If Euhydric and Isotonic Do Not Work, What Are Acceptable pH and Osmolality for Parenteral Drug Dosage Forms?

Parenteral products should aim toward being isotonic and euhydric (physiological pH). Yet, due to other considerations, this goal is often not reasonable or doable. There are no clear allowable ranges related to pH and osmolality, and thus, the objective of this review was to provide a better understanding of acceptable formulation pH, buffer strength, and osmolality taking into account the administration route (i.e., intramuscular, intravenous, subcutaneous) and administration technique (i.e., bolus, push, infusion). This evaluation was based on 3 different approaches: conventional, experimental, and parametric. The conventional way of defining formulation limits was based on standard pH and osmolality ranges. Experimental determination of titratable acidity or in vitro hemolysis testing provided additional drug product information. Finally, the parametric approach was based on the calculation of theoretical values such as (1) the maximal volume of injection which cannot shift the blood's pH or its molarity out of the physiological range and (b) a dilution ratio at the injection site and by verifying that threshold values are not exceeded. The combination of all 3 approaches can support the definition of acceptable pH, buffer strength, and osmolality of formulations and thus may reduce the risk of failure during preclinical and clinical development.