physical pharmaceutics, Lecture notes of Pharmaceutical Chemistry

Download physical pharmaceutics and more Lecture notes Pharmaceutical Chemistry in PDF only on Docsity!

FACULTY OF PHARMACEUTICAL SCIENCES,

RAMAUNIVERSITY, KANPUR

B.PHARM 3 rd^ SEM PHYSICAL PHARMACEUTICS-I BP 302 T MR. PEEYUSH Assistant professor Rama university, kanpur

Complexation

Overview Classification Introduction Metal ion complexes Organic Complexes Inclusion Complexes Methods of Analysis Method of Continuous Variation PH Titration Distribution Method Solubility Method Spectroscopy

Classification Introduction Metal ion complexes Organic Complexes Inclusion Complexes

INTRODUCTION

Complexes are compounds that result from donor–acceptor mechanisms between two or more chemical species. Complexes can be divided broadly into three classes depending the type of the acceptor substance:

1. Metal ion complexes
2. Organic molecular complexes
3. Inclusion complexes Intermolecular forces involved in the formation of complexes:
4. Van der Waals forces.
5. Hydrogen bonds (important in molecular complexes).
6. Coordinate covalence (important in metal complexes).
7. Charge transfer.
8. Hydrophobic interaction.

Introduction Types of Complexes Metal Ion Complexes A. Inorganic type B. Chelates C. Olefin type D. Aromatic type II. Organic Molecular Complexes A. Quinhydrone type B. Picric acid type C. Caffeine and other drug complexes D. Polymer type III. Inclusion Compounds A. Channel lattice type B. Layer type C. Clathrates D. Monomolecular type E. Macromolecular type Metal ion complex (coordination complex) consists of a transition-metal ion (e.g. cobalt, iron, copper, nickel and zinc) linked or coordinated with one or more counter ions or molecules to form a complex. The ions or molecules (e.g. Cl

• , NH 3 , H 2 O, Br - , I - , CN - , etc.) directly bound with the metal are called ligands. The interaction between the metal and the ligand represents a Lewis acid-base reaction in which the metal ion (Lewis acid) combines with a ligand (Lewis base) by accepting a pair of electrons from the ligand to form the coordinate covalent or electrostatic forces: Co3+^ + 6 : NH 3 ‹ [Co NH 3 6 ]3+

Compound (e.g. NH 3 ) which has a single pair of electrons for bonding with the metal ion, is called unidentate ligand. Ligands with two or three groups are known as bidentate or tridentate respectively. Ethylenediaminetetraacetic acid (EDTA) has six points for attachment (two nitrogen and four oxygen donor groups) and is called hexadentate. Metal ion Complexes Chelates Chelation is the formation of two or more coordinate bonds between a multidentate ligand (organic compound called chelating agent) and a single central atom. The bonds in the chelate may be ionic, primary covalent, or coordinate type. EDTA Complex

Organic Molecular Complexes Organic molecular complexes are formed as a result of non- covalent interactions between a ligand and a substrate. The interactions can occur through van der waals forces, charge transfer, hydrogen bonding or hydrophobic effects. Many organic complexes are so weak that they cannot be separated from their solutions as definite compounds, and they are often difficult to detect by chemical and physical means. Organic Molecular Complexes Complexation differs from the formation of organic compounds in the forces between the constituents: E.g. Dimethylaniline and 2,4,6-trinitroanisole react in the cold to give a molecular complex. However at elevated temperature, they react to yield a salt, in which the molecules are held together by primary valence bonds. Salt Complex

Organic Molecular Complexes 2 Quinhydrone Complex This molecular complex is formed by mixing equimolar quantities of benzoquinone with hydroquinone. Complex formation is due to overlapping of the w-framework of the electron-defficient benzoquinone with the w-framework of the electron-rich hydroquinone (charge transfer). Organic Molecular Complexes Picric Acid Complexes Picric acid (2,4,6-trinitrophenol), is a strong acid that forms complexes with many weak bases such as poly-nuclear aromatic compounds. An example is Butesin picrate (local anaesthetic) which is a complex formed between two molecules of butyl p- aminobenzoate with one molecule of picric acid.

