Introduction

For a newly discovered molecule to become an active drug it must traverse through a multitude of physiologic barriers, both aqueous and nonaqueous; these barriers exist to protect our body from the noxious agents that can be toxic to our body. The system by which Nature chose to protect us is based on the solubility of compounds. A compound highly soluble in water or highly insoluble in water would not be able to penetrate the deeper tissues and thus rendered ineffective. Neutral compounds without any polarizable centers often prove to be inert pharmacologically; for example, fluorinated hydrocarbons, such as perfluorodec-alin, which is a hexane structure with full fluorination. Fluorine is so highly electronegative that it pulls the electrons from the parent structure, making it an inert compound. Interactions at the site of action are often electrically driven and as a result, it is more likely that we will discover a compound that has weak acid or base properties as an active entity. This necessitates studies that would yield information on how well the compound will distribute throughout the body tissues and the lipophilic/hydrophilic balance of the molecular structure becomes the focus of studies at an early stage in preformulation.

Compounds that ionize in the aqueous phase are rendered water-soluble, because they can polarize the medium and can create solute-solvent electrostatic bonding to increase their solubility. The ionization of a compound depends on the strength of binding of the ionizable group to the core of the molecule, a property that is determined by the value of the dissociation constant; once ionized, the molecule acquires new solubility characteristics; when placed between aqueous and nonaqueous phases, the distribution between these two phases, generally called partitioning, will change. It is this partitioning behavior of drugs that makes them useful as drugs; without a significant degree of partition between aqueous and non-aqueous phases of body tissues, no molecule can become active. This ionization also determines the quantity of a solute that is eventually contained in a medium, aqueous or nonaqueous—the solubility of compound. So, what starts with dissociation affects both partitioning and the solubility of the compound, the two most important parameters that will determine if a newly discovered molecule will end up as an active drug or not. This chapter describes these three inter-related properties that form the first step in any prefor-mulation evaluation.

Maintaining The Body

Maintaining The Body

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