Complexation and protein binding:
Introduction, Classification of Complexation, Applications, methods of analysis, protein binding, Complexation and drug action, crystalline structures of complexes and thermodynamic treatment of stability constants.
The term complexation is used to characterize the covalent or non-covalent interactions between two or more compounds capable of independent existence. The ligand, a molecule, interacts with substrate the molecule to form a complex. Drug molecules can form complexes with
other small molecules or with macromolecules. Once complexation occurs, the solubility, stability,
partitioning, energy absorption and emission, and conductance of the drugs are changed. Drug complexation, therefore, can lead to beneficial properties such as enhanced aqueous solubility and stability. Complexation can also be useful in the optimization of delivery systems and affect the distribution in the body after systemic administration due to protein binding. The drug-protein binding in this unit is covered in depth in the later part. Contrary, complexation can also lead to
poor solubility or decreased absorption of drugs in the body. For certain drugs, complexation with certain hydrophilic compounds can enhance excretion. Overall, complexes can alter the
pharmacologic activity of drugs. After studying the contents of the chapter, students are expected to:
• Understand the significance of complexation in pharmaceutical products.
• Understand the fundamental forces that are related to the formation of drug complexes.
• Differentiate between different complexation types and understand the mechanism of complex formation.
• Relate the formation of complexes with improvements in the physicochemical properties and bioavailability of drugs.
• Identify the significance of protein-ligand interactions in drug action.
• Understand properties of plasma proteins and its mechanism of interactions with drugs.
• Understand the techniques of in vitro analysis and factors affecting complexation and protein binding.
1. Understand the significance of complexation in pharmaceutical products.
2. Appreciate the fundamental forces that are related to the formation of drug complexes.
3. Differentiate between co-ordination and molecular complexation.
4. Understand the mechanism of co-ordinate bond formation leading to the formation of co-ordinate complexes.
5. Appreciate the biological and pharmaceutical roles of co-ordinate complexes.
6. Describe the mechanism of inclusion complex formation, with special emphasis on drug- cyclodextrin complexes.
7. Relate the formation of drug-cyclodextrin complexes with improvements in the
physicochemical properties and bioavailability of drugs.
8. Determine the values of the association constant and the stoichiometry of association.
9. Understand the importance of the ion-exchange mechanism and its role in drug delivery and therapy.
10. Appreciate the significance of protein-ligand interactions.
11. Understand the significance of plasma protein binding for the distributive properties of drugs in the body.
12. Identify the important properties of plasma proteins and the mechanism of their interactions with drugs.
13. Appreciate equilibrium dialysis and other techniques for in vitro analysis of drug-protein binding.
14. Analyse protein-binding data by the double-reciprocal method and determine the values of the association constant and the number of binding sites.
15. Analyse protein-binding data by the Scatchard method and determine the values of the association constant and the number of binding sites.
16. Appreciate the advantages of the Scatchard method over the double-reciprocal method of analysis with respect to multiple binding affinities.
17. Define the three classes of complexes (co-ordination compounds) and identify
pharmaceutically relevant examples.
18. Describe chelates, their physically properties, and what differentiates them from organic molecular complexes.
19. Describe the types of forces that hold together organic molecular complexes and give examples.
20. Describe the forces involved in polymer–drug complexes used for drug delivery and situations where reversible or irreversible complexes may be advantageous.
21. Discuss the uses and give examples of cyclodextrins in pharmaceutical applications.
22. Determine the stoichiometric ratio and stability constant for complex formation.
23. Describe the methods of analysis of complexes and their strengths and weaknesses.
24. Discuss the ways that protein binding can influence drug action.
25. Describe the equilibrium dialysis and ultrafiltration methods for determining protein binding.
26. Understand the factors affecting complexation and protein binding.
27. Understand the thermodynamic basis for the stability of complexes.
