Zeren Wang and Rama A Shmeis

Boehringer-Ingelheim Pharmaceuticals, Inc. Ridgefield, Connecticut

5.1 Introduction 140

5.2 Theoretical Considerations for Dissolution Controlled 140 Release Matrix and Coated Systems

5.2.1 Dissolution of solid particles 140

5.2.2 Dissolution of coated systems 142

5.2.3 Dissolution of matrix systems 146

5.3 Parameters for Design of Dissolution Controlled 149 Release Matrix and Coated Systems

5.3.1 Parameters affecting dissolution 149 of solid particles

5.3.2 Parameters affecting dissolution 150 of coated systems

5.3.3 Parameters affecting dissolution of matrix systems 152

5.4 Applications and Examples of Dissolution Controlled 155 Release Matrix and Coated Systems/Technologies

5.4.1 Delivery systems based on dissolution 155 controlled release solid particles

5.4.2 Delivery systems based on dissolution controlled 156 release coated technologies

5.4.3 Delivery systems based on dissolution controlled 165 release matrix technologies

5.5 Future Potential for Dissolution Controlled Release 167 Drug Delivery Systems

5.5.1 Dissolution controlled release coated systems 167

5.5.2 Dissolution controlled release matrix systems 168 References 169

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5.1 Introduction

The dissolution process includes two steps, initial detachment of drug molecules from the surface of their solid structure to the adjacent liquid interface, followed by their diffusion from the interface into the bulk liquid medium. This process could be manipulated to design controlled release delivery systems with desired profiles and a desired rate. In general, either matrix- or barrier/membrane-based controlled release systems are applied to slow down, delay, and control the delivery and release of drugs. In the former, drug is uniformly dispersed in a matrix consisting mainly of polymers or waxes, whereas the latter refers to coated systems. Acombination of both (coated matrix) is also possible.1 The demarcation between a coated and a matrix-type pharmaceutical controlled release product is not always clear. Some of the materials used as coatings to control drug release also may be used for a similar function in matrix-type products.2

If the matrix or coated systems are made of water-soluble components, the rate-limiting step governing the release of drug from these systems will be dissolution. For many controlled release drug delivery systems, different mechanisms controlling the release profile and release rate are used in combination. In this chapter, only hydrophilic and water-soluble polymers used for matrix and coated systems are discussed. Release profiles from these systems are usually complicated and controlled by several mechanisms; however, only the effect of the dissolution of drug substances, as well as polymer matrices or polymer coatings, on release will be discussed in detail. Systems employing a mixture of soluble and insoluble coatings (dissolution and diffusion controlled) also will be introduced briefly.3

The dissolution controlled release matrix systems provide sustained release profiles; i.e., the active drugs in these systems are released continuously at a slow rate to provide a long-term therapeutic effect. Unlike diffusion controlled release coated systems, release profiles from dissolution controlled release coated systems do not follow zero-order kinetics but fall within the classification of delayed release systems,4 pulsatile or repeat-action systems,5 and sustained release systems.3

Although examples of delivery systems using the parenteral and oral (solid) routes are presented in this chapter, application of dissolution controlled release matrix and coated systems concepts can extended easily (and has been) used for many other delivery routes.

5.2 Theoretical Considerations for Dissolution Controlled Release Matrix and Coated Systems

5.2.1 Dissolution of solid particles

The dissolution process of solids consists of two steps. First, the molecules at the solid-liquid interface are solvated and detached from the solid surface. Second, the solvated molecules diffuse away from the interface to the bulk solution. It is commonly believed that the first step is much faster than the second step. Therefore, at the steady state of dissolution, the concentration of the dissolving substance at the dissolution interface is equal or close to its solubility (Fig. 5.1). Because the diffusion step is rate limiting, the dissolution flux (the amount of mass dissolved per unit time and per unit dissolving area) can be modeled by Fick's first law of diffusion:

A = dissolving surface area D = diffusion coefficient h = thickness of diffusion layer Cs = solubility

Cb = concentration in bulk solution

By simple manipulation, the rate of dissolution, the amount of dissolved solid per unit time, can be calculated by the Noyes and Whitney equation, written as dM D.„

The dissolving solid

Dissolution interface

The dissolving solid

Dissolution interface

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