COMPLEXATION AND

PROTEIN BINDING—UNIT IV
 INTRODUCTION TO -
Complexation
 Complexation is a process of complex formation wherein the complex formed constitutes a separate
class of compounds which results from some type of interactions among different chemical species.
 Complexation can be broadly defined as an association of two or more species capable of
independent existence. •
 Complexes or coordination compounds, result from a donor-acceptor mechanism or Lewis acid-
base reaction between two or more different chemical constituents.
 Any non-metallic atom or ion, whether free or contained in a neutral molecule or in an ionic
compound, that can donate an electron pair may serve as the donor (Lewis base).
 The acceptor (Lewis acids) or constituent that accepts the share in the pair of electrons, is frequently
a metallic ion, although it can be a neutral atom.
 A coordination complex is the product of a Lewis acid-base reaction in which the neutral molecules
or anions (called as ligands(e.g. water,ammonia,chloride ions) ) bond to a central metal atom(or
ion) by coordinate or covalent bonds.
 Contd……..

 Complex formation has been used to alter the physicochemical & biopharmaceutical properties of
drug. It might alter the stability, solubility, molecular size, partition coefficient & diffusion coefficient.
 Complexes possess some properties which are different from those of it’s components.
 Complex behavior is observed in number of situations including the handling of dosage forms, and
thus found to be of interest in the field of pharmacy.
INTERMOLECULAR FORCES OF INTERACTIONS
INVLOVED IN COMPLEX FORMATION
BROAD CLASSIFICATION OF
COMPLEXES

COMPLEXES
METAL

ORGANIC
MOLECULAR
INCLUSION
COMPOUNDS
CLASSIFICATION OF METAL COMPLEXES

INORGANIC TYPE CHELATES

METAL
COMPLEXES

OLEFIN TYPE AROMATIC TYPE

CLASSIFICATION OF ORGANIC
MOLECULAR COMPLEXES

DRUG CAFFEINE POLYMER TYPE

ORGANIC
MOLECULAR
COMPLEXES

PICRIC ACID TYPE QUINHYDRONE TYPE

CLASSIFICATION OF INCLUSION
COMPOUND BASED COMPLEXES

CHANNEL TYPE LAYER TYPE

INCLUSION
COMPOUNDS
BASED COMPLEXES

MONOMOLECULAR TYPE/
CLATHRATES TYPE
MACROMOLECULAR TYPE
 BENEFICIAL EFFECTS OF
COMPLEXATION

 Drug complexation can lead to beneficial properties such as enhanced aqueous solubility
( e.g. Theophylline complexation with ethylenediamine to form aminophylline) and stability
(e.g.inclusion complexes of labile drugs with cyclodextrins.

 Complexation may also aid in optimizing the drug delivery systems (e.g, ion-exchange resins )
and may affect the distribution in the body after systemic administration as a result of protein
binding.
 UNWANTED EFFECTS OF COMPLEXATION

 Decreased drug absorption due to complexation

• E.g:
- Impairment of antibiotic absorption after oral administration involve formation of complex between
Neomycin / Kanamycin & Bile salt.
-Interference of calcium ions with the intestinal absorption of Tetracycline.
-Coadministration of some drugs with antacids decreases absorption from the gastrointestinal tract.

 Increased excretion of certain drugs due to complexation

- For some drugs ,complexation with hydrophilic compounds may enhance the excretion rate .

 Poor solubility due to complexation

- For example, the aqueous solubility of tetracycline decreases substantially when it complexes with
calcium ions.
 CLASSIFICATION OF METAL COMPLEXES

INORGANIC TYPE CHELATES

Metal ion includes central atom as drug
and it interacts with the base ( electron pair
donor,ligand) forming co-ordination bonds
METAL between the species.
COMPLEXES

OLEFIN TYPE AROMATIC TYPE

Inorganic type
Chelates
  The aqueous solutions of metal ions like
Pt,Fe,Pd,Hg and Ag can absorb olefins
such as ethylene to yield the water
Olefin ttype soluble complexes.
 These are used as catalyst in the
manufacture of bulk drugs and analysis
of drugs
 Pi(π)complexes :–Aromatic bases
(Benzene,toluene and Xylene ) form the pi-
bond complexes with metal ions like Ag by
Lewis Acid Base Reactions.
Sigma (σ) complexes :
e.g. Sigma bond formation between metal
Aromatic type ions and the carbon atom of aromatic ring.
“ Sandwich “ compounds:
These are the stable ones ,in this type the
delocalized covalent bond between the
d-orbital of a transition metal and a molecular
orbital of the aromatic ring is involved.
e.g. Ferrocene (bisdicyclopentatedyl iron)
CLASSIFICATION OF ORGANIC
MOLECULAR COMPLEXES

DRUG CAFFEINE POLYMER TYPE

ORGANIC
MOLECULAR
COMPLEXES

PICRIC ACID TYPE QUINHYDRONE TYPE

 ORGANIC MOLECULAR
COMPLEXES-INTRODUCTION
In This Type Of Coordination Complexes, Components Are
Organic Molecules And These Are held Together By Weaker
Forces(London dispersion forces, dipole-induced dipole
interactions) Or Hydrogen Bonding.
The same components can also form molecular
compounds when experimental conditions are altered.
Hence, it’s mandatory to undertand the difference
between molecular compounds and molecular complex.
In this type, as observed in the inorganic metal complexes,
the electron donor-acceptor mechanism is involved.
The energy of attraction is less than 5kcal/mol
The bond distance between the components is more than
3.0A°. Hence covalent bond is not involved.

