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A case study is reported on anti-motion sickness transdermal patches sold in the Internet, claiming to contain only natural ingredients but, actually, containing undeclared medicinal active substances. The visual inspection of the samples evidenced many inconsistencies in secondary and primary packaging, missing of various legal information and a non-compliant "CE" mark.The qualitative analysis was performed by liquid chromatography - high resolution mass spectrometry and the quantitative by liquid chromatography with diode array detector.The analyses evidenced the presence of the antihistaminic drug Diphenhydramine and of other active substances (Capsaicin, a transdermal absorption enhancer, and Diclofenac in traces, probably a contaminant from other productions of the same plant). Moreover, the presence of several trace elements, including those potentially toxic to humans, was assessed by ICP-MS analysis.The case discussed is a new case of "medicines in disguise" never reported in literature, and shows the presence of tangible risks for public health.

This paper describes a case of medicine in disguise: seized tattoo inks containing lidocaine and tetracaine at high concentration. Identification of anaesthetics was performed by LC MS Q-TOF with ESI+ source, by accurate mass measurement and by comparing the fragmentation patterns of molecular ions, at 30 V and 10 V of collision-offset voltage, with reference standards. Quantification was also performed by LC MS Q-TOF on the chromatographic peaks in the extracted ion chromatograms, by calibration curves obtained at different standard concentrations and by standard additions approach. The measurement uncertainty was estimated from validation data. The paper gives also chromatographic parameters, MS and MS/MS data and a quantitation method, with a full validation, of other six “caines”. Thus the paper intends to provide a tool for identification and quantitation of the most common local anaesthetics that could be fraudulently added to tattoo inks. The results here reported show that the seized samples of inks represent a serious health risk owing to the high anaesthetic content – therapeutic-like dosage – found.

Ibuprofen is one of the widespread used non-steroidal anti-inflammatory drugs. Ibuprofen active ingredient is manufactured in many sites located all around the world. The aim of this paper was to classify the geographical source of ibuprofen active pharmaceutical ingredients (APIs) from the legal market, based on chemical characteristics and its impurity pattern and to define a geographical fingerprint.To classify ibuprofen in different geographical groups, the chemometrics by principal component analysis (PCA) and Cluster analysis was applied to HPLC, 1H-NMR data of twenty-four samples of APIs from approved manufacturers located in different European and Asian countries.The PCA showed clearly two different geographical groups, based on particular patterns of European or Indian samples; the cluster analysis showed the similarity of group.The chemometric analysis is an important tool for tracking the geographical origin of APIs. This could be useful to supplement the quality control ensuring safety of the medicinal products in legal market and dealing with the evolving changes of the illegal market.

Novel synthetic analogs of Sildenafil are constantly detected as adulterants in counterfeit drugs and dietary supplements. Their intake constitutes a serious health hazard as side effects are unknown. In this paper an investigation is carried out on NMR and MS/MS spectra of Sildenafil, Thiosildenafil, Acetildenafil and thirteen of their analogs: a list of key signals is reported and discussed with the intent to provide a tool that can help in detecting adulteration and in elucidating the structure of novel analogs. In this view extensive spectral data were reported, discussed and summarized in tables. A discussion on mass fragmentation and NMR chemical shifts is also provided to rationalize assignation. Moreover, a comprehensive information on the route of synthesis is provided for the benefit of those medicines control laboratories that need to synthesize analogs reference standards in-house.

The increasing illegal and on-line market of medicines and food supplements is helping the widespread diffusion of harmful counterfeit and forbidden products among consumers of developed countries. The objectives of this survey were the description of the main frauds recognized by public officers and the detection of illegal or counterfeit drugs and food supplements.Medicines and food supplements found by Police forces on the illegal market or resulting from seizures made by Italian Customs authorities were visually inspected and analysed to evaluate their quality and the presence of other undeclared substances.The visual inspection and the chemical analysis revealed unsuitable packaging (mostly lacking of adequate information for consumers), absence of the declared active substances and presence of undeclared active substances. Products containing doping agents, illegal substances and active ingredients requiring medical supervision were found.The present work confirmed the health risk associated with assumption of medicines purchased on the Internet and from the illegal supply chain and evidenced a new threat to consumer safety related to the presence of pharmaceutical active ingredients in food supplements claiming to contain only "natural ingredients".

