Introduction and Classification of Complexation, Applications and Methods of Analysis : Pharmaguideline -->

Editable Pharmaceutical Documents in MS-Word Format


Introduction and Classification of Complexation, Applications and Methods of Analysis

Complexation interaction, Classification of complexation, Inclusion complexes, Applications of complexations, Method of analysis.


As defined by the IUPAC, complex molecules may include bonds that are in most cases explained by classical valency theories between atoms, but one or more of these bonds may be anomalous in some way. Chemistry forces resulting from intermolecular interactions Covalent bonds Hydrogen bonds Vanderwall's forces Ion-dipole, dipole-dipole, dipole-induced dipole complexes Different solubility, conductivity, partitioning, chemical reactions.

Physicochemical properties change as a result of chemical and physical complexity.
  1. Theophylline is soluble in ethylenediamine (e.g., complexes with aminophylline derived from ethylenediamine)
  2. Including cyclodextrins in labile drugs will increase stability.
  3. Tetracycline with calcium forms an unabsorbable complex with Ca ions.
  4. A pharmacokinetic model (e.g., binding to proteins, renal excretion)
  5. A change in drug-receptor binding may affect pharmacodynamics (e.g., causing biological activity to change).

Complexation interaction

The interactions between molecules can be either coordinate bonds or the following:
  • Dipolar forces
  • Charge transfer
  • Van der Waals forces
  • Hydrophobic interactions
  • Hydrogen bonding
  • Electrostatic forces


Co-ordination complex - An electron coordination complex, composed of molecules of donor and acceptor molecules, results from Lewis acid-base reactions.

Atoms or molecules of an anion (called ligands) are bound to a central atom (or ion, which serves as a coordination center).

Co-ordination complex
  • Metallic ion
  • Central atom
  • Organic gr with free orbital (Lewis acid)
  • Non-metallic atom
  • Ligand gr
  • Ions and neutral molecules (Lewis base)

Classification of complexation

It is possible to categorize complexes roughly into three classes based on the type of acceptor substance:

Metal ion complex

Molecular complexes are formed by coordinating one or more transition-metal ions (e.g. copper, nickel, cobalt) to one or more counterions in the presence of one or more molecules. In this case, the ions or molecules directly bound to the metal are called ligands. Examples of these include Cl–, NH3, H2O, Br–, I–, CN–, etc. An ion's coordination number measures how many ligands it has bound to it. Coordination's usually determined the geometry of a complex.

Inorganic type- Werner postulates:

  1. Secondary valences (coordinates) differ from primary (ionic) valences.
  2. The same valence type can be held by either type of valence or by both types of valences for the same anion/radical/molecule.
  3. The number of non-ionic valences (co-ordination number) of a central atom is a given.
  4. Atoms that are not coordinated are located in the second sphere or the ionization sphere, whereas those that coordinate is located in the first sphere or the coordination sphere.
  5. Non-ionic valences can be satisfied by neutral molecules/ions.
  6. Non-ionic valences occupy specific spatial positions. Example - Ionization sphere Coordination sphere Cl2 Substrate [Co Cl (NH3)5].
  7. Chelates - The term chelates refers to groups of metal ion complexes that combine one or more metal ions with two or more donor groups. There are three types of ligaments: di-dentate, tridentate, and polydentate. Hexadentate - The hexadentate structure of ethylenediaminetetraacetic acid (EDTA) has six points for attachment of metal ions (four:0 and two: N). Sequestering – Suppressing a metal's properties without removing it from the solution is known as sequestering. Sequestering agent - A sequestering agent forms a stable, chelating metal compound in the presence of water, such as chlorophyll or hemoglobin. These complexes are formed when a substrate/ligand provides 2 or more donor groups for a metal ion to combine with.
  8. Olefin type - Acid-base reactions involving olefins under Lewis conditions. These complexes can be used as catalysts during the manufacturing process for bulk drugs, intermediates, and drug analysis.

Organic molecular complexes

A ligand and a substrate form an organic molecular complex when they interact noncovalently. These interactions can be caused by van der Waals forces, charge transfers, hydrogen bonds, or hydrophobic interactions.
  1. Complexes Mechanism of the drug-caffeine complex
  2. A dipole-dipole force/ hydrogen bonding occur between acid (H) atoms and caffeine carboxyl groups.
  3. Nonpolar substances interacting with each other Ex: Caffeine + Benzocaine. Acidic substances (benzocaine, procaine) interacting with caffeine
  4. Polymer type - PEG/CMC polymers + drugs (tannic acid/salicylic acid/phenols) + polymers with nucleophilic oxygen
Disadvantages -
  1. Various types of suspensions, emulsions, ointments are not compatible with each other.
  2. Compounds (polymers with nucleophilic oxygen such as PEG or CMC) + molecules (such as tannic acid, salicylic acid, and phenol)
  3. Picric acid type - Acid containing picric acid, a strong acid, plus weak base complexes containing picric acid. Example: BUTESIN PICRATE 1% ointment containing Picric acid (antiseptic) and Butesin (anesthetic) used on burns and abrasions.
Disadvantages - Carcinogenic Agents eSalt + Picric acid are disadvantages. PICRIC ACID (strong acid) + WEAK BASIS = PICRIC ACID (strong acid) + STRONGER BASIS.

