W5.2_Solubility

Question 1

What must be taken into account when formulating a drug? Define solution, dissolution, maximum stability, and supersaturation.

Answer 1

• When formulating a drug, its solubility and stability must be taken into account
• Solution: mixture with solute(s) and solvent(s), where solutes are dispersed in a solvent vehicle (suspension ≠ solution)
• Dissolution: molecules transfer from solid to liquid state (extent of dissolution at eqm: solubility)
• Maximum solubility: dictates rate of dissolution (has great pharmaceutical importance)
• Solubility limit reached (given temperature&pressure) -> saturated -addition of solute-> supersaturated

Question 2

Define the different ranges of solubilities in solutions.

Answer 2

• > 1000mg/mL: Very soluble
• 100-1000mg/mL: Freely soluble
• 33-100mg/mL: Soluble
• 10-33mg/mL: Sparingly soluble
• 1-10mg/mL: Slightly soluble
• 0.1-1mg/mL: Very slightly soluble
• <0.1mg/mL: Insoluble

Question 3

Describe the molecular aspect of dissolution and state the different factors that affect solubility.

Answer 3

• Molecular aspect: Need to remove a drug molecule from crystal/solid particle -> create a hole in solvent -> insert drug molecule in solvent -> create interaction between solvent and solute
• Large surface area of compound -> great energy required to create a large cavity -> low solubility
• Low boiling/melting point of drug -> easy to separate molecules from crystal/solid -> high solubility
• Other factors: solid state of drug (higher for amorphous solid, lower for crystalline solid), polymorph type, common ion effect (adding a ion that pre-exists reduces solubility), composition of aqueous media, pH, ionic strength of solution, temperature (usually increases solubility)

Question 4

Describe the general solubility of acidic and basic drugs. What are their Henderson-Hasselbach equations? Define amphoteric drugs.

Answer 4

• Ionised species are more soluble in water than unionised
• Henderson-Hasselbach equations: S: maximum saturated solubility, S0: solubility of unionised species
• Weak acids: pH-pKa=log((S-S0)/S0)
• Weak bases: pH-pKa=log(S0/(S-S0))
• Amphoteric drugs: have both +ve/-ve charges depending on pH, can be zwitterionic

Question 5

Define isoelectric point and describe its application.

Answer 5

• Isoelectric point pI=(pKa1+pKa2)/2, where pKa1 and pKa2 are boundaries of pH for zwitterions
• pH<pI: drug behaves as base
• pH>pI: drug behaves as acid

Question 6

Explain why drugs are often formulated as salts and describe the salting out effect with an example.

Answer 6

• Drugs are often formulated as salts to increase solubility, but choosing an appropriate salt is difficult as it influences physicochemical properties
• Ex.N+Cl-/SO42-/Br-/Cl-/PO43-/C4H2O42-/C6H5O73-/C2H3O2-//Na+/K+/Ca2+/Zn2+
• Salting in/salting out effect (in low but increasing ionic strength of solution)
• Solubility increases in presence of salt (salting in)
• Solubility decreases in high concentrations of salt (salting out) -> precipitation
• Ex. in gastric juice ([Cl-] increases), making solutions isotonic