Complex Formation

Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D

Department of PharmaceuticsFaculty of Pharmacy

Omer Al-Mukhtar UniversityTobruk, Libya.

E-mail: nanjwadebk@gmail.com

2014/03/16 1Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

CONTENTS

1. Definition

2. Metal Complex

3. Organic Molecular Complex

4. Inclusion Complex

5. Methods of Analysis

6. Continuous variation

7. Spectroscopy methods

8. Distribution methods

9. Protein Binding

10. Drug Action

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Definition

• Complex compounds are defined as those molecules in which most of the bonding structures can be described by classical theories of valency between atoms, but one or more of these bonds are somewhat anomalous(different).

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Metal Complex

• In this type, metal ion constitutes the central atom (substrate) and interacts with a base (electron-pair donor, ligand).

• This type of interaction leads to the formation of coordination bonds between the species.

Classification of metal complex

1. Inorganic types

2. Chelates

3. Olefin types2014/03/16 4Faculty of Pharmacy, Omer Al-Mukhtar University,

Tobruk, Libya.

1. Inorganic types• In inorganic metal complexes, the ligand provides

only one site for binding with metal.

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2. Chelates• Chelates are a group of metal ion complexes in which

a substance (ligand) provides two or more donor groups to combine with a metal ion.

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EDTA: Ethylenediamine tetraacetic acid

3. Olefin types

• These types of complexes are used as catalysts in the manufacture of bulk drugs, intermediates and in the analysis of drugs.

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Organic Molecular Complex

• In this type of coordination complexes, components are organic molecules and these are held together by weaker forces or hydrogen bonding.

Classification of organic molecular complex

1. Drug and caffeine complexes

2. Polymer types

3. Picric acid types

4. Quinhydrone types

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1. Drug and caffeine complexes• Drugs such as benzocaine, procaine and tetracaine

form complexes with caffeine.

• A number of acidic drugs are known to form complexes with caffeine.

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2. Polymer types

• Many pharmaceutical additives such as polyethylene glycols (PEGs), carboxymethyl cellulose (CMC) contain nucleophilic oxygen. These can form complexes with various drugs.

E.g. Polymers: carbowaxes, pluronics etc.

Drugs: tannic acid, salicylic acid, phenols etc.

Carboxyl methylcellulose (CMC) + Amphetamine = poorly absorbed complex (tablet additive – drug interaction)

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3. Picric acid types• Picric acid, being a strong acid, forms organic

molecular complexes with weak bases, whereas it combines with strong bases (anesthetic activity of butesin) to yield salts.

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4. Quinhydrone types• The molecular complex of this type is obtained by

mixing alcoholic solutions of equimolar quantities of hydroquinone and benzoquinone.

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Inclusion Complex

• These complexes are also called occlusion compounds in which one of the components is trapped in the open lattice or cage like crystal structure of the other.

Classifications of Inclusion complex

1. Channel types

2. Layer types

3. Clathrates

4. Monomolecular types2014/03/16 13Faculty of Pharmacy, Omer Al-Mukhtar University,

Tobruk, Libya.

1. Channel types

• Channels are formed by crystallization of the host molecules, the guest component is usually limited to long, unbranched straight chain compounds.

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2. Layer types

• Compounds such as clays, montomorillorite (constituent of bentonite), can entrap hydrocarbons, alcohols and glycols.

• They form alternate monomolecular (monoatomic) layers of guest and host.

• Their uses are currently quite limited; however these may be useful for catalysis on account of a larger surface area.

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3. Clathrates• It is available as white crystalline powder, during

crystallization, certain substances form a cage-like lattice in which the coordinating compound is entrapped.

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4. Monomolecular types• Monomolecular inclusion compounds involve the entrapment

of a single guest molecule in the cavity of one host molecule.

• Most of the host molecules are cyclodextrins.

• The interior of the cavity is relatively hydrophobic, whereas the entrance of the cavity is hydrophilic in nature.

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Methods of Analysis

• The analysis of complexes involves the estimation of two parameters.

1. The stoichiometric ratio of ligand-to-metal or donor-to-acceptor.

2. Stability constant of the complex.

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Methods of Analysis

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Continuous variation

• The physical properties, such as dielectric constant, refractive index and spectrophotometric extinction coefficient, are characteristics of a particular species.

• When there is no complexation between these species (A and B), the value of property is additive.

• This particular behaviour is represented in figure as dotted line. In case of complexation, these properties change, i.e. additive phenomena do not hold good.

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Continuous variation

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Spectroscopy methods

• The UV spectroscopy is used extensively in determining rate constants, equilibrium constants, acid-base dissociation constants etc for chemical reactions.

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Distribution methods

• The distribution behaviour of a solute between two immiscible liquids is expressed by distribution coefficient or partition coefficient.

• When a solute complexes with an added substance, the solute distribution pattern changes depending on the nature of a complex.

• A set of such experiments provides data for the estimation of complex equilibrium stability.

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Protein Binding • The phenomenon of complex formation with proteins

is called as protein binding of drugs.

Protein binding may be divided into:

1. Intracellular binding: These receptors with which drug interact to show response are called as primary receptors.

2. Extracellular binding: These receptors are called secondary or silent receptors.

2014/03/16 24Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

Equilibrium Dialysis Method

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Dynamic Dialysis Method

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Drug Action

• Protein binding inactivates the drug, because sufficient concentration of drug cannot be built up in the receptor site for action. Example is naphthoquinones.

• Certain drugs though bind to proteins, still retain the drug activity. Examples are penicillins and sulfadiazine.

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References

• Text book of Physical Pharmaceutics by Dr. CVS Subrahmanyam.

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THANK YOUe-mail: nanjwadebk@gmail.com

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