Physical Pharmaceutics I - Complexation Overview

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Questions and Answers

Which type of inclusion complex involves a host molecule forming a hollow chain-like structure?

Layer types

Monomolecular types

Channel types (correct)

Clathrates

What is a primary application of layer type inclusion complexes?

Gas storage

Volatility reduction

Drug absorption

Catalysis (correct)

In clathrates, what occurs during the formation of the complex?

Molecules are entangled in a tangled network.

Layering of host molecules surrounds the guest molecule.

One molecule crystallizes and traps another. (correct)

Covalent bonds form between the guest and host molecules.

Which of the following describes monomolecular inclusion complexes?

They contain a single guest molecule within one host molecule. Signup and view all the answers

What is a known use for hydroquinone in relation to inclusion complexes?

Storage of gases or volatile substances. Signup and view all the answers

What effect do polymers generally have when used to form complexes with drug molecules?

Loss of therapeutic activity. Signup and view all the answers

Caffeine's role in drug interactions is primarily to:

Enhance the solubility of certain compounds. Signup and view all the answers

Regarding polymer-drug complexes, which characteristic is commonly observed?

Enhancement of chemical stability and inhibition of reactions. Signup and view all the answers

What type of molecular complex is formed when Benzoquinone and Hydroquinone are combined in a 1:1 ratio?

Quinhydrone complex Signup and view all the answers

Which application of EDTA in pharmacy primarily involves its interaction with Calcium and Magnesium ions?

Purification of water Signup and view all the answers

What characterizes the formation of organic molecular complexes compared to molecular compounds?

Weak forces are involved in complexes. Signup and view all the answers

How does picric acid react when interacted with a weak base?

Forms a molecular complex Signup and view all the answers

What type of interactions facilitate the complexation between Caffeine and acidic drugs?

Dipole-dipole interactions Signup and view all the answers

Which of the following is an application of Hydroquinone?

Manufacturing of Quinhydrone electrode Signup and view all the answers

What essential characteristic distinguishes Molecular complexes from Molecular compounds?

Molecular compounds form under high-temperature conditions. Signup and view all the answers

What role do polymers play in drug formulations?

They serve as nucleophilic agents. Signup and view all the answers

Which of the following is NOT a type of inclusion complex?

Diatomic complexes Signup and view all the answers

What is the primary characteristic of chelates in complexation?

They include multiple donor groups binding to a metal ion. Signup and view all the answers

What is a significant application of complexation related to pharmaceuticals?

Stability of drugs. Signup and view all the answers

Which of the following types of complexes includes metal-ion interactions?

Metal-ion complexes Signup and view all the answers

What role do van der Waals forces play in complexation?

They provide a temporary interaction that stabilizes complexes. Signup and view all the answers

Which two components are primarily involved in the donor-acceptor mechanism of complexation?

Ligand and Substrate Signup and view all the answers

Which type of complex is known for its applications in providing antidotes for metal poisoning?

Chelates Signup and view all the answers

Which of the following best describes the interaction between caffeine and drugs in the context of complexation?

They form transient complexes that can alter drug efficacy. Signup and view all the answers

Study Notes

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

Feature	Molecular Complex	Molecular Compound
Formation	Reaction in cold conditions	Reaction at elevated temperatures
Bonding	Weak forces (dipole-dipole, H-bonding)	Strong electrostatic bonds
Separation	Cannot be separated from solutions	Can be separated from solutions

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.

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Description

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.