PHAYG062 – Preformulation

PBL workshop – 27 Nov 2017

In the module so far, we have looked at a range of physicochemical concepts and discussed how they
relate to the formulation of a drug. In this workshop, we will look at some exercises to see how these
properties will impact formulation decisions.

In advance of the workshop: Please have a look through the questions below and the material covered
to date, and make a list of things you are unsure of – we can discuss these before we start the
exercises.

In the workshop we will work through the exercises below together.

Exercises

1. A company is looking to develop a fast dissolving formulation of a drug D. The structure of D

is given below.

a) Consider the structure of D. Do you expect it to have high solubility in water? What about its
permeability?

Lots of hydrophobic groups, only 2 x OH which are even vaguely hydrophilic. This will make it very
water-insoluble, but because it is hydrophobic D should partition OK.

b) Experiments are performed to determine the partition coefficient for D. Explain what is meant
by the term partition coefficient, and explain why it is useful to determine its value.
The partition coeff is the distribution of a drug between two immiscible solvents, usually octanol and
water. This is useful because it gives us an idea of how permeable the drug will be in vivo – the latter
is very hard to measure.

c) 43.7 mg of D is dissolved in 170 mL of octanol, and 330 mL of water is added. After shaking,
the final concentration of D in the aqueous phase is 1.72 mg. Determine log P for D. Show your working
in full in your answer.

Po,w = Co / Cw
Cw = 1.72 / 330 = 0.005212… mg/mL
Co = (43.7 – 1.72) / 180 = 41.98 / 170 = 0.24694… mg/mL
Hence Po,w = 0.24694…. / 0.005212…. = 47.378....
And log P = log 47.378 = 1.68 (3 s.f.)

d) During preformulation studies, it is found that D exists as two polymorphs, form I and form II.
What is meant by the term “polymorphism”? What differences will there be between form I and form
II?

Polymorphism refers to the existence of different arrangements of the same molecule in the 3D
structure. Form I and II will contain the same molecule (D), but these will be arranged differently in the
solid state and thus I and II will have different unit cells.

e) Form I and form II of D have melting points of 67.2 and 123 °C respectively, and ΔfusH values
of 34.5 and 89.3 kJ mol-1. Calculate the ideal solubility of both polymorphs at 25 °C. What assumptions
are made in ideal solubility?

Ideal solubility assumes that ΔmixH = 0. Thus, we find:

  fus H  fus H
ln x2  
RT RTm
For Form I:
ln x2 = -34,500 /(8.314 x 298) + 34,500/(8.314 x [67.2+273]) = -13.9249 + 12.19761 = -1.72731
x2 = 0.178 (3 s.f.)

For form II:

ln x2 = -89,300 /(8.314 x 298) + 89,300 /(8.314 x [123+273]) = -13.9249 + 12.19761 = -8.91982
x2 = 1.34 x 10-4 (3 s.f.)

f) Which form is the most stable one?

II – higher MP and ΔfusH

g) When the solubility in water is measured, the x2 values for forms I and II are found to be 1.34
x 10-6 and 3.45 x 10-8 respectively. Compare and contrast these to the values you calculated in part e.
True values much lower than ideal – because ΔmixH is not zero. H bonding, dielectric constant etc will
cause deviations from ideal solubility.

h) The company attempt to formulate the metastable form of D into a tablet. They perform a
dissolution test for 24h, and obtain the data below. Explain these findings.

We see release up to 100% initially, but this then declines. This is presumably because the most stable
form II is crystallising out of solution.

i) Comment on the feasibility of making i) an immediate release and ii) an extended release
formulation of D.

D will be very difficult to formulate in any way – solubility is very very low!

j) How might the physical form of D be altered to improve the solubility?

Non-ionisable, so the only options are to try to find another metastable form of the drug, or make D
amorphous.

2. Ultimately, the company abandon their work on D, and start to explore a new drug, D’.

a) The structure of D’ is given below. How does this relate to the original active ingredient D?
Explain the rationale for the company’s shift to this new active.
One of the alcohol groups has been esterified to form a pro-drug of D. This should increase solubility
because it increases the number of polar groups present and (more importantly) introduces an acidic
group here.

b) The company want to formulate D’ as an immediate release formulation. Comment on the

likelihood of this.

D’ is acidic, and thus will have lowest solubility in the stomach, so not likely to be very suitable for IR.

c) The solubility of D’ is measured at a number of different pH values, and the results are given
in the table below. Use these data to calculate its intrinsic solubility. The pKa of D’ is 3.22.

pH Solubility (μg / mL)

1 0.571
2 0.602
4 3.99
For an acidic drug, H-H says:

So
pK a  pH + log or St  So [1  10pH - pK a ]
St  So
I have St values, so need to work back to S0. So = St / [1 + 10pH-pKa]

pH Solubility (μg / mL) 10pH-pKa = 10pH-3.22 1 + 10pH-pKa S0 =

= St
1 0.571 0.006025596 1.006025596 0.567579992
2 0.602 0.060255959 1.060255959 0.567787424
4 3.99 6.025595861 7.025595861 0.567923359

From the calculations, we can conclude that S0 = 0.568 μg/mL (3 s.f.)

d) The partitioning of D’ is studied at pH 1 and pH 4. 10 μg of drug is dissolved into 100 mL of an
aqueous buffer for each experiment, and this is then shaken with 100 mL of octanol. At pH 1, the
amount of drug in the water layer after this is found to be 0.237 μg, while at pH 4 1.45 μg of drug
remains in the aqueous phase. Calculate log Po,w and log Do,w at both pH values.

