PHAYG062 – Preformulation

Solubility: Consolidation questions

The questions below are designed to help you consolidate your learning. If you can answer them
all correctly, then you will do very well in the course. If not, then consult your lecture notes, the
course text (“Essentials of Pharmaceutical Preformulation” by Gaisford and Saunders), or me
(g.williams@ucl.ac.uk)! Please note that there is no obligation to do these questions: they do not
need to be handed in and will not be marked, but they offer you the opportunity to test your
understanding of the material covered.

1. What is meant by the term equilibrium solubility?

The concentration of drug obtained when the solid drug is in equilibrium with its solution.

2. Explain why the process of dissolution and the melting point of a drug are correlated.

A solid material is held together by intermolecular bonding interactions (e.g hydrogen-bonding,

dipole-dipole interactions). When a solid melts to form a liquid, these bonds must be broken. The
stronger the bonds are, the more energy required to effect the melting transition, and hence the
higher the melting point. When a solid drug dissolves, the intermolecular interactions between
drug molecules must also be overcome: hence, the stronger these are, the more difficult dissolution
will be. A higher melting point thus correlates with a reduced solubility.

3. Write an expression for the ideal solubility of a drug.

ln x2 = (-ΔfusH / RT) + (ΔfusH / RTm)

4. The melting point of diclofenac is 170.7 °C, and its heat of fusion is 18.95 kJ mol-1. Calculate the
ideal solubility (in terms of mol fraction) at (a) 25.0 °C; (b) 50.0 °C; and, (c) 74.01 °C.

ln x2 = (-ΔfusH / RT) + (ΔfusH / RTm)

ΔfusH = - 18,950 J mol-1; R = 8.314 J K-1 mol-1; Tm = 170.7 °C = 443.85 K.

a) T = 25.0 °C = 298.15 K

So ln x2 = [-18,950 / (8.314 x 298.15)] + [18,950 / (8.314 x 443.85)] = -2.5095

And x2 = e-2.5095 = 0.0813 (3 s.f.)

b) T = 50.0 °C = 323.15 K

So ln x2 = [-18,950 / (8.314 x 323.15)] + [18,950 / (8.314 x 443.85)] = -1.91808

And x2 = e-1.91808 = 0.147 (3 s.f.)

c) T = 74.01 °C = 347.16 K

So ln x2 = [-18,950 / (8.314 x 347.16)] + [18,950 / (8.314 x 443.85)] = -1.43026

And x2 = e-1.91808 = 0.2392 (4 s.f.)

5. In water, diclofenac is found to have a solubility of 2.37 mg/L. Comment on this given your
answer to Q4.

The temperature is not given here, which makes a direct comparison slightly difficult. However,
2.37 mg/L can be converted to a mol fraction:

RMM of diclofenac = 296 g/mol, so 2.37 mg = 8.00675 x 10-3….mmol

We can reasonably assume that the density of the drug solution is 1 g/mL, and hence total mass =
1 kg = 106 mg. Mass of water = 106 – 2.37 = 999,997.63 mg. And so no mmol water =
999,997.63/18 = 55,555.423… mmol.

Total no of mmol = 8.006 x 10-3 + 55555.423 = 55,555.4319 mmol

And so x2 = 8.006 x 10-3 / 55,563.42989 = 1.44 x 10-7 (3 s.f.)

The difference can be ascribed to non-ideal behaviour in water, as a result of H-bonding, dipole
interactions, and its dielectric constant.

6. An experimental drug is found to have a melting point of 237 °C, and a heat of fusion of 33.67
kJ mol-1. Calculate the ideal solubility (in terms of mol fraction) at (a) 22.5 °C; (b) 25.0 °C; and,
(c) 79.10 °C.

ln x2 = (-ΔfusH / RT) + (ΔfusH / RTm)

ΔfusH = - 33,670 J mol-1; R = 8.314 J K-1 mol-1; Tm = 237 °C = 510.15 K.

a) T = 22.5 °C = 295.65 K

So ln x2 = [-33,670 / (8.314 x 295.65)] + [33,670 / (8.314 x 510.15)] = -5.759498

And x2 = e-5.759498 = 0.00315 (3 s.f.)

b) T = 25.0 °C = 298.15 K

So ln x2 = [-33,670 / (8.314 x 298.15)] + [33,670 / (8.314 x 510.15)] = -5.64464

And x2 = e-5.64464 = 0.00354 (3 s.f.)

c) T = 79.10 °C = 352.25 K

So ln x2 = [-33,670 / (8.314 x 352.25)] + [33,670 / (8.314 x 510.15)] = -5.64464

And x2 = e-5.64464 = 0.02848 (4 s.f.)

7. Explain the factors which cause experimental solubility to deviate from the ideal value.

Dipole-dipole interactions; dielectric constant and H-bonding. In ideal solubility, we assume that
the heat of mixing is zero, but this is usually not the case. In order to dissolve a drug molecule from
a solid into solution we need to remove it from the solid lattice (taken into account in heat of
fusion), but also insert it into a “cavity” in the solvent. If the heat of mixing is zero, then the energy
taken to perform the latter process must also be zero, but if there are interactions between the
drug and solvent molecules (e.g. dipole-dipole or H-bonding) then this will give a negative
contribution to the heat of mixing (we are forming (intermolecular) bonds, which is an exothermic
process). However, to insert the drug molecule in the cavity we probably need to overcome
intermolecular forces already existing between the solvent molecules (e.g. H-bonding in water). To
do so will require energy (bond breaking is an endothermic process), providing a positive
contribution to the heat of mixing.

