Complexation

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Complexation

• Kausar Ahmad
• Kulliyyah of Pharmacy, IIUM

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Contents

• Lecture 1
• Formation of a complex ion
• Coordination compounds
• Ligands
• Types of bonding
• Shapes

• Lecture 2
• Chelates
• Organic molecular complexes
• Inclusion compounds
• Lecture 3
• Effect of complexation
• Applications

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Formation of a Complex Ion

• the filled ligand orbital overlaps the empty
  metal ion orbital.
• The ligand (Lewis base) donates the electron
  pair,
• The metal ion accepts it
• Form one of the covalent bonds of the complex
  ion.
• Such a bond, in which one atom in the bond
  contributes both electrons, is called a
  coordinate covalent bond.

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Complexes a.k.a. coordination compounds

• The substances contain at least one complex ion
• A species consisting of a central metal cation,
  either a transition metal or a main-group metal,
  that is bonded to molecules and/or anions (by
  co-ordinate bonds) called ligands.
• In order to maintain charge neutrality in the
  coordination compound, the complex ions is
  typically associated with other ions, called
  counter ions

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The nature of ligands

• Simple ligands include water, ammonia and
  chloride ions.
• Have active lone pairs of electrons in the outer
  energy level.
• These are used to form co-ordinate bonds with the
  metal ion.
• All ligands are lone pair donors. In other words,
  all ligands function as Lewis bases.

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Bonding in simple complex ionsAl(H2O)6 3

• What is the bonding in the complex ion formed
  when water molecules attach themselves to an
  aluminum ion to give Al(H2O)63?
• What is the structure of an aluminum ion before
  bonding?

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• aluminum has the electronic structure
• 1s22s22p63s23px1
• When it forms an Al3 ion it loses the 3-level
  electrons
• 1s22s22p6.....3s03px03py03pz03d03d0
• all the 3-level orbitals are now empty.
• The aluminum uses six of these to accept lone
  pairs from six water molecules.
• It re-organises (hybridises) the 3s, the three
  3p, and two of the 3d orbitals to produce six new
  orbitals all with the same energy.

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Al(H2O)6 3Why it chooses to use six orbitals?
..not four or eight?

• Six is the maximum number of water molecules
  possible to fit around an aluminum ion (and most
  other metal ions).
• By making the maximum number of bonds, it
  releases most energy and so becomes most
  energetically stable.

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Al(H2O)6 3

• Only one lone pair is shown on each water
  molecule.
• The other lone pair on O is pointing away from
  the aluminum and so is not involved in the
  bonding.
•                       

                       
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Al(H2O)6 3

• Because of the movement of electrons towards the
  centre of the ion, the 3 charge is no longer
  located entirely on the aluminum, but is now
  spread over the whole of the ion.
• Because the aluminum is forming 6 bonds, the
  co-ordination number of the aluminum is said to
  be 6. The co-ordination number of a complex ion
  counts the number of co-ordinate bonds being
  formed by the metal ion at its centre.
• Some ligands can form more than one co-ordinate
  bond with the metal ion.

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Shapes of Complex Ions

• For coordination compounds, the geometry of the
  complex ion is determined by
• The number and the type of metal-ion hybrid
  orbitals occupied by ligand lone pairs
• Linear
• Octahedral
• Square planar
• Tetrahedral

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Linear

• CuCl2-
• Ag(NH3)2
• AuCl2-

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Octahedral

• These are complex ions in which the central metal
  ion is forming six bonds. .or attached to six
  simple ligands.
• These ions have an octahedral shape. Four of the
  ligands are in one plane, with the fifth one
  above the plane, and the sixth one below the
  plane.

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Octahedral
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Tetrahedral

• E. g. CuCl42- and CoCl42-
• The copper(II) and cobalt(II) ions have four
  chloride ions bonded to them rather than six,
  because the chloride ions are too big to fit any
  more around the central metal ion.

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Tetrahedral
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A square planar complex

• A 4-co-ordinated complex
• E.g. cisplatin which is used as an anti-cancer
  drug. Cisplatin is a neutral complex
• Pt(NH3)2Cl2
• It is neutral because the 2 charge of the
  original platinum(II) ion is exactly cancelled by
  the two negative charges supplied by the chloride
  ions.

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A square planar complexCisplatin

• The platinum, the two chlorines, and the two
  nitrogens are all in the same plane.

