Effects of Submicron Particles on Formation of Micron-Sized Particles During Long-Term Storage of an Interferon-Beta-1a Solution

We present evidence that homogeneous submicron particles can influence the growth rate of larger particles upon long-term storage in a temperature-dependent manner. Interferon-beta-1a was thermally stressed at 50°C for 6 h and characterized using nanoparticle tracking analysis (NTA), microflow digital imaging (MFI), and circular dichroism (CD) spectroscopy. This study showed selective formation of submicron particles exhibiting a perturbed protein conformation. These thermally induced submicron particles were spiked into an unstressed solution at three levels, and then monitored for micron-sized particle formation upon storage at 5°C and 25°C for 12 months. The resulting particle growth effects were temperature dependent. NTA and MFI results at 5°C showed little evidence that initial submicron particle levels impacted particle growth across the range ~0.03-25 μm. In contrast, MFI results at 25°C indicated that particle growth in the 1-10 μm size range correlated strongly with initial submicron particle levels, and particle counts in the 10-25 μm size range were highest after 12 months for the samples with highest initial submicron particle content. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:347-351, 2013