Targeted and untargeted screening for impurities in losartan tablets marketed in Germany by means of liquid chromatography/high resolution mass spectrometry.

Technical advances in the field of quality analysis allow an increasingly deeper look into the impurity profile of drugs. The ability to detect unexpected impurities in addition to known impurities ensures the supply of high-quality drugs and can prevent recalls due to the detection of harmful unexpected impurities, as has happened recently with the N-nitrosamine and azido impurities in losartan (LOS) drug products. In the present study, the LC-MS/HRMS approach described by Backer et al. was applied to an even more complex system, being the investigation of 35 LOS drug products and combination preparations purchased in 2018 and 2022 in German pharmacies. The film-coated tablets were analysed by means of four LC-MS/HRMS method variants. For the separation a Zorbax RR StableBond C18 column (3.0 ×100 mm, particle size of 3.5 µm, pore size of 80 Å), a gradient elution and for mass spectrometric detection a qTOF mass spectrometer with electrospray ionization in positive and negative mode was used. An information-dependent acquisition method was applied for the acquisition of high-resolution mass spectrometry data. The combination of an untargeted and a targeted screening approach revealed the finding of eight impurities in total. Beside the five LOS related compounds, LOS impurity F, J, K, L, M, and related compound D from amlodipine besilate, LOS azide and an unknown derivative thereof were detected. Identification and structure elucidation, respectively, were successfully performed using in silico fragmentation. Differences in the impurity profiles of drug products from 2018 and 2022 could be observed. This study shows that broad screening approaches like this are applicable to the analysis of drug products and can be an important enhancement of the quality assurance of medicinal products.

Unveiling intricate transformation pathways of emerging contaminants during wastewater treatment processes through simplified network analysis.

As the key stage for purifying wastewater, elimination of emerging contaminants (ECs) is found to be fairly low in wastewater treatment plants (WWTPs). However, less knowledge is obtained regarding the transformation pathways between various chemical structures of ECs under different treatment processes. This study unveiled the transformation pathways of ECs with different structures in 15 WWTPs distributed across China by simplified network analysis (SNA) we proposed. After treatment, the molecular weight of the whole component of wastewater decreased and the hydrophilicity increased. There are significant differences in the structure of eliminated, consistent and formed pollutants. Amino acids, peptides, and analogues (AAPAs) were detected most frequently and most removable. Benzenoids were refractory. Triazoles were often produced. The high-frequency reactions in different WWTPs were similar, (de)methylation and dehydration occurred most frequently. Different biological treatment processes performed similarly, while some advanced treatment processes differed, such as a significant increase of -13.976 (2HO reaction) paired mass distances (PMDs) in the chlorine alone process. Further, the common structural transformation was uncovered. 4 anti-hypertensive drugs, including irbesartan, valsartan, olmesartan, and losartan, were identified, along with 22 transformation products (TPs) of them. OH2 and H2O PMDs occurred most frequently and in 80.81 % of the parent-transformation product pairs, the intensity of the product was higher than parent in effluents, whose risk should be considered in future assessment activity. Together our results provide a macrography perspective on the transformation processes of ECs in WWTPs. In the future, selectively adopting wastewater treatment technology according to structures is conductive for eliminating recalcitrant ECs in WWTPs.

Microextraction by packed sorbent of N-nitrosamines from Losartan tablets using a high-throughput robot platform followed by liquid chromatography-tandem mass spectrometry.

The development of a fast, cost-effective, and efficient microextraction by packed sorbent setup was achieved by combining affordable laboratory-repackable devices of microextraction with a high-throughput cartesian robot. This setup was evaluated for the development of an analytical method to determine N-nitrosamines in losartan tablets. N-nitrosamines pose a significant concern in the pharmaceutical market due to their carcinogenic risk, necessitating their control and quantification in pharmaceutical products. The parameters influencing the performance of this sample preparation for N-nitrosamines were investigated through both univariate and multivariate experiments. Microextractions were performed using just 5.0 mg of carboxylic acid-modified polystyrene divinylbenzene copolymer as the extraction phase. Under the optimized conditions, the automated setup enabled the simultaneous treatment of six samples in less than 20 min, providing reliable analytical confidence for the proposed application. The analytical performance of the automated high-throughput microextraction by the packed sorbent method was evaluated using a matrix-matching calibration. Quantification was performed using ultra-high-performance liquid chromatography-tandem mass spectrometry with chemical ionization at atmospheric pressure. The method exhibited limits of detection as low as 50 ng/g, good linearity, and satisfactory intra-day (1.38-18.76) and inter-day (2.66-20.08) precision. Additionally, the method showed accuracy ranging from 80% to 136% for these impurities in pharmaceutical formulations.

