Dissolution Rate Of Naproxen Research Articles

SMEDDS를 이용한 naproxen의 용출률 개선 및 in vivo 효능 평가

Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) administered to reduce pain, inflammation, and fever. The extended half-life of naproxen enables prolonged efficacy, leading to symptom relief and high patient satisfaction. However, naproxen has notably low solubility in water (15.9 mg/L). The present study aimed to enhance the solubility and dissolution rate of naproxen by using a self-microemulsifying delivery system (SMEDDS). Labrasol® was used as the primary oil and Labrafil® M1944 and Cremophor® RH-40 as the surfactants in the SMEDDS. The ratio of the selected oil to the surfactant was determined to identify the equilibrium range with good solubility. Subsequently, the efficacy was confirmed to be within the applicable range. The results indicated that the SMEDDS formulation showed higher dissolution rates than the salt-formulated purified naproxen product. Furthermore, the efficacy was compared with that of commercially available naproxen emulsion-filled soft gel capsules in an animal model of gastric ulcers, showing the excellent gastro-protective abilities of the naproxen SMEDDS. This study provides an appropriate oil and ratio for a naproxen SMEDDS, confirming it sefficacy, dissolution rate, and stability. These results will guide future directions in naproxen research and manufacturing.

A Novel Drug-Drug Salt of Naproxen and Vortioxetine: Synthesis, Characterization, and Solubility Study

Naproxen (NAP) is an aromatic propionic acid nonsteroidal anti-inflammatory drug, and vortioxetine (VOT) is a novel antidepressant drug. In this study, a new 1 : 1 drug-drug salt of NAP and VOT (namely, NAP-VOT) was designed and synthesized by liquid-assisted grinding and slow evaporation. The obtained salt was characterized by single-crystal X-ray diffraction, powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC). Single-crystal structure showed that NAP-VOT is a molecular salt. The NAP and VOT molecules in the salt were connected by N-H+⋯O hydrogen bonds between the carbonyl oxygen of NAP and the piperazine group of VOT. In addition, solubility and dissolution rate experiments were performed in water and pH 6.86 phosphate buffers, and the result suggested that salt formation could increase the solubility and dissolution rate of NAP and VOT in water. Furthermore, this study provides a new research idea to solve the problem of drug-drug combination by achieving drug-drug association at the molecular level.

Physicochemical characterization, solubility enhancement, molecular docking, and antibacterial activity of inclusion complexes of naproxen/β-cyclodextrin derivatives: A comparative study

Naproxen (NAP) is a nonsteroidal anti-inflammatory drug. The aim of this work is to enhance the aqueous solubility and dissolution rate of naproxen (NAP) by forming an inclusion complex with β-cyclodextrin derivatives (β-CDs) such as 2-hydroxypropyl-β-cyclodextrin (Hβ-CD), methyl-β-cyclodextrin (Mβ-CD), and sulfated-β-cyclodextrin (Sβ-CD). UV–vis and fluorescence spectroscopic techniques were applied to examine the interaction of the β-CDs:NAP inclusion complexes in pH 7.4 buffer solution. The 1:1 stoichiometry of the β-CDs:NAP inclusion complexes was confirmed by the Benesi-Hildebrand method. The solid-state β-CDs:NAP inclusion complexes were obtained by co-precipitation and were characterized by FTIR, XRD, SEM, and TGA-DSC analyses. Phase solubility diagrams were calculated linearly from the slope and intercept, where the maximum apparent stability constants (Ks) were found to be 1123, 1261, and 1131 M−1 for Hβ-CD, Mβ-CD, and Sβ-CD respectively, indicating formation of the β-CDs:NAP inclusion complexes. Molecular docking was used to systematically validate formation of the β-CDs:NAP inclusion complexes. The antibacterial activity of the β-CDs:NAP inclusion complexes was described here for the first time, and it was shown that the activity of NAP against Staphylococcus aureus (91 ± 0.12%) and Escherichia coli (87 ± 0.14%) was remarkably enhanced by encapsulation in the β-cyclodextrin derivatives. The prepared solid β-CDs:NAP inclusion complexes are highly stable in aqueous media, where the antibacterial activity can be enhanced by increasing the solubility of NAP.

