Journal
JOURNAL OF PHARMACEUTICAL SCIENCES
Volume 102, Issue 3, Pages 929-946Publisher
ELSEVIER SCIENCE INC
DOI: 10.1002/jps.23419
Keywords
non-viral gene delivery; nanoparticles; lyophilization; freezingdrying; stabilization; viscosity; freezing; cryoprotection
Funding
- The German Academic Exchange Service (DAAD)
- Federal Ministry of Education and Research [T12]
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The aim of the study was to comprehensively investigate the influence of the freezing step during lyophilization on the stability of gene-delivery particles in order to better understand particle stabilization during freezing. Particle size of plasmid/linear polyethylenimine (LPEI) polyplexes at two DNA concentrations and at increasing sucroseDNA ratios was investigated separately as a function of freezing procedure, ice-nucleation temperature, residence time of the particles in a partially frozen state, or incomplete freezing. Using a numerical model, the increase in sucrose concentration and system viscosity and corresponding bimolecular reaction rates were theoretically estimated. Freezing with a temperature-hold step after ice nucleation negatively influenced particle stability. Ice-nucleation temperature had an impact only at low DNA concentrations. Particle stability was highly reduced during the early part of freezing (<3 degrees C), especially at low shelf-ramp rates. In this phase, bimolecular reaction rates increase greatly at still low system viscosity. Below a critical temperature (approximate to 18 degrees C) and at high system viscosity, no further particle aggregation occurred. In conclusion, the initial sample viscosity rather than the unfrozen volume and the residence time of particles in the low-viscosity state are the predominant factors in particle stabilization, which likely apply to aggregation in any system. (c) 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:929946, 2013
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