Simultaneous quantification of losartan potassium and its active metabolite, EXP3174, in rabbit plasma by validated HPLC-PDA.

Herein, we report a novel, accurate and cost-effective validated analytical method for the quantification of losartan potassium and its active metabolite, EXP 3174, in rabbit plasma by reversed-phase high-performance liquid chromatography. Valsartan was used as an internal standard. The method was validated as per International Conference on Harmonization guidelines. The analytes were extracted in rabbit plasma using liquid-liquid extraction technique and analyzed at 247 nm after separation through a reverse-phase C18 column. The isocratic mobile phase used is a mixture of acetonitrile, water and glacial acetic acid in the ratio of 60:40:1 v/v/v maintained at pH 3.4. All calibration curves showed a good linear relationship (r > 0.995) within the test range. Precision was evaluated by intra- and interday tests with RSDs <1.91% and accuracy showed validated recoveries of 86.20-101.11%. Based on our results, the developed method features good quantification parameters and can serve as an effective quality control method for the standardization of drugs.

Development and validation of an analytical method for trace-level quantification of genotoxic nitrosamine impurities in losartan and hydrochlorothiazide fixed-dose combination tablets using ultra performance liquid chromatography triple quadrupole mass spectrometry.

RATIONALE: Since June 2018, globally large numbers of pharmaceuticals have been recalled due to the unexpected presence of nitrosamines. Beginning with the class of pharmaceuticals known as sartans, subsequent lines of inquiry included antidiabetic medicines, antihistamines, and antibiotics. A critical review of the U.S. Food and Drug Administration database reveals that the highest number of products recall due to the presence of unacceptable levels of nitrosamines were losartan potassium drug products and their coformulations with other drug substances. The problem can be mainly attributed to naively adopted approval revisions and the lack of sufficient current analytical technologies to detect those contaminants in time. In this work, we developed a specific, selective, accurate, precise, and robust ultra-performance liquid chromatography-triple quadrupole-mass spectrometry (UPLC-TQ-MS/MS) method for the estimation of eight genotoxic nitrosamine impurities in losartan and hydrochlorothiazide (HCTZ) tablets, which is the only fixed-dosage combination approved by the USFDA to treat hypertension. METHODS: All the nitrosamine impurities along with the drug substances were separated using an Agilent Pursuit XRs Ultra diphenyl column (150 × 2.0 mm, 2.8 µm) with mobile phase A (0.1% formic acid in water) and mobile phase B (0.1% formic acid in methanol) at a flow rate of 0.4 ml/min using the gradient elution program. The proposed method was validated per ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) Q2 (R1) guidelines to ensure the method is suitable for its intended purpose. RESULTS: Limit of detection and limit of quantification were obtained in the range of 0.25-0.5 ng/mL, which was very low compared to levels specified by the USFDA, European Medicines Agency (EMA), and other regulatory authorities that ensure the sensitivity of the method in its entire life cycle. CONCLUSIONS: The developed method can be incorporated into an official monograph and applied for routine quality control analysis of losartan and HCTZ fixed-dose combination tablets.

Sartan blood pressure regulators in classical and biofilm wastewater treatment - Concentrations and metabolism.