Introduction In developed countries the phenomenon of pharmaceutical counterfeiting is steadily increasing through the illegal and the Internet market. Medicines for the treatment of erectile dysfunctions containing phosphodiesterase type 5 inhibitors (PDE5) are especially prone to falsification. Aims To obtain evidence of the health risks for patients taking these products and to provide useful information to general practitioners and specialists in sexual medicine. Methods First the samples were visually inspected and then analyzed to get information about their identity and quality. Main Outcome Measures A survey on the PDE5 medicines analyzed by the Italian official medicines control laboratory between 2005 and 2011 was performed. All the analyzed medicines were gathered from the Italian illegal market (seizures by police forces) or were bought from illegal online pharmacies. Results The study revealed that 24% of the analyzed samples were counterfeit and 54% were illegal medicines. In 12% of the cases an intermediate classification ( illegal/counterfeit ) was assigned. Only 7% of the samples were original. Moreover, the examination of the packaging evidenced potential risks: outer and immediate packaging missing; inconsistency between the carton box and the blister as regards the expiry date and/or the batch number; expiry date or manufacturer's name or country missing. Conclusions In 19% of the samples a potential health risk for patients was identified due to either the presence in the sample of more than one undeclared PDE5(s) or an amount of the active ingredient higher than that declared (up to 190% of the maximum dose) or to the presence of potentially dangerous excipients of non‐pharmaceutical origin or quality (e.g., gypsum or non‐purified talc). Gaudiano MC, Manna L, Rodomonte AL, Bartolomei M, Bertocchi P, Gallinella B, Antoniella E, Muleri N, Civitelli G, Alimonti S, Romanini L, Rufini L, and Valvo L. A survey on illegal and counterfeit medicines for the treatment of erectile dysfunctions in Italy. J Sex Med 2012;9:2130–2137.

"For export only" anti-inflammatory and lightening creams are medicinal products sold in African countries for their skin whitening action. In the last years, Rapid Alerts from European Medicinal Regulatory Agencies evidenced the presence of a large number of illegal and counterfeit anti-inflammatory products advertised for their whitening action on black skin in the European market. These drugs, containing glucocorticoids, are illegally sold in Europe in unauthorized ethno-cosmetics-shops and mainly bought by immigrants. This paper reports a new RP-LC method for the rapid simultaneous screening of six different active ingredients in anti-inflammatory and whitening products (creams, ointment and suspension): betamethasone dipropionate, dexamethasone, fluocinonide, fluocinolone acetonide, clobetasol propionate, methyl-prednisolone acetate. The method was developed and validated in view of its possible application in quality control laboratories, mainly those appointed to the control of illegal/counterfeit medicinal products. The associated measurement uncertainty was calculated from validation data. The method was then applied to the analysis of whitening products obtained from the Italian illegal market.

The growth of pharmaceutical counterfeiting is a major public health problem. This growth is resulting in a proportional increase in the number of samples that medicines control laboratories have to test. Thus the need for simple and affordable preliminary screening methods to be used by inspectors to decide in the field whether to collect a sample for further laboratory analysis or not. This paper intends to evaluate the possibility to employ for preliminary examinations of suspicious samples an optical spectrophotometer (colorimeter) used in the graphic industry, capable of measuring the reflectance visible spectrum of solid materials. The colorimeter was tested on original and counterfeited Viagra, Cialis and Levitra by measuring the colour of tablets' surface and of a specific spot of the packages. Various batches of the original drugs were employed both to investigate precision and robustness of the technique and to build spectral libraries. These libraries were used to compare suspicious samples to the corresponding original by means of a wavelength distance pattern recognition method. The method was eventually tested on suspicious samples sized by police authorities in order to evaluate its effectiveness. The device resulted precise and robust toward ambient conditions changes, although some limits emerged: the libraries of original samples need a frequent update and a lower precision is to be expected for tablets which surface is extremely convex.

