A scalable process for the synthesis of high-purity penehyclidine hydrochloride (99.9% by HPLC area %) without purification by fractional distillation has been developed with significantly improved ...overall yield, where a robust and cost-effective Corey–Chaykovsky reaction was successfully explored. Critical parameters of each step and process-related impurities were identified, and all impurities reported in this work have been independently synthesized, which could promote the understanding of the impurity profile and potentially boost the upgrade of the drug standard.
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•GC-IR analysis of FRS distinguish between positional isomers of FRS compounds.•MS spectra alone may not always differentiate positional isomers of FRS.•New libraries of GC–MS and ...GC-IR spectra of 212 FRS are made available.•LODs for fentanyl using GC-IR range between 0.10 and 0.19 mg/mL.
Forensic laboratories routinely use gas chromatography mass spectrometry (GC–MS) in the identification of controlled substances using both retention time and electron impact ionization (EI) mass spectra. Certain drugs such as positional isomers of some fentanyl related substances (FRS) can produce indistinguishable EI mass spectra but may be differentiated using retention time. The core structure of fentanyl consists of an amide group, a piperidine ring, an aniline ring, and an N-alkyl chain, each providing opportunities for points of substitution that create FRS and corresponding positional isomers. For this study, the analysis by GC coupled to a vapor-phase infrared spectroscopy detector (GC-IR) was used as a complementary technique to GC–MS for the identification of positional isomers of FRS. The result is a novel fentanyl library consisting of 212 different FRS reference compounds. A collaboration among three different laboratories yielded correct identifications of twenty blind samples when searched against the GC-IR FRS library created at Florida International University (FIU). The expected limits of detection for fentanyl using GC-IR range between 0.10 and 0.19 mg/mL, depending on the sample introduction (injector) method and other instrumental parameters. The newly created GC-IR library and its GC–MS counterpart of 212 FRS are shared in the supplementary materials for future use by researchers and practitioners.
The study aimed to establish a high-performance liquid chromatography (HPLC) method for the quantitative analysis of the related substances of bedaquiline fumarate. Nuclear magnetic resonance and ...mass spectrometry were used for characterization and assay. A chromatographic method was used for separation. The conditions used were: gradient elution system composed of methanol 0.01mol/L KH2PO4 and 0.01 mol/L K2HPO4 (pH = 4.1) with a flow rate of 1 mL/min, at 224 nm as the detection wavelength. In this study, three degradation products of bedaquiline fumarate have been disclosed for the first time. The related impurities and degradation products of the drug were well separated. The method provided linear responses within the concentration range, which varied from 0.20 to 10.08 μg/mL with limits of detection of 0.10 μg/mL and limits of quantification of 0.20 μg/mL. The mean percent recovery varied between 91.64 and 105.89%. The method was validated for other parameters such as specificity, stability, and robustness. This method was validated and worked well for the impurity studies and quality control analysis of the laboratory-prepared samples of bedaquiline fumarate.
•The organic related-impurities are defined as organic chemical compounds appear during manufacturing process or storage. They can be the starting products, synthesis intermediates, by-products or ...the degradation products.•The control of organic related-impurities is a key component and a big challenge in pharmaceutical industry to assure effective and safe treatment.•Seven drug related-impurities were analyzed by High Performance Liquid Chromatography (HPLC-UV) in six samples of Metronidazole API, collected from six pharmaceutical industries installed in Algeria.•All samples collected had an impurities content meeting the standard except M5 sample which had a high content of unspecified impurity 0.170%.
The main objective of this work was to analysis seven drug related impurities by High Performance Liquid Chromatography (HPLC) in six samples of Metronidazole API, collected from six pharmaceutical industries installed in Algeria.
For the organic related-impurities analysis, a liquid chromatography apparatus HPLC-UV device equipped with an automatic injector and UV/Vis detector and a column (C18), deactivated for the bases, post-grafted (5 µm) and dimensions (w: 0.25 m, Ø: 4.6 mm) were used. Each sample of Metronidazole API was processed according to the related substances procedures of the European Pharmacopoeia (Eur pH), 8th edition.
The HPLC related-impurities analysis showed that the M1, M2, M3, M4 and M6 samples had an individual content of impurity A or any other unspecified impurity within the required standards and a total of all impurities present meeting the standard. M5 sample had a high content of unspecified impurity 0.170% compared to the general acceptance criterion, and a total of impurities 0.187% meeting the standard. This can be explained either by the degradation of the sample which may be due to poor storage conditions or the batch from which this sample comes was not well purified during the synthesis route.
Seven drug related impurities were analyzed in six samples of Metronidazole API by HPLC. The impurity A and the unspecified impurities were precisely determined in the different samples of Metronidazole analyzed. All samples had an individual content and a total of all impurities present meeting the standard except M5 sample had a high content of unspecified impurity 0.170% and a total of impurities 0.187% meeting the standard.
