A mathematical model of iontophoretic transdermal drug delivery was applied to study the effects of physical parameters on the cumulative amount of amitriptyline HCl collected. A graphical method, based on an analytical solution of the system, was first used to estimate the drug diffusion coefficient in the membrane and its surface concentration in the absence of an electric potential difference. These initial value's were improved by using an orthogonal collocation-based non-linear regression routine written in Mathematica (Wolfram Research Inc.). Assuming that the diffusion coefficient did not change, the surface concentration of the drug, following transdermal iontophoresis, was evaluated by a similar technique. Two case studies are presented. The first one, taken from the literature, verifies the validity of the procedure. The second case study is based on laboratory experiments using transport amitriptyline HCl across cadaver skin. Excellent agreement was observed between experimental and predicted values. The results support previous findings that the increase in the iontophoretic transdermal delivery of some drugs is mainly due to a rise in the surface concentration of the drug. (c) 2005 Elsevier B.V. All rights reserved.