeation parameters measured on linear films, and the experimental results in the case of low drug concentrations. Deviation of the release rate from the homogenous model at high drug concentrations could be explained by crystallization of the drug from the film.     

Effect of physical and chemical properties on drug release from selected thermosoftening vehicles.

The release profile of several drugs, (chlorpheniramine maleate, salicylic acid, hydrochlorothiazide, p-hydroxy benzoic acid, sulphafurazole, anhydrous theophylline) and the marker (D&C yellow No. 10) was detailed to determine the effect of physical and chemical properties on release from selected thermosoftening matrices (Gelucire 50/02 and 50/13). At a concentration of drug or marker of 2.5% w/w, hydrochlorothiazide showed the slowest release from G50/02, due to its low aqueous solubility, while theophylline showed the highest release owing to its low mol. wt and moderate aqueous solubility. Release reflected two of the selection criteria, aqueous solubility and mol. wt, set forth for the drug/markers used in the study. The hydrophobic matrix, G50/02, offered no enhancement in drug release and functioned in a manner commensurate with other hydrophobic matrices. No hydrogen bonding was noted between any of the drugs or markers and the matrix. As drug or marker concentration increased from 2.5 to 15% w/w, potential hydrogen bonding was noted between p-hydroxy benzoic acid and the matrix. Theophylline no longer had the highest release being replaced by chlorpheniramine maleate and D&C yellow No. 10. With Gelucire excipient G50/13, chlorpheniramine maleate showed the highest release; it dissolved within the matrix at experimental temperature and lowered the matrix melting point. The matrix swelled upon exposure to the dissolution medium and it was from this swollen layer that release occurred. Sulphafurazole, hydrochlorothiazide, salicylic acid and p-hydroxy benzoic acid exerted a similar effect to chlorpheniramine maleate on the matrix. No hydrogen bonding was observed between the drugs and matrix.(ABSTRACT TRUNCATED AT 250 WORDS)     

制霉菌素口腔双层贴膜在口腔内释药动态研究

目的：测定自制的制霉菌素口腔双层贴膜在口腔内释药过程。方法：采用剩余量法测定制霉菌素口腔双层贴膜在口腔内释药情况,测定制霉菌素口腔双层贴膜体外释放度,并比较体内外释放的相关性。结果：体外释放方程：ln（100-Q）=-0.089t＋4.998,r=0.997 0,口腔内释药方程为ln（100-P）=-0.022t＋5.014,r=0.993 5。以体内平均释放百分率（Y,%）对体外平均释放百分率（X,%）回归,得方程Y=0.990X＋0.372,r=0.998 0。结论：体内外释放度具有良好的相关性,可以用体外释放度来预测药物的释放。     

Placebo granules as cores for timed release drug delivery systems.

A drug delivery system is proposed constituted of spherical placebo granules as cores with polymeric surface films containing drug. This timed release dosage form has been prepared by means of a fluidized bed coating technique using ethyl cellulose as the polymeric film and caffeine and salicylic acid as model drugs. The release of the drugs from the dosage form (a) at different drug concentrations and (b) into solutions of different pH showed that drug release was linearly related to the square root of time. Good agreement was found between the theoretical release rate of caffeine, calculated according to Higuchi's equation for a homogenous matrix using membrane permeation parameters measured on linear films, and the experimental results in the case of low drug concentrations. Deviation of the release rate from the homogenous model at high drug concentrations could be explained by crystallization of the drug from the film.     

Effect of drug solubility on release behavior of calcium polysaccharide gel-coated pellets.

