Complexation: Methods of Preparation and Analysis, Applications and MCQs for GPAT, NIPER, Pharmacist and Drug Inspector exam

Complexation: Methods of Preparation and Analysis, Applications and MCQs for GPAT, NIPER, Pharmacist and Drug Inspector exam


Methods of Analysis:

A determination of the

(1) stoichiometric ratio of ligand to metal (or donor to acceptor) and the

(2) stability constant for complex formation are important in the study and application of complexes.

Several methods for estimation of these parameters have been developed:

  1. Method of continuous variation
  2. pH Titration method
  3. Distribution Method
  4. Solubility Method
  5. Spectroscopy                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      1. Method of Continuous Variation- The stoichiometry of a metal–ligand complexation reaction can be determined by three methods:

(A) Job’s method

(B) Mole ratio method

(C) Slope ratio method

  • In Job’s method, a series of solution are prepared with variable ratios of metal and ligand but with fixed total concentrations (the total ligand + metal concentration are the same for all solutions).

An additive property that is proportional to the concentration of the formed complex (e.g. absorbance) is measured and plotted against the mole fraction from 0 to 1 for one of the components of a mixture (e.g. Ligand).

  • In the mole ratio method, a series of solutions are prepared with a fixed amount of the metal and a variable amount of the ligand (or vice versa). An additive property that is proportional to the concentration of the formed complex (e.g. absorbance) is measured and plotted against the mole ratio of the component with the variable amounts (e.g. Ligand). Unlike Job’s method, the mole-ratio method can be used to investigate the formation of higher complexes in solution.
  • In the slope-ratio method two sets of solutions are prepared:

The first set of solutions contains a large excess of metal and a variable concentrations of ligand (all the ligand reacts in forming the metal–ligand complex). The absorbance of the formed complex is plotted against the ligand concentration and the slope of the line is determined.

A second set of solutions is prepared with a large excess of ligand and a variable concentration of metal (all the metal reacts in forming the metal–ligand complex). The absorbance of the formed complex is plotted against the metal concentration and the slope of the line is determined.

  1. pH Titration method- pH titration method can be used whenever the complexation is accompanied by a change in pH.
  2. Distribution Method- The method of distributing a solute between two immiscible solvents can be used to determine the stability constant for certain complexes.
  3. Solubility Method- Solubility method is the most widely used method is the study the inclusion complexation. According to the solubility method, excess quantities of the drug are placed in well-stoppered containers, with a solution of the complexing agent in various concentrations. The bottles are agitated in a constant temp. bath until equilibrium is reached. Then, the supernatant liquid are removed and analyzed to obtain the total drug concentration. The concentration of the drug is plotted against the concentration of caffeine to obtain a curve that can be used to calculate the stability constant. This method is used for charge transfer complexes.
  4. Spectroscopy- The UV spectroscopy is used extensively in determining rate constants, equilibrium constants, acid-base dissociation constants etc for chemical reactions.



