Evaluation of dissolution profile similarity - Comparison between the f(2), the multivariate statistical distance and the f(2) bootstrapping methods

摘要

A simulation study is presented, evaluating the performance of the f(2), the model-independent multivariate statistical distance and the f(2) bootstrap methods in the ability to conclude similarity between two dissolution profiles. Different dissolution profiles, based on the Noyes-Whitney equation and ranging from theoretical f(2) values between 100 and 40, were simulated. Variability was introduced in the dissolution model parameters in an increasing order, ranging from a situation complying with the European guidelines requirements for the use of the f(2) metric to several situations where the f(2) metric could not be used anymore. Results have shown that the f(2) is an acceptable metric when used according to the regulatory requirements, but loses its applicability when variability increases. The multivariate statistical distance presented contradictory results in several of the simulation scenarios, which makes it an unreliable metric for dissolution profile comparisons. The bootstrap f(2), although conservative in its conclusions is an alternative suitable method. Overall, as variability increases, all of the discussed methods reveal problems that can only be solved by increasing the number of dosage form units used in the comparison, which is usually not practical or feasible. Additionally, experimental corrective measures may be undertaken in order to reduce the overall variability, particularly when it is shown that it is mainly due to the dissolution assessment instead of being intrinsic to the dosage form. (C) 2016 Published by Elsevier B.V.