Crystal Structure and Physicochemical Properties of Crystalline Form of 2′-O-{3-[(7-chloro-4-quinolinyl)amino]propyl}-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A

• Published in: Journal of pharmaceutical sciences 2011-07, Vol.100 (7), p.2586-2598
• Main Authors: Filić, Darko, Starčević, Kristina, Pešić, Dijana, Jurmanović, Stella, Meenan, Eugene, Spezzaferri, Alberto, Đilović, Ivica, Prugovečki, Biserka
• Format: Article
• Language: English
• Subjects: Adsorption; Antimalarials - chemical synthesis; Antimalarials - chemistry; Biological and medical sciences; Buffers; Calorimetry, Differential Scanning; Chemistry, Pharmaceutical; Chromatography, Gas; Chromatography, High Pressure Liquid; crystal structure; crystallography; Crystallography, X-Ray; Drug Stability; Erythromycin - analogs & derivatives; Erythromycin - chemical synthesis; Erythromycin - chemistry; gas chromatography; Gastric Juice - chemistry; General pharmacology; Hydrogen-Ion Concentration; Intestinal Secretions - chemistry; Karl Fischer analysis; Medical sciences; Microscopy, Electron, Scanning; moisture adsorption; Molecular Structure; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; physicochemical characterization; Powder Diffraction; SEM; Solubility; stability; Surface Properties; Technology, Pharmaceutical - methods; thermal analysis (DSC and TGA); Thermogravimetry; Transition Temperature; Water - chemistry; X-ray powder diffractometry
• ISSN: 0022-3549; 1520-6017; 1520-6017
• DOI: 10.1002/jps.22511

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 4weeks, 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.