Novel Methods for Predictive Dissolution Measurements

Jon Greenacre, R&D, Pion Inc, Billerica, USA

It has been indicated in multiple studies that traditional dissolution measurements are not suited to predict an active pharmaceutical ingredient’s (API) pharmacokinetic (PK) profile, particularly for low soluble APIs and their formulations. One of the reasons for this limitation is that novel enabling formulations often target increasing an APIs solubility and may or may not lead to the improved API absorption

The goal of the presented studies was to investigate the driving force for drug absorption by introducing an absorption chamber and biomimetic membrane into both compendial and miniaturized dissolution apparati.

Methods

MacroFLUX™ and µFLUX™ devices (Pion Inc.) were used to monitor dissolution and absorption processes simultaneously. MacroFLUX consisted of 6 cylindrical absorption chambers with 15 mL working volume and a filter supported artificial lipophilic membrane (Double-Sink™ PAMPA model, Pion) with area 3.88 cm² attached to the bottom of the chambers. These compartments were inserted into modified vessel covers of the dissolution bath (Erweka Model DT 126 light). The µFLUX apparatus had 4 side-by-side dissolution/absorption pairs each containing up to 22 mL of media separated by a lipophilic membrane with area 1.54 cm². Concentration monitoring in both dissolution and absorption chambers was enabled through fiber optic UV probes connected to the Rainbow Dynamic Dissolution Profiling instrument (Pion Inc.).

The media change experiments usually began with simulated gastric fluid (SGF, pH 1.6)  or modified SGF (pH 4.5) media in the donor compartment and converted to fasted state simulated intestinal fluid (FaSSIF) after 30 min of dissolution. The receiver (absorption) chamber contained Acceptor Sink Buffer (ASB, pH 7.4) specially designed to create sink condition in the receiver compartment preventing quick equilibration of the API concentration.