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Complex Formation Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D Department of Pharmaceutics Faculty of Pharmacy Omer Al-Mukhtar University Tobruk, Libya. E-mail: [email protected] 2014/03/16 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 1 CONTENTS 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Definition Metal Complex Organic Molecular Complex Inclusion Complex Methods of Analysis Continuous variation Spectroscopy methods Distribution methods Protein Binding Drug Action 2014/03/16 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 2 Definition • Complex compounds are defined as those molecules in which most of the bonding structures can be described by classical theories of valency between atoms, but one or more of these bonds are somewhat anomalous(different). 2014/03/16 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 3 Metal Complex • In this type, metal ion constitutes the central atom (substrate) and interacts with a base (electron-pair donor, ligand). • This type of interaction leads to the formation of coordination bonds between the species. Classification of metal complex 1. Inorganic types 2. Chelates 3. Olefin types 2014/03/16 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 4 1. Inorganic types • In inorganic metal complexes, the ligand provides only one site for binding with metal. 2014/03/16 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 5 2. Chelates • Chelates are a group of metal ion complexes in which a substance (ligand) provides two or more donor groups to combine with a metal ion. EDTA: Ethylenediamine tetraacetic acid 2014/03/16 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 6 3. Olefin types • These types of complexes are used as catalysts in the manufacture of bulk drugs, intermediates and in the analysis of drugs. 2014/03/16 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 7 Organic Molecular Complex • In this type of coordination complexes, components are organic molecules and these are held together by weaker forces or hydrogen bonding. Classification of organic molecular complex 1. Drug and caffeine complexes 2. Polymer types 3. Picric acid types 4. Quinhydrone types 2014/03/16 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 8 1. Drug and caffeine complexes • Drugs such as benzocaine, procaine and tetracaine form complexes with caffeine. • A number of acidic drugs are known to form complexes with caffeine. 2014/03/16 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 9 2. Polymer types • Many pharmaceutical additives such as polyethylene glycols (PEGs), carboxymethyl cellulose (CMC) contain nucleophilic oxygen. These can form complexes with various drugs. E.g. Polymers: carbowaxes, pluronics etc. Drugs: tannic acid, salicylic acid, phenols etc. Carboxyl methylcellulose (CMC) + Amphetamine = poorly absorbed complex (tablet additive – drug interaction) 2014/03/16 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 10 3. Picric acid types • Picric acid, being a strong acid, forms organic molecular complexes with weak bases, whereas it combines with strong bases (anesthetic activity of butesin) to yield salts. 2014/03/16 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 11 4. Quinhydrone types • The molecular complex of this type is obtained by mixing alcoholic solutions of equimolar quantities of hydroquinone and benzoquinone. 2014/03/16 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 12 Inclusion Complex • These complexes are also called occlusion compounds in which one of the components is trapped in the open lattice or cage like crystal structure of the other. Classifications of Inclusion complex 1. Channel types 2. Layer types 3. Clathrates 4. Monomolecular types 2014/03/16 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 13 1. Channel types • Channels are formed by crystallization of the host molecules, the guest component is usually limited to long, unbranched straight chain compounds. 2014/03/16 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 14 2. Layer types • Compounds such as clays, montomorillorite (constituent of bentonite), can entrap hydrocarbons, alcohols and glycols. • They form alternate monomolecular (monoatomic) layers of guest and host. • Their uses are currently quite limited; however these may be useful for catalysis on account of a larger surface area. 2014/03/16 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 15 3. Clathrates • It is available as white crystalline powder, during crystallization, certain substances form a cage-like lattice in which the coordinating compound is entrapped. 2014/03/16 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 16 4. Monomolecular types • Monomolecular inclusion compounds involve the entrapment of a single guest molecule in the cavity of one host molecule. • Most of the host molecules are cyclodextrins. • The interior of the cavity is relatively hydrophobic, whereas the entrance of the cavity is hydrophilic in nature. 2014/03/16 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 17 Methods of Analysis • The analysis of complexes involves the estimation of two parameters. 1. The stoichiometric ratio of ligand-to-metal or donorto-acceptor. 2. Stability constant of the complex. 2014/03/16 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 18 Methods of Analysis 2014/03/16 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 19 Continuous variation • The physical properties, such as dielectric constant, refractive index and spectrophotometric extinction coefficient, are characteristics of a particular species. • When there is no complexation between these species (A and B), the value of property is additive. • This particular behaviour is represented in figure as dotted line. In case of complexation, these properties change, i.e. additive phenomena do not hold good. 2014/03/16 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 20 Continuous variation 2014/03/16 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 21 Spectroscopy methods • The UV spectroscopy is used extensively in determining rate constants, equilibrium constants, acid-base dissociation constants etc for chemical reactions. 2014/03/16 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 22 Distribution methods • The distribution behaviour of a solute between two immiscible liquids is expressed by distribution coefficient or partition coefficient. • When a solute complexes with an added substance, the solute distribution pattern changes depending on the nature of a complex. • A set of such experiments provides data for the estimation of complex equilibrium stability. 2014/03/16 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 23 Protein Binding • The phenomenon of complex formation with proteins is called as protein binding of drugs. Protein binding may be divided into: 1. Intracellular binding: These receptors with which drug interact to show response are called as primary receptors. 2. Extracellular binding: These receptors are called secondary or silent receptors. 2014/03/16 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 24 Equilibrium Dialysis Method 2014/03/16 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 25 Dynamic Dialysis Method 2014/03/16 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 26 Drug Action • Protein binding inactivates the drug, because sufficient concentration of drug cannot be built up in the receptor site for action. Example is naphthoquinones. • Certain drugs though bind to proteins, still retain the drug activity. Examples are penicillins and sulfadiazine. 2014/03/16 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 27 References • Text book of Physical Pharmaceutics by Dr. CVS Subrahmanyam. 2014/03/16 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 28 THANK YOU e-mail: [email protected] 2014/03/16 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 29