The Significance of Tablet Internal Structure on Disintegration and Dissolution of Immediate-Release Formulas: A Review

The internal microstructure of a tablet, such as pore geometry and pore volume, impacts the tablet’s disintegration kinetics. Ideally, one could design the microstructure to control dissolution onset and therapeutical performance of immediate-release formulas; however, manufacturing tablets with a desired microstructure can be challenging due to the interplay between formulation and process parameters.

Direct quantification of tablet microstructure can provide a framework for optimizing composition and process parameters based on a Quality-by-Design approach. This article reviews the importance of tablet microstructure design and liquid transport kinetics to help optimize the release and dissolution profiles of immediate-release products. Additionally, the formulation and process parameters influencing the tablet microstructure and liquid transport kinetics are discussed.

Introduction

Solid dosage forms, such as tablets, are important delivery systems for the oral administration of active pharmaceutical ingredients (APIs). The use of solid dosage forms for therapeutical treatment has some advantages due to their portability and compactness, noninvasive and self-administering capabilities, and promptness of production in discrete units. These characteristics facilitate dosing and are relatively cheaper to manufacture compared with liquid and parenteral formulas. Among the solid dosage forms, tablets have advantages over capsules due to their longer shelf life, higher dosing capacity, and tunable release mechanisms. For instance, tablets are generally designed to either be immediate- or modified-release products. An immediate-release product is used when rapid dissolution is required, while a modified-release product has gradual and sustained dissolution for selective absorption or a controlled release response. The release and dissolution of immediate-release formulas are generally more affected by the microstructure design that is dependent on the interplay between the formulation and process design.

Immediate-release tablets break into smaller particles through a process referred to as disintegration. Some limitations in developing direct techniques for evaluating disintegration profiles are linked to drawbacks in the disintegration testing apparatus and lack of theoretical models, difficulties in distinguishing the interplay between process and formulation parameters, and the complexity of tablet microstructure dynamics in liquids [1]. Often, the disintegration kinetics is not the rate-limiting process for complete drug dissolution but rather the limiting factor for drug liberation.

In general, in vitro experiments are used to estimate the in vivo performance of immediate-release tablets [2]. In addition to characterizing the release response, a dissolution test can be used to evaluate the variability in formulation and tablet properties. Identifying the root causes of variability is difficult due to the destructive nature of in vitro studies [2,3]. Additionally, in vitro trials do not differentiate between disintegration and dissolution. Semi-empirical models have been proposed to predict dissolution behavior; however, these models possess important limitations. For instance, a universal semi-empirical model is difficult to establish due to variability in mass transfer mechanisms [4]. Therefore, the translation of tablet properties from the bulk (i.e., friability and tablet breaking force) to the micro-level becomes paramount for controlling and troubleshooting problems in tablet manufacturing. It is known that a tablet’s in vitro performance can be controlled by the tablet’s formulation and structure, the latter being determined by processing conditions. The selection of process and formulation variables can help to tune the tablet’s pore structure, which controls the internal liquid transport and dissolution behavior [5,6]. To improve the control of liquid transport through tablet matrices, the Quality-by-Design (QbD) approach has gained momentum since it offers a framework that uses non-destructive techniques and statistical and machine learning to predict the disintegration and dissolution of tablets.

This literature review focuses on the fundamentals of liquid diffusion into a solid substrate and its importance in understanding the disintegration and dissolution of tablets. In addition, mathematical models that describe capillary transport are presented. Furthermore, a general overview of disintegration and dissolution kinetics are discussed in this review. A discussion on emerging technologies to assess internal microstructure and decouple disintegration and dissolution are also included in this review. The final section of this article presents an overview of the influence of formulation and process parameters on tablet microstructure and how it affects disintegration and dissolution kinetics. The final section also includes examples of the Quality-by-Design (QbD) approach in the design of immediate-release products.

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Jange, C.G.; Wassgren, C.R.; Ambrose, K. The Significance of Tablet Internal Structure on Disintegration and Dissolution of Immediate-Release Formulas: A Review. Powders 2023, 2, 99-123. https://doi.org/10.3390/powders2010008