Physicochemical, pharmacokinetics, and histological evaluation of new naproxen-quercetin co-lyophilizate to diminish drug-induced gastric irritations in rats

Quercetin (QUE) is a flavonoid found in several plants and commonly distributed in edible vegetables and fruits. To evaluate the effect of co-lyophilization of naproxen (NPX) with QUE at different weight ratios on physicochemical characteristics induced gastric irritation, and drug pharmacokinetics. NPX binary systems with QUE in different weight ratios were prepared by freeze-drying alkalinized solutions, and were characterized in terms of physicochemical properties as well as NPX dissolution rate in acidic pH. NPX-induced gastric inflammation studies were carried out in rats for 7 days. The pharmacokinetics of the two formulations were assessed to evaluate the bioavailability of NPX-QUE 1:2 co-lyophilizate. Westar rats were administered oral doses equivalent to 40 mg kg−1 of NPX and blood samples were taken from the retro-orbital vein of rats at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0 12.0, and 24.0 h post dosing. Co-lyophilization of NPX with QUE enhanced drug dissolution rate in the acidic medium, which was correlated with an increased QUE weight ratio in the co-lyophilizates. Rat stomachs from group V (NPX-QUE 1:2 co-lyophilizate) showed non-significant changes, and biopsies from this group showed no significant leukocyte infiltration and edema in the mucosa. The bioavailability of NPX-QUE 1: 2 co-lyophilizate was similar to the control sample. NPX-QUE 1: 2 co-lyophilizate could be an alternative to NPX in the treatment of arthritis as it minimizes the potential for gastric irritation and enhances safety while retaining the same efficacy and bioavailability.

Improvement of the surface hydrophilic properties of naproxen particles with addition of hydroxypropylmethyl cellulose and sodium dodecyl sulphate: In vitro and in vivo studies

In this study, a new surface-modified naproxen was developed to enhance brain concentration in acute migraine treatment. Fast-dissolving naproxen granules were made by mixing hydroxypropylmethylcellulose (HPMC) sodium dodecyl sulphate (SDS) and sodium croscarmellose with micronized naproxen particles. The aim of this study was to evaluate the effect of adding proportions of SDS to the HPMC film caused changes in the polymer chains of the HPMC, producing a new hydrophilic HPMC-SDS structure. These formulations with different HPMC/SDS ratios were characterised using electron microscopy (SEM), powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC). SDS 10% (w/w) produced a highly hydrophilic HPMC-SDS structure on the surface of the naproxen microparticles. The fast dissolution granules (SF-10%) showed a significant improvement in the dissolution rate of naproxen. Pharmacokinetic studies were conducted with mice, showing an improvement of Cmax (1.38 and 1.41-fold) and AUC0-2h (30% and 10% higher) for plasma and brain samples compared to the reference naproxen suspension. The faster Tmax ratio for SF-10% may be related to increased hydration in the gastrointestinal environment, enabling the drug to permeate the gastrointestinal hydration layer more easily due to the presence of the hydrophilic HPMC-SDS structure in the formulation.

Physicochemical characterization of naproxen solid dispersions prepared via spray drying technology

