SKKU Physical Pharmacy Laboratoryphysicalpharm.skku.edu/erp/erpmenus/lesson_pds/upLoad... · 2018-10-17 · SKKU Physical Pharmacy Laboratory 성균관대학교물리약학연구실

SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실


Introduction

Metal-ion coordinate complexes

Organic molecular complexes

Inclusion complexes

Cyclodextrin complexes

Ion-exchange resins


Introduction

SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실Montegiro, Komplete


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


Complexation of ligand with substrate

▪ Coordinate covalent bonding

▪ Noncovalent interactions▪ van der Waals forces

▪ Dipolar forces

▪ Electrostatic forces

▪ Hydrogen bonding

▪ Charge transfer

▪ Hydrophobic interaction


Metal-ion coordinate complexes


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


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]


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


Heme proteins

▪ Myoglobin & Hemoglobin ▪ Transport of oxygen in blood and tissues

▪ Cytochrome c ▪ Photosynthetic and respiratory system


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


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


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


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


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)


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


Chelating agents ▪ Treat toxicity of lead and mercury poisoning incidences

▪ Dicalcium salt of EDTA

▪ 2,3-dimercaptopropanol (BAL)

EDTA


Organic molecular complexes


Noncovalent interactions between ligand and substrate

▪ Oppositely charged ions (electrostatic forces)

▪ van der Waals forces

▪ Charge transfer


▪ 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\


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


Inclusion complexes


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


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


Bentonite ▪ Clay

▪ Montmorillonite

▪ Trap hydrocarbons, alcohols, and glycols between the layers of their lattices

Graphite


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


Monomolecular inclusion compounds:

Cyclodextrins


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


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


⇒ increase aqueous solubility of hydrophobic compounds


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


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


Ion exchange resins


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


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


Drug delivery

▪ Continuous exposure of resin to drug → drug-resin complex → releases free drug


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


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


(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

Documents

SKKU Physical Pharmacy Laboratoryphysicalpharm.skku.edu/erp/erpmenus/lesson_pds/upLoad... · 2018-10-17 · SKKU Physical Pharmacy Laboratory 성균관대학교물리약학연구실