Thus, where we have the possibility for dipole-dipole interactions, H-bonding, and where we have
solvents with high dielectric constants, deviations from ideality are frequently seen.

8. State the Henderson-Hasselbalch equation for acidic and basic drugs.

Acidic: pH = pKa + log ([A-] / [HA])

Basic: pH = pKa + log ([B]/[BH+])

9. Sketch a plot to show how the solubility of an acidic drug will change with pH.
Solubility

pH

10. A basic drug B with pKa = 6.79 is found to have an intrinsic solubility of 3.45 mg mL-1. Calculate
the total solubility at (a) pH 1.7; (b) pH 3.44; (c) pH 4.59; and, (d) pH 11.2.

St = S0 [1 + 10pKa-pH]

S0 = 3.45 mg mL-1; pKa = 6.79.

a) pH = 1.7. St = S0 [1 + 10pKa-pH] = 3.45 [1 + 106.79-1.7] = 3.45 x 123027.88 = 424446.176…

St = 4.24 x 105 mg/mL (3 s.f.) – very unlikely to be realistic! HH breaks down here.

b) pH = 3.44. St = S0 [1 + 10pKa-pH] = 3.45 [1 + 106.79-3.44] = 3.45 x 2239.72114 = 7727.03793

St = 7.73 x 103 mg/mL (3 s.f.)

c) pH = 4.59. St = S0 [1 + 10pKa-pH] = 3.45 [1 + 106.79-4.59] = 3.45 x 159.48932 = 550.238151

St = 550 mg/mL (3 s.f.)

d) pH = 11.2. St = S0 [1 + 10pKa-pH] = 3.45 [1 + 106.79-11.2] = 3.45 x 1.0000389 = 3.45013422

St = 3.45 mg/mL (3 s.f.) – essentially the same as S0.

11. An acidic drug A with a pKa of 4.33 is found to have an intrinsic solubility of 22.06 mg mL-1.
Calculate the total solubility at (a) pH 2.08; (b) pH 3.88; (c) pH 5.89; and, (d) pH 7.47.

St = S0 [1 + 10pH-pKa]

S0 = 22.06 mg mL-1; pKa = 4.33.

a) pH = 2.08. St = S0 [1 + 10pH-pKa] = 22.08 [1 + 102.08-4.33] = 22.06 x 1.0056234 = 22.1840525

St = 22.2 mg/mL (3 s.f.) – very similar to S0.

b) pH = 3.88. St = S0 [1 + 10pH-pKa] = 22.08 [1 + 103.88-4.33] = 22.06 x 1.3548134 = 29.8871834

St = 29.9 mg/mL (3 s.f.)

c) pH = 5.89. St = S0 [1 + 10pH-pKa] = 22.08 [1 + 105.89-4.33] = 22.06 x 37.307805 = 823.010189

St = 823 mg/mL (3 s.f.)

d) pH = 7.47. St = S0 [1 + 10pH-pKa] = 22.08 [1 + 107.47-4.33] = 22.06 x 1381.3843 = 30,473,3369

St = 30.5 x 103 mg/mL (3 s.f.) – unrealistic!

12. Comment on how the variation in solubility of ionisable drugs with pH influences their
behaviour in drug delivery systems.

Acidic drugs have lowest solubility in the stomach, with solubility increasing as the drug moves
through into the duodemum and small intestine (since pH increases). This makes acidic drugs
suitable for controlled release formulations. In contrast, basic drugs are most soluble in the
stomach, with solubility decreasing upon movement into the duodenum and small intestine. This
renders them useful for immediate release formulations, but we need to be aware of the risk that
they subsequently precipitate when moving to higher-pH media.

13. State the Noyes-Whitney-Nernst-Brunner equation.

dm/dt = (DA/h).(St – C)

14. Using your answer to Q13, explain how the dissolution rate for a tablet of drug X will be
affected by (a) doubling the surface area of the tablet; (b) reducing the thickness of the
boundary layer.
In the NWHB equation, dm/dt is the dissolution rate, D is the diffusion coefficient, A is the surface
area of the solid drug material, and h is the thickness of the boundary layer. Therefore, assuming
that everything else remains constant, doubling the surface area A will double the rate of
dissolution. Reducing the thickness of the boundary layer will also cause the dissolution rate to
increase.

15. State the advantages and disadvantages of dissolution testing.

The key advantages of dissolution testing are that it provides a simple and reproducible method by
which drug release from a formulation can be measured. This technique easily permits us to
compare different formulations and batches. The USP and BP define key specifications which must
be met by different formulation types, and so a dissolution test forms part of batch specification
testing, allowing us to confirm a formulation meets the required standard. The use of different
release media can enable different parts of the body to be modelled. However, dissolution testing
is not a truly representative model of what happens in vivo – there are a large number of
differences between the conditions in a dissolution experiment, and those in the human body. For
instance, a constant volume of solvent is used in a dissolution test, whereas the volume of fluid in
the body (e.g. in the intestine) will vary with time and depending on what has been eaten and
when.

16. Explain what is meant by the term “sink conditions” and detail why it is important to use skink
conditions in dissolution testing.

In dissolution testing, sink conditions refers to the situation where C = St/10. We employ these to
ensure that the amount of drug in the formulation can be easily and freely dissolved in the
available solvent. This is because we need the drug to be in solution to be able to quantify it! If we
did not do dissolution testing under sink conditions, then a situation may arise in which the
formulation released all the drug, but because the solution was saturated some of the drug was
present as a solid material, and thus could not be detected.