A solvent-modified micellar electrokinetic chromatography method was developed following the Quality by Design approach for the simultaneous determination of sitagliptin (SIT), an oral antihyperglycemic drug, and its main impurities derived from the synthesis process. The separation system was identified in the scouting phase and was made by sodium dodecyl sulphate (SDS) micelles with the addition of n-butanol and methanol. The knowledge space was investigated through an asymmetric screening matrix, taking into consideration eight critical method parameters (CMPs) involving the composition of the background electrolyte in terms of buffer concentration and pH, the concentration of surfactants and organic modifiers, and voltage. The critical method attributes (CMAs) were identified as analysis time and the distance between the tail of the electroosmotic flow system peak and the front edge of impurity I1 (sitagliptin triazole hydrochloride). A Box-Behnken Design was used in response surface methodology for calculating the quadratic models relating the CMPs to the CMAs. From the models it was possible to compute the method operable design region (MODR) through Monte-Carlo simulations. The MODR was identified in the probability maps as the multidimensional zone where the risk of failure to achieve the desired values for the CMAs was lower than 10 %. The experimental conditions corresponding to the working point, with the MODR interval, were the following: background electrolyte, 14 (10-18) mM borate buffer pH 9.20, 100 mM SDS, 13.6 (11.1-16.0) %v/v n-butanol, 6.7 (4.5-8.8) %v/v methanol; voltage and temperature were set to 28 kV and 22 °C, respectively. The developed CE method was validated in accordance with International Council for Harmonisation guidelines and was applied to the analysis of SIT tablets. The routine analysis for the quality control of the pharmaceutical product could be conducted in about 11 min.
Introduction: Conventional biopsy, based on extraction from a tumor of a solid tissue specimen requiring needles, endoscopic devices, excision or surgery, is at risk of infection, internal bleeding or prolonged recovery. A non-invasive liquid biopsy is one of the greatest axiomatic consequences of the identification of circulating tumor DNA (ctDNA) as a replaceable surgical tumor bioQpsy technique. Most of the literature studies thus far presented ctDNA detection at almost final stage III or IV of cancer, where the treatment option or cancer management is nearly impossible for diagnosis. Objective: Hence, this paper aims to present a simulation study of extraction and separation of ctDNA from the blood plasma of cancer patients of stage I and II by superparamagnetic (SPM) bead particles in a microfluidic platform for early and effective cancer detection. Method: The extraction of ctDNA is based on microfiltration of particle size to filter some impurities and thrombocytes plasma, while the separation of ctDNA is based on magnetic manipulation to high yield that can be used for the upstream process. Result: Based on the simulation results, an average of 5.7 ng of ctDNA was separated efficiently for every 10 μL blood plasma input and this can be used for early analysis of cancer management. The particle tracing module from COMSOL Multiphysics traced ctDNA with 65.57% of sensitivity and 95.38% of specificity. Conclusion: The findings demonstrate the ease of use and versatility of a microfluidics platform and SPM bead particles in clinical research related to the preparation of biological samples. As a sample preparation stage for early analysis and cancer diagnosis, the extraction and separation of ctDNA is most important, so precision medicine can be administered.
- MeSH
- Circulating Tumor DNA * MeSH
- Humans MeSH
- Magnetic Iron Oxide Nanoparticles MeSH
- Microfluidics MeSH
- Neoplasms * diagnosis MeSH
- Liquid Biopsy MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
An HPLC method with UV and electrospray ionization - mass spectrometry (ESI-MS) detection was developed for the separation and determination of obeticholic acid (OBE) and its related compounds in development process and quality control. OBE and its related compounds were classified into three major group based on the mass spectra profiles: (A) those containing a hydroxyl group at position 3 and 7, (B) those containing a hydroxyl group and/or carbonyl group at position 3, hydrogen, ethyl or ethylidene group at position 6 and a hydroxyl group and/or carbonyl group at position 7, and (C) those containing carbonyl groups at position 3 and 7. ESI-MS ionization of OBE and its related compounds often produced intense adduct ions [M+H+98]+ and/or [M+H+196]+ that were identified as the adduct ions of phosphoric acid ([M+H+H3PO4]+ and [M+H+2H3PO4]+) originating from the mobile phase. The separation on HPLC system was accomplished using stationary phase based on XSelect CSH C18 (3.0×150mm×2.5μm) and a linear gradient elution using acetonitrile and 0.05% of o-phosphoric acid. The condition of chromatographic system was set as follows: flow rate 0.7mL/min, temperature 45°C and UV detection at 192nm. The separation of the 19 compounds was finished in less than 18min (including equilibration time). The HPLC/UV method was partially validated according to International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines in terms of repeatability, selectivity, linearity and limit of quantification and detection.
