Unit IV PP-I PPT.ppt

COMPLEXATION
Prepared by:
Mr.B.S.Ankalgi
M.Pharm.
SPM College of Pharmacy,Akluj.

Def: 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/more of
these bonds are some what anomalous.
Interaction
between different
chemical species
Inter molecular
forces
Covalent bond
Hydrogen bond
Vanderwalls
forces
Ion-dole, ip
dipole-dipole,
dipole-induced
dipole
Different
solubility, conductivity,
partitioning, chemical
reactions

COMPLEXES
J
1. Inorganic types
2. Chelates
3. Olefin type
4. Aromatic type
Organic
molecula
r
complexe
s
Inclusion
compound
s
1. Drug-caffine 1. Channel type
complex 2. Layer type
2. Polymer type 3. Clathrates
3. Picric acid type 4. Mono
4. Quinhydrone molecular type
type

I) Metal complexes:
METAL
(substrate)
Central atom
BASE
(ligand)
Electron pair donor
COMPLEX
formed by
co-ordination
bond

I-A) INORGANIC COMPLEXES:
Werner postulates:
1. There are 2 types of valences primary (ionic), secondary
(coordinate).
2. Same type of anion/ radical/ molecule may be held by any one /
both type of valence.
3. Every central atom has fixed number of non-ionic valences
(coordination number)
4. The co-ordination atoms occupy the first sphere/coordination
sphere, other atoms occupy second/ ionization sphere.
5. Neutral molecules/ions may satisfy non-ionic valences.
6. The non-ionic valences are directed to specific positions in space.
Ionization sphere
Coordination sphere

Ex: [Co Cl (NH3)5] Cl2
1. Compound ionize to form [Co Cl (NH3)5]+2 and 2Cl-.
2. Central chlorine do not precipitate with silver nitrate.
3. Substrate and ligand are bonded with coordination bond.
4. Coordination number is maximum number of atoms and
groups that combine with central atom in coordination
sphere.
5. Co-ordination number for cobalt is 6.
Participate in
complexation

I-B) CHELATES:
These are group of metal ion complexes in which a substrate/ ligand
provides 2/more donor groups to combine with a metal ion.
Ligands- didentate, tridentate, polydentate.
® Hexadentate -
ethylenediaminetetraacetic acid (EDTA)-
Has a total of six points (4:0 and 2: N)
for attachment of metal ions.
Sequestering;
This is a process in which the property of
metal is suppressed without removing it
from the solution.
Sequestering Agent;
This is a ligand which forms a stable water
soluble metal chelate Ex: chlorophyll,
hemoglobin.

Chelates applications:
1. INCREASING SOLUBILITY:
Fruit juices and drugs (ascorbic acid) + Fe/Cu ^ oxidative
degradation.
Add EDTA + Fe/Cu ^ stable Chelate
2. PURIFICATION OF HARD WATER:
Hard water (Ca+2) + EDTA ^ EDTA-Ca+2 (ppt) ^ filter ^ Pure
water.
3. DURG ANALYSIS:
Procainamide + cupric ions (1:1) at pH 4-4.5 ^ Coloured complex ^
detect by Colourimetry.
4. ANTI-COAGULANT:
Blood (Ca+2) + EDTA/Citrates/Oxalates ^prevent thrombin
formation ^ no clotting.

1-C.D: OLEFIN AND AROMATIC TYPE:
a. These involves Lewis acid-base reactions
b. These type of complexes can be used as
catalysts in the manufacturing of bulk drugs,
intermediates and in drug analysis.

II. ORGANIC MOLECULAR COMPLEXES:
1. Interaction between 2 organic molecules ^ Complex
^temperature change ^ molecular compound.
2. These complexes have (H)bonds/ weak vander wall
forces/ dipole-induced dipole interactions.
3. Energy of attraction is 3K.Cal/mole
4. Bond distance is 3A0
Complex Molecular compound
Reaction in COLD TEMPERATURE Reaction in HOT TEMPERATURE
Weak attraction forces Strong electrostatic interactions
Complexes can not be separated
from solutions
Compounds can be separated
from solutions

PRINCIPLE/ MECHANISM:
1. Donar-Acceptor type:-
Bonds between uncharged species is formed and stabilized by dipole-dipole
interactions.
EX: N-Dimethyl aniline + 2,4,6-Trinitro anisole.
2. Charge transfer complexes:-
•One molecule polarizes other resulting in electrostatic interactions for
complex formation with high inter molecular bonding.
•Complex is stabilized by resonance.
Ex: Benzene + Trinitro benzene.

