Mycophenolate mofetil (MMF) is an immunosuppressive agent indicated for the prophylaxis of acute rejection in patients receiving allogeneic renal, cardiac, or hepatic transplants. It is a Biopharmaceutics Classification System Class II substance that has a strongly pH-dependent solubility profile. Consequently, differences in solid-state properties, formulation, and manufacturing processes of MMF can lead to disparities in bioavailability between brands of the same drug. This study was conducted to compare the in vitro dissolution profile of the original MMF innovator brand (CellCept, Roche) with available generic products. Two representative batches of CellCept 500-mg tablets and 14 different generic formulations were tested using different dissolution testing scenarios simulating conditions in the proximal gastrointestinal tract. These scenarios took into account stomach and small intestine media composition, surface tension, pH, increased buffer capacity, and osmolarity after food intake.Eight of the generic formulations tested passed the quality control dissolution test (pH 1.1) according to the specification Q = 75% after 5 min (i.e., all single units >80% dissolved), and 12 passed the specification Q = 85% after 15 min (i.e., all single units >90% dissolved). This suggests an almost homogenous dissolution rate between formulations in an acidic environment. However, at pH 4.5, large variations in the in vitro dissolution performance between generic formulations were observed (extremes resulting in greater than 60% dissolved difference after 30 min). Marked variability was seen among the different generic formulations and the innovator brand, CellCept. In conclusion, important differences exist among the different generic formulations with regard to in vitro performance. As MMF is required for life-long use, changes in drug performance as a result of switching between formulations may have serious clinical consequences (e.g., organ rejection). Therefore, clinical testing is necessary to evaluate the pharmacokinetics and the impact on clinical safety of a change of brands.

Adjusting dissolution testing conditions to match the behavior of the formulations in vitro with that in vivo by taking into account the properties of the drug and the formulation is a straightforward and useful approach in identifying a predictive method in the development of the IVIVC. These investigations will definitely help by derisking of new formulations as well as by rating changes in existing formulations with regard to their impact on bioavailability before entry into human.