Complexation- Application, Classification, Analysis and Drug action


Usually, non-covalent interaction between two or more compounds that are capable of independent existence is called a complexation. Generally, it results from a donor-acceptor mechanism or Lewis acid-base reactions between two or more different chemical constituents.

Any non-metallic atom or ionic (free or bound) that can donate electrons pair serves as a donor. The acceptor or constituent will accept the pair of electrons most of the time. It is a metallic ion.

Following intermolecular forces are involved in the formation of complexes.

  • Van der Waals forces
  • Dipolar or induced dipolar type
  • Hydrogen bonding
  • Covalent or co-ordinate bonds


  • 1. Physical state of a substance can be changed from liquid to solid. Liquid nitroglycerine is converted to solid by forming a complex with beta-cyclodextrin.
  • 2. Reduction in volatility: Reduction in volatility gives the advantage of odor reduction. E.g., Iodine is stabilized by forming a polyvinyl pyrrolidone complex.
  • 3. Stability of drugs can be increased through complexation if it undergoes chemical or physical changes. E.g. Complexation of Vit. D, Vit. A with beta-cyclodextrin.
  • 4. Solubility can be enhanced by complexing a drug. Solubility of PABA is increased by complexing with caffeine.
  • 5. Iron complexes with sulfate or carbonate salts. This reduces the G₁ irritation (on oral administration) and irritation at the site of injection.
  • 6. Diagnosis: Technitium 90 in the form of citrate complex, this complex is used in the diagnosis of kidney function and GFR.
  • 7. Preservation of blood: Blood is prevented from coagulation with the help of anticoagulants. These anticoagulants are used in the form of EDTA and citrate complexes.
  • 8. Antidote for metal poisoning.


  • (A) Metal Ion Complexes
    • (a) Inorganic type
    • (b) Chelates
    • (c) Olefin type
    • (d) Aromatic type
      • Pi-complexes
      • Sigma complexes
      • Sandwich compounds
  • (B) Organic Molecular Complexes.
    •  (a) Quinhydrone type
    • (b) Picric acid type
    • (c) Caffein and other drug complexes
    • (d) Polymer type
  • (C) Inclusion Compounds
    • (a) Channel lattice type
    • (b) Layer type
    • (c) Clathrates
    • (d) Mono molecular type
    • (e) Macromolecular type

Metal Complexes

Metal complexes consist of a central atom (metal ion called the substrate) which interacts with an electron-pair donor (ligand), forming coordination bonds between them.

(A) Inorganic Complexes

Ornar had first explained this in 1891. E.g. ammonia molecules in hexamine cobalt III chloride (CO(NH3)6)3 + Cl3.

In this, ligands are said to be coordinated with the cobalt ion. The coordination number of cobalt ions is 6 (six ammonic groups are attached to Co).

Each ligand donates a pair of electrons to form a coordinated bond between itself and the central ion having an incomplete electron shell.

(B) Chelates

Substances having two or more donor groups form a complex with the metal ion, that complex is known as a chelate. They may form ionic, primary covalent, or co-ordinate covalent bonds to form chelates.

When the ligand provides one group for attachment to the central ion, the chelate is called monodentate, molecules with two or three donor groups are called bidentate and tridentate, and EDTA is hexadentate i.e. six donor groups.

These complexes may form a precipitate or water-soluble complex. The ligands, which form soluble complexes, are called sequester agents. e.g. Citric acid, EDTA.

EDTA is used to sequester iron and copper ions so that they cannot catalyze the oxidative degradation of ascorbic acid in fruit juices and drug preparations. EDTA is also used to remove calcium ions from hard water. Chelation is used in the assay of drugs.

Organic Molecular Complex

The organic molecular complex involves the formation of a donor-acceptor type of hydrogen bond between different species (weak forces).

The bonding in molecular complexes, where hydrogen bonds are absent, is considered the involvement of electron donor-acceptor forces.