2-A) DRUG & CAFFINE COMPLEX:
Acidic drugs (benzocaine, procaine) + Caffeine ^ Complexes Mechanism:
1. dipole-dipole forces/ hydrogen bonding between acid (H) atom and
caffeine carboxyl group.
2. Interaction of non-polar parts
Ex: Caffeine + Benzocaine.

DRUG & CAFFINE COMPLEX Applications:
1. These complexes can improve / extend absorption and
bioavailability of drug.
2. These complexes can enhance/ inhibit solubility and
dissolution rate of drug.
3. Caffeine+ gentisic acid complexes mask bitter taste of caffeine.
2-B) POLYMER COMPLEXES:
Polymers with nucleophilic oxygen (PEG/CMC)
+Drugs(tannic acid/salicylic acid/phenols) ^ Complexes.
Disadvantages:
1. Incompatibilities in suspension, emulsion, ointments.
2. Complexes + Container^ drug loss
3. Complexes + preservatives ^ decrease preservative action.

2-C) PICRIC ACID COMPLEXES:
Picric acid (strong acid) + strong base ^Salt.
Picric acid (strong acid) + weak base ^ Complexes.
Ex: BUTESIN PICRATE
Picric acid (antiseptic) + Butesin (anesthetic)
1% ointment used for burns and abrasions.
DISADVANTAGES:
Picric acid + Carcinogenic Agents ^COMPLEX^ increase carcinogenic
activity.

2-d) QUINHYDRONE COMPLEXES:
Alcoholic solutions of equimolar quantities of Hydroquinone
and Benzoquinone form Quinhydrone complexes (green
crystals) Mechanism:
1. Overlapping of n electrons of molecules
2. (H) bonding for stabilizing complex.
Hydroquinone
Benzoquinone
Applications:
Used as electrode in pH determination.

3. INCLUSION COMPLEXES/OCCLUSION COMPOUNDS:
1. One compound is trapped in lattice/cage like structure of
other compound.
2. Interaction are due to suitable molecular structure.
3. Prediction of complex formation is difficult.
3-A) CHANNEL LATTICE TYPE.
Host (tubular channel)- Deoxycholic acid, urea, thiourea, amylose
Guest (long unbranched straight chain compounds)- paraffin, esters,
acids, ethanol.
Ex: Starch-iodine solution (starch-host)
Urea-methyl a-lipolate (urea-host)
Applications:
• Seperation of isomers:
Dextro, levo-terpineol are separated using Digitoxin.
• In analysis of dermatological creams, long chain
compounds interfere and removed by complexation with
urea.

3-B) LAYER TYPES:
Host (Layers With Gaps)- clays, bentonite, montmorillite
Guest (entrapped in gaps)- hydrocarbons, alcohols, glycols.
Use:
Due to their large surface area they are used as catalysts.

3-C)CLATHRATES: (cage like structure)
During crystallization some compounds (host) form cage like
structures in which coordinating compound (guest) is entrapped.
Ex: warfarin sodium (water + isopropyl alcohol)
Hydroquinone form cage with hydrogen bonds and hole have
diameter of 4.2A0.
This can entrap methanol, carbon dioxide, hydrochloric acid.
APPLICATIONS:
1. Synthetic metalo- alumino
silicates act as molecular sieves.
2. The pores store volatile gases
and toxic substances.
3. The entrapped molecule can
be removed by physical process.

3-D) MONO MOLECULAR INCLUSION COMPLEX:
Single guest molecule entrapped by single host molecule.
HOST- Cyclodextrins.
Cyclodextrins are cyclic oligo sacchirides containing minimum of 6 D-
gluco pyranose units attached by a-1,4 linkages.
Cyclodextrins Cavity diameter (Ao) Glucopyranose units
a 5 6
P 6 7
Y 8 8

MONO MOLECULAR INCLUSION COMPLEX APPLICATIONS:
1. Enhanced solubility:
Retonic acid (solubility= 0.5mg/ml)
Retonic acid + P-CD (solubility= 160
mg/ml)
2. Enhanced dissolution:
Famotidine/ Tolbtamide + P-CD
3. Enhanced stability:
Asprin/Ephedrine/Testosterone + P-CD (no
reaction with other functional groups)
4. Sustained release:
Ethylated P-CD + Diltiazem

