Case Study: Injection Site Reaction Screening Methodology

A key objective in parenteral drug formulation is to enhance drug solubility within the physiological pH range (approximately pH 7.2–7.4) and to prevent precipitation at the injection site. Precipitation upon injection can lead to injection site reactions (ISRs), which may cause pain, inflammation, or tissue damage, ultimately affecting patient adherence and the overall safety profile of the drug. This issue is particularly common with both small molecules and biologics that are often formulated at a pH where their solubility is highest — typically far from their isoelectric point (pI). However, when such formulations are injected into the body, the shift in pH toward physiological conditions can reduce solubility and result in precipitation.

To mitigate this, formulation strategies are focused on increasing the solubility of the drug at or near physiological pH. Achieving adequate solubility under these conditions not only helps minimize the risk of precipitation and ISR but also supports the development of high-concentration, low-volume injections. This is especially beneficial for subcutaneous administration, where reducing the injection volume can lead to improved patient comfort, lower injection force, and enhanced compliance. By optimizing solubility at physiological pH, developers can deliver therapeutically relevant doses efficiently while adhering to the maximum acceptable injection force for manual administration.