Oral controlled release dosage forms: dissolution versus diffusion

ABSTRACT

Introduction

Controlled release (CR) dosage forms comprise a wide range of technologies, which modify the drug pharmacokinetic (PK) profile by avoiding the immediate release (IR) of the active pharmaceutical ingredient (API). They are particularly of interest in chronic diseases, for narrow therapeutic index drugs or for targeting a particular gastrointestinal tract (GI) segment.

Areas covered

Diffusion and dissolution limited controlled release systems are described in terms of release kinetics and formulation strategies with e xamples marketed or under development. Additionally, the physiological variables affecting the release (such as fluid pH, volume and composition, physical forces, and transit times) and the in vitro dissolution techniques currently available are reviewed.

Expert opinion

Selection of the appropriate release mechanism is not a straightforward process, as it requires a balance based on the desired target, the API properties and the technological challenges of the dosage form structure. Diffusion, dissolution or a combination of both could be adequate without an absolute superiority of one mechanism over the other. The combination of in vivo predictive dissolution systems, with mathematical modeling of the release mechanism and its correlation with formulation composition could help to design prototype candidates, with enhanced probabilities of success in human clinical trials.

KEYWORDS:

• Oral controlled release
• dissolution
• diffusion
• release kinetics
• formulation selection
• predictive dissolution

Article highlights

• Controlled release can be achieved through several mechanisms, such as dissolution, diffusion, solvent-activation (as the osmotic pumps) or chemical-trigger (by hydrolytic or enzymatic reactions). Many marketed CR products are diffusion or dissolution limited or a combination of both mechanisms.

• In diffusion-limited CR formulations, insoluble polymers are used for controlling drug delivery and it is quite easy to obtain a zero-order kinetic, particularly in multiparticulate reservoir types. Diffusion through swellable hydrophilic polymers is a second alternative used mainly in matrix systems, easy to manufacture, and generally having a non-constant release rate.

• Dissolution-limited systems are either based on pH differential dissolution of a coating polymer or in the dissolution/erosion of soluble polymers. The former alternative performance may be affected by inter and intra individual variability on intestinal pH profiles. The later may need additives to render the dissolution pH-independent.

• Frequently, CR forms combine dissolution and diffusion release mechanisms in matrix type forms. In these cases, it is possible to say that if the drug is highly soluble, diffusion may be more relevant, peradventure the drug has low solubility, and then, matrix erosion may be more important.

• The main physiological factors affecting CR performance are intestinal fluids pH, volume and composition, physical forces, and transit times which determine the time of exposure to the particular segment conditions. Food influence depends on release mechanism.

• Several in vitro dissolution systems in combination with mechanistic mathematical modeling can be used as development tool for studying the kinetics of release and for predicting the in vivo behavior of a CR formulation with the aim of enhancing the probabilities of success in human clinical trials.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by Agencia Estatal de Investigación and European Union (grant number: SAF2016-78756 (AEI/FEDER, EU)). B Sanchez-Dengra received a grant from the Ministry of Science, Innovation and Universities of Spain [grant number FPU17/00530].