Reaction scale-up

Question 1

KiloLab

Answer 1

Generally in-house at most pharmaceutical companies

Apparatus usually contained in a walk-in fume hoods

Question 2

Features of a pilot plant

Answer 2

Used for synthesis of 10-100kg of material
Plants are multi-use, which means validated cleaning procedures must be developed and implemented after each batch is made to ensure compliance with good manufacturing practice
Plants often utilise a ‘top-down’ approach - reagents added at the top and product collected at the bottom
3 commonly used types of reaction vessel - glass, metal and metal with internal glass lining

Question 3

Glass vessels

Answer 3

Chemical inertness
Transparent

Comparatively weak material c.f. metal - can only hold up to ~100 litres

Question 4

Metal vessels

Answer 4

Strong - can be used on a much larger scale than glass

Opaque - therefore harder to perform phase separations etc
Reactivity - will react with certain reagents e.g. strong acids/reductants/oxidants

Question 5

Metal vessels with an internal glass lining

Answer 5

Combines chemical inertness of glass with strength of metal

Opaque
Cannot be used at high or low temperatures due to the different rates of expansion of glass and metal - would result in cracking

Question 6

Chromatography in pilot plants

Answer 6

Chromatography is not possible on a large scale except in very exceptional circumstances e.g. late stage purification of a very high-value compound
Would require an enormous volume of solvent/silica as well as an enormous amount of energy for evaporation of the solvent - process would be very uneconomical

Question 7

How are products purified in pilot plants?

Answer 7

Recrystallisation, precipitation or distillation

Question 8

Sampling a reaction in a pilot plant

Answer 8

Involves opening a sample port and using a dip-can to remove a sample of the reaction
But this carries the risk of exposure to solvent vapours and is not possible for air-sensitive reactions
Robust processes that do not require monitoring are preferred for pilot plants

Question 9

Can evaporation to dryness occur in pilot plants?

Answer 9

Evaporation to dryness is not possible
Impellers are only effective when the vessel is > 10 % full
Generally the best vacuum achievable is ~ 50 mBar

The consequence of this is that either the next step must function correctly with traces of previous solvent present, or the solid product must be isolated by filtration and dried (but this increases the number of steps and the cost)

Question 10

What temperatures are achievable in pilot plants?

Answer 10

Temps of +20 to +140 degrees are easily achievable
Higher temperatures may be reached by using a silicone-based heating fluid in the heating jacket
Cooling to -15 degrees can be effected by circulating chilled ethylene glycol
Even lower temps require a special vessel constructed from an inert alloy, with cooling effected by CO2 or liquid N2

Question 11

Filtration of solids in a pilot plant

Answer 11

Filtration of solids is effected by a pressure filter

Can filter the slurry of product without exposing it to the air as well as drying it in the same apparatus

Question 12

Discovery chemistry route to a drug

Answer 12

Cost of starting materials/reagents/solvents not important because only small quantities are used
Yields of individual steps not so important because only milligram quantities of the final compound are required for biological testing
Environmental concerns are rarely an issue due to the small quantities used - there are also fewer restrictions on the types of reagents and methods of purification
Intermediates are often not fully characterised
Less stringent purity constraints on the final product
Synthetic route is designed such that there is maximum flexibility in the number of analogues that can be synthesised

Question 13

Cost considerations for a process route to a drug

Answer 13

Cost of starting materials/reagents/solvents must be considered at every step - can cost millions
Also need to considering cost of attaining reaction conditions - i.e. heating a 1000 litre reaction to 150 degrees is very expensive due to the amount of energy required
Yield is directly related to cost - need a high yield for each step
Other cost considerations: transport of raw materials, safe disposal of waste, labour costs

Question 14

Linear vs. convergent syntheses

Answer 14

The more convergent a synthesis the better

Because the overall yield will be higher

Question 15

Telescoping reactions

Answer 15

= combining more than one reaction in the same vessel
Aim is to reduce the number of steps
Requires that the first step(s) is quantitative

Question 16

Reagent considerations for process routes

Answer 16

e.g.
Reductions
Acids/bases
Alkylations
Halogenations

Question 17

Reagent considerations for reductions

Answer 17

Common reductants e.g. LiAlH4, NaBH4 and DIBAL can be used
Iron metal is a cheap, non-toxic reductant
H2 gas is also very cheap but requires special facilities due to explosion risk

Question 18

Reagent considerations for reactions using acids/bases

Answer 18

Most common acids can be used - although HCl can corrode metal vessels and H3PO4 has issues with its viscosity
BuLi is typically the strongest base that can be used (but is pyrophoric)
NaOH is a preferred base to NH3 because aqueous waste with a high N2 content will have a high ‘biological oxygen demand’

Question 19

Reagent considerations for alkylations

Answer 19

Dimethyl sulphate is the preferred methylating agent because it is cheap and non-volatile
Methyl iodide is more reactive but is expensive and volatile, so poses a greater health risk

