Naji M. Najib

Improvement of the in vitro dissolution characteristics of famotidine by inclusion in β-cyclodextrin

Abstract An inclusion complex between famotidine and β-cyclodextrin was prepared by mixing the two components in a millimolar ratio in distilled water and heating under reflux for l h followed by stirring at room temperature for 5 days. Phase-solubility studies revealed the formation of a 1:1 complex of the AL type with a rate constant of 74.96 M−1. The formation of the complex in the solid state was confirmed by infrared spectroscopy and differential scanning calorimetry. The inclusion complex was shown by X-ray powder diffraction to be significantly less crystalline than any of the pure components. More significantly, the dissolution rate of the complex from constant surface-area discs was determined to be about twice and six times higher than that of the physical mixture and the pure drug, respectively.

A rapid and sensitive high-performance liquid chromatographic method for the determination of diclofenac sodium in serum and its use in pharmacokinetic studies

Abstract— A rapid, and sensitive high‐performance liquid chromatographic method has been developed for the determination of diclofenac sodium in serum using flufenamic acid as the internal standard. Serum protein was precipitated with acetonitrile. The drugs were eluted from a 5 μm C‐8 reversed‐phase column at ambient temperature with a mobile phase consisting of acetonitrile‐water (50:50% v/v) adjusted to pH 3.3 with glacial acetic acid, at a flow rate of 2 mL min−1 with UV detection at 280 nm. Each analysis required no longer than 10 min. Quantitation was achieved by the measurement of the peak‐height ratio and the relative and absolute recoveries varied from 90 to 98%. Detection limits for diclofenac sodium in serum is 25 ng mL−1. Intraday coefficients of variation (CV) ranged from 2.47 to 4.61 % and interday CVs from 3.52 to 7% at three different concentrations. Preliminary stability tests showed that diclofenac sodium is stable for at least 2 weeks in serum after freezing. The method is applied for the determination of the pharmacokinetic parameters of diclofenac after administration of two formulations (enteric‐coated tablet and slow‐release tablet), to a healthy male volunteer.

In Vitro and In Vivo Evaluation of Glibenclamide in Solid Dispersion Systems

The purpose of this work is to improve the dissolution and bioavailability characteristics of glibenclamide as compared to Daonil® tablets (Hoechst). Solid dispersions of glibenclamide in Gelucire 44/14 (Formula 1) and in polyethylene glycol 6000 (PEG 6000) (Formula 2) were prepared by fusion method. In vitro dissolution studies showed that the dispersing systems containing glibenclamide and Gelucire 44/14 or PEG 6000 gave faster dissolution rates than the reference product Daonil. The in vivo bioavailability study was assessed in six healthy male volunteers in crossover design with a 1‐week washout period. Both formulas were found to be significantly different from Daonil with regard to the extent of absorption as indicated by the area under serum concentration‐time curve. Both formulas are not significantly different from Daonil with respect to time of peak plasma concentration (Tmax). It is concluded from this pilot study that the ranking of the in vitro dissolution is similar to the ranking of in vivo availability. The ranking of the three preparations in term of dissolution rate and extent of absorption is as follows: Formula 2 > Formula 1 > Daonil.

Formulation and Release Behavior of Diclofenac Sodium in Compritol 888 Matrix Beads Encapsulated in Alginate

Sustained-release polymer beads containing diclofenac sodium (DNa) dispersed in Compritol 888 and encapsulated in calcium alginate shell were prepared utilizing 23 factorial design. The effect of sodium alginate concentration, drug:Compritol 888 weight ratio and CaCl2 concentration on drug content (%), time for 50% and 80% of the drug to be released, and mean dissolution time (MDT) were evaluated with analysis of variance (ANOVA). An increase in the level of all these factors caused retardation in the release, and t50%, t80%, and MDT were increased. The drug release was dependent on the pH of the release media. A formula that gives a release comparable to commercial products was prepared.

Characterization of a diflunisal polyethylene glycol solid dispersion system

Abstract This work involves the study of the nature of a possible interaction of diflunisal and polyethylene glylol (PEG) in solution and the solid state. Dynamic and equilibrium solubility studies, solvent power calculation and heat of solution determination were used to elucidate the mechanism of interaction in solution. Differential scanning calorimetric studies, infrared spectroscopy and hot stage microscopy were used to elucidate the mechanism of interaction in the solid state. From these studies it was concluded that no chemical interaction takes place between diflunisal and PEG neither in solution nor in the solid state. The increased solubility of diflunisal when dispersed in PEG could be attributed to one or more of several factors such as local solubilization action, reduction in particle size of the drug, alteration of the surface characteristics of the drug particles, increased thermodynamic activity and the high affinity of the drug to the polymer solution.