Sartans are a group of pharmaceuticals widely used to regulate blood pressure. Their concentration levels were monitored in 80 wastewater treatment plants (WWTP) in the Baltic Sea Region, reached from limit of detection up to 6 µg/L. The concentrations were significantly different in different countries, but consistent within the respective country. The degradation of sartans (losartan, valsartan, irbesartan) in moving bed biofilm reactors (MBBRs) that utilize biofilms grown on mobile carriers to treat wastewater was investigated for the first time, and compared with the degradation in a conventional activated sludge (CAS) treatment plant. The results showed the formation of six microbial transformation products (TPs) of losartan, four of valsartan, and four of irbesartan in biological wastewater treatment. Four of these metabolites have not been described in the literature before. Chemical structures were suggested and selected TPs were verified and quantified depending on availability of true standards. Valsartan acid was a common TP of losartan, valsartan, and irbesartan. Losartan and irbesartan also shared one TP: losartan/irbesartan TP335. Based on the mass balance analysis, losartan carboxylic acid is the main TP of losartan, and valsartan acid is the main TP of valsartan during the biotransformation process. For irbesartan, TP447 is likely to be the main TP, as its peak areas were two orders of magnitude higher than those of all the other detected TPs of this compound. The effects of adapting biofilms to different biological oxygen demand (BOD) loading on the degradation of sartans as well as the formation of their TPs were investigated. Compared to feeding a poor substrate (pure effluent wastewater from a CAS), feeding with richer substrate (1/3 raw and 2/3 effluent wastewater) promoted the metabolism of most compounds (co-metabolization). However, the addition of raw wastewater inhibited some metabolic pathways of other compounds, such as from losartan/irbesartan to TP335 (competitive inhibition). The formation of irbesartan TP447 did not change with or without raw wastewater. Finally, the sartans and their TPs were investigated in a full-scale CAS wastewater treatment plant (WWTP). The removal of losartan, valsartan, and irbesartan ranged from 3.0 % to 72% and some of the transformation products (TPs) from human metabolism were also removed in the WWTP. However, some of the sartan TPs, i.e., valsartan acid, losartan carboxylic acid, irbesartan TP443 and losartan TP453, were formed in the WWTP. Relative high amounts of especially losartan carboxylic acid, which was detected with concentrations up to 2.27 µg/L were found in the effluent.

Effect of losartan potassium, metformin hydrochloride, and simvastatin on in vitro bioaccessibility of Cu, Fe, Mn, and Zn in oat flour from Brazil.

BACKGROUND: The simultaneous administration of drugs with food can compromise the bioaccessibility and absorption of nutrients. The objective of this study was to evaluate the influence of the use of losartan potassium (LP), metformin hydrochloride (MH), and simvastatin (S) on the in vitro bioaccessibility of micronutrients (Cu, Fe, Mn, and Zn) in oat flour from Bahia, Brazil. METHODS: The experimental procedure consisted of the in vitro extraction of the bioaccessible fraction of Cu, Fe, Mn, and Zn in oat flour-with and without LP (50 mg), MH (500 mg), and S (20 mg)-using the unified bioaccessibility method (UBM), simulating the conditions of the gastrointestinal tract. For decomposition of the samples (oat flour and residue), a digester block with a closed system was used. To determine the total content (flour and residual fraction) and bioaccessible micronutrients, inductively coupled plasma optical emission spectrometry (ICP OES) was used. RESULTS: The bioaccessible contents (µg g-1) without the addition of drugs were: Cu 5.86 ± 0.21, Fe 32.80 ± 1.32, Mn 87.90 ± 1.90, and Zn 30.33 ± 2.05, with bioaccessibility ranging from 31.5 % for Fe to 99 % for Mn. The in vitro extraction method was validated by mass balance with recovery values from 89.78 % for Cu to 101.94 % for Mn. The range of bioaccessible contents (µg g-1) were: Cu (<4.14), Fe (32.10 ± 0.20-54.10 ± 2.03), Mn (81.40 ± 0.93-93.22 ± 0.80), and Zn (<10.80-29.11 ± 2.20). The estimation of the bioaccessibility of Cu, Mn, and Zn in oat flour were compromised in the presence of LP, MH, and S (p < 0.05). CONCLUSION: Chemical interactions can occur between drugs and micronutrients. Taken together, our results highlight that LP, MH, and S can interfere with the bioaccessibility of Cu, Fe, Mn, and Zn in oat flour in patients who use these drugs, suggesting its rational use in further investigations.

From data to reliable conclusions: Identification and comparison of persistent micropollutants and transformation products in 37 wastewater samples by non-target screening prioritization.

