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.

ChlorTox scale assessment, greenness, and whiteness evaluation of selective spectrophotometric analysis of dimenhydrinate and cinnarizine.

Nausea and vomiting are considered common series side effects induced by chemotherapy treatment in cancer patients. This annoying side effect can impair the patient's compliance to cancer treatment and affect their quality of life. Dimenhydrinate and cinnarizine in combined pharmaceutical dosage form is used to control chemotherapy induced nausea and vomiting in cancer patients. For safety, selective spectrophotometric methods based on novel dual resolution strategies were introduced to estimate dimenhydrinate and cinnarizine in presence of their harmful impurities namely benzophenone and 1- (diphenylmethyl)piperazine, respectively. These methods namely, dual ratio difference (DRD), dual ratio extraction (DRE) and dual absorbance extraction coupled with dual ratio extraction (DAE-DRE) were successfully performed to simultaneously analyze the drug of interests dimenhydrinate and cinnarizine in their pure form, synthetic mixtures and in market dosage form. Linearity ranges were 6.0-60.0 µg/mL and 3.0-30.0 µg/mL for dimenhydrinate and cinnarizine, respectively with good recovery% of Mean ± SD for all the proposed methods 99.82 ± 0.48, 99.79 ± 0.40, 100.14 ± 0.82, 100.03 ± 0.69, respectively. ICH guidelines were adhered in accordance with confirming validation of the proposed methods where fulfilling results were accomplished. Various unified greenness and whiteness assessment tools, such as the chlorTox scale, greenness index via spider chart, AGREE (The Analytical Greenness Metric), green certificate, and the RGB12 algorithm were employed in this research to assess the greenness and sustainability of the introduced UV-spectrophotometric methods in comparison to the reported HPLC method. As a result, these methods hold significant potential for utilization in the quality control department of pharmaceutical companies, contributing to enhanced pharmaceutical product analysis and overall sustainability practices.

HPLC-DAD technique for the quantification of a recently approved anti-diabetic triple combination along with two toxic official impurities: Toxicity confirmation aided by molecular docking application.

BACKGROUND: Gliflozins and gliptins are two distinct groups of pharmacological drugs that reduce blood glucose levels in individuals with type II diabetes in various ways that may perform their functions harmoniously. Trijardy® tablet, which contains empagliflozin, linagliptin, and metformin, was recently approved. The scientific database does not yet have a method that is sensitive enough to quantify the aforementioned medications in the presence of metformin official toxic impurities melamine and cyanoguanidine. Molecular docking modeling was utilized in this work to further prove the toxicity of melamine. METHODS: The five analytes listed before were quantified using RP-HPLC-diode array detector and a Zorbax® C8 column (4.6 × 250 mm, 5 µm) with isocratic mobile phase composed of acetonitrile and 0.05 M potassium dihydrogen phosphate buffer, which had been treated by ?-phosphoric acid to restore a pH of 4.0 (90:10, v/v) at a flow rate of 1.2 mL/min and the eluted peaks were scanned at 250 nm. CONCLUSION: The utilization of the simplest isocratic elution mode give the current technique a significant time-and cost-saving benefit. The current method can quantify the triple therapy agents in the presence of each other as well as with two official toxic impurities of metformin in one short analytical run.

Fermentation of biodiesel-derived crude glycerol to 1,3-propanediol with bio-wastes as support matrices: Polynomial prediction model.

