Lesson 2. States of Matter related to Pharmaceutical Formulations

Intermolecular Forces

forces of attraction and repulsion between atoms and molecules

Cohesive Forces

like molecules are attracted to each other such as beaker with water

Adhesive Forces

Different molecules are attracted in water such as pipette in water

Repulsive Forces

like poles will repel while unlike poles attract

gradual and negative (attractive)

Lennard-Jones Potential:

• as two molecules approach each other at a moderate distance, the energy changes are _________________ to a point where a minimum in the potential energy occurs

attractive forces

Low/Negative Potential Energy = __________________ = needs minimum energy

repulsive forces

At a close distance, the energy starts rising rapidly as the intermolecular distances become smaller and ________________ begin to dominate

repulsive forces

positive potential energy = ________________ = needs more energy

repulsion

Moving the molecules closer results in electron cloud a.__________, whereas separating the molecules apart increases the b.__________

a = ?

attraction

Moving the molecules closer results in electron cloud a.__________, whereas separating the molecules apart increases the b.__________

b = ?

1 – 7

Intermolecular Attractive Forces — Van der Waals Forces

dipole-dipole (Keesom forces)

• Energy (kcal/mole): ?

• Examples:

• Applications:

H2O, HCl, Alcohol, Acetone, Phenol

Intermolecular Attractive Forces — Van der Waals Forces

dipole-dipole (Keesom forces)

• Energy (kcal/mole):

• Examples: ?

• Applications:

stabilize protein secondary structure (α–helices)

Intermolecular Attractive Forces — Van der Waals Forces

dipole-dipole (Keesom forces)

• Energy (kcal/mole):

• Examples:

• Applications: ?

1-3

Intermolecular Attractive Forces — Van der Waals Forces

dipole-induced dipole (Debye forces)

• Energy (kcal/mole): ?

• Examples:

• Applications:

ethyl acetate, methylene chloride, ether

Intermolecular Attractive Forces — Van der Waals Forces

dipole-induced dipole (Debye forces)

• Energy (kcal/mole):

• Examples: ?

• Applications:

stabilizing effect on states of matter

Intermolecular Attractive Forces — Van der Waals Forces

dipole-induced dipole (Debye forces)

• Energy (kcal/mole):

• Examples:

• Applications: ?

0.5 - 1

Intermolecular Attractive Forces — Van der Waals Forces

induced dipole-induced dipole (London forces)

• Energy (kcal/mole): ?

• Examples:

• Applications:

Carbon disulfide, Carbon tetrachloride, hexane

Intermolecular Attractive Forces — Van der Waals Forces

induced dipole-induced dipole (London forces)

• Energy (kcal/mole):

• Examples: ?

• Applications:

liquefaction of gases; molecular interactions in solubility, complexation, other physical bonding phenomena

Intermolecular Attractive Forces — Van der Waals Forces

induced dipole-induced dipole (London forces)

• Energy (kcal/mole):

• Examples:

• Applications: ?

1 – 7

Intermolecular Attractive Forces — Ion-dipole Forces

ion-dipole

• Energy (kcal/mole): ?

• Examples:

• Applications:

quaternary ammonium ion with tertiary amine

Intermolecular Attractive Forces — Ion-dipole Forces

ion-dipole

• Energy (kcal/mole):

• Examples: ?

• Applications:

crystalline pharmaceutical salts

Intermolecular Attractive Forces — Ion-dipole Forces

ion-dipole

• Energy (kcal/mole):

• Examples:

• Applications: ?

none

Intermolecular Attractive Forces — Ion-dipole Forces

ion-induced dipole

• Energy (kcal/mole): ?

• Examples:

• Applications:

Potassium Iodide and Iodine

Intermolecular Attractive Forces — Ion-dipole Forces

ion-induced dipole

• Energy (kcal/mole):

• Examples: ?

• Applications:

solubility of ionic crystalline subs in H2O

Intermolecular Attractive Forces — Ion-dipole Forces

ion-induced dipole

• Energy (kcal/mole):

• Examples:

• Applications: ?

