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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
Introduction
Metal-ion coordinate complexes
Organic molecular complexes
Inclusion complexes
Cyclodextrin complexes
Ion-exchange resins
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
Introduction
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실Montegiro, Komplete
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
Complexation ▪ Covalent or noncovalent interactions between two or more compounds that are capable of
independent existence
▪ Ligand ▪ Molecule that interacts with another molecule, substrate, to form a complex
▪ Alteration of physical and chemical properties of complexing species▪ Solubility
▪ Theophylline + ethylenediamine → aminophylline
▪ Stability ▪ Labile drug + cyclodextrin → inclusion complex
▪ Partitioning
▪ Energy absorption & emission
▪ Conductance
▪ Optimization of delivery system▪ Ion-exchange resins
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
Complexation of ligand with substrate
▪ Coordinate covalent bonding
▪ Noncovalent interactions▪ van der Waals forces
▪ Dipolar forces
▪ Electrostatic forces
▪ Hydrogen bonding
▪ Charge transfer
▪ Hydrophobic interaction
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
Metal-ion coordinate complexes
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
Coordination complex (compound)
▪ Complex ion (Transition metal ion)
▪ Ligands
▪ Counterions
Lewis acid-base reaction
▪ Ag+ + 2(:NH3) → [Ag(NH3)2]+
▪ Ligand (base) : NH3▪ Metal ion (acid) : Ag+
▪ Coordinate complex : [Ag(NH3)2]+
▪ Counterion : Cl-
▪ Neutral complex : [Ag(NH3)2]Cl
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
Coordination number
▪ Maximum number of atoms (groups) that can combine in the coordination sphere with central metal atom
▪ K3[Fe(CN)6]
▪ Coordination number : 6
▪ Ligand (base) : CN-
▪ Metal ion (acid) : Fe3+
▪ Coordinate complex : [Fe(CN)6]3-
▪ Counterion : K+
▪ Neutral complex : K3[Fe(CN)6]
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
Unidentate ligand
▪ Single pair of electrons (basic group) bonding with metal ion
▪ Ammonia
Bidentate
▪ Two basic groups
▪ Ethylenediamine
Hexadentate
▪ Six points
▪ EDTA (EthyleneDiamine Tetraacetic Acid)
Multidentate (polydentate)
▪ Multiple binding sites
▪ Polymers
Chelate
▪ A complex that metal ion binds with two or more sites on multidentate ligand
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
Heme proteins
▪ Myoglobin & Hemoglobin ▪ Transport of oxygen in blood and tissues
▪ Cytochrome c ▪ Photosynthetic and respiratory system
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
Myoglobin
▪ Monomeric heme protein in muscle
▪ Intracellular storage site for oxygen
▪ Oxymyoglobin → deoxymyoglobin
▪ Release its bound oxygen for metabolic purpose
▪ Fe2+ (ferrous oxidation state) ⇔ Fe3+ (ferric oxidation state)
▪ Contain one heme group inserted into a hydrophobic cleft in protein
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
Hemoglobin
▪ Tetrameric heme protein [α(2):β(2)] in erythrocytes (red blood cells)
▪ Bind oxygen in lungs and transport bound oxygen throughout body
▪ Oxygen binds to an iron atom of deoxyhemoglobin→ pull iron atom into plane of heme→ conformational change→ new set of binding interactions between adjacent subunits
▪ CO (carbon monoxide)▪ Bind to heme iron protein 200 times stronger than oxygen
→ asphyxiation by carbon dioxide poisoning
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
Deferoxamine
▪ Chelating agent
▪ Treat acute iron overdose
▪ Chelation of Fe3+ (ferric iron)→ strong coordinated water-soluble ferrioxamine complex→ excrete through kidney
▪ Low affinity for divalent ions (Fe2+, Ca2+)
▪ 100-mg dose of deferoxamine can bind with 8.5 mg of Fe3+ ion
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
Platinum (II) complexes
▪ Cisplatin & Carboplatin
▪ Treat cancer (ovarian & lung cancer)
▪ Toxicity
▪ Cisplatin > Carboplatin
▪ Bidentate dicarboxylate ligand in carboplatin slows degradation of carboplatin into potentially damaging derivatives
▪ Half life : carboplatin - 30 h cisplatin - 1.5 ~ 3.6 h
▪ Ring size of ligand increase → more effective at killing cancer cell
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
Copper ion
▪ Proteins & enzymes
▪ Hemocyanin
▪ Superoxide dismutase
▪ Cytochrome oxidase
▪ Cu (I) : colorless tetrahedral complexes Cu (II) : blue
▪ When bound oxygen, transition to Cu (II)
Cobalt ion
▪ Vitamin B12 (cyanocobalamin)
▪ Center of conjugated corrin ring structure
▪ Co (II) and Co (III)
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
Zinc
▪ Crystalline insulin
▪ Insulin hexamer can bind up to 9 atoms of zinc
▪ Zinc finger (loop)
▪ Zn2+ binds tetrahydrally with 2 histidine and 2 cysteine residues of protein
▪ Carboxypeptidase
▪ Carbonic anhydrase
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
Chelating agents ▪ Treat toxicity of lead and mercury poisoning incidences
▪ Dicalcium salt of EDTA
▪ 2,3-dimercaptopropanol (BAL)
EDTA
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
Organic molecular complexes
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
Noncovalent interactions between ligand and substrate
▪ Oppositely charged ions (electrostatic forces)
▪ van der Waals forces
▪ Charge transfer
▪ Hydrogen bonding
▪ Hydrophobic effects
Small molecule & small molecule
▪ Ehtylenediamine + theophylline → aminophylline
Small molecule & large molecule
▪ Iodine + PVP → Povidone
Ion pairs
▪ Ion-exchange resins
