Stable Cocrystals and Salts of the Antineoplastic Drug Apatinib with Improved Solubility in Aqueous Solution

被引：30

作者：

Zhu, Bin ^{[1
]}

Wang, Jian-Rong ^{[3
]}

Zhang, Qi ^{[3
]}

Li, Meiqi ^{[3
,4
]}

Guo, Chunyang ^{[1
]}

Ren, Guobin ^{[1
,2
]}

Mei, Xuefeng ^{[3
]}

机构：

[1] East China Univ Sci & Technol, Lab Pharmaceut Crystal Engn & Technol, Sch Pharm, Shanghai 200237, Peoples R China

[2] East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, Shanghai 200237, Peoples R China

[3] Chinese Acad Sci, Pharmaceut Analyt & Solid State Chem Res Ctr, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China

[4] Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China

来源：

CRYSTAL GROWTH & DESIGN | 2018年 / 18卷 / 08期

基金：

中国国家自然科学基金;

关键词：

ACTIVE PHARMACEUTICAL INGREDIENTS; PHYSICOCHEMICAL PROPERTIES; CO-CRYSTALS; SOLID-STATE; DOSAGE FORM; DISSOLUTION; DESIGN; BIOAVAILABILITY; POLYMORPHISM; ADVANTAGE;

D O I：

10.1021/acs.cgd.8b00684

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Apatinib (APA) belongs to the targeted antineoplastic family of drugs by inhibiting the vascular endothelial cell growth factor receptor (VEGFR-2) of tyrosine kinase. APA encounters poor aqueous solubility problems, and its therapeutic dosage form, apatinib mesylate (ATM), is unstable and dissociates completely to APA in aqueous solution. Here, we synthesized and evaluated three new cocrystals of APA with adipic acid (APA + ADA), sebacic acid (APA + SEA), and D/L-mandelic acid (APA + D/L-MA), and four new salts with succinic acid (APA + SUA-H2O), salicylic acid (APA + SA), 1-hydroxy-2-naphthoic acid (APA + HNA), and saccharin (APA + SAC). All the solid forms were characterized by powder X-ray diffraction, infrared spectroscopy, differential scanning calorimetry, and dynamic vapor sorption. The molecular components and structures were confirmed by single crystal X-ray diffraction. APA + SEA is able to overcome the instability problem and has improved solubility compared with ATM. Hence, APA + SEA has the potential to be a superior candidate for this important drug.

引用

页码：4701 / 4714

页数：14