Description of Hydrogen Bonding

• strong type of dipole-dipole

• attraction of a hydrogen atom for a strongly negative atom

Application of Hydrogen Bonding

• protein α–helix and β–sheet structures

• conformation of proteins, physical properties of alcohols compared to alkanes

• carboxylic acids compared to esters, aldehydes, and ketones

• sugars

Description of Hydrophobic interaction

• forces of attraction between nonpolar atoms and molecules in water

Application of Hydrophobic Interaction

structure and stabilization of molecules including proteins and bilayer membrane structures

Gas

• higher kinetic energy

• weak intermolecular forces

Liquid

• denser possesses less kinetic energy than gases

Solid

• strong intermolecular forces

• little kinetic energy

PV = nRT

Ideal Gas Law Equation

directly

According to the Ideal Gas Law, Pressure and Volume are ______________ proportional to the number of moles and temperature.

Ideal Gas Law

useful in calculating properties of gases at atmospheric pressure and at temperatures above their boiling points

indirectly

According to the Boyle’s Law, Volume is ___________ proportional to the Pressure

directly

According to Charles’ Law, Volume is ___________ proportional to Temperature

directly

According to Avogadro’s Law, Volume is ___________ Proportional to the number of moles.

Anesthesia, Blood Gases, and Oxygen

Application of gas in medicine

blood gases

oxygen and carbon dioxide

Henry’s Law of Gas Solubility

the amount of gas dissolved in the plasma is proportional to the partial pressure of the gas in equilibrium with the plasma

Dalton’s Law of Partial Pressures

the partial pressure is the pressure a gas would exert if it alone occupied the whole volume of the mixture

increases

vapor pressure __________ with temperature

inversely

vapor pressure and boiling point are ____________ related

boiling point

temperature in which the vapor pressure of a liquid equals the atmospheric pressure

Surface Tension

force per unit length

decreases

surface tension ____________ with an increase in temperature

Crystalline solids

molecules or atoms are arranged in repetitious three-dimensional lattice units (unit cell) infinitely throughout the crystal

Cubic

Sodium Chloride

example of cubic

Tetragonal

urea

example of tetragonal

Orthorhombic

ritonavir form II

example of orthorhombic

Rhombohedral

iodine

example of rhombohedral

Hexagonal

iodoform

example of hexagonal

Monoclinic

sucrose, ritonavir form I

example of monoclinic

Triclinic

boric acid

example of triclinic

Carbon, Diamond

TYPES OF CRYSTAL BONDING:

Unit: Atom to atom

Example: ?

Bonding:

Physical Characteristics:

Strong carbon covalent bonds

TYPES OF CRYSTAL BONDING:

Unit: Atom to atom

Example:

Bonding: ?

Physical Characteristics:

Hard large crystals

TYPES OF CRYSTAL BONDING:

Unit: Atom to atom

Example:

Bonding:

Physical Characteristics: ?

Silver

TYPES OF CRYSTAL BONDING:

Unit: Metallic

Example: ?

Bonding:

Physical Characteristics:

Strong metal bond

TYPES OF CRYSTAL BONDING:

Unit: Metallic

Example:

Bonding: ?

Physical Characteristics:

positive ions in a field of freely moving electrons

TYPES OF CRYSTAL BONDING:

Unit: Metallic

Example:

Bonding:

Physical Characteristics: ?

Menthol, Paraffin

TYPES OF CRYSTAL BONDING:

Unit: Molecular

Example: ?

Bonding:

Physical Characteristics:

van der Waals forces

TYPES OF CRYSTAL BONDING:

Unit: Molecular

Example:

Bonding: ?

Physical Characteristics:

close packing, weakly held together, low melting point

TYPES OF CRYSTAL BONDING:

Unit: Molecular

Example:

Bonding:

Physical Characteristics: ?

Sodium Chloride

TYPES OF CRYSTAL BONDING:

Unit: Ionic

Example: ?

