Recognizing paracetamol formulations with the same synthesis pathway based on their trace-enriched chromatographic impurity profiles.

The development of a new drug substance is an expensive and time-consuming process. Therefore, the developers want to maximize the profit from the drug by patenting the concerned molecule as well as its synthesis pathway. In a later stage a faster or cheaper manufacturing process can be developed and patented. The aim of this study is to recognize paracetamol-containing drug formulations in relation to their synthesis pathways, in order to demonstrate the possibility to reveal fraudulently synthesized paracetamol. Since different synthesis pathways require different starting materials, solvents, reagents and catalysts and since they can produce different intermediates, it is expected that drug products originating from a different synthesis pathway will exhibit a different impurity profile. Therefore, in this study several paracetamol samples, synthesized in four different ways, are analyzed using trace-enrichment high-performance liquid chromatography (HPLC). The resulting chromatographic data were chemometrically treated in order to reveal clustering tendencies in the hope of distinguishing the different pathways. When performing principal component analysis (PCA) only 3 vaguely outlined clusters appeared. Projection pursuit (PP) was able to reveal 4 clusters and the samples with known synthesis pathway, except one, were classified in the different clusters. When hierarchical clustering and auto-associative multivariate regression trees (AAMRT) were applied, the samples of the four synthesis pathways could also be distinguished. AAMRT has an added value, since it can indicate the variables (peaks and thus also the impurities) that are responsible for the differences between the samples synthesized differently.

Isotopic ratios to detect infringements of patents or proprietary processes of pharmaceuticals: two case studies.

Because of the increasing problem of drug counterfeiting and the potential danger related as well as the economic losses involved, the pharmaceutical industry and the regulatory instances are interested in the development of anti-counterfeiting and patent protection methodologies. In this paper, the evaluation of measured isotopic ratios by means of explorative chemometric techniques was performed to distinguish groups in two data sets containing samples of acetyl salicylic acid and ibuprofen, respectively. The samples in the data sets originated from different countries and manufacturers. For both compounds a clear distinction of groups of samples could be obtained. These groups could be explained based on the origin of the samples, both geographically as well as based on the manufacturer. Hypotheses were formulated concerning the synthetic pathways of the molecules and they were linked to the groups obtained with the chemometric tools.

Chemometric treatment of vanillin fingerprint chromatograms. Effect of different signal alignments on principal component analysis plots.

This study describes the chemometric treatment of vanillin fingerprint chromatograms to distinguish vanillin from different sources. Prior to principal component analysis, which is used to discriminate vanillin from different origins, the fingerprints are aligned. Three alignment algorithms are tested, correlation optimized warping (COW), target peak alignment (TPA) and semi-parametric time warping (STW). The performance of the three algorithms is evaluated and the effect of the different alignments on the PCA score plots is investigated. The alignment obtained with STW differs somewhat from that with COW and TPA. However, equivalent score plots were obtained regarding the different vanillin groups.

[Obstetrical complications of adenomyosis. Literature review and two case reports]. / Les complications obstétricales de l'adénomyose. Revue de la littérature, à propos de 2 observations.

Adenomyosis of the uterus is a frequent disorder often associated with pregnancy. Diagnosis is difficult during pregnancy and usually is made after an obstetrical complication. In a review of the literature from 1904 to 1994, only 31 cases of obstetrical complications related to adenomyosis have been reported. We report two cases revealed by obstetrical complications: one causing spontaneous rupture of the uterus during labor in a primiparous woman and the other with cornual ectopic pregnancy diagnosed, due to an episode of massive intraperitoneal bleeding.

[Endometrial ossifications. A new case revealed by secondary sterility]. / Ossifications endométriales. A propos d'un nouveau cas révélé par une stérilité secondaire.

The authors give the case history of a patient with endometrial ossification revealed by an infertility. They recall the circumstances and the discovery of this uncommon affection and they summarize references in the literature concerning aetiopathogenic theories.