- MeSH
- Chemical Fractionation instrumentation methods MeSH
- Chemistry, Pharmaceutical methods MeSH
- Spectrometry, Mass, Electrospray Ionization instrumentation methods MeSH
- Drug Contamination prevention & control MeSH
- Chenodeoxycholic Acid analogs & derivatives analysis chemistry MeSH
- Limit of Detection MeSH
- Drug Compounding instrumentation methods MeSH
- Reproducibility of Results MeSH
- Quality Control * MeSH
- Sensitivity and Specificity MeSH
- Spectrophotometry, Ultraviolet instrumentation methods MeSH
- Chromatography, High Pressure Liquid instrumentation methods MeSH
- Publication type
- Journal Article MeSH
- Validation Study MeSH
Spiramycin is a 16-membered macrolide antibiotic produced by Streptomyces ambofaciens and used in human medicine for the treatment of various respiratory tract and genital infections. Several impurities were detected in spiramycin-fermentation broth, especially impurities D and F, which decreased the separation-extraction yield and increased production cost. Dextrins, as the main carbon source, influence the accumulation of spiramycin and impurities. In this work, two types of dextrin from vendor Y and Z were compared to study their influences on spiramycin production. Our results showed that final spiramycin production with dextrin Z was enhanced twofold as compared with dextrin Y; however, the content of impurities F and D were higher with dextrin Z relative to dextrin Y. Several parameters (adenosine triphosphate, total sugar, reducing sugar, and reducing sugar to total sugar) were analyzed to reveal differences in the fermentation process. In vitro dextrin hydrolysis by amylase revealed structural differences in the two types of dextrin, and real-time quantitative polymerase chain reaction analyses showed that the transcription of srm7 and srm21 (involved in forosaminyl methylation) was enhanced and potentially related to the reduced formation of impurity F with dextrin Y. Furthermore, the srm20/srm33 ratio, representing flux balance of forosaminyl and mycarosyl, was ~ 1, implying that forosaminyl and mycarosyl biosynthesis were well balanced, resulting in reduced production of impurity D with dextrin Y.
Two new impurities were described and determined using gradient HPLC method with UV detection in retigabine (RET). Using LC-HRMS, NMR and IR analysis the impurities were identified as RET-dimer I: diethyl {4,4'-diamino-6,6'-bis[(4-fluorobenzyl)amino]biphenyl-3,3'-diyl}biscarbamate and RET-dimer II: ethyl {2-amino-5-[{2-amino-4-[(4-fluorobenzyl) amino] phenyl} (ethoxycarbonyl) amino]-4-[(4-fluorobenzyl)amino] phenyl}carbamate. Reference standards of these impurities were synthesized followed by semipreparative HPLC purification. The mechanism of the formation of these impurities is also discussed. An HPLC method was optimized in order to separate, selectively detect and quantify all process-related impurities and degradation products of RET. The presented method, which was validated in terms of linearity, limit of detection (LOD), limit of quantification (LOQ) and selectivity is very quick (less than 11min including re-equilibration time) and therefore highly suitable for routine analysis of RET related substances as well as stability studies.
A new impurity was detected and determined using gradient ion-pair UHPLC method with UV detection in zolmitriptan (ZOL). Using MS, NMR and IR study the impurity was identified as (4S,4'S)-4,4'-(2,2'-(4-(dimethylamino)butane-1,1-diyl)bis(3-(2-(dimethylamino) ethyl)-1H-indole-5,2-diyl))bis(methylene)di(oxazolidin-2-one) (ZOL-dimer). The standard of ZOL-dimer was consequently prepared via organic synthesis followed by semipreparative HPLC purification. The UHPLC method was optimized in order to selectively detect and quantify other known and unknown process-related impurities and degradation products of ZOL as well. The presented method which was validated with respect to linearity, accuracy, precision and selectivity has an advantage of a very quick UHPLC chromatographic separation (less than 7 min including re-equilibration time) and therefore is highly suitable for routine analysis of related substances and stability studies of ZOL.
