CHEM5226

Case Studies in Fine Chemical and Pharmaceutical Synthesis

Technical Transfer of a
Medicinal Process
John Blacker

Adil Khan
Chemical Process Research & Development MSc
Personal Tutor: John Blacker
8th January 2016

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(ii)

How is the job of the medicinal chemist different to that of the process chemist?
5marks

A medicinal chemist is tasked with finding an active compound. He wants to find as many as possible,
researching many different molecules. A process chemist is more interested in researching and
improving the route for a particular molecular.

(iii)

Identify 5 aspects that make medicinal chemical routes difficult to scale-up? - 5 marks

Medicinal routes are difficult to scale up because:

o Low ratios of weight of product to volume of solvents/reagents used make the

process extremely wasteful at large scale
o Steps in the lab that take very little time in the lab can take hours to do on a plant.
For example, washing the flask/reactor vessel.
o Use of toxic substances. A medicinal chemist can be exposed to toxic substances for
a short time and experience little discomfort. However, at scale, some employees
might be in contact with toxic chemicals for years.
o Batch-mode operation, while common in medicinal chemistry, is potentially
dangerous at scale because of the high risk of explosion.
o The use of chromatography as a method of separation is not recommended at large
scale.

(iv)

Briefly explain why millions of compounds are screened to identify 1 commercial drug
product, include in your answer why drugs fail in Phase 1-3 clinical trials? 5 marks

Millions of compounds must be screened because we dont know exactly what compound we are
looking for. There are many changes that can be made to a molecule and some may improve it and
some may toxify it. There is no way to tell which without testing it. After screening drugs have to go
through 3 phases of clinical trials. Phase I is initial testing in healthy humans. If the drug shows signs
of toxicity then it will at Phase I. Phase II is to see if the drug has any biological effect. Drugs will fail
in Phase II if they are ineffective in treating the disease. Phase III trials are more rigorous and ensure
that drugs do what they are supposed to, are better than competing drugs and are safe to use. If a
drug does not fulfil these requirements it will fail Phase III.

(v)

The amount of drug substance (Active Pharmaceutical Ingredient, API) that is required
for testing, when entering into Phase I clinical trials, is usually about 1 kg. Manufacture
of this may start 6-9 months before it is required and is likely to involve a large team and
expensive materials. Given the failure rate in (iii) above, what strategies do companies
adopt to minimise the cost of these failures? 5 marks

To minimise the cost of failures, strategies need to ensure that the drug is both safe and effective.
This means that they need good screening methods. Also, any given drug is more likely than not to
1

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fail at Phase 1. Therefore, the manufacture of this drug should be as cheap as possible. For kg scale
production, it can help to:
Telescope solvents, rather than swapping them out
If producing multiple drugs containing the same building block, then produce the building
block on a larger scale. This also helps with having convergent routes, which generally have
greater yields.
o Question whether particular steps are necessary. Perhaps, the drug does not need to be
washed, or recrystallized.
o Using immobilised catalysts lowers catalyst loading and increases precious metal
recyclability.
o Minimise the amount that needs to be produced for Phase I.

(vi)
If a particular med. chem. route has 8 linear stages with an overall yield of 1.28%. How
many kgs of starting material of MW = 100 are required to produce 1 kg of product of
MW = 100? Show your workings in a table. 5 marks
o
o

Yield =

moles product

moles starting material

moles starting material =

moles product
1kg
=
= 78.125kg
Yield
0.0128

Assuming the yield is constant for each step.

Yield!"#$%&& = Yield!"#$ ! =0.0128 Yield!"#$ = 58%

Step
Product

78.13 45.31 26.28 15.24 8.84 5.13 2.97 1.72 1.00

(vii)

If the cycle-time (time to process one batch) is 2.5 days (including clean-out, and 5 day
working week), and the size of each batch is 100 litre with a concentration of 2% (w/v)
and yield of 58% (MW = 100 for all materials), make a table to show the amount of
material, volume, number of batches, and time taken to produce enough material at
each stage for the next, hence the overall time taken to make the 1kg API. Clearly show
your workings and assumptions 5 marks

In 2.5 days, 1 batch is made. 1 batch is 100 L and has a concentration of 2%(w/v), so 2 kg of product.
The yield is 58% of 2 kg, so 1.16 kg product.

We only want 1 kg product, so (1 kg/0.58=) 1.724 kg in solution in a volume of (1.724 kg/0.02=) 86.2
L. The time will still take 2.5 days.

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Material

1.724 kg

Volume

86.2 L

Batches

Time

2.5 days

(viii)

If the cost of employing the team of 6 (chemists, analyst, chemical engineer, project
manager) needed to do the project is 1m/52 working weeks, the cost of materials is
0.5m, and the cost of using the kilo lab 2m/52 working weeks. What is the cost of the
campaign to make 1kg of the API? - 5 marks
Cost =

(ix)

1m 0.5m 2m
+
+
= 67,000
52
52
52

Before scaling-up, chemical and operational safety studies are required. Explain briefly
what these might involve. 5 marks

COSHH (Control of Substances Hazardous to Health) Study the chemicals being used to see how
safe, polluting, toxic they are and whether their use is recommended for scale up.
Reactions hazards testing Need to know if a reaction will cause an explosion. This can be tested by
the evolution of heat and pressure within a test reactor.
IPPC The process must meet with regulations set down by the Integrated Pollution Prevention and
Control organisation.
Hazard and Operability study (HAZOP). A major component of front end engineering design. A
systematic approach to identifying and evaluate risks. Starting from the initial flowsheet, a
multidisciplinary team will usually work together on this.

(x)

Monitoring the reaction and analysing the product purity at each stage requires much
work to identify impurities, make standards and validate methods. A variety of different
analytical techniques are used for this. Describe the use of one technique for
determining the reaction conversion, and one technique for determining the purity of a
product. - 5 marks.

Technique for determine the reaction conversion: Measure the concentration of the reactant at the
end of the reaction using UV-vis. Multiply this by the solution volume and divide by the initial
quantity of reactant.
Technique for determining the purity of a product. This works if the product is acidic/basic. Dissolve
the product in a pH neutral solvent. Titrate it with a base/acid. The purity can be calculated using the
molar quantity needed to reach the equivalence point. E.g. if only 4.5 mol NaOH is needed for 5 mol
of aspirin, then the purity is 90%.

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(xi)

Based on the process described above in Q(v)-Q(vii) define a project plan for the
development and production by drawing a GANTT chart
(https://en.wikipedia.org/wiki/Gantt_chart) which should have at least 10 specific tasks
and timescale for producing 1kg of API. - 5 marks