2. 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).
A complex is a species formed by the reversible or
irreversible association of two or more interacting
molecules or ions.
Complexes have been usually referred to as coordination
compounds. 2
3. INTRODUCTION
Intermolecular forces involved in the formation of
complexes are
Coordinate covalence is important in metal complexes.
Van der Waals forces of dispersion
Hydrogen bonding: provide a significant force in some
molecular complexes
Hydrophobic interaction
3
4. INTRODUCTION
Once complexation occurs, the physical and chemical
properties of the complexing species are altered
(solubility, stability, partitioning, energy absorption, and
emission and conductance)
Complex formation usually alters the physical and
chemical properties of the drug. For examples:
(1) chelates of tetracycline with calcium are less water
soluble and are poorly absorbed. 4
5. INTRODUCTION
(2) Theophylline complexed with ethylenediamine to form
aminophylline is more water soluble and is used for
parenteral and rectal administration.
Theophylline Aminophylline
(Water-soluble)
5
6. INTRODUCTION
(3) cyclodextrins are used to form complexes with many
drugs to increase their water solubility.
Hydrophilic
exterior
Hydrophobic
interior
Hydrophobic
drug
6
7. INTRODUCTION:
Complexes, according to the classic definition, result from a
donor-acceptor mechanism or Lewis acid-base reaction
between two or more different chemical constituents.
A Lewis acid is a molecule or ion that accepts an electron pair
to form a covalent bond. The acceptor, or constituent that
accepts a share in the pair of electrons, is frequently a metallic
ion, although it can be a neutral ion.
A Lewis base (Ligand) is a molecule that provides a pair of
unshared electrons by which the base coordinates with the
acid. Any nonmetallic 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. 7
9. CLASSIFICATION OF COMPLEXES
Complexes may be divided broadly into two classes
depending on whether the acceptor component is a
metallic ion or an organic molecule; these are classified
according to one possible arrangement.
A third class, the inclusion / occlusion compounds,
involving the entrapment of one compound in the
molecular framework of another.
9
10. CLASSIFICATION OF COMPLEXES
1. Metal Ion Complexes:
a. Inorganic Type
b. Chelates
c. Mental-olefins
2. Organic molecular Complexes
a. . Drug and caffeine complexes
b. Polymer types
c. Picric acid types
d. Quinhydrone types
3. Inclusion/occlusion Complexes
a. channel lattice type
b. layer type
c. clathrates
d. monomolecular inclusion compounds
10
11. METAL COMPLEXES
In this type of coordination complexes, components
are organic molecules and these are held together by
weaker forces or hydrogen bonding.
11
12. INORGANIC COMPLEXES
The ammonia molecules in hexamminecobalt (III)
chloride, as the compound [Co(NH3)6] 3+ Cl3 - is
called, as the ligands and are said to be coordinated to
the cobalt ion.
The coordination number of the cobalt ion, or number of
ammonia groups coordinated to the metal ions, is six.
Other complex ions belonging to the inorganic group
include [Ag(NH3)2] + , [Fe(CN)6] 4-, and [Cr(H2O)6]
3+ .
Each ligand donates a pair of electrons to form a
coordinate covalent link between itself and the central
ion having an incomplete electron shell. 12
13. For example
13
Ligands such as H2O:, H3N: , NC:-, or Cl:- donate a
pair of electrons in forming a complex with a metal
ion, and the electron pair enters one of the unfilled
orbitals on the metal ion.
14. 14
Hybridization plays an important part in
coordination compounds in which sufficient bonding
orbital's are not ordinarily available in the metal ion.
15. CHELATES
When a ligand provides one group for attachment to the
central ion, then its called monodentate.
Molecules with two or three groups are called bidentate and
tridentate respectively (multidentate or polydentate).
If a metal ion binds to two or more sites on a multidentate
ligand, a cyclic complex is formed; this cyclic complex is
known as a chelate.
Chelates are complexes that typically involve a ring-like
structure formed by the interaction between a partial ring of
atom and a metal.
In chelates, ligands are usually organic molecules, known as
chelating agents, chelators, chelants or sequestering agents. 15
16. Some of the bonds in a chelate may be ionic or of the
primary covalent type, while others are coordinate
covalent links.
