title: Evaluation of dissolution profile similarity - Comparison between the f2, the multivariate statistical distance and the f2bootstrapping methods.
abstract: A simulation study is presented, evaluating the performance of the f2, the model-independent multivariate statistical distance and the f2bootstrap methods in the ability to conclude similarity between two dissolution profiles. Different dissolution profiles, based on the Noyes-Whitney equation and ranging from theoretical f2values 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 f2metric to several situations where the f2metric could not be used anymore. Results have shown that the f2is 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 f2, 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.
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003 Lisboa, Portugal. Electronic address: ppaixao@ff.ul.pt.
authors.forename: Paulo
authors.initials: P
authors.lastname: Paixão
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003 Lisboa, Portugal.
authors.forename: Luís F
authors.initials: LF
authors.lastname: Gouveia
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003 Lisboa, Portugal.
authors.forename: Nuno
authors.initials: N
authors.lastname: Silva
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003 Lisboa, Portugal.
authors.forename: José A G
authors.initials: JA
authors.lastname: Morais
mesh_terms: D008956:Models, Chemical; D015999:Multivariate Analysis; D012995:Solubility
keywords: Bootstrap f(2) method; Model-independent multivariate statistical distance; Regulatory acceptance of dissolution similarity; Similarity of dissolution profiles; Variability in dissolution profiles; f(2) metric