Solubility Of Celecoxib Research Articles

The use of spray-drying to enhance celecoxib solubility

The present research investigates the enhancement of the dissolution rate of celecoxib by using spray-drying to prepare a solid dispersion with various polymers, namely Kollicoat IR® (Kollicoat), polyvinyl alcohol (PVA) 22000, or polyethylene glycol 6000 (PEG). The investigated drug-to-polymer mass ratios were 1:1, 1:2, and 1:4 by weight. Hydroalcoholic or methylene chloride solvent systems were used. The obtained yields ranged from 65% to 78%, whereas the entrapment efficiencies were between 68% and 82%. The results revealed an increase in the dissolution rate of the prepared particles up to 200% within 20 min. The prepared particles were investigated using differential scanning calorimetry, scanning electron microscopy, X-ray diffraction, and Fourier transform infrared spectroscopy. The increased dissolution rate was attributed to hydrogen bond formation between celecoxib and each polymer together with the reduced size of the formed particles offering a greater overall surface area. It was concluded that spray-drying may be considered a successful one-step technique to improve the dissolution rate of celecoxib when using Kollicoat, PVA, or PEG as the carrier polymer.

Nanoemulsion: A promising tool for solubility and dissolution enhancement of celecoxib

The solubility and dissolution of the poorly soluble drug celecoxib (CXB) was enhanced using many techniques like nanoemulsion, solid lipid nanoparticle and solid dispersion in the present investigation. The solubility of CXB in each formulation was determined using the reported HPLC method at the wavelength of 250 nm. Dissolution studies of pure CXB and its formulations were performed using USP dissolution apparatus in distilled water. The highest solubility (228. 24 mg/mL) as well as % dissolution (99.9) of CXB was obtained with nanoemulsion technique. The results of solubility and dissolution were highly significant using the nanoemulsion technique as compared to other techniques (P < 0.01). All three formulations showed a sustained type of drug release. The best sustained type drug release was obtained with nanoemulsion. This indicated that nanoemulsion can be successfully used for sustained and controlled drug delivery of CXB. Overall these findings suggested that nanoemulsion is a promising vehicle for solubility and dissolution enhancement of CXB.

Caffeine: A potential complexing agent for solubility and dissolution enhancement of celecoxib

Complexation of caffeine with the drug celecoxib was used to enhance its solubility as well as in vitro dissolution in the present investigation. Caffeine was extracted from tea leaves using the sublimation method. A molecular complex (1:1) of caffeine–celecoxib was prepared using the solubility method. The solubility of celecoxib in distilled water and the caffeine complex was determined using a HPLC method at a wavelength of 250 nm. Dissolution studies of pure celecoxib, a marketed capsule (Celebrex®), and the complex were performed using USP dissolution apparatus I for pure celecoxib and the complex and apparatus II for the capsule in distilled water. The highest solubility (48.32 mg/mL) as well as percent dissolution (90.54%) of celecoxib was obtained with the caffeine–celecoxib complex. The results for solubility and dissolution were highly significant as compared to pure celecoxib and the marketed capsule (p < 0.01). These results suggest that caffeine is a promising complexing agent for solubility as well as dissolution enhancement of the poorly soluble drug celecoxib.

Preparation and evaluation of celecoxib-loaded microcapsules with self-microemulsifying core

The purpose of this study was to prepare alginate microcapsules with a self-microemulsifying system (SMES) containing celecoxib in the core. An Inotech IE-50 R encapsulator equipped with a concentric nozzle was used to prepare the microcapsules. The encapsulated SMES was shown to increase celecoxib solubility over that of the pure drug more than 400-fold. Microcapsules prepared with a high SMES:celecoxib ratio exhibited distinct core vesicles containing liquid SMES. By modifying the SMES and including an additional chitosan coating, drug loading in the range from 12–40% could be achieved with the degree of encapsulation ranging from 60–82%. Alginate microcapsules loaded with SMES and celecoxib showed increased dissolution rate of celecoxib over that of alginate microcapsules loaded with celecoxib or of the celecoxib alone. Compared to the previous report, drug loading capacity was significantly improved, enabling the formulation of dosage forms which are of suitable size for peroral application.