Pharmaceutical counterfeiting is a worldwide public health problem, often under-recognised, especially in developing countries where the percentage of counterfeit and sub-standard medicines is dramatically high. Antibiotics, among the most widespread drugs, have been particularly targeted by counterfeiters. World Health Organization emphasizes the need for development and distribution of screening methods explicitly targeted to counterfeit drugs. In this paper is presented a single method for the simultaneous analysis of some of the most common and counterfeited essential antibiotics: ampicillin, amoxicillin+clavulanic acid, doxycycline, cloxacillin, chloramphenicol. A full validation was performed in terms of linearity, precision, robustness and trueness; an assessment of uncertainty was carried out exploiting these data. A wide linearity range was investigated considering the specific nature of counterfeit and sub-standard drugs, whose content in active substance may be rather far from the declared amount. A large span in robustness parameters was considered and a complete intermediate precision assessment was conducted, envisaging the possibility of transferring the method to quality control laboratories, hopefully in developing countries. Finally, the method was successfully applied to the analysis of antibiotics purchased on the informal market in Chad, among which counterfeit and sub-standard samples were detected.

Diclofenac sodium is a non-steroidal anti-inflammatory drug widely used in painful and inflammatory diseases. It can exist in different hydrate phases. By exposure to different conditions of temperature and relative humidity can be isolated a trihydrate form never described in literature. The methods of preparation of the trihydrate form (named DSH3) were described and its physico-chemical properties were investigated. Data from FTIR spectroscopy, X-ray powder diffraction and thermal analysis were used for identification and characterisation of DSH3 in comparison with the anhydrous form (DS, the commercial form) and the hydrate form DSH (obtained by exposure of DS to relative humidity even below 60% and already described and characterised in a previous article of the same authors). Intrinsic dissolution studies were performed to compare the pharmaceutical properties of DS and DSH with DSH3, since this form was accidentally found on the Italian market as active pharmaceutical ingredient (API). This work stresses the importance of assessing the correct crystalline form also in API of well-established use to guarantee quality, safety and efficacy of the final dosage form. Furthermore, this study suggests that isomorphic hydrate forms with a different dislocation of water within the crystal structures can exist.

Diclofenac sodium is a non-steroidal anti-inflammatory drug widely used in painful and inflammatory diseases. In standard conditions, by exposure to relative humidity even below 60% at 25 °C, the anhydrous form DS gives rise to a hydrate species DSH, a tetrahydrate form different from that obtained by crystallisation from water and previously described. The method of preparation and the physico-chemical properties of the hydrate form were investigated. Data from FTIR spectroscopy, X-ray powder diffraction and thermal analysis were used for the identification and the characterisation of DSH. DS and DSH were easily differentiated by their IR spectra, X-ray patterns and thermal behaviour. DSH stability was followed at room temperature over a period of 1 year and under different conditions of temperature to verify the tendency to solid–solid transition and to study its existence range. Solubility and intrinsic dissolution studies were performed to compare the physico-chemical properties of DS and DSH. Differences in solubility and intrinsic dissolution rates were pointed out: these studies showed that DS dissolved faster than DSH. Storage under uncontrolled environmental conditions or contact with water vapour during manufacturing process could thus influence the performance of the final dosage form.

The polymorphism of (R,S) propranolol hydrochloride was investigated by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray powder diffractometry (XRPD) and thermomicroscopy (HSM) coupled with FT-IR spectroscopy. Propranolol hydrochloride existed in three different crystalline forms, denoted as forms I, II and III, according to their decreasing melting temperatures. Modification II was the commercial product. The forms I and III were obtained by melting form II in different experimental conditions. Form III was obtained only by solidification of the melt in the presence of an alkali halide matrix (as a crystalline film on an alkali halide window or as powder dispersion in a KBr pellet). Forms I and II were also obtained by crystallization from 95% aqueous ethanol and acetone, respectively. The three forms were easily differentiated by their IR spectra in the 3400–2000 cm −1 range. The different crystalline structures of forms I and II were characterized by means of their X-ray powder diffraction patterns.