Quinhydrone type - Towards the formation of Quinhydrone complexes (green crystals), alcohol solutions of Hydroquinone and Benzoquinone are equimolar. Atomic electrons overlap. The formation of hydrogen bonds in stabilizing complexes Applications - Used as an electrode to determine pH levels.

Inclusion complexes

Included in an inclusion complex are molecules of one chemical (the 'host') that are entrapped by molecules of another chemical (the 'guest'). There are generally no adhesive forces between molecules of these complexes, so they are also known as no-bond complexes.

1. Channel lattice-type - There are four lattice types for channels: deoxycholic acid, urea, thiourea, and amylose (tubular channels). Paraffin, esters, acids, and ethanol are guests (long, straight chains). The starch and iodine solutions (the hosts) and the urea-methyl α -lipolate solution (the hosts) are examples.
Applications -
  • Digitoxin is used to separate Dextro and Levo-terpineol isomers.
  • The urea complexation of long-chain compounds can interfere with the analysis of dermatological creams.
2. Layer type - A Layer type compound (or intercalation compound) is made up of layers of carbon atoms where the guest molecule is positioned between them, to form alternate layers of the guest and host molecule. Bentonite, for example, is composed primarily of Montmorillonite, which can trap hydrocarbons, alcohols, and glycols within its layers. Intercalated interlayer compounds are also possible in graphite.

3. Clathrates - A clathrate is any compound that crystallizes as a lattice in which its coordinating compound is encased. As part of the official FDA list, warfarin sodium is available in the crystalline clathrate form containing isopropyl alcohol and water. The process of separating optical isomers can be achieved using clathrates. The process of separating optical isomers can be achieved using clathrates.

4. Mono-molecular type - In monomolecular inclusion complexes, guest molecules are entrapped within the cage-like structure formed by a host molecule. Multiple oligosaccharides are formed from sugar molecules bound together by chains (cyclic oligosaccharides). Expressed as a, þ, and ç cyclodextrins, they contain 6, 7, and 8 units of glucose.

Applications of complexations

  • Drugs can be absorbed and bioavailable more quickly and efficiently if these complexes are present.
  • Drug solubility and dissolution rate can be enhanced or inhibited by these complexes. Complexes containing caffeine and gentisic acid mask caffeine's bitter flavor.
  • Increasing solubility - The increasing solubility of fruit juices and drugs (ascorbic acid) is a result of oxidative degradation of iron and copper elements. Mix EDTA and Fe/Cu stable chelate.
  • Purification of hard water - EDTA-Ca+2 (ppt) + hard water (Ca+2) + filter, Pure water.
  • Blood coagulation - The combination of blood (Ca+2) + EDTA/Citrates/Oxalates. Thrombin formation can be prevented the blood does not clot.
  • Drug analysis - At pH 4.5-4, a solution containing procainamide and cupric ion (1:1). Procainamide in the presence of cupric ions (1:1) at pH 4.5-4. Complexes of different colors. Colorimetry is used for detection.

Method of analysis

Two parameters are estimated.
1. A stoichiometric equation for Ligand: Metal/ Donor: Acceptor
2. Coefficient of stability for the complex.

1. pH titration method
If pH is changed by complexation, this method will work. Experiment:
  • The pH of 75 ml of glycine solution was measured after titration with NaOH.
  • pH is measured after titrating the glycine solution with the Cu+2 complex and NaOH. (Protons are released during complexation and the pH decreases.)
Alkali amount = concentration of bound ligands.Stability constant -

Log β = 2 X p [A] p [A] = pKa - pH - log ([HA] initial - [NaOH])

2. Method of continuous variation
  • The Refractive index
  • Dielectric constant
  • The physical characteristics of an animal are described by its spectrophotometric extinction coefficient. Complicated A+B Physical properties share additive values while Complexation A+B Physical properties have different values.
  • Physical properties can be either maximum or minimum due to complexation. Check the concentration of individual species at maximum and minimum points. Establish stoichiometry for the species.
3. Solubility method
The solubility of mixtures can increase or decrease when they form complexes. In experiments, parameters are estimated by the following:
  • Coffee (complexing agent) is taken at various concentrations
  • Filter, agitate and analyze drug content after adding PABA.
4. Distribution method
The coefficient of partition / The change of distribution due to the complexation process. To determine the stability constant, two experiments are conducted.
Get subject wise printable pdf documentsView Here

Ankur Choudhary is India's first professional pharmaceutical blogger, author and founder of, a widely-read pharmaceutical blog since 2008. Sign-up for the free email updates for your daily dose of pharmaceutical tips.
.moc.enilediugamrahp@ofni :liamENeed Help: Ask Question

1 comment: Post Yours! Read Comment Policy ▼

Please don't spam. Comments having links would not be published.

Popular Categories

QA SOPs QC SOPs Micro SOPs HVAC Production SOPs Stores SOPs Checklists Maintenance SOPs HPLC Sterile GLP Validation Protocols Water System GDP Regulatory Maintenance Calibration Warning Letters Education B.Pharmacy
Resume Pro


Show All ❭❭Jobs by PharmaJobs

Follow Pharmaguideline



Editable Pharmaceutical Documents in MS-Word Format. Ready to use SOPs, Protocols, Master Plans, Manuals and more...




Pharmaceutical Updates

✔ Worldwide Regulatory Updates
✔ Pharmaceutical News Updates
✔ Interview Questions and Answers
✔ All Guidelines in One Place


Recent Posts