Physical Pharmaceutics I - Complexation Overview

Physical Pharmaceutics I - Unit III: Complexation and Protein Binding

• Complexation is a process where complexes or coordination compounds are formed through the association or interaction of two or more chemical species.

• Complexes form due to donor-acceptor mechanisms. A donor (ligand) is a neutral molecule or non-metallic ion with lone electron pairs to donate. An acceptor (substrate) is a metallic ion or sometimes a neutral atom.

• A compound formed from interaction of two species is called a complex (e.g., mS + nL → SmLn).

• Intermolecular forces involved in complex formation include van der Waals forces, dipolar forces, hydrogen bonding, and covalent/coordinate bonds.

Applications of Complexation

• Complexation influences physical state, volatility, drug stability, solubility, dissolution, absorption, bioavailability, acting as antidotes for metal poisoning, and exhibiting antibacterial activity.

Classification of Complexes

• Metal Complexes: Inorganic types (chelates, olefin and aromatic types).

• Organic Molecular Complexes: Drug & Caffeine complexes, Polymer types, Picric acid types, Quinhydrone types.

• Inclusion Complexes: Channel type, Layer type, Clathrates, Monomolecular types.

Metal-ion complexes

• The metal ion is the central atom interacting with ligands. The coordination number is the maximum number of atoms or groups combining in the coordination sphere with the central atom.

• Chelates: A group of metal ion complexes where a substance (ligand) provides two or more donor groups to combine with the metal ion. EDTA is a common hexadentate ligand example.

Applications of Chelates

• Water purification (EDTA removes Ca2+ and Mg2+ ions).

• Enhancing drug stability.

• Drug molecule analysis.

• Blood anticoagulants.

Olefin and Aromatic Complexes

• Used as catalysts in drug production, intermediate synthesis, and drug analysis.

• Olefin complexes form through interaction of aqueous metal ions (e.g., platinum, mercury, silver) with olefins such as ethylene.

• Aromatic complexes form through interaction of metal ions with aromatic molecules like benzene, toluene, and xylene.

Organic Molecular Complexes

• Organic molecules are involved in complexation through weak forces (dipole-dipole, hydrogen bonding). Experimental conditions must remain constant.

• Complexes result in molecular compounds rather than molecular complexes (e.g., Iodine with Tolnaftate enhances antifungal activity).

Difference Between Molecular Complex and Molecular Compound

a) Quinhydrone Complex

• Formed by mixing alcoholic solutions of benzoquinone and hydroquinone in a 1:1 ratio. Green hydroquinone crystals form.
• Used in manufacturing quinhydrone electrodes for pH determination.

b) Picric Acid Complexes

• Picric acid is a strong acid.
• Reacting with a strong base forms molecular compounds.
• Reacting with a weak base forms a molecular complex.
• Example use in skin treatment ointments (e.g., Butesin Picrate).

c) Drug Caffeine Complexes

• Many acidic drugs form complexes with caffeine through dipole-dipole interactions.
• Used in chewable tablets

d) Polymer Complexes

• Polymers (e.g., PEG, CMC) are pharmaceutical additives with nucleophilic oxygen groups.
• They form complexes with drugs (e.g., phenol, tannic acid, salicylic acid).
• Disadvantages include loss of preservative action, altered absorption, and undesirable physical/chemical/pharmacological effects.
• Drug activity may be reduced when stored in polymer containers.

Inclusion Complexes

• Also known as occlusion compounds. One component is trapped within the crystal lattice (open lattice or cage-like structure) of the other component.
• Types include channel types, layer types, clathrates, and monomolecular types.

1) Channel Complexes

• Molecules crystallize into long chains, creating hollow channels. Other molecules are entrapped in these channels.
• Urea forms a hollow structure with methyl-a-lipoate being entrapped.
• Applications include separating optical isomers and analyzing dermatological creams.

2) Layer Complexes

• In layer complexes, one layer is sandwiched between two parallel layers of a host molecule.
• Clays and montmorillonite entraps hydrocarbons and alcohols/glycols.
• Applications include catalysis.

3) Clathrates

• Complexes form in a cage-like structure, where one molecule undergoes crystallization and the other is entrapped.
• Hydroquinone forms a small hole within its structure and entraps guest molecules.
• Used for storage of gases, toxic substances, and volatile compounds.

4) Monomolecular Complexes

• Single guest molecules are trapped in the cavity of a host molecule (e.g., cyclodextrins).
• Host molecule interiors are typically hydrophobic, while entrances are hydrophilic.

Application of Complexation

• Influences physical form (liquid to solid), reduction of drug volatility, improved solid-state stability, enhancing solubility, and altering chemical stability.

Protein Binding

• Complexation of drugs with proteins is called protein binding.

• Drugs bound to proteins aren't metabolized or excreted, thus they are pharmacologically inactive.

• Reversible protein binding involves weak chemical bonds (H-bonds, hydrophobic, ionic, van der Waals). Irreversible binding results from covalent bonds and can cause toxicity.

Proteins Bound by Drugs

• Human serum albumin (HSA): Synthesized in the liver, high concentration in extracellular fluid, 17-18 day elimination half-life, ~60% concentration, 4 binding sites.

• Alpha 1 acid glycoprotein (orosomucoid): Bound by hydrophobic bonds; used for certain basic drugs (imipramine, amitriptyline etc.).

• Lipoproteins: Large molecular weight; drug binding in lipid core (e.g., acidic drugs like diclofenac and neutral/basic drugs).

• Blood cells (e.g., hemoglobin, carbonic anhydrase inhibitors, red blood cell membrane).

Significance of Protein Binding

• Absorption and distribution of drugs
• Metabolism and biological half-life
• Drug elimination
• Disease diagnosis (use of radioactive substances)
• Site-specific drug delivery

Factors Affecting Protein Binding

• Drug Factors: Physicochemical properties, drug concentration, affinity for binding sites.

• Protein Factors: Physicochemical properties of protein, concentration of protein, number of binding sites.

• Drug Interactions: Displacement reactions, competition, allosteric changes.

• Patient Factors: Age, inter-subject variations, disease state.

Kinetics of Protein Binding

• Law of mass action applies. Association constant (Ka) is dependent on drug concentration & protein concentration. The total protein concentration (Pt) is composed of unbound and bound drug concentrations.

• Plotting methodology (direct plot, Scatchard plot, Klotz plot, Hitchcock plot) is used for measuring Ka and number of binding sites ('n').

Measurement of Protein Binding

• Techniques include equilibrium dialysis, dynamic dialysis, and ultrafiltration.

Equilibrium Dialysis

• Separation of solutions based on the differential ability of molecules to pass through the semipermeable membrane; drug concentration in the solution contacting the protein is measured.

Dynamic Dialysis

• Drug and protein are in a buffer solution; drug concentration in the dialysis component is measured over time.

Ultrafiltration

• Physical separation of unbound from protein-bound drug using centrifugation.

Thermodynamic Treatment of Stability Constants

• Stability constant of metal complexes is related to thermodynamic properties such as free energy charge (ΔG), enthalpy (ΔH), and entropy change (ΔS).

• These values are calculated using equations (ΔG = -2.303RT log K, ΔG= ΔH - TΔS)

• Obtained from the slope of a plot of log K and 1/T.

Explore the key concepts of complexation and protein binding in Physical Pharmaceutics I. This unit delves into the formation of complexes, the mechanisms involved, and their applications in drug stability and bioavailability. Understand the essential role of intermolecular forces in complex formation and their significance in pharmacology.