Types of complexes

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Chapter: Pharmaceutical Drugs and Dosage: Complexation and protein binding

Depending on the type of interactions involved in complexation, ligand- substrate complexes are classified as follows:

Types of complexes

Depending on the type of interactions involved in complexation, ligand– substrate complexes are classified as follows:

·           Coordination complexes: These are covalent complexes that form as a result of multiple Lewis acid–base reactions in which multiple neutral or anionic ligands bind a central, cationic substrate through multiple coordinate covalent bonds. Thus, the ionic covalent bonds are formed when an electron-rich atom on the ligand bonds with an electropositive atom of or on the substrate by donating its pair of elec-trons. Tetracycline complexation with divalent heavy metal cations is an example of a coordination complex.

·           Molecular complexes: These are noncovalent complexes formed by multiple attractive interactions between two molecules, such as hydrogen bonding, electrostatic attraction, van der Waals forces, and hydrophobic interactions.

Coordination complexes

Metal complexes are the most common coordination complexes. Their structure involves one or more central metal atom or cation, surrounded by a number of substrates with negatively charged ions (such as carboxyl-ate groups) or neutral molecules possessing lone pair of electrons (such as on nitrogen atoms of amine groups). The ions or molecules surrounding the metal are called ligands. The number of bonds formed between the metal ion and the ligand(s) is called the coordination number of the com-plex. Ligands are generally bound to a metal ion by a coordinate covalent bond (i.e., donating electrons from a lone electron pair into an empty metal orbital) and are thus said to be coordinated to the ion.

The interaction between the metal ion and the ligand is a Lewis acid– base reaction, in which the ligand (a base) donates a pair of electrons (:) to the metal ion (an acid) to form the coordinate covalent bond. For example,

Ag+ + 2(: NH3 ) [Ag(NH3)2 ]+

Where, silver ion (Ag+) is the central metal ion interacting with ammonia (NH3) to form the silver–ammonia [Ag(NH 3)2]+ coordination complex. Ligands, such as H2O:, NC:, and Cl: donate a pair of electron in forming a complex. For example, silver–ammonia complexes can be neutralized with Cl to form [Ag(NH3)2]Cl.

Several enzymes involve coordination complexation of their amino acids to one or more heavy metal atoms. Coordination complexes play a critical role in controlling the structure and function of many enzymes. Heavy metal ions present in physiological proteins and enzymes facilitate the for-mation of coordination complexes that result in the functionality of the protein or the enzyme. For example, copper ion is present in proteins and enzymes, including hemocyanin, superoxide dismutase, and cytochrome oxidase. Zinc is present in many proteins and confers structure and sta-bility, such as crystalline insulin. When present in deoxyribonucleic acid (DNA)-binding proteins, Zn2+ binds tetrahedrally with the two histidine and two cysteine residues of the protein to form a loop (zinc finger), which can fit into the major groove of genomic double-helical DNA (Figure 6.3).

Several nonenzymatic molecules of biological significance are coor-dination compounds. For example, vitamin B12 (cyanocobalamin) is a coordination complex of cobalt (Figure 6.2), and heme is a coordination complex of iron with the nitrogens of histidine residues of the pro-tein (Figure 6.2). Heme proteins of myoglobin and hemoglobin are iron complexes that are essential for the transport of oxygen in the blood and tissues. 

Figure 6.3 Formation of zinc finger due to zinc binding to histidine and cysteine residues in a peptide chain.

Each heme residue contains one central iron atom in the ferrous oxidation state (Fe2+) in coordinate bonds with a heterocyclic organic com-pound called porphyrin. The oxygen carried by heme proteins is bound directly to Fe2+ atom of the heme group. Oxidation of the iron to the ferric oxidation state (Fe3+) renders the molecule incapable of binding oxygen.

Figure 6.2 Examples of drugs that exist as complexes and/or have a high propensity for forming complexes.

Among drugs, anticancer drugs cisplatin and carboplatin are platinum (II) complexes (Figure 6.2). Rheumatoid arthritis drugs aurothiomalate (Myocrisin®), aurothioglucose (Solganol®), aurothiopropanol sulfonate (Allocrysin®), and nuranofin (Ridaura®) are gold complexes (Figure 6.2).

Molecular complexes

Molecular complexes involve noncovalent interactions between the ligand and the substrate, such as electrostatic attraction between oppositely charged ions, van der Waals forces, hydrogen bonding, and hydrophobic interactions. Molecular complexes can be subdivided based on the substrate and the ligand involved in complexation.

1. Small molecule–small molecule complexes

·           Molecules bearing functional groups with opposite polarity can interact with each other in solution. For example, benzocaine interacts with caf-feine as a result of a dipole–dipole interaction between the nucleophilic carbonyl oxygen of benzocaine and the electrophilic nitrogen of caffeine.

