ABSTRACT
The present study discusses the influence of sunlight on the photostability of levomepromazine (LV) and olanzapine (OLA) hydrochlorides in river water. Four samples of water from different rivers were used in the research. In their course, it turned out that levomepromazine easily underwent photooxidation under simulated environmental conditions, resulting in the generation of its sulphoxide. Olanzapine, on the other hand, appeared to be more resistant to sunlight, as its photodecomposition proceeded slowly, and only one product of its decomposition was detected spectrophotometrically during the process. The photodegradation was analyzed in detail using principal component analysis (PCA) and multivariate curve resolution alternating least squares (MCR-ALS) chemometric methods, and the outcomes verified by HPLC and GC-MS analysis. It can be stated that the rates of the observed processes heavily depended on the chemical composition of the fresh water used in the experiments.
Subject(s)
Benzodiazepines/radiation effects , Methotrimeprazine/radiation effects , Photolysis , Sulfoxides/radiation effects , Sunlight , Water Pollutants, Chemical/radiation effects , Benzodiazepines/chemistry , Chromatography, High Pressure Liquid , Gas Chromatography-Mass Spectrometry , Kinetics , Least-Squares Analysis , Methotrimeprazine/chemistry , Olanzapine , Principal Component Analysis , Rivers/chemistry , Sulfoxides/chemistry , Water Pollutants, Chemical/chemistryABSTRACT
A simple, sensitive and reproducible ultra performance liquid chromatography (UPLC) coupled with a photodiode array detector method was developed for the quantitative determination of olanzapine (OLN) in API and pharmaceutical dosage forms. The method is applicable to the quantification of related substances and assays of drug substances. Chromatographic separation was achieved on Acquity UPLC BEH 100-mm, 2.1-mm, and 1.7-µm C-18 columns, and the gradient eluted within a short runtime, i.e., within 10.0 min. The eluted compounds were monitored at 250 nm, the flow rate was 0.3 mL/min, and the column oven temperature was maintained at 27°C. The resolution of OLN and eight (potential, bi-products and degradation) impurities was greater than 2.0 for all pairs of components. The high correlation coefficient (r(2)>0.9991) values indicated clear correlations between the investigated compound concentrations and their peak areas within the test ranges. The repeatability and intermediate precision, expressed by the RSD, were less than 2.4%. The accuracy and validity of the method were further ascertained by performing recovery studies via a spike method. The accuracy of the method expressed as relative error was satisfactory. No interference was observed from concomitant substances normally added to the tablets. The drug was subjected to the International Conference on Harmonization (ICH)-prescribed hydrolytic, oxidative, photolytic and thermal stress conditions. The performance of the method was validated according to the present ICH guidelines for specificity, limit of detection, limit of quantification, linearity, accuracy, precision, ruggedness and robustness.
Subject(s)
Antipsychotic Agents/analysis , Benzodiazepines/analysis , Drug Contamination , Technology, Pharmaceutical , Antipsychotic Agents/radiation effects , Benzodiazepines/chemistry , Benzodiazepines/radiation effects , Chromatography, High Pressure Liquid , Drug Contamination/prevention & control , Drug Stability , Hot Temperature/adverse effects , Hydrogen-Ion Concentration , Limit of Detection , Olanzapine , Oxidation-Reduction , Quality Control , Reproducibility of Results , Spectrometry, Mass, Electrospray Ionization , Tandem Mass Spectrometry , Time Factors , Ultraviolet Rays/adverse effectsABSTRACT
A 30 second burst of microwave irradiation at an energy level insufficient to cause DNA denaturation or damage drives the covalent reaction between pyrrolobenzodiazepine (PBD) antitumour agents and double-stranded or hairpin oligonucleotides to completion, a process that normally takes between 3-24 hours and thus offering the opportunity for higher-throughput screening of covalent-binding DNA-interactive agents.
Subject(s)
Antineoplastic Agents/metabolism , Benzodiazepines/metabolism , DNA/metabolism , DNA/radiation effects , Microwaves , Pyrroles/metabolism , Antineoplastic Agents/chemistry , Antineoplastic Agents/radiation effects , Benzodiazepines/chemistry , Benzodiazepines/radiation effects , Binding Sites , Chromatography, High Pressure Liquid , DNA/chemistry , Ligands , Models, Molecular , Pyrroles/chemistry , Pyrroles/radiation effects , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Time FactorsABSTRACT
A 66-member C2-aryl pyrrolo[2,1-c][1,4]benzodiazepine (PBD) library has been successfully synthesized in parallel via Suzuki coupling using PS-PPh3Pd (catalyst) and PS-DEAM (scavenger) under microwave radiation. Library members were obtained in sufficient yield (up to 91%) and purity (85-98% crude) for biological evaluation.
Subject(s)
Benzodiazepines/chemical synthesis , Combinatorial Chemistry Techniques/methods , Benzodiazepines/chemistry , Benzodiazepines/radiation effects , Catalysis , Microwaves , Molecular Structure , Organometallic Compounds/chemistry , Palladium/chemistry , StereoisomerismABSTRACT
In relation to the phototoxicity of 7-chloro-I,4-benzodiazepine-N-oxides the photostability of some of these N-oxides and the thermostability of their photoproducts, the oxaziridines, were studied. Rather than a consequence of a direct phototoxic effect by the N-oxides the ultimate toxic effect in the test system Salmonella typhimurium appeared to be caused by products formed during and after the irradiation. For chlordiazepoxide (CDZ) and its main metabolites in man desmethylchlordiazepoxide (DES) and demoxepam (DEM) the formation of an oxaziridine is indeed a crucial factor for the onset of the toxic effect. However, DEM oxaziridine (DEM OX.) being very thermolabile in protic medium forms non-toxic conjugates with the solvent. CDZ OX. and DES OX. are thermally converted into their N-oxide, although DES OX. partly decomposes into 6-chloro-4-phenylquinazoline-2-carboxaldehyde as well. This compound proved to be an important factor in the toxic action of DES after irradiation.
