Wastewater-based estimation of diabetes mellitus prevalence in 237 cities: A cross-China study.

Diabetes mellitus, a metabolic disease characterized by hyperglycemia, has been witnessed as a rapidly escalating worldwide health crisis. China currently had 140.9 million diabetic population in 2021, which was the largest globally. DM has witnessed a significant surge in the past few decades, leading to an alarming rise in the overall burden caused by this disease. To monitor the near real-time DM prevalence and the consumption of first-line anti-diabetic drugs, a wastewater-based epidemiology (WBE) approach based on the back-calculation of metformin concentration was implemented in 237 cities in China. The quantitative analysis of metformin in wastewater was conducted by LC-MS/MS with satisfactory results of method validation. The average concentration of metformin in wastewater was 14.07 ± 13.16 µg/L, and the per capita consumption was 5.16 ± 2.08 mg/day/inh, ranging from 0.90 to 10.36 ± 4.63 mg/day/inh. The calculated metformin prevalence was found to be 0.52 % ± 0.28 %, and the final estimated DM prevalence was 11.33 % ± 4.99 %, which was nearly consistent with the result of the International Diabetes Federation survey of 9.98 %. The results suggested that metformin might be one of the suitable WBE biomarkers in DM monitoring and WBE strategy could potentially enable the estimation of DM prevalence in most of Chinese cities after reasonable correction of associated parameters.

Development of eco-friendly spectrophotometric methods for analysis of metformin hydrochloride and linagliptin in presence of metformin toxic impurity in their pure and dosage forms: Validation, practicality and greenness studies.

Metformin is considered as type 2 diabetes first line treatment according to American Diabetes Association and European Association. But, in some cases, di- or tri - therapy should be prescribed for glycemic management, prevention of the maximum dose side effects and induced effectiveness. Co-administration of Linagliptin with metformin has many benefits on diabetic patients such as decrease the possibility of hypoglycemia. For the first time, novel and reliable techniques were developed and verified for the concurrent quantification of metformin hydrochloride and linagliptin, while accounting for the existence of metformin toxic impurity 1-cyanoguanidine in their pure and dosage forms. Method (A) utilizes the zero-order spectrophotometric approach to quantitatively determine the concentration of linagliptin. The measurements are performed at a wavelength of 295 nm. The double divisor derivative ratio spectrophotometric method is used in Method (B) to measure the amounts of metformin and cyanoguanidine at 252 nm and 219 nm wavelengths, respectively. The spectrophotometric method (C) for determining metformin and cyanoguanidine at 252 nm and 223 nm, respectively, is based on the single divisor derivative ratio-zero crossing technique. The obtained findings were subjected to statistical comparison with the reported method, revealing no statistically significant differences. The Green Analytical Procedure Index (GAPI) and Analytical GREEnness Metric approach (AGREE) determined that these approaches had a high degree of environmental friendliness. Additionally, the proposed strategy was deemed to be practical according to the Blue Applicability Grade Index (BAGI) assessment tool.

Quantitative determination of potential genotoxic impurities in metformin hydrochloride and empagliflozin tablets through ultra-performance liquid chromatographymass spectrometry.

An increasing number of drug research institutions consider genotoxic impurity research a core task in drug research and development. Peroxides in drugs may directly or indirectly attack and damage cell DNA, posing a potential carcinogenic risk to the human body. Currently, the literature only studies hydroperoxide impurities, and benzyl peroxide has not been studied yet. In this study, an effective method for ultra-performance liquid chromatographymass spectrometry (UPLCMS/MS) was established and verified to detect and quantify the potential genotoxic impurity (PGI), empagliflozin benzyl peroxide, in metformin-empagliflozin combination formulations, which has not been reported thus far. A Waters ACQUITY UPLC HSS T3 (3.0 ×100 mm, 1.8 µm) column was used to achieve chromatographic separation with gradient elution. The mass spectrometry conditions were optimized using electrospray ionization in the negative mode. Following the International Conference of Harmonization (ICH) guidelines, this methodology can quantify PGIs at 1.35 ng/mL (5.4 ppm) in samples. This validated method exhibited good linearity over a concentration range of 5.4 to 36 ppm, and the accuracy of this method was in the range of 83.2-95.0% for empagliflozin benzyl peroxide. This approach fills the gap in the detection method for benzyl peroxide impurities in metformin hydrochloride and empagliflozin tablets, providing technical support for the quality control of the drug.