The aim of this study was to investigate the effect of drug solubility on the release behavior from calcium polysaccharide gel (CaPG)-coated pellets. Three different drugs with similar chemical structure, but different water solubility, namely caffeine (CAF), theophylline (TPL) and theobromine (TBR), were used. Drug-loaded spherical pellets were manufactured by an extrusion-spheronization method. The CaPG was applied on the pellets loaded with different drugs by interfacial complexation coating. The encapsulation efficiency of coated pellets was found to vary from 57.6 to 84.3%, depending on the solubility of the active drug and polysaccharide type. Drug release from different uncoated pellets was relatively unaffected by pH and release media but depended mainly on drug solubility. Release behavior was significantly modified in the pellets coated with CaPG, for all of the drugs tested. Drug release from coated pellets of the different drugs showed different release kinetics. The difference in the drug release is probably due to the difference in the drug dissolution within the core, before its partition and diffusion through the CaPG coat. The CAF dissolved faster and achieved a higher concentration in solution, which drove diffusion. The release of TBR from the coated pellets was much slower than that of the CAF or TPL because of its low solubility. However, the release of all drugs was about four- to sixfold slower for coated than uncoated pellets, suggesting that the coating influenced the retardation of drug release from the coated pellets. Therefore, the CaPG coating may provide a sustained release delivery system for all drugs tested.     

HPLC-Determination of some Antiinflammatory,Weak Analgesic and Uricosuric Drugs in Human Blood Plasma and its Application to Pharmacokinetics

Abstract: HPLC-determination of naproxen, indomethacin, ketoprofen, fenoprpfen, ibuprofen, diclofenac sodium, tolfenamic acid, phenylbutazone, mofebutazone, salicylic acid, acetylsalicylic acid, phenacetin, paracetamol, sulfinpyrazone and probenecid by means of an adjustable, rapid, accurate and specific method is described. Plasma samples of 0.2 ml were deproteinised and the drugs extracted simultaneously with pure acetonitrile. Aliquots of 25 μl of this primary extract were directly injected on the column. As elution solvent for drug screening was basically used 55% methanol in 50 mM phosphate buffer at pH 4.0. Optimal separation of some drugs or reasonable elution times for others were obtained by varying the methanol concentration of the elution solvent or possibly its pH. The method used for individual drug determinations is very applicable for therapeutic monitoring purposes as well as for use in pharmacokinetic investigations. As an example, the practical detection limit for naproxen in plasma was about 0.2 μgml^-1. By concentrating the extract this could be lowered to about 0.04 μg ml^-1. The method was applied in a study of the pharmacokinetics of naproxen in a person, who ingested a single oral dose of 2.5 mg kg^-1. Pronounced two-compartment kinetics were found. V_c was 0.038 1 kg^-1 V_das 0.138 1 kg^-1, t½ (β) 21.3 hrs, t½ (α) 0.99 hr and t½ (k_a) 0.67 hr.     

Effects of caffeine and paracetamol alone or in combination with acetylsalicylic acid on prostaglandin E(2) synthesis in rat microglial cells

Paracetamol has mild analgesic and antipyretic properties and is, along with acetylsalicylic acid, one of the most popular "over the counter" analgesic agents. However, the mechanism underlying its clinical effects is unknown. Another drug whose mechanism of action is unknown is caffeine, which is often used in combination with other analgesics, augmenting their effect. We investigated the inhibitory effect of paracetamol and caffeine on lipopolysaccharide (LPS)-induced cyclooxygenase (COX)- and prostaglandin (PG)E(2)-synthesis in primary rat microglial cells and compared it with the effect of acetylsalicylic acid, salicylic acid, and dipyrone. Furthermore, combinations of these drugs were used to investigate a possible synergistic inhibitory effect on PGE(2)-synthesis. Both paracetamol (IC(50)=7.45 microM) and caffeine (IC(50)=42.5 microM) dose-dependently inhibited microglial PGE(2) synthesis. In combination with acetylsalicylic acid (IC(50)=3.12 microM), both substances augmented the inhibitory effect of acetylsalicylic acid on LPS-induced PGE(2)-synthesis. Whereas paracetamol inhibited only COX enzyme activity, caffeine also inhibited COX-2 protein synthesis. These results are compatible with the view that the clinical activity of paracetamol and caffeine is due to inhibition of COX. Furthermore, these results may help explain the clinical experience of an adjuvant analgesic effect of caffeine and paracetamol when combined with acetylsalicylic acid.     

