Discriminative Power of the Flow through Cell Dissolution Tester in Predicting the In Vivo Performance of Pentoxifylline SR Product under Fed and Fasting Conditions

Abstract

This study explored, for the first time the role of different designs of the Flow-Through-Cell (FTC, USP IV) dissolution Tester in predicting the in-vivo performance of Pentoxifylline (PTX) sustained-release (SR) market product, under fed & fasting conditions. Release studies of Trental^® SR 400 mg (Sanofi, Egypt), were carried-out in the FTC under different conditions, including: different volumes / compositions of release media, variable FTC flow patterns as well as applying open / closed loop configuration setups. Pharmacokinetic (PK) data, obtained from literature, were converted to in-vivo fraction-absorbed [F_A] using Wagner-Nelson (WN) method. A 1:1 IVIVC was investigated by comparing PTX fraction-dissolved [F_D] under different FTC release designs versus calculated [F_A]. Predicted PK parameters were evaluated, and compared with actual data, with estimation of prediction-error (PE%). The suggested FTC design; a closed-loop setup, with turbulent-flow pattern of the dissolution medium; provided the most acceptable PTX release according to USP labeled limits (USP 27). Also, results showed that PTX release was pronouncedly increased in a finite-volume of gradient-buffer system rather than water, which guarantee complete resemblance to GIT environment. This release design presented the most predictive IVIVC model with PTX in-vivo performance under fasting / fed states, with acceptable PE% values in terms of C_max and AUCs. A suggested FTC design is proposed as an alternative dissolution model in the official USP-monograph for PTX SR products.

Graphical Abstract