Valuation of environmental influence of recently invented high-performance liquid chromatographic method for hypoglycemic mixtures of gliflozins and metformin in the presence of melamine impurities: Application of molecular modeling simulation approach.

Molecular modeling is the science of representing molecular structures numerically and simulating their behavior with the equations of quantum and classical physics. Coupling molecular modeling and simulation with chromatographic resolution for pharmaceutical products constitutes a new technique in pharmaceutical analysis. An innovative high-performance liquid chromatographic (HPLC) methodology was developed for the quantification of metformin hydrochloride (MET), empagliflozin (EMP), and canagliflozin (CAN) in bulk, laboratory-developed combinations, pharmaceutical tablets, and in the presence of melamine. Chromatographic separation was accomplished using a Symmetry column with 0.03 M potassium dihydrogen phosphate buffer and 0.02 M heptane sulphonic acid: acetonitrile as the mobile phase. Molecular modeling using molecular operating environment software was applied to properly select the stationary phase suitable for the developed HPLC method. Additionally, molecular modeling estimates and validates binding between the studied analytes and the stationary phase to clarify and explain the chromatographic separation and elution order. In accordance with the International Conference of Harmonization recommendations, the method was validated in terms of linearity, accuracy, precision, and selectivity. The linearity ranges (µg/ml) were 200-1500 (MET), 2-15 (EMP), and 20-150 (CAN) and the limit of detection values were in the ranges of 0.17-54.58 µg/ml. Analysis of pharmaceutical tablets using the suggested approach yielded satisfactory outcomes. As a result, it might be used in quality control laboratories to analyze the aforementioned medications.

Development and validation of a GC-MS method for determination of metformin in normal brain and in glioblastoma tissues.

Metformin hydrochloride (MH) has recently been repurposed as an anticancer agent, showing antiproliferative activity in vitro and in vivo. In particular, experimental evidence has suggested its potential clinical efficacy in glioblastoma (GBM), a very aggressive tumor frequently characterized by gloomy prognosis. Unfortunately, the published literature concerning experimental applications of MH in glioblastoma animal models report no data on metformin levels reached in the brain, which, considering the high hydrophilicity of the drug, are likely very low. Therefore, new sensitive analytical methods to be applied on biological tissues are necessary to improve our knowledge of MH in vivo biodistribution and biological effects on tumors. In this research work, a GC-MS method for MH quantification in brain tissues is proposed. MH has been derivatized using N-methyl-bis(trifluoroacetamide), as already described in the literature, but the derivatization conditions have been optimized; moreover, deuterated MH has been selected as the best internal standard, after a comparative evaluation including other internal standards employed in published methods. After ascertaining method linearity, its accuracy, precision, specificity, repeatability, LOD and LOQ (0.373 µM and 1.242 µM, respectively, corresponding to 0.887 and 2.958 pmol/mg of wet tissue) have been evaluated on mouse brain tissue samples, obtained through a straightforward preparation procedure involving methanolic extraction from lyophilized brain homogenates and solid phase purification. The method has been validated on brain samples obtained from mice, either healthy or xenografted with GBM cells, receiving metformin dissolved in the drinking water. This analytical method can be usefully applied in preclinical studies aiming at clarifying MH mechanism of action in brain tumors.

Ecofriendly appraisal of stability-indicating high-performance chromatographic assay of canagliflozin and metformin with their toxic impurities; in silico toxicity prediction.

