Reaction scale-up Flashcards
KiloLab
Generally in-house at most pharmaceutical companies
Apparatus usually contained in a walk-in fume hoods
Features of a pilot plant
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
Glass vessels
Chemical inertness
Transparent
Comparatively weak material c.f. metal - can only hold up to ~100 litres
Metal vessels
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
Metal vessels with an internal glass lining
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
Chromatography in pilot plants
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
How are products purified in pilot plants?
Recrystallisation, precipitation or distillation
Sampling a reaction in a pilot plant
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
Can evaporation to dryness occur in pilot plants?
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)
What temperatures are achievable in pilot plants?
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
Filtration of solids in a pilot plant
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
Discovery chemistry route to a drug
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
Cost considerations for a process route to a drug
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
Linear vs. convergent syntheses
The more convergent a synthesis the better
Because the overall yield will be higher
Telescoping reactions
= 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
Reagent considerations for process routes
e.g. Reductions Acids/bases Alkylations Halogenations
Reagent considerations for reductions
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
Reagent considerations for reactions using acids/bases
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’
Reagent considerations for alkylations
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
Reagent considerations for halogenations
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
Different types of drug formulation
Oral Inhaled Ophthalmic Otic Parenteral Topical Rectal/vaginal
Types of oral dosage forms
Tablets Capsules Sublingual (under tongue) tablets Buccal (cheek) tablets Powders/solutions/suspensions Elixirs (alcoholic solutions)
Tablets
Pressed form of the API mixed with excipients
Excipients
Biologically inactive ingredients
Types of excipients
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
Capsules
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
Hard shell capsules
2-parts
Generally used for dry powder APIs
Soft shell capsules
1-part
Generally used for oils or solutions in oils
Caplet
Tablet shaped like a capsule
Inhaled dosage forms
e.g. inhalers, nebulisers
Can be used for selective delivery to the respiratory system
Topical dosage forms
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
Rectal/vaginal dosage forms
Suppositories formulated with wax
Liquefy at body temperature to allow absorption
Parenteral dosage forms
Subcutaneous/intravenous
Bypasses digestive tract breakdown and first-pass liver metabolism
Salts
APIs that contain acidic or basic functional groups often administered as salts
Reasons for making salts
Aids purification by imparting crystallinity
Alters solubility/dissolution properties
Imparts stability
Properties of an ideal salt
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)
Polymorph
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
Different polymorphs have…
…different melting points and solubilities
12 principles of green chemistry
- Prevention - it is better to prevent waste than clean it up after it’s been generated
- Atom economy - syntheses should be designed to maximise the incorporation of the reactants into the products
- Use less hazardous chemicals - syntheses should use and generate substances that are minimally toxic to the public and the environment
- Design for safer chemicals - chemical products should not only perform their function but should also be less toxic in the short and long term
- Safer solvents and auxiliaries - use of solvents/separation agents should be minimised/avoided wherever possible
- Design for energy efficiency - energy requirements for a process should be minimised
- Use renewable feedstock - a raw material should be renewable rather than depleting if technically and economically viable
- Reduce derivatives - protecting/deprotection is inherently inefficient and should be avoided
- Catalysis - use of catalytic reagents is preferable to stoichiometric ones
- Design for degradation - chemicals should be designed to break down to innocuous byproducts after fulfilling their function
- Real-time analysis for pollution prevention - processes should be monitored and controlled in real-time, prior to the formation of hazardous substances
- Inherently safer chemistry for accident prevention - substances should be chosen to minimise the potential for accidents
Atom economy equation
% atom economy = 100 x (relative molecular mass of desired products/relative molecular mass of all reagents)
Why does atom economy need to be considered in process design?
Because any atoms not incorporated into the product will be incorporated into waste/a byproduct, which will require safe disposal
Examples of reactions with 100% atom economy
Claisen rearrangement
Diels-Alder
Michael addition
Alkene hydration
Commonly quoted measures of chemical toxicity
LD50
LC50
Lower value = more toxic
LD50
Lethal dose at which 50% of test organisms are killed
LC50
Lethal concentration at which 50% of test organisms are killed
How is the carcinogenicity of compounds assessed?
Using the Ames test