Biodiesel production from used cooking oil is sustainable alternative, for bio-energy production. The process generates residual crude glycerol (RCG) as the major energy-rich waste which can be used to produce various bio-based chemicals like 1,3-propanediol (1,3-PDO) through biotechnological interventions. This RCG contains several impurities like methanol, soap, organic materials, salts non-transesterified fatty acids and metals in varied concentrations. These impurities significantly affect yield and productivity of the bio-process due to their marked microbial toxicity. In this work, previously isolated Clostridium butyricum L4 was immobilized on various abundantly available cheap bio-wastes (like rice straw, activated carbon and corn cob) to explore advantages offered and improve tolerance to various feed impurities. Amongst these, shredded rice straw was found most suitable candidate for immobilization and results in maximum improvement in 1,3-PDO production (18.4%) with highest porosity (89.28%), lowest bulk density (194.48Kg/m3), and highest cellular biofilm density (CFU/g-8.4 ×1010) amongst the three matrices. For practical purposes, recyclability was evaluated and it was concluded that even after reusing for five successive cycles the production retained to ∼82.4%. Subsequently, polynomial model was developed using 30 runs central composite factorial design experiments having coefficient of regression (R²) as 0.9520, in order to predict yields under different immobilization conditions for 1,3-PDO production. Plackett-Burman was employed (Accuracy= 99.17%) to screen significant toxic impurities. Based on statistical analysis six impurities were found to be significantly influential on PDO production in adverse manner. With negative coefficient of estimate (COE) varying in decreasing order: Linoleic acid >Oleic acid >Stearic acid >NaCl>K2SO4 >KCl. The study illustrates practical application for repurposing waste glycerol generated from biodiesel plants, thus developing improved agnostic process along with yield production models.

Validated HPLC-PDA methodology utilized for simultaneous determination of Etoricoxib and Paracetamol in the presence of Paracetamol toxic impurities.

Etoricoxib (ETO), Paracetamol (PCM), and two toxic impurities for Paracetamol impurity K (4-aminophenol (PAP)) and impurity E (para-hydroxy acetophenone (PHA)) were separated using a simple and selective HPLC method that was tested for the first time. PCM is a commonly used analgesic and antipyretic medication that has recently been incorporated into COVID-19 supportive treatment. Pharmaceuticals containing PCM in combination with other analgesic-antipyretic drugs like ETO help to improve patient compliance. The studied drugs and impurities were separated on a GL Sciences Inertsil ODS-3 (250 × 4.6) mm, 5.0 µm column, and linear gradient elution was performed using 50 mM potassium dihydrogen phosphate adjusted to pH 4.0 with ortho-phosphoric acid and acetonitrile as mobile phase at 2.0 mL/min flow rate at 25 °C and UV detection at 220 nm. The linearity range was 1.5-30.0 µg/mL for ETO and PCM while 0.5-10.0 µg/mL for PAP and PHA, with correlation coefficients (r) for ETO, PCM, PAP, and PHA of 0.9999, 0.9993, 0.9996, and 0.9998, respectively. The proposed method could be used well for routine analysis in quality control laboratory.

Hydrofluoric Acid and Other Impurities in Toxic Perfluorooctane Batches.

PURPOSE: The complications with cytotoxic perfluorooctane (PFO) batches reported in 2015 were attributed to reactive underfluorinated impurities whose chemical identity and behavior still need to be clarified. MATERIAL AND METHODS: We analyzed original packaged samples of Ala®octa batches involved in several reported cases of retinal toxicity. (A) The impurity profile was determined. (B) pH and fluoride ion content were measured. (C) Extraction with olive oil was performed to investigate differences in lipophilia among perfluorinated liquid (PFCL) as a measure for penetration of lipophilic cell membranes followed by measurements (A) and (B). RESULTS: (A) The detected impurities can be divided into: (1) reactive underfluorinated compounds and their degradation products including hydrogen fluoride (HF), (2) nonreactive underfluorinated compounds, (3) surface active compounds, (4) nonreactive fluorinated compounds, and (5) leachables from primary packaging components. The highest acute toxic potential is associated with the impurities of group (1). (B) HF was detected as a degradation product of reactive underfluorinated impurities by relying on the pH values and fluoride ion content of the water extracts. (C) Lipophilic impurities dissolved in PFO migrate into lipophilic extraction medium. In particular, HF is rapidly transferred in this way. CONCLUSIONS: HF as degradation product of unstable or reactive underfluorinated contaminants seems of particular importance triggering the acute toxicity of affected PFO. Contamination related toxicity and unwanted side effects can only be reliably excluded via analytical controlled multistage, high-purification processes. TRANSLATIONAL RELEVANCE: In Ala®octa batches different impurities show retinal toxicity. HF seems of particular importance of the acute toxicity of PFO.