Factors Related to the Physicochemical Properties of the Drug Substance

The importance of the physicochemical properties on the dissolution of a drug substance into the dissolution medium is best illustrated by (3.4)-(3.6). Despite the fact that these three equations are derived from different diffusion mechanisms, they clearly show that the dissolution rate depends on the solubility and surface area of a drug substance.

3.4.1.1 Solubility

From (3.4)-(3.6), it is evident that compounds with high solubility generally exhibit higher dissolution rates. The solubility of ionizable drugs, such as weak acids and bases, depends upon both the pH of the medium and the pKa of the compound. Therefore, it is important to ascertain the aqueous solubility of the drug substance over the physiologically relevant pH range of 1-7.5 in order to predict the effect of solubility on dissolution. The study of Yu et al. shows that there is a good relationship between solubility and disk intrinsic dissolution rate unless an extremely high or low dose is used. Solubility data may also be used as a rough predictor for indicating any potential problems with oral absorption. For example, when the dose/solubility of the drug, which provides an estimate of the fluid volume required to dissolve an individual dose, exceeds about 1L, in vivo dissolution is often considered problematic (Yu and Amidon, 1999).

3.4.1.2 Particle Size

According to (3.4) and (3.6), the dissolution rate is directly proportional to the surface area of the drug. Reducing particle size leads to an increase in the surface area exposed to the dissolution medium, resulting in a greater dissolution rate. Thus, the dissolution rate of poorly soluble drugs can often be enhanced markedly by undergoing size reduction (e.g., through micronization). This is evidenced in the case of glyburide tablets (Stavchansky and McGinity, 1989). However, particle size reduction does not always improve the dissolution rate. This is in part attributed to adsorption of air on the surface of hydrophobic drugs, which inhibits the wetting and hence reduces the effective surface area. In addition, fine particles tend to agglomerate in order to minimize the surface energy, which also leads to a decrease in the effective surface area for dissolution.

3.4.1.3 Solid Phase Characteristics

A drug substance may exist in different solid-state forms (polymorphism). These different forms can be generally classified into three distinct classes including (1) crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice, (2) solvates that contain either stoichiometric or nonstoichiometric amount of a solvent, and (3) amorphous phases that do not possess a distinguishable crystal lattice. Differences in the lattice energies among various polymorphic forms can result in differences in the solubilities. Sometimes, the solubility of different drug substance polymorphs can vary significantly. For example, the solubility of amorphous forms can be several hundred times greater than that of the corresponding crystalline state. These solubility differences may alter drug product in vivo dissolution, hence affecting oral drug absorption.

3.4.1.4 Salt Effects

Salt formation is frequently used to increase the solubility of a weak acid and base. The solubility enhancement of a drug substance by salt formation is related to several factors including the thermodynamically favored aqueous solvation of cations or anions used to create the salt of the active moiety, the differing energies of the salt crystal lattice, and the ability of the salt to alter the resultant pH. In addition, even if the salt formation has no impact on the solubility of the drug, the dissolution rate of the salt will often be enhanced due to the difference in the pH of the thin diffusion layer surrounding the drug particles (Stavchansky and McGinity, 1989).

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