Fentanyls abuse is a persistent international concern. New fentanyl derivatives are constantly appearing, circumventing national and international laws. In this study, laboratory degradation ...experiment with different conditions such as pH, light, temperature and oxygen availability were compared to improve the understanding of the fentanyls degradation pathways. Twelve major degradants of sufentanil and alfentanil were detected and identified together using UHPLC-QTOF-MS. A total of thirty nine fentanyls including twelve typical fentanyl new psychoactive substances, eighteen manufacturing process-related substances and nine key degradants of sufentanil and alfentanil were screened in 120 sewage water samples collected from 20 sewage water treatment plants chosen among 6 urban cities in east China from July to August in 2020 using a validated UHPLC-MS/MS method. Three fentanyls (fentanyl, sufentanil, alfentanil), seven degradants and six manufacturing process-related substances were found in the test samples. The study could provide a useful tool for the monitoring of the abuses, illegal manufacturing or pharmaceuticals related pollutions of fentanyls and their analogs.
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•Twelve degradants were identified for sufentanil and alfentanil by UHPLC-QTOF-MS.•Thirty-nine fentanyls were screened in east China sewage water samples by UHPLC-MS/MS.•Some fentanyls were found in the screened sewage water samples.•Results were useful for fentanyls related drug enforcement.
Mycophenolate mofetil is an antiproliferative immunosuppressive agent. Since its clinical efficacy and safety highly depend on the quality, the stability, and impurity profiles of mycophenolate ...mofetil are paid ever‐increasing attention. However, there are few published studies reporting the complete characterization of both the process‐related substances and degradation products in mycophenolate mofetil. In the present study, a highly specific and efficient liquid chromatography coupled with quadrupole‐time of flight mass spectrometry method was developed for the separation and identification of all the potential impurities in mycophenolate mofetil. According to the ICH Q1A (R2) guideline, the forced degradation studies were conducted to elucidate the stability and degradation pathways of mycophenolate mofetil. A total of 15 related substances, including the process‐related substances and stress degradation products were characterized by the established hyphenated method, 11 of them have not been reported before. In view of the synthetic route and degradation pathways of mycophenolate mofetil, the origins and formation mechanisms of these related substances were discussed. Based on the obtained stability and impurity profiles, key points of the manufacturing process were proposed to deliver mycophenolate mofetil with high purity.
•Implementation of an assessment for unexpected impurities arising in drug synthesis.•Different ways impurities of Cetirizine dihydrochloride can arise are depicted.•Reaction matrices help to ...understand side products in synthesis.
Recently, the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) had reported on “unexpected” impurities in a couple of sartans, ranitidine, and metformin. These events led to a lot of discussion with regard to the risk assessment for the production process itself. Most of these discussions covered the field of nitrosamine impurities only, but that would be too short-sighted. One should expand that scope. It is impossible to synthesize a 100 % pure compound which holds true for all active pharmaceutical ingredients (APIs). Different synthetic routes result in different impurity profiles. Therefore, pharmacopoeias try to consider all possible impurities that can arise from different drug synthesis routes in one a single monograph for impurity assessment. However, API manufacturers cannot simply rely on the impurity profile reported in pharmacopoeias for the production of a high-quality product. They have to implement a whole risk assessment to rate the presence of impurities in the API. Here, a strategy to evaluate and minimize the load of potential risks of impurities during the manufacturing process of the drug substance cetirizine dihydrochloride within the frame of a detailed risk assessment report is demonstrated.
Abstract
Torasemide, a pyridine-3-sulfonylurea derivative, is a high-efficiency loop diuretic. During the process development of torasemide, five process-related substances, which have been specified ...in the pharmacopeia, would be produced. In this study, all these related substances, including compounds
A
–
E
, were synthesized via simple procedures and subsequently characterized by
1
H nuclear magnetic resonance (NMR),
13
C NMR, and mass spectrometry. Particularly, a simple synthetic method for compound
A
has not been found in previous literature. It is worth noting that other related substances could be prepared from compound
B
in one or two steps. The availability of these related substances could allow for quality control in the process of torasemide.
•Comprehensive review of applications of capillary electrophoresis to pharmaceutical analysis.•Determination of the active pharmaceutical ingredient, related substances, stereoisomeric impurities, as ...well as excipients and counter ions.•Discussion of recent trends in pharmaceutical analysis by capillary electrophoresis.
Capillary electromigration techniques have become important tools for the analysis of pharmaceutical drugs. The present review updates on recent developments of the analysis of small molecule drugs, excipients and counter ions dating between January 2014 and May 2017. Capillary electrophoresis (CE) continues to be a very popular method for the analysis of the active pharmaceutical ingredients and their related substances in pharmaceutical formulations, especially for the determination of the stereoisomeric purity of chiral drugs, which is evidenced by a large number of related literature reported in the reviewed period of time. The simultaneous analysis of several drugs has been easily achieved by CE. Moreover, the flexibility of the technique has been clearly illustrated by the application of various separation modes including capillary zone electrophoresis, isotachophoresis as well as various modes of electrokinetic chromatography such as micellar electrokinetic chromatography or microemulsion electrokinetic chromatography in combination with various detection modes including direct and indirect UV, laser-induced fluorescence, mass spectrometry and contactless conductivity detection. A general trend also observed in other analytical techniques is the application of quality by design principles in CE.
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