In the development of complex formulations such as high concentration protein solutions and biologics, syringeability and injectability are key parameters to take into account. Although these terms seem as though they relate to the same process, they are in fact two different parameters that must be considered.
Syringeability is the ease of withdrawal of a solution from vial to syringe, whereas injectability is “a term related to the ease of parenteral administration of a dosing solution, and includes dose preparation, dose administration, ergonomics related to these procedures, pain of injection, and other adverse events at the injection site” (Watt et al., 2018).
The viscosity of a solution has direct effects on the syringeability and the injectability. In different applications where solutions have to be injected, whether that be vaccinations, injectable therapeutics or others, there are different variables that have to be taken into account. For example, when making high concentration protein formulations, there are major concerns with syringeability and injectability due to these solutions often being stored refrigerated, this causes the viscosity of the solution to increase significantly (Zhang et al., 2018). In addition to this, the rheological behaviour of proteins in aqueous solutions change as they age, the ageing process can alter the injection force required due to the metastability of the protein formulation, which directly influences the ease of which it can be administered. When developing drugs, the ageing process is a factor that is vital to know, by measuring the viscosity of the formulation when first developed, it is possible to gauge how close it is to the viscosity limit for injection, which can then be used to extrapolate when the drug can no longer be administered.
With different types of injection such as subcutaneous, intravenous and intramuscular, the syringeability and injectability are important factors to consider as there is a direct effect on the shear rate applied whilst injecting . When developing the syringe-needle-formulation system, it is vital to find a compromise that ensures that the solution can still be administered with ease. The physical properties of protein formulations at a high concentration can impact the ease at which they can be delivered. Concentrated solutions can often exhibit high viscosities, which can prevent them from flowing easily through syringe needles.
Syringeability relates to factors such as ease of withdrawal, clogging and foaming tendencies as well as accuracy of dose measurements; injectability is related to both injection speed and product viscosity. Other factors that can affect syringeability and injectability include the needle geometry (needle length, inner diameter, shape of opening), the inner diameter of the syringe barrel and the injection force required (Cilurzo et al., 2011).
It is of the utmost importance to investigate the relationship between viscosity and protein concentration, especially in instances where the formulations are used in autoinjectors and are self-administered. If the solution is a high concentration protein formulation, the solution will have a higher viscosity, meaning a higher injection force is required. The design of autoinjectors must take this into account to allow patients with functional impairments (e.g. suffering from psoriatic or rheumatoid arthritis) to be capable of successfully exerting the injection force.
Typically, the shear rate in a needle during injection can be around 100,000 s-1 so it is important to mimic injection conditions when developing formulations, to observe the behaviour and to see how the viscosity is affected. A property which is inherent in many injectable drugs is that they often go through ‘shear dilution’. This is when the viscosity decreases as the shear rate increases, meaning a reduced injection force is required compared to Newtonian behaving fluids. This is due to the solution having a shear thinning behaviour and acting as a non-Newtonian fluid (Allmendinger et al., 2014).
VROC® technology allows characterisation of Newtonian and non-Newtonian solutions up to a shear rate of 1,400,000 s-1. With a minimum sample volume of 50 µL and measurements up to a temperature of 70 °C, VROC® technology can eliminate the guesswork out of injectability studies in early stage formulation development by giving an accurate estimate of injection force.
For more information on injectability, syringeability and protein solutions, visit the Rheosense website for application notes and blog posts.
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