Aim: Comparison of Captopril generic formulations on the Romanian market with the reference formulation Capoten (Bristol Myers Squibb), in terms of in vitro release kinetics of active substance and in vivo pharmacokinetics.
Materials and methods: Dissolution studies were performed using Apparatus 1 (Basket), DT 800H, Erweka, Germany in acidic medium (0.01 N hydrochloric acid) and an agitation speed of 50 rpm. Experiments were run on 12 tablets of each formulation. Quantification of Captopril was achieved by using a spectrophotometric method, λ=205nm. Clinical pharmacokinetics was determined in the frame of four different bioequivalence studies comparing a single dose four different Captopril 50mg generic tablet products to the innovator drug, Capoten 50mg (Bristol Myers Squibb).
Results: Different batches of the reference formulations achieved dissolution profiles of the same form and very closed to each other at all dissolution points. Dissolution profiles of the tested formulations shown similar behavior for all references. Two generic formulations achieved a slower release at early dissolution time points, their release being "diffusion controlled", described by law of Higuchi. In vivo, products proved to be bioequivalent, but variability of space distribution and forms of plasma profiles was much bigger than for the in vitro release curves. Due to very rapid in vitro dissolution, a direct Level A in vitro-in vivo correlation was not possible, but, strangely, the fraction absorbed vs. time clearly followed the same Higuchi law.
Conclusion: All the studied formulations achieved more than 85% dissolution after 15 minutes which means that whatever the values of dissolution metrics f1 and f2, formulations behave like a solution and generally should not have therapeutic equivalence problems. Slower dissolution profiles correlates with in vivo absorption being described by the same square root law of Higuchi which describe diffusion controlled transport phenomena.
Keywords: bioequivalence; captopril formulations; release kinetics; square root law.