Vitamin manufacture

It can be estimated that approximately 3,000,000,000 of vitamins were sold in 1996. Market growth is slightly higher than population growth, but varies widely by individual vitamin, geographical area, and/or appHcation. The largest vitamin manufacturer is Hoffmann-La Roche. Other significant producers include BASE, Takeda, Eisai, and Rhc ne-Poulenc. Additional vitamins are produced in China, Russia and India. 

The history, world consumption, and production, analogues, substitutes, and derivatives of linalool have been reviewed by Clark (151). Estimates of market size vary. Another source (83) estimates the total production volume of linalool and its esters as 6000 tpa, whereas Clark (151) states that the output of three of the main producers is 10,000 tpa. Such variances probably stem from the fact that linalool is used per se and as an intermediate for both other aroma chemical and vitamin manufacture and the result will depend on how the volume is estimated. 

Ionone (334) is also very widespread in nature being found in, among others, rose, osmanthus, raspberries, cherries, tobacco, carrots, and capsicums. It has a warm woody, dry, and fruity odor and is greener than a-ionone. However, it is less useful than the latter and is used particularly in woody perfumes. In production terms, it is the most important of all the ionones because of its use in vitamin manufacture. 

Sorbitol is manufactured by the reduction of glucose in aqueous solution using hydrogen with a nickel catalyst. It is used in the manufacture of ascorbic acid (vitamin C), various surface active agents, foodstuffs, pharmaceuticals, cosmetics, dentifrices, adhesives, polyurethane foams, etc. 

Two molecules of vitamin A are formed from one molecule of -carotene. Vitamin A crystallizes in pale yellow needles m.p. 64 C. It is optically inactive. It is unstable in solution when heated in air, but comparatively stable without aeration. Vitamin A is manufactured by extraction from fish-liver oils and by synthesis from / -ionone. The role of vitamin A in vision seems to be different from its systemic function. See also relincne and rhodopsin. 

Uses. Although cyanoacetic acid can be used in appHcations requiring strong organic acids, its principal use is in the preparation of malonic esters and other reagents used in the manufacture of pharmaceuticals, eg, barbital, caffeine, and B vitamins (see Alkaloids Hypnotics Vitamins). Cyanoacetic acid can be used for the preparation of heterocycHc ketones. 

Uses. Butanediol is used to manufacture the insecticide Endosulfan, other agricultural chemicals, and pyridoxine (vitamin B ) (see Vitamins) (116). Small amounts are consumed as a diol by the polymer industry. 

Because of the simplicity of swiae and poultry feeds, most feed manufacturers add vitamins (qv) and trace minerals to ensure an adequate supply of essential nutrients. Amino acids (qv) such as methionine [7005-18-7] lysiae [56-87-17, threonine [36676-50-3] and tryptophan [6912-86-3], produced by chemical synthesis or by fermentation (qv), are used to fortify swiae and poultry diets. The use of these supplements to provide the essential amino acids permits diets with lower total cmde proteia coateat. 

In pharmaceutical appHcations, the selectivity of sodium borohydride is ideally suited for conversion of high value iatermediates, such as steroids (qv), ia multistep syntheses. It is used ia the manufacture of a broad spectmm of products such as analgesics, antiarthritics, antibiotics (qv), prostaglandins (qv), and central nervous system suppressants. Typical examples of commercial aldehyde reductions are found ia the manufacture of vitamin A (29) (see Vitamins) and dihydrostreptomycia (30). An acyl azide is reduced ia the synthesis of the antibiotic chloramphenicol (31) and a carbon—carbon double bond is reduced ia an iatermediate ia the manufacture of the analgesic Talwia (32). 

X5lenol is an important starting material for insecticides, xylenol—formaldehyde resins, disinfectants, wood preservatives, and for synthesis of a-tocopherol (vitamin E) (258) and i7/-a-tocopherol acetate (USP 34-50/kg, October 1994). The Bayer insecticide Methiocarb is manufactured by reaction of 3,5-x5lenol with methylsulfenyl chloride to yield 4-methylmercapto-3,5-xylenol, followed by reaction with methyl isocyanate (257). Disinfectants and preservatives are produced by chlorination to 4-chloro- and 2,4-dich1oro-3,5-dimethylpheno1 (251). 

