Science of Medicines Week 6 Flashcards
Why do we need to study the solubility of drugs?
there are changes in pH within the GI tract, so changes in ionisation and solubility and drugs could precipitate
Henderson-Hasselbalch equation for a weak acid
log [A-] / [HA] = pH - pKa
When is [A-] greater than [HA]?
when pH is greater than pKa
When is [HA] greater than [A-]?
when pH is less than pKa
Henderson-Hasselbalch equation for a weak base
log [B] / [BH+] = pH - pKa
When is [B] greater than [BH+]?
when pH is greater than pKa
When is [BH+] greater than [B]?
when pH is less than pKa
What is the solubility of a weak acid like in low pH?
you decrease pH by adding H+, so there will be an increased proportion of HA, which is unionised, so low solubility
What is the solubility like of a weak acid at high pH?
you increase pH by removing H+, so higher proportion of ionised form, which is highly soluble
Weak acid as salt equilibrium equation
Na+ A- + H2O <=> NaOH + HA
What is S0?
the saturation solubility of the undissociated species HA
What is Cs?
the ‘total saturation solubility’ of the weak acidic drug –> interpreted as the initial concentration of salt added to solution
What does Cs equal?
Cs = S0 + [A-]
What information do you need to predict the solubility of a weakly acidic drug?
- pH of the solution
- the pKa
- the solubility of the free (unionised) form of the drug (S0)
What is the solubility equation for a weakly acidic drug?
log (Cs-S0) / S0 = pH - pKa
When pH = pKa, what is the Cs of a weakly acidic drug?
Cs = 2 x S0
The solubility of a weakly acidic drug increase by about …. for each pH unit above the pKa
10x
The solubility of a weakly acidic drug approaches S0 as….
pH decreases below the pKa
The solubility of a weakly acidic drug equal 2 x S0 when…
the pH equals the pKa
When is a weakly basic drug more soluble?
when pH is decreased by adding H+, so there is an increased proportion of BH+, so higher solubility
When is a weakly basic drug less soluble?
when pH is increased by removing H+, so there is a smaller proportion of BH+ and higher of B, so lower solubility
Equation for weak bases forming salts
BH+ Cl- + H2O <=> B + H+ Cl- + H2O
What is Cs equal to for a weakly basic drug?
Cs = S0 + [BH+]
When pH = pKa, what is the Cs of a weakly basic drug?
2 x S0
The solubility of a weakly basic drug increases by about … for each unit of pH below the pKa
10x
The solubility of a weakly basic drug approaches S0 as…
the pH increases above the pKa
The solubility of a weakly basic drug equals 2 x S0 when…
pH = pKa
What happens to the pH of a solution when the salt of a weak acid is used instead of the free form?
the pH increases
What happens to the solubility to the salt of a weak acid instead of the free form?
solubility increases
When may the precipitation of the salt of a weak acid occur?
when pH is the solution is lowered
What happens to the pH of the solution of the salt of a weak base instead of the free form?
the pH of the solution decreases
What happens to the solubility of the salt of a weak base instead of the free form?
solubility increase
When may precipitation occur with the salt of a weakly basic drug?
if pH is increased
BCS class 1
high solubility and permeability, use simple solid oral dosage form
BCS class 2
low solubility, high permeability, need techniques to increase surface area OR use solvents or surfactants
BCS class 3
high solubility, low permeability, need to include permeability enhances
BCS class 4
low solubility and permeability, combine 2 and 3
What happens to a weak base in the GI tract?
it will have a high dissolution rate in the stomach, but this falls as the pH of the GI tract rises
What happens to a weak acid in the GI tract?
it will have minimal dissolution in the stomach as pH is so low, but it increases down the gut with pH
How does the salt of a weak acid increase the pH of the diffusion layer?
- Na+ + Cl- + H2O Na+ + OH- + HA
- Cl- reacts with water, forming -OH, increasing pH
How does the salt of a weak base decrease the pH of the diffusion layer?
- BH+ + Cl- + H2O = H2O + B + H+ + Cl-
- BH+ can donate a proton to water through H30+, which forms H2O and H+, decreasing pH
What is the major advantage of using the salt form of a drug?
results in a controlled pH of the diffusion layer no matter where in the GI tract it is
When does precipitation of a drug occur?
when the pH of solution is adjusted to a value that produces mostly unionised molecules exceeding solubility
How can the solubility of non-polar compounds in water be improved?
adding water-miscible solvents in which the compound IS soluble
define co-solvent
vehicles used with water to increase the solubility of a drug
What is the purpose of cosolvents? (3)
- get aqueous systems where the drug is more soluble
- formulate higher concentrations of the drug
- improve stability of the formulation
What are the 3 factors a cosolvent needs?
- to be an organic compound
- miscible with water
- better solvent than water for the drug
How do cosolvents works?
- they decrease the hydrogen bond density of the aqueous system
- reduce the cohesive interactions of water
- reduce the polarity of the solution
How does solubility increase with increasing cosolvent concentration?
exponentially
