Statistical comparison of dissolution profiles

Abstract

Statistical methods to assess similarity of dissolution profiles are introduced. Sixteen groups of dissolution profiles from a full factorial design were used to demonstrate implementation details. Variables in the design include drug strength, tablet stability time, and dissolution testing condition. The 16 groups were considered similar when compared using the similarity factor f2 (f2 > 50). However, multivariate ANOVA (MANOVA) repeated measures suggested statistical differences. A modified principal component analysis (PCA) was used to describe the dissolution curves in terms of level and shape. The advantage of the modified PCA approach is that the calculated shape principal components will not be confounded by level effect. Effect size test using omega-squared was also used for dissolution comparisons. Effects indicated by omega-squared are independent of sample size and are a necessary supplement to p value reported from the MANOVA table. Methods to compare multiple groups show that product strength and dissolution testing condition had significant effects on both level and shape. For pairwise analysis, a post-hoc analysis using Tukey's method categorized three similar groups, and was consistent with level-shape analysis. All these methods provide valuable information that is missed using f2 method alone to compare average profiles. The improved statistical analysis approach introduced here enables one to better ascertain both statistical significance and clinical relevance, supporting more objective regulatory decisions.

Effective Biomass Fractionation through Oxygen-Enhanced Alkaline–Oxidative Pretreatment

“…Data were analyzed by one-way analysis of variance with Unscrambler v10.5 software (CAMO software, Japan), followed by Tukey's post hoc test. 45 Significant differences between treatment conditions were evaluated at p ≤ 0.05.…”

A Critical Overview of FDA and EMA Statistical Methods to Compare In Vitro Drug Dissolution Profiles of Pharmaceutical Products

“…When the ƒ 2 statistic is not suitable, then the EMA guidelines [ 12 ] suggest that “ (…) the similarity may be compared using model-dependent methods or model-independent methods (…) ” and these alternative methods must be “ (…) statistically valid and satisfactorily justified ”. Except for the f 2 statistic, several model-independent approaches have been developed and investigated, e.g., the Rescigno indices [ 16 ], ratio-test approaches [ 17 ], methods based on the analysis of variance (ANOVA) model [ 18 , 19 , 20 ], or calculation of the dissolution efficiency based on the area under the curve [ 21 , 22 ]. Unfortunately, the EMA and FDA guidelines [ 12 , 13 ] are not clear about the acceptability of the above-mentioned examples of model-independent methods.…”

Probing Differences in Mass-Transfer Coefficients in Beaker and Stirrer Digestion Systems and the USP Dissolution Apparatus 2 Using Benzoic Acid Tablets

“…Therefore, since the tablet typically remains in the recirculation zone below the paddle, the effect of the volume of solution on the mass-transfer coefficients for tablets below the stirrer should be small, as observed, provided that there is enough solution to cover the paddle, as was the case for the measurements with 200 mL of water in this work. Significant variability in dissolution times has been widely reported with the USP dissolution apparatus 2 (paddle) due to the tendency of the tablet to move into different regions of the equipment where there are different shear stresses and shear rates [12,[14][15][16][17]19,20]. This greater variability can also be seen in the analysis of variance in Table 3 (beaker and stirrer) and Table 4 (USP dissolution apparatus 2), where the standard error for the USP dissolution apparatus 2 of 2.90 × 10 −6 m s −1 is greater than that from the beaker and stirrer system of 2.64 × 10 −6 m s −1 .…”