Question 20

Reagent considerations for halogenations

Answer 20

Chlorine and bromine regularly used for electrophilic addition/substitution
Iodine is more expensive and less readily available (so other halogens preferred)
Fluorine too reactive to be used in a standard pilot plant - if an API contains fluorine, it is more common to buy the fluorine-containing fragment from a specialist supplier and the incorporate this into the synthesis

Question 21

Different types of drug formulation

Answer 21

Oral
Inhaled
Ophthalmic
Otic
Parenteral
Topical
Rectal/vaginal

Question 22

Types of oral dosage forms

Answer 22

Tablets
Capsules
Sublingual (under tongue) tablets
Buccal (cheek) tablets
Powders/solutions/suspensions
Elixirs (alcoholic solutions)

Question 23

Tablets

Answer 23

Pressed form of the API mixed with excipients

Question 24

Excipients

Answer 24

Biologically inactive ingredients

Question 25

Types of excipients

Answer 25

Binders e.g. sucrose, lactose, starch, cellulose that hold the tablet together
Lubricants e.g. magnesium stearate that ensure the tablets do not stick in the press and are easy to swallow
Flavourings/sweeteners to mask an unpleasant flavour
Pigments - different colours/lettering can be useful for patients who take multiple medications
Disintegrants that expand in contact with water and ensure the tablet breaks up in the stomach/gut

Question 26

Capsules

Answer 26

API encased in gelatin-based capsule
Dissolution of capsule determines absorption
Capsules can be used to protect the API from the strongly acidic stomach environment

Question 27

Hard shell capsules

Answer 27

2-parts

Generally used for dry powder APIs

Question 28

Soft shell capsules

Answer 28

1-part

Generally used for oils or solutions in oils

Question 29

Caplet

Answer 29

Tablet shaped like a capsule

Question 30

Inhaled dosage forms

Answer 30

e.g. inhalers, nebulisers

Can be used for selective delivery to the respiratory system

Question 31

Topical dosage forms

Answer 31

e.g. creams, gels, lotions, ointments, transdermal patch

Can be used to deliver API selectively to the skin if it would have toxic systemic effects

Question 32

Rectal/vaginal dosage forms

Answer 32

Suppositories formulated with wax

Liquefy at body temperature to allow absorption

Question 33

Parenteral dosage forms

Answer 33

Subcutaneous/intravenous

Bypasses digestive tract breakdown and first-pass liver metabolism

Question 34

Salts

Answer 34

APIs that contain acidic or basic functional groups often administered as salts

Question 35

Reasons for making salts

Answer 35

Aids purification by imparting crystallinity
Alters solubility/dissolution properties
Imparts stability

Question 36

Properties of an ideal salt

Answer 36

Crystalline
Non-hygroscopic
Physical stability
Sufficient solubility under physiological conditions
Good organoleptic properties (i.e. palatable)
A single polymorph (or controlled crystallisation to give a single polymorph)

Question 37

Polymorph

Answer 37

A compound (or particular salt) that can exist in more than one crystalline form
Generally the most thermodynamically stable (highest-melting) polymorph is preferred for the API, because it will not isomerise to another polymorph upon prolonged storage

Question 38

Different polymorphs have…

Answer 38

…different melting points and solubilities

Question 39

12 principles of green chemistry

Answer 39

1. Prevention - it is better to prevent waste than clean it up after it’s been generated
2. Atom economy - syntheses should be designed to maximise the incorporation of the reactants into the products
3. Use less hazardous chemicals - syntheses should use and generate substances that are minimally toxic to the public and the environment
4. Design for safer chemicals - chemical products should not only perform their function but should also be less toxic in the short and long term
5. Safer solvents and auxiliaries - use of solvents/separation agents should be minimised/avoided wherever possible
6. Design for energy efficiency - energy requirements for a process should be minimised
7. Use renewable feedstock - a raw material should be renewable rather than depleting if technically and economically viable
8. Reduce derivatives - protecting/deprotection is inherently inefficient and should be avoided
9. Catalysis - use of catalytic reagents is preferable to stoichiometric ones
10. Design for degradation - chemicals should be designed to break down to innocuous byproducts after fulfilling their function
11. Real-time analysis for pollution prevention - processes should be monitored and controlled in real-time, prior to the formation of hazardous substances
12. Inherently safer chemistry for accident prevention - substances should be chosen to minimise the potential for accidents

Question 40

Atom economy equation

Answer 40

% atom economy = 100 x (relative molecular mass of desired products/relative molecular mass of all reagents)

Question 41

Why does atom economy need to be considered in process design?

Answer 41

Because any atoms not incorporated into the product will be incorporated into waste/a byproduct, which will require safe disposal

Question 42

Examples of reactions with 100% atom economy

Answer 42

Claisen rearrangement
Diels-Alder
Michael addition
Alkene hydration

Question 43

Commonly quoted measures of chemical toxicity

Answer 43

LD50
LC50
Lower value = more toxic

Question 44

LD50

Answer 44

Lethal dose at which 50% of test organisms are killed

Question 45

LC50

Answer 45

Lethal concentration at which 50% of test organisms are killed

Question 46

How is the carcinogenicity of compounds assessed?

Answer 46

Using the Ames test