Dissolution tests - Delayed release (enteric coated)
Delayed release formulations are intended to remain intact until they reach the gut segment in which they are supposed to disintegrate and liberate its content. Usually the dosage form has a coating, which dissolves at designated pH values. Classical delayed release formulations are enteric-coated dosage forms, which protect the compound from gastric fluids at low pH and liberate it at higher pH values in the intestine. It is therefore useful to investigate the formulation quality and dissolution behaviour of compounds in biorelevant media, which can interact with the coating of these formulations. The following section will describe options for testing delayed release formulations under biorelevant conditions.
Paddle (USP 2 apparatus) – reverse dumping method
The USP 2 apparatus can be easily used to investigate the quality and dissolution behaviour of delayed release formulations. The change of environment, which takes place during the passage of the formulation from the stomach into the intestine, can be simulated with the dumping method. This experiment is specifically useful for monolithic formulations, such as delayed release capsules and tablets and can predict the behaviour of such dosage forms under real physiological conditions.
The acceptor vessel is filled with biorelevant medium simulating the stomach fluid (e.g. FaSSGF) and installed in the USP 2 apparatus. The medium simulating the intestinal fluid (e.g. FaSSIF) is poured in the donor vessel. The donor vessel does not have to be installed in the apparatus. Both media are warmed up to 37° C and the paddle rotation is turned on. Then, the formulation is dropped into the acceptor vessel. The formulation remains there for a designated time. Subsequently the simulated intestinal fluid in the donor vessel is “dumped” into the acceptor vessel. Samples are taken from the acceptor compartment with the help of a syringe (with sampling attachment and pre-filter) at defined time points. Then the samples are filtered through a low pore size filter (<0.45 µm) and prepared for analysis
Transfer model (Gastric emptying model)
The transfer model can be particularly useful to investigate the quality and dissolution behaviour of multiparticulate delayed release dosage forms. It simulates the physiological conditions of gastric emptying and can help you to predict the “in vivo” performance of your delayed release formulation.
The transfer model consists of a donor compartment (e.g. Mini Paddle vessel) simulating the stomach and an acceptor compartment (e.g. USP 2 vessel) simulating the intestine. Gastric emptying is mimicked with the help of a peristaltic pump, which connects the donor compartment with the acceptor compartment. Contemporary pumps can be programmed to run nonlinear transfer kinetics, which enable the imitation of first order gastric emptying in the fasted state (without food).
The biorelevant medium simulating the stomach fluid is poured in the donor vessel (e.g. FaSSGF) and the medium simulating the intestinal fluid (e.g. FaSSIF) is poured in the acceptor vessel. The media are warmed up to 37° C and the paddle rotation is turned on. Then the formulation is placed in the donor compartment. The peristaltic pump is turned on to transfer the contents of the donor compartment into the acceptor compartment. Samples are drawn from the acceptor vessel with the help of a syringe (with sampling attachment and pre-filter) at defined time points. Then the samples are filtered through a low pore size filter (<0.45 µm) and prepared for analysis.
BioDis (USP 3 apparatus)
The USP 3 apparatus (BioDis) can be utilised to investigate the quality and dissolution behaviour of delayed release formulations. It can simulate a transit of a compound through different sections of the digestive tract. This system can be used to test monolithic formulations such tablets, but also multiparticulate systems such as coated pellets.
The BioDis apparatus comprises 6 dissolution compartments with up to 8 rows per compartment. Up to 48 vessels can be placed in the BioDis. Each row is be filled with a biorelevant medium simulating a section of the digestive tract. For example, the first row would represent the stomach, the second row the duodenum, the third row the upper jejunum, etc. The delayed release formulation is placed into a containment cell, which runs from row to row and is dipped into vessels simulating the different simulated gut sections. This simulated gut transit can help you to assess quality of your formulation and predict the dissolution behaviour of delayed release dosage forms under physiological conditions.
In practice BioDis vessels are filled with 200ml of biorelevant medium, placed in the apparatus and heated up to 37° C. The formulation is then placed in the containment cell. The dipping rate is programmed according to the section the formulation is in (e.g. 12 dips per minute in simulated stomach, 10 dips per minute in the simulated small intestine). Samples are drawn from the acceptor vessel with the help of a syringe (with sampling attachment and pre-filter) at defined time points. Then the samples are filtered through a low pore size filter (<0.45 µm) and prepared for analysis.
USP 4 apparatus / Flow-through tester
USP apparatus 4 (flow-through tester) is commonly used for the analysis of modified release dosage forms. An exchange of media is possible to simulate different environments of the digestive tract. It therefore represents another approach for the investigation of delayed release formulations under biorelevant conditions.
A glass cell is used to hold the formulation. To simulate the transit of the formulation through different sections of the digestive tract (e.g. transit from the stomach into the intestine) an exchange of biorelevant media is required (e.g. FaSSGF exchanged by FaSSIF).
In practice the dissolution medium is warmed up to 37° C and pumped through the cell at a preset pumping rate, which depends on the simulated prandial state (e.g. with or without food) and gut segment (e.g. stomach, intestine). Samples are usually drawn via an internal sampling and filtration device.