The Pharmaceutical Industry

The average cost of developing a new drug is estimated to be about US 1-1.2 billion, including expenditures on failed projects. This amount is about four times the price of an Airbus A380 at US 270 milhon, or hve times that of a Boeing B-787 Dreamliner at US 200 milhon. 

Typically, tens of thousands of compounds are screened and tested, and only a handful make it onto the market as drug products. The statistics are such that, of the 5000-10,000 compounds that show initial promise, five will go into human clinical trials, and only one will become an approved drug. 

Sources. (1) PhRMA (Pharmaceutical Research and Manufacturers of America) Press Release dated November 14, 2006. http //www.who.int/mediacentre/factsheets/fs310/en/ index.html [accessed April 19, 2007], (2) CNN.com. Largest Passenger Jet Unveiled, January 18,2005. http //www.cnn.eom/2005/BUSINESS/01/18/airbus.380/ [accessed April 19, 2007], (3) Tufts Center for the Study of Drug Development, http //www.bizjournals.com/ sanfrancisco/stories/2006/12/04/newscolumn3.html [accessed September 26,2007]. 

Subsequent chapters will elaborate on each of these processes. An overview of the complexity, time, and cost of developing a new drug is shown in Exhibit 1.2. 

The pharmaceutical industry as we know it today started in the late 1800s. It started with the synthetic versions of natural compounds in Europe (refer to Appendix 1). 

The industry has diversified from its earlier focusing on infectious diseases to look for therapies in areas such as heart disease, gastric ulcers, mental disorders, fertility, arthritis, allergy and cancer. After a period of very rapid growth in the 1960s with many new product introductions, growth has slowed in many developed countries both in terms of new products and sales value, as a consequence of the difficulty in finding new improved medicines and the establishment of limits on public expenditure in the health-care field. 

The pharmaceutical industry has many features which distinguish it from other parts of the chemical industry. In addition to research, manufacturing and sales we need to consider the interfaces which the industry has with 

North America Latin America Western Europe Africa, Asia, Australasia and Japan 

In 1982 the total market for pharmaceutical products in the non-communist world was estimated to be 36 700 million. Such an estimate and comparisons for different regions and years are complicated by currency fluctuations. However the regional figure are shown for 1982 in Table 4.1. Table 4.2 shows the position for the six major markets. 

These data show that the top six countries account for about two-thirds of the world market. Their identity is not surprising since they are the most populous, wealthy and industrially advanced nations. Many of the smaller Western European nations have a per capita expenditure on pharmaceuticals similar to that of their larger neighbours. 

Replacement of the chemical step with a biocatalytic step is the first move toward green chemistry, which is followed by replacing the entire multiple-step process with a single fermentation process. Also, scientists have realized that biotechnology routes are inherently safe and mild and do not adversely impact the environment. Heterogeneous catalysis also appears to offer several advantages since the reactions are clean and selective. Also, the spent catalyst can be filtered and recovered for later use. 

The semiconductor, tannery, dyes, paper and pulp, sugar and distillery, and textile industries are reeling from large amounts of toxic effluents. Pressures from government and NGOs are pushing these industries to the corner. They need to embrace the concepts 

Anastas, P. T. and Warner, J. C., Green Chemistry Theory and Practice, Oxford University Press, New York, 1998. 

Anastas, P. T., Heine, L. G., and Williamson, T. C., eds.. Green Chemical Syntheses and Processes, American Chemical Society, Washington, DC, 2000, p. 1. 

Anonymous, Promoting sustainability through green chemistry, Chem. Week, 165(24) 14, 2003. 

The pharmaceutical industry is one of the most important sectors of health care worldwide. Pharmaceutical materials are all manufactured in very small quantities relative to other types of compounds, but their dollar value is exceedingly high. 

The pharmaceutical industry must invest more in research and development than any other industry to discover innovative drugs and therapies to fulfill medical needs. Because of the high R D cost and to meet growth expectations and goals for new product launches, many companies are constantly reorganizing their research operations to be more effective [1]. 