Characterization of famotidine polymorphic forms

Famotidine, crystallized from different solvents and solvent mixtures, was found to exist in three crystal forms, A, B, and C, depending on the solvent system used. This was confirmed by differential scanning calormimetry (DSC), infra-red (IR) spectroscopy, X-ray powder diffraction, thermomicroscopy, scanning electron microscopy and equilibrium solubility. The A, B, and C forms which melt at 171.3°C, 166.4°C and 160.9°C, respectively, were obtained in pure form by crystallization, as indicated from their DSC thermograms. The B form, which is the commercial form of famotidine, is probably the most stable and has therefore the lowest aqueous solubility (0.55 mg/ml). The solubility of the A form (0.82 mg/ml) is comparable to that of the C form (0.85 mg/ml).

Adsorption of ketotifen onto some pharmaceutical excipients

Abstract The adsorption of a drug onto solid dosage form excipients may influence its dissolution characteristics, analytical testing and bioavailability. This is particularly important for drugs which are normally used in low doses such as ketotifen fumarate. Ketotifen fumarate, an orally active prophylactic agent used for the management of bronchial asthma and allergic disorders, was found to adsorb onto microcrystalline cellulose, croscarmellose sodium and pregelatinized starch. Croscarmellose exhibited the highest affinity followed by micorocrystalline cellulose and then pregelatinized starch. The Freundlich adsorption isotherm was found to best describe the adsorption data indicating that adsorption is a continuous function of the initial drug concentration. The extent of adsorption of ketotifen onto croscarmellose showed dependency on the pH of the media. In addition, a correlation between adsorption of the drug and its solubility at different pH values was observed. The low and negative values of the heat of adsorption (AH) of ketotifen obtained in case of croscarmellose sodium and the pH dependency in case of its adsorption onto microcrystalline cellulose suggest that the predominant mechanism of ketotifen adsorption is physical and exothermic in nature.

Isolation and physicochemical characterization of solid forms of glibenclamide

Abstract Two polymorphs and two pseudo-polymorphs of glibenclamide were obtained by crystallization from a number of solvents. They were characterized by thermal microscopy, differential scanning calorimetry, thermogravimetry, X-ray powder diffraction, infrared spectroscopy, and dynamic and equilibrium solubility studies. Substantial differences were detected between the polymorphs and pseudo-polymorphs. Particularly, the pentanol and toluene solvates were significantly different with regard to dissolution rate and equilibrium solubility from each other and from the two polymorphs.

Release of salicylic acid, diclofenac acid and diclofenac acid salts from isotropic and anisotropic nonionic surfactant systems across rat skin

Release of salicylic acid, diclofenac acid, diclofenac diethylamine and diclofenac sodium, from lyotropic structured systems, namely; neat and middle liquid crystalline phases, across mid-dorsal hairless rat skin into aqueous buffer were studied. Release results were compared with those from the isotropic systems. The donor systems composed of the surfactant polyoxyethylene (20) isohexadecyl ether, HCl buffer of pH 1 or distilled water and the specific drug. High performance liquid chromatography (HPLC) methods were used to monitor the transfer of the drugs across the skin barrier. Results indicated that the rate-determining step in the transport process was the release of the drug from the specified donor system. Further, apparent zero order release was demonstrated with all systems. Except for diclofenac sodium, drug fluxes decreased as the donor medium changed from isotropic to anisotropic. The decrease in fluxes was probably due to the added constrains on the movement of drug molecules. By changing the anisotropic donor medium from neat to middle phase, drug flux decreased in case of salicylic acid and diclofenac sodium. In the mean time, flux increased in case of the diethylamine salt and appeared nearly similar in case of diclofenac acid. Rates of drug transfer across the skin from the anisotropic donors seemed to be largely controlled by the entropy contribution to the transport process. The type and extent of drug-liquid crystal interactions probably influenced the latter.

RP-LC method for the determination of cetirizine in serum

The development and evaluation of HPLC method for quantifying cetirizine in human serum is described. The method involves liquid phase extraction of cetirizine in methylene chloride, adding diazepam as an internal standard, followed by separation on a reversed phase C18 Novapak column (150 x 3.9 nm; 4 microm), and employing a UV-detection set at 230 nm at ambient temperature. The mobile phase consists of a 13 mM phosphoric acid solution and acetonitrile (61:39 v/v) adjusted to pH 2.8 with 5 M NaOH. The assay is linear from 10 to 500 ng ml(-1) with a detection limit of 5 ng ml(-1) and a mean recovery of 96.5%. The applicability of this method in pharmacokinetic studies is evaluated.