COMPLEXATION : A solubilization technique for poorly soluble drugs

Seminar submitted during I M.Pharmacy (pharmaceutics)

I  Semester Course

By

J.Keerthi Priya , B.Pharm.

Under the supervision of

Dr.S.A.Azeez , M.Pharm. PGDM.Ph.D.

Professor & Principal

JAN – 2012

SIMS college of pharmacy, Mangaldas Nagar,

Guntur.

Solubility: The concentration of the solute in a saturated solution at a certain temperature.

Or The spontaneous interaction of two or

more substances to form a homogenous molecular dispersion.

drug molecules in solution

Solubilization: A process of dissolving poorly soluble solute molecules in solvent in the presence of a component or components.

INTRODUCTION

Process of solubilization

WHAT IS THE NEED OF SOLUBILIZATION

NEED OF SOLUBILIZATION

NEED OF SOLUBILIZATION

Poorly soluble drug

Poorly soluble drug after solubilization

SOLUBILIZATION TECHNIQUES1.Physical Modifications: i. Particle size reduction Micronization Nano suspension Sonocrystalisation Supercritical fluid process ii. Modification Of the crystal habit Polymorphs Pseudo polymorphs iii. Drug dispersion in carriers Eutectic mixtures Solid dispersions Solid solutions

iv. Complexation: Use of complexating agents

V. Solubilization By surfactants: Microemulsions Self microemulsifying drug delivery systems2) Chemical modifications: Other methods Co crystallisation Co solvency Hydro trophy Solvent deposition Selective adsorption on insoluble carrier Use of soluble prod rug Functional polymer technology Porous micro particle technology Nanotechnology approaches

COMPLEXATION A complex is a species formed by the association of two or more interacting molecules or ions.

Or A complex is a species of definite substrate to ligand stoichiometry that can be formed in an equilibrium process in solution and also may exist in solid state.Substrate(S) is the interactant whose physical or chemical properties are observed experimentally.Ligand (L) is the second interactant whose concentration may be varied independently in an experimental study.

mS + nL SmLn

Classification of complexesI. Metal ion complexes a. Inorganic type b. Chelates c. Olefin type d. Aromatic type

i) Pi ) complexes ii) Sigma complexes iii) Sandwich complexes

II. Organic molecular complexes a. Quinhydrone type b. Picric acid type c. Caffeine other drug complexes d. Polymer type

III. Inclusion / occlusion complexes a. Channel lattice type b. Layer type c. Clathrates d. Monomolecular type e. Macromolecular type

METAL ION COMPLEXES

METAL ION COMPLEXES Metal ion constitutes the central atom (substrate) and interacts with a base (electron pair donor, ligand) , leading to the formation of coordination bonds between the species.Inorganic complexes: Each ligand donates a pair of electrons to form a coordinate covalent link between itself and the central ion having an incomplete electron shell.

Alfred Werner

E.g.: The coordination number of cobalt is 6.Trivalent cobalt ion Co(III) :

The electronic configuration of metal ion leading to filled 3d levels is

Bond types of representative compounds

Mono dentate: ligand that bonds through one of its atoms to the metal ion.

_____ ____ ____

E.g. : H2O, NH3, CO, CN, OH , Cl , etc.,

Depending on the number of donor groups available for complexation , ligands are called Monodentate Polydentate Bidentate Tridentate Tetradentate Hexadentate

Mono dentate ligands can be further classified based on the charge Cationic Neutral Anionic

MONO DENTATE LIGANDS

Anionic ligands

MONO DENTATE LIGANDS

Neutral ligands

Cationic ligands

• Bidentate (two groups): ligand that bonds through two of its atoms with the metal Ion.

E.g.:

Ethylenediamine Ethyl acetoacetate

POLYDENTATE LIGANDS

POLYDENTATE LIGANDS

CHELATES If a metal ion binds to two or more sites on a multidentate ligand , a cyclic complex is formed , this cyclic complex is a chelate.

Produce a precipitate or a stable water soluble compound.

If the ligand forms water soluble metal chelate, it is said to be a sequestering agent.

E.g.: citric acid , tartrates , EDTA etc.,

chelate formation is involved in a number of number of biological processes and renders valuable functions.

E.g.: chlorophyll , hemoglobin , etc.,

Examples of chelating agents

Ethylene diamine

E.g.: Nickel (II)

Chelate with one ethylene diamine ligand

Chelate with two ethylene diamine ligand

Chelate with three ethylene diamine ligand

Examples of chelating agents

porphine Heme

Examples of chelating agents

Applications of chelates Increase in stability E.g. : inhibit oxidative degradation of ascorbic acid in fruit juices and in drug preparations.

Purification of hard water E.g. : remove calcium ions from hard water.

Analysis of drugs E.g. : assay of procainamide in injectable solution.

Anticoagulant E.g. : citrates , oxalates, EDTA.

Olefin and aromatic types These types of complexes are used as catalysts in the manufacture of

I. bulk drugs II. intermediates and III. in the analysis of

drugs

Organic molecular complexes In this type of co ordinate complexes components are organic molecules and these are held together by weaker forces or H-bonding. Force of interaction F = -

Noncovelent forces :1.Electrostatic forces among ions and molecules possessing permanent dipole moments.2.Induction or polarization forces between ion and a nonpolar molecule or a polar molecule and a non polar molecule.3.Dispersion (London) force, which operate between all the molecules.

dV

dr

Classification of organic molecular complexes1. Donor-acceptor type: Bond is between uncharged species , but lacks charge transfer. Dipole-dipole and London dispersion forces are responsible for its stability.

