RESUMO
The intent of the study was to prepare and characterize crystalline form of 2'-O-{3-[(7-chloro-4-quinolinyl)amino]propyl}-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A (1), a novel 15-membered azalide derivative with antimalarial activity. The crystalline material was prepared by crystallization from acetonitrile reproducible in high yield and purity. Single crystal X-ray studies, X-ray powder diffractometry, differential scanning calorimetry, thermogravimetric analysis, moisture adsorption, Karl Fischer titration, gas chromatography, scanning electron microscopy, optical microscopy, solubility, and solid-state and solution stability were conducted to investigate physicochemical properties of the existing crystalline form. Crystalline 1 is not hygroscopic, does not contain solvents, is physicochemically stable in solid state for up to 4 weeks, and is highly soluble at pH values below 6 and in biorelevant media (simulated gastric fluid, fed simulated intestinal fluid, and fasted simulated intestinal fluid). Solution stability studies (buffers and biorelevant media) indicated that this compound is stable in solutions at pH values 5-6, and that stability is influenced by pH and temperature.
Assuntos
Antimaláricos/química , Eritromicina/química , Adsorção , Antimaláricos/síntese química , Soluções Tampão , Varredura Diferencial de Calorimetria , Química Farmacêutica , Cromatografia Gasosa , Cromatografia Líquida de Alta Pressão , Cristalografia por Raios X , Estabilidade de Medicamentos , Eritromicina/análogos & derivados , Eritromicina/síntese química , Suco Gástrico/química , Concentração de Íons de Hidrogênio , Secreções Intestinais/química , Microscopia Eletrônica de Varredura , Estrutura Molecular , Difração de Pó , Solubilidade , Propriedades de Superfície , Tecnologia Farmacêutica/métodos , Termogravimetria , Temperatura de Transição , Água/químicaRESUMO
A multi-technique approach was applied in order to fully characterize four low-level unknown impurities of GW876008, a novel CRF(1) receptor antagonist. Liquid chromatography (LC)-NMR spectroscopy was used in combination with LC-MS to obtain detailed information regarding the structure of the two major impurities present in batches of GW876008 and observed in the first synthetic scale-up for preclinical use. Two additional impurities were unexpectedly found at greater levels in a large scale synthesis for clinical use and their structure was elucidated by means of high resolution (HR)-MS and HR-NMR, after a small scale preparative HPLC purification step. This structural information was useful in terms of shedding light on the typical impurity profile of this new chemical entity with the aim to support the early development package for Phase I clinical studies.