Combined effect of hydroxypropyl methylcellulose and hydroxypropyl-β-cyclodextrin on physicochemical and dissolution properties of celecoxib

Investigation on the influence of hydroxypropyl methylcellulose (HPMC) on solubility and dissolution properties of celecoxib/hydroxypropyl-β-cyclodextrin system was carried out, with the ultimate goal of enhancing the drug bioavailability. 1H-NMR and 13C-NMR spectroscopy were first performed to elucidate the type of interactions between celecoxib (CEL) and hydroxypropyl-β-cyclodextrin (HP-β-CD). Then, solubility studies in the absence and in the presence of HPMC were carried out in aqueous solution. After heating in autoclave of CEL/HP-β-CD/HPMC suspensions a synergistic increasing effect on the aqueous solubility of CEL was observed. In fact, the presence of both HP-β-CD (0.05 M) and HPMC (0.25% w/v) gave rise to a 330-fold CEL solubility increase, whereas the cyclodextrin alone provided a 34-fold increase. Gibbs free energy values calculated from phase solubility data were all negative, indicating the spontaneous nature of CEL solubilization, and they decreased in the presence of HPMC, demonstrating that the solubilization conditions became more favorable. CEL/HP-β-CD and CEL/HP-β-CD/HPMC solid systems (physical mixtures and coevaporated products) were characterized by differential scanning calorimetry and infrared spectroscopy. Results suggested that the coevaporation method yields a high degree of amorphous entities and indicated the formation of a CEL/HP-β-CD complex in the coevaporated products. The positive effect of HPMC is particularly evident when looking at the CEL dissolution rate from the binary and ternary solid systems. Specifically, the percent of CEL dissolved after 10 min. resulted 84.21% for ternary coevaporated product and 50.18% for binary coevaporated product with respect to 13.10% for the drug alone.

Multivesicular Liposomes Bearing Celecoxib-β-Cyclodextrin Complex for Transdermal Delivery

In our work depot delivery systems of celecoxib were developed using multivesicular liposomes. Moreover, the solubility of celecoxib was enhanced by complexing drug with cyclodextrin to overcome the limitation of conventional therapy. The multivesicular liposomes (MVLs) bearing celecoxib-β -cyclodextrin inclusion complex were prepared by reverse phase evaporation method, and multilamellar vesicles (MLVs)-bearing drug complex was prepared by the cast film method. The formulations were characterized for vesicle size, encapsulation efficiency, and in vitro drug release. In vivo performance of multivesicular liposomes bearing celecoxib-β -cyclodextrin inclusion complex was evaluated by assessing anti-inflammatory activity using carrageenan-induced rat paw edema volume method. The results were compared with that of celecoxib-cyclodextrin complex and MLVs containing celecoxib-β -cyclodextrin inclusion complex in equal amounts. Phase solubility studies for the celecoxib-β -cyclodextrin inclusion complex clearly indicated an increase in aqueous solubility of celecoxib with an increase in β –CD concentration. The in vitro release studies reveal that MLVs release more than 80% drug within 48 hr whereas MVL formulations release nearly the same amount of drug in 120 hr. In vivo data reveal that reduction in paw volume with MVL formulation was not rapid and fast, but the effect was maintained for prolonged periods, and even after 24 hr there was 40.7 ± 3.40% reduction in paw volume. MVL formulation showed more sustained and prolonged anti-inflammatory effect compared with plain drug and MLVs. We concluded that multivesicular liposome can be successfully utilized for the sustained delivery of celecoxib.

Influence of polymers on the bioavailability of microencapsulated celecoxib

Celecoxib, a selective COX-2 inhibitor, primarily used in treatment of osteoarthritis, rheumatoid arthritis and acute pain was encapsulated in microparticles composed of various polyesters, polymethacrylates or cellulose derivatives used alone or blended. The influence of polymers on microparticle mean diameter, encapsulation efficiency and in vitro and in vivo celecoxib release was investigated. Microparticles were in the size range 11–37 µm. Encapsulation efficiency was optimal due to poor aqueous solubility of celecoxib. Considering in vitro release, microparticles could be divided into drug delivery systems with fast and slow release profiles. Microparticles prepared with poly-ε-caprolactone, Eudragit® RS and low viscosity ethylcellulose, together with physical mixture of celecoxib with lactose and Celebrex®, were tested in vivo. Relative bioavailability of celecoxib was below 20% in all cases and was probably the consequence of a slow in vivo release of celecoxib from microparticles or low wettability in the case of Celebrex® and physical mixture.

