Dissolution tests - Immediate release
Immediate release dosage forms are intended to liberate a compound directly when entering the digestive tract. These formulations disintegrate and release the compound in the stomach and also in the upper small intestine. Most of these formulations are simple tablets or capsules, but could also be solutions, suspensions, emulsions, granulates and powders.
With dissolution tests you can evaluate the performance of your compound and immediate release dosage form when it is taken without food or with food. It will give you a better understanding of your test compound and dosage form, and help you to find solutions for formulation development and improvement.
There are several ways of testing the behaviour of immediate release dosage forms under real human conditions. The experimental outline can be very simple, but it can get more complicated when certain physiological behaviour, such as gastric emptying is involved. The next sections will describe the most usual ways of running dissolution investigations on immediate release formulations under physiological gut conditions.
Paddle (USP 2 apparatus)
The USP 2 dissolution apparatus is standardised heatable vessel and rotating paddle system, which enables formulation quality and compound liberation investigations under gut conditions. With this assembly it is possible to simulate the individual compartments of the digestive tract, for example the stomach or the intestine. The paddle apparatus helps to predict the performance of your immediate release compound or formulation in the human or animal stomach and intestine.
Before starting a biorelevant dissolution experiment, it should be decided which gut region (stomach or intestine) and which prandial state (with or without food) should be simulated. On this basis the biorelevant medium is selected. For example: FaSSIF is utilized to simulate the fasted intestine, or FeSSIF to simulate the fed intestine. Usual volumes of biorelevant medium are 500ml for compound and formulation development, and 900ml for quality control. The paddle rotation speed is based on the simulated prandial state. In the simulated fasted state (without food) the speed is usually 75-100rpm, whereas in the simulated fed state (with food) it is typically lower with around 50rpm.
A test in the USP 2 apparatus is prepared by pouring the biorelevant medium in the vessels. The biorelevant medium is heated up to the physiological temperature of 37 °C and the paddle rotation is turned on. The test is started though introduction of the compound or formulation into the vessels. The samples are taken 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.
Mini Paddle (miniaturised USP 2 apparatus)
The Mini Paddle assembly is a miniature version of an USP 2 apparatus. The vessels and the paddles are reduced in size to simulate gut compartments, which comprise low volumes of fluid such as the stomach without food (fasted state). The Mini Paddle apparatus helps to predict the performance of your immediate release compound or formulation in the human or animal digestive tract, especially in the fasted stomach.
The experimental procedure is the same as in the USP 2 apparatus. The usual volumes are between 250ml and 500ml. For example: 250ml of FaSSGF are utilized to simulate the fasted stomach conditions.
A test in the Mini Paddle apparatus is prepared by pouring the biorelevant medium in the vessels. The biorelevant medium is heated up to the physiological temperature of 37 °C and the paddle rotation is turned on. The test is started though introduction of the compound or formulation into the vessels. The samples are taken 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)
Certain compounds supersaturate and precipitate when leaving the stomach and entering the intestine. This behaviour can be investigated using the transfer model, which simulates the transit of the compound or formulation from the stomach into the intestine. It helps you to predict the performance of your immediate release compound and formulation under physiological gastric emptying conditions.
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. The pumping rate can be set up according to the desired simulation of the prandial state (with or without food). 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).
Transfer experiments can be performed in different ways. One of the classical approaches is to pour the biorelevant medium simulating the stomach fluid into the donor vessel (e.g. FaSSGF) and the medium simulating the intestinal fluid into the acceptor vessel (e.g. FaSSIF). The media are warmed up to 37° C and the paddle rotation is turned on. Then the compound or formulation is introduced into the donor medium. The peristaltic pump is turned on to transfer the contents from the donor compartment into the acceptor compartment. 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.
Christian Wagner et al.: Predicting the oral absorption of a poorly soluble, poorly permeable weak base using biorelevant dissolution and transfer model tests coupled with a physiologically based pharmacokinetic model (2012)
The µDiss Profiler is a multifunctional apparatus, which can be used for compound dissolution assessment. The advantage of using µDiss is that no additional equipment is required to perform the tests. The apparatus uses fibre optics, which enable direct concentration measurement of the compound in solution. This avoids taking physical samples. However the regular volume in this apparatus is 20ml, which underrepresents the physiological volumes of the digestive tract. The system is therefore useful for development purposes, especially when little amounts of compound are available.
The biorelevant medium of choice is poured into the µDiss vessels and warmed up to the physiological temperature of 37° C. Then, the stirring is initiated and the compound is introduced into the vessels. The µDiss Profiler measures the concentration of the compound at designated time points.