Roles of Fatty Acid Chain Length and Enzyme-Oriented Drug Controlled Release from pH-Triggering Self-Assembled Fatty Acid Conjugated Quetiapine Nanosuspensions

Hy D Nguyen,1 Hai V Ngo,1 Van Hong Nguyen,2 Myung-Chul Gil,1,3 Beom-Jin Lee1,4 1College of Pharmacy, Ajou University, Suwon, 16499, Republic of Korea; 2Department of Life Sciences, University of Science and Technology of Hanoi, Vietnam Academy of Science and Technology, Hanoi, 10000, Vietnam; 3PLUTO Inc, Seongnam, 13453, Republic of Korea; 4Institute of Pharmaceutical Science and Technology, Ajou University, Suwon, 16499, Republic of KoreaCorrespondence: Beom-Jin Lee, College of Pharmacy, Ajou University, Suwon, 16499, Republic of Korea, Tel +82 31 219 3442, 3430, Fax +82 31 212 3653, Email bjl@ajou.ac.krBackground: Quetiapine (QTP) is a first-line antipsychotic drug, but its therapeutic druggability and patient adherence were limited due to high oral dose strength, low bioavailability and physicochemical/biopharmaceutical issues.Purpose: To investigate the roles of fatty acid chain length and enzyme-oriented QTP controlled release from pH-triggering self-assembled fatty acid conjugated QTP nanosuspensions (NSPs).Methods: QTP was conjugated with different chain length fatty acids (C10–decanoic acid, C14–myristic acid, C18–stearic acid) to obtain QTP-fatty acid conjugates (QFCs: QD, QM, QS) by exploiting 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/4-dimethylaminopyridine (EDC/DMAP) conjugation chemistry. Then, the solubility, partitioning coefficient (log P), cell viability and cleavage kinetics of QFCs were evaluated. The pH-triggering self-assembled behaviors of QFCs to form QTP-fatty acid NSPs (QDN, QMN, QSN) by varying pH, QFC concentration and proton-to-QTP ratios were characterized. The morphological images, critical micelle concentration (CMC), physicochemical properties and enzyme-oriented QTP controlled release of NSPs were examined.Results: Three QFCs were synthesized with different chain length fatty acids from QTP after desalting fumarate from QTP fumarate. The pH, QFC concentration and proton-to-quetiapine molar ratio could influence physicochem