The bioavailability of Naproxen (NPX), a non-steroidal anti-inflammatory drug, is limited after oral administration due to its low solubility in biological fluids. The aims of this study were preparation and characterization of NPX solid dispersions benefitting hydrophilic polymers. Solid dispersions of NPX were prepared at different drug to polymer ratios (1:0.5, 1:1 and 1:2) using crosspovidone and HPMC E4M by means of spray drying method. The dissolution rate of NPX from the solid dispersions, drug/polymer physical mixtures and pure drug was determined at two pH values of 3 and 7.4 simulating gastric and intestinal fluids using USP dissolution apparatus II. The physicochemical properties of the prepared solid dispersions were also characterized by differential scanning calorimetry (DSC), scanning electron microscopy (SEM), X-ray diffractometry (XRD), and Fourier transform infrared spectroscopy (FT-IR). The dissolution rate of NPX was noticeably increased in the solid dispersions so that almost 90% of drug was released at 60 min while the corresponding value for the physical mixtures and pure drug was revealed to be around 40%. The dissolution rates of the formulations were dependent on the nature and ratio of drug to carriers as well as pH of the medium. DSC and X-ray diffraction displayed reduced drug crystallinity in the solid dispersions. Scanning electron microscopy revealed significant decreased particle size of the drug in the solid dispersions. FT-IR spectroscopy demonstrated no obvious interactions between the drug and polymers.

Preparation of microparticles of naproxen with Eudragit RS and Talc by spherical crystallization technique

Microparticles of naproxen with Eudragit RS and talc were prepared by the spherical crystallization technique, i.e. quasi-emulsion solvent diffusion method. The obtained microparticles were evaluated by micromeritic properties, yield, encapsulation efficiency, drug physical state and dissolution rate of drug. The influence of formulation factors and preparation condition (drug: polymer ratio, talc: polymer ratio, SLS concentration, stirring speed) on the properties of the microparticles were also examined. The resultant microparticles were finely spherical and uniform with high incorporation efficiency and yield. Greater encapsulation efficiency was obtained by increasing the drug: polymer ratio and talc: polymer ratio and by reducing the SLS %. The dissolution rate of naproxen from microparticles was enhanced significantly with increasing the ratio of drug: polymer and stirring rate, and sustained by increasing SLS % in crystallization medium. The results of X-ray diffraction and differential scanning calorimeter analysis indicated that naproxen was highly dispersed in microparticles, so as amorphous state. Studies carried out to characterize the micromeritic properties of formulations, such as flowability and packability showed that microparticles were suitable for further pharmaceutical manipulation (e.g. capsule filling). Hence, the spherical crystallization technique can be successfully used for obtaining spherical microparticles, generating a heterogeneous matrix system and providing sustained drug release.

Preparation of Spherical Crystal Agglomerates of Naproxen Containing Disintegrant for Direct Tablet Making by Spherical Crystallization Technique

The purpose of this research was to obtain directly compressible agglomerates of naproxen containing disintegrant by spherical crystallization technique. Acetone-water containing hydroxypropyl celloluse (HPC) and disintegrant was used as the crystallization system. In this study croscarmellose sodium (Ac-Di-Sol) was employed as disintegrant. The agglomerates were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (XRPD), and scanning electron microscopy and were evaluated for flow, packing and tableting properties and drug release. The growth of particle size and the spherical form of the agglomerates resulted in formation of products with good flow and packing properties. The improved compaction properties of the agglomerated crystals were due to their fragmentation occurred during compression. DSC and XRPD studies showed that naproxen particles, crystallized in the presence of HPC and Ac-Di-Sol did not undergo structural modifications. The dissolution rate of naproxen from tablets made of naproxen-(Ac-Di-Sol) agglomerates was enhanced significantly because of including the disintegrant in to the particles. This was attributed to an increase in the surface area of the practically water insoluble drug is exposed to the dissolution medium. In conclusion the spherical crystallization technique developed in this study is suitable for obtaining agglomerates of drug with disintegrant.

