fine chemical fine chemical in chemistry, fine chemicals are complex, single, pure chemical substances, produced in limited quantities in multipurpose plants by multistep batch chemical or biotechnological processes. they are described by exacting specifications, used for further processing within the chemical industry and sold for more than $10/kg (see the comparison of fine chemicals, commodities and specialties). the class of fine chemicals is subdivided either on the basis of the added value (building blocks, advanced intermediates or active ingredients), or the type of business transaction, namely standard or exclusive products. definition of fine chemicals (as opposed to commodities and specialties) fine chemicals are produced in limited volumes (< 1000 tons/year) and at relatively high prices (> $10/kg) according to exacting specifications, mainly by traditional organic synthesis in multipurpose chemical plants. biotechnical processes are gaining ground. fine chemicals are used as starting materials for specialty chemicals, particularly pharmaceuticals, biopharmaceuticals and agrochemicals. custom manufacturing for the life science industry plays a big role; however, a significant portion of the fine chemicals total production volume is manufactured in-house by large users. the industry is fragmented and extends from small, privately owned companies to divisions of big, diversified chemical enterprises. the term "fine chemicals" is used in distinction to "heavy chemicals", which are produced and handled in large lots and are often in a crude state. since the late 1970s, fine chemicals have become an important part of the chemical industry. their global total production value of $85 billion is split about 60-40 between in-house production in the life-science industry—the products' main consumers—and companies producing them for sale. the latter pursue both a "supply push" strategy, whereby standard products are developed in-house and offered ubiquitously, and a "demand pull" strategy, whereby products or services determined by the customer are provided exclusively on a "one customer / one supplier" basis. the products are mainly used as building blocks for proprietary products. the hardware of the top tier fine chemical companies has become almost identical. the design, lay-out and equipment of the plants and laboratories have become practically the same globally. most chemical reactions performed go back to the days of the dyestuff industry. numerous regulations determine the way labs and plants must be operated, thereby contributing to the uniformity. history the term "fine chemicals" was in use as early as 1908. the emergence of the fine chemical industry as a distinct entity dates to the late 1970s, when the overwhelming success of the histamine h2 receptor antagonists tagamet (cimetidine) and zantac (ranitidine hydrochloride) created a strong demand for advanced organic chemicals used in their manufacture. as the in-house production capacities of the originators, the pharmaceutical companies smith, kline, & french and glaxo, could not keep pace with the rapidly increasing requirements, both companies (now merged as glaxosmithkline) outsourced part of the manufacturing to chemical companies experienced in producing relatively sophisticated organic molecules. lonza, switzerland, which already had supplied an early intermediate, methyl acetoacetate, during drug development, soon became the main supplier of more and more advanced precursors. the signature of a first, simple supply contract is generally acknowledged as the historical document marking the beginning of the fine chemical industry. the beginning: supply contract between smith kline french and lonza for cimetidine precursors in subsequent years, the business developed and lonza was the first fine chemical company entering in a strategic partnership with skf. in a similar way, fine organics, uk became the supplier of the thioethyl-n'-methyl-2-nitro-1,1-ethenediamine moiety of ranitidine, the second h2 receptor antagonist, marketed as zantac by glaxo. other pharmaceutical and agrochemical companies gradually followed suit and started outsourcing the procurement of fine chemicals. an example in case is f.i.s., italy, which partnered with roche, switzerland for custom manufacturing precursors of the benzodiazepine class of tranquilizers, such as librium (chlordiazepoxide hcl) and valium (diazepam). the growing complexity and potency of new pharmaceuticals and agrochemicals requiring production in multipurpose, instead of dedicated plants and, more recently, the advent of biopharmaceuticals had a major impact on the demand for fine chemicals and the evolution of the fine chemical industry as a distinct entity. for many years, the life science industry continued considering captive production of the active ingredients of their drugs and agrochemicals as a core competency. outsourcing was