COMPLEX

• A co-ordination compound (complex) is a product

formed by donor-acceptor mechanism or acid-base
reaction. Any nonmetallic atom or ion that can donate a
pair of electrons serves as donor . A metallic ion that
accepts a pair o electrons is called acceptor. In
coordination compound a number of molecules or ions
are attached to the central atom or ion is greater than
the number possible on the basis of electrovalent or
covalent bonding.” OR “ Complex compounds are
defined as those molecules in which most bonding
structures can be described by classical valence
theories between atoms, but one or two or more of
these bonds are somewhat anamolous.”.
 COMPLEXATION
• Complexation is the association between two
or more molecules to form a non- bonded
entity.
• Used to characterize covalent or non covalent
interactions between two or more compounds
that are capable of independent existance
Contd.

• The intermolecular forces involved in complex

formation are the covalent bond, the vanderwall
forces, dipole-dipole interactions & H- bonding, etc.
• Complexes are formed because of the donor-
acceptor mechanism or Lewis acid base reaction
between two or more different chemical
constituent.
• Donor is the neutral molecule or ion of non- metallic
substance, that can donate lone pair of electrons.
Acceptor is the metallic ion, can be neutral.
Contd.

• Once complexation occurs, the physical and

chemical properties of the complexing species
are altered. These properties include
solubility, stability, partitioning, energy
absorption and emission, and conductance of
the drug 
 APPLICATIONS
• 1. Drug complexation can lead to beneficial
properties such as enhanced aqueous solubility (e.g.
theophylline complexation with ethylenediamine to
from aminophylline).
• 2. Increase in stability (e.g. inclusion complexes of
labile drugs with cyclodextrins)
• 3. Complexation also can aid in the optimization of
delivery systems (e.g. ion-exchange resins) and affect
the distribution in the body after systemic
administration as a result of protein binding.
Contd..
• 4. Drug complexation with hydrophilic compounds also
can enhance excretion.
• 5.Chelating agents are used as antidote in heavy metal
poisoning.
• 6. Solubility enhancement of some drugs.
• 7. Stability enhancement
• 8. As therapeutic agent
• 9. In diagnosis of conditions such as kidney function,
GFR, etc.
• 10. Assay of drug by complexometric titration.
• 11. Development of novel drug delivery systems.
 Classification of complexation: 
•  (A) Metal complexes or co-ordination complexes :
Contain a central metal atom or ion that is bonded to
one or more ligands.
• Can be neutral, positively charged or negatively
charged.
• Co-ordination number- ‘the total number of ligands
attached to a central metal atom or ion‘ e.g. [Cu
(NH3)4]
• 1. Inorganic type
• 2. Chelates
• 3. Olefin type
• 4. Aromatic type 
 (B) Organic molecular complexes

• 1. Quinnhydrone type
• 2. Caffeine complex
• 3. Picric acid type
• 4. Polymeric Complex 
 C) Inclusion/ occlusion complexes

• 1. Clathrate Complex
• 2. Channel lattice
• 3. Layer type
• 4. Monomolecular
• 5. Macromolecular
 METAL ION COMPLEXES
• 1. Inorganic type: The ligand provides only one
site for binding with metal. • Metal & ligands
bonded to each other by electrostatic or
covalent bond.
• The ammonia mol. In hexamminecobalt III
chloride are called ligands and coordinated to
cobalt ion. Each ligand donates a pair of
electrons. The Coordination no. of cobalt is six.
Co3+ + 6 NH3 = [Co(NH3)6]3+Cl3
METAL ION COMPLEXES contd.

• 2. Chelates: • A substance (ligand) containing

two or more donor groups may combine with a
metal to form a special type of Complex know
as a chelate. ( Gr. 'kelos- claw) • E.g. EDTA
• Two geometric forms of chelates-
1. Cis isomer. E.g. Alcohol dehydrogenase
enzyme containing Zn
2. 2.Trans isomer. E.g. Vit B12 & hemeproteins. •
Naturally occurring chelates- chlorophyll,
hemoglobin, albumin which binds Cu and
Nickle.
 LIGAND:
• “The molecules or ions attached to the central atom”
OR “The ligand is a molecule that interacts with another
molecule (the substrate) by co-ordinate bond & form a
complex.”