·           Self-association complexes form when drug molecules in solution inter-act with one another to form dimers, trimers, or higher-order-association structures, including micelles. For example, daunomycin, mitoxantrone, and brivanib alaninate are known to self-associate in aqueous solution.

3. Small molecule–large molecule complexes

·           Drugs often interact with macromolecules in vitro. For example, cationically charged drugs may interact with anionically charged excipients and polymers in the dosage form, such as tablet, to form a complex. Commonly encountered anionic hydrophilic polymers in the dosage form include the superdisintegrants croscarmellose sodium and sodium starch glycolate.

·         Drugs can also form complexes with ion-exchange resins. Such com-plexation can lead to incomplete drug release from the dosage form. Examples of drugs that can form such complexes include basic drugs amitriptyline, verapamil, diphenhydramine, alprenolol, and atenolol. Ion-exchange resins that strongly bind drugs are also used to make sustained-release dosage forms. For example, ion-exchange resins carboxylic acid and sulfonic acid can bind cationic drugs and those with quaternary ammonium groups can bind anionic drugs.

·    Several water-soluble pharmaceutical polymers, including polyethylene glycols (PEGs), polyvinylpyrrolidone (PVP), polystyrene, carboxymethylcellulose (CMC), and similar polymers containing nucleophilic oxygen, can form complexes with drugs in solution.

·           Plasma protein binding. Drug–protein complexation between small-molecule drugs and large protein molecules in the plasma is mediated by reversible molecular interactions.

·           Enzyme–substrate interactions. Enzyme–substrate interactions involve very specific noncovalent bonds between various amino acids of the enzyme folded into the substrate-recognition site. The require-ment of formation of multiple specific bonds in specific orientation and location within the substrate-binding site for enzyme action ensures substrate recognition for activation of the enzyme.

·           Inclusion/occlusion complexes. These complexes involve the entrapment of one compound in the molecular framework of another. Inclusion complexes are exemplified by the complexation of hydro-phobic drugs by cyclodextrin molecules, which totally enclose the substrate. Occlusion complexes are exemplified by a specific case of cyclodextrin complexes where only the hydrophobic portion of an amphiphilic molecule is complexed by cyclodextrin.

Cyclodextrins are donut-shaped molecules of β-D-glucopyranose with 6, 7, or 8 cyclic residues of d-glucose, known as α-, β-, or γ-cyclodextrins, respectively (Figure 6.4). The cavity size ranges from 5Å for α-cyclodextrin to 8 Å for γ-cyclodextrin. In addition, several cyclodextrin derivatives, such as methyl-, dimethyl-, 2-hydroxypropyl, and sulfobutyl ether substitutions on the hydroxyl groups of the cyclodextrin, lead to different physicochemi-cal properties. For example, Figure 6.5 shows the ampicillin–cyclodextrin occlusion complex.

Figure 6.4 Chemical structure of cyclodextrin.

Figure 6.5 Example of complexation of ampicillin by cyclodextrin.

Cyclodextrins are used to complex hydrophobic molecules or hydro-phobic portions of a molecule. Complexation is mediated primarily by van der Waals force of attraction and hydrophobic interaction. The surface of cyclodextrins is highly hydrophilic because of the multiple hydroxyl (−OH) functional groups that can hydrogen bond with water. Thus, cyclodex-trins can form reversible water-soluble inclusion or occlusion complexes of hydrophobic compounds. Cyclodextrins are nontoxic and do not illicit immune response. Cyclodextrin complexation can, therefore, serve as an effective means of increasing the aqueous solubility, stability, absorption, and bioavailability of hydrophobic drugs. Cyclodextrins have been used to complex and increase the solubility of various hydrophobic drugs, such as paclitaxel and hydrocortisone.

3. Large molecule–large molecule complexes

·           Large molecule–large molecule complexes are exemplified by polyacids, which can form hydrogen-bonded complexes with PEGs (Figure 6.6). In addition, PVP can form complexes with poly(acrylic acids).

·           Base–base interactions in DNA helix through interactions between the nucleotide bases involve hydrogen bonding and are responsible for the unique double-helical structure of the double-stranded DNA. The DNA double helix is stabilized by the hydrogen bond interactions among nucleotides. Adenine (A) forms two hydrogen bonds with thy-mine (T), and guanine (G) forms three hydrogen bonds with cytosine (Figure 6.7).

Figure 6.6 Example of macromolecule–macromolecule interaction. Interaction between polyacid and polyethylene glycol.

Figure 6.7 Complexation between bases in DNA molecules.

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