  • Physical state: Complexation process improves processing characteristics by converting liquid to soild complex.
  1. β-cyclodextrine complexes with nitroglyerine.
  • Volatility: Complexation process reduces Drug volatility for following benefits;
  1. Stabilise system.
  2. Overcome unpleasant odour (I2 complexes with Poly Vinyl Pyrollidone, PVP).
  • Solid state stability:
  1. Complexation process enhances solid state stability of drugs.
  2. β-cyclodextrine complexes with Vitamin A and D.
  • Chemical stability:
  1. Complex formation inhibit chemical reactivity (Mostly inhibit).
  2. The hydrolysis of Benzocaine is decreased by complexing with Caffeine.
  • Solubility:
  1. Complexation process enhances solubility of drug.
  2. Caffeine enhances solubility of PABA (Para Amino Benzoic Acid) by complex formation.
  • Dissolution:
  1. Complexation process enhances dissolution of drug.
  2. β-cyclodextrine increases the dissolution of Phenobarbitone by inclusion complex.
  • Partition co-efficient:
  1. Complexation process enhances the partition coefficient of certain drugs.
  2. Permanganate ion with benzene.
  • Absorption and Bioavailability:
  1. Complexation process reduces the absorption of Tetracycline by complexing with cations like Ca+2, Mg+2 and Al+3 .
  2. Complexation process enhances the aborption of Indomethacine and Barbiturates by complexing with β-cyclodextrine.
  • Reduced toxicity:
  1. β-cyclodextrine reduces ulcerogenic effects of Indomethacine.
  2. β-cyclodextrine reduces local tissue toxicity of Chlorpromazine.
  • Antidote for metal poisoning: BAL (British Anti Lewisite) reduces toxicity of heavy metals by complexing with As,Hg and Sb.
  • Drug acting through Metal Poisoning: 8-Hydroxy quinoline complexes with Fe exhibit greataer antimalaria activity.
  • Antitubercular activity: PAS (Para Amino Salysylic acid) complexes with Cupric ion exhibit greater Antitubercular activity.
  • Development of Novel Drug delivery system: The Comlexation of drug with polymers used in the formulation of sustained drug delivery device.
  • Assay of Drugs: The complexometric titrations are used to assay of the drug containing the metal ion.
  • As therapeutic Tools: Both CITRATES and EDTA are used as preservation of blood as anti-coagulant.
  • As Diagnostic agent: Ta90 complexes with citrate are used for diagnosis of Kidney and measurement of Glomerular Filtration Rate.

Multiple choice questions (MCQs)

1.EDTA is an example of

a)Unidentate ligand

b)Bidentate ligand

c)Tetradentate ligand

d)Hexadentate ligand

2.Which of the following is not a multidentate ligand?




d)Dimethyl glyoxime

3.The cytotoxic drug cisplatin is an example of


b)Olefin complex

c)Inclusion complex

d)Organic molecular complex

4.Which of the following is a multidentate ligand?



c)Dimethyl glyoxime

d)Povidone iodine

5.The stability constant is increased in complexation if the ligand has

a)High solubility

b)Bulky group

c)High electron density on the donor

d)Low ionization potential

6.Desferoxamine can be categorized as



c)Inclusion complexes

d)Organic molecular complexes

7.In a metal ion complex, the metal ion and ligand respectively are

a)Lewis acid and base

b)Lewis base and acid

c)Nucleophile and electrophile

d)Donor and acceptor

8.Glycine forms complex with cupric ions only at the pH range:

a)About neutral



d)Both acidic and alkaline

9.Complexation between metal and ligand is possible as 1:1 and 1:2. Statistically speaking the formation of 1:1 complex favored over 1:2 complex by

a)Four times

b)Same extent

c)Sixteen times

d)Two times

10.Iodine forms a complex when it is dissolved in an organic solvent

a)Carbon tetrachloride




11.Which one of the following compounds electron donor does strongly interact with electron acceptor in forming a complex?


b)Hexamethyl benzene


d)Trimethyl benzene

12.Pick up the electron acceptor, which is capable of forming organic molecular complexes

a)Carbon tetrachloride


c)Picric acid


13.The role of hydrogen bonding between species in complexes can be highlighted when the solvent employed is

a)Non polar




14.Which of the following is not classification of organic molecular complex

a)Quinhydrone typr

b)Caffeine complex

c)Acetic acid type

d)Polymeric complex

15.Following is type of metal complexes


b)Quinhydrone type


d)Channel type


  1. d) Hexadentate ligand
  2. b) ammonia
  3. d) Organic molecular complex
  4. c) Dimethyl glycosime
  5. a) high solubility
  6. b) ligand
  7. d) Donor and acceptor
  8. d) Both acidic and alkaline
  9. a) four times
  10. d) toluene
  11. b) hexamethylbenzene
  12. c) picric acid
  13. a) non polar
  14. c) acetic acid type
  15. a) chelates


1. GAURAV KUMAR JAIN – THEORY & PRACTICE OF PHYSICAL PHARMACY, 1st edition 2012 Elsevier, page no. 177-189.

2. Martins Physical Pharmacy, 6th edition 2011, page no. 382-398.

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