Many organic complexes are too weak to separate themselves from their solutions as a whole compound. In addition, they are difficult to detect by chemical as well as physical methods. The energy of attraction for such complexes is less than 5 kcal/ml. In these complexes, one molecule polarizes the other resulting in a type of ionic interaction or charge transfer. These molecular complexes are called charge-transfer complexes.

e.g. Iodine forms a 1: 1 charge-transfer complex with tolnaftate. Tolnaftate contains ‘S’ which has a charge which gets transferred to iodine.

(A) Quinhydrone Complexes

If 1: 1 molar concentrations of benzoquinone and hydroquinone are mixed in an alcoholic solution, they yield quinhydrone. This complex is settled as a green crystal. When an aqueous solution is saturated with quinhydrone, the complex dissociates into equivalent amounts of quinone and hydroquinone and is used as an electrode in pH determinations.

The II framework in quinine is electron-deficient and that of hydroquinone is comparatively electron-rich. The interaction between the II framework of the two molecules results in the formation of the quinhydrone 1:1 complex.

(B) Picric Acid Complexes.

Picric acid is a strong acid that reacts with strong bases to form salts and with weak bases to form molecular complexes.

Bateson picrate is a complex of buttes and picric acid (zil proportion) used as a 1% ointment for burns and painful skin abrasions. Picric acid has antiseptic properties and butsin has anesthetic action.

(c) Drug Complexes

 Caffeine can form complexes with several acidic drugs (like sulphonamide or barbiturates). They possess dipole-dipole or hydrogen bonding between the polarized carbonyl groups of caffeine and the hydrogen atom of the acid. A secondary interaction probably occurs between the non-polar parts of the molecules and the resultant complex is squeezed out of the aqueous phase due to the great internal pressure of water.

A complexation of esters is particularly important in pharmacy. Many drugs can form complexes with esters e.g. Amine phenols, ethers, and ketones. There is the occurrence of hydrogen bonding between the nucleophilic carbonyl oxygen and active hydrogen.

(D) Polymer Complexes

The polymers that contain nucleophilic oxygens (polyethylene glycols, polystyrene, CMC, etc.) can form complexes with various drugs. Polymers like carbowaxes, pluronic, and tweens can form complexes with tannic acid, salicylic acid, phenol, etc.

These types of complexes occur in the emulsions, suspensions, and suppositories as incompatibility. This kind of incompatibility exerts some effects on formulation like precipitation, flocculation, delayed absorption, loss of preservative action, etc.

Crospovidone is also able to form complexes with some drugs due to its dipolar character (Acetaminophen, benzocaine, benzoic acid, caffeine, tannic acid).

(c) Inclusion Compounds

Inclusion compounds are also called occlusion compounds. They involve morphological characters of compounds rather than chemical characteristics. One component of the complex is trapped in the open lattice or cage-like crystal structure of the other to yield a stable compound.

It can be considered as a host-guest combination in which one compound (host) forms a cavity in which another molecule of another compound (guest) fits.

(A) Channel Lattice Type

The cholic acids (deoxycholic acid) can form complexes with paraffin, organic acids, esters, ketones, aromatic compounds, ether alcohol, etc. The arrangement of crystals of deoxycholic acid can form a channel into which a guest molecule is fitted. Urea and thiourea crystallize in the channel-like structure, which forms an inclusion complex with alcohols, ketones, organic acids, etc.

(B) Layer Type

In this type, the guest molecule is diffused between the layers of the carbon atom, hexagonally oriented to form alternate layers of guest and host molecules. E.g., Montmorillonite can trap hydrocarbons, alcohols, and glycols between the layers of their lattices.

(C) Clathrates

The clathrates crystallize in the form of a cage-like lattice in which the guest is entrapped. The size of the host and guest is important, particularly information on clathrates. The guest compound may be a solid, liquid, or gas and may be separated from the complex by dissolving, heating, or grinding the clathrate.

Clathrates are prepared by dissolving host substances in a solution of guest followed by crystallization of host, which on crystallization entraps the guest molecules due to difference in the sizes.

(D) Monomolecular Inclusion Compounds

Monomolecular inclusion complexes involve the entrapment of a single guest molecule in a cavity of one host molecule. Monomolecular host structures are represented by cyclodextrins. These are cyclic oligosaccharide compounds containing a minimum of six D-(+)-glucopyranose units attached by a-1, 4 linkages.