Use of calcined Mg–Al–hydrotalcite to enhance the stability of celecoxib in the amorphous form

The use of compound in amorphous forms is a promising approach to improve solubility of poorly water-soluble drugs. However, during storage, amorphous state can spontaneously transform to the lower energy crystalline form and this is a limiting factor for a large commercial use of drugs. In this paper, calcined hydrotalcite was employed to support amorphous celecoxib and several preparations at different weight drug/carrier ratio were prepared. Solubility of celecoxib from the prepared systems was evaluated and its physical stability during storage at different conditions was examined as well. The results show that HTlc-calc can be used as a support of amorphous celecoxib with consequent improvement of drug solubility and physical stability.

Bovine and Porcine Transscleral Solute Transport: Influence of Lipophilicity and the Choroid–Bruch’s Layer

To determine the influence of the choroid-Bruch's layer and solute lipophilicity on in vitro transscleral drug permeability in bovine and porcine eyes. The in vitro permeability of two VEGF inhibitory drugs, budesonide and celecoxib, which are lipophilic and neutral at physiologic pH, and of three marker solutes, 3H-mannitol (hydrophilic, neutral), sodium fluorescein (hydrophilic, anionic), and rhodamine 6G (lipophilic, cationic), were determined across freshly excised scleras, with or without the underlying choroid-Bruch's layer. Select studies were performed using porcine sclera with and without choroid-Bruch's layer. Neural retina was removed by exposure of the eyecup to isotonic buffer and wherever required, the retinal pigment epithelial (RPE) layer of the preparation was disrupted and removed by exposure to hypertonic buffer. Because of the poor solubility of celecoxib and budesonide, permeability studies were conducted with 5% wt/vol of hydroxypropyl-beta-cyclodextrin (HPbetaCD). For other solutes, permeability studies were conducted, with and without HPbetaCD. Partitioning of the solutes into bovine sclera and choroid-Bruch's layer was also determined. The calculated log (distribution coefficient) values were -2.89, -0.68, 2.18, 3.12, and 4.02 for mannitol, sodium fluorescein, budesonide, celecoxib, and rhodamine 6G, respectively. Removal of RPE was confirmed by transmission electron microscopy and differences in the transport of mannitol. The order of the permeability coefficients (Papp) across sclera and sclera-choroid-Bruch's layers in bovine and porcine models was 3H-mannitol > fluorescein > budesonide > celecoxib > rhodamine 6G, with HPbetaCD, and 3H-mannitol > fluorescein > rhodamine 6G, without HPbetaCD. The presence of choroid-Bruch's layer reduced the bovine scleral permeability by 2-, 8-, 16-, 36-, and 50-fold and porcine tissue permeability by 2-, 7-, 15-, 33-, and 40-fold, respectively, for mannitol, sodium fluorescein, budesonide, celecoxib, and rhodamine 6G. The partition coefficients measured in bovine tissues correlated positively with the log (distribution coefficient) and exhibited a trend opposite that of transport. The partition coefficient ratio of bovine choroid-Bruch's layer to sclera was approximately 1, 1.5, 1.7, 2, and 3.5, respectively, for the solutes, as listed earlier. The choroid-Bruch's layer is a more significant barrier to drug transport than is sclera. It hinders the transport of lipophilic solutes, especially a cationic solute, more than hydrophilic solutes and in a more dramatic way than does sclera. The reduction in transport across this layer directly correlates with solute binding to the tissue. Understanding the permeability properties of sclera and underlying layers would be beneficial in designing better drugs for transscleral delivery.

Beta-cyclodextrin complexes of celecoxib: molecular-modeling, characterization, and dissolution studies.

Celecoxib, a specific inhibitor of cycloxygenase-2 (COX-2) is a poorly water-soluble nonsteroidal anti-inflammatory drug with relatively low bioavailability. The effect of beta-cyclodextrin on the aqueous solubility and dissolution rate of celecoxib was investigated. The possibility of molecular arrangement of inclusion complexes of celecoxib and beta-cyclodextrin were studied using molecular modeling and structural designing. The results offer a better correlation in terms of orientation of celecoxib inside the cyclodextrin cavity. Phase-solubility profile indicated that the solubility of celecoxib was significantly increased in the presence of beta-cyclodextrin and was classified as A(L)-type, indicating the 1:1 stoichiometric inclusion complexes. Solid complexes prepared by freeze drying, evaporation, and kneading methods were characterized using differential scanning calorimetry, powder x-ray diffractometry, and scanning electron microscopy. In vitro studies showed that the solubility and dissolution rate of celecoxib were significantly improved by complexation with beta-cyclodextrin with respect to the drug alone. In contrast, freeze-dried complexes showed higher dissolution rate than the other complexes.

