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After completing this chapter, the reader should be able to:

  • ► Understand the significance of complexation in pharmaceutical products.

  • ► Appreciate the fundamental forces that are related to the formation of drug complexes.

  • ► Differentiate between coordination and molecular complexation.

  • ► Understand the mechanism of coordinate bond formation leading to the formation of coordinate complexes.

  • ► Appreciate the biological and pharmaceutical roles of coordinate complexes.

  • ► Describe the mechanism of inclusion complex formation, with special emphasis on drug-cyclodextrin complexes.

  • ► Relate the formation of drug-cyclodextrin complexes with improvements in the physicochemical properties and bioavailability of drugs.

  • ► Determine the values of the association constant and the stoichiometry of association.

  • ► Understand the importance of the ion-exchange mechanism and its role in drug delivery and therapy.

  • ► Appreciate the significance of protein-ligand interactions.

  • ► Understand the significance of plasma protein binding for the distributive properties of drugs in the body.

  • ► Identify the important properties of plasma proteins and the mechanism of their interactions with drugs.

  • ► Appreciate equilibrium dialysis and other techniques for in vitro analysis of drug-protein binding.

  • ► Analyze protein-binding data by the double-reciprocal method and determine the values of the association constant and the number of binding sites.

  • ► Analyze protein-binding data by the Scatchard method and determine the values of the association constant and the number of binding sites.

  • ► Appreciate the advantages of the Scatchard method over the double-reciprocal method of analysis with respect to multiple binding affinities.


Complexation, a term with a broad definition, is used in the context of this chapter to characterize the covalent or noncovalent interactions between two or more compounds that are capable of independent existence.1 The ligand is a molecule that interacts with another molecule, the substrate, to form a complex. Drug molecules can form complexes with other small molecules or with macromolecules such as proteins. Once complexation occurs, the physical and chemical properties of the complexing species are altered.2 These properties include solubility, stability, partitioning, energy absorption and emission, and conductance of the drug. Drug complexation, therefore, can lead to beneficial properties such as enhanced aqueous solubility (e.g., theophylline complexation with ethylenediamine to form aminophylline) and stability (e.g., inclusion complexes of labile drugs with cyclodextrins). Complexation also can aid in the optimization of delivery systems (e.g., ion-exchange resins) and affect the distribution in the body after systemic administration as a result of protein binding. The topic of drug-protein binding is covered in depth in the later part of the chapter. In some instances, complexation also can lead to poor solubility or decreased absorption of drugs in the body. For example, the aqueous solubility of tetracycline decreases substantially when it complexes with calcium ions, and coadministration of some drugs with antacids decreases absorption from the gastrointestinal tract. For some drugs, complexation with certain hydrophilic compounds can enhance excretion. Finally, complexes can alter the pharmacologic ...

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