Canagliflozin is an oral hypoglycemic drug recently formulated in combination with a biguanide, metformin hydrochloride, for improving its hypoglycemic action. Canagliflozin has one reported major degradation product, also metformin hydrochloride has one reported major degradation product, cyanoguanidine, and has a potential toxic impurity, melamine, that is reported to cause crystalluria that causes chronic kidney inflammation and nephrolithiasis leading to a renal failure. As per International Conference of Harmonization guidelines; a drug degradation product is classified as a type of drug impurities. Toxicity profiles of canagliflozin and metformin major degradation products were studied where in silico data disclosed toxicity too; the development of a specific chromatographic thin layer chromatographic assay was a must for quantification of such toxic related components along with the drugs in laboratory-prepared mixtures as a superior study. The proposed method was validated as per the International Conference of Harmonization and applied for the assay of Vokanamet tablets. The separation was achieved using acetone:ethyl acetate:acetic acid (8:2:0.2, by volume) as scanning eluted bands at 205 nm. For minimal environmental impact; greenness profile appraisal of the proposed assay was performed by three greenness assessment approaches; analytical Eco-Scale, Green Analytical Procedure Index, and Greenness metric approaches.

Development of metformin HCl granules using brown flaxseed mucilage as a retardant polymer: effects of polymer and drug ratio

Abstract Flaxseed (Linum usitatissimum L.) is the seed of a multipurpose plant of pharmaceutical interest, as its mucilage can be used as a natural matrix to develop extended-release dosage forms and potentially replace synthetic polymers. In this study, a 3² factorial design with two replicates of the central point was applied to optimize the development of extended-release granules of metformin HCl. The total fiber content of the mucilage as well as the friability and dissolution of the formulations were evaluated. The lyophilized mucilage presented a high total fiber content (42.63%), which suggests a high efficiency extraction process. Higher concentrations of the mucilage and metformin HCl yielded less friable granules. In addition, lower concentrations of metformin HCl and higher concentrations of the mucilage resulted in slower drug release during the dissolution assays. The release kinetics for most formulations were better represented by the Hixson-Crowell model, while formulations containing a higher concentration of the mucilage were represented by the Korsmeyer-Peppas model. Nonetheless, five formulations showed a longer release than the reference HPMC formulation. More desirable results were obtained with a higher concentration of the mucilage (13-18%) and a lower concentration of metformin (40%).

Evaluation and optimization of a HS-SPME-assisted GC-MS/MS method for monitoring nitrosamine impurities in diverse pharmaceuticals.

The probable carcinogenic nitrosamine impurities, such as N-nitrosodiethylamine (NDEA) and N-nitrosodimethylamine (NDMA), have been detected from various pharmaceuticals in recent years. The sensitive chromatographic methods, including liquid chromatography (LC) and gas chromatography (GC), have been applied for analyzing nitrosamines in the pharmaceutical substrates, such as sartans, ranitidine and metformin. In comparison of LC, the efficacy of GC for analyzing multiple nitrosamines in diverse pharmaceuticals will be limited or attenuated owing to the chemical properties of target analytes or matrix hinderance of pharmaceutical substrates. To extend the applicability of GC analysis for multiple nitrosamines in pharmaceuticals, this study presented a gas chromatograph tandem mass (GC-MS/MS) method for monitoring 14 nitrosamines within 44 pharmaceuticals, whereas the headspace-solid phase microextraction (HS-SPME) sampling mode was introduced. Chromatographic separation was achieved on a DB-heavyWax column (30 m × 0.25 mm; i.d., 0.25 µm), whereas the HS-SPME sampling mode with a 50/30 µm DVB/CAR/PDMS extracting fiber was applied for comparison of the direct injection mode. Meanwhile, the HS-SPME conditions were optimized to evaluate the effects of the parameters on analyzing total nitrosamines in pharmaceuticals by GC-MS/MS. The optimal conditions of HS-SPME were as follows: extracting solution of 90% NaCl, HS incubation time 1 min, SPME adsorbing at 80 â„ƒ for 30 min, and desorbing at 250 â„ƒ for 5 min. The limit of quantification (LOQ) for 14 nitrosamines in pharmaceutical matrices under the optimal conditions was 0.05 µg/g for the optimal HS-SPME, whereas the value was 0.05-0.25 µg/g for direct injection.

A high-performance liquid chromatography method for simultaneous quantification of metformin and ferulic acid in solid dosage forms.

