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
| ION PAIRS | COORDINATION COMPLEXES |
| formed solely by electrostatic attraction | large covalent component to bonding |
| ions often separated by coordinated waters | ligand and metal joined directly |
| short-lived association | longer-lived species |
| no definite geometry | definite geometry |
| also called outer-sphere complexes | also called inner-sphere 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
| COMPLEX | MOLECULAR COMPOUND |
| Reactions occur in cold conditions | Reactions occur in hot conditions |
| Weaker forces of attraction | Strong electrostatic interaction |
| Cannot be separated from solutions | Can be separated from solutions |
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
| Property | Drug Examples |
| Enhanced aqueous solubility | prostaglandins; ketoprofen and NSAIDs |
| Improved stability | aspirin, atropine, procaine, digoxin, |
| Enhanced absorption and bioavailability | phenytoin, digoxin, diuretics |
| Change from liquid to solid | nitroglycerin, methyl salicylate, oil soluble vitamins |
| Decreased volatility | iodine, camphor, menthol, salicylic acid |
| Improved taste and odor | prostaglandins, NSAIDs, |
| Decreased stomach irritation | indomethacin, NSAIDs |
| Inhibit RBC lysis | antibiotics, menandione, |
| Prevention of incompatibilities | vitamins |
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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