1. UllmannsFine Chemicals

2. UllmannsFine Chemicals 3. Editor-in-Chief:Dr. Barbara Elvers, Hamburg, GermanyAll books published by Wiley-VCH are carefullyproduced. Nevertheless, authors, editors, and publisher donot warrant the information contained in these books,including this book, to be free of errors. Readers areadvised to keep in mind that statements, data, illustrations,procedural details or other items may inadvertently beinaccurate.Library of Congress Card No.:applied forBritish Library Cataloguing-in-Publication DataA catalogue record for this book is available from theBritish Library.Bibliographic information published bythe Deutsche NationalbibliothekThe Deutsche Nationalbibliothek lists this publication inthe Deutsche Nationalbibliografie; detailed bibliographicdata are available on the Internet at . 2014 Wiley-VCH Verlag GmbHCo. KGaA,Boschstr. 12, 69469 Weinheim, GermanyAll rights reserved (including those of translation into otherlanguages). No part of this book may be reproduced in anyform by photoprinting, microfilm, or any other means nortransmitted or translated into a machine language withoutwritten permission from the publishers. Registered names,trademarks, etc. used in this book, even when not specificallymarked as such, are not to be considered unprotected by law.Print ISBN: 978-3-527-33477-3Cover Design Grafik-Design SchulzTypesetting Thomson Digital, Noida, IndiaPrinting and Binding Markono Print Media Pte Ltd,SingaporePrinted on acid-free paper 4. Vol. 1 Preface VPrefaceThis handbook features selected articles from the 7th edition of ULLMANNS Encyclopedia ofIndustrial Chemistry, including newly written articles that have not been published in a printed editionbefore. True to the tradition of theULLMANNS Encyclopedia, products and processes are addressedfrom an industrial perspective, including production figures, quality standards and patent protectionissues where appropriate. Safety and environmental aspects which are a key concern for modernprocess industries are likewise considered.More content on related topics can be found in the complete edition of the ULLMANNSEncyclopedia.About ULLMANNSULLMANNS Encyclopedia is the worlds largest reference in applied chemistry, industrial chemis-try,and chemical engineering. In its current edition, the Encyclopedia contains more than 30,000pages, 15,000 tables, 25,000 figures, and innumerable literature sources and cross-references, offeringa wealth of comprehensive and well-structured information on all facets of industrial chemistry.1,100 major articles cover the following main areas:. Agrochemicals. Analytical Techniques. Biochemistry and Biotechnology. Chemical Reactions. Dyes and Pigments. Energy. Environmental Protection and Industrial Safety. Fat, Oil, Food and Feed, Cosmetics. Inorganic Chemicals. Materials. Metals and Alloys. Organic Chemicals. Pharmaceuticals. Polymers and Plastics. Processes and Process Engineering. Renewable Resources. Special TopicsFirst published in 1914 by Professor Fritz Ullmann in Berlin, the Enzyklopadie der TechnischenChemie (as the German title read) quickly became the standard reference work in industrial chemistry.Generations of chemists have since relied on ULLMANNS as their prime reference source. Threefurther German editions followed in 19281932, 19511970, and in 19721984. From 1985 to 1996,the 5th edition of ULLMANNS Encyclopedia of Industrial Chemistry was the first edition to bepublished in English rather than German language. So far, two more complete English editions havebeen published; the 6th edition of 40 volumes in 2002, and the 7th edition in 2011, again comprising 40volumes. In addition, a number of smaller topic-oriented editions have been published.Since 1997, ULLMANNS Encyclopedia of Industrial Chemistry has also been available inelectronic format, first in a CD-ROM edition and, since 2000, in an enhanced online edition. Bothelectronic editions feature powerful search and navigation functions as well as regular content updates. 5. Vol. 1 Contents VIIContentsVolume 1...............................................Symbols and Units................................. IXConversion Factors ................................ XIAbbreviations......................................... XIIICountry Codes ....................................... XVIIIPeriodic Table of Elements ................... XIXFine Chemicals ...................................... 1Alcohols, Polyhydric ............................. 37Aldehydes, Araliphatic .......................... 59Allyl Compounds................................... 67Aluminum Compounds, Organic .......... 91Amines, Aliphatic .................................. 113Amino Acids.......................................... 165Antimony Compounds, Organic............ 223Arsenic Compounds, Organic ............... 227Aziridines............................................... 233Benzenesulfonic Acids and theirDerivatives ............................................. 241Benzidine and Benzidine Derivatives ... 279Benzoic Acid and Derivatives............... 297Benzoquinone ........................................ 311Benzyl Alcohol........................................ 317Benzyl Chloride and Other Side-ChainChlorinated Aromatic Hydrocarbons ....... 327Boron Compounds ................................. 345Bromine Compounds, Organic.............. 367Butyrolactone......................................... 391Carbamates and Carbamoyl Chlorides.. 399Carbonic Esters...................................... 407Volume 2...............................................Carboxylic Acids, Aliphatic .................. 435Carboxylic Acids, Aromatic.................. 449Chloroacetaldehydes.............................. 461Chloroacetic Acids ................................ 473Chloroamines ......................................... 491Chloroformic Esters............................... 497Chlorohydrins ........................................ 505Chlorophenoxyalkanoic Acids .............. 519Cinnamic Acid....................................... 529Crown Ethers ......................................... 533Cyanuric Acid and Cyanuric Chloride.. 543Cyclododecatriene, Cyclooctadiene, and4-Vinylcyclohexene ............................... 565Cyclopentadiene and Cyclopentene ...... 569Dicarboxylic Acids, Aliphatic ............... 583Dithiocarbamic Acid and Derivatives... 601Epoxides.................................................... 629Ethylenediaminetetraacetic Acid andRelated Chelating Agents ................... 645Glyoxal...................................................... 651Guanidine and Derivatives ....................... 657Hydrides.................................................... 673Hydroxycarboxylic Acids, Aliphatic........ 703Hydroxycarboxylic Acids, Aromatic ...... 715Imidazole and Derivatives........................ 725Indole ........................................................ 735Ionic Liquids............................................. 741Iron Compounds, Organic ........................ 771Isocyanates, Organic................................. 781Ketenes...................................................... 801Ketones ..................................................... 817Lithium Compounds, Organic.................. 839Magnesium Compounds, Organic............ 845Malonic Acid and Derivatives ................. 851Volume 3..................................................Mercaptoacetic Acid and Derivatives ...... 869Naphthalene Derivatives........................... 873Nickel Compounds, Organic .................... 927Nitriles ...................................................... 933Nitrilotriacetic Acid.................................. 949Nitro Compounds, Aliphatic .................... 955Nitro Compounds, Aromatic .................... 965Oxocarboxylic Acids ................................ 1015Pentanols ................................................... 1023Phenol Derivatives.................................... 1037Phosphorus Compounds, Organic ............ 1099Purine Derivatives .................................... 11312-Pyrrolidone ............................................ 1137Quinoline and Isoquinoline ...................... 1145Sulfinic Acids and Derivatives................. 1151Sulfones and Sulfoxides ........................... 1169Terpenes.................................................... 1185Thiocyanates and Isothiocyanates,Organic...................................................... 1203Thiols and Organic Sulfides ..................... 1213Thiophene ................................................. 1241Thiourea and Thiourea Derivatives.......... 1255Tin Compounds, Organic ......................... 1269Urea Derivatives ....................................... 1273Author Index ........................................... 1285Subject Index........................................... 1291 6. Vol. 1 Symbols and Units IXSymbols and UnitsSymbols and units agree with SI standards (for conversion factors see page XI). The following list gives the mostimportant symbols used in the encyclopedia. Articles with many specific units and symbols have a similar list asfront matter.Symbol Unit Physical QuantityaB activity of substance BAr relative atomic mass (atomic weight)A m2 areacB mol/m3, mol/L (M) concentration of substance BC C/V electric capacitycp, cv J kg1K1 specific heat capacityd cm, m diameterd relative density (r/rwater)D m2/s diffusion coefficientD Gy (J/kg) absorbed dosee C elementary chargeE J energyE V/m electric field strengthE V electromotive forceEA J activation energyf activity coefficientF C/mol Faraday constantF N forceg m/s2 acceleration due to gravityG J Gibbs free energyh m heighth Ws2 Planck constantH J enthalpyI A electric currentI cd luminous intensityk (variable) rate constant of a chemical reactionk J/K Boltzmann constantK (variable) equilibrium constantl m lengthm g, kg, t massMr relative molecular mass (molecular weight)n20D refractive index (sodium D-line, 20 C)n mol amount of substanceNA mol1 Avogadro constant (6.0231023 mol1)P Pa, bar* pressureQ J quantity of heatr m radiusR JK1 mol1 gas constantR W electric resistanceS J/K entropyt s, min, h, d, month, a timet C temperatureT K absolute temperatureu m/s velocityU V electric potential 7. X Symbols and Units Vol. 1Symbols and Units (Continued from p. IX)Symbol Unit Physical QuantityU J internal energyV m3, L, mL, mL volumew mass fractionW J workxB mole fraction of substance BZ proton number, atomic numbera cubic expansion coefficienta Wm2K1 heat-transfer coefficient (heat-transfer number)a degree of dissociation of electrolytea] [102deg cm2g1 specific rotationh Pas dynamic viscosityq C temperaturek cp/cvl Wm1K1 thermal conductivityl nm, m wavelengthm chemical potentialn Hz, s1 frequencyn m2/s kinematic viscosity (h/r)p Pa osmotic pressurer g/cm3 densitys N/m surface tensiont Pa (N/m2) shear stressj volume fractionc Pa1 (m2/N) compressibility*The official unit of pressure is the pascal (Pa). 