2.Charge transfer complexes: one molecule polarizes the other. Resonance makes the main contribution for stability.

Classification of organic molecular complexes

Classification of organic molecular complexes

1. Drug – polymer complexes

2. Polymer complexes

3. Picric acid complexes

4. Quinhydrone complexes

Drug and polymer complexesDipole – dipole force or hydrogen bonding

between the polarized carbonyl groups of caffeine and the hydrogen atom of the acid.

Interaction between nonpolar parts. This interaction leads to squeezing out the complex from the aqueous environment.

Applications Preparation of chewable tablets . E.g.: caffeine and gentisic acid complex

Enhance the solubility .

Improve or extend the absorption and bioavailability of drugs.

Polymer complexes Pharmaceutical additives which contain nucleophilic oxygen form complexes with various drugs. E.g.: polymers : PEG s , CMC , carbowaxes , pluronics . drugs : tannic acid , salicylic acid , phenols .

Produces incompatibilities in the dosage forms such as suspensions emulsions and ointments.

delay of absorption, loss of preservative action and produce undesirable physical ,chemical and pharmacological effects.

E.g.: Polymer container and drug product interactions (methylparaben / propylparaben with container).

Picric acid complexes• Strong acids form organic molecular complexes

with weak bases.

E.g.: 2,4,6-trinitrophenol (picric acid) reacts with butesin ( 2:1)to form butesin picrate.

Quinhydrone complexes• These are formed by mixing alcoholic solutions of

equimolar quantities of benzoquinone and hydroquinone.• The complex settles as green crystals.• This complex can dissociate into equivalent amounts of

Quinone and Hydroquinone when saturated in aqueous solution.

Mechanism: a) overlapping of the pi framework of molecules. b) Hydrogen bonding stabilizes the association.

Inclusion complexesAlso called as occlusion compounds , in which one of

the compound is trapped in the open lattice or cage like crystal structure of the other.

The interaction is not due to the chemical reactivity , but because of the favorable molecular architecture.

The forces of interaction are weaker.

It is difficult to predict the formation of inclusion compounds between two selected compounds.

Channel lattice types In this type a channel is formed into which the complexating molecule fits.

Channel forming substances (Host): Deoxycholic acid, urea , thiourea , amylose etc., Guest agents : paraffins , esters , acids , ethyl alcohol , dioxane etc.,

Host molecule (urea)

Guest molecule (methyl α -lipoate)

Hexagonal channel

Layer typesCompounds such as clays , monomorillorite

(constituent of bentonite) entrap hydrocarbons , alcohols and glycols.

They form alternate monomolecular (monoatomic) layers of guest and host.

Uses are limited however these may be useful for catalysis.

Clathrates During crystallization, certain substances form a cage like lattice in which the coordinating compound is entrapped. E.g.: Hydroquinone molecules crystallize in a cage-like structure with H-bonding. They permit entrapment of small molecules such as CH3OH , CO2 , HCl.

Hole have diameter Of 4.2Å

Mono molecular inclusion complexes It involves the entrapment

of single guest molecule in the cavity of one host molecule.

Most of the host molecules are cyclodextrins .

Cyclodextrins are cyclic oligo saccharides containing 6, 7 ,8 units of glucose which are named α , β and γ respectively.

α- cyclodextrins have smallest cavity.

Cyclodextrin (cycloamylose)

Mono molecular inclusion complexes

Mitomycin C partly enclosed in cyclodextrin to form an inclusion complex

Representation of cyclodextrin as truncated cone

β and γ cyclodextrins have larger internal diameter (6 – 8 Å , respectively ) and are useful to pharmaceutical technology.

The structures of cyclodextrin assume a truncated cone and can accommodate a wide variety of compounds.

The interior of the cavity is relatively hydrophobic . The entrance of the cavity is hydrophilic in nature.

HydrophobicInterior

Hydrophilicentrance

Host molecule(β-cyclodextrin)

Applications Enhanced solubility: E.g.: Retinoic acid (0.5µg/liter) is increased to 160 mg/liter by complexation with β- cyclodextrin .

Enhanced dissolution : E.g.: Famotidine, tolbutamide by complexation with β- cyclodextrin.

Enhanced stability: E.g.: Aspirin, Benzocaine, Ephedrine, Testosterone by complexation with β- cyclodextrin.

Sustained release: E.g.: Diltiazem, Isosorbide dinitrate when complexed with ethylated β- cyclodextrin.

REFERENCE1. Martin’s physical pharmacy and pharmaceutical sciences.

2. Remington the science and practice of pharmacy.

3. Textbook of physical pharmaceutics by C.V.S. Subrahmanyam.

4. http://encyclopedia2.thefreedictionary.com/Inclusion+compound

5. http://www.transtutors.com/chemistry-homework-help/co-ordination-chemistry/ligands.aspx

6. http://www.scifun.org/chemweek/chelates/chelates.html

7. http://chemistry.about.com/od/imagesclipartstructures/ig/Vitamin-Chemical-Structures/Vitamin-B12.htm