Organic Molecular Complexes ð+ ð– ð+ (^) ð– ð– ð Caffeine Complexes Caffeine forms complexes with a number of drugs owing to the following factors: Hydrogen bonding between the polarizable carbonyl group of caffeine and the hydrogen atom of the acidic drugs such as p-amino benzoic acid and gentisic acid. Dipole-dipole interaction between the electrophilic nitrogen of caffeine and the carboxy oxygen of esters such as benzocaine or procaine Organic Molecular Complexes Caffeine Complexes Caffeine forms water soluble complexes (more soluble than caffeine itself) with organic acid anions , but the complexes formed with organic acids, such as gentisic acid, are less soluble than caffeine alone. Such insoluble complexes provide caffeine in a form that masks its normally bitter taste in chewable tablets.

Inclusion Complexes

An inclusion compound is a complex in which one chemical compound (the ‘host’) forms a cavity in which molecules of a second compound (‘guest’) are entrapped. These complexes generally do not have any adhesive forces working between their molecules and are therefore also known as no-bond complexes. Inclusion Complexes Channel Lattice Type In this complex, the host component crystallizes to form channel-like structure into which the guest molecule can fit. The guest molecule must possess a geometry that can be easily fit into the channel-like structure Channel lattice complexes provides a mean of separation of optical isomers. The cholic acids (bile salt) is an example of this complex type. The crystals of deoxycholic acid are arranged to form a channel into which the complexing molecule can fit. The well-known starch–iodine complex is a channel-type complex consisting of iodine molecules entrapped within spirals of the glucose residues

Inclusion Complexes

Channel Lattice Type Inclusion Complexes Layer Type Layer type complex (or intercalation compound) is a type of inclusion compound in which the guest molecule is diffused between the layers of carbon atom, to form alternate layers of guest and host molecules. Montmorillonite, the principal constituent of bentonite, can trap hydrocarbons, alcohols, and glycols between the layers of their lattices. Graphite can also intercalate compounds between its layers.

Inclusion Complexes Monomolecular Inclusion Compounds: Cyclodextrins Monomolecular inclusion complex involves the entrapment of guest molecules into the cage-like structure formed from a single host molecule. Cyclodextrins are a family of compounds made up of sugar molecules bound together in a ring (cyclic oligosaccharides) They consist of 6, 7, and 8 units of glucose referred to as a, þ, and ç cyclodextrins, respectively. Cyclodextrin type Glucose Internal Aqueous solubility USP name Inclusion Complexes Monomolecular Inclusion Compounds: Cyclodextrins Cyclodextrons have truncated cone structure with a hydrophobic interior cavity because of the CH 2 groups, and a hydrophilic exterior due to the presence of hydroxyl group. units diameter a-cyclodextrins 6 4.7-5.3 Å 14.5 g/100 mL Alfadex þ-cyclodextrins 7 6.0-6.5 Å 1.85 g/100 mL Betadex ç-cyclodextrins 8 7.5-8.3 Å 23.2 g/100 mL Gammadex

Inclusion Complexes Monomolecular Inclusion Compounds: Cyclodextrins Molecules of appropriate size and stereochemistry get entrapped in the cyclodextrin cavity by hydrophobic interaction by squeezing out water from the cavity. Inclusion Complexes Monomolecular Inclusion Compounds: Cyclodextrins Cyclodextrins can enhance the solubility and bioavailability of hydrophobic compounds due to the large number of hydroxyl groups on the CDs. Cavity size is the major determinant as to which cyclodextrin is used in complexation. a-Cyclodextrins have small cavities that are not capable of accepting many molecules. ç-Cyclodextrins have much larger cavities than many molecules to be incorporated. The cavity diameter of þ-cyclodextrins has been found to be the most appropriate size for most drugs. For this reason, þ- cyclodextrin is most commonly used as a complexing agent

Inclusion Complexes Monomolecular Inclusion Compounds: Cyclodextrins In addition to hydrophilic derivatives, hydrophobic forms of þ- CD have been used as sustained release drug carriers.

Inclusion Complexes Monomolecular Inclusion Compounds: Cyclodextrins In addition to improving the solubility of compounds, complexation with cyclodextrin has been used to improve the stability of many drugs by inclusion of the compound and protecting certain functional groups from degradation. Complexation with cyclodextrins has also been used to mask the bitter taste of certain drugs such as femoxetine. Inclusion Complexes Macromolecular Inclusion Compounds Macromolecular inclusion compounds, ( molecular sieves ) include substances such as zeolites, dextrins, and silica gel. The atoms are arranged in three dimensions to produce cages and channels in which the guest molecules are entrapped. Synthetic zeolites can be made to a definite pore size to separate molecules of different dimensions.