Metformin is one of the most commonly used drugs in the world for the treatment of type 2 diabetes, while ferulic acid is a molecule that stands out for its antioxidant potential. Recent studies demonstrate hypoglycemic synergy between these molecules. The objective of this study is to develop and validate an analytical methodology by high-performance liquid chromatography for the simultaneous quantification of these drugs in pharmaceutical formulations. The method used an octadecylsilane column and a mobile phase composed of 6 mM sodium lauryl sulfate in 15 mM phosphate buffer:ACN (65:35). Ferulic acid and metformin were monitored at 232 nm, with a mobile phase flow rate of 1 ml/min and oven temperature at 40°C. The method was linear in the range of 5-25 µg/ml for both molecules. In the presence of degradation products, satisfactory selectivity was achieved. Accuracy values were close to 100% and standard deviations in precision were less than 2%. In the robustness evaluation, the proposed variations did not interfere with the quantification. Therefore, it is concluded that the present method can be safely applied to the quality control of ferulic acid and metformin raw materials, as well as when they are combined in pharmaceutical formulations.

A nationwide wastewater-based assessment of metformin consumption across Australia.

Metformin is the most widely used drug to treat type 2 diabetes. Monitoring spatial patterns of metformin use could provide new insights into treatment of type 2 diabetes and the distribution among populations. This study applied a wastewater-based epidemiological (WBE) approach to estimate metformin use in different populations across Australia and compared these estimates with traditional approaches of surveys and prescription data. Twenty-four-hour influent samples were collected from 75 wastewater treatment plants (WWTPs) across Australia in 2016 and analysed for metformin. Metformin was detected in all samples ranging in concentration from 8.2 to 191 µg/L (median 58 µg/L). Concentrations were converted to population-weighted average consumption at the national level, resulting in an average consumption of 28.6 g/day/1000 people across Australia, which was within 7% of estimates from national prescription statistics. In addition, results for five out of seven states had an estimated prevalence of type 2 diabetes within 20% compared to the traditional epidemiology surveys. Spatial patterns were also observed between urban and rural settings, with higher consumption rates of metformin found in Major Cities (22.5 ± 10.9 g/d/1000 people) and Inner Regional cities (25.4 ± 13.4 g/d/1000 people) than in Outer Regional (17.0 ± 8.1 g/d/1000 people) and Remote areas (15.1 ± 7.4 g/d/1000 people). Consumption estimates were also correlated against socioeconomic factors of the specific catchment areas. Greater metformin use was correlated with populations of lower education and income levels, while positive correlations were found between metformin consumption and consumption of allopurinol, caffeine and venlafaxine. Our study provides more evidence on the distribution of metformin use across Australia, which can be used to develop public health strategies to reduce the overall burden of type 2 diabetes in specific regions.

International Regulatory Collaboration on the Analysis of Nitrosamines in Metformin-Containing Medicines.

Recalls of some batches of metformin have occurred due to the detection of N-nitrosodimethylamine (NDMA) in amounts above the acceptable intake (AI) of 96 ng per day. Prior to the recalls, an international regulatory laboratory network had been monitoring drugs for nitrosamine impurities with each laboratory independently developing and validating multiple analytical procedures to detect and measure nitrosamines in metformin drugs used in their jurisdictions. Here, we provide an overview of the analysis of metformin active pharmaceutical ingredients (APIs) and drug products with 1090 samples (875 finished dosage forms (FDFs) and 215 API samples) tested beginning in November of 2019 through July of 2020. Samples were obtained internationally by a variety of approaches, including purchased, received from firms via information requests or selected by regional regulatory authorities (either at wholesalers or during GMP inspections). Only one nitrosamine (NDMA) was detected and was only present in some batches of metformin products. For API samples, 213 out of 215 lots tested had no measurable level of NDMA. For FDF samples tested, the number of batches with NDMA above the AI amount for patient safety was 17.8% (156/875). Based on these data, although the presence of NDMA was of concern, 82.2% of the samples of metformin drug products tested met quality and safety standards for patients. Regulatory agencies continue to collaborate extensively and work with marketing authorization holders to understand root causes of nitrosamine formation and agree on corrective actions to mitigate the presence of NDMA in future metformin batches.

DoE-Based Analytical Failure Modes Critical Effect Analysis (AFMCEA) to a Multipurpose-RP-HPLC Method for the Estimation of Multiple FDC Products of Metformin Hydrochloride Using an Analytical Quality by Design Approach.