COMPLEXATION
•Physical state
•Volatility
•Solid state Stability
•Chemical stability
•Solubility
•Dissolution

-Applications in pharmacy
•Partition coefficient
•Absorption & bioavailability
•Reduced toxicity •Antidote in
metal poisoning •Drug action
through metal poisoning
•Antibacterial activity

1. Physical state:
Liquid substance Solid complex ^ improve process
characteristics.
Ex: Nitroglycerine (Explosive) + P-CD ^ Explosion proof
Complex
2. Volatility:
Substances ^Complex ^ Reduce volatility
(volatile / unpleasant odour) & Mask odour
3. Solid state stability
Vitamin-A,D + P-CD Chemically stable solid complex.

4. Chemical stability
Complexation Reduce Reactivity, Improve stability. Ex:
Caffeine + Benzocaine Complex ^ Prevent
benzocaine hydrolysis.
5. Solubility:
PABA (insoluble) + Caffine ^ Complex improves
solubility of PABA
6. Dissolution:
Phenobarbitol (insoluble) + P-CD ^ Complex improves
Solubility & Dissolution.

7. Partition Coefficient:
(Water + Benzene) + Permanganate ions ^ Partition in to
WATER.
(Water + Benzene) + Permanganate ions + Crown ether ^
Partition in to Benzene.
8. Absorption & bioavailability
P-CD + Barbiturates ^ Complex Improves
Bioavailability
Tetracyclines + Ca+2 / Mg+2 ^ Insoluble metal Complex
Reduced Absorption & Bioavailability
9. Reduced Toxicity:
P-CD + Indomethacin Reduce ulcerogenic effect P-CD +
Chlorpramazine Reduce local tissue toxicity.

10. Antidote in metal poisoning:
Arsenic, Mercury (Toxic metal ions) + (-SH) groups of
enzymes ^ Effect normal functioning.
Dimercaprol + Arsenic, ^ Complex ^ Easily eliminated
Mercury from body.
11. Drug action through metal poisoning:
8-Hydroxy Quinoline + Iron ^ Complex ^ Enter malarial
parasite Accumulation of metal Anti-Malarial action.
12. Antibacterial activity:
PAS + Cupric ions ^ Cupric Complex + Chelates. (anti-
Tubercular drug)
Chelates ^ 30 times more fat soluble Penetrate in to cells ^
High anti-Tubercular action.

Method of analysis:
Estimation of 2 parameters
1. Stoichiometric ratio of Ligand: Metal / Donar :
Acceptor
2. Stability Constant of complex.
Methods:
1. Method of continuous variation.
2. Distribution method
3. Solubility method
4. pH titration method.

General procedure:
Equation for complexation
M + n A ^ MAn
Stability constant
_ [MAn]
K ~ [M] [A]n
Applying Log on both sides
Log [MAn] = log K + log [M] + n log
[A]

1. Method of continuous variation.
1. Dielectric constant

1. Due to
complexation
physical properties
result may be
maximum or
minimum.
2. At maximum/
minimum point
note concentration
of individual
species.
3. Calculate
stoichiometric ratio
of species.

2. Distribution method:
• Partition coefficient / Distribution changes due to complexation.
• By conducting 2 experiments stability constant is estimated.
[K-IJI
Pbj [K-11
Iodine + CCL4 (30 ml) + Water (30 ml)
Aqeous layer Organic layer
Titration
Sodium
0.1 >
0.01> thiosulphate
Starch Indicator
Iodine concentration
m Aueous & organic phases
Iodine + CCU (30 ml)+ Potassium
iodide
SHAKE
I
Titration
I
0.1N

3. Solubility method:
• When mixture form complexes solubility may increase/ decrease.
• Experiments are conducted to estimate parameters Experiment:
1. Caffeine (Complexing agent) taken in different concentrations
2. Add PABA, Agitate, Filter & analyze drug content.
[PABA-Caffeine] ” [PABA]
[Caffeine]

4. pH titration method.
ThismethodissuitableifcomplexationproduceschangeinpH.
Experiment:
1. Glycinesolution(75ml)titratedwithNaoH,pHisrecorded.
2. Glycinesolution(75ml)+Cu+2 ComplextitratedwithNaoH,pHis
recorded.(ComplexationreleasesProtonsandpHdecreases)>Quantityof
alkali=Concentrationofligandbound.

Unit IV PP-I PPT.ppt

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Unit IV PP-I PPT.ppt