Development of in vitro - in vivo correlations for newly optimized Nimesulide formulations

Use of the human volunteers in bioequivalence studies is being discouraged by the Food and drug administration after the introduction of biowaiver approaches. In-vitro in-vivo correlation (IVIVC) with the level A is accepted for the registration of new molecules. In the present study deconvolution technique with numeric approaches was applied after compressing and in vitro validating the 100mg Nimesulide immediate, intermediate and slow release tablets. Single centered, crossover, randomized study was conducted in four phases with a two-week washout period to obtain the plasma drug concentration data after administrating test and reference products in male healthy volunteers. Kinetica(TM) 4.4.1 (Thermoelectron corp, USA) was used for the calculation of two ways ANOVA with 90% CI from both log transformed and non- transformed data and Phoenix WinNonlin 7 and it's IVIVC toolkit version 7.0 was used for the application of numeric approaches of IVIVC. Results revealed that the individual internal percentage prediction error for AUC(inf) and C(max) were found to be < 15% while their average values were < 10% in all medium. Numeric values of % PE at pH 6.8 and pH 7.4 (50 rpm in USP II and 100 rpm in USP I and II apparatus) were found to be (2.5842, 2.9789 and, 7.1732; 7.0944, 2.4721 and 4.350) for AUC(inf) and (2.5842, 0.5736 and 4.6928; 5.6214, 3.0551 and -2.4711) values for C(max) respectively. The low values of prediction errors demonstrate that the correlation model is projecting the in vivo response of each formulation. Percentage External error (% PE) was not required because individual values of percentage internal error (%PE) of C(max) and AUC(last) were not >15. In order to predict point to point correlation between fraction drug dissolved and drug absorbed, their mean r(2) value was found to be > 0.9112 which showed a linear correlation in slightly alkaline pH.