Level A IVIVC for immediate release tablets confirms in vivo predictive dissolution testing for ibuprofen

A bioequivalence study comparing two fixed dose combination tablets containing 200 mg ibuprofen and 30 mg pseudoephedrine hydrochloride showed bioequivalence for pseudoephedrine AUC and C_max, but the reference product showed higher C_max than the test product in fasted conditions. The main difference between products was the presence of tribasic calcium phosphate in the reference tablet, resulting in an increased surface pH of the dissolving ibuprofen particles under gastric and intestinal conditions and, consequently, higher solubility of ibuprofen.

A mechanistic model based on mass balance and ionization equilibria was used to calculate the pH of the particle surface under different buffer conditions. The discrepancies in surface pH between test and reference tablet were pronounced in 0.1 M and 0.01 M hydrochloric acid and in diluted maleate 7 mM pH 6.5 and phosphate 5 mM pH 6.7 buffers (but negligible in compendial phosphate buffer pH 6.8. Only those dissolution tests using pre-treatment in acidic conditions could be used to build a one-step in vitro-in vivo correlation (IVIVC).

This work shows the potential of these discriminatory and in vivo predictive dissolution methods to obtain IVIVCs for BCS class IIa drugs and for extending BCS biowaivers to BCS class IIa drugs.

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Materials: All used reagents were of at least analytical grade. Sodium chloride, hydroxy napthole blue disodium salt, EDTA disodium salt solution 0.05 mol/L, triethanolamine and potassium dihydrogen phosphate were purchased from Carl-Roth GmbH & Co. KG (Karlsruhe, Germany). Acetonitrile HPLC Grade, concentrated hydrochloric acid (37 %) and sodium hydroxide were obtained at VWR Chemicals S.A.S. (Fontenay-sous-Bois, France).