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

Paul Ashall, 2008

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.

Paul Ashall, 2008

Classification of chemical products

• Bulk chemicals e.g. sulphuric acid

• Fine chemicals e.g. ‘ibuprofen’

• Speciality chemicals e.g. adhesives

• Inorganic/organic

Paul Ashall, 2008

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.

Paul Ashall, 2008

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

Paul Ashall, 2008

Raw material consumption (kg/kg)

high low

Energy consumption (kJ/kg)

high low

uses specific diverse

Value added high low

Molecular complexity

high low

Paul Ashall, 2008

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

Paul Ashall, 2008

Chemical & pharmaceutical companies

Paul Ashall, 2008

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.

Paul Ashall, 2008

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’)• Ethanoletc

Paul Ashall, 2008

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 productsetc

Paul Ashall, 2008

Process obsolescence - case study

• Routes to ibuprofen (see EP0284310A1)

Paul Ashall, 2008

Product obsolescence

• Sulphonamide drugs

Paul Ashall, 2008

Choice of route

Case study: 3, 3-dimethylindoline

Paul Ashall, 2008

System model of a chemical process

Inputs: reactants, solvents, catalysts, energy etc

Outputs: product, by-products, co-products, spent catalyst, solvents, waste, energy etc

Paul Ashall, 2008

Chemical process operations are of two basic types:

• Batch processes, which operate according to batch cycles,

• Continuous processes, which operate continuously under steady conditions.

Paul Ashall, 2008

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.

Paul Ashall, 2008

Chemical processes

Operation equipmentChemical reaction reactorDistillation distillation

columnFiltration filter unitsDrying dryers (various

types)Fluid transport pipes, valves, pumps etcProcess control measurement devices, controllers, control valves etcEvaporation evaporatorsCentrifugation centrifugesHeat transfer heat exchangersGranulation granulatoretc

Paul Ashall, 2008

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

Paul Ashall, 2008

Equipment

• Batch reactors• Filter driers e.g Cogeim Nutsche• Crystallisers• Double cone vacuum driers• Mixers and granulators• Fluid bed driers• centrifuges• etc

Paul Ashall, 2008

Separation and purification processes

Why do we need separation and purification processes in the production of chemicals?

Paul Ashall, 2008

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.

Paul Ashall, 2008

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

Paul Ashall, 2008

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

Paul Ashall, 2008

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

Paul Ashall, 2008

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

Paul Ashall, 2008

Material storage

• Reactants

• Products

• intermediates

• Solvents

• Catalysts

• reagents

• etc

Paul Ashall, 2008

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).

Paul Ashall, 2008

Flowsheets

• Schematic representations• Arrangement of equipment• Interconnections• Movement of material• Stream connections• Stream flows/quantities• Stream compositions• Operating conditionsetc

Paul Ashall, 2008

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).

Paul Ashall, 2008

Process flowsheet

• Symbols

• Stream information

• Layout

Paul Ashall, 2008

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

Paul Ashall, 2008

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

Paul Ashall, 2008

Exercise

Construct a process flowsheet for a batch esterification reaction from the information given.

Paul Ashall, 2008

Exercise

Construct a process flowsheet for a batch process to produce aspirin from the information given.

Paul Ashall, 2008

ExerciseChoose 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-VCHSurvey of Industrial Chemistry, P. J. Chenier, 2002

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