BACKGROUND: Metformin hydrochloride is the first-choice antihyperglycemic agent and its several fixed-dose combinations (FDCs) with pioglitazone hydrochloride, sitagliptin phosphate, and gliclazide are used for the management of type II diabetes. Numerous reversed-phase HPLC (RP-HPLC) and HPTLC methods have been reported for estimation of FDCs of metformin but each FDC needs separate and dedicated chromatographic conditions for analysis. No RP-HPLC method has been reported yet which promotes synchronous estimation of FDC products of metformin to save time, resources, cost, and organic solvent for analysis. OBJECTIVE: Hence, an economical and eco-friendly RP-HPLC method was developed for the synchronous estimation of FDCs of metformin hydrochloride using an enhanced analytical quality by design (AQbD) approach. METHODS: The AQbD approach was implemented using analytical-failure modes critical effects analysis (FMCEA) as per International council for harmonisation (ICH) Q8 and Q9 guidelines. The analytical-FMCEA was applied by identification of potential analytical failure modes followed by their risk assessment by a risk priority number (RPN) ranking and filtering method. Further, the risk of critical failure modes was controlled and mitigated by a design of experiments (DoE)-based Box-Behnken design by navigation of method operable design ranges (MODR). RESULTS: From the set of control strategies, the RP-HPLC method was developed using a Shim-Pack ODS C18 column and acetonitrile-0.1% triethylamine (40:60, v/v) triethylamine in water (pH 3.2 adjusted by perchloric acid). The method was found to be validated as per ICH Q2 (R1) guideline. The synchronous estimation of different FDCs of metformin hydrochloride was carried out by the developed method. CONCLUSION: The developed method can be used as a multipurpose chromatography method as an alternative to published chromatography methods for QC of FDCs of metformin hydrochloride in the pharmaceutical industry. HIGHLIGHTS: The multipurpose RP-HPLC method has been developed and validated for the synchronous estimation of multiple combined pharmaceutical dosage forms of metformin hydrochloride. The method was developed by the implementation of the AFMCEA-based AQbD approach as per the regulatory requirements of ICH.

Spectrophotometric Determination of Metformin in Different Pharmaceutical Combinations With Glipizide or Sitagliptin in Presence of Toxic Impurities of Metformin.

BACKGROUND: The presented quadruple divisor spectrophotometric method was able to resolve and analyze a complex quintuple drug matrix with severe overlapped spectra without previous separation or extraction steps or need of complicated apparatus like chromatographic methods and had the advantage of being green as the solvent used was water. METHOD: A simple, sensitive, and precise quadruple devisor spectrophotometric method was developed for simultaneous determination of metformin, glipizide, and sitagliptin in the presence of metformin potential impurities melamine and cyanoguanidine. The proposed method was applied for analysis of metformin, glipizide, and sitagliptin in pure form and pharmaceutical formulation (tablets). The developed method was validated and met the requirements for ICH guidelines with respect to linearity, accuracy, precision, specificity, and robustness. RESULTS: A linear response was observed in the range of 2-27, 2-20, 1-20, 0.5-10, and 1-10 µg/mL for metformin, glipizide, sitagliptin, melamine, and cyanoguanidine, respectively, with a correlation coefficient of 0.9996, 0.9998, 0.9997, 0.9997, and 0.9996 for metformin, glipizide, sitagliptin, melamine, and cyanoguanidine, respectively. CONCLUSIONS: The validated method was successfully applied for determination of the studied drugs in Janumet® and Engilor® tablets; moreover, the results were statistically compared to those obtained by the reported RP-HPLC method and no significant difference was found between them, indicating the ability of the proposed method to be used for routine quality-control analysis of these drugs. HIGHLIGHTS: Novel application of quadruple divisor spectrophotometric technique is introduced for resolving mixtures containing five components with severely overlapping spectra. A simple and sensitive spectrophotometric method was developed for simultaneous determination of metformin, glipizide, and sitagliptin in the presence of metformin potential impurities melamine and cyanoguanidine. The validity of the proposed method was revealed as per ICH guidelines.

Application of experimental design in HPLC method optimization and robustness for the simultaneous determination of canagliflozin, empagliflozin, linagliptin, and metformin in tablet.