used only in exceptional cases, such as capacity shortfalls, processes requiring hazardous chemistry or new products, where uncertainties existed about the chance of a successful launch. products in terms of molecular structure, one distinguishes first between low-molecular-weight (lmw) and high-molecular-weight (hmw) products. the generally accepted threshold between lmw and hmw is a molecular weight of about 700. lmw fine chemicals, also designated as small molecules, are produced by traditional chemical synthesis, by microorganisms (fermentation or biotransformation), or by extraction from plants and animals. in the production of modern life science products, total synthesis from petrochemicals prevails. the hmw products, respectively large molecules, are obtained mainly through biotechnology processes. within lmws, the n-heterocyclic compounds are the most important category; within hmws they are the peptides and proteins. small molecules as aromatic compounds have been exhausted to a large extent as building blocks for life science products, n-heterocyclic structures prevail nowadays. they are found in many natural products, such as chlorophyll, hemoglobin, and the vitamins biotin, folic acid, niacin (pp), pyridoxine (vitamin b6), riboflavin (vitamin b2), and thiamine (vitamin b1). in synthetic life science products, n-heterocyclic moieties are widely used in both pharmaceuticals and agrochemicals. thus, β-lactams are structural elements of penicillin and cephalosporin antibiotics, imidazoles are found both in modern herbicides, e.g. arsenal (imazapyr) and pharmaceuticals, e.g. the antiulcerants tagamet (cimetidine. see above) and nexium (omeprazole), the antimycotics daktarin (miconazole), fungarest (ketoconazole) and travogen (isoconazole). tetrazoles and tetrazolidines are pivotal parts of the "sartan" class of hypertensives, e.g. candesartan cilexetil (candesartan), avapro (irbesartan), cozaar (losartan) and diovan (valsartan). chemical structure of diovan (valsartan) a vast array of pharmaceuticals and agrochemicals are based on pyrimidines, such as vitamin b1 (thiamine), the sulfonamide antibiotics, e.g. madribon (sulfadimethoxime) and –half a century later– the sulfonyl urea herbicides, e.g. eagle (amidosulfuron) and londax (bensulfuron-methyl). benzodiazepine derivatives are the pivotal structural elements of breakthrough cns drugs, such as librium (chlordiazepoxide) and valium (diazepam). pyridine derivatives are found in both well-known diquat and chlorpyrifos herbicides, and in modern nicotinoid insecticides, such as imidacloprid. even modern pigments, such as diphenylpyrazolopyrazoles, quinacridones, and engineering plastics, such as polybenzimidazoles, polyimides, and triazine resins, exhibit an n-heterocyclic structure. big molecules big molecules, also called high molecular weight (hmw) molecules, are mostly oligomers or polymers of small molecules or chains of amino acids. thus, within pharmaceutical sciences, peptides, proteins and oligonucleotides constitute the major categories. peptides and proteins are oligomers or polycondensates of amino acids linked together by a carboxamide group. the threshold between the two is as at about 50 amino acids. because of their unique biological functions, a significant and growing part of new drug discovery and development is focused on this class of biomolecules. their biological functions are determined by the exact arrangement or sequence of different amino acids in their makeup. for the synthesis of peptides, four categories of fine chemicals, commonly referred to as peptide building blocks (pbbs), are key, namely amino acids (=starting materials), protected amino acids, peptide fragments and peptides themselves. along the way, the molecular weights increase from about 102 up to 104 and the unit prices from about $100 up to $105 per kilogram. however, only a small part of the total amino acid production is used for peptide synthesis. in fact, l-glutamic acid, d, l-methionine, l-aspartic acid and l-phenylalanine are used in large quantities as food and feed additives. about 50 peptide drugs are commercialized. the number of amino acids that make up a specific peptide varies widely. at the low end are the dipeptides. the most important drugs with a dipeptide (l-alanyl-l-proline) moiety are the "-pril" cardiovascular drugs, such as alapril (lisinopril), captoril (captopril), novolac (imidapril) and renitec (enalapril). also the artificial sweetener aspartame (n-l-α-aspartyl-l-phenylalanine 1-methyl ester) is a dipeptide. at the high end there is the anticoagulant hirudin, mw ≈ 7000, which is composed of 65 amino acids. apart from pharmaceuticals, peptides are also used for diagnostics and vaccines. the total production volume (excl. aspartame) of chemically synthesized, pure peptides is about 1500 kilograms and sales approach $500 million on the active pharmaceutical (api) level and $10 billion