Self-association to form aggregates
▪ Surfactant micelles\
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
Drug complexes▪ Caffeine interacts with several drugs (e.g., benzocaine)
→ alteration of physicochemical properties(solubility, dissolution rate, etc)
Polymer complexes▪ Incompatibilities of certain polymers (Carbowaxes, Pluronics, and Tweens)
with tannic acid, salicylic acid, and phenol is due to formation of complexes
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
Inclusion complexes
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
Inclusion (occlusion) complexes
▪ Compounds resulting more from architecture of molecules than from chemical affinity
▪ Channel lattice type
▪ Layer type
▪ Clathrates
▪ Monomolecular inclusion compounds: Cyclodextrins
▪ Molecular sieves
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
Choleic acid▪ Deoxycholic acid is arranged to form a channel
into which the complexing molecule can fit
Urea ▪ Crystallize in a channel-like structure
permitting enclosure of unbranched paraffins, alcohols, ketones, organic acids, and others
Thiourea
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
Bentonite ▪ Clay
▪ Montmorillonite
▪ Trap hydrocarbons, alcohols, and glycols between the layers of their lattices
Graphite
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
Coordinating compound is entrapped in the form of a cage-like lattice
▪ Molecular size of encaged components is important
Hydroquinone (quinol)▪ Cage-like hydrogen-bonded structure
▪ 4.2 Å hole
▪ Entrap one small molecule to every two quinol molecules
▪ Molecules like MeOH, CO2, HCl can be trappedbut smaller molecules (H2) and larger molecules (EtOH) cannot be accommodated
Warfarin sodium
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
Monomolecular inclusion compounds:
Cyclodextrins
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
Cyclodextrin
▪ Isolated 1891, Villiers
▪ Characterized 1904, Schardinger
▪ Donut-shaped molecules of D-glucopyranose
Cyclodextrintype
No. Of Glucose residues
Molecular weight
Internal cavity
dimension, Å
Melting point, ℃
Aqueous solubility, g/100 mL
Alpha (α) 6 973 5 275 15
Beta (β) 7 1135 6 280 1.9
Gamma (γ) 8 1297 8 275 23
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
Cyclodextrin
▪ No toxicity
▪ 1.6 g/kg in rats
▪ Low aqueous solubility of β-cyclodextrin
▪ 1.9 g/100 mL
▪ Synthesize substituted form
▪ Methyl-, dimethyl-, 2-hydroxypropyl-→ aqueous solubility excess of 60 g/100 mL
▪ Nonpolar nature of cavity
▪ Hydrophilic nature of surface▪ Multiple hydroxyl (-OH) functional groups
▪ Hydrogen bonding
⇒ increase aqueous solubility of hydrophobic compounds
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
Applications of cyclodextrin
▪ Food preparation▪ Stabilize flavors
▪ Eliminate unpleasant tastes and odors
▪ Cosmetics & dentifrices▪ Preparation of long-acting deodorants and emulsion bases
▪ Pesticides▪ Decrease in volatility and decomposition
⇒ easier application and decrease negative environmental consequences
▪ Analytic chemistry▪ Enhance signal
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
Pharmaceutical applications
▪ Conversion of liquid products into powders
▪ Decreased toxicity of drug in GI tract▪ Aspirin + cyclodextrin
▪ Decreased volatility
▪ Enhancement of aqueous solubility, absorption, and bioavailability
▪ Improved stability
▪ Masking of unpleasant taste and odors
▪ Prevention of incompatibilities
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
Ion exchange resins
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
Ion exchange▪ Electrostatic interactions between bound ions on a solid particle (resin)
and oppositely charged ions in solution
▪ Organic (polymer)
▪ Polystyrene (cross-linked with divinylbenzene)
▪ Inorganic (mineral)
▪ Zeolites (natural, aluminum silicate chemistry)
▪ Cation exchangers
▪ Replace (+) ion on surface with similarly charged ion
▪ Anion exchangers
▪ Replace (-) ion on surface with similarly charged ion
▪ Purification, drug delivery
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
Ion-exchange chromatography (separation)
▪ Chemicals are removed selectively from solution by passing through solid resin bed (stationary phase)
Hardness of water
▪ Ca2+, Mg2+ ion
▪ Zeolite (Permutite) replace undesirable ions to Na+ ion▪ Saturated with metal ion → wash with Na+ solution
Amberlite ion exchange and XAD adsorbent resins
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
Drug delivery
▪ Continuous exposure of resin to drug → drug-resin complex → releases free drug
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
Cross-linked poly(styrene sulfonate) resins
▪ Amphetamine (Biphetamine capsules)
▪ Phentermine (Ionamin)
▪ Codeine, morphine (hydrocodone, chloropherinamine in Tussionex)
Delsym (Penn kinetic system)
▪ Dextromethorphan-resin complex
▪ Coated with ethylcellulose
▪ 12 h of release
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
Therapeutic action
▪ Kayexalate (+)▪ Sodium polystyrene sulfonate in 70% sorbitol suspension
▪ Treat hyperkalemia
▪ Renagel (-)▪ Cross-linked alylamine HCL
▪ Treat hyperphosphatemia
▪ Cholestyramine & Colestipol (+)▪ Cross-linked polystyrene
▪ Bind with bile acid → decrease cholesterol
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SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실
(1) Mansoor M. Amiji and Beverly J. Sandmann
(2) Patrick J. Sinko
(3) Alexander T. Florence and David
Attwood
(4) David Attwood and Alexander T. Florence