Paul Ashall, 2008

An Introduction to

Pharmaceutical & Chemical

Process Technology

Paul Ashall

Paul Ashall, 2008

Aspects of Industrial Chemical

Processes

• Products

• Types of process

• Flowsheets

• Mass balances

• Energy balances

• Heat transfer and heat exchangers

• Reactor design and operation

• Separation and purification processes

Paul Ashall, 2008

Aspects of chemical processes

cont.

• Process instrumentation and process control

• Materials handling

• Process economics

• Safety and environmental issues

• Quality

etc

Paul Ashall, 2008

Industrial Chemical Processes

Chemical processes are used to produce chemical

products and are by definition processes which

include chemical transformation(s).

Specific products produced by the chemical and

pharmaceutical industry include: aspirin,

ibuprofen, paracetamol, naproxen, labetalol, etc

These active pharmaceutical ingredients (APIs) are

produced by chemical reactions involving organic

chemicals (organic chemistry).

Paul Ashall, 2008

Chemical processes cont.

• Route (materials, steps, operations etc)

• ‘Recipe’(materials, quantities, steps)

• Plant equipment (operations)

• Process operating conditions

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Many chemicals are mixed with other chemicals to produce formulations suitable for consumer use. These include consumer products such as paints, fragrances, pesticides and medicinal products. For example ibuprofen is the active pharmaceutical ingredient (API) in the OTC product ‘Nurofen’, which contains other ingredients called excipients.

Paul Ashall, 2008

Specific processes have been developed to

produce specific chemicals. Particularly

well established processes are given names.

For example the process used to

manufacture sulphuric acid is called the

‘Contact’ process.

In some cases a chemical may be produced by

more than one process.

Paul Ashall, 2008

The chemical industry consists of many different

sectors (or product groups), each with their own

characteristics. For example pharmaceuticals,

pesticides, fertilisers, petrochemicals, dyestuffs etc

The type of chemical produced will determine the

particular characteristics of the process (or

processes) used to produce the product. For

example compare the processes used to

manufacture ammonia and aspirin.

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Classification of chemical products

• Bulk chemicals e.g. sulphuric acid

• Fine chemicals e.g. ‘ibuprofen’

• Speciality chemicals e.g. adhesives

• Inorganic/organic

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continued

Bulk chemicals are characterised by a combination of two parameters – large volume production, which is supported by market demand, and lower unit costs, where the principle of economy of scale is important.

Fine chemicals are produced on a relatively smaller scale in more versatile (less dedicated generally) production units using batch operations. Product specifications may be more exacting and unit cost is relatively higher. Fine chemicals may be used as ingredients in formulations or as intermediates in the production of more complex

chemicals. For example bulk pharmaceuticals.

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Characteristics of fine versus

bulk chemicals

characteristic Fine chemical

e.g. ibuprofen

Bulk chemical

e.g sulphuric

acid

scale small large

price 22 $/kg 0.08 $/kg

Process type batch continuous

synthesis Multi-step Few steps

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Raw material

consumption

(kg/kg)

high low

Energy

consumption

(kJ/kg)

high low

uses specific diverse

Value added high low

Molecular

complexity

high low

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Speciality chemicals

These are chemically formulated products

manufactured from basic chemicals which

are used by industry and domestic

consumers for specific purposes. For

example: coatings, adhesives,

pharmaceutical products, pesticides,

cosmetics, disinfectants etc

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Chemical & pharmaceutical

companies

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Integration of the chemical

industry with manufacturing

industry in general

For example the manufacture of polyester

textiles. crude oil naphtha terephthalic acid/ethylene glycol PET

polyester fibres textiles

Discuss production of ibuprofen.

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Choice of process

Examples include:

• Ibuprofen (Boots route and Hoechst-Celanese route)

• Acetic acid

• Adipic acid

• Ethylene oxide

• Vinyl chloride (ethyne and ethene based routes)

• Titanium dioxide (‘sulphate process’, ‘chloride process’)

• Ethanol

etc

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General factors to be considered • Yield, conversion, selectivity/mass balances

• Energy usage/energy balances

• Kinetics/rates and productivity (kg/hr)

• Number of synthetic reaction steps/reaction chemistry

• Scale of operation

• Manufacturing costs

• Separations required

• Operating conditions

• Environmental factors – waste, environmental impact, emissions, effluent, solid waste, hazardous waste

• Health and safety factors – process safety/operating conditions, use of hazardous materials

• Material availability

• Quality issues

• By products and co products

etc

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Process obsolescence - case study

• Routes to ibuprofen (see EP0284310A1)

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Product obsolescence

• Sulphonamide drugs

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Choice of route

Case study: 3, 3-dimethylindoline

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System model of a chemical

process

Inputs: reactants, solvents, catalysts, energy

etc

Outputs: product, by-products, co-products,

spent catalyst, solvents, waste, energy etc

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Chemical process operations are of two basic

types:

• Batch processes, which operate according

to batch cycles,

• Continuous processes, which operate

continuously under steady conditions.