In this study, micropollutants in wastewater effluents were prioritized by monitoring the composition of influent and effluent wastewater by liquid chromatography - high-resolution mass spectrometry (LCHRMS) non-target screening (NTS) analysis. The study shows how important data pre-processing and filtering of raw data is to produce reliable NTS data for comparison of compounds between many samples (37 wastewater samples) analyzed at different times. Triplicate injections were critical for reducing the number of false-positive detections. Intensity drift corrections within and between batches analyzed months apart made peak intensities comparable across samples. Adjustment of the feature detection threshold was shown to be important, due to large intensity variations for low abundance compounds across batches. When the threshold correction cut-offs, or the filtering of relevant compounds by the occurrence frequency, were too stringent, a high number of false positive transformation products (TPs) were reported. We also showed that matrix effect correction by internal standards can over- or under-correct the intensity for unknown compounds, thus the TIC matrix effect correction was shown as an additional tool for a retention time dependent matrix effect correction. After these preprocessing and filtering steps, we identified 78 prioritized compounds, of which 36 were persistent compounds, defined as compounds with a reduction in peak intensity between influent and effluent wastewater <50%, and 13 compounds were defined as TPs because they occurred solely in the effluent samples. Some examples of persistent compounds are 1,3-diphenylguanidine, amisulpride and the human metabolites from losartan, verapamil and methadone. To our knowledge, nine of the identified TPs have not been previously described in effluent wastewater. The TPs were derived from metoprolol, fexofenadine, DEET and losartan. The screening of all identified compounds in effluent samples from eight wastewater treatment plants (WWTPs) showed that potential drugs of abuse, anti-psychotic and anti-depressant drugs were predominant in the capital city region, whereas the anti-epileptic agents and agricultural pesticides were dominant in more rural areas.

First-derivative synchronous spectrofluorimetric method for estimation of losartan potassium and atorvastatin in their pure forms and in tablets.

Losartan potassium (LOS) and atorvastatin (ATR) are used in combination for long-term treatment of stroke and for treatment of hypertension with high-level cholesterol. Both drugs were simultaneously determined and validated using a novel, easy, fast, and economical first-derivative synchronous fluorescence spectroscopic method. Methanol was used as the solvent for both drugs at a Δλ 80 nm and with a scanning rate of 600 nm/min. Peaks were determined as at 288.1 nm and 263.6 nm for LOS and ATR, respectively. The proposed method was validated according to International Conference on Harmonization guidelines and, subsequently, the developed method was applicable to the analysis of the two compounds in their different formulations without interference from each other. Amplitude-concentration plots were rectilinear over the concentration ranges 1.0-10.0 µg/ml and 0.5-5.0 µg/ml for LOS and ATR, respectively. Detection limits were found to be 0.096 µg/ml and 0.030 µg/ml and quantitation limits were 0.291 µg/ml and 0.093 µg/ml for LOS and ATR, respectively. The proposed method was successfully applied to the analysis of both compounds in synthetic mixtures and in laboratory-prepared tablets. These results were in accordance with the results acquired using the comparison method, high-performance liquid chromatography.

HPLC method transfer study for simultaneous determination of seven angiotensin II receptor blockers.

In this study, a sensitive high-performance liquid chromatography method was developed and validated for the simultaneous determination of seven angiotensin II receptor blockers, namely, hydrochlorothiazide, chlorthalidone, eprosartan mesylate, valsartan, losartan potassium, irbesartan, and candesartan cilexetil. Different chromatographic parameters were tested and fully optimized. Best chromatographic separation was accomplished on a reversed-phase octadecylsilyl column (250 × 4.6 mm id; 5 µm) under gradient elution using methanol/sodium phosphate monobasic buffer (0.01 M, pH 6.5) as mobile phase. The detection of target analytes was obtained at 254 nm. The pH of the buffer has been selected according to Marvin® sketch software. The proposed method was validated according to ICH guidelines and showed good precision (relative standard deviation < 1), good linearity (square of correlation coefficient ≥ 0.999), and high accuracy (between 98 and 102%) with detection limit and quantitation limit (40 and 160 ng/mL, respectively) for all the detected analytes.

SERS determination of the antihypertensive drugs prazosin and losartan by using silver nanoparticles coated with ß-cyclodextrin.

A surface-enhanced Raman scattering (SERS) method is described for the determination of prazosin (PRH) and losartan (LOS). Silver nanoparticles modified with ß-cyclodextrin (CD-S-Ag NPs) were prepared and serve as a sensitive SERS substrate. ß-CD is both a reductant for silver ions and a host molecule that binds the analytes which leads to strong SERS enhancement. The method has distinct features: (a) The linear response extends from 0.1 to 60 µM for PRH, and from 1.0 to 100 µM for LOS; (b) the respective limits of detection are as low as 15 nM and 0.92 µM; and (c) the specific SERS bands of PRH and LOS are located at 703 and 1298 cm-1 respectively. The method was successfully applied to the determination of PRH and LOS illegally added to healthcare products. The recovery of PRH and LOS from spiked samples ranges between 91.3 and 109.3%, and from 87.4 to 105.2%, respectively, both with relative standard deviation of <5%. Graphical abstractSchematic representation of a SERS method involving ß-CD-S-Ag nanoparticles for determination of prazosin and losartan via formation of an inclusion complex.

