title: Physicochemical characterization of asulacrine towards the development of an anticancer liposomal formulation via active drug loading: stability, solubility, lipophilicity and ionization.
abstract: To facilitate the development of a liposomal formulation for cancer therapy, the physicochemical properties of asulacrine (ASL), an anticancer drug candidate, were characterized. Nano-liposomes were prepared by thin-film hydration in conjugation with active drug loading using ammonium sulphate and post-insertion with Poloxamer 188. A stability-indicating HPLC assay with diode array detection was developed for the determination of ASL concentrations. The U-shaped pH-solubility profile in aqueous solutions, with a lowest solubility at pH 7.4 (0.843 μg/mL), indicated that ASL is an ampholyte, and dilution or neutralization of acidic drug solutions used in clinical trials with physiological fluids may cause drug precipitation. The basic pKa value measured by absorbance spectroscopy was 6.72. The logD value at pH 3.8 was 1.15 which increased to 3.24 as pH increased to 7.4. ASL was found to be the most stable in acidic conditions and degraded most rapidly in alkaline conditions. An extra-liposomal pH of 5.6 during drug loading was found to be optimal to achieve the highest drug loading (DL) of 4.76% and entrapment efficiency (EE) of 99.9%. At this pH, >90% of ASL was ionized conferring high drug solubility (1mg/mL) and acted as a reservoir of unionized ASL to be transported into liposomal cores. As a suspension the optimized liposomes showed great physicochemical stability for five months at 4°C. In summary, the obtained physicochemical parameters provided insightful information useful to maximise DL into the liposomes, and explain a tendency of drug precipitation of pH-solubilized formulations following intravenous infusion.
authors: School of Pharmacy, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 114, New Zealand.
authors: Esther
authors: E
authors: See
authors: School of Pharmacy, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 114, New Zealand.
authors: Wenli
authors: W
authors: Zhang
authors: China Pharmaceutical University, Nanjing 210009, PR China.
authors: Jianping
authors: J
authors: Liu
authors: School of Pharmacy, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 114, New Zealand.
authors: Darren
authors: D
authors: Svirskis
authors: Auckland Cancer Society Research Centre, University of Auckland, New Zealand.
authors: Bruce C
authors: BC
authors: Baguley
authors: School of Pharmacy, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 114, New Zealand.
authors: John P
authors: JP
authors: Shaw
authors: China Pharmaceutical University, Nanjing 210009, PR China.
authors: Guangji
authors: G
authors: Wang
authors: School of Pharmacy, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 114, New Zealand. Electronic address: z.wu@auckland.ac.nz.
authors: Zimei
authors: Z
authors: Wu
mesh_terms: D000677:Amsacrine / Q000031:analogs & derivatives* / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D008081:Liposomes; D012995:Solubility
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D000677:Amsacrine; C042315:asulacrine
keywords: 1,2-Dipalmitoyl-rac-glycero-3-phosphocholine (CID 6139); Asulacrine; Asulacrine (CID 107924); Asulacrine isethionate salt (CID 157348); Cholesterol (CID 5997); Ionization constant; Lipophilicity; Liposomes; Poloxamer 188 (CID 24751); Post-injection drug precipitation; Remote drug loading; Stability