A considerable quantity of oil can be extracted from waste material from shelling and processing plants, eg, the inedible kernels rejected during shelling and fragments of kernels recovered from shells. About 300 t of pecan oil and 300—600 t of English walnut oil are produced aimuaHy from such sources. The oil is refined and used for edible purposes or for the production of soap the cake is used in animal feeds (see Feeds and feed additives). Fmit-pit oils, which closely resemble and are often substituted for almond oil, are produced on a large scale for cosmetic and pharmaceutical purposes (143). For instance, leaves, bark, and pericarp of walnut may be used to manufacture vitamin C, medicines, dyes and tannin materials (144). 

Cyanide Wastes. Ozone is employed as a selective oxidant in laboratory-scale synthesis (7) and in commercial-scale production of specialty organic chemicals and intermediates such as fragrances, perfumes (qv), flavors, antibiotics (qv), hormones (qv), and vitamins (qv). In Japan, several metric tons per day (t/d) of piperonal [120-57-0] (3,4-methylenedioxybenzaldehyde) is manufactured in 87% yield via ozonolysis and reduction of isosafrole [93-16-3], Piperonal (or heHotropine [120-57-0]) has a pleasant odor and is used in perfumery. Oleic acid [112-80-1/, CH3(CH2 )7CH—CH(CH2 ). C02H, from tall oil (qv) is ozonated on a t/d scale to produce pelargonic, GgH2yG02H, and azelaic, H02G(GH2)yG02H, acids. Oleic acid also is ozonated in Japan... 

The quaHty, ie, level of impurities, of the fats and oils used in the manufacture of soap is important in the production of commercial products. Fats and oils are isolated from various animal and vegetable sources and contain different intrinsic impurities. These impurities may include hydrolysis products of the triglyceride, eg, fatty acid and mono/diglycerides proteinaceous materials and particulate dirt, eg, bone meal and various vitamins, pigments, phosphatides, and sterols, ie, cholesterol and tocopherol as weU as less descript odor and color bodies. These impurities affect the physical properties such as odor and color of the fats and oils and can cause additional degradation of the fats and oils upon storage. For commercial soaps, it is desirable to keep these impurities at the absolute minimum for both storage stabiHty and finished product quaHty considerations. 

The 1995 Canadian and United States sugar alcohol (polyol) production is shown in Table 2. The market share of each is also given. Liquids comprise 48% crystalline product comprises 39% and mannitol comprises 13% of the polyol market. An estimate of total U.S. sorbitol capacity for 1995 on a 70% solution basis was 498,000 t. ADM, Decatur, lU., produced 68,200 t Ethichem, Easton, Pa., 13,600 t Lon2a, Mapleton, lU., 45,400 t Roquette America, Gurnee, lU., 68,200 t and SPI Polyols, New Castle, Del., 75,000 t (204). Hoffman-LaRoche, which produces sorbitol for captive usage in the manufacture of Vitamin C (see Vitamins), produced about 27,300 t in 1995. 

Manufacture of vitamin C starts with the conversion of sorbitol to L-sorbose. Sorbitol and xyHtol have been used for parenteral nutrition following severe injury, bums, or surgery (246). An iron—sorbitol—citric acid complex is an intramuscular bematinic (247). Mannitol administered intravenously (248) and isosorbide administered orally (249) are osmotic diuretics. Mannitol hexanitrate and isosorbide dinitrate are antianginal dmgs (see Cardiovascular agents). 

Geranyl acetone is an important intermediate in the synthesis of isophytol [505-32-8], famesol [106-28-5], and neroHdol [40716-66-3]. Isophytol is used in the manufacture of Vitamin E. 