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Geometric isomerism

• This occurs in planar complexes like the
  cisplatin.
• There are two completely different ways in which
  the ammonias and chloride ions could arrange
  themselves around the central platinum ion

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How cisplatin works..

• Cisplatin may work by
• lying within the cancer cells DNA double helix
• Such that a donor atom on each strand
• Replaces a Cl- ligand
• And binds the Pt(11) strongly
• Preventing DNA replication

End of lecture 1/3
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• End of lecture 1/3

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Chelates

• A substance, chelating agent, containing
• Two (2) or more donor groups
• combine with a metal
• to form a complex known as a
• chelate.

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Complex metal ions containing more complicated
ligands

• If one ligand forms only one bond - unidentate.
• It only has one pair of electrons that it can use
  to bond to the metal - any other lone pairs are
  pointing in the wrong direction.
• Some ligands, however, have more than one lone
  pair of electrons - multidentate or polydentate
  ligandsbidentate, quadridentate, hexadentate

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Bidentate ligands

• Bidentate ligands have two lone pairs, both of
  which can bond to the central metal ion.
• e.g. 1) 1,2-diaminoethane
• (old name ethylenediamine - often given the
  abbreviation "en"),
• e.g. 2) ethanedioate ion (old name oxalate).

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Continue Bidentate ligands

• In the ethanedioate ion, there are lots more lone
  pairs than the two shown,
• but these are the only ones important.

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• You can think of these bidentate ligands rather
  as if they were a pair of headphones, carrying
  lone pairs on each of the "ear pieces".
• These will then fit snuggly around a metal ion.

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Ni (NH2CH2CH2NH2)3 2 or Ni(en)3 2
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A quadridentate ligand

• A quadridentate ligand has four lone pairs, all
  of which can bond to the central metal ion.
• E.g. haemoglobin
• The functional part of this is an iron(II) ion
  surrounded by a complicated molecule called haem
  (heme).
• Haem is a hollow ring of carbon and hydrogen
  atoms, at the centre of which are 4 nitrogen
  atoms with lone pairs on them.

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Haem

• Haem is one of a group of similar compounds
  called porphyrins.
• They all have the same sort of ring system, but
  with different groups attached to the outside of
  the ring.
• Each of the lone pairs on the nitrogen can form a
  co-ordinate bond with the iron(II) ion - holding
  it at the centre of the complicated ring of atoms.

• We could simplify the haem with the trapped iron
  ion as

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Haemoglobin

• The iron forms 4 co-ordinate bonds with the haem,
  but still has space to form two more - one above
  and one below the plane of the ring.
• The protein globin attaches to one of these
  positions using a lone pair on one of the
  nitrogens in one of its amino acids.

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Haemoglobin

• Overall, the complex ion has a co-ordination
  number of 6 because the central metal ion is
  forming 6 co-ordinate bonds.
• The water molecule which is bonded to the bottom
  position in the diagram is easily replaced by an
  oxygen molecule (again via a lone pair on one of
  the oxygens in O2)
• and this is how oxygen gets carried around the
  blood by the haemoglobin.

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• When the oxygen gets to where it is needed, it
  breaks away from the haemoglobin which returns to
  the lungs to get some more.
• carbon monoxide is poisonous and it reacts with
  haemoglobin.
• It bonds to the same site that would otherwise be
  used by the oxygen - but it forms a very stable
  complex.
• The carbon monoxide doesn't break away again, and
  that makes the haemoglobin molecule useless for
  any further oxygen transfer.

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A hexadentate ligand

• A hexadentate ligand has 6 lone pairs of
  electrons - all of which can form co-ordinate
  bonds with the same metal ion.
• The best example is EDTA.
• EDTA is used as a negative ion - EDTA4-.
• Used as anti-coagulant for blood in laboratory.

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EDTA in laboratory

• EDTA binds to clotting factors e.g. fibrinogen.
• Fibrinogen becomes inactive i.e. cannot function
  as a coagulant.
• This prevents blood from clotting.

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Cu(EDTA)2-

• The EDTA ion entirely wraps up a metal ion using
  all 6 of the positions.
• The co-ordination number is again 6 because of
  the 6 co-ordinate bonds being formed by the
  central metal ion.