• Types: 1. Unidentate/ monodentate: single pair of

electrons (basic group) for binding eg.
Ammonia,pilocarpine..
• 2. Bidentate: has two basic groups eg. ethylenediamine.
• 3. Multidentate/ Polydentate: multiple binding sites eg
polymers.
• 4. Hexadentate: has 6 donor groups eg. EDTA
Applications of chelation or chelating agent:

•  1. Chelating agent (EDTA, phosphonates) are used

in water treatment program, i.e. Softening of water.
• 2. Oxidative degradation of drugs & citric acid in
fruit juices can be prevented by chelation with EDTA
• 3. EDTA is, in-vitro anticoagulant
• 4. Detoxification of poisonous metal agents, such as
mercury, arsenic & lead.
• 5. To remove colour impurities from antibiotic
preparations.
Contd..

• 6. Chelate Complex of gadolinium are often used as

contrast agents in MRI scans.
• 7. Auranofin, a chelate complex of gold, is used in
treatment of rheumatoid arthritis.
• 8. Penicillamine forms chelate complex with copper,
used in treatment of Wilson’s disease & cystinuria.
• 9. Metal chelate compounds are common
components of fertilizers to provide micronutrients.
  METAL ION COMPLEXES contd.
3. Olefin type Complex:
Interaction of aqueous solutions of metal ions
(such as iron, mercury, silver, etc) with olefin
( alkene) form olefin type complexes.
• The first organotransition metal complex, Zeinse’s
salt [KPtCl3(C2H4)] H2O, was an olefin complex.
• These are water soluble.
• E.g. Ethylene,cyclo-octene, butadiene,
cyclooctadiene & norbornadiene.
Example of olefin complex
METAL ION COMPLEXES contd.

4. Aromatic type complexes:

• Interaction of metal ion with aromatic
molecule such as benzene toluene and xylene
form aromatic complexes.
• According to the nature of bond between
metal ion and aromatic compound complexes
are Pi bond complex and sigma bond complex
or sandwich compounds.
 (B) Organic molecular Complex:
• This type of complexes are formed by non covalent
interactions and held together by weak forces of
donor acceptor type or by hydrogen bonds.
• Energy of attraction is probably less than 5
Kcal/mole.
• Because of the bond distance between the
components of the complex is greater than 3 A° a
covalent link is not involved instead one molecule
polarizes the other resulting in a type of ionic
interaction or charge transfer.
Organic molecular Complex contd.

1. Quinnhydrone type: 
• When alcoholic solution of benzoquinone and
alcoholic solution of hydroquinone are mixed
in equal molar concentration they form
quinnhydrone complex.
Organic molecular Complex cont.

2. Drug & caffeine complex:

• A number of acidic drugs are known to form
complex with caffeine drugs such as benzocaine,
procaine, tetracaine form complex with caffeine. •
Mechanism- a) hydrogen bonding between carbonyl
grp of caffeine & H atom if acidic drugs. b) Induced
dipole- dipole force between carboxy Oxygen of
drug & electrophilic Nitrogen of caffeine.
• Caffeine-drug Complex- may enhance solubility .
Mask bitter taste of drug . Improve stability
Organic molecular Complex cont.

3. Picric acid Complex:

• Picric acid forms organic molecular complexes
with weak bases.
• Butesin has anaesthetic property and picric
acid has antiseptic property. Butesin
complexes with picric acid and form butesin-
picrate. Ointment of the complex is used in
treatment of burns.
Organic molecular Complex cont.

4. Polymer complexes:
• Polymeric materials such as PEG, carbowaxes, pluronics,
CMC, etc contain nucleophillic oxygen and form complex
with various drugs this type of interaction produce
incompatibilities in suspensions, emulsions, suppositories
and ointments.
• It may lead to precipitation, flocculation, delayed
absorption, loss of preservative action and other
undesirable physical, chemical and pharmacological
effects.
• Eg.a) Dissolution rate of Ajmaline is enhanced by
complexation with PVP. b) Polythene container interact
with drug & results in loss of active component.
 (C) Inclusion or occlusion complexes:

• One of the component is trapped in open

lattice or cage like crystal structure of the
other.
• Interaction is due to suitable molecular
structure.
Inclusion or occlusion complexes contd.