These complexes are further classified as

1. Donor-acceptor type
2. Charge transfer type
Difference between :
Molecular complex and compound

Molecular complex Molecular compound

 Reactions occur in cold conditions
 Weaker forces of interactions are
involved.
 Complexes cannot be separated from
solutions. Hence difficult to identify
them by physical or chemical means.
 Reactions occur at elevated
temperatures.
 Stronger electrostatic intercations are
involved.
 They can be separated from solutions.
 DONOR-ACCEPTOR TYPE CHARGE TRANSFER TYPE
In this type, one molecule polarizes the other . e.g.
Bond is between uncharged species,but polar groups of nitrobenzene induce a dipole in a
lacks charge transfer readily polarizable benzene molecule.

Ionic interactions are observed between the species

Stability– Dipole –dipole And London and the electrostatic interactions lead to formation of
dispersion forces are responsible. the complex. Intemolecular bonding is quite higher
than the donoracceptor type.

e.g. of Molecular complex of such type: N-

dimethyl aniline and 2,4,6-trinitro anisole Stability: Resonance is the main contributor
reacts in cold condition

Stearic factor is also desirable for the

 QUINHYDRONE COMPLEXES

Mechanism involved:
Overlapping of Pi
It is obtained by mixing alcoholic solutions of equimolar framework of
quantities of benzoquinone and hydroquinone.
molecules.
Hydrogen bonding
stabilizes the
Complex appears as green crystals association.

This complex can dissociate into individual

components in an aqueous solution when saturated.

It is used as an electrode in pHdetermination.

 POLYMER COMPLEXES

Many pharmaceutical additives such as Polyethylene glycols (PEGs), carboxymethyl cellulose (CMC)
contain nucleophilic oxygen. These can form complexes with various drugs.
A few examples are : Polymers : carbowaxes, pluronics
Drugs: tannic acid, salicylic acid, phenols

This complexation produces incompatabilities in the dosage form such as

suspensions, emulsions and ointments.

Incompatabilities may delay the absorption, loss of preservative action and

produce undesirable physical, chemical and pharmacological effects.

Polymer containers-drug product interactions may also result in loss of

active component in liquid dosage forms .
 PICRIC ACID COMPLEXES

In this type, the antiseptic activity of picric acid is combined with

the anaesthetic activity of butesin.

Butesin picrate is used as 1% ointment for burns and painful skin

abrasions.

Picric acid being a strong acid, forms organic molecular

complexes with weak bases, whereas it combines with strong
bases to yield salts.

Picric acid forms complex many carcinogenic agents. The

complex stability constant is indicative of the magnitude of
carcinogenic activity. Higher the constant greater is the
carcinogenic activity of ligand.
DRUG AND CAFFEINE COMPLEXES
CLASSIFICATION OF INCLUSION
COMPOUND BASED COMPLEXES

CHANNEL TYPE LAYER TYPE

INCLUSION
COMPOUNDS
BASED COMPLEXES

MONOMOLECULAR TYPE/
CLATHRATES TYPE
MACROMOLECULAR TYPE
 INCLUSION COMPLEXES

• Also called as Occlusion compounds in which one of the compound ( the host) forms a cavity
or, in the case of crystal , the open lattice of cage like crystal structure and the guest molecule
trapped into this .

• In this type, the interaction is not due to chemical reactivity ,but is because of the favourable
molecular architecture.

• The force of interactions are weaker.

 CHANNEL LATTICE TYPES

Applications
• For the separation of optical
Well known of this type : Starch – Iodine solution
isomers. e.g. di-terpineol resolved
Here, the iodine molecules are trapped within the spirals of
byuse of digitonin.
the glucose molecules.
• Interference in the analysis of
dermatological creams shown by
Channel forming substances(host):
the long chain compounds is
Deoxycholic acid, urea, thiourea, amylose etc…
. removed by use of this type of
Guest agents:
complexes.with urea.
Paraffins, acids, esters, ethyl alcohol, dioxane etc…

Since channels are formed by crystallization of the host

molecules, the guest components usually are long,
unbranched straight chain compounds.
 LAYER TYPE

• Compounds such as clays and montomorillorite

(constituent of bentonite ) can entrap
hydrocarbons,alcohols and glycols.

• These form alternate monomolecular (monoatomic)

layers of guest and host.

• The use of these complexes are currently limited.

• They may be useful for catalysis on account of a

large surface area.
 CLATHRATES TYPE

Application

Synthetic metal silicates known to be

used as molecular sieves are used to
Warfarin sodium USP is a clathrate of water and isopropyl alcohol. It store gaseous ,volatile and toxic
is available as white crystalline powder. substances by the mechanism of
clathrates.
During crystallization , certain substances form a cage like lattice in The clathrate guest molecule can be
which the coordinating compound is entrapped. later removed by a simple physical
process.
For e.g. hydroquinone molecules crystallises in the cage like
structure with hydrogen bonding.
The holes have a diameter of 4.2 A° and permit the entrapment of
small molecules such as methyl alcohol, carbondioxide and
hydrochloric acid.
MONOMOLECULAR INCLUSION
COMPLEX