Complexation

Complexation

Contents of
this chapter

• Definition of complexes

• Ion pair and co-ordination complexes

• Applications of complexes in pharmaceuticals

• Classification of complexes

• Metal ion complexes and its types

• Organic molecular complexes and its types

• Inclusion and Occlusion complexes

• Analysis of complexes by different methods

Learning
Objectives

• At the end of this lecture, student will be able to

– Define complexation

– Compare Ion pair and co-ordination complexes

– Explain concepts of ligand and substrate

– Discuss the applications of complexes

– Classify complexes

– Explain the types and properties of metal ion complexes

– Discuss the types and properties of organic molecular
complexes

– Explain the types and properties of inclusion complexes

– Explain the types and properties of occlusion complexes

– Discuss the concepts of analysis of complexes

– Explain the methods of analysis of complexes

DEFINITIONS

Coordination (complex
formation) – any combination of cations with molecules or anions containing
free pairs of electrons. Bonding may be electrostatic, covalent or a mix.

Central atom
(nucleus) – the metal cation.

Ligand – anion or
molecule with which a cation forms complexes

Multidentate ligand –
a ligand with more than one possible binding site.

Chelation –
complex formation with multidentate ligands.

• Multi- or
poly-nuclear complexes – complexes with more than one central atom or nucleus.

• Ligand – which
donates a pair of electrons

• Subtrate –
which accepts a pair of electrons

Ligand + Substrate ———- Complex

Species – refers
to the actual form in which a molecule or ion is present in solution.

Coordination number –
total number of ligands surrounding a metal ion.

Ligation number –
number of a specific type of ligand surrounding a metal ion.

Colloid –
suspension of particles composed of several units, whereas in true solution we
have hydration of a single molecule, atom or ion.

FORMS OF
OCCURRENCE OF METAL SPECIES

Coordination
numbers

Coordination numbers 2, 4, 6, 8, 9 and 12 are most common
for cations

ION
PAIRS  Vs. COORDINATION COMPLEXES

Applications
of complexation

• Physical state:
liquid to solid-nitroglycerine inclusion complex with beta Cyclodextrin—-15%
nitroglycerine containing complex

• Explosion proof Volatility:
Reduce volatility and odor. Ex. PVP iodine complex.

• Solid stability:
stability of drug enhanced. Ex. β cyclodextrin with vitamin A and D

• Chemical stability:
Alter the chemical reaction by (inhibitory or catalytic) Benzocaine- caffeine
complex

• Solubility:
solubility enhanced. Ex. low concentration of Caffeine enhance the solubility
of PABA

• Dissolution:
Increase solubility –   dissolution also
increased. Ex. Phenobarbital inclusion complex with β cyclodextrin

• Absorption and
bioavailability: Tetracycline complex with cal., mag., Alu – in soluble
complex β cyclodextrin complex with indomethacin, barbiturates—- more soluble
complex.

• Reduced toxicity:
cyclodextrin reduce ulcerogenic effect of indomethacin and local tissue
toxicity of chlorpromazine

• Antidote for metal
poisoning: toxic metal ions- arsenic, mercury, antimony

– Compound dimercaprol —form a water soluble
complex-eliminate rabidly from body Beryllium poisoning-salicylic acid Lead
poisoning-EDTA

• Drug action through
metal poisoning: 8-hydroxyquinoline complex with iron-penetrate through the
malarial parasite membrane – better antimalarial action PVP iodine complex:
water soluble, low toxicity and prolong action                                                                                                             

• Use of ion exchange principle:
Cholestyramine resin (quaternary ammonium anion exchange resin). Used to relief
pruritis, the resin exchange chloride ion from bile this result in increased
elimination of bile through faeces.

• In diagnosis:
Technetium 90 (a radionuclide) is prepared in the form of citrate complex this
complex is used in diagnosis of kidney function & GFR. Squibb (complex of a
dye Azure A with carbacrylic cation exchange resin): used for detection of
achlorhydria due to condition such as carcinoma, pernicious anaemia.

