Xu Zhengguo, Cuquerella-Gilabert Marina, Zarzoso-Foj Javier, Merino-Sanjuan Matilde, Mangas-Sanjuan Victor, García-Arieta Alfredo
R&D Clinical Development, Towa Pharmaceutical Europe, S.L., Calle Sant Martí, 75-79, Martorelles, 08107, Barcelona, Spain; Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, Av. Vicent Andrés Estellés, s/n, Burjassot, 46100, Valencia, Spain; Interuniversity Research Institute for Molecular Recognition and Technological Development, University of Valencia, Av. Vicent Andrés Estellés, s/n, Burjassot, 46100, Valencia, Spain.
Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, Av. Vicent Andrés Estellés, s/n, Burjassot, 46100, Valencia, Spain; Interuniversity Research Institute for Molecular Recognition and Technological Development, University of Valencia, Av. Vicent Andrés Estellés, s/n, Burjassot, 46100, Valencia, Spain.
Eur J Pharm Biopharm. 2025 Nov;216:114839. doi: 10.1016/j.ejpb.2025.114839. Epub 2025 Aug 26.
The most widely used method to compare dissolution profiles is the similarity factor f method. When the regulatory requirements to apply the f method are not fulfilled, alternative methods should be used. In the current study two commonly used methods, 90% confidence intervals (CI) of different f estimators using bootstrap methodology and the Euclidean Distance of the Non-standardized Expected (EDNE) values, are compared using two different simulation approaches. For the first approach, the reference and test population profiles were simulated based on the multivariate normal distribution with different target population f values, variability, and sample sizes. For each pair of randomly simulated profiles, 90% CI of various f estimators and the EDNE values were calculated. For the second approach, the first-order release model-based simulation, one million individual dissolution profiles were simulated for the reference and test populations with different variability and predefined target population f values, random samples of different sizes were taken from those populations to obtain 90% CI of the same f estimators and the EDNE values. The whole process was repeated 10000 times for both approaches to evaluate the type I error and statistical power of the methods by calculating the percentages of replicates where the dissolution profiles are similar. When the true populations of test and reference profiles are not similar, this percentage of similarity represents the type I error; when the true populations of test and reference profiles are similar, this percentage represents the statistical power. The results shows that the EDNE method has much higher statistical power than the bootstrap f methods, but the associated type I errors are also unacceptably higher, making it unsuitable for regulatory adoption. The best method is the 90% CI of the expected f, therefore, this method is recommended. In addition, sample sizes should be increased to account for the low statistical power when using bootstrap methods.
