Multicomponent System of NPS-1034, an Orally Administered Lung Cancer Drug Candidate, with Sulfonic Acids and Solid State Characterization

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• 作者：Jangmi Lee ; Suzie Park ; Seon-Joo Yoon ; Yong Woo Jung ; Youngjoo Byun ; Soon Hong Yuk ; Min Keyong Jeon ; Sung Kwon Kang ; Eun Hee Lee
• 刊名：Crystal Growth & Design
• 出版年：2013
• 出版时间：September 4, 2013
• 年：2013
• 卷：13
• 期：9
• 页码：3958-3968
• 全文大小：835K
• 年卷期：v.13,no.9(September 4, 2013)
• ISSN：1528-7505

文摘

NPS-1034 is a drug candidate targeted for the regulation of c-MET/AXL receptor tyrosin kinase activity. NPS-1034 was developed to improve efficacy and reduce toxicity by targeting c-MET/AXL related signaling pathways. However, NPS-1034 is practically insoluble in almost all organic solvents as well as aqueous media (pH 1, 4.5, and 7.5). We attempted to improve the physicochemical properties of NPS-1034 by forming multicomponent systems with a wide variety of sulfonic acids including methanesulfonic acid, 1,2-ethanedisulfonic acid, p-toluenesulfonic acid, and camphorsulfonic acid. Solid state characterization of NPS-1034 salts and amorphous with sulfonic acids was conducted, and the crystal structures of four salts and NPS-1034 were compared and investigated. Sulfonic acid salts of NPS-1034 decreased the melting point of NPS-1034 as much as 鈭?55.43 掳C. Solubilities of NPS-1034 and salts of NPS-1034 were measured to develop lipid-based formulation for the GLP toxicity study. Solvents studied include oleic acid, poly(ethylene glycol) 400, and ethanol. Solubility of amorphous of NPS-1034 with camphorsulfonic acid showed a significant increase in all three solvents. This work will give some insight into how various types of sulfonic acids interact with pharmaceutically important compounds containing the pyrrolepyridine moiety.