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Organic Molecular Complexes

• Organic coordination compounds are held together
  by weak valence forces.
• Dipole-dipole, London forces, hydrogen bonding
• Cannot be separated from solutions
• Difficult to detect presence
• Possible if there is no steric hindrance

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e.g. 1) Quinhydrone Complexes
Whitening agent

• A complex of benzoquinone and hydroquinone
• Resulted from overlap of pi-framework of
  electron-rich hydroquinone
• Molecules polarise one another - charge transfer
  complexes
• May be contributed by hydrogen bonding
• E.g. quinhydrone of salicylic acid
• Use as organic electrode

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e.g. 2) Picric Acid Complexes

• Reaction between picric acid and weak bases
• E.g. Butesin2 picrate
• Reaction between picric acid and carcinogenic
  agents
• Complexation due to carcinogenic activity
• Reduces carcinogenicity

anaesthetic
antiseptic
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e.g. 3) Drug Complexes

• Interaction between caffeine and sulfonamide due
  to
• dipole-dipole force
• or hydrogen bonding between polarized carbonyl
  group of caffeine and hydrogen atom of acid
• Secondary non-polar interaction
• Reduced solubility of complex is possible!!!

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e.g. 4) Polymer complexes
Xlinked polyvinyl pyrrolidone

• Crosspovidone, porous polymer and dipolar, binds
  with acetaminophen due to phenolic interaction
  (drug)
• Negative effect Tweens and salicylic acid
• Polyolefin container interaction with drugs
  depends on octanol-water partition coefficient
• Liquid form -gt loss of active component
• Drugs may precipitate, flocculate, -gtdelayed
  biological absorption

End of lecture 2/3
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• End of lecture 2/3

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Inclusion Compounds

• These complexes are formed when a guest
  molecule is partially or fully included inside a
  host molecule .
• physicochemical parameters of the guest molecule
  are disguised or altered
• improvements in the molecule's solubility,
  stability, taste, safety, bioavailability, etc.

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Types of Inclusion Compounds

• Channel lattice type
• Layer type
• Clathrates or cage type
• Monomolecular inclusion compound
• Macromolecular inclusion compound

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Channel lattice type

• The crystals are arranged to form a channel
• Other molecules can fit into these channels
• Examples
• deoxycholic acid with paraffins, organic acids
• Urea thiourea with unbranched paraffins
• Starch-iodine solution
• Use of urea to separate long chain compounds?

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Channel type inclusion compound

• The TANO radical, C9H16NO2, forms stable
  channel-type inclusion compounds with a large
  variety of linear molecules.
• The TANO host-matrix contains parallel channels
  of 5 angstroms in diameter in which guest chains
  are packed end to end.
• Figures L guest in TANO matrix, RDiameter of
  the channel

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Molecular structure of inclusion compound of
(4R,5R)-4,5-bis(hydroxydiphenylmethyl)2,2-dimethy
l-1,3-dioxolane with ethanol.
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Layer type

• The crystals are arranged to form layers
• Other molecules can fit into these layers
• Examples
• Montmorrillonite clay to trap HCs
• Graphite

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Clathrates

• The crystals are cage-like
• Guest is trapped in this cage
• Stability due to strength of cage
• Examples
• Hydroquinone allows specific size to be
  entrapped such as methyl alcohol, HCl, CO2
• Warfarin sodium USP

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Monomolecular Inclusion Compounds

• A single guest molecule
• is entrapped in the cavity of
• one host molecule.

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e.g. Cyclodextrin

• A macromolecule cyclic oligosaccharides
• To increase solubility of poorly soluble drugs
• Hydrophobic interior, hydrophilic entrances
• Arrangement of the glucose units allows
  accommodation of e.g. mitomycin C, aspirin,
  morphine.
• Activity of drugs depends on orientation in the
  cavity and nature of reaction e.g. pH dependency.

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Cyclodextrin structure
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History of Cyclodextrin

• discovered in 1891 crystallization occurring in
  a bacterial digest of starch.
• evaluation of the unusual crystalline dextrins in
  1903 suggested their cyclic nature but their
  complete structural definition did not occur
  until the 1940s.
• This coincided with the identification of the
  enzyme responsible for their production (Bacillus
  macerans amylase, now referred to as cyclodextrin
  glucosyltransferase), and the recognition of the
  complexing properties of the CD cavity.
• In the next 3040 years, extensive work resulted
  in the ability to produce each of the parent CDs
  in bulk quantities.
• derivatives were prepared with the goal of
  improving characteristics such as complexing
  ability, solubility, and safety.