The formation of chelate complexes is controlled by
stringent steric requirements on both the metal ion and
the ligand.
16
17. 17
Many biologically important molecules (e.g.
hemoglobin, insulin, cyanocobalamine, chlorophyll) are
chelates.
Other biological chelates include albumin, the most
common plasma protein which acts as a carrier of
various metal ions (Cu2+ and Ni2+) and small molecules
in the blood.
18. Hemoglobin also contains a porphyrin chelating agent
bonded to an iron II ion.
In chlorophyll the central ion is magnesium, and the
large organic molecule is a porphyrin. The porphyrin
contains four nitrogen atoms that form bonds to
magnesium in a square planar arrangement.
18
19. Ethylenediamine tetraacetic acid (EDTA) has six points
for attachment to the metal ion and accordingly is
hexadentate.
19
20. EDTA is a synthetic chelating agent used to sequester
ions (iron and copper) that catalyzes oxidative
degradation reactions in drug preparation.
EDTA is also widely used to sequester and remove
calcium ions from hard water.
20
21. The chelating properties of procainamide (Sodium
channel blocker, Class IA antiarrhythmic) has been used
as an assay for its content in pharmaceutical
preparations.
Complex formation with Cu2+ results in a colored
compound that can be measured by visible
spectrophotometry.
Thus calorimetric methods to assay procainamide in
injectable solutions is based on the formation of a 1:1
complex of procainamide with cupric ion at pH 4 to 4.5.
21
22. 22
Tetracycline antibiotics are capable of acting as chelating
agents and binding a variety of polyvalent metal ions
(Fe2+, Mg2+, Al3+, Bi3+ ).
The complexation results in changes in both the drugs’
and the metal ions’ physical and chemical properties.
The complexation between tetracycline antibiotics and
metal ions either in food (cabbage) or in pharmaceutical
preparations (iron containing supplements) has been
found to reduce both the solubility and bioavailability of
the antibiotics.
23. 23
Tetracyclines are contraindicated in pediatric patients
since they are prone to tetracycline complexation of
calcium in teeth and bones resulting in teeth
discoloration and bone growth problems.
24. OLEFIN TYPES
These types of complexes are used as catalysts in the
manufacture of bulk drugs, intermediates and
in the analysis of drugs.
24
25. 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
a. Drug and caffeine complexes
b. Polymer types
c. Picric acid types
d. Quinhydrone types
25
26. ORGANIC MOLECULAR COMPLEX
Hydrogen bonds - Here dipole-dipole and london type of
forces are responsible for its stability.
The compounds N-dimethyl aniline and 2,4,6-
trinitroanisole react in the cold to give a molecular
complex:
26
27. 27
Charge transfer complexes- In this type one molecule
polarize other, resulting in electrostatic interaction
forming a complex with ionic type of interaction.
Resonance make the main contribution for stability.
For example, the polar nitro groups of trinitrobenzene
induce a dipole in the readily polarizable benzene
molecule, and the electrostatic interaction that results
leads to complex formation:
28. 28
Electron donor–acceptor mechanism :- The type of
bonding existing in molecular complexes in which
hydrogen bonding plays no part is not fully understood,
but it may be considered as electron donor–acceptor
mechanism.
29. A. DRUG AND CAFFEINE COMPLEXES
Caffeine complexing with a number of acidic drugs, such
as sulfonamide or barbiturate.
Mechanism: a. dipole–dipole force or hydrogen bonding
between the polarized carbonyl groups of caffeine and
the hydrogen atom of the acid.
b. interaction probably occurs between the
nonpolar parts of the molecules, and the resultant
complex is “squeezed out” of the aqueous phase owing
to the great internal pressure of water.
29
30. In caffine molecule Nitrogen becomes more strongly
electrophillic or acid due to withdrawal of oxygen from
both the sides, forming a positive center which is offered
for complexation.
In benzocaine molecule ester become polarize in such a
way that carboxy oxygen acts as neutrophill or base.
The complex result in formation of dipole dipole
interaction between carboxy oxygen group of benzocaine
and electrophillic Nitrogen of caffine.