Release of drugs from fatty suppository bases I. The release mechanism

A model for drug release from fatty suppository bases is presented that explains in vitro measurements on drugs with various physicochemical characteristics, such as paracetamol (slowly dissolving in water) sodium salicylate (rapidly dissolving in water) and salicylic acid (soluble in lipid).The in vitro results are compared with in vivo experiments on rectal absorption in man. Results indicated that for suspensions of all the drugs investigated, dissolution takes place at the interface between the suppository base and the surrounding fluid. The release process therefore includes a flow of particles in the suppository base into the direction of the interface and a flow of solute away from the interface. Either of these flows may be rate limiting dependent on the water solubility of the drug, and may determine the effect of concentration and particle size on release rate.     

A Modification of the Extended Hildebrand Approach to Predict the Solubility of Structurally Related Drugs in Solvent Mixtures

Abstract— A modification of the extended Hildebrand equation is proposed to estimate the solubility of an organic drug in solvent mixtures. The equation accurately reproduces the solubility of four sulphonamides in dioxane-water mixtures without requiring the heat of fusion of the solute. A single equation is obtained for predicting the solubility of related drugs using the solubilities of the drugs in the pure solvents, dioxane and water, and solute-solvent interaction terms consisting of the solubility parameter, δ₂, of the solute and the solubility parameter, δ₁, and basic partial solubility parameter, δ_1b, of the solvent mixture. By this procedure a single equation was obtained to estimate the solubilities of three xanthines in dioxane-water and another equation to obtain the solubilities of four sulphonamides. The equation obtained for sulphonamides is able to predict the experimental solubilities of two parent compounds, sulphasomidine and sulphathiazole, and the solubilities of a drug of different structure, p-hydroxybenzoic acid. This suggests that the intermolecular solute-solvent interaction of sulphonamides and p-hydroxybenzoic acid are similar. The results indicate that the solubility behaviour of drugs having different structures may be modelled using a common equation provided that they show similar solute-solvent interactions.     

Influence of ethanol on swelling and release behaviors of Carbopol®-based tablets

The aim of this work was to investigate the effect of ethanol on the in vitro swelling and release behaviors of Carbopol^®-based tablets. The swelling behavior of drug-free compacts and the release of model drugs (metformin HCl, caffeine and theophylline) from matrix tablets were evaluated in acidic and buffered media with 0, 20 and 40% (v/v) ethanol. Release data were analyzed by fitting to Higuchi and Peppas models and calculation of similarity factor (f₂). ANOVA tests were performed to determine significant factors on swelling and release. It was found that ethanol affects swelling and erosion of drug-free Carbopol^® compacts, and the effect was highly dependent on medium pH. For matrix tablets, no dose dumping due to ethanol was manifested. The release rate and mechanism, however, were significantly affected by ethanol concentration as indicated by ANOVA applied to the constant, K_H, from Higuchi model and the exponent, n, from Peppas model, respectively. The effect of ethanol on release was further confirmed by similarity factor results, which indicated that ethanol led to different release profiles (f₂ < 50) in seven of eight cases for matrices containing metformin HCl and in three of eight cases for matrices containing caffeine and theophylline.     

Study of gel-forming properties of sucrose esters for thermosensitive drug delivery systems

Sucrose esters (SEs) are non-toxic, biodegradable, non-ionic surfactants. They have a wide range of hydrophilic–lipophilic balance values (1–16) and are usually applied as surfactants, or as solubility or penetration enhancers. The aims of this work were to study the gelling behaviour of SEs and the effects of this property on drug release. The gelling characteristics of two different SEs (P1670 and S970) were investigated by rheological measurements, and compared with each other. The effects of the gel-forming SEs on model drug (paracetamol) release were evaluated by in vitro drug release studies. The kinetics of the dissolution process were studied by analysing the dissolution data through the use of various kinetic equations. The results revealed that the gelling of the SEs is temperature- and concentration-dependent. The examined sucrose stearate (S970) has a stronger gel structure than that of sucrose palmitate (P1670) and this behaviour has a significant effect on the drug release. The analysis of the dissolution kinetic data in this study revealed that the dissolution follows the Korsmeyer–Peppas (paracetamol–P1670) or Higuchi (paracetamol–S970) equations.     

