“…All derivatives up to second order, which are used for the calculations of the Hessian needed for a robust performance of IPOPT, are calculated by automatic differentiation using CppAD, [9,8]. For the solution of the differential equations within the optimization problem, which are commonly stiff in chemical and biochemical applications, we have implemented a fully variable step, variable order (order 1 to 6), Backward differentiation formulae (BDF) method, based on Nordsiek array polynomial interpolation similar to the EPISODE BDF method by Byrne and Hindmarsh [16], but with the step size selection strategy of Calvo and Rández [17]. For the generation of sensitivities we have adopted the sophisticated principles of internal numerical differentiation developed by Albersmeyer and Bock [2,1] in forward and adjoint mode.…”