Particle design of naproxen-disintegrant agglomerates for direct compression by a crystallo- co-agglomeration technique

The purpose of the present research was to obtain directly compactible agglomerates of naproxen containing disintegrant by a novel crystallo- co-agglomeration (CCA) technique. Acetone–water containing hydroxypropylcellulose (HPC) was used as the crystallization medium. Acetone acted as a good solvent for naproxen as well as a bridging liquid for agglomeration of crystallized drug with disintegrant and aqueous phase as non-solvent. The agglomerates were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (XRPD) and scanning electron microscopy. The agglomerates were compressed at different compression pressures and dissolution studies were carried out for the tablets produced at lowest compression force. The growth of particle size and the spherical form of the agglomerates resulted in formation of products with good flow and packing properties. The improved compaction properties of the agglomerated crystals were due to the fragmentation which occurred during compression. DSC and XRPD studies showed that naproxen particles, crystallized in the presence of HPC and disintegrant did not undergo structural modifications. The dissolution rate of naproxen from the agglomerates could be controlled by the amount of included disintegrant, being enhanced as the latter was increased. Moreover, the results showed that when the disintegrants were included both intragranularly and extragranularly during agglomeration of naproxen particles, tablets containing these agglomerates dissolved at a faster rate than the tablets containing crystallized naproxen with the same amount of disintegrant incorporated only extragranularly by physical mixing. In conclusion, the properties of agglomerated crystals, such as flowability, compactibility and dissolution rate were improved profoundly using the developed technique resulting in successful direct tableting without need to additional process of physical blending of agglomerates and disintegrants.

Solid-state characterization and dissolution properties of Naproxen–Arginine–Hydroxypropyl-β-cyclodextrin ternary system

The effect of ternary complexation of naproxen, a poorly water soluble anti-inflammatory drug, with hydroxypropyl-β-cyclodextrin and the basic aminoacid L-arginine on the drug dissolution properties has been investigated. Equimolar binary (drug–cyclodextrin or drug–arginine) and ternary (drug–cyclodextrin–arginine) systems were prepared by blending, cogrinding, coevaporation, and characterized by differential scanning calorimetry, thermogravimetric analysis, FT-IR spectroscopy, X-ray diffractometry. The dissolution behavior of naproxen from the different products was evaluated by means of a continuous flow through method. The results of solid state studies indicated the presence of strong interactions between the components in ternary coevaporated and coground systems, which were both of totally amorphous nature. In contrast, the presence of either free drug or free arginine was detected when the third component (cyclodextrin or aminoacid) was physically mixed, respectively, to the drug–arginine binary system (as physical mixture, coevaporate, or coground product) or to the drug–cyclodextrin binary system (as physical mixture, coevaporate, or coground product). All ternary combinations were significantly ( P<0.001) more effective than the corresponding binary drug-cyclodextrin and drug–arginine systems in improving the naproxen dissolution rate. The best performance in this respect was given by the ternary coevaporate, with about 15 times increase in terms of both drug relative dissolution rate and dissolution efficiency. The synergistic effect of the simultaneous use of arginine and cyclodextrin on the dissolution rate of naproxen was attributed to the combined effects of inclusion in cyclodextrin and salt formation, as well as to a specific role played by arginine in this interaction.

PREPARATION AND EVALUATION OF NAPROXEN ADSORBATE AS AN ATTEMPT TO IMPROVE DRUG DISSOLUTION CHARACTERISTICS

Naproxen is a nonsteroidal anti-inflammatory drug which shows variable absorption and bioavailability due to its poor solubility. In this study we aimed to improve the dissolution rate of the drug by solvent deposition onto certain adsorbents including porous silica, Avicel and Bentonite. Physical mixtures of naproxen with the investigated adsorbents were also prepared. The molecular behavior of naproxen in the investigated systems were studied using infrared absorption spectra, differential scanning calorimetry and X-ray diffraction analysis. The dissolution rate of the drug was also investigated. The obtained results indicated that naproxen was transformed to the amorphous state in case of mixtures loaded with porous silica. This transformation resulted in a significant enhancement of the dissolution rates of the drug. In addition, it was noticed that, the drug: adsorbents weight ratio of the prepared mixtures influenced the drug dissolution rate enhancement. Accordingly, it can be concluded that, by increasing the weight ratio of the used adsorbent in the mixture, the larger the enhancement in the dissolution rate of naproxen will be obtained.