Petrochemical-based methods of citral manufacture are very important for the large-scale manufacture of Vitamin A and carotenoids. Dehydrolinalool and its acetate are both made from the important intermediate, P-methyUieptenone. 

Phytol [505-06-5] (111) and isophytol [150-86-7] (112) are important intermediates used in commercial synthesis of Vitamins E and K. There is a variety of synthetic methods for their manufacture. Chlorophyll [479-61-8] is a phytyl ester. 

The first commercial synthesis of a vitamin occurred ia 1933 when the Reichsteia approach was employed to manufacture vitamin C (6). AH 13 vitamins ate available ia commercial quantities, and their biological functions have largely been estabUshed (7). A Hst of Nobel prize winners associated with vitamin research is given ia Table 2. 

More than one process is available for some of the vitamins. Further, manufacturers have developed variants of the classical syntheses during Optimization. Whereas some of this information is available, as described in the individual sections on vitamins, much is closely held as trade secrets. Judging from the more recent patent Hterature, the assessment can be made that vitamin production technologies are in general mature. However, the economic value of these products drives continuing research aimed at breakthrough processes. Annual production of vitamins varies gready, from ca 10 metric tons of vitamin B 2 to ca 50,000 metric tons of vitamin C. 

Vitamin C was the first vitamin to be manufactured by chemical synthesis on an iadustrial scale. Major suppHers of vitamin C are Hoffmaim-La Roche, BASF, Takeda, E. Merck, and various companies ia China. Additional production occurs ia Eastern Europe and India. 

Animals cannot synthesize vitamin A-active compounds and necessary quantities are obtained by ingestion of vitamin A or by consumption of appropriate provitamin A compounds such as P-carotene. Carotenoids are manufactured exclusively by plants and photosynthetic bacteria. Until the discovery of vitamin A in the purple bacterium Halobacterium halobium in the 1970s, vitamin A was thought to be confined to only the animal kingdom (56). Table 4 Hsts RDA and U.S. RDA for vitamin A (67). 

Vitamin A is manufactured by Hoffmaim-La Roche (Switzerland), BASF (Germany), and Rhc ne-Poulenc (France), as well as by some smaller suppliers in India, China, and Russia. The worldwide production is estimated to be 2500 to 3000 metric tons. About three-quarters of this production is for animal feed the remainder is for food fortification and pharmaceuticals (qv). The main trade names of feed products are Rovimix, Lutavit, and Microvit. Prices depend on appHcation forms and are approximately 60— 70/10 lU retinol (1995) ie, 200— 233/10 RE. One lU is equivalent to 0.300 )lg of aH-Zra/ j -retinol and 1 RE is equivalent to 1 ) g of all-retinol. 

French firms, Rhc ne-Poulenc and, to a lesser extent, Roussel-Uclaf. Smaller amounts are produced in Japan by Nippon Petrochemical, in Hungary by Medimpex-Richter, and by minor producers in several other countries. Barber manufacturers, particularly Merck (U.S.) and Glaxo (U.K.), have exited the market. Although estimates vary, it appears that ca 10,000 kg/yr of vitamin is produced (1). 

Fish-hver oil, Hver, milk, and eggs are good natural sources of the D vitamin. Most milk sold in the United States is fortified with manufactured vitamin D. Fish oil is the only commercial source of natural vitamin D, and the content of the vitamin varies according to species as well as geographically, ie, Adantic cod contain 100 lU/g where lU (International Unit) = 0.025 /ig of vitamin D, whereas oriental tuna (Percomofpk) contain 45,000 lU/g oil. 

Provitamin. The chemistry of the D vitamins is intimately involved with that of their precursors, the provitamins. The manufacture of the vitamins and their derivatives usually involves the synthesis of the provitamins, from which the vitamin is then generated by uv irradiation. The chemical and physical properties of the provitamins are discussed below, followed by the properties of the vitamins. 

Fig. 3. Photochemical and thermal isomerization products of vitamin D manufacture (49). The quantum yields of the reactions ate hsted beside the arrows...

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