Ion exchange resins - Physical Pharmacy Laboratory

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SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

Introduction

Metal-ion coordinate complexes

Organic molecular complexes

Inclusion complexes

Cyclodextrin complexes

Ion-exchange resins
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Introduction
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
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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
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
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Metal-ion coordinate complexes
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
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
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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) : CNMetal ion (acid) : Fe3+
Coordinate complex : [Fe(CN)6]3Counterion : K+
Neutral complex : K3[Fe(CN)6]
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
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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
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
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Heme proteins
 Myoglobin & Hemoglobin
▪ Transport of oxygen in blood and tissues
 Cytochrome c
▪ Photosynthetic and respiratory system
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
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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
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
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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
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
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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
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
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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
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
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Copper ion
 Proteins & enzymes
▪ Hemocyanin
▪ Superoxide dismutase
▪ Cytochrome oxidase
 Cu (I) : colorless tetrahedral complexes
Cu (II) : blue
 When bound oxygen, transition to Cu (II)
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Cobalt ion
 Vitamin B12 (cyanocobalamin)
 Center of conjugated corrin ring structure
 Co (II) and Co (III)
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
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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
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
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Chelating agents
▪ Treat toxicity of lead and mercury poisoning incidences
 Dicalcium salt of EDTA
 2,3-dimercaptopropanol (BAL)
EDTA
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Organic molecular complexes
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
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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\
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
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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
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Inclusion complexes
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
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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
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
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Choleic acid


Urea


Deoxycholic acid is arranged to form a channel
into which the complexing molecule can fit
Crystallize in a channel-like structure
permitting enclosure of
unbranched parrafins, alcohols,
ketones, organic acids, and others
Thiourea
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
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Bentonite

Clay
 Montmorillonite
 Trap hydrocarbons, alcohols, and glycols between the layers of their lattices

Graphite
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
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Coordinating compound is entrapped in the form of a cage-like lattice
 Molecular size of encaged components is important
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Hydroquinone (quinol)

Cage-like hydrogen-bonded structure
 4.2 Å hole
 Entrap one small moelcule to every two quinol molecules
 Molecules like MeOH, CO2, HCl can be trapped
but smaller molecules (H2) and larger molecules (EtOH)
cannot be accommodated

Warfarin sodium
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Monomolecular inclusion compounds:
Cyclodextrins
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
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Cyclodextrin
 Isolated 1891, Villiers
 Characterized 1904, Schardinger
 Donut-shaped molecules of D-glucopyranose
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
Cyclodextrin
type
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
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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
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
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Applications of cyclodextrin
 Food preparation
▪ Stabilize flavors
▪ Eliminate unpleasant tastes and odors
 Cosmetics & dentifrices
▪ Preparation of long-acting deodrants and emulsion bases
 Pesticides
▪ Decrease in volatility and decomposition
⇒ easier application and decrease negative environmental consequences
 Analytic chemistry
▪ Enhance signal
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
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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
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Ion exchange resins
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
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
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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
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
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Drug delivery
 Continuous exposure of resin to drug
→ drug-resin complex → releases free drug
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
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
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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
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
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(1) <Applied Physical Pharmacy 6th > Mansoor M. Amiji and Beverly J. Sandmann
(2) <Martin’s Physical Pharmacy and Pharmaceutical Sciences 5, 6th> Patrick J. Sinko
(3) <Physicochemical Principles of Pharmacy 4th > Alexander T. Florence and David
Attwood
(4) <Fast Track – Physical Pharmacy> David Attwood and Alexander T. Florence
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실

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