Influence of chitosan and its glutamate and hydrochloride salts on naproxen dissolution rate and permeation across Caco-2 cells

Chitosan and its glutamate and hydrochloride salts were evaluated for their efficacy in improving the dissolution behaviour of naproxen (a poorly water-soluble antiinflammatory drug) and its transport in vitro across Caco-2 cell monolayers. Drug–polymer physical mixtures and coground products, prepared at two different w/w ratios (30/70 and 10/90), were characterized by differential scanning calorimetry, X-ray powder diffractometry, scanning electron microscopy, and tested for dissolution properties. Coground systems were more effective than physical mixtures in improving drug dissolution and chitosan base, in spite of its lower water solubility, showed higher solubilizing power than its salts. According to the solid state analyses results, this effect was directly related to its stronger amorphizing power. Transport studies showed that only coground mixtures with chitosan glutamate salt allowed a significant drug apparent permeability improvement; however, they did not exhibit appreciable effects on the Caco-2 tight junctions (measured by the trans-epithelial electrical resistance variations), thus indicating that their enhancer effect was mainly due to an improved naproxen transport by transcellular passive diffusion rather than through the paracellular route. The direct compression properties and antiulcerogenic activity together with the demonstrated dissolution and permeation enhancer abilities toward naproxen make chitosan glutamate an optimal carrier for developing fast-action oral solid dosage forms of this drug.

Interaction of Naproxen with Crystalline and Amorphous Methylated β-Cyclodextrin in the Liquid and Solid State

Interactions of naproxen (NAP) with amorphous, randomly methylated β-cyclodextrin at a degree of substitution per anhydroglucose unit of 1.8 (RAMEB) and with crystalline heptakis-(2,6-di-O-methyl)-β-cyclodextrin (DIMEB) were studied in aqueous solution and in the solid state using, respectively, phase-solubility analysis (at 25 °C, 37 °C and 47 °C) and differential scanning calorimetry (DSC) supported by X-ray powder diffractometry. RAMEB and DIMEB displayed similar solubilizing and complexing abilities towards NAP, suggesting analogous inclusion modes of the drug in the host cavity in aqueous solution. Differences were instead observed in interactions in the solid state, where the amorphizing capacity of RAMEB toward NAP (evaluated by DSC) was about twice that of DIMEB at each drug-to-carrier ratio. Assuming that inclusion complexation is also involved in solid-state interactions, molecular modelling accounted for the experimental results in terms of structural features of DIMEB, i.e. the particular inwards orientation of O-6-C-8 groups of three alternate glucoses on the primary hydroxyl side which hampers a deep penetration of NAP in the DIMEB cavity in the solid state. On the contrary, no obstruction of the cavity apparently occurs with RAMEB due its noncrystalline state. The aqueous dissolution rate of NAP from NAP-RAMEB and NAP-DIMEB blends containing 0.59, 0.73, 0.85, and 0.92 mass fraction of carrier linearly increased at decreasing drug-to-carrier ratios. The improvement was 5 to 20 times (from powders) and 50 to 200 times (from discs) the dissolution rate of NAP alone for both carrier. Therefore the choice of the amorphous RAMEB in pharmaceutical formulations can be recommended mainly for economic reasons, though the anhydrous and non-hygroscopic nature of crystalline DIMEB might be of particular advantage in case of moisture sensitive formulations.

Effect of PEG 4000 on the dissolution rate of naproxen.