30
31. Caffeine forms complexes with organic acid anions that
are more soluble than the pure xanthine, but the
complexes formed with organic acids, such as gentisic
acid, are less soluble than caffeine alone.
Such insoluble complexes provide caffeine in a form that
masks its normally bitter taste and should serve as a
suitable state for chewable tablets.
31
32. B. POLYMER TYPES
Polyethylene glycols, polystyrene, carboxymethylcellulose,
and similar polymers containing nucleophilic oxygens can
form complexes with various drugs., can be attributed to these
interactions. The interactions that may occur in suspensions,
emulsions, ointments and suppositories.
The incompatibilities of certain polyethers, such as the
Carbowaxes, Pluronics, and Tweens with tannic acid, salicylic
acid, and phenol may be manifested as a
precipitate,
flocculate,
delayed biologic absorption,
loss of preservative action,
undesirable physical, chemical, and pharmacologic effects. 32
33. C. 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.
Picric acid complexes – such as Butesin picrate which
combines the antiseptic property of picric acid and
anesthetic property of Butesin used as a 1% ointment for
burns and painful skin abrasions.
33
35. Quinhydrone complexes – quindrone complex is
formed by mixing alcoholic solutions of benzoquinone
and hydroquinone forming green crystals.
Quinhydrone, the complex disassociates into equivalent
amounts of quinone and hydroquinone in an Aqueous
Saturated solution.
35
36. 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.
A class of addition compounds where one of the
constituent of the complex is trapped in the the other to
yield a stable layout.
Type of Host-Guest compound.
Depends on the architecture arrangement rather than the
chemical affinity.
36
37. CHANNEL TYPES
When the powder (host) crystallizes in the form of
channels, these channels have specific characteristics and
stereochemistry that allows only Specific type of guest
molecule to fit in.
A very common example of such complexes is the one
formed by starch and iodine where iodine molecules are
trapped within channels consisting of spirals of glucose
residues of starch; other materials capable of forming
these channels include bile acids, urea and theorem.
37
38. LAYER TYPE
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.
38
39. CLATHRATES
39
The clathrates crystallize in the form of a cage like lattice
in which the coordinating compound is entrapped.
Chemical bonds are not involved in these complexes, and
only the molecular size of the encaged component is of
importance.
The stability of a clathrate is due to the strength of the
structure, that is, to the high energy that must be
expended to decompose the compound.
40. the highly toxic agent hydroquinone (quinol) crystallizes
in a cage like hydrogen-bonded structure.
The holes have a diameter of 4.2 A and permit the
entrapment of one small molecule to about every two
quinol molecules. Small molecules such as methyl
alcohol, CO2, and HCl may be trapped in these cages,
But larger molecules such as ethanol cannot be
accommodated.
40
41. 41
Cagelike structure formed through hydrogen bonding of hydroquinone molecules.
Small molecules such as methanol are trapped in the cages to form the clathrate
42. In this class of inclusion compounds, a single guest
molecule is entrapped in the cavity of one host molecule.
A representative example of such compounds is
cyclodextrins.
Cyclodextrins are cyclic oligosaccharides containing a
minimum of six D (+) glucopyranose units attached by
an -1,4 linkage.
Cyclodextrins are produced from starch by the action of
bacterial amylase.
42
44. The interior of the CD cavity is usually hydrophobic
because of the CH2 groups, while the exterior of the
cavity is hydrophilic because of the presence of the
hydroxyl groups.
Complexation with CD does not ordinarily involve the
formation of covalent bonds. Molecules of appropriate
size and stereochemistry can be included in the
cyclodextrin cavity by hydrophobic interaction.
44
45. The naturally occurring α-CD, β-CD and γ-CD contain 6,
7 and 8 units of glucose respectively.
The cyclodextrins form a ring and the molecule actually
exists as a truncated cone in which guest molecules can
be accommodated to form an inclusion complex.
The size of the cavity increases by increasing the number
of glucose units, α -CD being the smallest, α -CD is not
very useful for pharmaceutical applications, β-CD and
γ-CD are more useful owing to the large cavity.
45
