In Vitro Screening Methods To Assess the Potential of In Vivo Precipitation of Injectable Formulations upon Intravenous Administration.

In vivo precipitation of injectable formulations upon intravenous administration is a major concern in formulation development. In this work, two in vitro screening tools, static dilution and dynamic injection, are developed to assess the potential of in vivo precipitation of active pharmaceutical ingredients from injectable formulations upon intravenous administration. Nine model injectable formulations are studied. These include marketed formulations as well as formulations from Merck programs. Results from these models are compared with reports of precipitation from product labels, the Physicians Desk Reference, and literature reports. Good correlation is observed between results from the static dilution and dynamic injection models. The in vitro data correlates well with precipitation reported during clinical evaluations and animal experiments. The importance of protein in dilution medium, prototype formulations for screening studies, and optical microscopy for studying phase behavior is demonstrated. This work demonstrates the utility of using these models as a valuable screen during injectable formulation development. LAY ABSTRACT: In vivo precipitation of injectable formulations upon intravenous administration is a major concern in formulation development. Although animal models are routinely used for this purpose, they require strict protocol and are expensive. Furthermore, their results are far from ideal. This work describes the development of two in vitro screening tools, static dilution and dynamic injection, to assess the potential of in vivo precipitation of active pharmaceutical ingredients from injectable formulations upon intravenous administration. The utility of using these models as a valuable screen during injectable formulation development is demonstrated through the use of several model compounds.