Are antibiotics substandard in Lebanon? Quantification of active pharmaceutical ingredients between brand and generics of selected antibiotics.

BACKGROUND: In developing countries, brand-generic substitution is not based on validated scientific evidence that confirm the therapeutic equivalence of the generic to the originator. Rather, decisions are made based on the availability of generic medications. Substitution by inappropriate preparations applies to antibiotics, which may increase the risk of resistance in case of underdosing. This analytical study aims to dose and assess for the accuracy of labeling three oral antibiotic preparations, namely ciprofloxacin hydrochloride, amoxicillin trihydrate and amoxicillin trihydrate-clavulanate potassium, the active pharmaceutical ingredients (APIs) found in brand and generic tablets available on the Lebanese market. METHODS: One brand and 4 generics of ciprofloxacin tablets, 3 generic amoxicillin tablets, and 1 brand and 4 generics of amoxicillin-clavulanic acid medications, were quantified, taking 2 batches of each. According to the United States Pharmacopeia (USP) guidelines, ultra-high pressure liquid chromatography was used to measure the APIs content within tablets. The USP required assay limit of the API was taken as the main comparison criteria. RESULTS: Out of the 5 ciprofloxacin medications tested, all 5 were out of the 2% required range, thus being substandard. For amoxicillin, all 3 medications were within the 20% range. As for amoxicillin-clavulanic acid medications, 4 out of 5 medications met the 30% required range of clavulanic acid and one exceeded the claimed amount of clavulanic acid, while all 5 met the assay limit for amoxicillin. CONCLUSION: These findings raise safety and efficacy concerns, providing solid grounds for potential correlations of antibiotic resistance/substandard antibiotics.

Drug Quality in South Africa: A Field Test.

To assess drug quality and pharmaceutical care in South Africa, "mystery" (i.e., anonymous) customers collected 316 samples from July to September 2016. Solid dosage forms containing amoxicillin alone or in combination with clavulanic acid as well as analgesics containing paracetamol alone or in combination with other drugs were sampled in a randomized fashion from the formal market (pharmacies) and by convenient sampling from the informal market. Visual inspection, uniformity of dosage units, and dissolution testing were performed to evaluate adherence to pharmacopoeial quality standards and to identify counterfeit, degraded, or substandard drugs. Although no counterfeited products were identified, only 55.4% (173/312) of samples were able to fulfill all pharmacopeial requirements for quality. Most of the 139 samples that failed were unable to pass the visual inspection due to inappropriate labeling and packaging. In addition, several substandard products were identified: 17 (5.4%) samples failed dissolution testing and 15 (4.8%) failed the content uniformity test. To improve drug quality and the quality of pharmaceutical care, better education of pharmaceutical professionals and monitoring of the pharmaceutical supply chain in South Africa are needed. Further field studies are necessary to evaluate risks and quality issues for other drug classes and distribution channels.

Rapid Analysis of the Quality of Amoxicillin and Clavulanate Potassium Tablets Using Diffuse Reflectance Near-Infrared Spectroscopy.

The cycle-closed dimer of amoxicillin influences its critical quality and is an important impurity in amoxicillin and clavulanate potassium tablets. The quality of the tablets could be rapidly evaluated using the impurity as an indicator. Here, we report a quantitative model to determine the cycle-closed dimer in samples from different manufacturers using diffuse reflectance near-infrared (NIR) spectroscopy by partial least squares regression for one y variable (PLS1) and hierarchical cluster analysis. Because the contents of the (active pharmaceutical ingredients) APIs (amoxicillin and clavulanate potassium) and water are also the important indexes of the tablet quality, three other quantitative models were used to confirm the API data and water content. All of the four models facilitate rapid and complete control of the tablet quality. In addition, quantitative models were validated in terms of specificity, linearity, accuracy, repeatability, and intermediate precision according to the International Conference on Harmonisation guidelines by evaluating the characteristics of the NIR spectra. These results confirmed that the models were satisfactory.

[The control of the critical quality attributes of amoxicillin and clavulanate potassium tablet].

The critical attribute was analyzed in clavulanate potassium tablet of amoxicillin according to the principle QbD. By investigation of the drug impurity profile, the cycle-closed dimer and penicilloic acid of amoxicillin were considered to be the critical impurities, and the sources and the degradation pathways of these two impurities were discussed. The research confirmed that crystal form was the critical attribute of drug substance. The drying process in the tablet granulation was regarded as the critical process parameter. The tablet formulation was also another factor in the impurity generation. This study provides a new idea for the evaluation of drug quality.

Solid-state stability and compatibility studies of clavulanate potassium.

The kinetic and thermodynamic parameters of degradation of clavulanate potassium in the solid state were studied by using a reversed phase high performance liquid chromatography (RP-HPLC) method. The degradation of clavulanate potassium was a first-order reaction depending on the substrate concentration at an increased relative air humidity (RH) and in dry air. The dependence ln k = f(1/T) became the ln k = (0.026 ± 166.35)-(2702.82 ± 1779.43)(1/T) in dry air and ln k = (1.65 ± 100.40) × 10(3)-(5748.81 ± 3659.67)(1/T) at 76.4% RH. The thermodynamic parameters Ea, ΔH(≠a), ΔS(≠a) of the degradation of clavulanate potassium in the solid state were calculated. The dependence ln k = f (RH%) assumed the form ln k = (8.78 ± 5.75) 10 (-2) (RH%) + (2.64 × 10(-8 )± 40.41). The compatibility of clavulanate potassium with commonly used excipients was studied at an increased temperature and in dry air. The geometric structure of molecule, highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) orbitals were also determined in order to predict the structural changes and reactive sites in clavulanate potassium during degradation and compatibility studies in the solid state. The ultraviolet (UV), Fourier transform infrared spectroscopy (FT-IR) and Raman spectra of degraded samples of the compound were analyzed.