S. Alimonti

Medicines informal market in Congo, Burundi and Angola: counterfeit and sub-standard antimalarials

BackgroundThe presence of counterfeits and sub-standards in African medicines market is a dramatic problem that causes many deaths each year. The increase of the phenomenon of pharmaceutical counterfeiting is due to the rise of the illegal market and to the impossibility to purchase branded high cost medicines.MethodsIn this paper the results of a quality control on antimalarial tablet samples purchased in the informal market in Congo, Burundi and Angola are reported. The quality control consisted in the assay of active substance by means of validated liquid chromatographic methods, uniformity of mass determination, disintegration and dissolution tests. Moreover, a general evaluation on label and packaging characteristics was performed.ResultsThe results obtained on thirty antimalarial tablet samples containing chloroquine, quinine, mefloquine, sulphadoxine and pyrimethamine showed the presence of different kinds of problems: a general problem concerning the packaging (loose tablets, packaging without Producer name, Producer Country and sometimes without expiry date); low content of active substance (in one sample); different, non-declared, active substance (in one sample); sub-standard technological properties and very low dissolution profiles (in about 50% of samples). This last property could affect the bioavailability and bioequivalence in comparison with branded products and could be related to the use of different excipients in formulation or bad storage conditions.ConclusionThis paper evidences that the most common quality problem in the analysed samples appears to be the low dissolution profile. Here it is remarked that the presence of the right active substance in the right quantity is not a sufficient condition for a good quality drug. Dissolution test is not less important in a quality control and often evidences in vitro possible differences in therapeutic efficacy among drugs with the same active content. Dissolution profile can be dramatically affected by the choice of excipients in the oral solid formulation and, in many cases, is out of specifications due to the absence of formulation studies by producers of developing countries.

Development of a simple liquid chromatographic method with UV and mass spectrometric detection for the separation of substances related to amoxicillin sodium

Abstract The development of a selective method for the separation and identification of amoxicillin sodium-related substances is described. It is based on reversed-phase liquid chromatography followed either by UV detection (LC–UV) or by mass spectrometry (LC–MS). Mass detection was carried out by an atmospheric pressure ionization source and ionspray interface. Flow injection analyses–MS gave positive-ion mass spectra exhibiting abundant peaks due to their protonated molecules without significant fragmentation. The protonated molecules were used for selected ion monitoring LC–MS analyses. The method allowed the resolution of 13 available potential impurities from amoxicillin and from each other. Its applicability to an MS detector also permits a rapid identification of the impurities in the lack of the corresponding reference substances.

An LC method for the simultaneous screening of some common counterfeit and sub-standard antibiotics Validation and uncertainty estimation.

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.

A liquid chromatographic lon-pairing method for simultaneous determination of benazepril hydrochloride, fosinopril sodium, ramipril and hydrochlorothiazide in pharmaceutical formulations

SummaryA rapid and accurate reversed-phase ion-pairing liquid chromatographic method with UV detection was developed for the simultaneous assay of the angiotensin-converting enzyme inhibitors benazepril hydrochloride, fosinopril sodium and ramipril, and the diuretic hydrochorothiazide.The separation was achieved on a LC-8 (125×4.0 mml.D.; 5μm particle size) column.The mobile phase consisted of 20 mM sodium heptanesulphonate (pH=2.5) and methanol (32:68v/v).Validation of the method showed it to be precise, accurate and linear over the concentration range of analysis with a limit of detection of 1 ng for hydrochorothiazide, 2 ng for ramipril and benazepril and 8 ng for fosinopril.The method developed was applied to the analysis of three different binary commercial formulations.

Development and validation of a liquid chromatographic method for the determination of related substances in verapamil hydrochloride.

The development of a reversed-phase liquid chromatographic method for the determination of related substances in verapamil hydrochloride is described. The method is based on the use of a simple mobile phase on a specialty base-deactivated reversed-phase column. It enables the resolution of 13 related compounds from the parent drug and from each other. Validation of the method showed it to be reproducible, selective, accurate and linear over the concentration range of analysis with a limit of detection of 0.5 microgram ml-1. The developed method proved to be a real improvement compared with the LC test for chromatographic purity described in the USP monograph for verapamil hydrochloride.

Investigation of a new amoxicillin sodium impurity unstable in solution.

A new amoxicillin sodium impurity was detected by reversed-phase HPLC in commercial injectable preparations only when examined very soon after the drug was dissolved in the solvent vial (within about 10 min). The stability of this impurity was investigated by the degradation kinetic of its aqueous solutions. Ionspray mass spectrometry with flow-injection analysis and HPLC-MS methods were used to establish its nature. Some hypotheses concerning its chemical structure were formulated. The most likely assumption referred to the (5S,6R) amoxicillin piperazinedione diasteroisomer. The presence of the amoxicilloic acid methyl ester, an intermediate of the amoxicillin degradation process, was also hypothesized.

A Survey on Illegal and Counterfeit Medicines for the Treatment of Erectile Dysfunctions in Italy

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 manufacturers 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).

Amoxicillin sodium-potassium clavulanate: evaluation of gamma radiation induced effects by liquid chromatography on both the individual drugs and their combination.

The effects of gamma irradiation on the stability of potassium clavulanate, amoxicillin sodium and their combination were investigated. A decrease in purity and increase in degradation products up to 30 days after the irradiation were evaluated by reversed phase HPLC. The comparison between unirradiated and irradiated amoxicillin sodium, performed within 24 h following the irradiation process, showed no significant increase in the pre-existing impurities and no evidence of newly induced degradation products. On the contrary, an appreciable increase in the content of some impurities was evidenced 30 days after the irradiation. The chromatographic profile of irradiated potassium clavulanate showed the appearance of one unidentified new product and a slight increase of one pre-existing impurity. No further change in the impurity content was noted 30 days after the irradiation. The amoxicillin sodium-potassium clavulanate combination underwent the same kind of radiation induced degradation as the single compounds.