8. Vol. 1 Conversion Factors XIConversion FactorsSI unit Non-SI unit From SI to non-SI multiply byMasskg pound (avoirdupois) 2.205kg ton (long) 9.842104kg ton (short) 1.102103Volumem3 cubic inch 6.102104m3 cubic foot 35.315m3 gallon (U.S., liquid) 2.642102m3 gallon (Imperial) 2.200102TemperatureC F Cl.832ForceN dyne 1.0105Energy, WorkJ Btu (int.) 9.480104J cal (int.) 2.389101J eV 6.2421018J erg 1.0107J kWh 2.778107J kpm 1.020101PressureMPa at 10.20MPa atm 9.869MPa bar 10kPa mbar 10kPa mm Hg 7.502kPa psi 0.145kPa torr 7.502Powers of Ten1E (exa) 1018 d (deci) 102P (peta) 1015 c (centi) 103T (tera) 1012 m (milli) 106G (giga) 109 m (micro) 109M (mega) 106 n (nano) 1012k (kilo) 103 p (pico) 1015h (hecto) 102 f (femto) 1018da (deca) 10 a (atto) 10 9. Vol. 1 Abbreviations XIIIAbbreviationsThe following is a list of the abbreviations used in the text. Common terms, the names of publicationsand institutions, and legal agreements are included along with their full identities. Other abbreviationswill be defined wherever they first occur in an article. For further abbreviations, see page IX, Symbolsand Units; pageXVI, Frequently Cited Companies (Abbreviations), and pageXVII, Country Codes inpatent references. The names of periodical publications are abbreviated exactly as done by ChemicalAbstracts Service.abs. absolutea.c. alternating currentACGIH American Conference of GovernmentalIndustrial HygienistsACS American Chemical SocietyADI acceptable daily intakeADN accord europeen relatif au transportinternational des marchandises danger-eusespar voie de navigation interieure(European agreement concerning theinternational transportation of dangerousgoods by inland waterways)ADNR ADN par le Rhin (regulation concerningthe transportation of dangerous goods onthe Rhine and all national waterways ofthe countries concerned)ADP adenosine 50-diphosphateADR accord europeen relatif au transportinternational des marchandises danger-eusespar route (European agreementconcerning the international transporta-tionof dangerous goods by road)AEC Atomic Energy Commission (UnitedStates)a.i. active ingredientAIChE American Institute of ChemicalEngineersAIME American Institute of Mining,Metallurgical, and Petroleum EngineersANSI American National Standards InstituteAMP adenosine 50-monophosphateAPhA American Pharmaceutical AssociationAPI American Petroleum InstituteASTM American Society for Testing andMaterialsATP adenosine 50-triphosphateBAM Bundesanstalt fur Materialprufung(Federal Republic of Germany)BAT Biologischer Arbeitsstofftoleranzwert(biological tolerance value for aworking material, established by MAKCommission, see MAK)Beilstein Beilsteins Handbook of Organic Chem-istry,Springer, Berlin Heidelberg New YorkBET Brunauer Emmett TellerBGA Bundesgesundheitsamt (FederalRepublic of Germany)BGB1. Bundesgesetzblatt (Federal Republicof Germany)BIOS British Intelligence Objectives Subcom-mitteeReport (see also FIAT)BOD biological oxygen demandbp boiling pointB.P. British PharmacopeiaBS British Standardca. circacalcd. calculatedCAS Chemical Abstracts Servicecat. catalyst, catalyzedCEN Comite Europeen de Normalisationcf. compareCFR Code of Federal Regulations (UnitedStates)cfu colony forming unitsChap. chapterChemG Chemikaliengesetz (Federal Republicof Germany)C.I. Colour IndexCIOS Combined Intelligence Objectives Sub-commiteeReport (see also FIAT)CLP Classification, Labelling and PackagingCNS central nervous systemCo. CompanyCOD chemical oxygen demandconc. concentratedconst. constantCorp. Corporationcrit. criticalCSA Chemical Safety Assessment accordingto REACHCSR Chemical Safety Report according toREACHCTFA The Cosmetic, Toiletry andFragrance Association(United States)DAB Deutsches Arzneibuch, DeutscherApotheker-Verlag, Stuttgartd.c. direct currentdecomp. decompose, decompositionDFG Deutsche Forschungsgemeinschaft(German Science Foundation) 10. XIV Abbreviations Vol. 1dil. dilute, dilutedDIN Deutsche Industrienorm (FederalRepublicof Germany)DMF dimethylformamideDNA deoxyribonucleic acidDOE Department of Energy (United States)DOT Department of Transportation Materials Transportation Bureau(United States)DTA differential thermal analysisEC effective concentrationEC European Communityed. editor, edition, editede.g. for exampleemf electromotive forceEmS Emergency ScheduleEN European Standard (EuropeanCommunity)EPA Environmental Protection Agency(United States)EPR electron paramagnetic resonanceEq. equationESCA electron spectroscopy for chemicalanalysisesp. especiallyESR electron spin resonanceEt ethyl substituent (C2H5)et al. and othersetc. et ceteraEVO Eisenbahnverkehrsordnung (FederalRepublic of Germany)exp (. . .) e(. . .), mathematical exponentFAO Food and Agriculture Organization(United Nations)FDA Food and Drug Administration(United States)FDC Food, Drug and Cosmetic Act(United States)FHSA Federal Hazardous Substances Act(United States)FIAT Field Information Agency, Technical(United States reports on the chemicalindustry in Germany, 1945)Fig. figurefp freezing pointFriedlander P. Friedlander, Fortschritte derTeerfarbenfabrikation und verwandterIndustriezweige Vol. 125, Springer,Berlin 18881942FT Fourier transform(g) gas, gaseousGC gas chromatographyGefStoffV Gefahrstoffverordnung (regulations inthe Federal Republic of Germany con-cerninghazardous substances)GGVE Verordnung in der BundesrepublikDeutschland uber die Beforderunggefahrlicher Guter mit der Eisenbahn(regulation in the Federal Republic ofGermany concerning the transportationof dangerous goods by rail)GGVS Verordnung in der BundesrepublikDeutschland uber die Beforderunggefahrlicher Guter auf der Strae(regulation in the Federal Republic ofGermany concerning the transportationof dangerous goods by road)GGVSee Verordnung in der BundesrepublikDeutschland uber die Beforderunggefahrlicher Guter mit Seeschiffen(regulation in the Federal Republic ofGermany concerning the transportationof dangerous goods by sea-goingvessels)GHS Globally Harmonised System of Chemi-cals(internationally agreed-upon system,created by theUN, designed to replace thevarious classification and labeling stan-dardsused in different countries by usingconsistent criteria for classification andlabeling on a global level)GLC gas-liquid chromatographyGmelin Gmelins Handbook of InorganicChemistry, 8th ed., Springer, Berlin Heidelberg New YorkGRAS generally recognized as safeHal halogen substituent (F, Cl, Br, I)Houben-WeylMethoden der organischenChemie, 4th ed., Georg Thieme Verlag,StuttgartHPLC high performance liquidchromatographyH statement hazard statement in GHSIAEA International Atomic Energy AgencyIARC International Agency for Research onCancer, Lyon, FranceIATA-DGR International Air TransportAssociation, Dangerous GoodsRegulationsICAO International Civil AviationOrganizationi.e. that isi.m. intramuscularIMDG International Maritime DangerousGoods CodeIMO Inter-Governmental Maritime Consul-tiveOrganization (in the past: IMCO)Inst. Institutei.p. intraperitonealIR infraredISO International Organization forStandardizationIUPAC International Union of Pure andApplied Chemistry 11. Vol. 1 Abbreviations XVi.v. intravenousKirk-OthmerEncyclopedia of Chemical Technology,3rd ed., 19911998, 5th ed., 20042007,John WileySons, Hoboken(1) liquidLandolt-BornsteinZahlenwerte u. Funktionen aus Physik,Chemie, Astronomie, Geophysik u.Technik, Springer, Heidelberg 19501980; Zahlenwerte und Funktionen ausNaturwissenschaften und Technik,Neue Serie, Springer, Heidelberg,since 1961LC50 lethal concentration for 50% of the testanimalsLCLo lowest published lethal concentrationLD50 lethal dose for 50% of the test animalsLDLo lowest published lethal doseln logarithm (base e)LNG liquefied natural gaslog logarithm (base 10)LPG liquefied petroleum gasM mol/LM metal (in chemical formulas)MAK Maximale Arbeitsplatzkonzentration(maximum concentration at theworkplace in the Federal Republic ofGermany); cf. Deutsche Forschungsge-meinschaft(ed.): Maximale Arbeits-platzkonzentrationen(MAK) undBiologische Arbeitsstofftoleranzwerte(BAT), WILEY-VCH Verlag,Weinheim (published annually)max. maximumMCA Manufacturing Chemists Association(United States)Me methyl substituent (CH3)MethodicumChimicumMethodicum Chimicum, Georg ThiemeVerlag, StuttgartMFAG Medical First Aid Guide for Use inAccidents Involving DangerousGoodsMIK maximale Immissionskonzentration(maximum immission concentration)min. minimummp melting pointMS mass spectrum, mass spectrometryNAS National Academy of Sciences (UnitedStates)NASA National Aeronautics and SpaceAdministration (United States)NBS National Bureau of Standards(United States)NCTC National Collection of Type Cultures(United States)NIH National Institutes of Health(United States)NIOSH National Institute for OccupationalSafety and Health (United States)NMR nuclear magnetic resonanceno. numberNOEL no observed effect levelNRC Nuclear Regulatory Commission(United States)NRDC National Research DevelopmentCorporation (United States)NSC National Service Center (United States)NSF National Science Foundation(United States)NTSB National Transportation Safety Board(United States)OECD Organization for Economic Cooperationand DevelopmentOSHA Occupational Safety and HealthAdministration (United States)p., pp. page, pagesPatty G.D. Clayton, F.E. Clayton (eds.):Pattys Industrial Hygiene andToxicology, 3rd ed., Wiley Interscience,New YorkPB Publication Board Report (U.S.report Department of Commerce, Scientificand Industrial Reports)PEL permitted exposure limitPh phenyl substituent (C6H5)Ph. Eur. European Pharmacopoeia, Council ofEurope, Strasbourgphr part per hundred rubber (resin)PNS peripheral nervous systemppm parts per millionP statement precautionary statement in GHSq.v. which see (quod vide)REACH Registration, Evaluation, Authorisationand Restriction of Chemicals (EUregulation addressing the productionand use of chemical substances, andtheir potential impacts on both humanhealth and the environment)ref. refer, referenceresp. respectivelyRf retention factor (TLC)R.H. relative humidityRID reglement international concernant letransport des marchandises dangereusespar chemin de fer (international con-ventionconcerning the transportation ofdangerous goods by rail)RNA ribonucleic acidR phrase risk phrase according to(R-Satz) ChemG and GefStoffV (FederalRepublic of Germany)rpm revolutions per minuteRTECS Registry of Toxic Effects ofChemical Substances, edited by the 12. XVI Abbreviations Vol. 1National Institute of OccupationalSafety and Health (United States)(s) solidSAE Society of Automotive Engineers(United States)SAICM Strategic Approach on InternationalChemicals Management (internationalframework to foster the sound man-agementof chemicals)s.c. subcutaneousSI International System of UnitsSIMS secondary ion mass spectrometryS phrase safety phrase according to(S-Satz) ChemG and GefStoffV (FederalRepublic of Germany)STEL Short Term Exposure Limit (see TLV)STP standard temperature and pressure (0C,101.325 kPa)Tg glass transition temperatureTA Luft Technische Anleitung zur Reinhaltungder Luft (clean air regulation in FederalRepublic of Germany)TA Larm Technische Anleitung zum Schutzgegen Larm (low noise regulation inFederal Republic of Germany)TDLo lowest published toxic doseTHF tetrahydrofuranTLC thin layer chromatographyTLV Threshold Limit Value (TWAand STEL); published annually bythe American Conference of Govern-mentalIndustrial Hygienists (ACGIH),Cincinnati, OhioTOD total oxygen