RESUMO
The solid-state properties of drug candidates play a crucial role in their selection. Quality control of active pharmaceutical ingredients (APIs) based on their structural information involves ensuring a consistent crystal form and controlling water and residual solvent contents. However, traditional crystallographic techniques have limitations and require high-quality single crystals for structural analysis. Microcrystal electron diffraction (microED) overcomes these challenges by analyzing difficult-to-crystallize or small-quantity samples, making it valuable for efficient drug development. In this study, microED analysis was able to rapidly determine the configuration of two crystal forms (Forms 1, 2) of the API ranitidine hydrochloride. The structures obtained with microED are consistent with previous structures determined by X-ray diffraction, indicating microED is a useful tool for rapidly analyzing molecular structures in drug development and materials science research.
Assuntos
Ranitidina , Ranitidina/química , Cristalização , Estrutura Molecular , ElétronsRESUMO
Henna is a plant-based dye obtained from the powdered leaf of the pigmented plant Lawsonia inermis, and has often been used for grey hair dyeing, treatment, and body painting. As a henna product, the leaves of Indigofera tinctoria and Cassia auriculata can be blended to produce different colour variations. Although allergy from henna products attributed to p-phenylenediamine, which is added to enhance the dye, is reported occasionally, raw material plants of henna products could also contribute to the allergy. In this study, we reported that raw material plants of commercial henna products distributed in Japan can be estimated by LC-high resolution MS (LC-HRMS) and multivariate analysis. Principal Component Analysis (PCA) score plot clearly separated 17 samples into three groups [I; henna, II; blended henna primarily comprising Indigofera tinctoria, III; Cassia auriculata]. This grouping was consistent with the ingredient lists of products except that one sample listed as henna was classified as Group III, indicating that its ingredient label may differ from the actual formulation. The ingredients characteristic to Groups I, II, and III by PCA were lawsone (1), indirubin (2), and rutin (3), respectively, which were reported to be contained in each plant as ingredients. Therefore, henna products can be considered to have been manufactured from these plants. This study is the first to estimate raw material plants used in commercial plant-based dye by LC-HRMS and multivariate analysis.
Assuntos
Espectrometria de Massas , Análise Multivariada , Folhas de Planta/química , Lawsonia (Planta)/química , Indigofera/química , Corantes/química , Corantes/análise , Cassia/química , Cromatografia Líquida , Cromatografia Líquida de Alta Pressão , Análise de Componente Principal , Naftoquinonas/química , Naftoquinonas/análise , Estrutura MolecularRESUMO
The recent discovery of N-nitrosodimethylamine (NDMA), a mutagenic N-nitrosamine, in pharmaceuticals has adversely impacted the global supply of relevant pharmaceutical products. Contamination by N-nitrosamines diverts resources and time from research and development or pharmaceutical production, representing a bottleneck in drug development. Therefore, predicting the risk of N-nitrosamine contamination is an important step in preventing pharmaceutical contamination by DNA-reactive impurities for the production of high-quality pharmaceuticals. In this study, we first predicted the degradation pathways and impurities of model pharmaceuticals, namely gliclazide and indapamide, in silico using an expert-knowledge software. Second, we verified the prediction results with a demonstration test, which confirmed that N-nitrosamines formed from the degradation of gliclazide and indapamide in the presence of hydrogen peroxide, especially under alkaline conditions. Furthermore, the pathways by which degradation products formed were determined using ranitidine, a compound previously demonstrated to generate NDMA. The prediction indicated that a ranitidine-related compound served as a potential source of nitroso groups for NDMA formation. In silico software is expected to be useful for developing methods to assess the risk of N-nitrosamine formation from pharmaceuticals.
Assuntos
Gliclazida , Indapamida , Nitrosaminas , Ranitidina , Dimetilnitrosamina , Preparações FarmacêuticasRESUMO
Quantitative NMR (qNMR), particularly 1H-qNMR, is useful for determining the absolute purity of organic molecules. However, identifying the target signal(s) for quantification is difficult, because of the overlap and complexity of organic molecules. Therefore, we focused on the 31P nucleus, owing to the simplicity of its signals, and investigated the 31P-qNMR absolute determination method by using organophosphorus drugs, water-soluble cyclophosphamide hydrate (CP), and water-insoluble sofosbuvir (SOF). The optimized and reproducible 31P-qNMR conditions, such as qNMR sample preparation [i.e., selecting suitable deuterated solvents and a reference standard (RS) for 31P-qNMR], hygroscopicity and solution stability of the analyte and RS, and qNMR measurements-such as acquisition time, relaxation delay time, and spectral width-were examined. The CP purities determined using 31P-qNMR agreed well with those for the established 1H-qNMR method in D2O. In contrast, the SOF purity determined using 31P-qNMR was 1.6% higher than that for 1H-qNMR in the protic solvent CD3OD. Therefore, using a protic solvent, such as CD3OD, was not suitable for 31P-qNMR; the deuterium exchange with the RS for 31P-qNMR (i.e., phosphonoacetic acid) resulted in a small integrated intensity. Consequently, the aprotic solvent DMSO-d6 was employed to determine the SOF purity. The data revealed that the SOF purities determined using 31P-qNMR agreed well with the established 1H-qNMR values, indicating that the absolute quantification of SOF using both 31P-qNMR and 1H-qNMR is possible in DMSO-d6. Thus, we established an optimized and reproducible 31P-qNMR method in validation study across multiple laboratories.
Assuntos
Dimetil Sulfóxido , Compostos Organofosforados , Água , Solventes , Preparações FarmacêuticasRESUMO
A novel trimeric monoterpenoid indole alkaloid, vincarostine A (1) consisting of an aspidosperma-iboga-aspidosperma type skeleton, was isolated from the whole plant of Catharanthus roseus. The structure including absolute stereochemistry was elucidated on the basis of 2D NMR data and CD spectrum. Vincarostine A (1) showed anti-malarial activity.
Assuntos
Antimaláricos , Catharanthus , Alcaloides de Triptamina e Secologanina , Catharanthus/química , Antimaláricos/química , Antimaláricos/farmacologia , Estrutura Molecular , Alcaloides de Triptamina e Secologanina/química , Alcaloides de Triptamina e Secologanina/isolamento & purificação , Espectroscopia de Ressonância Magnética , Plasmodium falciparum/efeitos dos fármacos , Extratos Vegetais/químicaRESUMO
A new dimeric indole alkaloid, vincazalidine A consisting of an aspidosperma type and a modified iboga type with 1-azatricyclo ring system consisting of one azepane and two piperidine rings coupled with an oxazolidine ring was isolated from Catharanthus roseus, and the structure including absolute stereochemistry was elucidated on the basis of spectroscopic data as well as DP4 statistical analysis. Vincazalidine A induced G2 arrest and subsequent apoptosis in human lung carcinoma cell line, A549 cells.