Bonding:

Physical Characteristics:

Electrostatic Ionic Bond

TYPES OF CRYSTAL BONDING:

Unit: Ionic

Example:

Bonding: ?

Physical Characteristics:

Hard, close packing, strongly held together, high melting point

TYPES OF CRYSTAL BONDING:

Unit: Ionic

Example:

Bonding:

Physical Characteristics: ?

Polymorphs

• may exist in more than one crystalline structure

• changes in crystalline forms: changes in intermolecular bonding patterns conformational changes in the molecule molecular orientations between neighboring molecules in solid

• physical properties: melting point, solubility, stability

Hydrate

• water is included in a lattice

• commonly used as drug substances

• multiple hydrates can exist for a drug substance

• less soluble in water or aqueous mixtures than anhydrous forms

Solvate

• solvent is incorporated into the lattice

• not chosen as drug substances due to possible toxicity of common solvents

Salt crystals

• lattice accommodating other molecules to form salts

• 2 ionized compounds will interact with the lattice to form a crystalline salt

drug substance

can be a weak acid or a weak base

counterion

corresponding compound in a salt

properties

melting point, stability, solubility, dissolution, bioavailability

Cocrystal

• homogeneous multicomponent phase of fixed stoichiometry where the chemical entities are held together in a crystal lattice by intermolecular forces

• also contain water and solvents to form cocrystalline hydrates

• good option to change properties when an ionizable group is not available

Amorphous

• no long-range order over many molecular units to produce a lattice or crystalline structures

• do not possess melting points

• less physically stable than crystalline, more soluble than crystalline materials

glasses

nonequilibrium solid form

supercooled liquids

viscous equilibrium liquid form

glass transition (Tg) temperature

• temperature where an amorphous material converts from a glass to a supercooled liquid (rubbery) upon heating

Amorphous dispersion

• amorphous drug is stabilized by a polymer or a combination of polymers or surfactants

• increased solubility of amorphous material with physical stability closer to crystalline material

• drug : polymer ratio

Polymeric Solids

• large molecules formed by covalent assembly of smaller molecules (monomers) into chain or network of repeating structural units

• stabilize the amorphous drug in solid state

• help prevent crystallizations

• used as excipients in solid, semisolid, and liquid formulations

Natural Polymers

• rubber, polypeptides, cellulose

Synthetic and Semisynthetic Polymers

• polyvinylchloride, polyethylene, polystyrene, polyvinyl acetate, polyactides, methylcellulose derivatives

Liquid to Gas

• intermolecular forces are related to heat of vaporization and to molecular weight

• ↑ MW = ↑ intermolecular points of contact = ↑ intermolecular interactions [↑ HV , ↑BP, ↓VP]

Heat of vaporization

heat absorbed when 1 g or 1 mole of liquid is vaporized

Solid to Liquid

• intermolecular forces are related to heat of fusion and to molecular weight

• ↑ MW = ↑ intermolecular forces [↑ Hf , ↑MP]

Melting point

temperature at which the solid changes into a liquid

Heat of fusion

heat required to increase the interatomic or intermolecular distance in the solid state to form the liquid state

Pliaglis Cream

Lidocaine and Tetracaine Eutectic Mixtures:

• topical local analgesia for superficial dermatological procedures

Synera Patch

Lidocaine and Tetracaine Eutectic Mixtures:

• local dermal analgesia for superficial venous access and superficial dermatological procedures

Emla Cream

Lidocaine and Prilocaine Eutectic Mixtures:

• topical anesthetic and local analgesia

Oraqix Periodontal Gel

Lidocaine and Prilocaine Eutectic Mixtures:

• local anesthetic indicated for adults who require localized anesthesia in periodontal pockets

Chemical Stability

• involves the molecule degrading into other products

• oxidation, hydrolysis, cyclization

• interaction of drug molecules with excipients or other drug molecules in dosage forms

• chemical degradation in surface solution phase and true solid state