demandTRK Technische Richtkonzentration(lowest technically feasible level)TSCA Toxic Substances Control Act(United States)TU V Technischer Uberwachungsverein(Technical Control Board of the FederalRepublic of Germany)TWA Time Weighted AverageUBA Umweltbundesamt (FederalEnvironmental Agency)Ullmann Ullmanns Encyclopedia of IndustrialChemistry, 6th ed., Wiley-VCH,Weinheim 2002; Ullmanns Encyclo-pediaof Industrial Chemistry, 5th ed.,VCH Verlagsgesellschaft, Weinheim19851996; Ullmanns Encyklopadie derTechnischen Chemie, 4th ed., VerlagChemie, Weinheim 19721984; 3rd ed.,Urban und Schwarzenberg, Munchen19511970USAEC United States Atomic EnergyCommissionUSAN United States Adopted NamesUSD United States DispensatoryUSDA United States Department of AgricultureU.S.P. United States PharmacopeiaUV ultravioletUVV Unfallverhutungsvorschriften der Ber-ufsgenossenschaft(workplace safetyregulations in the Federal Republic ofGermany)VbF Verordnung in der BundesrepublikDeutschland uber die Errichtung undden Betrieb von Anlagen zurLagerung, Abfullung und Beforderungbrennbarer Flussigkeiten (regulation inthe Federal Republic of Germany con-cerningthe construction and operationof plants for storage, filling, and trans-portationof flammable liquids; classi-ficationaccording to the flash point ofliquids, in accordance with the classifi-cationin the United States)VDE Verband Deutscher Elektroingenieure(Federal Republic of Germany)VDI Verein Deutscher Ingenieure (FederalRepublic of Germany)vol volumevol. volume (of a series of books)vs. versusWGK Wassergefahrdungsklasse (water hazardclass)WHO World Health Organization (UnitedNations)Winnacker-KuchlerChemische Technologie, 4th ed., CarlHanser Verlag, Munchen, 1982-1986;Winnacker-Kuchler, Chemische Tech-nik:Prozesse und Produkte, Wiley-VCH, Weinheim, 20032006wt weight$ U.S. dollar, unless otherwise stated 13. Vol. 1 Frequently Cited Companies (Abbreviations) XVIIFrequently Cited Companies(Abbreviations)AirProductsAir Products and ChemicalsAkzo Algemene Koninklijke ZoutOrganonAlcoa Aluminum Company of AmericaAllied Allied CorporationAmer. American CyanamidCyanamid CompanyBASF BASF AktiengesellschaftBayer Bayer AGBP British Petroleum CompanyCelanese Celanese CorporationDaicel Daicel Chemical IndustriesDainippon Dainippon Ink and Chemicals Inc.DowThe Dow Chemical CompanyChemicalDSM Dutch Staats MijnenDu Pont E.I. du Pont de NemoursCompanyExxon Exxon CorporationFMC Food MachineryChemicalCorporationGAF General AnilineFilm CorporationW.R.W.R. GraceCompanyGraceHoechst Hoechst AktiengesellschaftIBM International Business MachinesCorporationICI Imperial Chemical IndustriesIFP Institut Francais du PetroleINCO International Nickel Company3M Minnesota Mining andManufacturing CompanyMitsubishi Mitsubishi Chemical IndustriesChemicalMonsanto Monsanto CompanyNippon Nippon Shokubai Kagaku KogyoShokubaiPCUK Pechiney Ugine KuhlmannPPG Pittsburg Plate Glass IndustriesSearle G.D. SearleCompanySKF Smith KlineFrench LaboratoriesSNAM Societa Nazionale MetandottiSohio Standard Oil of OhioStauffer Stauffer Chemical CompanySumitomo Sumitomo Chemical CompanyToray Toray Industries Inc.UCB Union Chimique BelgeUnionUnion Carbide CorporationCarbideUOP Universal Oil Products CompanyVEBA Vereinigte Elektrizitats- und Bergwerks-AGWacker Wacker Chemie GmbH 14. XVIII Country Codes Vol. 1Country CodesThe following list contains a selection of standard country codes used in the patent references.AT AustriaAU AustraliaBE BelgiumBG BulgariaBR BrazilCA CanadaCH SwitzerlandCS CzechoslovakiaDD German Democratic RepublicDE Federal Republic of Germany(and Germany before 1949)*DK DenmarkES SpainFI FinlandFR FranceGB United KingdomGR GreeceHU HungaryID IndonesiaIL IsraelIT ItalyJP Japan*LU LuxembourgMA MoroccoNL Netherlands*NO NorwayNZ New ZealandPL PolandPT PortugalSE SwedenSU Soviet UnionUS United States of AmericaYU YugoslaviaZA South AfricaEP European Patent Office*WO World Intellectual PropertyOrganization*For Europe, Federal Republic of Germany, Japan, and the Netherlands, the type of patent is specified:EP (patent), EP-A (application), DE (patent), DE-OS (Offenlegungsschrift), DE-AS (Ausleges-chrift),JP (patent), JP-Kokai (Kokai tokkyo koho), NL (patent), and NL-A (application). 15. Fine ChemicalsPETER POLLAK, Fine Chemicals Business Consultant, Reinach, SwitzerlandRAYMOND VOUILLAMOZ, Granois (Saviese), Switzerland1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . 11.1. History. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.2. Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . 22. The Fine Chemical Industry . . . . . . . . . . . . 32.1. Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . 32.2. Fine Chemical/Custom ManufacturingCompanies . . . . . . . . . . . . . . . . . . . . . . . . . . 32.3. Contract Research Organizations . . . . . . . . 52.4. Laboratory Chemical Suppliers. . . . . . . . . . 63. Products. . . . . . . . . . . . . . . . . . . . . . . . . . . . 73.1. Small Molecules. . . . . . . . . . . . . . . . . . . . . . 73.2. Big Molecules. . . . . . . . . . . . . . . . . . . . . . . . 74. Technologies . . . . . . . . . . . . . . . . . . . . . . . . 94.1. Traditional Chemical Synthesis . . . . . . . . . . 94.2. Biotechnology . . . . . . . . . . . . . . . . . . . . . . . 104.2.1. White Biotechnology . . . . . . . . . . . . . . . . . . . 114.2.2. Red Biotechnology . . . . . . . . . . . . . . . . . . . . 145. Production . . . . . . . . . . . . . . . . . . . . . . . . . . 165.1. Plant Design. . . . . . . . . . . . . . . . . . . . . . . . . 165.2. Plant Operation . . . . . . . . . . . . . . . . . . . . . . 236. Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236.1. Offering (Standard/Custom Manufacturing) 236.2. Market Size . . . . . . . . . . . . . . . . . . . . . . . . . 256.3. Target Markets . . . . . . . . . . . . . . . . . . . . . . 256.3.1. Pharmaceuticals. . . . . . . . . . . . . . . . . . . . . . . 256.3.2. Agrochemicals . . . . . . . . . . . . . . . . . . . . . . . 266.3.3. Other Specialty Chemical Industries . . . . . . . . 287. Regulatory Requirements . . . . . . . . . . . . . . 288. Safety, Health and Environment . . . . . . . . . 308.1. Safety and Occupational Hygiene . . . . . . . . 308.2. Risk Minimization . . . . . . . . . . . . . . . . . . . . 308.3. Environment: Waste Elimination . . . . . . . . 319. Economic Aspects . . . . . . . . . . . . . . . . . . . . 329.1. Investment Cost . . . . . . . . . . . . . . . . . . . . . . 329.2. Manufacturing Costs . . . . . . . . . . . . . . . . . . 329.3. Profitability . . . . . . . . . . . . . . . . . . . . . . . . . 34References . . . . . . . . . . . . . . . . . . . . . . . . . . 341. Introduction1.1. HistoryThe roots of both the term fine chemicalsand the emergence of the fine chemical industryas a distinct entity date back to the second halfof the 1970s. As an illustrative example, theUS/UK pharmaceutical company Smith, Kline French (now GlaxoSmithKline) was over-whelmedby the success of its new anti-ulcerdrug Tagamet (cimetidine), the first represen-tativeof a new therapeutic class, namely, H2receptor antagonists, which inhibit gastric acidsecretion and prevent stomach ulcer. As thedemand by far exceeded SKFs in-house pro-ductioncapacity, third-party chemical compa-nieswith capabilities in organic intermediatesmanufacture were approached for custommanufacturing parts of the cimetidine activeingredient. Lonza, Switzerland, became themain supplier of precursor fine chemicals. Ina similar way, Fine Organics, UK became thesupplier of the thioethyl-N0-methyl-2-nitro-1,1-ethenediamine moiety of ranitidine, the secondH2 receptor antagonist, marketed as Zantac byGlaxo. Other pharmaceutical and agrochemicalcompanies gradually followed suit and alsostarted outsourcing the procurement of finechemicals.In the 1980s the fine chemical industrydeveloped rapidly. The first multipurposeplants designed purposely for custommanufacturing came on-stream. In the case ofimportant projects, engineering and financialsupport by the customers was not unusual. Thelatter often were Anglo-Saxon pharmaceuticaland agrochemical companies, which both had aUllmanns Fine Chemicals 2014 Wiley-VCH Verlag GmbHCo. KGaA, Boschstr. 12, 69469 Weinheim, GermanyISBN: 978-3-527-33477-3 / DOI: 10.1002/14356007.q11_q01 16. 2 Fine Chemicals Vol. 1large demand for fine chemicals and wereprone to outsourcing.In the 1990s the industry benefited fromstrong demand. The pharmaceutical industrylaunched a large number of new proprietarydrugs. The record year was 1997 with 53 newdrug launches. The emergence of generics ex-pandedthe customer base. The agrochemicalindustry launched a new category of highlyactive, low-volume products. Lacking in-houseproduction capabilities for the production ofthese sophisticated compounds, it turned to out-sourcing.Management had to cope with rapidlyincreasing regulatory requirements. In produc-tion,tight operating guidelines, the so-calledGood Manufacturing Practices (GMP), were im-posedby the U.S. FDA. As a result, a kind ofstandard, cross-contamination-proof, multipur-poseplant for the production of complex phar-maceuticalfine chemicals (PFCs) with molecularweight up to 500 became the state of the art. Theobservance of more severe legislation regardingsafety, health, and environment necessitated in-frastructureexpansions, e.g., for waste incinera-torsand water-treatment plants.In the early 2000s the irrational exuberanceof the nineties came to a sudden halt. Anunfortunate coincidence of sluggish demand andthe emergence of many new plants, particularlyin China and India, led to overcapacity, which, inturn, impaired the profitability of the wholeindustry.In terms of process technology, biotechnol-ogyunlocked promising new opportunities. Inconventional small-molecule synthesis, bioca-talysisenables both more economical and moreecological production processes. For activeingredients for the emerging biopharmaceuti-cals,demanding mammalian cell culturetechnology is needed. The production of thesevery expensive ( $106/kg) high molecularweight fine chemicals requires special high-containmentplants.1.2. DefinitionFine chemicals are complex, single, pure chemi-calsubstances. They are produced mainly bytraditional organic synthesis in multipurposeplants in limited volumes ( 1000 t/a) and atrelatively high prices ( $10/kg) according toexacting specifications (see Table 1). Biotechni-calprocesses are gaining ground. Whereas thedelineations between commodities and both fineand specialty chemicals are clear-cut, the transi-tionbetween commodities and fine chemicals isgradual (see [1, p. 4]). Fine chemicals are used asstarting materials for specialty chemicals, partic-ularlypharmaceuticals and agrochemicals. Cus-tommanufacturing for the life sciences industryplays a big role.The class of fine chemicals is further subdi-videdon the basis of1. The added value or degree of sophistication.It extends all the way from small or lowmolecular weight (LMW) to big or highmolecular weight (HMW) substances. Theformer are conventionally called buildingblocks, unregulated and regulated inter-mediates,and active ingredients. The lattercomprise inter alia proteins and nucleotides(see Section 3.2).2. The pharmaceutical industry distinguishesbetween drug substance, which is the activeingredient, a fine chemical, and drug product,which is the formulated, finished drug, aspecialty.3. The type of business transaction, namely,standard or exclusive products (seeSection 6.1).Table 1. Definition of fine chemicalsCommodities Fine chemicals SpecialtiesIdentity single pure chemical substances mixturesCharacteristic specifications performanceTotal production value $1012 $90109 $1.4109Production volume per product 1000 t/a 1000 t/a undifferentiatedPlant type dedicated, continuous multipurpose, batch formulation (dissolution, mixing)Sales channel business to business business to business, captive use business-to-consumer 17. Vol. 1 Fine Chemicals 32. The Fine Chemical Industry2.1. OverviewWithin the chemical universe, the fine chemicalindustry is positioned between the commodityand specialty chemical industries, which aretheir suppliers and customers, respectively.Among the customers, life sciences, especiallythe pharmaceutical industry, prevail (seeChap. 