Pharmaceuticals development

Indeed, these reactions proceed at 25 °C in ethanol-aqueous media in the absence of transition metal catalysts. The ease with which P-H bonds in primary phosphines can be converted to P-C bonds, as shown in Schemes 9 and 10, demonstrates the importance of primary phosphines in the design and development of novel organophosphorus compounds. In particular, functionalized hydroxymethyl phosphines have become ubiquitous in the development of water-soluble transition metal/organometallic compounds for potential applications in biphasic aqueous-organic catalysis and also in transition metal based pharmaceutical development [53-62]. Extensive investigations on the coordination chemistry of hydroxymethyl phosphines have demonstrated unique stereospe-cific and kinetic propensity of this class of water-soluble phosphines [53-62]. Representative examples outlined in Fig. 4, depict bidentate and multidentate coordination modes and the unique kinetic propensity to stabilize various oxidation states of metal centers, such as Re( V), Rh(III), Pt(II) and Au(I), in aqueous media [53 - 62]. Therefore, the importance of functionalized primary phosphines in the development of multidentate water-soluble phosphines cannot be overemphasized. 

Traditionally, in pursuit of their structure-activity relationships, medicinal chemists had focused almost exclusively on finding compounds with greater and greater potency. However, these SARs often ended up with compounds that were unsuitable for development as pharmaceutical products. These compounds would be too insoluble in water, or were not orally bioavailable, or were eliminated too quickly or too slowly from mammalian bodies. Pharmacologists and pharmaceutical development scientists for years had tried to preach the need for medicinal chemists to also think about other factors that determined whether a compound could be a medicine. Table 1.1 lists a number of factors that determine whether a potent compound has what it takes to become a drug. Experimentally, it was difficult to quantitate these other factors. Often, the necessary manpower resources would not be allocated to a compound until it had already been selected for project team status. 

Research reports—Research reports such as stability reports, method validation and transfer reports, and pharmaceutical development reports are key documents used for NDA/MAA filings. These documents are strictly version controlled. 

FDA. Guidance for Industry. PAT—A Framework for Innovative Pharmaceutical Development, Mannfactnring, and Qnality Assurance, http //www.fda.gov/cder/ guidence/6419fnl.htm... 

Pharmaceutical development traditionally involves a linear, sequential series of structured events. This is true on both a macro (program) level as well as... 

Rowe RC, Roberts RJ. Expert systems in pharmaceutical development. In Swarbrick J, Boylan JC, editors. Encyclopedia of pharmaceutical technology 2nd edition. New York Marcel Dekker, 2002. pp. 1188-1210. 

Bourquin J, Schmidli H, van Hoogevest P, Leuenberger H. Basic concepts of artificial neural networks (ANN) modelling in the application to pharmaceutical development. Pharm Dev Technol 1997 2 95-109. 

Obviously, the greater the number of subjects studied, the larger the cost. Nevertheless, having too few subjects may lead to inconclusive results, requiring that the study be repeated. Another important consideration is the availability of qualified participants. If the inclusion and exclusion criteria are very restrictive, the cost of recruiting subjects may exceed that of the actual testing. In pharmaceutical development trials, it is not unusual to see recruitment budgets of US 500- 1000 per randomized subject. Thus, for a Phase III development study with several hundred participants, often more than US 500 000 in cost is allotted to efforts to identify qualified subjects who are interested in participation. 

Colin, H. and Krstulovic, A. M., The theory of retention in reversed-phase high-performance liquid chromatography, in Liquid Chromatography in Pharmaceutical Development, Wainer, I. W., Ed., Aster Publishing, 1985, 171. 

Table 6 Considerations in the Pharmaceutical Development and Clinical Use of Both Soluble Macromolecular and Particulate Biotechnical and Site-Specific Drug-Delivery... 

In most pharmaceutical situations, however, there is often insufficient latitude in the formula or process to allow the necessary experimentation. The pharmaceutical industry is subject to regulatory constraints that make EVOP impossible to employ in validated production processes and, therefore, impractical and expensive to use. Moreover, EVOP is not a substitute for good laboratory-scale investigation and, because of the necessarily small changes utilized, is not particularly suitable to the laboratory. In pharmaceutical development, more efficient methods are desired. 

The basis for applications will follow the principles laid down in basic European level legislation for the pharmaceutical sector. This is more or less common regardless of the actual mechanism used to gain an approval. The basic requirements for pharmaceutical marketing authorization applications are laid down in Directive 65/65/EEC (as amended). There are no specific requirements for pharmaceutical development or process validation included in the text of that document. 

Biopharmaceutical issues to be addressed will include a discussion of the pharmaceutical development process as it relates to in vivo and in vitro performance and the general approach taken concerning bioavailability, bioequivalence, and in vitro dissolution profiles. There should be a comparative analysis of relevant studies—objectives, study design, conduct, outcome, and data analyses. The effects of formulation changes (including different strengths of product and... 

This part of the chapter is based on consideration of the published EPARs at the EMEA s web site. At the time of writing there were more than 60 EPARs available. The contents of the pharmaceutical assessment section of each of these were examined, and detailed notes were made from more than 50 of those documents. The amount of information in the different EPARs varies considerably. Some have specific sections with the heading development pharmaceutics, while others include relevant information in the text without a heading. In some cases there are simple statements to the effect that satisfactory pharmaceutical development data were submitted. Therefore, an attempt has been made to glean information of a general nature, and this will be presented as a discussion of relevant topics by dosage form. 

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