Effect of pH, ionic strength and oxygen burden on the chemical stability of EPC/cholesterol liposomes under accelerated conditions. Part 1: Lipid hydrolysis.
The accelerated stability of purified egg phosphatidylcholine (EPC)/cholesterol liposomes was studied under various formulation conditions using a 2(3) factorial experimental design. The three factors included in the study were pH, ionic strength of the buffer and the headspace oxygen content in the container. The results showed that lipid hydrolysis followed pseudo first-order kinetics. Data analysis using factorial design revealed that pH of the buffer was the predominant factor influencing the rate of lipid hydrolysis. Neither the ionic strength of the buffer, nor the presence of oxygen in the headspace of the container significantly affected the EPC hydrolysis. The hydrolysis rate of EPC at pH 4.0 buffer was at least 1.75 times greater than that at pH 4.8. A prediction based on the Arrhenius equation suggests that the EPC/cholesterol liposomes should be formulated in a buffer with pH equal to or greater than 4. 2 in order to have a shelf-life longer than 1 year at 5 degrees C.
Zhang
J A
JA
Baxter Pharmaceutical Products, Inc., New Providence, NJ 07974, USA. zhangal@baxter.com
Pawelchak
J
J
D002021:Buffers; D002626:Chemistry, Pharmaceutical; D002784:Cholesterol / Q000737:chemistry*; D004337:Drug Carriers; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D008081:Liposomes; D009994:Osmolar Concentration; D010100:Oxygen / Q000737:chemistry*; D010713:Phosphatidylcholines / Q000737:chemistry*; D013696:Temperature
D002021:Buffers; D004337:Drug Carriers; D008081:Liposomes; D010713:Phosphatidylcholines; D002784:Cholesterol; D010100:Oxygen