If we ignore the ionisation, we are considering both charged and neutral D’, and are calculating

Do,w = Co /Cw

From H-H we know that the ionisation % is given by:

௣ு ି௣௄௔

௣ு ି௣௄௔

So we can calculate fionised at each pH as:

fionised = 0.00599 at pH 1 and
fionised = 0.857663… at pH 4.
Since funion = 1 – fionised, then:

fionised = 0.99401 at pH 1 and

fionised = 0.14234… at pH 4.
Now calculate Do,w at both pH values:

At pH 1 we get Do,w = (10 – 0.237) / 0.237 = 41.194…

At pH 4 we get Do,w = (10 – 1.45) / 1.45 = 5.89655…

And now we calculate Po,ws from the eqn Do,w = Po,w x fuinion => Po,w = Do,w / funion

So at pH 1, Po,w = 41.194… / 0.99401 = 41.44231

At pH 4, Po,w = 5.98655… / 0.14234… = 41.42679

And finally:

At pH 1, log D = 1.61 and log P = 1.62 (3 s.f.)

At pH 4, log D = 0.771, log P = 1.62 (3 s.f.)

Log P is the same at both pHs, because it considers only the unionised drug.

e) Although the company find that D’ performs better than D, they are still not happy with its
performance. Thus, they consider forming a salt. Suggest some suitable salt formers to use with D’.

D’ is an acid, so we will need something which can take a proton from it – i.e. a base such as NaOH,
KOH etc. Also need to make sure that the difference in pKa is at least 2 to ensure that you have 100%
(or close to 100%) ionisation.
f) In dissolution tests of some salts of D’, it is found that the rate of dissolution at pH 2
(representative of the stomach) is very similar to that at pH 6.8 (representing the lower parts of the
gastrointestinal tract). Explain why these observations are seen.

pHmicroenvironment is constant, regardless of the pH of the bulk medium. See salts lecture notes.

g) The dissolution rate is found to be too slow for practical applications of the D’ salts. How might
the company solve this problem?

The best way would be to reduce the size of the particles – this will accelerate dissolution as per Noyes-
Whitney. An alternative would be to try to make the material amorphous, but this would be difficult
for a salt – v strong interactions between the ions!

3.

a) Pseudopolymorphs such as co-crystals can be used to give active pharmaceutical ingredients

improved properties. Explain what is meant by the terms pseudopolymorph and co-crystal, and explain
how a co-crystal differs from a solvate.

A pseudopolymorph contains both the drug substance and a second moiety in the unit cell of the
material [5%]. A cocrystal combines the API and a co-former which is a solid at RTP in the unit cell of
the lattice [10%]. This differs from a solvate because in a solvate the co-former is a liquid (nor water)
at RTP [5%].

b) What benefits can co-crystals have in pharmaceutical formulation? Give examples of co-
crystal systems for each benefit you give.

- Improve solubility/disso rate [2.5%] e.g. fluoxetine HCl/succinic acid co-xtl [2.5%];
- Enhance stability to heat/light [2.5%] e.g. nitrofurantoin/4-hydroxybenzoic acid co-xtl [2.5%];
- Improve mech properties during tableting [2.5%] e.g. caffeine/methyl gallate [2.5%];
- Gain enhanced efficacy through combining 2 APIs in a co-xtl [2.5%] e.g.
meloxicam/paracetamol [2.5%].
- Mask bad tastes [2.5%] e.g. using carbamazepine/saccharin [2.5%]

But: making a co-xtl can make things worse as well as better – need to assess on a case-by-case basis,
and cannot make sweeping generalisations [5%].

c) A company prepares co-crystals of a new drug E and suberic acid. The structures of each are
given below, together with some dissolution data. Rationalise the observations seen in the dissolution
experiment.
The co-crystal clearly dissolves more slowly than E alone. This can be rationalised by looking at the
structures of the two molecules. The ends of the two molecules are very complementary, with NH---
HOOC H-bonds possible; this may result in a high lattice energy [5%]. Second, the suberic acid is rather
hydrophobic, with a C6H12 aliphatic chain in the centre of the molecule [5%] – this is likely to slow down
dissolution because there will be unfavourable interactions between this hydrophobic chain and the
water molecules [5%]. In contrast, E has COOH and F functional groups along its backbone, making it
much more hydrophilic then suberic acid, and thus is likely to dissolve much more quickly [5%].

d) E is intended to be taken alongside another drug, F. The structure of F is shown below. In in

vivo experiments on rats, kidney problems are observed to arise after approximately two weeks of
taking both active ingredients simultaneously. Explain why this occurs.

Looking at the structures of E and F, we can see that the structures can form many H-bonds (a diagram
to show this would be helpful here) [5%]. This means that there will be very strong interactions between
the molecules, and therefore they are likely to form a co-crystal with a very high lattice energy [5%],
which will hence be very insoluble [5%]. These insoluble adducts will likely be trafficked to the kidney,
where they can cause toxicity [5%].

e) How are co-crystals usually produced in industry? Why can this method be problematic?

Solvent evaporation [5%]. This is a problem because it is very low throughput, making it hard to
produce large amounts of material [5%].