6). Fine chemical companies representa wide variety of several 1000 enterprisesoffering mainly products and services alongthe drug supply chain (see Fig. 1). They extendfrom small, privately owned laboratories all theway to large, publicly owned manufacturingcompanies. Large Western fine chemical com-paniesstill dominate in sales revenues. Most ofthe small ones are located in Asia, particularlyin China and India.A comprehensive list of about 1400 finechemical companies (including traders) can befound in the event catalogue of the CPhIexhibition [2].The main raison d^etre of the fine chemicalindustry is to satisfy the product and processdevelopment needs of the life sciences, primarilypharmaceutical and agrochemical industries, andother specialty chemical firms. It has its owncharacteristics with regard to finance, RD,production, and marketing. The RD expendi-tureis highest within the industry. Its main task isprocess development (small r, big D). Produc-tiontakes place in asset-intense multipurposeplants.Depending on their specific activities, onedistinguishes three types of fine chemical compa-nies,namely fine chemical/custom manufactur-ingcompanies (CM or CMO), contract researchorganizations (CRO), and laboratory chemicalsuppliers.2.2. Fine Chemical/CustomManufacturing CompaniesFine chemical/custom manufacturing companiesare active in process development, scale up, pilotplant (trial) production, industrial-scale manu-facture,and marketing. Custom manufacturingor its counterpart, outsourcing, has remained themost important discipline of the Western firms(see Chap. 6). Due to their advantage of lowcosts, the Asian companies have a strong positionin active ingredients for generics [3].Figure 1. Drug development stages (HTS: high-throughput synthesis) Source: Lonza 18. 4 Fine Chemicals Vol. 1Table 2. Top ten fine chemical companies or units (Sources: Company Annual Reports 2011,* authors estimate)Company Fine chemicals unitName Salesa Name Salesa NotesLonza, Switzerland 2900 Custom Manufacturing 1440 HMW/LMW 55/45Sumitomo Chem., Japan 24 300 Fine Chemicals 1090 includes some polymer additivesDSM, The Netherlands 18 300 DPPb, DSPc 890 joint venture for b-lactam APIsBoehringer-Ingelheim, Germany 17 100 Industrial Customersd 800 HMW/LMW 85/15Sigma-Aldrich, USA 2500 SAFCe 730 custom cell engineering, HPAIsBASF, Germany 97 750 P.I.Sf 660 includes excipientsLanxess, Germany 11 700 Saltigo 550* ex Bayer Fine ChemicalsCSPCg, P.R. China 1500 Pharma F.C.s 550E mainly APIs for antibioticsEvonik-Degussa, Germany 18 900 Exclusive Synthesish 500 amino acidsDr. Reddys, India 2 000 PSAIi 492a$106 (2011).bDSM Pharmaceutical Products.cDSM Sinochem Pharmaceuticals.dBiopharmaceuticals and Pharmaceutical Production.e Sigma Aldrich Fine Chemicals.fPharmaceutical IngredientsServices, business unit of Care Chemicals.g Shijiazhuang Pharmaceutical Group, PRC.hNext higher level is Consumer, HealthNutrition Div.; sales $6.4109.iPharmaceutical ServicesActive Ingredients.Despite some consolidation, mainly amongthe Western players, the fine chemical industry isstill fragmented. The top ten companies have acombined market share of 25%. In comparisonthe top ten pharmaceutical companies have morethan 40%. The top ten individually have sales of$(0.51.5)109 per year (see Table 2). Most aredivisions of large, diversified chemical compa-nies.Six are headquartered in Europe, and oneeach in China, India, Japan, and the USA. All areactive both in standard products (especially API-for-Generics) and custom manufacturing. Theyhave extensive resources in terms of specialists,plants, process knowledge, backwards integra-tion,international presence, etc. The manufactur-ingplants spread over many different locations.Many have grown to their present size throughmassive acquisitions.The portfolios of the midsized companies alsocomprise both exclusive synthesis and API-for-Generics. Sales are in the range of $100500 106 per annum. They include both subsidiaries ofmajor public companies and family owned in-dependents.Examples of the latter are Bachem,Switzerland; Dishman, India; F.I.S. and SIMS,Italy; Hikal, India; and Hovione, Portugal. Mostof the midsized fine chemical companies arelocated in Europe, particularly in France,Germany, Italy, the UK, and Switzerland. Italyand Spain, where international drug patent lawswere not recognized until 1978 and 1992, respec-tively,are strongholds of API-for-Generics (seeSection 6.1). Because of a lack of economy insize, the large fine chemical companies tradition-allydo not perform better than the midsized ones.As most fine chemicals are produced in quantitiesof not more than a few tens of tonnes per annumin multipurpose plants (see Section 5.1), theproduction trains are similar in size throughoutthe industry. Their main constituents, the reac-tionvessels, have a median size of 46 m3.Various products are made throughout a year incampaigns. Therefore, the unit cost per cubicmeter per hour (see Section 5.2) hardly dependson the size of the company. Last but not least, thelarge fine chemical companies operate manysmall rather sites than one big one. An examplein case is Lonza. The Custom Manufacturingdivision alone operates 11 sites worldwide.Finally, there are hundreds of small indepen-dentswith sales below $100 million per annum.Most of them are located in Asia. They have onlylimited capabilities and often specialize in nichetechnologies, such as reactions with hazardousgases (e.g., ammonia/amines, diazomethane,ethylene oxide, halogens, hydrogen cyanide,hydrogen sulfide, mercaptans, ozone, nitrousoxides, and phosgene). 19. Vol. 1 Fine Chemicals 5The plants of big and medium-size fine chem-icalcompanies comply with current goodmanufacturing practice (cGMP) regulationsgoverning the production of pharmaceutical finechemicals (see Chap. 7). With the exception ofbiopharmaceuticals, which are manufactured byonly a few, the technology toolboxes of all thesecompanies are similar. This means that they cancarry out most types of chemical reactions. Theydiffer in the breadth and quality of the offeredservice.The minimum economical size of a fine chem-icalcompany depends on the availability ofinfrastructure. If a company is located in anindustrial park, where analytical services; utili-ties,safety, health, and environmental (SHE)services, and warehousing are readily available,there is practically no lower limit.Several large pharmaceutical companiesmarket fine chemicals by themselves as sub-sidiaryactivity to their production for captiveuse, e.g., Abbott, USA; Bayer ScheringPharma, Boehringer-Ingelheim, Germany;Daiichi-Sankyo (after the takeover of Ran-baxy),Japan; JohnsonJohnson, USA; andMerck KGaA, Germany; and Pfizer (formerlyUpjohn), USA.Whereas the pharmaceutical industry is thedominant customer base for most fine chemicalcompanies, some have a significant share ofproducts and services for the agrochemical in-dustry.Examples are Archimica, Saltigo (bothGermany), DSM (The Netherlands), Pyosa(Mexico), and Hikal, India.2.3. Contract Research OrganizationsContract research organizations (CROs) con-centrateon research and process development,providing laboratory-scale process developmentand bench-scale synthesis services to the special-tychemical industry along product development.There are more than 2000CROs operating world-wide,representing revenues of more than $20 109. One distinguishes between patient CROsand product CROs.Product CROs, a.k.a. chemicalCROs, provideprimarily process research and development ser-vices.An overlap with CMOs exists with regardto pilot plants (100 kg quantities), which are partof the arsenal of both CMOs and product CROs.Their tasks are described in Table 3. Companiesoffering both contract research and manufactur-ingservices (CRAMS), a.k.a. one-stop shops,also exist.The offerings of patient CROs, a.k.a. clinicalCROs, comprise more than 30 tasks addressingthe clinical part of pharmaceutical developmentat the interface between drugs, physicians, hos-Table 3. Tasks of product contract research organizations*Task DescriptionSample preparationSynthetic PFCs laboratory preparation of PFCs, impurities, metabolites, etc.Natural products product extraction, purification, and characterizationProcess developmentGeneral upgrading of laboratory procedures to economically and ecologically viable industrial-scalemanufacturing processes (including examination of process parameters)Route screening evaluation of themost suitable synthetic or biotechnological route (mostly by literature search)Proof of principle confirmation of selected route based upon economic and quality criteria, equipmentspecifications, etc.Sample preparation referenceimpurity standards of PFCsSafety and toxicology studies hazard and toxicological (including genotoxicity) tests required for industrial-scalemanufactureAnalytics analytical method development and validationProcess research process optimization, definition of the parameters for industrial-scale manufacture,method validation, stability studiesRegulatory affairs production permits, API submissions (IND, NDA support)Scale-up (kg laboratory/pilot and industrial-scaleplant production)confirmatory testing of the process, preclinical and clinical trial quantities, validationmanufacturing (Phase III and beyond)* Source: Jan Oudenes, Alphora Research, Mississauga, Canada (personal communication). 20. 6 Fine Chemicals Vol. 1pitals, and patients. Only in a few cases (e.g.,Aptuit, Cardinal Health, and Charles River Lab-oratories)do they also provide chemical RDservices.There are about 50100 product CROs indeveloped countries, either standalone compa-niesor divisions of larger chemical companies,with a widely differing degree of width and depthof their offerings. Major customers for CROservices are the large global pharmaceuticalcompanies. Half a dozen Big Pharmas (Pfizer,GlaxoSmithKline, Sanofi-Aventis, AstraZeneca,JohnsonJohnson, and Merck) alone absorbabout one-third of all CRO spending. As forCMOs and also for CROs, biotech start-up com-panieswith their dichotomy between ambitiousdrug development programs and limited re-sourcesare the second most promising prospectsafter Big Pharma. Contrary to manufacturingcompanies, the currency of CROs is not theunit product price, but full-time equivalents(FTEs), that is, the cost of a scientist workingone year on a given customer assignment. Asian,especially Chinese and Indian, companies areemerging as low-cost contract research provi-ders.The largest Chinese chemicalCROis WuXiAppTec, Shanghai WaiGaoQiao Free TradeZone. Set up in the year 2001 and led by 50returnees. 