7,8-dihydroquinoline-4,5 (1 H ,6 H )-dione ( 1 ) and 7,8-dihydroquinoline-2,5-(1 H ,6 H )-dione ( 2 ) in their tautomeric oxo and hydroxy forms have been studied by ab initio Hartree-Fock calculations; tautomerization energies predict a more stable hydroxy structure having an intramolecular hydrogen bond for compound 1, whereas the oxo form is slightly-preferred for compound 2. Fourier Transform-Infra Red (FT-IR) spectra in CHCl 3 solution indicate that the predicted most stable tautomers in the vapour phase remain as such.

Solid-phase decomposition of benomyl has been investigated by thermogravimetric analysis; the degradation process (heating rate of 1 o C min -1 under nitrogen flux) starts at c. 65 o C. Semi-empirical quantum mechanical methods have been used to characterize the benomyl molecule and to obtain information on a possible degradation mechanism

Diclofenac sodium is a nonsteroidal anti-inflammatory drug widely used in painful and inflammatory diseases. It can exist in different hydrate phases. Recently the physico-chemical and pharmaceutical properties of a trihydrate form, named DSH3 were reported by the same authors. This short communication discusses how samples of a same polymorphic form can display dissimilar analytical signatures when obtained by different routes. Data from hot-stage microscopy, FT-IR spectroscopy, X-ray powder diffraction (XRDP) and thermal analysis were used to characterise the DSH3 samples prepared by different methods. Through the case study of diclofenac sodium, this work highlights how the method used to prepare a specific crystal modification can generate samples with different morphologies and therefore different properties and physical stability.

A measurement result cannot be properly interpreted if not accompanied by its uncertainty. Several methods to estimate uncertainty have been developed. From those methods three in particular were chosen in this work to estimate the uncertainty of the Eu. Ph. chloroquine phosphate assay, a potentiometric titration commonly used in medicinal control laboratories. The famous error-budget approach (also called bottom-up or step-by-step) described by the ISO Guide to the expression of Uncertainty in Measurement (GUM) was the first method chosen. It is based on the combination of uncertainty contributions that have to be directly derived from the measurement process. The second method employed was the Analytical Method Committee top-down which estimates uncertainty through reproducibility obtained during inter-laboratory studies. Data for its application were collected in a proficiency testing study carried out by over 50 laboratories throughout Europe. The last method chosen was the one proposed by Barwick and Ellison. It uses a combination of precision, trueness and ruggedness data to estimate uncertainty. These data were collected from a validation process specifically designed for uncertainty estimation. All the three approaches presented a distinctive set of advantages and drawbacks in their implementation. An expanded uncertainty of about 1% was assessed for the assay investigated.

Flunisolide exists in at least two different anhydrous crystalline forms (I and II) and in a hemihydrate form with distinctly different physico-chemical properties. Modification II and the hemihydrate form are the commercial products. Form I was obtained by heating all other forms above 230 degrees C. The different crystalline forms of flunisolide were investigated by FTIR spectroscopy, X-ray powder diffractometry, differential scanning calorimetry (DSC), thermogravimetric analysis and thermomicroscopy both coupled with FTIR spectroscopy (TG-FTIR and FTIR thermomicroscopy). The three forms were easily differentiated by their IR spectra, X-ray powder diffraction patterns and thermal behaviour. Their stability was investigated under different experimental conditions to verify the tendency to solid solid transition and to study the existence range of the three forms. The relationship among the two anhydrous polymorphs and the hemihydrate form and their equilibrium solubilities in water at 20 degrees C were also investigated.