on the finished drug level, respectively. the bulk of the production of peptide drugs, which comprise also the first generation anti-aids drugs, the "...navirs", is outsourced to a few specialized contract manufacturers, such as bachem, switzerland; chengu gt biochem, china; chinese peptide company, china; lonza, switzerland, and polypeptide, denmark. proteins are "very high-molecular-weight" (mw > 100,000) organic compounds, consisting of amino acid sequences linked by peptide bonds. they are essential to the structure and function of all living cells and viruses and are among the most actively studied molecules in biochemistry. they can be made only by advanced biotechnological processes; primarily mammalian cell cultures. monoclonal antibodies (mab) prevail among human-made proteins. about a dozen of them are approved as pharmaceuticals. important modern products are epo (binocrit, neorecormon, erythropoietin), enbrel (etanercerpt), remicade (infliximab); mabthera/rituxin (rituximab), and herceptin (trastuzumab). pegylation is a big step forward regarding administration of peptide and protein drugs. the method offers the two-fold advantage of substituting injection by oral administration and reducing the dosage, and therefore the cost of the treatment. the pioneer company in this field is prolong pharmaceuticals which has developed a pegylated erythropoietin (peg-epo). oligonucleotides are a third category of big molecules. they are oligomers of nucleotides, which in turn are composed of a five-carbon sugar (either ribose or desoxyribose), a nitrogenous base (either a pyrimidine or a purine) and 1–3 phosphate groups. the best known representative of a nucleotide is the coenzyme atp (=adenosine triphosphate), mw 507.2. oligonucleotides are chemically synthesized from protected phosphoramidites of natural or chemically modified nucleosides. the oligonucleotide chain assembly proceeds in the direction from 3'- to 5'-terminus by following a procedure referred to as a "synthetic cycle". completion of a single synthetic cycle results in the addition of one nucleotide residue to the growing chain. the maximum length of synthetic oligonucleotides hardly exceeds 200 nucleotide components. from its current range of applications in basic research as well as in drug target validation, drug discovery, and therapeutic development, the potential use of oligonucleotides is foreseen in gene therapy (antisense drugs), disease prevention and agriculture. antibody-drug conjugates (adc) constitute a combination between small and big molecules. the small molecule parts, up to four different apis, are highly potent cytotoxic drugs. they are linked with a monoclonal antibody, a big molecule which is of little or no therapeutic value in itself, but extremely discriminating for its targets, the cancer cells. the first commercialized adcs were isis's fomivirsen and, more recently, pfizer's (formerly wyeth) mylotarg (gemtuzumab ozogamicin). examples of adcs in phase iii of development are abbott's / isis's alicaforsen and eli lilly's aprinocarsen. technologies several key technologies are used for the production of fine chemicals, including chemical synthesis, either from petrochemical starting materials or from natural products extracts biotechnology, for small molecules biocatalysis (enzymatic methods), biosynthesis (fermentation), and, for big molecules, cell culture technology extraction from animals, microorganisms, or plants; isolation and purification, used, for example, for alkaloids, antibacterials (especially penicillins), and steroids hydrolysis of proteins, especially when combined with ion exchange chromatography, used, for instance, for amino acids chemical synthesis and biotechnology are most frequently used; sometimes also in combination. traditional chemical synthesis a large toolbox of chemical reactions is available for each step of the synthesis of a fine chemical. the reactions have been developed on laboratory scale by academia over the last two centuries and subsequently adapted to industrial scale, for instance for the manufacture of dyestuffs & pigments. the most comprehensive handbooks describing organic synthetic methods is methods of molecular transformations. about 10% of the 26,000 synthetic methods described therein are currently used on an industrial scale for fine chemicals production. amination, condensation, esterification, friedel–crafts, grignard, halogenation (esp. chlorination), and hydrogenation, respectively reduction (both catalytic and chemical) are most frequently mentioned on the websites of individual companies. optically active cyanohydrins, cyclopolymerization, ionic liquids, nitrones, oligonucletides, peptide (both liquid- and solid-phase), electrochemical reactions (e.g., perfluorination) and steroid synthesis are promoted by only a limited number of companies. with the exception of some stereospecific reactions, particularly