- MeSH
- Mass Spectrometry methods MeSH
- Drug Contamination MeSH
- Limit of Detection MeSH
- Magnetic Resonance Spectroscopy methods MeSH
- Oxazolidinones chemistry isolation & purification MeSH
- Oxazoles isolation & purification MeSH
- Spectrophotometry, Infrared methods MeSH
- Spectrophotometry, Ultraviolet methods MeSH
- Chemistry Techniques, Synthetic methods MeSH
- Tryptamines chemistry isolation & purification MeSH
- Chromatography, High Pressure Liquid methods MeSH
- Publication type
- Journal Article MeSH
- MeSH
- Technology, Pharmaceutical standards MeSH
- Drug Evaluation standards MeSH
- Clinical Trials as Topic MeSH
- Drug Contamination MeSH
- Laboratories standards MeSH
- Pharmaceutical Preparations MeSH
- Pharmacies standards MeSH
- Drug-Related Side Effects and Adverse Reactions MeSH
- Quality Control MeSH
- Drug Approval MeSH
- Device Approval standards MeSH
- Guidelines as Topic MeSH
- Publication type
- Clinical Trial MeSH
... EXPOSURE 15 -- 3.1 Natural occurrence 15 -- 3.2 Anthropogenic sources 16 -- 3.2.1 Production levels and processes ... ... 16 -- 3.2.1.1 Manufacturing process 16 -- 3.2.1.2 Impurities 16 -- 3.2.1.3 Other sources 17 -- 3.2.1.4 ... ... -- 7.5.2.1 Oral 53 -- 1.5.22 Inhalation 53 -- 7.5.2.3 Intraperitoneal 55 -- 7.6 Mutagenicity and related ...
Environmental health criteria, ISSN 0250-863X No. 191
XVIII, 106 s. : il. ; 20 cm
... CONTENTS -- WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR LINEAR ALKYLBENZENE SULFONATES AND RELATED ... ... THE CRITERIA MONOGRAPHS 3 -- ENVIRONMENTAL HEALTH CRITERIA FOR LINEAR ALKYLBENZENE SULFONATES AND RELATED ... ... 36 -- A3.1 Natural occurrence 36 -- A3.2 Anthropogenic sources 36 -- A3.2.1 Production levels and processes ... ... Hi -- A7.5 Reproductive toxicity, embryotoxicity, and teratogenicity 116 -- A7.6 Mutagenicity and related ... ... -- B3.1 Natural occurrence 180 -- B3.2 Anthropogenic sources 180 -- B3.2.1 Production levels and processes ...
Environmental health criteria ; 169
328 s. : tab. ; 23 cm
- MeSH
- Detergents adverse effects MeSH
- Sulfonic Acids analogs & derivatives MeSH
- Environmental Exposure MeSH
- Conspectus
- Lékařské vědy. Lékařství
- NML Fields
- environmentální vědy
- toxikologie
- environmentální vědy
- NML Publication type
- publikace WHO
... CHEMICAL PROPERTIES, AND ANALYTICAL METHODS -- 2.1 Identity 31 -- 2.1.1 Technical product 31 -- 2.1.2 Impurities ... ... EXPOSURE 41 -- 3.1 Natural occurrence 41 -- 3.2 Anthropogenic sources 41 -- 3.2.1 Production levels and processes ... ... 41 -- 3.2.1.1 World producers 41 -- 3.2.1.2 Production figures 41 -- 3.2.1.3 Production processes 42 ... ... degradation 52 -- 4.2.2.2 Photochemical degradation 52 -- 4.2.2.3 Degradation by physico-chemical processes ... ... Sensitization 93 -- 7.5 Reproductive toxicity, embryotoxicity and teratogenicity 94 -- 7.6 Mutagenicity and related ...
Environmental health criteria ; 179
163 s. : tab. ; 23 cm
- MeSH
- Environmental Pollutants MeSH
- Morpholines toxicity MeSH
- Solvents MeSH
- Environmental Exposure MeSH
- Conspectus
- Lékařské vědy. Lékařství
- NML Fields
- environmentální vědy
- toxikologie
- environmentální vědy
- NML Publication type
- publikace WHO
