A new approach in the prediction of the dissolution behavior of suspended particles by means of their particle size distribution.

Though various attempts have been made in literature to model the particle size distribution of an active pharmaceutical ingredient (API) in function of the required release profile of the pharmaceutical product, so far one has not succeeded to develop a universal approach in the correlation of particle size distribution and in vitro dissolution data. In this publication, a new approach is presented on the use of particle size distribution data in the prediction of the in vitro dissolution profile of a suspension formulation. For this purpose, various theoretical experiments were done simply on paper and based on the Noyes-Whitney [A.A. Noyes, W.R. Whitney, J. Am. Chem. Soc. 19 (1897) 930-934] equation, the normalized dissolution profiles of various imaginary size distributions were calculated. For each size distribution, its weighted mean diameters were then calculated. Based on these theoretical data, a model could be developed which scientifically explains the dissolution profile of a suspension in function of its volume-weighted mean particle size (D[4, 3]). The applicability of this correlation model could experimentally be confirmed by evaluation of laser diffraction and in vitro dissolution data as they were obtained for different batches of a suspension formulation. This new approach in the correlation between particle size and dissolution may be an important analytical tool in the engineering of the particle size distribution of drug substance, and more precisely monitoring the D[4, 3] volume-weighted mean diameter may allow one to model the dissolution profile of a suspension formulation and thereby its in vivo release profile.

Laser diffraction and image analysis as a supportive analytical tool in the pharmaceutical development of immediate release direct compression formulations.

Immediate release direct compression tablet formulations require a strict control of the particle characteristics (i.e. particle size (distribution) and shape) of both the active pharmaceutical ingredient (API) and the excipients. In this publication, the development of a dry dispersion laser diffraction (LD) method has been outlined. With this method, the chemical development of an API meant for the manufacturing of an immediate release direct compression tablet formulation can be supported. Comparison with static image analysis (SIA) and scanning electron microscopy (SEM) data often shows laser diffraction to generate different size data. However, since LD is fast and frequently shows an adequate precision over a wide particle size range, the technique is still considered as a valuable analytical tool in the screening of the particle size distribution of API batches. In the future, automated (static) image analysis and dynamic image analysis are believed to become more and more important, since these techniques will allow the fast analysis of large amounts of particles with a minimum intervention of the operator.

Determination of pilocarpine, isopilocarpine, pilocarpic acid and isopilocarpic acid in human plasma and urine by high-performance liquid chromatography with tandem mass spectrometric detection.

A method is described for the determination of pilocarpine and its degradation products isopilocarpine, pilocarpic acid and isopilocarpic acid in human plasma and urine. The method is based on a simple sample preparation step -- ultrafiltration for plasma and dilution for urine samples -- followed by a reversed-phase liquid chromatographic separation of the analytes and detection by means of tandem mass spectrometry. Parameters affecting the performance of these steps are discussed. The high sensitivity and selectivity of the method allow low ng/ml concentrations to be determined for all compounds in plasma and undiluted urine, which enables the investigation of the metabolic fate and elimination of pilocarpine after oral administration to humans.

Validated method for the determination of idazoxan in human plasma by liquid chromatography with tandem mass spectrometric detection.

A liquid chromatography-tandem mass spectrometry method for the determination of idazoxan in human (heparin) plasma is presented, which was developed and validated using 500 microl of sample. Sample preparation consisted of the addition of fluoroidazoxan as the internal standard, extraction at alkaline conditions into tert.-butyl methyl ether, followed by centrifugation, evaporation of the solvent and reconstitution in methanol. After a short chromatographic run, detection took place by ionspray tandem mass spectrometry in positive ion mode. Validation results on linearity, specificity, accuracy, precision and stability, as well as application of the method to samples from a clinical trial, are shown. The validated calibration range is from 0.300 to 100 ng/ml, with accuracy (bias) and precision (coefficient of variation) being below 15% at all levels. A sample throughput of, typically, 150 per day can be achieved.

Pseudo-electrochromatography--negative-ion electrospray mass spectrometry of aromatic glucuronides and food colours.

Pseudo-electrochromatography is a combination of liquid chromatography and an electromigration technique, especially directed at the separation of ionic compounds prior to mass spectrometric detection with a mobile phase composition compatible with mass spectrometry. The application of pseudo-electrochromatography to the separation of food colours and aromatic glucuronides is described. An example of selectivity tuning by applying voltages of differing polarity during the chromatographic run is given. The coupling of pseudo-electrochromatography with electrospray mass spectrometry is demonstrated. Differences in the effects of the axial potential over the column between silica-based and polymeric packing materials are discussed.