Solubility properties of racemic praziquantel and its enantiomers.

The purpose of this study was to characterize the solubility and thermodynamic properties of the optical isomers of the anti-schistosomal drug, praziquantel (PZQ) and to compare these properties to those of the racemic product used in commercial preparations (Biltricide, generic drugs). The crystalline enantiomers of PZQ exhibited different thermal properties than the racemic drug. The melting points and the enthalpies of fusion obtained from the differential scanning calorimetry (DSC) scans were nearly identical between the isomers and were substantially lower than those of racemic PZQ [(+/-)-PZQ]. The DSC results indicate that (+/-)-PZQ is a racemic compound and not a racemic mixture. This was confirmed by powder x-ray diffraction analysis and the IR spectra. The 30 degrees decrease in the melting point was reflected in increased solubility of the enantiomers, which amounted to twice that of the racemic PZQ. The behavior of the isomers in the presence of beta-cyclodextrin (beta-CD) was studied in water at 37 degrees C. The solubility data (phase solubility diagrams) were linear for up to the highest concentration of added beta-CD investigated. The apparent stability constants determined from the phase solubility diagrams showed that both the (+) and (-) enantiomers as well as (+/-)-PZQ exhibited moderate affinity to form a 1:1 complex in solution with beta-CD. The findings of this study may be of importance when efforts are considered to improve pharmaceutical formulation of this anti-schistosomal drug.

Dissolution properties of praziquantel--PVP systems.

The dissolution behavior of poorly water-soluble anti-schistosomal drug, praziquantel (PZQ) from coprecipitates (dispersions) and physical mixtures of the drug with polyvinylpyrrolidone (PVP) was characterized. The dissolution data obtained for different PZQ-PVP systems covering a range of drug loading from 10% to 100% w/w of PZQ in 10% increments were used in order to compare the release kinetics between the mixtures and the coprecipitates. The parameters estimated from release models showed that the coprecipitates exhibited an increase in the release rate in relation to intact PZQ but to a lesser extent than the equivalent physical mixtures. Furthermore, they exhibited different release behavior than the physical mixtures. According to solubility studies of PZQ in the presence of PVP the formation of a PZQ-PVP complex can be assumed. This hypothesis led to consistent interpretations of the dissolution profiles. In the coprecipitates the presence of PVP led to near zero-order release. The release kinetics were interpreted in terms of critical percolation thresholds according to the percolation theory.

Dissolution properties of praziquantel-beta-cyclodextrin systems.

The purpose of this study was to characterize the dissolution behavior of a poorly water-soluble antischistosomal agent, praziquantel (PZQ), from PZQ-beta-cyclodextrin systems containing 20-100% w/w of drug. Dissolution parameters obtained from the release data of simple physical mixtures and inclusion compounds prepared by the solvent method were employed to characterize the effect of drug loading on the release kinetics of PZQ. All the systems investigated showed improved dissolution in comparison with the free drug due to the ability to form a complex in solution. The systems prepared by the solvent method showed different characteristics and mechanism of dissolution than the physical mixtures: At low beta-cyclodextrin (beta-CD) weight fractions (high drug loading) their dissolution profiles were higher than those of the physical mixtures. At high polymer weight fractions (low drug loading and equimolar ratio) the physical mixtures exhibited a 7-fold higher dissolution rate than the pure drug. The inclusion systems, on the other hand, showed an improvement in the dissolution rate, but to a lesser degree than the physical mixtures. The observed changes in the mechanism of release kinetics of the different PZQ-beta-CD systems were interpreted using the principles of percolation theory and the results of thermal analysis of the physical mixtures and the inclusion compounds.

Use of fractal dimension in the study of fractured surfaces of insulin zinc crystals.

The micromorphology of two types of insulin zinc crystals was characterized by computerized image analysis. It was demonstrated that one can identify the recombinant DNA crystals from those of animal origin in a blinded sample by perimeter fractal dimension analysis. Fractal dimension analysis was also applied in the study of irregularly fractured surfaces produced by thermal and mechanical stress. The results obtained suggest that the fractal dimension is related to the intensity of applied stress. The characterization of newly formed boundaries of insulin zinc crystals produced by mechanical or thermal stress could determine various surface-related kinetic processes.

Determination of khellin in serum by gas chromatography.

A rapid gas chromatographic assay has been developed for the separation and determination of khellin in human serum. Using a DB-17 capillary column and a simple chloroform extraction, khellin and an internal standard, trioxsalen, were separated from endogenous substances without further clean-up. Spiked serum samples in the range 0.11-1.1 micrograms/ml were assayed and a linear calibration curve obtained.

Theophylline-controlled release preparations and fatty food: an in vitro study using the rotating dialysis cell method.

The in vitro dissolution behavior of four controlled-release theophylline products was investigated utilizing the rotating dialysis cell method. The effects of pH, oil, and enzymes on the dissolution profiles were studied. The wide range of pH values and the content of oil and enzymes in the dissolution media in the dialysis cell, which functioned as an in vitro model, were simulated to mimic physiological changes due to food along the entire gastrointestinal tract. Treatment with oil affected the dissolution behavior of Uniphyl and especially Theo-Dur Sprinkle but had little or no effect on the dissolution profiles of Theo-Dur tablets and Theo-24 capsules. The in vitro observations of the oil effect were related to the food effect obtained from published in vivo studies. The rotating dialysis cell can be a useful tool in studying factors which may be responsible for dissolution-related food effects on the absorption of controlled-release products.