Simultaneous detection of nitrosamines and other sartan-related impurities in active pharmaceutical ingredients by supercritical fluid chromatography.

Since July 2018, the pharmacological class of "sartans" has been the subject of considerable media and analytical interest, as it became known that they are contaminated with nitrosamines such as N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA) and N-nitrosodiisopropylamine (NDiPA). Previous compendial methods are not able to detect these new contaminants. Using the latest and innovative Quality-by-Design (QbD) approach, it has now been possible to develop an analytical method that enables to investigate sartans, such as valsartan and losartan. Also a large class of different nitrosamines in the ppb range and sartan-related impurities can thus be determined simultaneously in a single analysis using supercritical fluid chromatography (SFC). By using SFC, a broad spectrum of nonpolar and very polar impurities can be separated and analyzed in under 20 min. The analytical method developed is validated for limit testing according to ICH Q2(R1) and fulfills default thresholds of EMA and FDA for testing of drug substances and genotoxic impurities. Additionally, it can also be adapted to other pharmaceuticals that may be contaminated with nitrosamines, since tetrazole synthesis as the underlying cause of nitrosamine contamination is important for a set of other non-sartan drug substances.

LC-MS/MS analysis of the plasma concentrations of a cocktail of 5 cytochrome P450 and P-glycoprotein probe substrates and their metabolites using subtherapeutic doses.

Drug transporters and CYP enzymes are important sources of pharmacokinetics (PK) variability in drug responses and can cause various pharmacological and toxicological consequences, leading to either toxicity or an insufficient pharmacological effect. In recent years, the cocktail approach was developed to determine in vivo CYP and transporters activities, but these approaches are somewhat limited. We described the development and validation of three sensitive and specific LC-MS/MS assays for the determination of P-gp and major human CYP isoenzyme activities following oral administration of a drug cocktail of subtherapeutic doses (lower than 10 times) of caffeine (CAF), omeprazole (OME), losartan (LOS), midazolam (MDZ), metoprolol (METO) and fexofenadine (FEX) in healthy volunteers. The three validated methods were selective for all tested analytes. No interference or matrix effect was observed for the mass transition and retention times for all compounds monitored. Additionally, assays were linear over a wide range, and limits of quantification varied between 0.01-5 ng/mL plasma. The coefficients of variation obtained in the precision studies and the inter- and intra-assay accuracies were less than 15%, guaranteeing the reproducibility and repeatability of the results. All substrates and metabolites were stable in plasma during freeze-thaw cycles. Three healthy volunteers were selected based on genotyping for CYP2C9, CYP2C19 and CYP2D6. One volunteer was genotyped as an extensive metabolizer (EM) for all tested CYP isoforms, one volunteer was genotyped as a poor metabolizer (PM) for the CYP2C9 isoform (CYP2C9*3/*3), and one volunteer was genotyped as a PM for the CYP2D6 isoform (CYP2D6*4/*4). The methods allowed the quantification of all analytes over the entire sampling period (12 h) in all studied genotypes. Thus, the analytical methods described here were sufficiently sensitive for use in low-dose pharmacokinetic studies.

Spectroscopic and cytotoxic studies of losartan complexes.

Use of drug-metal complexes for the treatment of several human diseases has resulted in significant progress in the field of medicinal inorganic chemistry. The current study describes the synthesis and characterization of Cu (II) and Ni (II) complexes of Losartan, an antihypertensive drug. These complexes were evaluated for their cytotoxic activity against four human cancer cell lines; SNB-19, HCT-15, COLO-205 and KB-3-1. Spectroscopic characterization revealed that during complex formation, the metal was bound through the nitrogen atoms of the tetrazole moiety of the losartan molecule. The molecular formulas of copper ([Cu (LS) 2 Cl2].6H2O) and nickel ([Ni (LS) 2Cl2]. H2O) complexes were found to be in agreement with the analytical data obtained through elemental analysis. For both the complexes, metal to ligand ratios of 1:2 were calculated. As revealed by FTIR, UV-Visible, and 1H-NMR studies, both the complexes displayed octahedral geometries. Scanning electron microscopy (SEM) revealed marked changes in the morphology of the complexes, compared to the pure drug. From XRD studies, characteristic crystalline peaks of pure losartan were observed whereas no prominent peaks were observed for its complexes. Complexes were found to be inactive in the cytotoxic activity test performed using SNB-19, HCT-15, COLO-205 and KB-3-1 cell lines.

