Critical Roles of Porosity in Tableting Properties Characterization and Solids Formulation Development
Changquan Calvin Sun, Ph.D.
Pfizer, Inc.
Introduction
Quality of pharmaceutical oral solids products has been routinely assessed by monitoring their mechanical strength, disintegration time, dissolution rates, chemical stability, content uniformity, and pharmaceutical elegance. These properties are also carefully characterized and optimized during formulation and process development. However, these tests are often performed on an empirical basis. A fundamental understanding of factors that control these tablet properties has obvious importance to formulation scientists. During compaction, the powder bed is continuously consolidated to bring particles closer together as pressure is applied. This consolidation of powder causes deformation, e.g., plastic, elastic, fragmentation, of particles. As a result of the deformation, a significant amount of inter-particulate molecular interactions, or bonding occurs. These bonds, after surviving the subsequent decompression and ejection phases of manufacturing, collectively produce the mechanical strength of a tablet. Disruption of these bonds is a prerequisite for disintegration and subsequent drug release upon administration of a tablet. Clearly, the structure of a tablet, i.e., how particles are arranged with respect to adjacent particles in a three dimensional space within a tablet, has a significant impact on its physical properties. Most compressed tablets are porous in nature. It is therefore appropriate to use porosity to quantify changes of tablet structure. A good understanding of how tablet porosity influences various tablet properties is of practical importance for efficient development of robust pharmaceutical formulations and processes. In this paper, effects of porosity on tablet physical properties, formulation and process development, and tableting data analysis are discussed.
Terminology
The Porosity of a tablet, ε, is defined as the volume fraction of pores in a specimen. It can be calculated using Equation 1. Sometimes, the term “solid fraction” is used in pharmaceutical literature. Solid fraction (SF) is defined as the volume fraction of solid in a tablet. It equals the ratio of specimen apparent density, ρtablet, to true density of the solid, ρtrue (Equation 1). The sum of porosity and solid fraction of a given specimen equals to unity by definition.
Because of the simple relationship between porosity and solid fraction, the two terms can be practically interchangeable. A recent survey of literature in the field of compaction and tableting revealed that ~6,000 research articles between 1971- 2004 contain the concept of porosity but, only 316 articles in the same period contain the concept of solid fraction. Thus, the appearance of porosity is about 20 times of that of solid fraction. Because “porosity” is more frequently used in the literature, we use porosity in this paper.
Effects of Porosity on Tablet Mechanical Strength
The mechanical strength of a solid specimen may be measured by tensile strength, hardness, and elastic modulus. The dependence of the tensile strength of a compact on its porosity was initially described by Ryshkewitch [1]. It was found that the tensile strength of sintered alumina and zirconia compacts decreased exponentially with increasing porosity according to an empirical relationship (Equation 2).
Where σ is tensile strength; σ0 is the tensile strength at zero porosity; b is a constant. It was subsequently shown that Equation 2 is also applicable to many pharmaceutical powders. Moreover, the same expression is valid for elastic modulus in many powder systems [2]. The relationship between tablet tensile strength and porosity represented in Equation 2 is termed compactability [3,4]. Compactability plots of some common pharmaceutical powders are shown in Figure 1. When only a limited amount of powder is available, one may collect data using only a few tablets and fit the data to Equation 2 to get an expression that can be subsequently used to predict tensile strength of compacts of that powder at any other porosities of interest.
Effects of Porosity on Tablet Disintegration Time
Disintegration of tablets and granules is a prerequisite for drug dissolution and absorption in gastro-intestinal tract. However, the influence of tablet structures on disintegration time has not been extensively reported and is not clearly understood. It is conceivable that the rate of water penetration into a tablet is sensitive to size and number of pores in tablets of a given powder. Two immediate release tablet formulations using typical but different sets of binders, fillers, and disintegrants were compressed at different pressures to obtain tablets of different porosities. The subsequent tests showed that tablet disintegration time decreases with increasing tablet porosity (Figure 2). Qualitatively, the direction of effects is understandable since the water penetration rate is higher and inter-particulate bonding is weaker in a tablet with a higher porosity. However, the functional dependence is linear in one case (Figure 2a) but almost exponential in the other (Figure 2b). Reasons for the different effects of tablet porosity on disintegration time are currently being investigated. To improve the robustness of a formulation, the exponential relationship in the second case is less desirable during formulation development because a slight change in porosity may have significant consequences in tablet disintegration properties. A prolonged disintegration time may inadvertently affect drug dissolution performance of tablets in vivo.
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