Chem & Phys Properties/Solubility/Partition Coefficient

Key chemical & physical properties that influence drug behavior

physical state, arrangement of molecules of drug, particle size, partition co-efficient, pKa, chemical stability

Intramolecular forces

chemical bonds between the atoms within a molecule

Intermolecular forces

bonds between different molecules

Intermolecular forces effect on physical state

ionic bonds, mostly solid at room temperature

Intramolecular forces effect on physical state

covalent bonds, can be gas, liquid, or solid

Hydrogen bond

a weak chemical bond formed between a hydrogen atom and another electronegative atom

Ion-dipole interaction

electrostatic attractive forces between a charged ion and a polar molecule’s dipole

Dipole-dipole interaction

an electrostatic force of attraction between the partially negative end of one molecule is attracted to the partially positive end of another molecule

Pi-pi stacking

the attractive, non-covalent interaction between the pi systems of aromatic rings in molecules

Electrognegativity

a chemical property of an atom that describes its ability to attract shared electrons in a chemical bond

ΔE < 0.5

nonpolar covalent

0.5 <= ΔE <= 2

polar covalent

ΔE > 2

ionic

Effect of melting point on intermolecular interactions

the stronger the intermolecular interactions, the higher the melting point

Amorphous form

molecules are arranged in a random manner, no specific melting point

Crystalline form

orderly arrangement of the components in the solid state permitting optimal attractive interactions between adjacent molecules within the solid

Polymorph

when a substance exists in more than one crystalline form, one will be the most stable

Solvate

orderly arrangements of drug molecules that include solvent molecules in the crystalline lattice

Hydrates

when the solvent molecules of a solvate are water; thermodynamically stable

Co-crystals

a crystalline material composed of an API and a coformer

What do ionic bonds dissolve into in water?

ions

What do covalent bonds dissolve into in water?

individual molecules

Solute

the substance being dissolved

Solvent

the substance doing the dissolving

Solution

a homogenous mixture where a solute is being dissolved in a solvent

Solubility

the extent to which the dissolution proceeds under a given set of experiment conditions

Dissolution

the transfer of molecules or ions from a solid state into solution

Solubility expression

mass or volume of solute/mass or volume of solvent

US & European pharmacopeia solubility terms & interpret drug solubility data

solubility greater than 10mg/mL is optimal for oral delivery, solubility less than 1 mg/mL may be problematic

Unsaturated solution

less than the maximum amount of solute in solution

Saturated solution

maximum amount of solute in solution

Supersaturated solution

greater than the maximum amount of solute in solution

Why is aqueous solubility critical for dosage form development?

many dosage forms are solutions of drug in water; dosage forms that are not solutions must dissolve in aqueous body fluids

Polar solvents dissolving ability

dissolves polar solutes, ionic compounds and polar covalent compounds

Non-polar solvent dissolving ability

dissolves nonpolar solvents, nonpolar covalent compounds

How does drug surface area affect solubility and dissolution rate?

greater surface area, greater solubility, faster dissolution rate

How does reducing particle size improve drug solubility and bioaviliability?

increases surface area, thus increasing dissolution rate

What is a potential risk or limitation of particle size reduction for solubility enhancement?

instability, aggregation

Stagnant/diffusion layer

the thin liquid film immediately forming around the surface of a solid when introduce into a solvent

Bulk solution

the portion of the solvent beyond the diffusion layer

Saturation solubility concentration (Cs)

maximum concentration of a solute that can dissolve at the solid-liquid interface

Bulk concentration (C)

concentration of dissolved solute in the bulk solution away from the solid surface

Diffusion layer thickness

the distance from the solid surface of the solute to the stagnant boundary layer

Impact of diffusion layer thickness on dissolution rate

lower the diffusion layer thickness, higher the dissolution rate

Partition-coefficient (log P)

the ratio of equilibrium concentration of a drug in water (aqueous phase) and in organic liquids (organic phase)

Why does adding polar groups to a drug molecule generally increase solubility?

increases solubility in water because it is a polar solvent

Hydrophilic drug molecule

drugs that favor water phase, poorly absorbed after oral administration, preferred route is parenteral

Lipophilic drug molecule

drugs that are well absorbed after oral administration

log P > 0

lipophilic

log P < 0

hydrophilic

How can prodrug formation improve oral bioavailability?

can improve solubility or lipophilicity

Biopharmaceutics classification system

classifies drugs according to dose and their solubility and permeability

BCS I

high solubility, high permeability

BCS II

low solubility, high permeability

BCS III

high solubility, low permeability

BCS IV

low solubility, low permeability

Why does high solubility or high lipophilicity not always guarantee good bioavailability?

a drug must be able to both dissolve and permeate membranes

Crystalline melting point

sharp

Amorphous melting point

no sharp melting point

Solubility expressions

mg/mL, g/L, %w/v, %wt

log P > 3

susceptible to metabolism