4500 employees generated sales of$334106 in 2011.Contract research and manufacturing orga-nizations(CRAMs) are hybrids combining theactivities of CROs andCMOs[4]. Their history iseither a forward integration of a CRO, whichadds industrial-scale capabilities (an early exam-pleis Suven, India; recent ones are AMRI Globaland Cambridge Major in the USA), or backwardsintegration of a CMO. It is questionable, though,whether one-stop shops really fulfill a need. Thepros and cons are summarized in Table 4.The first pro entry in Table 4, chance toestablish. . . is particularly noteworthy. Mostnew drugs fail in early-stage development. Thesituation has worsened over the years. Nowadays,even for developmental drugs in phase II, theprobability of reaching the market is less than10%. Furthermore, as there is little repeat busi-ness,and as in Big Pharma different functions arein charge of placing orders, CRO projects onlyrarely evolve to industrial-scale supplies. Actual-ly,the large fine chemical companies consider thepreparation of samples more as a marketing tool(and expense) rather than a profit contributor.2.4. Laboratory Chemical SuppliersBefore the life sciences industry, colleges anduniversities, medical research institutions, hos-pitalresearch labs, government agencies, andother facilities can initiate any chemical researchactivity they need chemicals (a.k.a. reagents),solvents, and laboratory equipment. The labora-torychemical suppliers offer a large number(tens of thousands) of fine chemicals in smallquantities for research purposes. Their combinedrevenues are about $10109. Major companiesor business units are listed in Table 5. Onlineordering is possible from all these companies.Apart from the top five, there are many labo-ratorychemical suppliers with smaller catalo-guesgeared to specific needs, such as HoneywellRiedel-de-Haen for inorganic chemicals, BioCa-talytics,which offers a ketoreductase kit withTable 4. Pros and cons of the one-stop-shop conceptPros ConsFine chemical/custom manufacturing company. Chance to establish a relationshipwith a drug company early on. Higher overall added value. In 90% of cases, projects are stopped at thelab-sample stage. Need to master two different skills. quick and dirtylab scale vs. economically viable and ecologically safelarge-scale productionPharmaceutical company. Reduction of number of suppliers . In contrast to the policy of selecting specialistsfor each step of drug development. Overdependence on one supplier 21. Vol. 1 Fine Chemicals 7about 100 enzymes, or Chiral Technologies, adivision of Daicel, Japan, which offers a range of175 immobilized and coated polysaccharide chi-ralstationary phases for use with high-pressureliquid chromatography (HPLC), supercriticalfluid (SCF), and simulated moving-bed (SMB)equipment. A selection of N-heterocyclic com-pounds,especially azaindoles, naphthyridines,pyridines, and pyrrolidines, is offered by Adesis,USA. Peptide building blocks are offered byBachem, Switzerland (9000 products).3. ProductsIn terms of molecular structure, one distin-guishesfirst between low molecular weight(LMW) and high molecular weight (HMW)products. The generally accepted threshold be-tweenLMW and HMW is a molecular weightof about 700. The LMW fine chemicals, alsodesignated small molecules, are produced bytraditional chemical synthesis, by white bio-technology(see Section 4.2.1), or by extractionfrom plants and animals. In the production ofmodern life sciences products, total synthesisfrom petrochemicals prevails. The HMW finechemicals, a.k.a. big molecules, are obtainedmainly by red biotechnology processes. Peptidesand proteins are the most important productcategories.3.1. Small MoleculesMany natural or synthetic LMW fine chemicalscontain heterocyclic moieties. Widely occurringnatural products are chlorophyll, hemoglobin,nucleosides (e.g., uridine), and the vitamins bio-tin(H), folic acid, niacin (PP), pyridoxine HCl(B6), riboflavin (B2), and thiamine (B1).In life sciences, eight out of the top ten small-moleculeproprietary pharmaceuticals containone or more heterocyclic moieties; six of themcontain an N heterocycle, one an S heterocycle,and one both an N and an S heterocycle (seeTable 12). The same 8/10 share of molecules witha heterocyclic moiety is found within the top tenagrochemicals (see [1, Table 11.7, p. 118]. Fur-therexamples of pharmaceuticals are theb-lactam and quinolone antibiotics, the benzodi-azepineantidepressants and the -vir antivirals.Widely used heterocyclic agrochemicals are thedipyridyl and triazine herbicides, the neonicoti-noid,pyrazole, and anthranilic diamide insecti-cidesand triazole conazole and aminopyrimi-dineand benzimidazole fungicides.Even modern pigments, such as diphenylpyr-azolopyrazoles,quinacridones, and engineeringplastics, such as polybenzimidazoles, polyi-mides,and triazine resins, exhibit an N-heterocyclicstructure.3.2. Big MoleculesBig molecules are mostly oligomers or polymersof small molecules or chains of amino acids.Thus, within pharmaceutical sciences, peptides,Table 5. Laboratory chemical suppliersCompany Laboratory chemicalsName Sales* Business unit Sales* Products Notes1 Sigma-Aldrich 2505 Research Specialties 924 167 000 chemicals2 VWR International 4100 Chemicals 820 750 000 including equipment3 Thermo-Fisher Scientific 11 790 Laboratory Products Group 578 15 000 fine organic chemicals5 Johnson Matthey 18 800 Alfa Aesar 124 18 000 research chemicals4 Tokyo Chemical Industries (TCI) N/A Fine Chemicals N/A 22 000 organic chemicals* $106 (2011). 22. 8 Fine Chemicals Vol. 1proteins, and oligonucleotides constitute themajor categories.Peptides and proteins are oligomers or poly-condensatesof amino acid residues linked to-getherby a carboxamide group. The thresholdbetween the two is as at about 50 amino acidresidues. Because of their unique biologicalfunctions, a significant and growing part of newdrug discovery and development is focused onthis class of biomolecules.For the synthesis of peptides, four categoriesof fine chemicals, commonly referred to as pep-tidebuilding blocks (PBBs), are used. In order ofincreasing sophistication they are amino acids( starting materials), protected amino acids,peptide fragments, and peptides themselves [5](see also Section 4.1). Along the way, the mo-lecularweights increase from about 102 up to 104and the unit prices from about $100 up to $105 perkilogram. However, only a small part of the totalamino acid production is used for peptide syn-thesis.In fact, L-glutamic acid, D,L-methionine, L-asparticacid, and L-phenylalanine are used inlarge quantities as food and feed additives. Now-adays,about 50 peptide drugs are commercial-ized.The number of amino acid residues thatmake up a specific peptide varies widely. At thelow end are the dipeptides. The most importantdrugs with a dipeptide (L-alanyl-L-proline) moi-etyare the -pril cardiovascular drugs, such asenalapril, captopril, imidapril, and lysinopril.Also the artificial sweetener Aspartame (N-L-a-aspartyl-L-phenylanaline 1-methyl ester) is adipeptide. At the high end there is the anticoagu-lanthirudin(MW7000), which is composed of65 amino acids.The total production volume (excluding As-partame)of chemically synthesized, pure pep-tidesis about 1500 kg and sales approach $500106 on the API level and $10109 on the finisheddrug level. The numbers would be much higher,about 10% of total pharma sales, if also pepti-domimeticsand APIs which contain peptidesequences as part of a molecule were included,such as the above mentioned -prils or the firstgeneration anti-AIDS drugs, the -navirs. Thebulk of the production of peptide drugs is out-sourcedto a few specialized contract manufac-turers,such as Bachem Switzerland; Chengu GTBiochem, China; Chinese Peptide Company,China; Lonza, Switzerland; and Polypeptide,Denmark.Proteins are very high molecular weight (M100 000) fine chemicals consisting of amino acidsequences linked by peptide bonds. They areessential to the structure and function of all livingcells and viruses and are among the most activelystudied molecules in biochemistry. They can bemade only by advanced biotechnological pro-cesses,primarily mammalian cell cultures (seeSection 4.2.2). Monoclonal antibodies (mAb)prevail among human-made proteins. About adozen of them are approved as pharmaceuticals,of which five rank among the top ten drugs (seeTable 6).Oligonucleotides are a third category of bigmolecules. They are oligomers of nucleotides,which in turn are composed of a five-carbonsugar (either ribose or desoxyribose), a nitroge-nousbase (a pyrimidine or a purine), and 13phosphate groups. The best known representa-tiveof the nucleotides is the coenzyme adenosinetriphosphate (ATP, M 507.2). The maximumlength of synthetic oligonucleotides hardlyexceeds 200 nucleotide components.Adenosine triphosphatePeptides and oligonucleotides are now oftensummarized under the heading tides. They areused in a variety of pharmaceutical applicationsincluding antisense agents, which inhibit unde-sirablecellular protein production, antiviralagents, and protein binding agents. An antisensedrug in advanced (phase III) development isGenzymes cholesterol-lowering drug Kynamro(mipomersen).Antibodydrug conjugates (ADC) are a com-binationbetween small and big molecules. Thesmall-molecule parts, up to four different APIs,are highly potent cytotoxic drugs. They arelinked with a monoclonal antibody, a big mole-culewhich is of little or no therapeutic value initself but extremely discriminating for its targets,the cancer cells. The first commercialized ADCswere Isiss Formivirisen and, more recently, 23. Vol. 1 Fine Chemicals 9Pfizers (formerly Wyeth) Mylotarg (gemtuzu-mab,ozogamicin), a conjugate of N-acetyl-g-calicheamicinwith the humanized mouse mono-clonalIgG4 k antibody hP67.6.4. TechnologiesSeveral key technologies are used for the pro-ductionof fine chemicals, including. Chemical synthesis, either from petrochemicalstarting materials or from extracts from naturalproducts.. Biological sourcesthere are an estimate of10100 million different life forms on earthare still only scarcely investigated. For in-stance,out of an estimated number of 1.5million fungi, only 70 000 are known; and outof an estimated 0.43 million bacteria, only6000 are known. Biotechnology, in particular biocatalysis (en-zymaticmethods), fermentation, and cell cul-turetechnologies.. Extraction from animal tissues, microorgan-isms,or plants; isolation and purification, used,for example, for alkaloids, antibacterials(especially penicillins), and steroids.. Hydrolysis of proteins, especially when com-binedwith ion-exchange chromatography,used, for instance, for amino acids.Chemical synthesis and biotechnology aremost frequently used, sometimes also