Definition of Design Space for Preparation and Stability of Tramadol Hydrochloride Loaded Nanoparticles Using OFAT Experiments for Infusion in Pain Management

This paper presents an experimental study on preparation of tramadol hydrochloride (TrH) loaded nanoparticles, and stability determination in various infusion solutions. In this study, various nanoparticle preparation parameters based on w/o/w emulsification solvent evaporation method, including stabilizer type, stabilizer concentration, polymer concentration, homogenization speed and initial drug amount were systematically tested to verify their versatility for preparing nanoparticles. Initially both particle size and encapsulation efficiency of nanoparticles were changed significantly with the change in surfactant and polymer ratio (p<0.05). However, homogenization speed only changed particle size (average size 339.3±1.8 nm for 15000 rpm, 318.9±6.4 nm for 20000 rpm and 237.2±7.8 nm for 25000 rpm) (p<0.05) and initial drug concentration is only affected the encapsulation efficiency (34.2±0.7% for 4 mg/mL and 33.2±0.9 for 1.6 mg/mL) (p<0.05). Storage at room temperature for 3 months resulted in an increase in particle size and polydispersity index. Prepared nanoparticles showed the best stability after storage at – 20 °C for in 3 months. Finally, storage of nanoparticles in various infusion solutions resulted an undesirable changes for 6% Hydroxyethyl starch in 0.9% sodium chloride injection, 10% Dextran 40 and 4% Succinyl gelatin solutions. It was shown that an appropriate delivery of TrH loaded PLGA nanoparticles as infusion can be prepared only in water for injection, 20% Mannitol, 0.9% Sodium chloride and 5% Dextrose solutions.