Industry pharmaceutical

Fine Chemicals The Industry and the Business, by Peter Poliak Copyright 2007 by John Wiley Sons, Inc. 

Big pharma 20 Global companies with sales 5 billion many blockbusters, large in-house capabilities in R D, manufacturing marketing See Table 11.2 

Medium pharma 50-100 Sales 0.5- 5 billion, regional reach, 300 m reactor volume, limited R D capabilities, mainly unlicensed drugs and generics. Barr, Forest, Sepracor, USA Altana, Merck, Stada, Germany Sankyo, Japan Dr Reddy s, Ranbaxy, India 

Virtual pharma 4000- 5000 Venture capital funded, 1-2 developmental drugs, mainly biopharmaceuticals, small R D, no production, no M S organization Cell Therapeutics, Gilead, Trimeris, Vertex, USA Alizyme, UK Morphosys, Germany Actelion, Speedel, Switzerland 

Some big and medium pharma companies are hybrids in the sense that they also offer pharmaceutical fine chemicals and custom manufacturing services and therefore compete with their PFC suppliers. 

However it is essential, in an industrial context, to have traceable and validated bases for the determination of target parameters whatever the experimental technique used. Microcalorimetry is no exception and a standard test and reference reaction has been described that fulfils this need. The imidazole-catalysed hydrolysis of triacetin has, as a result of an international multi-laboratory study, been selected as this test and 

Calorimetric techniques have been applied across the range of issues concerned with drug development from lead discovery to formulated medicine and in aspects of this process - discovery, characterisation, formulation development, process development and scaleup - that are the subject of this chapter. As most studies have been concerned with stability and compatibility issues, it seems logical to consider these applications in almost reverse order. 

Conventionally, stability testing is performed in an accelerated reaction regime i.e. at elevated temperatures ( 323 K) and at controlled humidity (say 70% RH). Derived reaction rate constants are used to predict, through application of the Arrhenius equation, the rate constant at the proposed storage conditions of the medicine. This extrapolation depends on the constancy of the reaction mechanism over the temperature range concerned. It would clearly be better to have direct determination of reaction rate constants under the storage environmental conditions. 

Until around 1995, it was unusual to find kinetic data determined from isothermal microcalorimetric studies - and this was especially true for long, slow reaction systems. However, the modem microcalorimeter has excellent long-term stability (1 /xW or better over 24 h) and hence slow reactions can readily be investigated even those for which a complete reaction is not observed. Willson et al. showed that quantitative kinetic and thermodynamic data could be determined for reactions that had half lives of up to 2500 years. Commencing with a conventional (here simple for clarity) rate expression such as 

It is this calorimetric form of this equation (and the more complex equations that can be developed and used to describe sequential, parallel and more complex reacting systems) that can be analysed to yield values for the target parameters, n, k, H, K, G, S and E. References 6 and 7 provide details on the derivation of calorimetric kinetic equations and describe how to manipulate calorimetric data to determine equilibrium constants, Gibbs functions, entropies and activation energies. The approach described shows that, under normal storage conditions ( room temperature i.e. 298 K and ambient humidity), it is possible, from only 50 h of power time (the calorimetric output is of W vs. t) data, through these techniques, to distinguish between a 

The word pyrogen means fever-producing and has been used to cover any substance which causes a body temperature increase on injection. In fact, the first compendial pyrogen test was published in the 1942 edition of the United States Pharmacopeia. It involved the measurement of the rise of body temperature in rabbits upon intravenous injection of a test product. More recently (1977), the FDA approved the Limulus amebocyte lysate (LAL) test which can be run for less than 10% of the cost of a rabbit test. 

Because of their fever-producing capability, pyrogens must be barred entrance to the blood stream, particularly in persons who are ill or whose immune systems are weaker than normal. It is well known that pyrogens can produce shock and even death.47 

In the early years of process development, chemistry, variables were optimized sequentially and through multiple loops. The variables are rarely independent, and this is a slow and inefficient process. More modern work optimizes variables simultaneously, using multiple parallel experiments with computer analysis of the outcomes. 

In the few pages available here, it s impossible to do justice to the modern pharmaceutical industry its social and economic importance cannot be overestimated. Until the mid-nineteenth century, most medicinal compounds were herbal remedies. Many of these traditional medicines were successful, and their descendants are still widely used. Aspirin, 24.1, is derived from salicylic acid (24.2) in willow bark (Latin, salix, willow tree), and willow bark preparations have been known to have analgesic effects since the Paleolithic. The narcotic effects of 

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Steel framed buildings Steel bridges Fertilizer factories Oil refineries Chemical industries Pharmaceutical industries Machinery parts... 

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 ... 

Foremost we hope - and believe - that chemoinformatics will become of increasing importance in the teaching of chemistry. The instruments and methods that are used in chemistry will continue to swamp us with data and we have to manage these data to increase our chemical knowledge. We have to understand more deeply, and exploit, the results of our experiments. Concomitantly, demands on the properties of the compounds that are produced by the chemical and pharmaceutical industries will continue to rise. We will need materials that are better we need them to be more selective, have fewer undesirable properties, able to be broken down easily in the environment without producing toxic by-products, and so on. This asks for more insight into the relationships between chemical structures and their properties. Furthermore, we have to plan and perform fewer and more efficient experiments. 

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... 

HPLC is routinely used for both qualitative and quantitative analyses of environmental, pharmaceutical, industrial, forensic, clinical, and consumer product samples. Figure 12.30 shows several representative examples. 

Polymeric resins [81133-25-7], widely used in the food and pharmaceutical industries as cation—anion exchangers for the... 

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. 

BRS Online Products. This vendor comprises BRS Online Service, BRS/Colleague, BRS/After Dark, and BRS/Morning Search (35). The strength of BRS is in medical, physical, and social sciences as well as business and news databases of value to the health care and pharmaceutical industries... 

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). 

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