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 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 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 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 Heme proteins Myoglobin & Hemoglobin ▪ Transport of oxygen in blood and tissues Cytochrome c ▪ Photosynthetic and respiratory system 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 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 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 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 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) 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 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 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 Organic molecular complexes 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\ 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 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 Inclusion complexes 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 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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 Bentonite Clay Montmorillonite Trap hydrocarbons, alcohols, and glycols between the layers of their lattices Graphite 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 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 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 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 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 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 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 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 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 (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