Gliflozins and gliptins represent two different pharmacological drug classes that exert different and potentially complementary glucose-lowering effect in patients with type II diabetes mellitus. A novel, selective, and sensitive HPLC method was developed for the determination of canagliflozin, empaglifozin, linagliptin, and metformin in pure form, in laboratory prepared mixtures, and in pharmaceutical dosage form. Experimental design optimization was applied by using Plackett-Burman and face-centered composite designs to achieve the best resolution with minimum experimental trials. Three significant variables affecting optimization, namely buffer pH, percentage of methanol, and percentage of acetonitrile, were studied. Chromatographic separation was achieved using an Agilent Eclipse C8 column, and column temperature was kept at 45°C. The mobile phase was composed of dipotassium hydrogen phosphate buffer (0.05 M, adjusted to pH 6 using o-phosphoric acid):acetonitrile:methanol (50:25:25, v/v/v) at a flow rate of 1.5 mL/min. Sharp and well-resolved peaks of the cited drugs were obtained. The method was fully validated in terms of linearity, accuracy, precision, selectivity and robustness in agreement with the International Council of Harmonization (ICH) guidelines Q2 (R1). Satisfactory results were obtained by the analysis of tablets through applying the developed method. Therefore, it could be performed for the analysis of the cited drugs in quality control laboratories.

Simple TLC-spectrodensitometric method for studying lipophilicity and quantitative analysis of hypoglycemic drugs in their binary mixture.

A selective and simple salting-out-assisted thin-layer chromatographic methodology was developed for the simultaneous determination of two oral hypoglycemic drugs, dapagliflozin (DAPA) and metformin (MET) in their pure forms, tablets and spiked human plasma samples. Silica gel 60 F254 plates were used in the separation of the two drugs using a mobile phase consisting of 0.5 m (NH4 )2 SO4 and methanol (3:7, v/v). The plates were scanned in the reflectance mode at λmax = 237 nm. The obtained retardation factor (Rf ) values for DAPA and MET were 0.77 ± 0.02 and 0.25 ± 0.02, respectively. The thin-layer chromatography method was validated according to International Conference on Harmonization guidelines. The peak areas were linearly increased with the increases in concentrations of 45-1,000 and 50-1,500 ng/band for DAPA and MET, respectively. Moreover, the method was applied to estimate the molecular lipophilicity parameters of DAPA and MET via retention data. The suggested method was efficiently utilized for the analysis of DAPA and MET in pharmaceutical tablets and plasma samples with recoveries 98.4-100.4 and RSDs in the ranges of 1.4-2.6 and 2.2-3.0% for DAPA and MET, respectively.

Investigating the root cause of N-nitrosodimethylamine formation in metformin pharmaceutical products.

BACKGROUND: FDA limited N-nitrosodimethylamine (NDMA) - a carcinogenic impurity formed during metformin (MET) tablets manufacturing - level to 96 ng/day; a step which led to recall of MET products. This work aims to investigate the root cause of NDMA formation during MET tablets manufacturing. RESEARCH DESIGN AND METHODS: We focused on three main contributing causes: use of water and heat during intra-granulation, and the nitrite/nitrate quantities in excipients. Thirteen MET tablet formulations (immediate or sustained-release) were manufactured, on batch level. Each batch was manufactured using one excipient and excluding one cause at a time and NDMA level was assayed. RESULTS: NDMA traces were undetectable in MET tablets manufactured using polyvinyl pyrrolidone or hydroxypropyl cellulose SSL, even when water and/or heat were employed during intra-granulation. Levels of NDMA in MET tablets with hydroxypropyl methyl cellulose (HPMC) E5 or carboxymethyl cellulose sodium 4000 were 67.08 ± 2.3 and 66.21 ± 2.5 ng/day, in the presence of water and/or heat. No impact of employing extra-granular PolyoxTM, HPMC E5 or HPMC K15 on NDMA formation, despite the high nitrite and nitrate content in these excipients. CONCLUSIONS: Water, heat, and excipients' nitrite and nitrate levels are the key players, which should collectively exist, to cause NDMA formation during MET tablets manufacturing.