Pharmaceutical preparations are drugs formulated and fabricated into their final form for direct consumption (tablets, capsules, etc.). The industry has grown rapidly in the past 30 years especially in pharmaceutical production. Examples of biological products are bacterial and virus 

The effect of the modem dmg industry on the life expectancy in the U.S. can be seen in Table 23.1. In 1900 infectious diseases accounted for 500 deaths per 100,000 Americans today the figure has dropped to 50. But many problems still face the industry, including most forms of cancer, arthritis, diabetes, senility, and viral diseases, even including the common cold. 

There are five basic sources of pharmaceuticals. By dollar value of products, fermentation is probably the most important, whereas by tonnage, chemical synthesis is dominant. Fermentation is used for antibiotics such as penicillins and tetracyclines. Chemical synthesis provides drugs such as the psychotropics and antihistamines. Animal extracts provide hormones. Biological sources lead to vaccines and serums. Vegetable extracts provide steroids and alkaloids. The top ten pharmaceutical companies in order of revenues are the following Merck, Pfizer, Bristol-Myers Squibb, Johnson  

Johnson, Aventis, Glaxo Wellcome, Novartis, Roche, Eli Lilly, and SmithKline Beecham. 

Although some efficacious drugs have been known for centuries, such as the antimalarial quinine first used in 1639, most important discoveries are of more recent origin. Smallpox vaccine was discovered around 1800, morphine in 1820, aspirin in 1894, and phenobarbital in 1912. But the discovery of the antibacterial activity of sulfur drugs in 1932 and penicillin in 1940 started the golden era of rapid expansion and discovery in the industry. Nearly all important drugs today have been discovered since 1940, some very recently. 

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Chetnoinformatics has matured to a sdentific discipline that will change - and in some cases has already changed - the way in which we perceive chemistry. The chemical and, in particular, the pharmaceutical industry are in high need of che-moinformatics specialists. Thus, this field has to be taught in academia, both in specialized courses on chemoinformatics and by integrating chemoinformatics into regular chemistry curricula. 

The cutoff values of this Rtile of Five the thresholds are a multiple of five) differ slightly within the pharmaceutical industry. Sometimes the Rule of Five" is extended by a fifth condition ... 

In order to parameterize a QSAR equation, a quantihed activity for a set of compounds must be known. These are called lead compounds, at least in the pharmaceutical industry. Typically, test results are available for only a small number of compounds. Because of this, it can be difficult to choose a number of descriptors that will give useful results without htting to anomalies in the test set. Three to hve lead compounds per descriptor in the QSAR equation are normally considered an adequate number. If two descriptors are nearly col-linear with one another, then one should be omitted even though it may have a large correlation coefficient. 

The pharmaceutical industry has developed and studied a number of anabolic steroids for use in vet erinary medicine and in rehabilitation from injuries that are accompanied by deterioration of muscles The ideal agent would be one that possessed the an abolic properties of testosterone without its andro genic (masculinizing) effects Methandrostenolone (Dianabol) and stanozolol are among the many syn thetic anabolic steroids that require a prescription... 

Memfield s concept of a solid phase method for peptide synthesis and his devel opment of methods for carrying it out set the stage for an entirely new way to do chem ical reactions Solid phase synthesis has been extended to include numerous other classes of compounds and has helped spawn a whole new field called combinatorial chemistry Combinatorial synthesis allows a chemist using solid phase techniques to prepare hun dreds of related compounds (called libraries) at a time It is one of the most active areas of organic synthesis especially m the pharmaceutical industry... 

The behavior of drops in the centrifugal field has been studied (211) and the residence times and mass-transfer rates have been measured (212). PodbieHiiak extractors have been widely used in the pharmaceutical industry, eg, for the extraction of penicillin, and are increasingly used in other fields as weU. Commercial units having throughputs of up to 98 m /h (26,000 gal/h) have been reported. 

Pharmaceutical Processes. The pharmaceutical industry is a principal user of extraction because many pharmaceutical intermediates and products ate heat-sensitive and cannot be processed by methods such as distillation. A usehil broad review can be found in the Hterature (241). 

The combined pharmaceutical appHcations account for an estimated 25% of DMF consumption. In the pharmaceutical industry, DMF is used in many processes as a reaction and crystallizing solvent because of its remarkable solvent properties. For example, hydrocortisone acetate [50-03-3] dihydrostreptomycin sulfate [5490-27-7] and amphotericin A [1405-32-9] are pharmaceutical products whose crystallization is faciHtated by the use of DMF. Itis also a good solvent for the fungicide griseofulvin/72%(97-< 7 and is used in its production. 

