Metal-ion coordination complexes, sometimes simply called metal complexes, consist of a central metal ion bonded to one or more ligands that are electron-pair donors such as a nitrogenous base (e.g., ammonia), an ion (e.g., chloride ion), or an aromatic compound (e.g., ferrocene). The number of bonds between the metal ion and the ligand or ligands is called the coordination number of the complex. Metal ions can have more than one coordination number. The maximum number is defined by the size, charge and electronic structure of the metal ion. Coordination numbers are normally between 2 and 9 with the most common coordination numbers being 4 and 6. For example, the anticancer drug cisplatin has a coordination number of 4 (Fig. 1).

Inorganic Complexes

The trans stereoisomer of cisplatin is transplatin (Fig. 1). Both of these geometrical isomers have square planar structure, that is, the metal substrate and the four ligand groups all lie in the same plane. Most metal-ion coordination complexes of coordination number 4 have a square planar structure but some are tetrahedral where the central metal ion is in the center of a tetrahedron with each of the four ligands located in the four corners. Most complexes with coordination number 6 are octahedral, that is, the bonds lie along the x, y, and z axes of a coordinate system with the metal ion at the origin. Example of such a complex are the cis and trans isomers of dichlorotetraamminecobalt(III) chloride (Figure 2).

Metal ions that are found within cells form coordination complexes with small molecules such as porphyrins that are themselves bound to proteins. The function of such metalloproteins can be the transport of oxygen or nitric oxide, or can be enzymatic in nature. For example, the heme unit is a coordination complex of iron and a porphyrin that is responsible for binding oxygen in hemoglobin and myoglobin.

Chelates

A chelate is formed when a ligand uses more than one donor atom to bind a single metal atom. Such ligands are called chelating agents, chelants, or chelators. Chelates tend to be more stable than comparable complexes containing only one binding site and are used in drug formulations to, for example, bind metal ions that catalyze drug oxidation, thus increasing the shelf-life of the drug product. Examples of such chelating agents include citric acid, tartaric acid and EDTA (ethylenediamine tetraacetic acid).

Some drugs can also be chelating agents and bind ions. For instance tetracycline forms hydrophilic chelates with ions such as calcium (Ca⁺²), iron (Fe⁺³, Fe⁺²), aluminium (Al⁺³), and magnesium (Mg⁺²), i.e. complexes that possess poor oral bioavailability (Fig. 3). Milk and milk products, mineral supplements and antacids containing polyvalent cations ingested simultaneously with tetracycline antibiotics can reduce their oral bioavailability by as much as 90%.4 Nalidixic acid, ciprofloxacin and other quinolones do also form chelates with polyvalent ions that can reduce their oral bioavailability. The intensity of the effect depends both on the nature of the drug and the cation, as well as on the doses used. The drugs that bind metal ions should be taken either two to three hours after or before ingestion of cation containing products such as dairy products, antacids and mineral supplements.

β-Lactam antibiotics form chelates with metal ions such as Cu⁺² (Fig. 4). The β-lactam ring is much more susceptible to specific base hydrolysis (i.e., toward OH^– attack) when complexed than when uncomplexed. Thus, formation of such chelates can significantly decrease the shelf-life of β-lactam antibiotics.

Reference:

• Sinko, P. (2011). Martin’s Physical Pharmacy and Pharmaceutical Sciences. Baltimore, : Lippincott Williams & Wilkins, a Wolters Kluwer business.
• Felton. L. (2013). Remington Essentials of Pharmaceutics. London. UK: Pharmaceutical Press.