Local Concentrating, Not Shear Stress, That May Lead to Possible Instability of Protein Molecules During Syringe Injection: A Fluid Dynamic Study with Two-Phase Flow Model.

Abstract

A two-phase flow computational fluid dynamic (CFD) model was developed to study the hydrodynamic forces and the protein concentration changes of a protein solution in a syringe injector. Proteins were assumed to be nanosized solid spheres commensurate with their molecular weight and suspended in an aqueous environment, passing through the rapidly constricted sections of the syringe. Interaction between the solid and the liquid phase was taken into account, and four laminar flow cases were studied under the extensional flow. Profiles of pressure, velocity, and shear stress of the different cases were examined and compared. Hydrodynamic forces on a single protein particle were further analyzed. Our results indicate that the hydrodynamic forces are too small to affect significant conformational changes in proteins. The plunger rate showed limited impact on the distribution of protein particles inside the syringe. Nonetheless, the larger velocity gradient at the connection section of the hub toward the needle resulted in considerable accumulation of proteins. Such a concentrating effect may lead to protein aggregation and subsequent structural changes and will be examined in future studies.LAY ABSTRACT: Concentrated protein in the liquid form has become a preferred formulation strategy for delivering protein products, but it suffers from a high possibility of aggregation and precipitation, which may trigger a structural change and denaturation of the protein molecules and eventually cause the loss of the therapeutic functions of the protein products. To understand the effect of hydrodynamic forces on the change in local protein concentration in a syringe injector, we developed a two-phase flow computational fluid dynamic (CFD) model in this work. It was found that the local concentration of protein strongly depends on the velocity gradient of the fluid. A higher amount of proteins accumulates at the connection section of the hub toward the needle where the maximum velocity gradient is exhibited. The model results also imply a limited effect by hydrodynamic forces on possible unfolding of protein molecules. The local concentrating effect may enhance the possibility of molecular collision, resulting in aggregation and structural change.