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Chemical processes

Chemical processes consist of a number of

sequential and integrated operations carried out in

appropriate equipment.

For example chemical reaction carried out in a

chemical reactor.

The precise operations, sequence of operations and

equipment specifications depend on the nature of

the process, operating conditions, materials used

and product produced.

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Chemical processes

Operation equipment

Chemical reaction reactor

Distillation distillation column

Filtration filter units

Drying dryers (various types)

Fluid transport pipes, valves, pumps etc

Process control measurement devices, controllers, control valves etc

Evaporation evaporators

Centrifugation centrifuges

Heat transfer heat exchangers

Granulation granulator

etc

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Multi-purpose /product plant for

bulk active pharmaceutical

ingredients • Batch reactors (stainless steel, agitator, glass-

lined, reflux condenser, jacket etc)

• Material feed system to reactors

• Separation and purification equipment ( crystallisers, filtration, centrifuges, dryers, distillation unit etc)

• Material storage

• Process support services/Utilities (incl. heat transfer fluids)

• Waste treatment

• Emissions control

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Equipment

• Batch reactors

• Filter driers e.g Cogeim Nutsche

• Crystallisers

• Double cone vacuum driers

• Mixers and granulators

• Fluid bed driers

• centrifuges

• etc

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Separation and purification

processes

Why do we need separation and purification

processes in the production of chemicals?

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Separation processes

A typical sequence of separation processes

used in the production of bulk

pharmaceutical products is: crystallisation

(from mother liquour), filtration or

centrifugation and drying.

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Separation processes

Factors to be considered in choosing separation/purification process(es):

• Quantity of material to be separated

• Rate of separation required

• Feasibility

• Selectivity

• Economics

• Quality

• Equipment

• Mode of operation

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Process support services/Utilities (or

plant services) • Steam

• Cooling water

• Chilled water

• Other heat transfer fluids

• Inert gases

• Compressed air

• Electricity

• Demineralised water/deionised water

• UP water

• Distilled water

• Effluent treatment

• etc

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Purified Water/WFI

• Obtained from potable water

• Specified in pharmacopoeias

• Storage

• Depth filter

• Organic trap

• Carbon filter

• DI

• Filtration (0.45 micron)/UV (254 nm)

• UF (0.22 micron)

• Distillation/RO

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WFI distribution

• Sealed storage

• Ring main (loop) circulation under turbulent

flow conditions at 85 deg cent

• No ‘dead legs’ in pipe distribution system

• UV irradiation

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Material storage

• Reactants

• Products

• intermediates

• Solvents

• Catalysts

• reagents

• etc

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Flowsheets

Flowsheets are used to describe the operating

details of chemical processes. There are a

number of basic types:

Flowcharts (or block diagrams),

Process flowsheets (or Process Flow

Diagram),

Piping and Instrumentation Diagrams (PID).

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Flowsheets

• Schematic representations

• Arrangement of equipment

• Interconnections

• Movement of material

• Stream connections

• Stream flows/quantities

• Stream compositions

• Operating conditions

etc

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Flowcharts

Simple flowcharts can be used to show the

main material routes through the process

(lines and arrows) and to depict the main

operations (blocks).

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Process flowsheet

• Symbols

• Stream information

• Layout

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P and I Diagram

• Equipment details and arrangement (item no., name, dimensions, materials of construction, rate or capacity, occupation time, T, P, materials handled, heat duty, power)

• Pipe details

• Valves

• Ancillary fittings

• Pumps

• Instrumentation and control loops

• Services (utilities)

• Symbols

• Layout

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For a large chemical plant a large number of such flowsheets will be required to specify the process. These will be grouped into individual plant operating areas.

Refer to examples

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Exercise

Construct a process flowsheet for a batch

esterification reaction from the information

given.

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Exercise

Construct a process flowsheet for a batch

process to produce aspirin from the

information given.

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Exercise Choose a chemical product and from the information

sources given below write a process description and draw a block flow diagram of the reaction and separation steps.

Examples: aspirin, penicillin, paracetamol.

Chemical Process Industries, R. N. Shreve and J. A. Brink, 4th ed.,

McGraw-Hill.

Ullmans Encyclopedia of Industrial Chemistry, 6th ed., Wiley-VCH

Survey of Industrial Chemistry, P. J. Chenier, 2002

Kirk-Othmer Encyclopedia of Chemical Technology, 4th ed.