The effect of the aqueous solubility of xanthine derivatives on the release mechanism from ethylcellulose matrix tablets

Release data from ethylcellulose (EC) matrix tablets was analyzed to determine which release equation provides the best fit to the data and to observe the effect of drug solubility on the release mechanism(s). Tablets were prepared by direct compression of drug, EC, and lubricant in an appropriate mass ratio to achieve a high and a low drug loading. Theophylline, caffeine, and dyphylline were selected as non-electrolyte xanthine derivatives with solubilities from 8.3 to 330 mg/ml at 25 degrees C. Drug release studies were conducted in 37 degrees C water with UV detection at 272 nm. Several equations to characterize release mechanisms were tested with respect to the release data. Drug diffusion, polymer relaxation, and tablet erosion were the mechanisms considered. Parameters were generated and ANOVA data presented by WinNonlin Pro(R) software. The Akaike Information Criterion was also considered to ascertain the best fit equation. At high drug loading, drug was released by a diffusion mechanism with a rate constant that increased with an increase in aqueous solubility. At low drug loading, polymer relaxation also became a component of the release mechanism. However, its contribution to drug release was less pronounced as solubility decreases, becoming negligible in the case of theophylline.     

Influence of membrane-solvent-solute interactions on solute permeation in model membranes

The interaction of the components of topical formulations with the skin is an important consideration for effective drug delivery and efficacy. The relative importance of solubility parameters and other solvent properties on membrane diffusion processes has not been fully elucidated in the literature. In this paper, the effect of different vehicles on the permeation of caffeine, salicylic acid and benzoic acid through silicone membranes was evaluated. Polydimethylsiloxane membranes were used as model membranes for comparing the release characteristics of saturated solutions of model permeants because of their homogeneity and uniformity. Log P (octanol-water partition coefficient) and solubility parameter values were calculated for the compounds under study. In vitro diffusion studies indicated that the permeation profiles of all solutes showed a similar pattern. The permeation rates of benzoic acid and salicylic acid through silicone membrane from saturated solutions were higher than those for caffeine reflecting the more lipophilic nature of these compounds in comparison with caffeine. Solvent uptake studies confirmed that the vehicles that were highly sorbed by the membrane altered its properties and hence the flux. Vehicles that were not sorbed by the membrane showed similar steady-state fluxes for the model drugs. This suggests that the diffusion process is mainly influenced by the interactions between the vehicles and the membrane. Solubility parameter alone cannot explain the interactions between the membrane and the vehicles in all cases. Rather, it is likely that membrane flux reflects a combination of different solvent and solute characteristics, such as size, shape and charge distribution.     

Drug release from tableted wet granulations comprising cellulosic (HPMC or HPC) and hydrophobic component.

The effects of component nature, proportion and processing on the release rate and mechanism were investigated for tablets comprising drug, cellulosic polymer and hydrophobic components. Four drugs differing in solubility (diclofenac sodium, ibuprofen, naproxen and indomethacin), two cellulosic polymers (HPC and HPMC) and hydrophobic Emvelop were used in two levels of mass fraction and weight ratio of drug:carrier and of cellulosic-hydrophobic component. Compression was applied after granulation or physical mixing. Drug release was evaluated in pH 6.5 phosphate buffer BP and elucidation of the release mechanism was attempted by fitting kinetic models. Statistical significance of the effects of formulation variables on the release rate and mechanism expressed by the coefficient, k, and exponent, n, of the power law kinetic model, respectively, was evaluated by ANOVA. It was found that for the release mechanism most significant is the effect of drug solubility followed by cellulosic polymer type, mixing procedure and drug mass fraction. Significant interaction between drug solubility and type of cellulosic polymer indicated that alteration in the swelling of HPMC and HPC is caused by the drug solubility. Weight ratio of cellulosic-hydrophobic component does not affect the release mechanism, but only the release rate. Similarly, for the release rate most significant was found the effect of drug solubility, followed by cellulosic polymer type, weight ratio of cellulosic-hydrophobic component, mixing method and drug mass fraction. Also significant were the interactions of drug solubility with the type and proportion of the cellulosic polymer and the processing applied. Depending on the drug solubility and type of polymer present, wet granulation can increase or decrease the release rate.     

