PHAY0032 – Preformulation
Problem-based learning workshop
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?
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.
c) 43.7 mg of D is dissolved in 170 mL of octanol, and 330 mL of water is added. After shaking, the final amount of D in the aqueous phase is 1.72 mg. Determine log P for D. Show your working in full in your answer.
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?
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?
f) Which form. is the most stable one?
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.
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.
i) Comment on the feasibility of making i) an immediate release and ii) an extended release formulation of D.
j) How might the physical form. of D be altered to improve the solubility?
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.
b) The company want to formulate D’ as an immediate release formulation. Comment on the likelihood of this.
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
|
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.
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’.
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.
g) The dissolution rate is found to be too slow for practical applications of the D’ salts. How might the company solve this problem?
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.
b) What benefits can co-crystals have in pharmaceutical formulation? Give examples of co-crystal systems for each benefit you give.
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.
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.
e) How are co-crystals usually produced in industry? Why can this method be problematic?