RESUMO
The preparation of stable amorphous pemetrexed disodium of pharmaceutical purity as well as the process optimization for the preparation of the hemipentahydrate form of pemetrexed disodium are described. Analytical methods for the polymorphic and chemical purity studies of pemetrexed disodium and pemetrexed diacid forms were developed. The physicochemical properties of the amorphous and hydrate forms of pemetrexed disodium, as well as new forms of pemetrexed diacid (a key synthetic intermediate) were studied by thermal analysis and powder X-ray diffraction. High-performance liquid chromatography and gas chromatography methods were used for the chemical purity and residual solvents determination. In order to study the polymorphic and chemical stability of the amorphous and hemipentahydrate forms, a hygroscopicity test (25 °C, 80% RH) was performed. Powder diffraction and high-performance liquid chromatography analyses revealed that the amorphous character and high chemical purity were preserved after the hygroscopicity test. The hemipentahydrate form transformed completely to the heptahydrate form of pemetrexed disodium. Both pemetrexed disodium forms were produced with high efficiency and pharmaceutical purity in a small commercial scale. Amorphous pemetrexed disodium was selected for further pharmaceutical development. Two new polymorphs (forms 1 and 2) of pemetrexed diacid were used for the preparation of high purity amorphous pemetrexed disodium.
Assuntos
Conformação Molecular , Pemetrexede/química , Pemetrexede/síntese química , Tecnologia Farmacêutica/métodos , Varredura Diferencial de Calorimetria , Química Farmacêutica , Cromatografia Líquida de Alta Pressão , Difração de Pó , Temperatura , Termogravimetria , Molhabilidade , Difração de Raios XRESUMO
The methods for controlling volatile impurities, including reagent and starting material, in Nepafenac active pharmaceutical ingredient, are reported. The proposed methods were developed using gas chromatography (GC) and gas chromatography with headspace injection (GC-HS) and validated according to the requirements of the ICH (International Conference of Harmonization) validation guidelines Q2R1 and the guideline for residual solvents Q3C.
Assuntos
Anti-Inflamatórios não Esteroides/análise , Benzenoacetamidas/análise , Cromatografia Gasosa/métodos , Contaminação de Medicamentos , Fenilacetatos/análise , Solventes/isolamento & purificação , Compostos Orgânicos Voláteis/isolamento & purificação , Anti-Inflamatórios não Esteroides/normas , Benzenoacetamidas/normas , Contaminação de Medicamentos/prevenção & controle , Limite de Detecção , Fenilacetatos/normas , Reprodutibilidade dos TestesAssuntos
Anti-Hipertensivos/análise , Contaminação de Medicamentos , Ionização de Chama/métodos , Solventes/isolamento & purificação , Sulfonamidas/análise , Compostos Orgânicos Voláteis/isolamento & purificação , Anti-Hipertensivos/normas , Bosentana , Limite de Detecção , Padrões de Referência , Reprodutibilidade dos Testes , Sulfonamidas/normasRESUMO
The gas chromatography method with direct injection for quantitative determination of residual nonvolatile solvents such as 2-(2-chloroethoxy)ethanol (CEE) and N-methyl-2-pyrrolidinone (NMP) in quetiapine--the pharmaceutical active substance has been validated. Validation was performed according to the requirement of ICH validation guidelines Q2A and Q2B. Specificity, precision, accuracy, linearity, limits of detection and quantitation and robustness were determined and excellent results were obtained.