Inhibition of Prostaglandin Synthesis in Rat Brain

Abstract Rats were injected with one of five drugs alleged to inhibit brain prostaglandin (PG) synthesis: indomethacin, diclofenac, naproxen, aspirin and paracetamol. Animals were killed after 30 min. and the endogenous formation of PGF_2α and PGE₂ in brain homogenates was measured by mass fragmentography using deuterium labelled PGF_2α and PGE₂ as internal standards. Diclofenac, indomethacin, and naproxen inhibited dose dependently, the synthesis of PGF_2α. The ED50 for diclofenac was 0.4 mg/kg, for indomethacin 1 mg/kg and for naproxen 2 mg/kg. In equieffective doses indomethacin had the longest duration. The time taken for the inhibition to decline to half its maximal value was 32 hrs for indomethacin and about 15 hrs for diclofenac and naproxen. Under the present conditions aspirin and paracetamol failed to produce significant reduction of PG synthesis in the rat brain homogenates in doses up to 100 mg/kg.     

The effect of the physicochemical properties of a drug on its release from chitosonium malate matrix tablets

The effect of the physico-chemical properties of an active compound (such as solubility and molecular size) on its release characteristics from chitosonium malate matrix tablets has been investigated. For this purpose, the release of 11 drugs of various solubilities (1 in < 1 to 1 in 10000) and molecular weights (138–375) through chitosonium malate matrix tablets was studied. It may be concluded that, in addition to the solubility, the molecular size of drug is of importance in the drug release characteristics from the chitosonium malate matrix. When the release data (< 60%) were fitted to the simple power law equation, the mode of drug release from the chitosonium malate matrix was generally non-Fickian and Super Case II type. These drugs (timolol maleate, ephedrine, propranolol hydrochloride, acetylsalicylic acid, naproxen, sulphadiazine, indomethacin and pindolol) can be released at a nearly zero-order rate through the matrix.     

Pharmacokinetic interaction of tetracycline with non-steroidal anti-inflammatory drugs via organic anion transporters in rats.

The present study aims to investigate the pharmacokinetic interaction between non-steroidal anti-inflammatory drugs and tetracycline in rats. Pharmacokinetic parameters were determined following an intravenous administration of tetracycline (5 mg kg(-1)) to rats in the presence and absence of naproxen or diclofenac (20 mg kg(-1)). Compared to the control (given tetracycline alone), pretreatment with naproxen or diclofenac 30 min prior to tetracycline administration significantly altered the pharmacokinetics of tetracycline. Renal clearance of tetracycline was reduced by approximately three-fold in the presence of naproxen or diclofenac. Consequently, the systemic exposures (AUC) of tetracycline in the rats pretreated with naproxen or diclofenac were significantly (p < 0.05) higher than those from the control group given tetracycline alone. Furthermore, mean terminal plasma half-life of tetracycline was enhanced by two- to five-folds under the pretreatment with naproxen or diclofenac. Those results suggest that NSAIDs such as naproxen and diclofenac are effective to alter the renal elimination and pharmacokinetic profiles of tetracycline. Therefore, concomitant use of naproxen or diclofenac with tetracycline may require close monitoring for clinical consequence of potential drug interaction.