A1. Binding Forces Between Molecules

A. Physical Pharmacy Principles

Physical Pharmacy

Application of physical, chemical, and biological principles in the formulation of a drug product

Physical Pharmacy

To understand and develop dosage forms and drug delivery systems

Drug

agent or substance intended for use in the diagnosis, cure, mitigation, treatment and prevention of disease

Dosage form

form suited for administration to the patient

Drug Product

a finished dosage form that contains an active drug ingredient (palatable, convenient, safe, and effective)

Physical Pharmacy

Deals with the physicochemical principles underlying the development of a successful dosage form

Quantitative and theoretical approach

Physical Pharmacy has 2 approaches

Pharmaceutics

Is a branch of pharmaceutical sciences that deals with:

a. Investigations of physical and chemical properties of drug molecules

b. Design, fabrication and evaluation of drug delivery systems

c. Monitoring how drug products are absorbed, distributed, metabolized and excreted in the body

d. Mechanism of drug action

Intramolecular Forces

“within molecules”

• Ionic Bonds

• Covalent Bonds

• Metallic bonds

• Hydrogen Bonds

4 types of Intramolecular Forces

• Van der Waals Forces

• Ion-Dipoles

• Ion-Induced Dipole Interaction

• Hydrogen Bonds

4 types of Intermolecular Forces

Both intra and inter

Hydrogen Bonds: Intermolecular or Intramolecular Force?

Ionic Bonds

It involves transfer of e-: Ionic or Covalent Bonds

Covalent

It involves sharing of e-: Ionic or Covalent Bonds

Pure Covalent

Bond type that has a EN Difference of <0.4

Polar Covalent

Bond type that has a EN Difference of 0.4-1.7(2.0)

Ionic

Bond type that has a EN Difference of >1.7(2.0)

Water

It is the most common polar substance

1. Electronegativity difference

2. Symmetry of the molecule

What are the requirements for polarity?

Higher polarity

Higher EN difference = (higher or lower) polarity

H–H < S–H < Cl–H < O–H < F–H

Arrange in increasing polarity:

• S–H

• F–H

• H–H

• Cl–H

• O–H

Nonpolar molecules with perfect symmetry = zero dipole moments

Identify: CO2

Choices:

• Nonpolar molecules with perfect symmetry = zero dipole moments

• Polar molecules = asymmetric and have nonzero dipole moments

Nonpolar molecules with perfect symmetry = zero dipole moments

Identify: CCl4

Choices:

• Nonpolar molecules with perfect symmetry = zero dipole moments

• Polar molecules = asymmetric and have nonzero dipole moments

Polar molecules = asymmetric and have nonzero dipole moments

Identify: HCl

Choices:

• Nonpolar molecules with perfect symmetry = zero dipole moments

• Polar molecules = asymmetric and have nonzero dipole moments

Polar molecules = asymmetric and have nonzero dipole moments

Identify: H2O

Choices:

• Nonpolar molecules with perfect symmetry = zero dipole moments

• Polar molecules = asymmetric and have nonzero dipole moments

Polar molecules = asymmetric and have nonzero dipole moments

Identify: NH3

Choices:

• Nonpolar molecules with perfect symmetry = zero dipole moments

• Polar molecules = asymmetric and have nonzero dipole moments

Symmetric

Nonpolar molecules: symmetric or asymmetric

Asymmetric

Polar molecules: symmetric or asymmetric

Zero dipole moments

Nonpolar molecules: zero or nonzero dipole moments

Nonzero dipole moments

Polar molecules: zero or nonzero dipole moments

Cohesive forces

Attractive forces between like molecules

Adhesive forces

Attractive forces between unlike molecules

3-4 × 10^-8 cm

At what distance the attractive and repulsive forces are equal?

Keesom, Debye, London

3 types of Van der Waals Forces

Keesom Forces

Orientation/Alignment effect

Choices:

• Keesom

• Debye

• London

Keesom Forces

Dipole-Dipole Forces

Choices:

• Keesom

• Debye

• London

Keesom Forces

Polar molecule + Polar molecule

Choices:

• Keesom

• Debye

• London

Keesom Forces

Ex. Water, alcohols, acetone

Choices:

• Keesom

• Debye

• London

Keesom Forces

1-7 kcal/mole

Choices:

• Keesom

• Debye

• London

Debye Forces

Induction effect

Choices:

• Keesom

• Debye

• London

Debye Forces

Dipole-Induced dipole Forces

Choices:

