Process Research and Development Chemistry 15 03 31

Paul L. Fishbein, Ph.D.31 MAR 2015

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Chemical Process Research and Development

•What is it?

•Why is it important?

•How is it done?

•What further reading is available?


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Process Chemistry is the “How to make it”

• Applies to any stage of development of the chemical.

• Applies to formulation.

• Applies to packaging.

• Process Development sometimes refers to optimization or fit to equipment.


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"It is no good offering an elegant, difficult and expensive process to an industrial chemist, whose ideal is something to be carried out in a disused bathtub by a one-armed man who cannot read, the product being collected continuously through the drain-hole in 100% purity and yield.”

- Sir John Cornforth, Nobel laureate, 1975


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Chemical Process R&D is Required to make Commercial Products

• All processes are constrained by time and space.

• With rare exceptions, all products must make a profit.

• To minimize costs, processes should be robust, reliable, sustainable, and safe.


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Chemical Process R&D Starts withRoute Selection

• Review journal and patent literature. Keep up with it.• Remove chromatography. Recrystallization is usually a

good replacement.• Remove evaporation to dryness. Precipitation is usually

a good replacement.• Avoid drying agents. Azeotropic distillation is usually a

good replacement.

• Remove addition of solids to processing that is underway. Add reaction solution to solid or add solid as solution or slurry.

• Avoid using metal catalyst in last step.


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Chemical Process R&D Starts withRoute Selection (Cont)

• Starting materials should be readily available.• Learn how long a starting material can be stored before

it must be retested.• Identify all impurities and by-products. Provide samples

to analytical chemists. Avoid routes with genotoxic impurities.

• Try optimizing the chemistry by minimizing the impurities and by-products.


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Chemical Process R&D Starts withRoute Selection (Cont)

• Analytical chemists should be involved from the very beginning since methods must be developed for raw materials, in-process reaction completion, and final product testing.

• Always provide analytical chemists with in-process samples so they can develop methods in the same matrix they are likely to see.


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Development of the Process Optimizes the Selected Route

• Volume.– Keep the concentration of the reaction step between

20 g product/100 mL solvent and 5 g product/100 mL solvent.

– Keep minimum concentration for recrytallization no less than 5 g product/100 mL solvent.

– Keep the filled volume of a reactor no less than 20% and no more than 80% the nominal volume of the reactor.

– Keep the difference between the minimum and maximum volumes of the processing step no more than a factor of four.


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Development of the Process Optimizes the Selected Route (Cont)

• Raw Material Addition.– Explore changing the order of addition.– Consider the impact of adding liquids by pressure, gravity,

suction, or pump.– Recommend if a raw material should be added above, at, or

below the surface of what it is going into.– Consider if a raw material should be added dispersed, as a

stream, portionwise, or continuously.– Take into account the qualitative viscosity of liquids in case they

must be thinned to be manipulated. This includes the reaction solution.

– Figure out what will control an addition rate such as time, temperature, pH, etc.


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• In-process Reaction Completion Testing.– There should always be an in-process reaction completion test.– Decide if the sample must be quenched.– Devise a safe way to sample the reaction.– Devise a safe way to clean up any spillage during or after

sampling.– Use a Sample Plan for pilot, validation, and first commercial lots.– Develop a contingency plan in case the reaction or processing

operation does not go to completion.


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• Mass Balance.

– Obtain a key raw material mass balance.

– If possible, obtain an overall mass balance.


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• Stress Testing and the Effect of Time Dilation.

– Everything takes longer the larger the scale.

– Effect of extended time on processing steps and stability of solutions.

– Effect of interrupted processing.

– Impact of small amounts of water.


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• Safety– Decide on safe handling and storage of raw materials.– Write down a balanced chemical reaction for every chemical

step including quenching.– Determine if a runaway reaction is possible and how it could be

stopped.– Make sure all materials of composition are compatible with the

process stream.– Determine how to handle any spills.– Assess any potential reaction between the heat transfer fluid and

the reaction.


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• Safety (Cont).– Devise a way to wipe down PPE while it is still being worn to

ensure decontamination.

– Identify all exothermic reactions, including heats of solution and recrystallization, for later determination if it can be safely controlled on scale.

– Identify any step, including waste handling, that evolves a gas so handling can be determined.

– Utility interruptions should be taken into account even in a lab environment, including their unexpected return.


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An Ideal Process Optimizes 14 Different Parameters

• Raw material costs <$64/kg product at scale.• Overall yield >85%; average yield >92%.• Throughput time <80 h reaction vessel occupation

excluding drying times.• Throughput volume <15 gal/kg product. Throughput

volume is the sum of the minimum total reactor space, including free volume required for each step to produce 1 kg of final product.

• Synthetic steps producing isolated intermediates or solutions excluding purification steps <4.


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An Ideal Process Optimizes 14 Different Parameters (Cont)

• No specialized pieces of equipment.• Step yield variation ≤5%.• No sensitive parameters/procedures.• Linear synthesis with <3 steps or a convergent synthesis

with a branch at next-to-last step or last step.

• Only wastes generated are aqueous with low levels of innocuous inorganics or 5% levels of readily biodegradable organics, or readily recoverable or incinerable nontoxic organics.


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An Ideal Process Optimizes 14 Different Parameters (Cont)

• Contain only routine or low hazard risks.

• Raw materials are available from at least two sources which are commercial and geographically/politically distinct.

• No potential for regulatory change.

• Patent protection available in US and foreign countries.


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References

• Anderson, N.G., Practical Process Research & Development, 2nd ed., (San Diego: Academic Press, 2012).

• McConville, F.X., The Pilot Plant Real Book, 2nd ed., (Worcester, MA: FXM Engineering and Design, 2007).

Documents

Process Research and Development Chemistry 15 03 31