Pharmaceutical manufacture reduction

The concept of validation came up in the 1970s in association with sterilization procedures and was extended to all steps of pharmaceutical manufacturing procedures. Validation means proving that any and all procedures, processes, equipment, material, operations, and systems comply with the expected performance. Well-planned and well-conducted validation studies constitute GMP principles once they guarantee a consistently safe and efficacious final product. Validation is important for companies, first for QA, and also for cost reduction, decreasing failures, rejection, reworks, recalls, and complaints. The positive aspect of validation is an increase in productivity, as a consequence of a well-controlled process. Validation is required by the regulatory agencies of many countries. 

The correct choice of membrane should be determined by the specific objective, such as the removal of particulates or dissolved solids, the reduction of hardness for the production of ultra pure water or the removal of specific gases/chemicals. The end use may also dictate the selection of membranes in industries such as potable water, effluent treatment, desalination, or water supply for electronic or pharmaceutical manufacturing. 

With the access to diverse and stable biocatalysts, more and more conventional chemical processes (first generation) in pharmaceutical manufacturing have been replaced by second-generation biocatalysis processes with substantial impact on the pharmaceutical industry. In this chapter, some commonly used biocatalytic reactions for chiral preparation, including hydrolytic reactions, acyl and glycosyl transfer reactions, asymmetric reduction/ oxidation reactions, and asymmetric formation of C-C bonds, are introduced and exemplified by the research achievements developed by the authors laboratory as well as other research groups. Some of the bioprocesses described herein have been successfully applied on pilot or even industrial scale. ... 

The chief outlets are for polyurethane (di-isocyanates) 40%, rubber chemicals, herbicides minor users include dye makers (approx. 5%) and pharmaceutical manufacturers. Benzene is the feedstock and the traditional route is to nitrate this and then to reduce the nitrobenzene to aniline. Catalytic hydrogenation has displaced iron/ferrous chloride reduction in this and analogous reductions e.g. in the manufacture of toluidines. Amination of phenol manufactured from cumene (Vol. I, p. 366) has been patented (Figure 2.8). The yield claimed is 99% though the economic viability is uncertain. 

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. 

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). 

The control of chemical reactions (e.g., esterification, sulfonation, nitration, alkylation, polymerization, oxidation, reduction, halogenation) and associated hazards are an essential aspect of chemical manufacture in the CPI. The industries manufacture nearly all their products, such as inorganic, organic, agricultural, polymers, and pharmaceuticals, through the control of reactive chemicals. The reactions that occur are generally without incident. Barton and Nolan [1] examined exothermic runaway incidents and found that the principal causes were ... 

Fine chemicals are often manufactured in multistep conventional syntheses, which results in a high consumption of raw materials and, consequently, large amounts of by-products and wastes. On average, the consumption of raw materials in the bulk chemicals business is about 1 kg/kg of product. This figure in fine chemistry is much greater, and can reach up to 100 kg/kg for pharmaceuticals (Sheldon, 1994 Section 2.1). The high raw materials-to-product ratio in fine chemistry justifies extensive search for selective catalysts. Use of effective catalysts would result in a decrease of reactant consumption and waste production, and the simultaneous reduction of the number of steps in the synthesis. 

Catalytic transformations can be divided on the basis of the catalyst-type - homogeneous, heterogeneous or enzymatic - or the type of conversion. We have opted for a compromise a division based partly on type of conversion (reduction, oxidation and C-C bond formation, and partly on catalyst type (solid acids and bases, and biocatalysts). Finally, enantioselective catalysis is a recurring theme in fine chemicals manufacture, e.g. in the production of pharmaceutical intermediates, and a separate section is devoted to this topic. 

The manufacture of fine chemicals and pharmaceuticals generates in the order of 25-100 times more waste than product [52], Inorganic salts account for the bulk of the waste and are most often produced by neutralization of acidic or basic solutions [53]. Salts can pollute soil and ground water, lower the pH of atmospheric moisture and they may contribute to acid dew or acid rain [6]. For cleaner production, their minimization is essential and hence our concentration on new processes, such as the etherification (discussed in Sect. 2.6.3.1) and hydrogen transfer reduction (Sect. 2.6.3.2), that avoid salt formation and the use of salts. 

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