• Keesom

• Debye

• London

Debye Forces

Polar molecule + Nonpolar molecule

Choices:

• Keesom

• Debye

• London

Debye Forces

Ex. Ether, ethylacetate

Choices:

• Keesom

• Debye

• London

Debye Forces

1-3 kcal/mole

Choices:

• Keesom

• Debye

• London

London Forces

Dispersion effect

Choices:

• Keesom

• Debye

• London

London Forces

Induced dipole-Induced dipole

Choices:

• Keesom

• Debye

• London

London Forces

Originate from molecular vibrations

Choices:

• Keesom

• Debye

• London

London Forces

Non-polar + Nonpolar

Choices:

• Keesom

• Debye

• London

London Forces

Ex. Hexane, CCl4

Choices:

• Keesom

• Debye

• London

London Forces

0.5-1 kcal/mole

Choices:

• Keesom

• Debye

• London

Ion-Dipole Forces

(+ / -) charged ion + polar

Choices:

• Ion-Dipole Forces

• Ion-Induced Dipole

Choices:

• Ion-Dipole Forces

• Ion-Induced Dipole

Ion-Dipole Forces

Ex. Quaternary ammonium + Tertiary amine, solubility of salts in water

Choices:

• Ion-Dipole Forces

• Ion-Induced Dipole

Ion-Induced Dipole

(+ / -) charged ion + nonpolar

Choices:

• Ion-Dipole Forces

• Ion-Induced Dipole

Ion-Induced Dipole

Ex. Iodine + KI (formation of tri-iodide complex)

Choices:

• Ion-Dipole Forces

• Ion-Induced Dipole

Hydrogen Bonds

Interaction between molecules containing H and highly EN atom (F, S, O, N)

Hydrogen Bonds

Special type of dipole-dipole interaction

Hydrogen Bonds

Has 2-8 kcal/mole

Water, Alcohol, Carboxylic acids, Esters, Aldehyde

5 functional groups that have hydrogen bonds

Ethers, Ketones

2 functional groups that have no hydrogen bonds

HIGH dielectric, LOW vapor pressure, HIGH BP

Hydrogen bonds are responsible for the unusual properties of water such as (1) (high/low) dielectric constant, (2) (high/low) vapor pressure, and (3) (high/low) boiling point

Proteins: a helices, b sheets

Nucleic acids: DNA (A-T and G-C bonds)

Hydrogen bonds can exist intramolecularly in (2)

A-T: 2 H bonds

G-C: 3 H bonds

How many H bonds have A-T and G-C have?

STRONGER interaction, HIGHER BP, MP, viscosity, surface tension

The stronger IMFA = (1) (stronger/weaker) interaction = (higher/lower) BP, MP, viscosity, surface tension

-161 deg C

Boiling Point of Methane (CH4)

-24 deg C

Boiling Point of Chloromethane (CH3Cl)

80 deg C

Boiling Point of Methanol (CH3OH)

London Dispersion Forces

Dominant Intermolecular Force in Methane

Dipole-Dipole Interactions

Dominant Intermolecular Force in Chloromethane

Hydrogen Bonding

Dominant Intermolecular Force in Methanol

London Dispersion < Dipole-Dipole < Hydrogen Bonding

Arrange in increasing bond strength:

• Dipole-Dipole

• Hydrogen Bonding

• London Dispersion

CH₄ < CH₃Cl < CH₃OH

Arrange in increasing boiling point:

• CH3OH

• CH4

• CH3Cl

Additive, Constitutive, Colligative

3 Physical Properties of Drug Molecules

Additive Property of Drug Molecules

Derived from the sum of individual properties of atoms or functional groups present in molecules

Choices:

• Additive

• Constitutive

• Colligative

Additive Property of Drug Molecules

Example properties are mass, molecular weight, volume

Choices:

• Additive

• Constitutive

• Colligative

Constitutive Property of Drug Molecules

Dependent on the structural arrangement of the atoms within the molecule

Choices:

• Additive

• Constitutive

• Colligative

Constitutive Property of Drug Molecules

Example properties are optical activity, surface tension, viscosity

Choices:

• Additive

• Constitutive

• Colligative

Colligative Property of Drug Molecules

Dependent upon the total number of non volatile solute particles present in the solution

Choices:

• Additive

• Constitutive

• Colligative

Colligative Property of Drug Molecules

Example properties are vapor pressure lowering, BP elevation, FP depression, osmotic pressure

Choices:

• Additive

• Constitutive

• Colligative

Molar Refraction

Combined Additive-Constitutive Property