• Complexation as a
therapeutic tool: Complexing agent are suggested for variety of uses, many
of are related to chelation of metal ion. One of the important use is
Preservation of blood, both EDTA & CITRATES are employed for in-vitro to
prevent clotting. -Anticoagulant acid citrate dextrose solution &
-Anticoagulant

Metal Ion
Complexes

• Inorganic type
complex

NH3 + Cobalt chloride ————-> Hexamine Cobalt III
chloride

Ammonia donates a pair of electrons (Ligand) and forms co-
ordinate bond with cobalt ion

Werner’s Theory:

Cobalt (III)
complex containing six ammonia ligands, which are monodentate.

• Within a ligand,
the atom that is directly bonded to the metal atom/ion is called the donor
atom.

• A coordinate
covalent bond is a covalent bond in which one atom (i.e., the donor atom)
supplies both electrons

• If the
coordination complex carries a net charge, the complex is called a complex ion.

• Compounds that
contain a coordination complex are called coordination compounds.

• The
coordination number is the number of donor atoms bonded to the central metal
atom/ion.                                                         

Chelates

• These are group
of metal ions in which Ligand provides 2 or more donor groups to combine with
metal ion

• Provides more
than one site for Complexation

One – Monodentate

Two- Bidentate

Three – Tridentate

More than 3 – Poly dentate

• Eg.
Chlorophyll, Haemoglobin, EDTA, Serum albumin

• Increases
stability of compounds, Hard water purification, Analysis of drugs – Assay of
procainamide and  Anti-coagulant

Chelates

Natural occuring chelates: chlorophyll, hemoglobin and
albumin

Olefins

• Used as
catalysts

• Olefins acts as
ligands combines with metal ions

• Eg. Aqueous
solution of platinum or silver absorb olefins forming a water soluble complex

Aromatic
type complex

• Aromatic bases
with metal ions forms complex

• Based on Lewis
acid – base reaction

• PIE BOND
COMPLEX – Benzene and toluene with silver ions

• SIGMA BOND
COMPLEX – Carbon of aromatic rings with aluminium – based on Friedel – Crafts
reaction

• SANDWICH COMPLEX
– Ferrocene

• Which is
dicyclopentadienyl iron II

• Iron is
sandwiched between 2 molecules of cyclopentadienyl

Complex or Organic
Molecular Complexes

Quinhydrone
Complex

• Alcoholic
solution of benzoquinone and hydroquinone forms Purple Crystals as complex

• Forms by
hydrogen bonding or overlapping of pie bond of molecules

• Used as
electrode in pH determination

Picric Acid
Complex

• Picric acid
with Butesin —- Butesin Picarate, a YELLOW powder having antiseptic and
anaesthetic property

• 1% ointment in
burns and skin abrasions

• Reduces
Carcinogenicity

Polymer
Type Complex

• PEG, CMC,
Polystrenes, carbowaxes forms complexes with drugs

• But cause
incompatibilities in dosage forms that may retard the activity

• Dissolution,
absorption, pharmacological action and undesirable physical and chemical
effects

• It modifies the
biopharmaceutical parameters of drugs

POLYMER
COMPLEXES

• PVP binding with benzoic acid and nicotine derivatives –
increases phosphate buffer solutions and decreases as the temperature is
raised.

• Crosspovidone binds with acetaminophen, benzocaine,
benzoic acid, caffeine, tannic acid, and papaverine HCl due to its dipolar character
and porous structure.

• Polyolefin interact with drugs depends linearly on the
octanol water partition coefficient of the drug; which can result in loss of
the active component in liq dosage forms

• Dissolution rate of ajmaline is enhanced by Complexation
with PVP due to the aromatic ring of ajmaline and the amide groups of PVP to
yield a dipole dipole induced complex.

Caffeine
Complex

• Eg. Caffeine
with Gentisic acid ——- Chewable tablets

• Acidic drugs
with caffeine —- Due to Dipole-dipole interactions or Hydrogen bonding

• For extended
release of drug

• Improve or
impair drug absorption and bioavailability

Inclusion
compounds

• A class of addition compounds where the constituent of the
complex is trapped in the open lattice or cage like crystal structure of the
other of the other to yield a stable arrangement.