The crystallisation conditions and the physicochemical properties of the modifications I and II of (R,S) propranolol hydrochloride were investigated. Detailed methods of preparation of the two forms were described. Data from FTIR spectroscopy, X-ray powder diffraction, thermal analysis, solubility and dissolution studies were used for the identification and the characterisation of the two forms. The forms I and II were easily differentiated by their IR spectra, X-ray patterns and thermal behaviour. The two polymorphs were found to be enantiotropically related to each other. Their stability was followed at room temperature over a period of 1 year and under different conditions of temperature, grinding and compression to verify the tendency to solid–solid transition and to study the existence range of the two forms. The equilibrium solubilities of the two polymorphs in n -octanol were determined as well as their dissolution profiles as pellets in aqueous medium. These studies showed that form I, the less thermodynamically stable, was more soluble (by more than 34%) and dissolved faster than form II in agreement with the thermodynamic rules (A. Burger, R. Ramberger, Mikrochim. Acta II (1979) 259–271).

Gamma radiation treatment plays an increasingly important role in the sterilization/sanitization of pharmaceutical products. However, irradiation may affect the stability of the product and thus its safety of use. We investigated the influence of ionizing radiation on modified release microparticulate drug delivery systems made of two types of polylactide-co-glycolide copolymers (PLG): RG 503 and RG 503H; these polymers have identical molecular weights but different chemical structures. The effect of γ radiation on polymer stability of the raw polymers (P) and related microspheres (Ms) was evaluated. Samples were irradiated at different irradiation doses (5, 15 and 25 kGy) using 60 Co as radiation source. The microspheres were prepared using the spray drying technique. Degradation of PLG and related microspheres was evaluated during six months in terms of average molecular weight ( M w ) loss by gel permeation chromatography (GPC) and variation in glass transition temperature ( T g ) using differential calorimetry (DSC). The presence of free radicals in the product was tested by electron paramagnetic resonance (EPR). Both P and Ms showed a trend in decreasing their M w at time 0 as a function of irradiation dose. For RG503 the decay in M w is always negligible for doses below 15 kGy while it is about 10% for 25 kGy. After 150 days M w decay was 25% in the microspheres and 20% in the raw polymer. It was not possible to evaluate the radiation effect, at different storage times, for RG503H because this polymer resulted to be unstable even in the regular storage conditions without being irradiated. The concentration of radiation-induced free radicals was higher in RG 503H (both P and Ms) and they were more stable than the free radicals species observed in the case of polymer RG 503. Alterations and/or production of new radicals were observed on exposure of RG 503H microspheres to the light. Radiolytic degradation of RG 503 under vacuum is characterized by a prevalence of the chain scission events leading to a decrease of M w . Some crosslinking can occur mainly in the post irradiation stage through the decay and coupling of the hydrogen abstraction radicals. A hydroperoxydative cycle, whose mechanism is suggested, is generated in the presence of oxygen.

Three crystalline modifications of fluocinolone acetonide, A, B and C, were characterized by means of FTIR, DSC, TG-FTIR, MICRO-FTIR and X-ray diffractometry. They were easily differentiated by their IR absorption bands in the 3600-3400 cm-1 range. The thermal behavior was also elucidated using combined techniques; thermomicroscopy and thermogravimetry coupled with Fourier transform infrared spectroscopy were found to be very useful tools for a better understanding of thermal events. On heating, form A and C were fully converted into form B. Polymorph A was found to be enantiotropically related to B, while form C was monotropically related to B. The existence of three polymorphs was confirmed by means of their different X-ray diffraction patterns. Detailed methods of preparation of the three modifications are also described.

Inclusion complex formation between pyridoxine and β- and γ-cyclodextrins in aqueous solution has been investigated by 1H NMR and UV spectroscopy. Both complexes exhibited a 1:1 stoichiometry and the inclusion process has been shown to perturb the equilibrium between the lactim and the lactam tautomer of pyridoxine, with a preferential inclusion of the former, less polar tautomer.