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

Area of Science:

• Pharmaceutical Sciences
• Drug Formulation and Delivery
• Pharmacokinetics

Background:

• Bioequivalence studies are crucial for generic drug approval.
• Fixed-dose combination tablets of ibuprofen and pseudoephedrine hydrochloride were compared.
• Differences in excipients, specifically tribasic calcium phosphate, can affect drug dissolution and bioavailability.

Purpose of the Study:

• To compare the bioequivalence of two fixed-dose combination tablets (200 mg ibuprofen/30 mg pseudoephedrine HCl).
• To investigate the impact of tribasic calcium phosphate on ibuprofen solubility and dissolution.
• To establish an in vitro-in vivo correlation (IVIVC) for drug dissolution.

Main Methods:

• Bioequivalence study comparing ibuprofen and pseudoephedrine AUC and Cmax.
• Mechanistic modeling based on mass balance and ionization equilibria to calculate particle surface pH.
• Dissolution testing under various acidic and buffer conditions, including pre-treatment steps.

Main Results:

• Bioequivalence was demonstrated for pseudoephedrine, but the reference product showed higher ibuprofen Cmax in fasted conditions.
• Tribasic calcium phosphate in the reference tablet increased surface pH, enhancing ibuprofen solubility.
• Surface pH discrepancies were significant in specific acidic and diluted buffer conditions, enabling discriminatory dissolution testing.

Conclusions:

• The presence of tribasic calcium phosphate significantly influences ibuprofen dissolution and solubility.
• Discriminatory dissolution methods, particularly with acidic pre-treatment, are essential for developing IVIVCs.
• This study demonstrates the potential for IVIVCs in BCS Class IIa drugs and supports biowaiver extensions for this class.