Evaluating the dissolution behavior of zinc-complexed protein suspensions by computer modeling and simulation

In vitro dissolution of zinc insulin suspensions can be promoted by the complexation of zinc with an ionic species for which the zinc ion has a greater affinity. Studies conducted by our group have previously shown that the rate-limiting steps that govern the dissolution of zinc-complexed insulin suspension may be (1) chemical complexation (surface reaction) and (2) subsequent drug mass transport (diffusion and solubility). The purpose of this work was to use a computer simulation model to predict the dissolution behavior of zinc-complexed insulin suspensions and determine the influence of the above rate-limiting steps on the overall process of dissolution. A quasi-steady-state model was chosen which included the effects of a shrinking particle radius, the drug's solubility, and a convective mass transfer term. Based on this model, the computer simulation program evaluated dissolution behaviors of various model drugs, including zinc insulin suspensions. The experimental data obtained from actual dissolution experiments were superimposed on computer-generated profiles that incorporated quantitative values to key terms, namely the alpha (diffusion resistance) and beta (surface reaction resistance) values. Results demonstrated that the computer simulations could be used to predict the dissolution behavior of zinc-complexed protein suspensions by manipulating the alpha and beta values. Overall, the computer simulations indicated the involvement of both the surface reaction and the diffusion rate-limiting steps in zinc insulin dissolution, which was consistent with the results obtained from actual experimental studies.