incombination.4.1. Traditional Chemical SynthesisExamples of the reactions used to synthesize anumber of well-known pharmaceuticals areshown in Table 6. The number of synthetic stepsrequired to make the desired APIs ranges fromtwo (acetaminophen) to seven (omeprazole).For each step of a synthesis, a large toolbox ofchemistries is available. Most of them have beendeveloped on laboratory scale by academia overthe last century and subsequently adapted toindustrial scale. For example, evaporating todryness had to be elaborated to concentrate ina thin-filmevaporator and precipitate by additionof propan-2-ol. The two most comprehensiveTable 6. Reactions used to synthesize selected APIs*API ReactionsName Chemical nameAcetaminophen (Paracetamol) N-(4-hydroxyphenyl)acetamide partial hydrogenation of nitrobenzene, N-acetylationAmoxicillin 6-[D-a-amino-p-hydroxyphenylacetamido]penicillanic acid aromatic alkylation, amination, imine formation, amidation (side chain), fermentation anddeamidation (penicillin nucleus)Cephalexin 7-(D-a-aminophenylacetamido) cephalosporanic acid aromatic alkylation, amination, imine formation, amidation (side chain) fermentation,deamidation (penicillin nucleus), acid-catalyzed ring expansionGuaifenesin glycerol mono (2-methoxyphenyl) ether peracid oxidation of phenol, partial N-methylation, nucleophilic displacement of glycidolIbuprofen ()-2-(4-isobutylphenyl)propionic acid aromatic alkylation, HF-catalyzed aromatic acetylation, Pd-catalyzed carbonylation, alkenehydrationLisinopril (S)-1-N2-[(1-carboxy-3-phenylpropyl)-L-lysyl] L-proline dihydrate Pd-catalyzed carbonylation, hydroxylation of a double-bond, chemical resolution, amidation,N-protection (using trifluoroacetic anhydride), carbonyl activation (using phosgene)Omeprazole 5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl}-1H-benzimidazoleO-methylation, imidazole ring formation using thiourea, N-oxidation, nucleophilicdisplacement, N-methylation, S-oxidationSulfamethoxazole 4-amino-N-(5-methyl-3-isoxazolyl)benzenesulfonamide sulfonylation of aniline, sulfoamidation with 3-amino-5-methylisoxazole* Source: adapted from Brychem Business Consulting. 24. 10 Fine Chemicals Vol. 1handbooks describing organic synthetic methodsin general are the Encyclopedia of Reagents forOrganic Synthesis [6] and Houben-Weyl, Meth-odsof Organic Chemistry [7]. For the synthesisof pharmaceutical fine chemicals (PFCs), consultPharmaceutical Substances [8].More than 150 types of reaction offered by thefine chemical industry are listed in the processdirectory Section of the Informex Show Guide[9]; 45 of them are organic name reactions,representing 10% of a more extensive listing inthe Merck Index [10]. They range from acetoa-cetylationto Wittig reactions. Each of the 430companies participating at the survey indicatedcompetence for close to 30 types of reaction onaverage. Amination, condensation, esterifica-tion,FriedelCrafts, Grignard, halogenation (es-peciallychlorination), and hydrogenation andreduction (both catalytic and chemical) are mostfrequently mentioned. Optically active cyanohy-drin,cyclopolymerization, ionic liquids, ni-trones,oligonucleotides, peptide (both liquid-andsolid-phase), electrochemical reactions(e.g., perfluorination), and steroid synthesis arepromoted by only a limited number ofcompanies.The commercial importance of single-enantiomerfine chemicals has increased steadilysince the mid-1990s. They constitute about halfof both existing and developmental drug APIs. Inthis context, the ability to synthesize chiral mo-leculeshas become important. Two types of basicprocesses are available, namely, traditional phys-icalseparation of the enantiomers and stereospe-cificsynthesis using chiral catalysts. Among thelatter, enzymes and synthetic BINAP types areused most frequently. Large volume ( 103 106 t/a) processes using chiral catalysts includethe manufacture of the perfume ingredient l-mentholas well as Syngentas Dual (metola-chlor)and BASFs Outlook (dimethenamid-P)herbicides. Examples of originator drugs whichapply asymmetric technology are AstraZenecasNexium (esomeprazole), which uses chiral oxi-dation,and Mercks Januvia (sitagliptin), forwhich asymmetric hydrogenation of an unpro-tectedenamine is carried out in the final steps ofthe synthesis.The physical separation of chiral mixturesand purification of the desired enantiomer canbe achieved by classical crystallization (havinga low-tech image, but still widely adopted),making use of standard multipurpose equip-ment,or by various types of chromatographicseparations, such as standard column, simulat-edmoving bed (SMB), or supercritical fluid(SCF) techniques. The latter are advancedchromatographic technologies for the separa-tionof demanding racemates and eliminationof trace impurities.Solid-phase peptide synthesis was pioneeredby R. B. MERRIFIELD in the early 1960s. Nowa-days,the leading solid phases are the 2-chlorotrityl chloride resins. They consist of apolystyrene-base resin cross-linked with a smallamount of divinylbenzene and functionalizedwith 2-chlorotrityl chloride.With the exception of some stereospecificreactions, particularly biotechnology (see be-low),mastering these technologies does notrepresent a distinct competitive advantage.Most reactions can be carried out in standardmultipurpose plants. The very versatile organ-ometallicreactions (e.g., conversions with lith-iumaluminum hydride, boronic acids) mayrequire temperatures as low as 100C, whichcan be achieved only in special cryogenicreaction units, either by using liquefied nitro-genas coolant or by installing a low-tempera-tureunit. Other reaction-specific equipment,such as ozone or phosgene generators, can bepurchased in many different sizes. The instal-lationof special equipment generally is not acritical path on the overall project for develop-ingan industrial-scale process of a new molec-ularentity.4.2. BiotechnologyBiotechnology is more and more used in the finechemical industry for partial or total synthesis,either by conversion of renewable resources,such as sugar or vegetable oils, or the moreefficient transformation of conventional raw ma-terials.One distinguishes between white, red, andgreen biotechnology. As opposed to green andred biotechnology, which relate to agricultureand medicine, respectively, white, or industrial,biotechnology, enables the production of ex-istingproducts in a more economic and sus-tainablefashion on the one hand, and providesaccess to new products, especially biopharma-ceuticalson the other. Three different process 25. Vol. 1 Fine Chemicals 11technologiesbiocatalysis, biosynthesis (micro-bialfermentation), and cell culturesare used.4.2.1. White BiotechnologyBiocatalysis, also termed biotransformationand bioconversion, makes use of natural ormodified isolated enzymes, enzyme extracts,or whole-cell systems for enhancing the pro-ductionof small molecules [11]. The synthesesare shorter, less energy intensive, generate lesswaste, and hence are both environmentally andeconomically more attractive than convention-almethods. It requires only mild reaction con-ditions(ambient temperature and pressure atphysiological pH) and affords high chemo-,regio-, and stereoselectivities. Furthermore, itgenerally needs fewer steps, e.g., by eliminat-ingthe need for protection and deprotectionsteps (see Figs. 2 and 3) and avoids the use ofenvironmentally unattractive organic solvents.A starting material is converted by the biocat-alystto the desired product. Enzymes are dif-ferentiatedfrom chemical catalysts particularlywith regard to stereoselectivity, regioselectiv-ity,and chemoselectivity. Whereas they weretraditionally associated with the metabolicpathway of natural substances, they can alsobe tailored for use in chemical synthesis. Bio-catalystsare applied like chemical catalysts,either in solution or on solid supports. Immo-bilizedenzymes can be recovered by filtrationafter completion of the reaction. Conventionalplant equipment can be used with minoradaptations.The International Union of Biochemistry andMolecular Biology (IUBMB) has developed aclassification for enzymes. The main categoriesare oxidoreductases, used inter alia in the syn-thesisof chiral molecules; transferases, whichtransfer a functional group, e.g., CH3 or OPO3;hydrolases, used inter alia to catalyze theCN ! CONH2 reaction for the synthesis ofacrylamide from acrylonitrile or nicotinic acidfrom 3-pyridylnitrile; and lyases, isomerases,and ligases, which bond two molecules withcovalent bonds.Whereas in the past, only about 150 out of3000 known enzymes were used commercially,new developments in technology are increasingthis number dramatically. Both natural diversityand synthetic reshuffling are being exploitedto obtain enzymes with a large variation inproperties. Companies specializing in makingenzymes, such as Novozymes and Danisco (Gen-encor),or modifying (tailoring) them to spe-cificchemical reactions, such as Codexis, haveyielded enormous progress regarding areas ofapplication, specificity, concentration, through-put,stability, ease of use, and economics. None-theless,the commercialization of many enzymat-icprocesses is hampered by the lack of opera-tionalstability, coupled with their relatively highprice.In the manufacture of fine chemicals, enzymesare the single most important technology forradical cost reductions. This is particularly thecase in the synthesis of molecules with chiralcenters. Here, it is possible to substitute theformation of a salt with a chiral compound,e.g., ()-a-phenylethylamine, crystallization,salt breaking, and recycling of the chiral auxilia-ry,resulting in a theoretical yield of not morethan 50%, with a one-step, high-yield reactionresulting in a product with a very high enantio-mericexcess. Two prime examples areAstraZenecas blockbuster drug Crestor (rosu-vastatin,see Fig. 2) and the widely used genericdilthiazem (see Fig. 3).The two main advantages of the process,which was developed by DSM, are operationalsimplification (much smaller plant, ten timeshigher throughput) and cost savings on raw ma-terials,mainly 2-aminothiophenol, which is usedin a later stage in the process. The resulting costreduction of the API is 40%.Further examples of blockbuster drugs forwhich enzymes are used in the synthesis, arePfizers Lipitor (atorvastatin), for which thepivotal intermediate (R)-3-hydroxy-4-cyano-butyrateis now made with a nitrilase, andMercks Zocor (simvastatin) and Singulair(montelukast), for which the reduction of aketone to an S alcohol, which required stoi-chiometricamounts of expensive and moisture-sensitive()-DIP chloride has now beenreplaced by a ketoreductase enzyme catalyststep.Similar rewarding switches from chemicalsteps to enzymatic ones have also beenachieved in steroid synthesis. Thus, it has beenpossible to reduce the number of steps requiredfor the synthesis of dexamethasone from bile 26. 12 Fine Chemicals Vol. 1Figure 2. Chemical versus enzymatic synthesis of Crestor (rosuvastatin)4-Cl-AA-OEt Ethyl 4-chloro acetoacetatefrom 28 to 15, and further reductions are in themaking.Biosynthesis by microbial fermentation, i.e.,the conversion of organic materials to fine che-micalsby microorganisms, has been used for10 000 years to produce food products, like alco-holicbeverages, cheese, yogurt, and vinegar.Nowadays, it is applied for the production of 27. Vol. 1 Fine Chemicals 13Figure 3. Chemical versus enzymatic synthesis of Dilthiazem 28. 