Background A French pharmacovigilance centre recorded the case of a 40-year-old woman hospitalised for severe loss of weight (16 kg in 3 months) associated with hypokalaemia, inflammatory syndrome and psychotic decompensation, after taking a slimming preparation. It was sold on the internet as an herbal medicine containing natural authorised substances. Purpose The expertise of the French Health Agency (ANSM) was requested to find, identify and measure the active substances (ASs) contained in the product. Materials and Methods At first, the analysis strategy was a general screening method to search for ASs in the product, performed with gas chromatography–mass spectrometry [GC-MS] and high performance liquid chromatography-mass spectrometry [HPLC-MS]. Then a specific method confirmed the identification and quantified the AS using ultra performance liquid chromatography-diode array detection [UPLC-DAD]. Results The slimming preparation was presented in capsules containing a fine, brown homogeneous powder. Gas Chromatography revealed two main ASs and the mass spectrometry analysis identified them as sibutramine and phenolphthalein. The result of HPLC/MS also revealed two main ASs on chromatogram with molecular masses of 279 g.mol-1 and 318 g.mol-1. The UPLC-DAD, using the method ‘search for and quantification of 34 ASs in a slimming formulation’, confirmed these preliminary results and also gave a quantity of 8 mg of sibutramine and 20 mg of phenolphthalein per capsule. Conclusions Sibutramine is the AS in Sibutral (10 and 15 mg), an anti-obesity medicine, withdrawn from the market in January 2010 because of increased cardiovascular risk and an unfavourable benefit-risk assessment. Because of its carcinogenic potential phenolphthalein (a laxative) has been forbidden in France since 1999. Sibutramine and phenolphthalein were probably responsible for the clinical symptomatology in this patient. These slimming products sold outside the pharmaceutical distribution network have not been approved by the authorities resulting in a health risk, including fatal outcomes. No conflict of interest.

The presence on the market of illegal products for slimming purposes or the treatment of overweight is a public health issue. These products may contain illicit chemicals in order to improve their effectiveness. Some of these weight-loss compounds are responsible for adverse events, including fatal outcomes. A general strategy for the analysis of any suspect formulation begins with a large screening for the general search of a wide range of compounds. A methodology for the qualitative and quantitative determination of 34 compounds in slimming preparations (such as dietary supplements or medicinal products) was used for the control of slimming formulations from the market, including over the Internet. The fast liquid chromatography system (ultra-high-pressure liquid chromatography) used a gradient of solvent (phosphate buffer and acetonitrile), a C18 endcapped column and a diode array detector. This system allows dual identification based on retention time and UV spectra. The analytical method is simple, fast and selective since 34 weight-loss compounds can be detected in a 15-min run time. Thus, 32 commercial slimming formulations were analysed using this method, allowing the detection and quantification of hazardous active substances: caffeine, clenbuterol, nicotinamide, phenolphthalein, rimonabant, sibutramine, didesmethylsibutramine, synephrine and yohimbine.

This study was initiated by the laboratories and control department of the French Health Products Safety Agency (AFSSAPS) as part of the fight against the public health problem of rising counterfeit and imitation medicines. To test the discriminating ability of Near InfraRed Spectroscopy (NIRS), worse cases scenarios were first considered for the discrimination of various pharmaceutical final products containing the same Active Pharmaceutical Ingredient (API) with different excipients, such as generics of proprietary medicinal products (PMP). Two generic databases were explored: low active strength hard capsules of Fluoxetine and high strength tablets of Ciprofloxacin. Then 4 other cases involving suspicious samples, counterfeits and imitations products were treated. In all these cases, spectral differences between samples were studied, giving access to API or excipient contents information, and eventually allowing manufacturing site identification. A chemometric background is developed to explain the optimisation methodology, consisting in the choices of appropriate pretreatments, algorithms for data exploratory analyses (unsupervised Principal Component Analysis), and data classification (supervised cluster analysis, and Soft Independent Modelling of Class Analogy). Results demonstrate the high performance of NIRS, highlighting slight differences in formulations, such as 2.5% (w/w) in API strength, 1.0% (w/w) in excipient and even coating variations (<1%, w/w) with identical contents, approaching the theoretical limits of NIRS sensitivity. All the different generic formulations were correctly discriminated and foreign PMP, constituted of formulations slightly different from the calibration ones, were also all discriminated. This publication addresses the ability of NIRS to detect counterfeits and imitations and presents the NIRS as an ideal tool to master the global threat of counterfeit drugs.

Ethyl methanesulfonate (EMS) is a potential human mutagenic and carcinogenic compound which has been found by Roche laboratories in nelfinavir mesylate, the active pharmaceutical ingredient of Viracept. In order to verify the quality of the medicinal product, a gas chromatographic method using mass spectrometry detection was developed for the trace analysis of EMS in Viracept 250 mg tablets from Roche laboratories. Combined with suitable sample preparation including a liquid/liquid extraction this method allows the EMS quantification with a reporting limit of 5 ppm. The extract is injected on a gas chromatographic system with a CP624-CB capillary column. Selected Ion Monitoring mode was used for the EMS quantification. Some validation elements of the method are reported. The validation study was performed over a range from 5 ppm to 100 ppm.