Channel
lattice type

• Examples are deoxycholic acid with other complexes; urea
and thiourea complexes and the starch-iodine solution.

• Eg. Starch – Iodine complex —– where iodine molecules
are trapped within spirals of glucose

• Channel forming host – Urea, thiourea, amylose

• Guest agents – Paraffins, esters, acids, ethyl alcohol

• Used in separation of optical isomers

Layer type complex

• Clays, Montomorillorite entraps hydrocarbons, alcohol and
glycols

• They engulf the molecules between their lattices

• Used as catalysts

• intercalate compounds between its layers

Clatharates

• Eg. Warfarin Sodium USP — clathrate of water and
isopropyl alcohol

• They crystallize in the form of cage in which the coordinating
compound is entrapped

• Due to its high energy, complex will be stable

• Used to resolve optical isomers, in molecular
separation                           

Monomolecular
inclusion compounds

• Involve entrapment of a single quest molecule in the
cavity of one host molecule.

Gamma-Cyclodextrin accomodating mytomycin C and beta-CD
accomodating indomethacin (in reactivity) and retinoic acid (in aq solubility),
famotidine and tolbutamide(in dissolution rate).

Cyclodextrin are used to trap, stabilize and solubilize
sulfonamides, tetracyclines, morphine, aspirin, benzocaine, ephedrine,
reserpine and testosterone.

• Amorphous derivatives of beta-CD and gamma-CD –in complex
with testosterone allow an efficient transport of hormone into the circulation
via sublingual route.

• Water-soluble CCB diltiazem and ISDN complex with
ethylated beta- CD- produce a sustained release effect.

• Femoxetine complex with beta-CD – oral liquid suspension
bitter taste is suppressed.                                                                                  
                     

CYCLODEXTRIN COMPLEXES

• One of the most important molecular complexations is the interaction
between molecules and cyclodextrin to form reversible inclusion complexes.

• Types:

– Alpha

– Beta

– Gamma

Improvements
in Properties of Drug Compounds by Complexes with Cyclodextrins

Macromolecular
inclusion compounds

• Molecular sieves

• Atoms are arranged in three dimensions to produce cages
and channels

• Eg. Zeolites (of varying pore size), dextrins, silia gels

ANALYSIS OF
COMPLEXES

Complexes are analysed for

• Stoichiometric ratio of Ligand to Metal

• Stability constant

Methods to determine the above parameters are

1. Job’s
Method of Continuous Variation

a. By measurement of
Dielectric Constant

Prepare solutions of 2 compounds A and B in mole fractions
of

A+B as 0.9A+0.1B, 0.8+0.2, 0.7+0.3, 0.6+0.4, 0.5+0.5,
0.4+0.6, 0.3+0.7, 0.2+0.8,  0.1+0.9,
0.0+1.0

• Determine the Dielectric constants of all the solutions

• Plot graph mole fraction on X axis and dielectric constant
on Y axis

Straight line = No complex formation

If curve shows maximum or minimum = Complex formation
between A and B

Change in slope = Ratio of Ligand to metal

b. By measurement of
Absorbance

• Prepare solutions of 2 compounds A and B in mole fractions
of A+B as

0.9A+0.1B, 0.8+0.2, 0.7+0.3, 0.6+0.4, 0.5+0.5, 0.4+0.6,
0.3+0.7, 0.2+0.8, 0.1+0.9,  0.0+1.0

• Measure the absorbance of all the solutions

• From the observed value subtract the expected theoretical
value

If difference is zero = No complexation

If difference was observed then,

– Plot graph mole fraction on X axis and absorbance on Y
axis

From the curve maximum, the molar ratio of the complex can
be found out

2. pH
Titration Method

–  Only when there is
change in pH during complexation

• Glycine solution was titrated against NaOH and pH profile
was noted

• Copper-Glycine complex solution was titrated against NaOH
and pH profile was noted

