A study of factors controlling dissolution kinetics of zinc complexed protein suspensions in various ionic species

The presence of bound and unbound zinc in the crystal matrix of protein sus pensions helps physically stabilize the crystal and limits the dissolution of the drug. In case of zinc insulin suspensions, dissolution can be promot ed by complexation of zinc with an ionic species for which the zinc has a g reater affinity, these complexing ions having either formulation and/or phy siological relevance. The purpose of this work was to use ligand-complexed formulations of insulin suspensions to gain an understanding of these produ cts' dissolution performance and to establish a fundamental understanding o f the rate-limiting steps in zinc insulin dissolution. Our group has sugges ted that the critical factors to zinc insulin dissolution are: (1) chemical complexation (zinc with ionic species); and (2) drug transport (insulin di ffusion and solubility). Dissolution studies conducted using different ioni c species (acetate, phosphate, citrate and EDTA) in a spin-filter device de monstrated a rank order correlation for different sources of zinc insulin; it was observed that human zinc insulin dissolved faster than bovine insuli n, these differences attributed to their binding properties and the respect ive affinities to the various ionic species used. Also, as the amount of cr ystallinity increased in a formulation, a rank order increase in dissolutio n times was observed. The project also identified a sensitive and reproduci ble dissolution testing methodology. Overall, this study demonstrated that: (I) the complexation rate-limiting step was more significant in the dissol ution of zinc insulin than the diffusion rate-limiting step; and (2) that d issolution kinetics depended primarily on the source and solid state differ ences and the binding affinities of the zinc insulin. (C) 2001 Elsevier Sci ence B.V. All rights reserved.