Formulation Design of Self-Microemulsifying Drug Delivery Systems for Improved Oral Bioavailability of Celecoxib

Celecoxib is a hydrophobic and highly permeable drug belonging to class II of biopharmaceutics classification system. Low aqueous solubility of celecoxib leads to high variability in absorption after oral administration. Cohesiveness, low bulk density and compressibility, and poor flow properties of celecoxib impart complications in it's processing into solid dosage forms. To improve the solubility and bioavailability and to get faster onset of action of celecoxib, the self-microemulsifying drug delivery system (SMEDDS) was developed. Composition of SMEDDS was optimized using simplex lattice mixture design. Dissolution efficiency, t(85%), absorbance of diluted SMEDDS formulation and solubility of celecoxib in diluted formulation were chosen as response variables. The SMEDDS formulation optimized via mixture design consisted of 49.5% PEG-8 caprylic/capric glycerides, 40.5% mixture of Tween20 and Propylene glycol monocaprylic ester (3:1) and 10% celecoxib, which showed significantly higher rate and extent of absorption than conventional capsule. The relative bioavailability of the SMEDDS formulation to the conventional capsule was 132%. The present study demonstrated the suitability of mixture design to optimize the compositions for SMEDDS. The developed SMEDDS formulations have the potential to minimize the variability in absorption and to provide rapid onset of action of celecoxib.

Solubility enhancement of Cox-2 inhibitors using various solvent systems.

This study examined the solubility enhancement of 4 cox-2 inhibitors, celecoxib, rofecoxib, meloxicam, and nimesulide, using a series of pure solvents and solvent mixtures. Water, alcohols, glycols, glycerol, and polyethylene glycol 400 (PEG 400) were used as solvents and water-ethanol, glycerol-ethanol, and polyethylene glycol-ethanol were used as mixed-solvent systems. A pH-solubility profile of drugs was obtained in the pH range 7.0 to 10.9 using 0.05 M glycine-sodium hydroxide buffer solutions. Lower alcohols, higher glycols, and PEG 400 were found to be good solvents for these drugs. The aqueous solubility of celecoxib, rofecoxib, and nimesulide could be enhanced significantly by using ethanol as the second solvent. Among the mixed-solvent systems, PEG 400- ethanol system had highest solubilization potential. In the case of meloxicam and nimesulide, solubility increased significantly with increase in pH value. Physico-chemical properties of the solvent such as polarity, intermolecular interactions, and the ability of the solvent to form a hydrogen bond with the drug molecules were found to be the major factors involved in the dissolution of drugs by pure solvents. The greater the difference in the polarity of the 2 solvents in a given mixed solvent, the greater was the solubilization power. However, in a given mixed-solvent system, the solubilization power could not be related to the polarity of the drugs. Significance of the solubility data in relation to the development of formulations has also been discussed in this study.

Enhancement of Solubility and Dissolution Rate of Poorly Water Soluble Drug using Cosolvency and Solid Dispersion Techniques

The low aqueous solubility of celecoxib (CB) and thus its low bioavailability is a problem. Thus, it is suggested to improve the solubility using cosolvency and solid dispersions techniques. Pure CB has solubility of 6.26±0.23µg/ml in water but increased solubility of CB was observed with increasing concentration of cosolvents like PEG 400, ethanol and propylene glycol. Highest solubility (791.06±15.57mg/ml) was observed with cosolvency technique containing the mixture of composition 10:80:10%v/v of water: PEG 400: ethanol. SDs with different polymers like PVP, PEG were prepared and subjected to physicochemical characterization using Fourier-transform infrared (FTIR) spectroscopy, X-ray diffractometry (XRD), differential scanning calorimetry (DSC), solubility and dissolution studies. These studies reveals that CB exists mainly in amorphous form in prepared solid dispersions of PVP, PEG4000 and PEG6000 further it can also be confirmed by solubility and dissolution rate studies. Solid dispersions of PV5 and PV9 have shown highest saturation solubility and dissolution rate