Large-scale manufacture

Very few papers exist in the open literature where pharmaceutical companies describe examples of specific chemical reactions that have been performed within microreactors. A recent paper by Zhang et al. from Johnson and Johnson Pharmaceuticals [39] describes a series of reactions performed using the CPC microreactor system [13]. The paper details a wide variety of reactions that have been used successfully to prepare kilogram quantifies of products. The system has been used to conduct exothermic reachons, high temperature reactions, reachons involving unstable intermediates and reactions involving unstable reagents. 

Microreactors New Technology for Modem Chemistry, Wiley-VCH, Weinheim, 2000. 14 

Oosterbroek, A. van den Berg, Lah-on-a-Chip Miniaturised Systems for (Bio)Chemical Analysis and Synthesis, 

Fundamentals of Microfabrication, CRC Press, Boca Raton, FL, 1997. 

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Acetyl chloride can be used as a substitute for acetic anhydride in many reactions. Whereas the anhydride requites a mineral acid catalyst for acetylation, acetyl chloride does not. Acetyl chloride is utilized in a wide range of reactions wherein its comparatively high price is offset by convenience. Should its nominal cost be lowered, acetyl chloride would be a powerhil competitor for acetic anhydride in large scale manufacturing. 

Eastman Goal Chemicals. In 1983 Eastman Chemical Co. became the first chemical producer in the United States to return to coal as a raw material for large-scale manufacture of industrial chemicals (35). In that year, Eastman started manufacturing acetic anhydride from coal. Acetic anhydride is a key intermediate for production of coatings, ceUulosic plastics, and cellulose acetate fibers. Acetic anhydride from other sources also is used in the manufacture of pharmaceuticals, starches and sweeteners, and flavors and fragrances. 

History. Methods for the fractionation of plasma were developed as a contribution to the U.S. war effort in the 1940s (2). Following pubHcation of a seminal treatise on the physical chemistry of proteins (3), a research group was estabUshed which was subsequendy commissioned to develop a blood volume expander for the treatment of military casualties. Process methods were developed for the preparation of a stable, physiologically acceptable solution of alburnin [103218-45-7] the principal osmotic protein in blood. Eady preparations, derived from equine and bovine plasma, caused allergic reactions when tested in humans and were replaced by products obtained from human plasma (4). Process studies were stiU being carried out in the pilot-plant laboratory at Harvard in December 1941 when the small supply of experimental product was mshed to Hawaii to treat casualties at the U.S. naval base at Pead Harbor. On January 5, 1942 the decision was made to embark on large-scale manufacture at a number of U.S. pharmaceutical plants (4,5). 

Small-area thin-film CdTe solar cells have been fabricated with sunlight-to-electricity conversion efficiencies near 16%, comparable to crystalline siUcon solar cells in large-scale manufacturing. Large-area monolithic integrated CdTe modules have been fabricated with efficiencies of ca 10%, comparable to crystalline siUcon modules commercially available. 

Catalytic hydtogenation is the most efficient method for the large scale manufacture of many aromatic and ahphatic amines. Some of the commercially important amines produced by catalytic hydrogenation include aniline (from nitrobenzene), 1,6-hexanediamine (from adiponitrile), isophoronediamine (from 3-nitro-l,5,5-trimethylcyclohexanecarbonitrile), phenylenediamine (from dinitrobenzene), toluenediamine (from dinitrotoluene), toluidine (from nitrotoluene), and xyhdine (from nitroxylene). As these examples suggest, aromatic amines ate usually made by hydrogenating the... 

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. 

The zinc. salts of these acids are extensively used as additives to lubricating oils to improve their extreme-pressure properties. The compounds also act as antioxidants, corrosion inhibitors and detergents. Short-chain dialkyl dithiophosphates and their sodium and ammonium salts are used as flotation agents for zinc and lead sulfide ores. The methyl and ethyl derivatives (RO)2P(S)SH and (RO)2P(S)CI are of particular interest in the large-scale manufacture of pesticides such as parathion, malathion, dimethylparathion, etc. For example parathion. which first went into production as an insecticide in Germany in 1947. is made by the following reaction sequence ... 

However, only one-sixth of the halogen present is oxidized and alternative routes are more generally preferred for large-scale manufacture. Thus, the most important halate, NaC103, is manufactured... 

TPBS, although already used in the USA, was first written about in Germany by Hoechst AG. On account of the limited availability of propylene in Germany, the product at first had no significant importance in Germany. As such the development of a large-scale manufacturing process was undertaken in the USA where propylene was readily available. 

First large-scale manufacturing pracess of Syntex ... 

These processes are very rapid and allow the preparation of inorganic supports in one step. This technique allows large-scale manufacturing of supports such as titania, fumed silica, and aluminas. Sometimes the properties of the material differ from the conventional preparation routes and make this approach unique. Multicomponent systems can be also prepared, either by multimetallic solutions or by using a two-nozzle system fed with monometallic solutions [22]. The as-prepared powder can be directly deposited onto substrates, and the process is termed combustion chemical vapor deposition [23]. 

It is a well-known fact (or urban myth. ) that small-scale operations favor batch processes while large-scale manufacture requires continuous processing. Consider the typically assumed general trends (Figure 14.5) where the capital costs of batch... 

Bray BL (2003) Large-scale manufacture of peptide therapeutics by chemical synthesis. Nat Rev Drug Discov 2 587-593... 

While implementing production processes into multi kilogram batch sizes for NHC complexes (Fig. 14.1), a complete quality control of the imidazolium or imi-dazolidinium starting material was required. Therefore, Umicore has implemented large-scale manufacturing of the salts in-house, resulting in stable and reproducible synthetic protocols for the transition metal complexes. 

IEC is also important in large-scale manufacturing of gene vectors such as plasmid DNA. In one process flow scheme, IEC and size exclusion chromatography (SEC) were used sequentially to purify the plasmid after lysis... 

Injections and infusion fluids must be manufactured in a manner that will minimize or eliminate extraneous particulate matter. Parenteral solutions are generally filtered through 0.22 pm membrane filters to achieve sterility and remove particulate matter. Prefiltration through a coarser filter is often necessary to maintain adequate flow rates, or to prevent clogging of the filters during large-scale manufacturing. A talc or carbon filtration aid (or other filter aids) may also be necessary. If talc is used, it should be pretreated with a dilute acid solution to remove surface alkali and metals. 

H. E. Hempel, Large scale manufacture of parenterals, Bull. Parenter. Drug Assoc., 30, 88-95 (1976). 

UCB announcement UCB Pharma (Belgium) announced in 1997 its decision to install a SMB made of columns of 45 cm i.d. in order to perform large-scale manufacturing for a promising new class of drugs. UCB decided to replace a classical chemical process used in the pharmaceutical industry by SMB technology. 

Table 11.3 Native and engineered human insulin preparations that have gained approval for general medical use. Reproduced in updated form with permission from Walsh, G. 2005. Therapeutic insulins and their large-scale manufacture. Applied Microbiology and Biotechnology, 67, 151-159...

Walsh, G. 2005. Therapeutic insulins and their large scale manufacture. Applied Microbiology and Biotechnology 67, 151-159. 

Figure 14.7 Large-scale manufacture of adenoviral vectors for use for gene-therapy-based clinical protocols. Refer to text for details...

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