Biomedical subjects

Michel Bauer

Publications and source records attributed to Michel Bauer.

6 recordsLinked to original sources

PubMed2006

Relationship between HPLC precision and number of significant figures when reporting impurities and when setting specifications.

The rounding of an analytical result is a process that should take into account the uncertainty of the result, which is in turn assessed during the validation exercise. Rounding rules are known in physical and analytical chemistry since a long time, but are often not used or misused in pharmaceutical analysis. The paper describes the theoretical background of the most common rules and their application to fix the rounding of results and specifications. The paper makes use of uncertainty values of impurity determination acquired during studies of reproducibility and intermediate precision with regards to 22 impurities of drug substances or drug products. As a general rule, authors propose the use of sound and well-established rounding rules to derive rounding from the results of the validation package.

Chromatography, High Pressure Liquid↗

PubMed2005

Checking for optimal solutions in some NP-complete problems.

For some weighted NP-complete problems, checking whether a proposed solution is optimal is a nontrivial task. Such is the case for the traveling salesman problem, or the spin-glass problem in three dimensions. In this Letter, we consider the weighted tripartite matching problem, a well known NP-complete problem. We write mean-field finite temperature equations for this model and derive their zero temperature limit. We show that any solution of the zero temperature equations provides an exact absolute ground state of the system. As a consequence, we propose a criterion which can be checked in polynomial time, and such that given a putative optimal solution, if the criterion is satisfied, then the solution is indeed optimal. This criterion is generalized to a class of variants of the multiple traveling salesmen problems.

Journal Article↗

PubMed2005

Gene essentiality and the topology of protein interaction networks.

The mechanistic bases for gene essentiality and for cell mutational resistance have long been disputed. The recent availability of large protein interaction databases has fuelled the analysis of protein interaction networks and several authors have proposed that gene dispensability could be strongly related to some topological parameters of these networks. However, many results were based on protein interaction data whose biases were not taken into account. In this article, we show that the essentiality of a gene in yeast is poorly related to the number of interactants (or degree) of the corresponding protein and that the physiological consequences of gene deletions are unrelated to several other properties of proteins in the interaction networks, such as the average degrees of their nearest neighbours, their clustering coefficients or their relative distances. We also found that yeast protein interaction networks lack degree correlation, i.e. a propensity for their vertices to associate according to their degrees. Gene essentiality and more generally cell resistance against mutations thus seem largely unrelated to many parameters of protein network topology.

Computational Biology↗

PubMed2005

Studies on the crystallinity of a pharmaceutical development drug substance.

The crystallinity and amorphous content of a micronized pharmaceutical development drug substance have been independently determined. An evaluation of different techniques for this purpose has been carried out, and it was found that solid-state nuclear magnetic resonance (ss NMR) and X-ray powder diffraction (XRPD) were suitable for the former and latter, respectively. The baseline intensities of X-ray powder diffractograms, associated with the amorphous component of the sample, have been used to detect levels of non-crystalline material greater than 5%w/w with an absolute accuracy of +/-3%. ss NMR has been employed to quantify crystalline defects at levels of greater than 3%w/w with an estimated uncertainty of +/-2%. It is proposed that such crystalline defects arise from molecular conformational differences that only have a small effect on crystal lattice parameters and, by implication, only have small effects on X-ray powder diffractograms. In both cases the techniques are shown to be highly reproducible and require minimal sample preparation. Excellent linearity is demonstrated for the determination of amorphous material using prepared standards. The present account describes the choice of analytical method, method validation and the results obtained for typical samples of drug substance. It is demonstrated that solid-state NMR should be used as a complementary technique with respect to XRPD for studying crystallinity.

Calorimetry, Differential Scanning↗

PubMed2004

Stabilization of rasburicase and physico-chemical characterization of the resulting injectable formulation.

Rasburicase (Fasturtec/Elitek) is a new generation of recombinant urate oxidase administred therapeutically by intravenous infusion for the prevention or treatment of hyperuricemia during chemotherapy. To ensure a long storage period, a freeze-dried formulation was developed to guarantee the molecular integrity and enzyme activity. Screening of potential excipients was the first stage of the preformulation study. The selection was based on stability results (rasburicase solution with excipient) obtained with the isoelectric focusing profiles and residual enzyme activity. The different excipients were classified as stabilising, neutral or destabilising. A stability study was then carried out on different freeze-dried formulations containing the usual bulking agents for freeze-drying, excipients with a high glass transition temperature or competitive enzyme inhibitors having a stabilising effect. A mannitol/alanine mixture in phosphate buffer was selected from these preliminary results. Finally, the optimal content of mannitol and alanine in the freeze-dried powder was determined by an experimental design study. The water content and the appearance of the "cake", the osmolality, pH, clarity, and enzyme activity of the reconstituted solution were assessed. The formula with a mannitol/alanine ratio of 0.7 was found to be the best composition. Differential scanning calorimetry and ThermoStimulated Current technique experiments were carried out to study the amorphous phase. A glass transition temperature of about 45-500 degrees C was found. Glassy state is known to preserve stability, which was verified by the real stability data. X-ray diffraction studies have shown that alanine is in a crystallised state and that mannitol remains amorphous. Crystallised excipients participate in forming the structure of the powder and therefore help to prevent any collapse. Amorphous mannitol creates a surrounding medium favourable to the stability of the protein.

Alanine↗

PubMed2002

Molecular mobility study of amorphous and crystalline phases of a pharmaceutical product by thermally stimulated current spectrometry.

Two crystalline forms and the amorphous state of irbesartan, a pharmaceutical drug chosen as a model, were analyzed by Thermally Stimulated Current (TSC) spectroscopy, a powerful technique currently used in polymer science to investigate the molecular dynamics of heterogeneous and complex materials. Whereas no specific dielectric response was noted for the B crystalline form, the A form of irbesartan exhibited molecular motions localized inside its channel structure. The dynamics involved in the dielectric glass transition of amorphous samples followed a compensation law characteristic of highly cooperative relaxation processes. Concerning the amorphous content in physical mixtures, a calibration curve and a limit of detection (2.5%) were established. The limit of detection could be improved by optimizing the TSC experimental parameters. The amorphous sample recrystallized at a single temperature was interpreted by the "idealized one-state model" defined here to describe systems composed of identical semicrystalline particles in which amorphous and crystalline phases are independent of each other (i.e., no chemical and physical interaction between the two phases). Therefore, the idealized one-state model may be simulated by a two-state model, which is representative of the two-phase model. Other samples recrystallized through a complex annealing stage were explained by the classical one-state model in agreement with the three-phase model used to describe bulk semicrystalline systems. These results demonstrate that, as for polymers, the semicrystalline state of pharmaceutical drugs should not be considered as a single state but as a more complex system that can be described as an idealized one-state model or a one-state model depending on the applied thermal treatment. These results give a new view that should be taken into account in the development of amorphous pharmaceutical drugs and formulations.

Antihypertensive Agents↗