14 Fine Chemicals Vol. 1both small molecules (using enzymes in wholecell systems) and less complex, nonglycosylatedbig molecules, including peptides and simplerproteins. In contrast to biocatalysis, a biosynthet-icprocess does not depend on chemicals asstarting materials, but only on cheap naturalfeedstocks such as glucose to serve as nutrientfor the cells. The enzyme systems triggered in theparticular microorganism strain lead to the ex-cretionof desired product into the medium or, inthe case of HMW peptides and proteins, to theaccumulation within inclusion bodies in the cells.The key elements of fermentation developmentare strain selection and optimization, media, andprocess development. For the large-scale indus-trialproduction of fine chemicals and proteins,dedicated plants are used. As the volume pro-ductivityis low, the bioreactors, called fermen-ters,need to be large. Their volumes can exceed250 m3. Product isolation was previously basedon large-volume extraction of the medium con-tainingthe product. Modern isolation andmembrane technologies, like reverse osmosis,ultra- and nanofiltration, or affinity chro-matographicmethods, can help to remove saltsand byproducts and to concentrate the solutionefficiently and in an environmentally friendlymanner under mild conditions. Final purifica-tionis often achieved by conventional chemicalcrystallization processes.In contrast to the isolation of small mole-cules,the isolation and purification of micro-bialproteins is tedious and often involves anumber of expensive large-scale chro-matographicoperations.Examples of large-volume LMW productsmade by modern industrial microbial biosynthet-icprocesses are monosodium glutamate (MSG),vitamin B2 (riboflavin), and vitamin C (ascorbicacid). Since the discovery of penicillin byFLEMING in 1928 many more antibiotics and othersecondary metabolites have been isolated andmanufactured by microbial fermentation on alarge scale. Important ones besides penicillin arecephalosporins, azythromycin, bacitracin, genta-mycin,rifamycin, streptomycin, tetracycline,and vancomycin.More recently, GlaxoSmithKline patented anefficient fermentation route for the biosyntheticproduction of thymidine (thymine-2-desoxyribo-side).Key to the invention is a recombinant strainthat efficiently produces high titers of thymidineby blocking some enzymes in the thymidineregulating pathway. This microbial process hasnow replaced the chemical route and has enabledGSK to supply the anti-AIDS drug AZT (zido-vudine)to third-world countries at low cost.4.2.2. Red BiotechnologyMammalian cell culture, also known as recom-binantDNA technology, serves for producingbig-molecule fine chemicals, including glyco-proteinsand monoclonal antibodies [12]. Thefirst products made were interferon (discoveredin 1957), insulin, and somatropin. The need forcell culture technology stems mainly from thefact that bacteria do not have the ability toperform many of the post-translational modifica-tionsthat most large proteins require for in vivobiological activity. For mammalian cell culture,specific cell lines are developed. They are uni-formcell populations that can be cultured con-tinuously.Commonly used cell lines are Chinesehamster ovary (CHO) cells or plant cell cultures(see below).Mammalian cell culture is a much moresophisticated and demanding technology thantraditional organic synthesis (see Table 7,[13]). Since mammalian cells are heat- andshear-sensitive, the bioreactor batch requiresmore stringent control of operating parameters.In addition, the very low growth rate of mam-maliancells results in cycle times ranging from10 d to several months, as opposed to severaldays for white biotechnology. Production vo-lumesare tens of kilograms as opposed tohundreds of tonnes. The low productivity ofthe animal culture makes it very vulnerable tocontamination, because a small number of bac-teriawould soon outgrow a larger population ofanimal cells.Typical production volumes for biopharma-ceuticalsmade by mammalian cell technologyare EPO-alpha, 7 kg (worldwide); Etanercept,463 kg (USA), Rituximab, 418 kg (USA); andAdalimumab, 61 kg (USA).As the resulting manufacturing costs are high-erby a factor of 105 ($106/kg vs. $10/kg), mam-maliancell technology is only used when strictlyindispensable.Given the fundamental differences betweenthe two process technologies, plants for mam- 29. Vol. 1 Fine Chemicals 15Table 7. Characteristics of mammalian cell culture and synthetic chemical technologies (all figures are illustrative only) [13]Mammalian cell technology Chemical technologyWorldwide reactor volume 3 000 m3 (fermenters) 80 000 m3Investment per m3 reactor volume $ 5106$ 500 000Production per m3 reactor volume and year several 10 kg several 1000 kgSales per m3 reactor volume and year$ 510106$ 250 000500 000Value of 1 batch$ 5106 (20 000 L fermenter)$ 500 000Product concentration in reaction mixture26 (10) g/L100 g/L (10%)Typical reaction time20 d6 hProcess development time3 years (one step) 23 months per stepCapacity expansion projects many, doubling of actual capacity few, mainly in Far EastGoverning rules cGMP, BLA* cGMP, ISO 14000Scale-up factor (1st lab process to industrial scale)109 (mg ! 1 t)106 (10 g ! 10 t)Process development time3 years (one step) 23 months per stepPlant construction time 46 years 23 yearsShare of outsourcing early stage 55% 25% of chemical prod.commercial 20% 45% of chemical prod.malian cell culture technologies have to bebuilt ex novo. The production of biopharma-ceuticalsstarts by cultivating the cells, fol-lowedby inoculating a nutrient solution withcells from a cell bank. The latter are allowed toreproduce in stages on a scale of up to severalthousand liters. The cells secrete the desiredproduct, which is then isolated from the solu-tion,purified, and formulated. Because of thesensitive nature of most biopharmaceuticals,their dosage forms are limited to injectablesolutions, which must be kept at low tempera-ture.Biopharmaceuticals are therefore strictlymade to order. A process flow sheet for proteinproduction from mammalian cells is shown inFigure 4.* Biological license application (product specific).Figure 4. 5000 L process for protein production from mammalian cells 30. 16 Fine Chemicals Vol. 1Leading producers are Boehringer-Ingelheims biopharmaceuticals division, Lonza,and Piramal Healthcare (formerly Avecia). Theinherent intricacies of mammalian cell technolo-gyled several companies opt out or to substan-tiallyreduce their stake. Examples of fine chem-icalcompanies are Cambrex and Dowpharma inthe USA; Avecia, DSM, and Siegfried in Europe;and WuXi Pharma Tec in China.Plant cell culture is gaining ground as alter-nativetechnology. Plants produce a wide rangeof secondary metabolites, some of which havebeen found to be pharmacologically active.However, these compounds are generally pro-ducedin very small amounts over a long periodof time, making commercially viable extractiondifficult. The technology shows promise for theselective synthesis of chiral compounds with apolycyclic structure, as found in many cyto-statics,such as camptothecine, vinblastine, andpaclitaxel. The new process for the last-named,introduced by Bristol Myers Squibb in 2002, isa brilliant example of the industrial-scale ap-plicationof plant cell fermentation. It startswith clusters of paclitaxel-producing cells fromthe needles of the Chinese yew, T. chinensis,and was introduced in 2002. The API is isolatedfrom the fermentation broth and purified bychromatography and crystallization. The chem-icalprocess to paclitaxel includes 11 syntheticsteps, starting from 10-deacetylbaccatin (III)and has a modest yield. A plant cell process isalso in the making for insulin, demand forwhich is expected to reach 12 000 kg by2012. The Canadian firm SemioSys Genetics,which is developing the process based on saf-flower,anticipates capital costs of 70% andproduct costs of 40% as compared to exitinginsulin production relying on genetically en-gineeredyeast (Saccaromyces cerevisiae) orEscherichia coli. Elelyso (taliglucerase alfa)from Protalix, Israel is the first approved drugmade by plant expression technology. It isderived from a proprietary plant cell basedexpression platform using genetically engi-neeredcarrot cells.The Deutsche Sammlung von Mikroorganis-menund Zellkulturen GmbHDSMZ(German Collection of Microorganisms and CellCultures) is the most comprehensive biologicalresource center in Europe. The nonprofit organi-zationcounts more than 18 000 microorganisms,1200 plant viruses, 600 human and animal celllines, 770 plant cell cultures, and more than 7100cultures deposited for the purpose of patenting.In conclusion, biocatalysis should be, orbecome, part of the technology toolbox of anyfine chemical company. Cell culture fermenta-tion,on the other hand, should be consideredonly by large fine chemical companies with afull war chest and a long-term strategicorientation.5. Production5.1. Plant DesignFine chemical plants are either located on aseparate industrial site or are part of a largerchemical complex. Only the production buildingis fine chemical specific (see Fig. 5). As finechemicals are produced in limited quantities perdefinition, the multipurpose (MP) plant is theprevailing basic configuration. An overview canbe found in [14]. It must be capable of handling aseries of unit operations and performing manytypes of chemical reactions. It typically consistsof three distinct sections: a reaction part, alsoreferred to as wet section (Fig. 6); a productfinishing part, also referred to as dry section, andan administrative part, comprising quality con-trollaboratories, offices, maintenance, changingrooms, and other services. The main pieces ofequipment used are agitated, jacketed vessels forcarrying out the reaction, filters or centrifuges forsolid/liquid separation, and dryers. In the sameplant up to 20 or more different process steps canbe executed per year.As the requirement for single fine chemicalsrarely exceeds 100 t/a (see Fig. 7), and becausethe majority of fine chemicals can be produced instandardized equipment, it does not make senseto build dedicated production units for individualproducts. Moreover, the product portfolio is re-generatedat a fast pace, so that a specific productcan be obsolete before the investment for adedicated plant is recovered.In commercial plants the volume of the re-actors,which determine the production capacity,ranges typically between 4 and 6 m3 (sometimesbetween 1 and 10 m3, or even more). As theannual capacity for a one-step synthesis processaverages approximately 1530 t of product per 31. Vol. 1 Fine Chemicals 17Figure 5. Fine chemical complex Source: Lonza, Visp, Switzerland,Lonza Ltd., Basel, Switzerland1 m3 of reactor volume, a production bayequipped with 4 and 6 m3 reaction vessels issuitable for the production of around 100 t of astep per year. As illustrated in Figure 4, thiscorresponds to a typical production volume ofan API. Whereas one-third of the top 500 drugsare produced in the volume range of 10100 t/a,the requirement of 7% of the APIs exceeds1000 t/a.Standard reaction conditions and standardconstruction materials in multipurpose plants areusually:Temperature 20 to 200CPressure 10 mbar to 3 barConstruction material stainless steel and glass-linedThese properties are adequate for the vastmajority of production processes. To make amultipurpose plant more versatile, special fea-turesare available. Flexibility, however, al-wayshas its price. Highly specialized equip-mentshould only be installed if there is aspecific requirement. Excessive flexibility iscounterproductive. In industrial practice, it hasproved to be a good solution to provide spaceFigure 6. Pharmaceutical fine chemical plant, wet section 32. 