Ecotoxicological effects of losartan on the brown mussel Perna perna and its occurrence in seawater from Santos Bay (Brazil).

The antihypertensive losartan (LOS) has been detected in wastewater and environmental matrices, however further studies focused on assessing the ecotoxicological effects on aquatic ecosystems are necessary. Considering the intensive use of this pharmaceutical and its discharges into coastal zones, our study aimed to determine the environmental concentrations of LOS in seawater, as well as to assess the biological effects of LOS on the marine bivalve Perna perna. For this purpose, fertilization rate and embryolarval development were evaluated through standardized assays. Phase I (ethoxyresorufin O­deethylase EROD and dibenzylfluorescein dealkylase DBF) and II (glutathione S-transferase GST) enzymes, glutathione peroxidase (GPx), Cholinesterase (ChE), lipoperoxidation (LPO) and DNA damage were used to analyze sublethal responses in gills and digestive gland of adult individuals. Lysosomal membrane stability was also assessed in hemocytes. Our results showed the occurrence of LOS in 100% of the analyzed water samples located in Santos Bay, Sao Paulo, Brazil, in a range of 0.2 ng/L-8.7 ng/L. Effects on reproductive endpoints were observed after short-term exposure to concentrations up to 75 mg/L. Biomarker responses demonstrated the induction of CYP450 like activity and GST in mussel gills exposed to 300 and 3000 ng/L of LOS, respectively. GPx activity was also increased in concentration of exposure to 3000 ng/L of LOS. Cyto-genotoxic effects were found in gills and hemocytes exposed in concentrations up to 300 ng/L. These results highlighted the concern of introducing this class of contaminants into marine environments, and pointed out the need to include antihypertensive compounds in environmental monitoring programs.

A nanocomposite prepared from a polypyrrole deep eutectic solvent and coated onto the inner surface of a steel capillary for electrochemically controlled microextraction of acidic drugs such as losartan.

The authors describe a new coating for use in electrochemically controlled in-tube solid phase microextraction (EC-IT-SPME). It consists of a nanocomposite that was prepared from polypyrrole and deep eutectic solvent (DES) by electrochemical deposition on the inner walls of a stainless steel capillary that serves as a working electrode. The hypertension drug losartan acts as an acidic model analyte. The extraction efficiency, mechanical stability, chemical stability and lifetime of the coating were investigated. It is found to be quite stable in relatively acidic and basic media and to be re-usable >450 times without decrease in extraction efficiency. Its extraction capability in comparison to the commercial polypyrrole coating is better by a factor of 1.5. The coated steel capillary was used as the anode (anion-exchanger), and a platinum electrode was used as the cathode. By passing a sample solution through the electrode, losartan can be extracted by applying a positive potential to the flow. In the next step, losartan is electrochemically desorbed and subjected to HPLC analysis with UV detection. Under optimal conditions, losartan can be quantified with limits of detection that range from 50 to 500 ng L-1 depending on the sample matrix. Response is linear in the 0.1-500 µg L-1 concentration range. The inter- and intra-assay precisions (RSDs; in %, for n = 3) are in the range from 2.4-4.6% and from 1.9-3.9%, respectively. Graphical abstract Schematic of the preparation of a nano-structured polypyrrole-deep eutectic solvent nanocomposite coating placed on the inner surface of a stainless steel capillary and used for electrochemically controlled in-tube solid phase microextraction of losartan from biological samples.

A clean photometric method for the determination of losartan potassium in pharmaceuticals exploiting light scattering effect and employing a multicommuted flow analysis approach.

This paper describes an environmentally friendly procedure for the determination of losartan potassium (Los-K) in pharmaceuticals. The photometric method was based on the light scattering effect due to particles suspension, which were formed by the reaction of Los-K with Cu (II) ions. The method was automated employing a multicommuted flow analysis approach, implemented using solenoid mini-pumps for fluid propelling and a homemade LED based photometer. Under the optimized experimental conditions, the procedure showed a linear relationship in the concentration range of 23.2-417.6mgL-1 (r=0.9997, n=6), a relative standard deviation of 1.61% (n=10), a limit of detection (3.3*σ) estimated to be 12.1mgL-1, and a sampling rate of 140 determinations per hour. Each determination consumed 12µg of copper (II) acetate and generated 0.54mL of waste.

