Development and assessment of a standard dissolution methodology for protein-based injectable suspensions.

To date, no standard dissolution methodology is recognized in the official compendia for protein-based injectable suspensions. Development of a sensitive dissolution method would have utility as an in vitro quality control tool and an indicator of associated in vivo product performance. Using the spin-filter as the dissolution device of choice, the objective of these studies was to develop a standard dissolution methodology for protein-based suspensions. Secondarily, the objective was to elucidate the steps which critically influence ion-complexed protein dissolution, and assess the magnitude of their effect. In Phase I of dissolution methodology development, studies of the device hydrodynamics concluded that uniform and reproducible mixing patterns occurred throughout the 180 ml dissolution device in a reasonable time frame. Furthermore, the tangential component of fluid velocity was dominant, with radial and axial mixing appearing adequate for distribution of the drug. The performance of the 180 ml dissolution vessel was considered to be acceptable; however, certain test conditions need to be tightly controlled. Slight modifications to the device may further improve its mixing and assay characteristics. It was observed that the dosage form could be introduced into the dissolution vessel with ease, with the optimum position for injection of sample being around the filter. There was minimal risk of fracturing the brittle crystals due to mild agitation. Phase II studies showed that, of the two steps that are assumed to be controlling the dissolution process of zinc insulins, the complexation step seems to be more rate-limiting, although the diffusion transport step also plays a role in the dissolution process. Computer-based simulations confirmed the above results. Device and methodology sensitivity were amply demonstrated using different solid state forms and sources of the zinc insulin suspensions. A dissolution medium was chosen in which zinc insulin dissolution would be reasonably rapid from a quality control point of view and be sensitive for drug detection. Other results also identified factors such as the optimum position of sample injection, speed of stirring required for particle lift, the ideal particle size range, position of stirrer component inside the device and the flow patterns and mixing conditions for optimum dissolution. These results demonstrated the extent of the device\u27s potential for application as a dissolution tool