lecture 2: salt and solubility II

factors of drug molecule effecting solubility of drug

Structure-related: hydrophobicity, size, the ability to form ions or hydrogen bonds

factors of environment effecting solubility of drug

pH, ionic strength, buffer type, etc

Formation of salt

salt

an ionic compound that is produced when an acid reacts with a base

All salts

are strong electrolytes bc it produces ions in solution bc it dissociates into ions

Inorganic salts

when drug w/ a acidic or basic functional group and react it w/ an inorganic acid/base

Inorganic salts increases

water solubility

Organic salts

drug w/ acidic or basic functional group is added w/ organic acid/base

Organic salts can increase either

lipid solubility or water solubility

Water-soluble organic counterion

can help increase water solubility

Lipid-soluble organic counterion

can help increase lipid solubility

acidic drug

drugs ion is negative and needs a positive counterion

basic drug

drugs ion is positive and needs a negative counterion

Naproxen is an acidic drug

so the drug’s ion becomes negative and needs a positive counterion (Na+)

Converting a drug into a salt enhances

solvation, dissolution, and water solubility

bond formed with salts

ion dipole forces with water molecules being formed

not covalent bonds

Organic salts use an organic counterion

the water/lipid solubility depends on the chemical structure of that organic counterion

Lipid-soluble organic salts

decrease the water solvation, dissolution, and
solubility of drug molecules
-enhance lipid solubility of drug molecule

lipid-soluble organic salts used for

suspension or oil-based formulation for intramolecular depot injections

lipid-soluble organic salts enhances

oral bioavailability of acid labile (easily degraded/destroyed by acid) drug molecules

palatability of dosage forms

increased by additions of lipid-soluble organic salts

two things happening simultaneously

Salt formation can increase dissolution compared with the parent/free drug

Environmental pH still affects how well that salt/drug dissolves

higher plasma drug concentrations

salt forms → faster/better dissolution → more drug available for absorption

higher Cmax

salts impact on physicochemical properties of the drug

Solubility, dissolution rate, crystal form, chemical stability, mechanical properties

salts impact on pharmaceutical properties required for dosage form

Bioavailability, stability (both chemical and physical), manufacturability

pharmaceutical equivalents

Same active moiety + same salt

pharmaceutical alternatives

Same active moiety + different salts

Why is precipitation dangerous

If a drug precipitates, you now have solid particles in something that's supposed to be a solution

matters especially for IV/injections solutions

For precipitation to occur

drug needs to become poorly water-soluble enough that its concentration exceeds its solubility limit

pathway of precipitation

pH change → more unionized/neutral drug → ↓ water solubility → if there's more drug than can stay dissolved → precipitation

For a weak base/salt of a weak base

high pH make B unionized → less water soluble and cause precipitation

pH > pKa

For a weak acid/salt of a weak acid

low pH so HA is protonated and unionized → less water soluble and cause precipitation

pKa > pH

new insoluble organic salt formed

positively charged drug ion and negatively charged drug ion can pair together and form a new organic salt that has very low water solubility → precipitation

conditions to form undesirable organic salt precipitation

1. Is one drug acidic and the other basic?
2. At this pH, do they have opposite charges?

only needs at least one condition

Cefepime and Gentamicin

can form a salt complex → can cause precipitation