Lecture 17 - Drug solubility and dissolution rate 2 Flashcards
Give four examples of weakly acidic drugs
Naproxen, phenobarbital, nitrofurantoin, phenylbutazone
What proportion of drugs are weak acids/weak bases
20% = weak acids
70% = weak bases
Give four examples of drugs which are weak bases. Most ………… drugs are weakly basic.
cocaine, metoclopramide, ropinirole, chlorpromazine
amine drugs
Give the Henderson Hasselbach equation for weak acid- show the process of how we reach the Henderson Hasselbach equation from rate equation of acid.
For a weak acid, when do we get high percentage of ionisation? when do we get less ionisation? Draw the curve for pH-pKa against % of ionised A-.
- for a weak acid, when pH is higher (H+ is removed) than pKa, we get more ionisation.
- when pH is lower (lots of H+) than pKa, we get less ionisation- this is because the position of equilibrium shifts to the left because H+ concentration is so high.
Give the Henderson Hasselbalch equation for a weak base- show how we reach the HH equation form the Ka equation.
Explain at what pH a weak base is ionised/not ionised. Draw the % ionisation curve for weak base.
For weak base, if the pH is higher than pKa (less H+), we get less ionisation- the position of equilibrium shifts to the right to increase the H+ concentration. If the pH is lower than the pKa of the base (add H+), we get more ionisation (position of equilibrium shifts to the left)
Draw the curve for %ionised form of a weak acid AND a weak base as a function of pH
Draw curve for %unionised form of a weak acid and a weak base as a function of pH
Write the equation for the dissociation of weak acid
Which form of a weak acid has low solubility- ionised or unionised?
unionised
Unionized form of weak acid has low solubility- low So. What is meant by So?
the saturation solubility of undissociated specie- intrinsic solubility.
What can you do to pH to increase the proportion of the unionised form of weak acid, HA?
decrease pH/add H+ - more H+ to react with A- so more HA is formed
At low pH, there is lots of unionised acid molecules. What forms because of this?
precipitation occurs- precipitate forms because solubility of unionized species is less than the ionized form.
What can you do to pH of solution of weakly acidic drug/salt of drug to increase the proportion of the ionised form of weak acid, HA?
The ionized form is more…
Increase the pH- remove H+. Less H+ means more HA dissociates to compensate for the loss of H+ so more ionized form, A- is formed.
The ionized form is more soluble.
Write the equation for dissociation of weak base.
Which is more soluble- the ionized form of weak base or unionized? Which has low solubility/low So?
ionized. The unionized form has low solubility- low So.
How can you increase the proportion of the ionised form of the weak base?
decrease pH/ add H+
How can you increase the proportion of the unionised form of the weak base?
increase pH/remove H+. This shifts the position of equilibrium to the right and the proportion of the unionised form is therefore increased.
So, at low or high pH do we see precipitation in weak base?
high pH
What is the Cs of a weak acid?
The maximum concentration- the total saturation solubility of a weakly acidic drug in aqueous solution at any pH.
What is the equation for Cs? There are two because [HA]sat = So
Cs = [HA]sat + [A-]
Or
Cs = So + [A-]
Substitute the Cs equation for a weak acid into the Henderson Hasselbalch equation for weak acid.
So, we can predict the total solubility of a weakly acidic drug- Cs if we are given what three things?
- pH of solution
- pKa of the acid
- solubility of the unionised form of the drug, HA (so basically the So value or [HA])
Give three properties of the solubility of a weakly acidic drug and draw the curve for pH against Cs of weakly acidic drugs.
Assume So = 0.05M and pKa = 7
Now, suppose we make a 0.5M solution of Na+A-. What is the [HA] at pH of 10, 9 and 8? If we go any lower than pH of 8 why would the weak acid precipitate?
So tells us the amount of HA which is soluble, so if [HA] increases above So, the excess amount would not dissolve it would form a precipitate.
Below what pH would phenobarbital- a weak acid- begin to precipitate to form a solution initially containing 1.3% w/v of sodium phenobarbital?
What is Cs of a weak base?
Cs= the maximum concentration of weak base in an aqueous solution at any pH.
What is So of a weak base?
The saturation solubility of an unionised B species.
Give the Cs equation of a weak base. Remember, there are two ways to write it.
Cs = [B]sat + [BH+]
[B]sat is the same as S0 – saturation solubility of the unionized B species.
Therefore, [BH+] = Cs – So
Write the HH of weak base and substitute the Cs equation into it.
The solubility of a weakly basic drug can be predicted when we are given three things…
the pH of the solution, the pKa and the solubility of the unionised form of the drug- So
Give three properties of the solubility of a weakly basic drug and draw the curve for pH against Cs of weakly basic drugs.
At what pH will thioridazine (weak base) begin to precipitate to form a solution initially containing 0.407% w/v of the hydrochloride salt?
Solubility of the free base= 1.5x10^-6M, pKa=9.5 and MW=407
If the salt of a weak acid is used instead of the free form…
pH of solution increases and solubility increases
If the salt of a weak base is used…
pH of solution falls and solubility increases.