Developing an analytical method by HPLC for simultaneous quantification of methylene blue and metformin applied to in vitro skin permeation and retention studies.

The aim of this study was to develop an HPLC method for simultaneous quantification of metformin (MET) and methylene blue (MB) in in vitro skin permeation/retention studies, in which retention was evaluated in the different layers of the skin [stratum corneum (SC) and the viable epidermis + dermis (VE + D)]. The method was validated considering the following parameters: specificity, linearity, quantitation limit (LOQ), recovery, precision and accuracy. Calibration curves were obtained using the following six matrices: methanol, water, methanolic extracts from the SC and VE + D spiked with the drugs and drugs extracted from the SC and VE + D. The precision, accuracy and LOQ of the method were evaluated in water and in VE + D and SC, applying the drug extraction process. The results show that the method is selective and linear for both drugs. The precision and accuracy values, independent of matrix and drug, were below the limit of 15%. The LOQ of MB was defined as 0.4 µg/ml in the VE + D and SC and 0.8 µg/ml in water. The LOQ of MET was defined as 0.8 µg/ml in the VE + D and SC and 0.4 µg/ml in the water. The recovery of the method was adequate, consistent and reproducible for the concentration range of 0.4-10 µg/ml for MB (73.3-92.1%) and 0.8-10.0 µg/mL for MET (72.4-94.4%). This method has a potential application in the development of formulation for skin delivery of MB and MET.

Sensitive detection of antidiabetic compounds and one degradation product in wastewater samples by a new SPE-LC-MS/MS method.

As environment emerging contaminants of anthropogenic origin, antidiabetic drugs are present in the range of high ng/L to ng/mL in the influent and the effluent of the waste water treatment plant (WWTP). The metformin compound is the most used hypoglycemic agent in the world. The aim of this study was to develop a new analytic method, based on solid phase extraction followed by liquid chromatography coupled with mass spectrometric detector (SPE-LC-MS/MS), for identification and quantification of 5 antidiabetic compounds (glibenclamide/glyburide, glimepiride, metformin, glipizide, guanyl urea, gliclazide) and one degradation product (guanyl urea). The investigated environmental samples were the influent and the effluent of four urbans WWTP's. By validating of the analytical method, it was obtained low LOQ's (0.2-4.5 ng/L), satisfactory recovery rates (53.6-116.8%), and corresponding performance parameters: inter-day precision (4.9-8.4%) and reproducibility (11.3-14.6%). The concentrations of antidiabetics were as follow in influent and effluent: metformin 76-2041ng/L and 2-206ng/L, gliclazide (14.1-42.4 ng/L, and 3.3-19.1), glipizide (7.5-11.2 ng/L and 6.5-10ng/L), guanyl urea (6.2-7.3 and 8.3-21.3 ng/L). The efficiency of elimination of the antidiabetics in WWTP's was maximum for metformin (67.6-98.5%), followed, by gliclazide (72.9-78.2%). The lowest elimination efficiency was calculated for glipizide (10.7-13.3%). The guanyl urea undergoes a formation process (74.5-84.2%) in effluent, from the metformin contained in influent.

Metformin environmental exposure: A systematic review.

This review discussed the occurrence, ecological impacts, and effects of metformin, a drug used for type 2 diabetes among other diseases. It is one of the most commonly found medicines in aquatic environments owing to its incomplete metabolism in the human body, and is eventually disposed in wastewater. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses were followed as a guide. After searching various databases, 48 eligible studies were selected for the review. Metformin reportedly occurs in different environmental matrices, as measurable concentrations of metformin are found in sewage (urban and hospital), influent/sludge/effluent from wastewater treatment plants, surface water (rivers, lakes, estuaries, oceans, and non-specific sources), tap/drinking water, and sediment (lake and recipient seawaters). Data on metformin detection in aquatic environments in 14 countries were studied, but a consensus on the risk patterns of pharmaceutical products was not determined. Many studies have been conducted on different test organisms, demonstrating that metformin can drive the expression of diverse genes, particularly those responsible for endocrine hormone pathways. Chronic exposure to metformin can be tested using models and other tools to understand this field, which remains largely unexplored. Our results contribute to the current ecotoxicology knowledge related to typically used drugs and provide a basis for further investigations.