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Macromolecular Inclusion Compounds

• A.k.a molecular sieves
• Atoms are arranged in three dimensions to produce
  cages and channels
• Examples
• Zeolites (different pore size), dextrins, silica
  gels

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Effects of Complexation

• Interaction between poorly soluble drug and a
  soluble material may form a soluble
  intermolecular complex.
• Improved bioavailability e.g.
• Complexation of iodine with 10-15
  polyvinylpyrrolidone to improve aqueous
  solubility of active agent.
• interaction of salicylates and benzoates with
  xanthines, such as theophylline or caffeine.

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Continue Effects of Complexation

• Enhanced effect
• E.g. stimulant effect of caffeine increases in
  the presence of ventolin
• Reduced absorption
• Iron absorption is poor when taken with tea due
  to complexation of Fe3 with tenate and phytate

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Applications

• Complexation to enhance the physicochemical
  properties of pharmaceutical compounds.
• based on the types of interactions and species
  involved, e.g.,
• metal complexes,
• molecular complexes,
• inclusion complexes, and
• ion-exchange compounds.

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Drugs with ?-cyclodextrins

• Iodine/?-CD (gargle solution)
• Chloramphenicol/Me- ?-CD (eye drop)
• Cephalosporin ME 1207/?-CD (tablet)
• Dexamethasone/ ?-CD (ointment)
• From
• Encyclopedia of Pharmaceutical Technology 2nd.
  Ed.

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Example CAPTISOLCyDex's SBE7-ß-CD product.

• a polyanionic ß-cyclodextrin derivative with a
  sodium sulfonate salt separated from the
  lipophilic cavity by a butyl ether spacer group,
  or sulfobutylether (SBE).
• does not exhibit the nephrotoxicity associated
  with parent ß-cyclodextrin.
• comparable or higher complexation characteristics
  and superior water solubility

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Example CAPTISOL Extent of Drug Stability

• The extent of stabilization observed is related
  to
• the concentration of CAPTISOL
• the strength of the complex
• pH
• storage conditions

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Example CAPTISOL Improves Physical stability

• The shelf life of fosphenytoin, at pH 7.4 and
  25C is increased from lt1 year to gt4.5 years
• solubilizes the hydrolytically produced phenytoin
  and prevents it from precipitation.
• stabilizes some protein and peptide formulations
  by minimizing aggregation, preventing adsorption
  to containers and aiding in refolding.
• The presence of SBE-CDs has been shown to
  decrease the aggregation of insulin and nearly
  doubles subcutaneous bioavailability to 96.

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Oral Clathration Therapy

• clathration therapy has many documented benefits
  over chelation therapy
• use for heavy metal poisoning, and for children
  experiencing behavioral disorders including
  attention deficit/hyperactivity disorder, bouts
  of violence, and impaired IQ.

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Clathration Therapy vs. Chelation

• glycoproteins and peptides form inclusion complex
  and multiple receptor sites attach to a toxic
  molecule with irreversible bonds, literally
  wrapping around the toxic substance to prevent
  additional reactions with tissues or organs as it
  is eliminated from the body.
• Not one but three major types of bonds at
  multiple points are created ionic, covalent and
  hydrogen bonds.
• Clinical reports indicate clathration therapy
  might be a more effective heavy metal
  detoxification therapy .

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• heavy metal chelation agents include
• ethylene diaminetetraacetic acid (EDTA),
• d-penicillamine
• dimercaptoproponol.
• oral clathration agents include
• PCA and PCA-Rx from ASN/Maxam Nutraceutics
  peptide clathration formula ever created for
  natural detoxification
• PCA-Rx is said to have a high bonding affinity
  for heavy metals.

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References

• ME Aulton, Pharmaceutics The Science of Dosage
  Form Design, Churchill Livingstone (2002) Chapter
  21
• MS Silberberg, Chemistry The Molecular Nature of
  Matter and Change 3rd. Ed., McGraw-Hill (2003)
  Chapter 23
• H. Dodziuk (ed.), Cyclodextrins and Their
  Complexes, Wiley-VCH Weinheim (2006)
• http//www.cydexinc.com/faq.htm
• http//www.ru.ac.za/library/theses/temp/chen/Chapt
  er7d.pdf