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.

Synthesis of new antioxidant conjugates and their in vitro hydrolysis with Stratum corneum enzymes.

The aim of this study was to synthesize new precursors, combinations of well-known antioxidant molecules: resveratrol, lipoic acid and vitamin E to improve their photo-stability and to modulate their lipophylic character. Active antioxidants are available through a controlled release by the action of skin enzymes upon a topic application. Two conjugates are described, the combinations of resveratrol-lipoic acid (6) and resveratrol-vitamin E (10). Both compounds are new molecules. This work describes their synthesis, characterization, stability study and in vitro biohydrolysis. Stratum corneum enzymes efficiently hydrolysed in vitro precursor 6 and liberate both active molecules, resveratrol and lipoic acid over the period of 72 h. Precursor 10 was hydrolysed in vitro by combination of Stratum corneum enzymes and the cholesterol esterase. A simple technique of preparation of the human Stratum corneum hydrolases is also described.

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.

Acylation and related reactions under microwaves. 4. Sulfonylation reactions of aromatics.

Solvent-free sulfonylation of benzene and its activated or deactivated derivatives were carried out under microwave (MW) irradiation and a catalytic amount of iron(III) chloride, which, under these conditions, is more active than other metallic salts. With more reactive and/or nonvolatile reagents (anisole, xylenes, mesitylene) expeditious conditions (short reaction time at constant MW power without control of the temperature) were used. With less reactive and/or low-boiling reagents (benzene, toluene, halobenzenes), the rise in temperature and the increase of reaction time were controlled either by sequential MW irradiation or by a temperature order. It was shown that MWs cause preferential interactions with polar species present in the reaction, especially the aryl sulfone and its FeCl3-complexed form. A MW nonthermal effect was not observed when identical temperature gradients were produced by classical heating and MW irradiation, and if reaction temperature was strictly controlled.

Enantioselective synthesis of both enantiomers of methyl dihydrojasmonate using solid-liquid asymmetric phase-transfer catalysis.

Both enantiomers of methyl dihydrojasmonate (-)-1 and (+)-1 were obtained by a short route using asymmetric Michael addition of dimethyl malonate onto pentyl enone 3, followed by nonracemizing demethoxycarbonylation. The key enantioselective step involves a new system of asymmetric solid-liquid phase-transfer catalysis using solvent-free conditions. Enantiomeric excess as high as 90% (91% yield) was achieved.

A short synthesis of troglitazone: an antidiabetic drug for treating insulin resistance.

Troglitazone was obtained in 5 steps from 4-bromo-1,1-dimethoxy-3-methylbut-2-ene with an overall yield of 7.5%. The formation of the chromane ring was achieved by condensing an unsaturated acetal with trimethylhydroquinone in the presence of bis(trifluoromethylsulfonyl)imide.