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.