18 Fine Chemicals Vol. 1Figure 7. Production volumes of APIs for prescription drugs (sample: top 500 drugs)for special equipment in the basic design and toorder and install it only in case of a realdemand.Examples of special equipment for the wetsection of the plant are low-temperature or cryo-genicreactors, allowing for temperatures as lowas 100C, high-temperature reactors (up to300C), high-pressure reactors, fractional rec-tificationcolumns, thin-film evaporators, liquidliquid extractors, and various types of chro-matographiccolumns. In addition to traditionalstainless steel and glass lining, more exotic ma-terialsof construction such as Hastelloy, tanta-lum,zirconium, and Inconel alloys are used.In the dry section of the building, microniza-tionequipment, conventional dryers, nutschedryer combinations, spray dryers, air classifiers,sieving equipment, packaging/labeling ma-chines,and other equipment can be considered.Another option is to create semi-specific pro-ductionbays, For example, for hydrogenations,phosgenizations, FriedelCrafts alkylations, andGrignard reactions.The choice of the proper piping concept isessential for a valid multipurpose plant design.The basic requirements for a piping system are,beside corrosion resistance against a wide arrayof substances, ease of cleanability (due to qualityand costs), and a high degree of flexibility toensure the required multipurpose character of theplant.The complexity of the plant design, the degreeof sophistication, and the quality requirements ofthe fine chemicals to be produced; the necessityto process hazardous chemicals; the sensitivity ofproduct specifications to changes of reactionparameters; and the availability of a skilledworkforce all determine the degree of automa-tionthat is advisable. Full process control com-puterizationfor a multipurpose plant is muchmore complex than for a dedicated single-prod-uctplant and therefore will be also be much moreexpensive. The fact that automation systemsneed to be validated has become a critical aspectof all automation systems that are being appliedfor cGMP productions.Fine chemical plants have only evolved infew aspects and discrete steps such as contain-ment,automatic process control, and wastepretreatment over the past 25 years [15]. Dif-ferentinitiatives for radical improvements areunder way. With modular multipurpose plantsan efficient combination of the flexibility ofbatch plants with the high performance andeasier scale-up of continuous flow chemistryis sought. For the PFC industry the EuropeanRoadmap for Process Intensification has for-mulatedefficiency targets for an overall cost 33. Vol. 1 Fine Chemicals 19reduction of 20% in 510 years and 50% in1015 years [16].Along the same lines, the FDA has started aninitiative towards knowledge-based processingcalled Quality by Design It is summarized in areport [17]. Radically new concepts are de-scribedhereafter:. F3 Factory [18], i.e., flexible, fast, andfuture factory, is an ambitious privatepublicproject aimed at developing the chemicalplant of the future. The plant incorporatesadvances in process intensification conceptsand modular plug-and-play chemical pro-ductiontechnology. It is intended to be moreeconomic, eco-efficient, and sustainable thanconventional processes, both in continuouslyoperating large-scale plants and in small andmedium-sized batch plants. To demonstratethe technical feasibility, a modular continu-ousplant is being built at Chempark Lever-kusen,Germany).. Microreactors or microreactor technology(MRT), as a part of process intensification,is being developed at several universities, e.g.,ETHZ, Switzerland; MIT, USA; and MCPT,Japan, as well as leading fine chemical com-panies.The main advantages of microreactorsare (1) much better heat and mass transfer,allowing energetic reactions to be carried outsafely and rapidly with higher yields, selectiv-ities,and product quality. (2) Processes do notneed cumbersome scale-up from laboratory topilot plant to industrial-scale plant [19]. Ca-pacityincreases are achieved both by scale-outof module volume and numbering up,i.e., using more units in parallel. Disadvan-tagesare the high investment cost, problemsassociated with solids handling (precipitationof a byproduct can already cause clogging), thedifficulty in precisely assigning feed streamsfor multiple units, and equipment cleaningaccording to cGMP procedures. According toexperts in the field, 70% of all chemical reac-tionscould be done in microreactors, but only1015% are economically justified.The firstindustrial scale use of MRT for producing aPFC under cGMP conditions is for the devel-opmentalnonsteroidal anti-inflammatory drugNaproxcinod. The pivotal step of the synthesisis the highly energetic, selective mononitrationof butane-1,4-diol. The production asset of thecustom manufacturer, DSM, consists of a clus-terof microreactors, continuous extractioncolumns, centrifugal extractors, and distilla-tionequipment. The name-plate annual pro-ductioncapacity is 16 t [20].. Industrial multicolumn chromatography(MCC), a.k.a., simulated moving-bed (SMB)technology. MCC is mainly used for the sepa-rationand purification of PFC mixtures, par-ticularlychiral separation of enantiomers. De-pendingon the type of stationary phase, alsoheterogeneous chemical reactions can be car-riedout, e.g., solid-phase peptide synthesis[21]. The plant shown in Figure 8 has a capaci-tyof several hundreds of tonnes of high-purityproduct.. Plants for small-volume production (kilogramsper month) of high-potency active ingredients(HPAIS), particularly cytotoxic material. Theapproximately $3.5109 market is growingrapidly. The bench-type equipment is mountedin glove boxes.. High-containment plants for producing bio-pharmaceuticalsequipped with single-usebags allow simplification of product change-overby reducing cleaning (including validat-ingthe cleaning process) and reassembling.Figure 8. Industrial simulated moving bed chromatographyunit (column 1000 mm)Source: Ampac Fine Chemicals, Rancho Cordova, CA, USA 34. 20 Fine Chemicals Vol. 1Three examples of state-of-the-art multipur-poseplants are shown in Figures 911. Theyrepresent (1) a typical pharmaceutical finechemical plant of a small Swiss company,namely, RohnerChem; (2) a large fine chemicalplant with an innovative layout built by theGerman pharmaceutical company Schering (nowBayer Schering Pharma) for its captive APIFigure 9. Multipurpose plant example 1Figure 10. Multipurpose plant example 2 Source: Bayer Schering Pharma AG, Bergkamen, Germany 35. Vol. 1 Fine Chemicals 21Figure 11. Multipurpose plant example 3 Source: Lonza Visp, Switzerland 36. 22 Fine Chemicals Vol. 1requirements; and (3) the equipment scheme of aproduction bay from a concept study, namely,Fine Chemicals Complex 2 (FCC-2) in LonzasVisp, Switzerland plant.Operating principles of multipurpose plantexample 1 (Fig. 9) are as follows:. Bay concept: the logical operating unit ofthe plant is a bay. A typical bay consists oftwo to three multipurpose reactors (up to amaximum volume of 10 m3 each), one filtra-tionunit (nutsche or centrifuge), and onedryer.. Production flow of the plant: charging of start-ingmaterials (level 4), reaction (level 3), crys-tallization(level 2), filtration (level 1), anddrying and blending (level 0).. Material flow area: reserved zone for materialflow.. Open structure: manufacturing in a maxi-mum-flexibility and minimal-segregation en-vironment;six bays in the same area. Thereactors and filtration units of the differentbays can be connected as needed. This ap-proachalso allows for maximum capacityutilization.. Containment area: manufacturing combinedwith maximum segregation; six compart-ments,each housing one bay.. Headblock containing in-process control lab-oratories,offices, lockers, and meeting rooms,integrated into the main structure of thebuilding.. Infrastructure: chiller, off-gas treatment, air-conditioningsystems, process water, spares,and other facilities, located in the basementor as open-air installations on the roof of theplant.. Manufacturing standard: cGMP, intermedi-ates,key intermediates, and active pharmaceu-ticalingredients (APIs).Operating principles of multipurpose plantexample 2 (Fig. 10) are as follows:. The futuristic-looking hexagon-shaped plantdesign with satellite buildings is the result ofa newly developed safetyecologyoperatingconcept.. The building complex, which tops 42 m inheight and has a diameter of 88 m, and aworking area of over 28 000 m2, is operatedby over 100 chemical operators, engineers, andchemists.. The satellite buildings contain service areas,laboratories, storage areas, offices, and variousutilities (ventilation, electricity, brine, steam,inert gas, and water for fire protection).. For the processing flow, a top-down approachwas chosen, utilizing gravitational force when-everpossible.. The plant houses six segregated and indepen-dentmanufacturing areas, in order to separate,for example, corrosive chemistry from finalpurification steps of APIs.. The core of the hexagon-shaped building isused for the central services and supply ofliquid and gaseous media via a ring pipe.. Manufacturing standard: cGMP, intermedi-ates,key intermediates, and active pharmaceu-ticalingredients (APIs).Operating principles of multipurpose plant 3(Fig. 11) are as follows:. The building is subdivided vertically into tenbays for PFC/API production and horizontallyinto five floors. On floor 5, a condenser and avacuum pump for the evacuation of the nutscheare installed, as well as an overhead condenserfor the reaction vessel (see below). Floor 4houses a contained cabin for charging solid rawmaterials and intermediates and an agitated1.6 m3 feeding tank for catalyst slurries. Thelatter is connected to a plate filter for catalystand charcoal recovery, a filling station for bigbags, and an overhead condenser. The jacketed6.3 m3 glass-lined reaction vessel is installedon floor 3. The main piece of equipment is aHastelloy filter nutsche ( 2100 mm) forliquidsolid separation. The mother liquor isdischarged to a holding tank. The unit is con-nectedto a heating/cooling temperature con-trolmodule (TCM). The filter cake is dis-chargedto a silo and then filled into big bagsor drums. It is further processed in a separatedryingsievingfilling station.. The building will also contain absorptioncolumns for pretreatment of waste gases aswell as distillation columns for sol