1. Channel type:
• Channels are formed by crystallization of host
molecules.
• Host molecules are usually tubular channel (e.g.
Deoxycholic acid, urea, thiourea, amylose).
• Guest component is usually long unbranched straight
chain compounds ( E.g. Paraffin, esters, acids,
ethanol, etc)
• E.g. Urea- methyl Alpha lipoate Complex, starch-
iodine complex
• These are useful for separation of isomers & analysis
of dermatological creams.
Example of channel lattice complex
Inclusion or occlusion complexes contd.

2. Layer type:
• Guest molecule is entrapped inside layers.
• E.g. Clay montmorillonite( main constituent of
bentonite) can trap hydrocarbons, alcohols,
glycols.
• Due to larger surface area, these are used as
catalyst.
Layer lattice type
Inclusion or occlusion complexes contd.

3. Clathrates:
• During crystallization, some compounds (host)
form cage like structures in which co-
ordinating compound (guest) is entrapped.
• E.g. a) warfarin sodium (water+ alcohol)
b) Hydroquinone form cage with hydrogen
bonds & hole have diameter of 4.2 A°. This can
entrap methanol, CO2, HCl.
Clathrate complex
Inclusion or occlusion complexes contd.

4. Monomolecular & macromolecular complex:

• Involves entrapment of single guest molecule
in the cavity of one host molecule.
• Most of the host molecules are cyclodextrins.
• The entrance cavity is hydrophobic & interior
cavity is hydrophilic in nature.
 Methods of analysis of complex:
• The analysis of Complex involves estimation of two
parameters
1. Stoichiometric ratio of ligand to metal or donor to acceptor.
2. Stability constant of the complex.
• Equation for complexation is written as
D + C = DC
stability constant, K
K = [ DC] / [ D] [C]
• Keeping the conc. of metal ion or drug constant, the conc of
ligand may be varied.
• The corresponding changes in the conc of DC can be
estimated by suitable analytical method.
 Methods of analysis of complex contd.

• 1. Method of continuous variation

• 2. Distribution method
• 3. Solubility method
• 4. pH titration method
• 5. Spectroscopy & charge transfer
complexation
• 6. Miscellaneous method
 Method of continuous variation (JOB’s
method):
 • Determines the stoichiometric ratio of certain additive
properties such as of the complex like dielectric constant,
absorbance, RI, etc.
• According to this, when two components of complex are
mixed & if no interaction occurs between them, the value
of properties is additive.
• If additive property such as dielectric constant is plotted
against the mole fraction, a linear relationship is observed
when no complexation occur.
• If complex is formed, value of additive property changes,
slope change occur.
 2. Distribution method:
• This method describes distribution of a solute between
two immiscible liquids as expressed by distribution
coefficient or partition coefficient.
• When solute complexes with an added substance,
solute distribution pattern changes depending on the
nature of a complex.
• E.g. Iodine complexes with potassium iodide.
I2 + KI = KI3
• Partition coefficient of iodine is 625, where as that of
iodine- potassium iodide is 954.
 3. Solubility method:
• When components in a mixture form complex,
solubility of one of the component may be
enhanced or reduced.
• In this method, excess amount of drug along with
solution of complexing agent is placed in container,
agitated at constant temperature till equilibrium is
achieved. The liquid portion is removed & analyzed
for complex formation.
• E.g. Estimation of complexation of PABA & caffeine.
 4. pH titration method:
• This method is used when complexation is
achieved by change in pH.
• E.g. Chelation of cupric ion by glycine.
• Titration curve is obtained by adding a strong
base (NaOH) to solution of glycine & to another
solution containing glycine & cupric ion.
• Average number of ligand bound per metal ion
present is given by- . N = total number of ligand
bound/ total number of metal ion
 5. Miscellaneous methods:
•  1. Nuclear magnetic resonance (NMR)
• 2. Infrared spectroscopy (IR)
• 3. Polarography
• 4. X- ray diffraction & electron diffraction
• 5. Reaction kinetics
• 6. Circular dicromism.
 PROTEIN BINDING
• “ The phenomenon of complex formation of drugs
with proteins is called protein binding”. • A protein
bound drug is neither metabolised nor excreted
hence it is pharmacologically inactive.
Types: 1. Reversible binding- involves weak chemical
bonds such as H-bonds, hydrophobic bonds, ionic
bonds, van der waal’s forces.
2. Irreversible binding- arises as a result of covalent
bonding & is often a reason for carcinogenecity or
toxicity of drug.
 Proteins which can be bounded by drugs:

• 1. Human serum albumin

• 2. Alpha 1 acid glycoprotein
• 3. Lipoproteins
• 4. Blood cells
Contd..

•  Human serum albumin: • Molecular weight: 65000-

69000 • Synthesized in liver. • Conc of albumin in
extracellular fluid is about 60% • Elimination half
life: 17-18 days • Conc: 3.5- 5.5 % (w/w) • Possess 4
binding sites.
•  Alpha 1 acid glycoprotein (orosomucoid): •
Molecular weight: 44000 • Bound by hydrophobic
bonds. • E.g. Basic drugs such as imipramine,
amitriptyline, lidocaine, nortryptyline, Quinidine,
disopyramide, etc bound to this.
Contd..

• Lipoproteins: • Molecular weight: 2-3 lakhs to 34

lakhs. • Bound drug dissolve in lipid core. • E.g. Acidic
drugs ( diclofenac), neutral (cyclosporine), basic drug
(chlorpromazine).
•  Blood cells: 1. Hemoglobin 2. Carbonic anhydrase
inhibitors 3. Red blood cells membrane
• Order of binding: albumin> Alpha 1 acid
glycoprotein>lipoproteins> globulins
Significance/ effects of protein binding:
• 1. Absorption- protein binding with drugs decreases
free drug conc & disturbs abs equilibrium.
• 2. Decrease in Distribution of drugs
• 3. Decrease metabolism by preventing entry of drug to
metabolizing organs & enhances biological half life.
• 4. Only unbound drug is capable of being eliminated
• 5. Diagnosis of diseases or disorders by using radio
active substance
• 6. Site specific drug delivery of hydrophilic moieties.
 Factors affecting protein binding:
• (A) Drug factors (B) Protein related factors (C) Drug
interactions (D) Patient related factors
•  (A) Drug factors:
• 1. Physicochemical properties of drug: • Increase in
lipophillicity increases extent of binding. • Acidic/ anionic
drugs bind to HSA, basic/ cationic drugs bind to Alpha 1 acid
glycoprotein, neutral/ unionized drugs binds to lipoproteins.
• 2. Conc. of drugs: • At higher conc., more free drugs may be
present owing to saturation of binding sites on protein.
• 3. Affinity of drug for binding sites:
Contd.

• (B) Protein related factors: 1. Physicochemical

properties of protein 2. Conc of protein 3.
Number of binding sites on the protein
•  (C) Drug interactions: 1. Displacement
reactions: competition between drugs for the
binding sites. 2. Competition between drugs
and normal body constituents 3. Allosteric
changes in protein molecules
Contd.
• (D) Patient related factors: 1. Age: neonates
have low level of albumin & change in albumin
content affects the drug binding. 2.
Intersubject variations 3. Disease states
 Importance of Complexation & Drug Action:

• ·Once complexation occurs, the physical and chemical

properties of the complexing species are altered.
• These properties include solubility, stability, partitioning,
energy absorption and emission, and conductance of the
drug .
• Drug complexation can lead to beneficial propertiessuch as
enhanced aqueous solubility (e.g. theophylline complexation
with ethylenediamine to from aminophylline) and stability
(e.g. inclusion complexes of labile drugs with cyclodextrins).
• ·Complexation also can aid in the optimization of delivery
systems (e.g. ion-exchange resins) and affect the distribution
in the body after systemic administration as a result of
protein binding..
Contd.
• In some instances, complexation also can lead
to poor solubility or decreased absorption of
drugs in the body.
• Aqueous solubility of tetracycline decreases
substantially when it complexes with calcium
ions and coadministration of some drugs with
antacids decreases absorption from the
gastrointestinal tract.
Contd.
• Drug complexation with hydrophilic compounds also can enhance
excretion.
• ·Complexes can alter the pharmacologic activity of the agent by
inhibiting interactions with receptors.
• Complexation of a ligand with a substrate molecule can occur as a
result of coordinate covalent bonding or one or more of the
following noncovalent interactions:
•  
• Van der Waals forces
• Dipolar forces
• Electrostatic forces
• Hydrogen bonding
• Charge transfer
• Hydrophobic interactions.
•  
•  
• Protein binding: Binding of drugs into proteins may
• Facilitate the distribution of drugs into the body.
• Inactivating the drug
• Retarding the excretion of drug
• Interaction of a drug with proteins
• Displacement of body hormones or coadministered agent.
•  
• Formation of drug-protein complex that is biologically active.
• Important proteins: albumin and alpha1-acid glycoprotein
• Types of drug- protein binding:
• Reversible Covalent interaction
• Irreversible Covalent interaction
•  
•  
• Irreversible: Covalent interaction:
• Accounts for certain toxicities of drugs and carcinogens
• E.g. high dose of acetaminophen causes hepatotoxicity
 Effect of Protein Binding:
• The pharmacokinetic/pharmacodynamic (PK/PD) profiles of a drug are
largely affected by the reversible binding to plasma proteins
• The binding of small molecules to plasma proteins is a very important
parameter in drug metabolism and pharmacokinetic studies.
• Generally, only free drugs are available for diffusion and transport
across cell membranes to its target sites.
• Protein binding inactivates the drug, because sufficient concentration
of drug cannot be built up at the receptor site for action.
• High degree of protein binding in the blood circulation prevents
urinary excretion
• Drug/protein complexes may act as a “storage depot” in the blood
circulation due to its prolonged circulation time
• Determining the level of protein binding is critical and directly
correlates with the in vivo efficacy of a drug
Crystalline Structure of Complexes
• A crystal or crystalline solid is a solid material,
whose constituent atoms, molecules, or ions are
arranged in an orderly repeating pattern extending
in all three spatial dimensions. - Examples:
Diamond, Nacl, Kcl, Copper, Silver, and Aluminium.
Amorphous (Non-crystalline) Solid is composed of
randomly orientated atoms, ions, or molecules that
do not form defined patterns or lattice structures. -
Examples: amorphous silicon, plastics, and glass.
Contd.

• Lattice Points: The points in the space,

replacing the atoms in the structure of a
crystal, with regular periodic arrangement and
have identical environment with respect to
Crystal Lattice: The regular orderly
arrangement of lattice points in space which
resembles the atoms or molecules in a crystal
such that every point has same environment
with respect to all other points. other points. 
 Thermodynamic stability •
• As for as complexes in solutions are concerned there
are two kinds of stabilities • Thermodynamic
stability – Measure of the extent to which the
complex will be formed or will be transformed into
another species, when the system has reached
equilibrium.
• Kinetic stability – refers to the speed with which the
transformations leading to equilibrium will occur. •
Under this , the rates of substitutions, racemisations
and their mechanisms. 
 Overall stability constant
 • If the complex formation is considered as a single step
process
M + nL MLn = [MLn] / [M] [L]ᵝn 
Trends in stability constants [Cu(OH2)4]2+ + NH3
[Cu(OH2)3(NH3)]2+ + H2O log K1 = 4.22
[Cu(OH2)3(NH3)]2+ + NH3
[Cu(OH2)2(NH3)2]2+ + H2O log K2 = 3.50
[Cu(OH2)2(NH3)2]2+ + NH3
[Cu(OH2)(NH3)3]2+ + H2O log K3 = 2.92 [Cu(OH2)
(NH3)3]2+ + NH3
[Cu(NH3)4]2+ + H2O log K4 = 2.18
• Generally the stepwise stability constant values decrease
with successive replacement by the ligands