Cyclodextrin structure forms a doughnut-shaped ring. The interior of the cavity is relatively hydrophobic because of the CH₂ groups, whereas the exterior is hydrophilic due to the presence of hydroxyl groups. Molecules of appropriate size and stereochemistry get entrapped in the cyclodextrin cavity by hydrophobic interaction by squeezing out water from the cavity.

Inclusion complexes of cyclodextrins with drugs are generally employed to enhance solubility. In addition, they can import stability to the drug. Drugs:- Sulphonamides, tetracyclines, morphine, benzocaine, ephedrine.

(E) Macromolecular Inclusion (Molecular Sieves)

These include zeolites, dextrins, silica gels, and related substances. The atoms are arranged in a 3-dimensional structure to produce cages and channels. Synthetic zeolites can be prepared to have a required pore size focus to separate molecules of different dimensions and they are capable of ion exchange.


Complexes are analyzed for the stoichiometric ratio of ligand to metal or donor to acceptor and for determining a quantitative expression for the stability constant for the complex formation.

Continuous Variation Method

First used by Job. He had shown that addictive properties like spectrophotometric extinction coefficient, dielectric constant, or the square of refractive index could be used for measurement of complexation considering two molecules host and guest have two different dielectric constants. If their dielectric constants are measured and plotted as mole fractions against the dielectric constant (addition) will give a linear curve if complexation does not occur. If a complex is formed, it will not show a linear relationship. The curve will shift either to the maximum or the minimum. The line on a graph shows a break of change in slope that point suggests the 1:1 concentration of complex.

By Spectroscopy

The equimolar solutions for guests and hosts are prepared separately. The absorbance is taken. Then solutions are mixed gradually and absorbance is taken. The observed values at different mole fractions are then subtracted from the corresponding values that would have been expected if the complex was not formed. A zone difference in values indicates no complexation. If there is a difference, then it is plotted against the mole fraction.

pH Titration Method (Potentiometric Method)

It is the most reliable method but can be used only when complex formation involves the solution of glycine that can be titrated against standard NaOH solution. The complexation of the change in the pH of the solution. It is measured by using a potentiometer (pH meter). The cupric ion and glycine to give copper glycine complex is one such example that is accompanied by a change in pH.

Distribution Method

The method of distributing a solute between two immiscible solvents can be used to determine the stability constant for certain complexes.

The complexation between iodine and potassium iodide can be used as an example of this method.

Solubility Method

The complex is more soluble than the drug itself. This fact is utilized to determine complexation.

According to this method, excess quantities of the drug are placed in well-stoppered containers, together with a solution of the complexing agent in various concentrations, and the bottles are agitated at a constant temperature until equilibrium is attained. Aliquot portions of the supernatant liquid are removed and analyzed.

The solubility of the drug increases as the complexing agent is added due to the formation of the solution complex. At one point the solution becomes saturated for both the

drug and the complex. As the addition of the complexing agent is continued, the complex continues to form and precipitates from the saturated solution.


Complexation influences drug action in both a positive, as well as a negative way, which means it increases or may decrease the effectiveness of the drug.

  • 1. Complexation of iron with sulfate and carbonate salt increases the absorption of iron, also reduces GI irritation.
  • 2. Decrease in drug action due to decrease in drug absorption. Interference in intestinal absorption of tetracycline due to complexation with calcium.
  • 3. Increase in action due to increased absorption intestinal absorption of tetracyclines can be increased with the addition of citric acid or glucosamine use of tetracycline phosphate complex. EDTA also increases the absorption of some drugs (e.g. Quaternary) ammonium compounds.
  • 4. Influence on preservative action of drugs. Many preservatives can strongly interact with materials such as suspending and emulsifying agents, excipient in the dosage form. Such increasing may reduce the concentration of unbound preservatives to such a level that it no longer remains effective as an antimicrobial agent.
  • 5. Drug action can be enhanced by increasing solubility.

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