An Introduction to Pharmaceutical & Chemical Process Technology

1. An Introduction to Pharmaceutical & Chemical Process Technology NIKAM N. D. DEPARTMENT OF CHEMISTRY

2. 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

3. Aspects of chemical processes cont. • Process instrumentation and process control • Materials handling • Process economics • Safety and environmental issues • Quality etc Paul Ashall, 2008

4. 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

5. Chemical processes cont. • Route (materials, steps, operations etc) • ‘Recipe’(materials, quantities, steps) • Plant equipment (operations) • Process operating conditions Paul Ashall, 2008

6. 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

7. 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

8. 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

9. 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

10. 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

11. Characteristics of fine versus bulk chemicals Paul Ashall, 2008

12. Paul Ashall, 2008

13. 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

14. Chemical & pharmaceutical companies Paul Ashall, 2008

15. 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

16. 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 Paul Ashall, 2008

17. 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 Paul Ashall, 2008

18. Process obsolescence - case study • Routes to ibuprofen (see EP0284310A1) Paul Ashall, 2008

19. Product obsolescence • Sulphonamide drugs Paul Ashall, 2008

20. Choice of route Case study: 3, 3-dimethylindoline Paul Ashall, 2008

21. 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

22. 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

23. 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

24. Chemical processes Operationequipment 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 Paul Ashall, 2008

25. 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

26. 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

27. Separation and purification processes Why do we need separation and purification processes in the production of chemicals? Paul Ashall, 2008

28. 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

29. 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

30. 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

31. 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

32. 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

33. Material storage • Reactants • Products • intermediates • Solvents • Catalysts • reagents • etc Paul Ashall, 2008

34. 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

35. Flowsheets • Schematic representations • Arrangement of equipment • Interconnections • Movement of material • Stream connections • Stream flows/quantities • Stream compositions • Operating conditions etc Paul Ashall, 2008

36. 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

37. Process flowsheet • Symbols • Stream information • Layout Paul Ashall, 2008

38. 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

39. 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

40. Exercise Construct a process flowsheet for a batch esterification reaction from the information given. Paul Ashall, 2008

41. Exercise Construct a process flowsheet for a batch process to produce aspirin from the information given. Paul Ashall, 2008

42. 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. Paul Ashall, 2008