Full details of this work were pubHshed (6) and the processes, or variants of them, were introduced in a number of other countries. In the United States, the pharmaceutical industry continued to provide manufacturing sites, treating plasma fractionation as a normal commercial activity. In many other countries processing was undertaken by the Red Cross or blood transfusion services that emerged following Wodd War II. In these organisations plasma fractionation was part of a larger operation to provide whole blood, blood components, and speciaUst medical services on a national basis. These different approaches resulted in the development of two distinct sectors in the plasma fractionation industry ie, a commercial or for-profit sector based on paid donors and a noncommercial or not-for-profit sector based on unpaid donors. 

The majority of the imported gum karaya is used by the pharmaceutical industry as a bulk laxative, in dental adhesives, and in sealing gaskets for colostomy bags. 

The number of microencapsulated commercial oral formulations available and the volume of these formulations sold annuaUy is comparatively smaU. This may reflect the difficulty of developing new dmg formulations and bringing them successfully to market or the fact that existing microencapsulation techniques have had difficulty economically producing mictocapsules that meet the strict performance requirements of the pharmaceutical industry. One appHcation that is a particularly active area of development is mictocapsules or microspheres for oral deUvery of vaccines (45,46). 

Pharmaceutical Industry. In the pharmaceutical industry, sterility of deionized water systems is maintained by using an ozone residual. The ozone residual concentration is maintained at >0.3 ppm ppm in the water recirculation loop. Prior to product compounding, the ozone residual is removed by contact with uvirradiaton for <1 s. Ozone also is used to oxidize pyrogens from distilled water destined for intravenous solutions. 

The pharmaceutical industry employs ozone in organic reactions to produce peroxides as germicides in skin lotions, for the oxidation of intermediates for bacteriostats, and in the synthesis of steroids (qv) such as cortisone (see Disinfectants and antiseptics). Vitamin E can be prepared by ozonation of trimethyUiydroquinone. 

There is increasing pressure to develop homochiral dmgs (34). Growing demands are faced by the pharmaceutical industry in dmg development to consider chiral issues in the eady preclinical phases of dmg design and synthesis. 

A noteworthy development is the use of KH for complexing alkylboranes and alkoxyboranes to form various boron hydrides used as reducing agents in the pharmaceutical industry. Potassium tri-j -butylborohydride [54575-50-7] KB(CH(CH2)C2H )2H, and potassium trisiamylborohydride [67966-25-0] KB(CH(CH2)CH(CH2)2)3H, are usefiil for the stereoselective reduction of ketones (66) and for the conjugate reduction and alkylation of a,P-unsaturated ketones (67). 

One appHcation patented ia 1989 is the injection of sodium alumiaate into silica-containing formations for enhanced petroleum recovery (39). Additionally, the pharmaceutical industry uses sodium alumiaate as an alkaline source of aluminum for the production of certain antacids (40). 

The derivatives of the aminophenols have important uses both in the photographic and the pharmaceutical industries. They are also extensively employed as precursors and intermediates in the synthesis of more compHcated molecules, especially those used in the staining and dye industry. All of the major classes of dyes have representatives that incorporate substituted aminophenols these compounds produced commercially as dye intermediates have been reviewed (157). Details of the more commonly encountered derivatives of the aminophenols can be found in standard organic chemistry texts (25,158). A few examples, which have specific uses or are manufactured in large quantities, are discussed in detail in the following (see Table 6). 

Although the techniques described have resulted in the determination of many protein stmctures, the number is only a small fraction of the available protein sequences. Theoretical methods aimed at predicting the 3-D stmcture of a protein from its sequence therefore form a very active area of research. This is important both to understanding proteins and to the practical appHcations in biotechnology and the pharmaceutical industries. 

Flexible Tube. The simplicity of design and the absence of seals and valves make the flexible tube or peristaltic pump a good choice for low capacity and low pressure appHcations in the pharmaceutical industry or wherever shear-sensitive or moderately abrasive fluids are pumped. Because of the continuous flexing of the tube, the tube material of constmction presents a challenge regarding life cycle. For the same reason, pressures are kept relatively low. 

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