• Plot graph Ml of NaOH on X axis and pH on Y axis

• Complex curve will be below the pure glycine

• This confirms that the complex formation took place in
most titration ranges

• By titration concentration of ligand bound to metal ion
can be determined

• Horizontal distance between the 2 curves gives the amount
of NaOH consumed

• This quantity of NaOH = Concentration of ligand bound to
metal ion

• Average no. of ligand bound to metal ion

n = Total conc. of ligand bound / Total conc. of metal ion

• Stability Constant

P(A) = Logβ/2 at n=1         (1)

and

P(A) = pKa- pH – Log{ (HA)_initial – (NaOH) }       (2)

Conc. of ligand bound          

Conc. of glycine at initial stage         

Horizontal distance in in terms of moles/liter of NaOH at
that pH

3.
Distribution Method

• Based on “Distribution Co-efficient or Partition
Co-efficient”

• Eg. Complex between Iodine and Potassium Iodide

• Iodine with CCl4 and water – Amount of Iodine present in
each layer

• Iodine with CCl4 and KI – Amount of Iodine present in each
layer

• Conc. of complexed Iodine = (I2) Aq. Total – (I2) Aq.
Free

• Stability constant K = (Complex)/ (I2) Free X (KI) Free

Other examples – Benzoic acid with caffeine, Salicylic acid
with PVP

4.
Solubility Method

• Stoppered flasks containing complexing agent and excess
quantity of drug

• Placed in constant temperature water bath and agitated
until equilibrium is attained

• Remove supernatant and analysed and results are plotted as
graph

• A = saturation point with respect to drug and complex

• B = All excess drug has been used for complexation

• On further addition one or more secondary complexes will
be formed

• Amount of drug entering into complex from A to B à difference between the
total amount of drug added and amount of drug in solution at point A

• Amount of complexing agent = Moles of drug in complex/
Moles of complexing agent in complex

• Eg. Drug – Caffeine complex

5.
Spectroscopy Method

• Using absorption spectrum in UV and Visible region

• Used for investigating interaction of nucleic acid bases
with catechol and epinephrine

• Other Methods include = NMR spectroscopy, IR spectroscopy,
Polarography, X-ray diffraction studies

Summary

• Coordination (complex formation) – any combination of
cations with molecules or anions containing free pairs of electrons. Bonding
may be electrostatic, covalent or a mix.

• Species – refers to the actual form in which a molecule or
ion is present in solution.

• Coordination number – total number of ligands surrounding
a metal ion.

• Ligation number – number of a specific type of ligand
surrounding a metal ion.

• Applications of complexation includes Physical state,
Explosion proof Volatility, Solid stability, Chemical stability, Solubility and
Dissolution, Absorption and bioavailability, Reduced toxicity, Antidote for
metal poisoning, Use of ion exchange principle, in diagnosis and as a
therapeutic tool

 • Inorganic type
complex is Cobalt (III) complex containing six ammonia ligands, which are
monodentate.

• These are group of metal ions in which Ligand provides 2
or more donor groups to combine with metal ion

• Olefins acts as ligands combines with metal ions

• Aromatic bases with metal ions forms complex

• PVP binding with benzoic acid and nicotine derivatives,
increases phosphate buffer solutions and decreases as the temperature is
raised.

• Acidic drugs with caffeine forms complex due to
dipole-dipole interactions or hydrogen bonding and is used for extended release
of drug

• Inclusion compounds are class of addition compounds where
the constituent of the complex is trapped in the open lattice or cage like
crystal structure of the other of the other to yield a stable arrangement

• Monomolecular inclusion complexes involve entrapment of a
single quest molecule in the cavity of one host molecule

• One of the most important molecular complexations is the
interaction between molecules and cyclodextrin to form reversible inclusion
complexes.

• Molecular sieves are atoms are arranged in three
dimensions to produce cages and channels

• Complexes are analysed for Stoichiometric ratio of Ligand
to Metal and Stability constant

• Complexes are analysed by 5 different methods

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