Molecular insight into atypical instability behavior of fixed-dose combination containing amlodipine besylate and losartan potassium.

Combination therapy with the use of fixed-dose combinations (FDCs) is evincing increasing interest of prescribers, manufacturers and even regulators, evidently due to the primary benefit of improved patient compliance. However, owing to potential of drug-drug interaction, FDCs require closer scrutiny with respect to their physical and chemical stability. Accordingly, the purpose of the present study was to explore stability behavior of a popular antihypertensive combination of amlodipine besylate (AML) and losartan potassium (LST). Physical mixtures of the two drugs and multiple marketed formulations were stored under accelerated conditions of temperature and humidity (40°C/75% RH) in a stability chamber and samples were withdrawn after 1 and 3 months. The physical changes were observed visibly, while chemical changes were monitored by HPLC employing a method that could separate the two drugs and all other components present. The combination revealed strong physical instability and also chemical degradation of AML in the presence of LST. Interestingly, three isomeric interaction products of AML were formed in the combination, which otherwise were reported in the literature to be generated on exposure of AML free base above its melting point. The same unusual products were even formed when multiple marketed FDCs were stored under accelerated conditions outside their storage packs. However, these were absent when AML alone was stored in the same studied conditions. Therefore, reasons for physical and chemical incompatibility and the mechanism of degradation of AML in the presence of LST were duly explored at the molecular level. The outcomes of the study are expected to help in development of stable FDCs of the two drugs.

Simultaneous Determination of Hydrochlorothiazide and Losartan Potassium in Osmotic Pump Tablets by Microemulsion Liquid Chromatography.

A rapid and efficient oil-in-water microemulsion liquid chromatographic (MELC) method has been optimized and validated for the determination of hydrochlorothiazide (HCT) and losartan potassium (LOP) in osmotic pump tablets. Samples were injected into a C18 (150 mm × 4.6 mm ID, 5 µm particle size) analytical column, which was maintained at 30°C. The most effective MELC system had a mobile phase consisting of 95% (v/v) of 3.0% (w/w) SDS, 6.0% (w/w) n-butanol, 0.8% (w/w) n-octane, 90.2% (w/w) water and 5% (v/v) acetonitrile (pH 5). The flow rate was 1.0 mL min(-1) and UV detection was performed at 265 nm. Linearity ranged from 2.5 to 12.5 µg mL(-1) for HCT and 10.0-60.0 µg mL(-1) for LOP (r > 0.999 for both drugs). The proposed method was rapid, precise (RSDs < 1.4%) and accurate (98.9% recovery for HCT and 101% recovery for LOP). It is applicable to simultaneous determination of HCT and LOP in osmotic pump tablets.

Application of modified stir bar with nickel:zinc sulphide nanoparticles loaded on activated carbon as a sorbent for preconcentration of losartan and valsartan and their determination by high performance liquid chromatography.

In this study, the stir bar was coated for the first time with the ​nicel:zins sulphide nanoparticles (Ni:ZnS NPs) loaded on activated carbon (AC) (Ni:ZnS-AC) as well as 1-ethyl-3-methylimidazolium hexafluorophosphate ionic liquid (IL) using sol gel technique and was used for stir bar sorptive extraction (SBSE) of losartan (LOS) and valsartan (VAL) as the model compounds. The extracted analytes were then quantified by high performance liquid chromatography (HPLC) equipped with an ultra violet detector. The best extraction performance for LOS and VAL was obtained through the optimization of the parameters affecting SBSE including pH of sample solution, ionic strength, extraction time, volume of desorption solvent, desorption time, and stirring speed. The fractional factorial design (FFD) was used to find the most important parameters, which were then optimized by the central composite design (CCD) and the desirability function (DF). Under the optimal experimental conditions, wide linear ranges of 0.4-50µgL(-1) and 0.5-50µgL(-1) and good RSDs (at level of 5µgL(-1) and n=6) of 4.4 and 4.9% were obtained for LOS and VAL, respectively. With the enrichment factors (EFs) of 188.6 and 184.8-fold, the limits of detection (LODs, S/N=3) of the developed method were found to be 0.12 and 0.15µgL(-1) for LOS and VAL, respectively. The developed method was successfully applied to the determination of LOS and VAL in urine and plasma matrices.