Dissolution-controlled release mechanisms

Equation (6.94) illustrates that zero-order release kinetics are obtained if drug dissolution controls the release kinetics. However, as soon as the last particle in the matrix dissolves, the controlling mechanism of drug release shifts to Fickian diffusion. Figure 6.19 shows the dissolution-controlled release of KC1 at the early stage of release and the diffusion-controlled release at the later stage of release from an ethyl cellulose tablet. 

Mechanisms of dissolution kinetics of crystals have been intensively studied in the pharmaceutical domain, because the rate of dissolution affects the bioavailability of drug crystals. Many efforts have been made to describe the crystal dissolution behavior. A variety of empirical or semi-empirical models have been used to describe drug dissolution or release from formulations [1-6]. Noyes and Whitney published the first quantitative study of the dissolution process in 1897 [7]. They found that the dissolution process is diffusion controlled and involves no chemical reaction. The Noyes-Whitney equation simply states that the dissolution rate is directly proportional to the difference between the solubility and the solution concentration ... 

Another important consequence of the constant rate of release diffusion model is that it mimics many of the features that have commonly been attributed to surface reaction (matrix dissolution) control. If one were to account for changes in surface area over time, the predicted long-term dissolution rate due to surface reaction control would also yield constant element release. In surface reaction controlled models, the invariant release rate with respect to time is considered to be the natural consequence of the system achieving steady-state conditions. Other features of experiments commonly cited as evidence for surface reaction control, such as relatively high experimental activation energies (60-70 kJ/ mol), could be explained as easily by the diffusion-control model. These findings show how similar the observations are between proponents of the two models it is only the interpretation of the mechanism that differs. 

In this section the controlled release delivery systems applying dissolution as the major release mechanism are discussed. Since many of these systems actually apply to both the concepts of dissolution and diffusion in the design, only the dissolution parameters affecting the release profiles and the release rates of these systems are analyzed. 

The current regulatory climate of QbD places an emphasis on clinically relevant specifications and methods for in vitro dissolution.20 Development scientists should identify dissolution methodology that has been closely examined for its relevance to in vivo performance, as well as for mechanistic information. In other words, the release mechanism of the product should be understood and the dissolution test should be able to detect changes reflecting deviation of the mechanism. There is also the quality control (QC) side of dissolution testing, which, until the process analytical technology (PAT) develops beyond the current capabilities, is very important for stability and end-product release testing. 

Since the dissolution of polymeric materials is the key to this mechanism, the polymers used must be water-soluble and/or degradable in water. The choice of a particular polymer for a particular controlled release dosage form depends on various factors such as the dissolution mechanism, delivery period, delivery route, the drag etc. In general, synthetic water-soluble polymers tend to be widely used for oral-controlled release dosage forms. Biodegradable polymers tend to be used for injectable, or implantable, drag delivery systems. 

Schultz, P. Kleinebudde, P. A new multiparticulate delayed release system part I. Dissolution properties and release mechanism. J. Control. Release 1997, 47, 181-189. 

The textural and solid-state characteristics of sulfur coatings on urea were investigated in the laboratory to identify the controlling factors. The objective was to determine how the interrelated properties of sulfur coatings affect the dissolution mechanism of sulfur-coated urea (SCU) as a controlled-release nitrogen fertilizer. The fine textural details of the sulfur coatings required that the primary investigation be done by scan-... 

Gao, H., Tan, T., Wang, D., 2004. Dissolution mechanism and release kinetics of phosphate controlled release glasses in aqueous medium. Journal of Controlled Release 96, 29—36. 

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