Naproxen is a nonsteroidal anti-inflammatory drug characterized by its low wettability and poor water solubility. Solid dispersions naproxen:PEG 4000 have been prepared in order to improve the solubility and dissolution rate of the drug, since these factors can be the limiting steps for absorption and bioavailability of poorly soluble drugs. X-ray diffraction analysis, infrared spectroscopy and differential scanning calorimetry detected no physico-chemical interaction between the drug and the inert carrier PEG 4000. The phase diagram of the naproxen-PEG 4000 system produced by DSC and hot stage microscopy is reported. The intrinsic dissolution rate of naproxen is calculated. The dissolution kinetics of solid dispersions prepared by the solvent and melt methods are compared with those of free drug and physical mixture. The studies were carried out at 37 degrees C and pH 1.2 according to the dispersed amount method. The dissolution profiles obtained indicate that a significant dissolution enhancement occurs with solid dispersions in comparison with the physical mixture. In addition, the physical mixture showed a dissolution rate higher than the free drug. Dissolution rate constants were determined by fitting the experimental data to the cube root function, to get straight line plots.

Enhancement of solubility and dissolution rate of poorly water-soluble naproxen by complexation with 2-hydroxypropyl-β-cyclodextrin

The solubility and dissolution rate of naproxen (NPX) complexed with 2-hydroxypropyl-β-cyclodextrin (2-HPβCD) using coprecipitation, evaporation, freeze-drying and kneading method were investigated. Solubility of NPX linearly increased (correlation coefficient, 0.995) as 2-HP-βCD concentration increased, resulting in AL type phase solubility curve. Inclusion complexes prepared by four different methods were compared by differential scanning calorimetry (DSC). The NPX showed sharp endothermic peak around 156°C but inclusion complexes by evaporation, freeze-drying and kneading method showed very broad peak without distinct phase transition temperature. In contrast, inclusion complex prepared by coprecipitation method resulted in detectable peak around 156°C which is similar to NPX, suggesting incomplete formation of inclusion complex. Dissolution rate of inclusion complexes prepared by evaporation, freeze-drying and kneading except coprecipitation method was largely enhanced in the simulated gastric and intestinal fluid when compared to NPX powder and commercial NAXEN® tablet. However, about 65% of NPX in gastric fluid still remained unreleased but most of NPX dissolved within 5 min in intestinal fluid. In case of inclusion complex prepared by coprecipitation method, formation of inclusion complex appeared to be incomplete, resulting in no marked enhancement of dissolution rate. From these findings, inclusion complexes of poorly water-soluble NPX with 2-HPβCD were useful to increase solubility and dissolution rate, resulting in enhancement of bioavailability and minimization of gastrointestinal toxicity of drug upon oral administration of inclusion complex.

Influence of Method of Preparation on Inclusion Complexes of Naproxen with Different Cyclodextrins

AbstractThe aim of this study is to increase the solubility of naproxen by inclusion complex formation with α, β, γ, hydroxypropylbeta and dimethylbetacyclodextrin. The apparent stability constants were calculated from the slope and intercept of the AL-solubility diagrams. The solid inclusion complexes of naproxen with cyclodextrins in 1:1 molar ratio were prepared by the kneaded-mix, spray-drying and freeze-drying method. The formation of inclusion complexes in the solid state were confirmed by X-Ray diffractometry I.R. spectroscopy and differential scanning calorimetry. The dissolution rate of naproxen from the inclusion complexes was much more rapid than naproxen alone. The best results were obtained with β-cyclodextrin inclusion complex prepared by the spray-drying method.

A study of the inclusion complex of naproxen with β-cyclodextrin

The aim of this study was to increase the solubility and dissolution rate of naproxen (NAP) by inclusion complex formation with β-cyclodextrin (β-CD). The solubility of NAP with β-CD in aqueous solution was determined. The apparent stability constant, K c, was calculated from the slope and intercept of the AL solubility diagram as 568 M −1. The solid complexes of NAP with β-CD in 1:1 molar ratio were prepared by the freeze-drying and neutralization method. The formation of an inclusion complex with β-CD in solid state was confirmed by X-ray diffractometry, IR spectroscopy and differential scanning calorimetry (DSC). The dissolution rate of NAP from the inclusion complex was much more rapid than of NAP alone. The amount of NAP released from the tablet surfaces was determined for tablets pressed under 3500 kg/cm 2. It was seen that the total released amount of NAP from the NAP/β-CD complex was greater than that of intact NAP.