Active pharmaceutical ingredients development

S. H. Nusim, ed., Active Pharmaceutical Ingredients Development, Manufacturing and Regulation, Taylor Francis, Boca Raton, EL, 2005. 

Active Pharmaceutical Ingredients Development, Manufacturing, and Regulation... 

These and other FDA policy decisions launched the pharmaceutical industry and academia into a new era of developing stereoselective processes for the manufacture of enantiopure active pharmaceutical ingredients (APIs). 

However, compared with the traditional analytical methods, the adoption of chromatographic methods represented a signihcant improvement in pharmaceutical analysis. This was because chromatographic methods had the advantages of method specihcity, the ability to separate and detect low-level impurities. Specihcity is especially important for methods intended for early-phase drug development when the chemical and physical properties of the active pharmaceutical ingredient (API) are not fully understood and the synthetic processes are not fully developed. Therefore the assurance of safety in clinical trials of an API relies heavily on the ability of analytical methods to detect and quantitate unknown impurities that may pose safety concerns. This task was not easily performed or simply could not be carried out by classic wet chemistry methods. Therefore, slowly, HPLC and GC established their places as the mainstream analytical methods in pharmaceutical analysis. 

The use of palladium as a catalyst is common in the development and synthesis of active pharmaceutical ingredients (APIs). Palladium is an expensive metal and has no known biological function. Therefore, there is a need to recover spent palladium, which is driven both by cost and by government regulations requiring residual palladium in APIs to be <5 ppm (1). Thus, much research has been conducted with the aim of heterogenizing active palladium that can then be removed via simple filtration and hopefully reused without significant loss of activity. 

Tao, J., Zhao, L. and Ran, N. (2007) Recent advances in developing chemoenzymatic processes for active pharmaceutical ingredients. Organic Process Research Development, 11, 259-267. 

This chapter provides an introduction to the pharmaceutical sector, and the business of developing new active pharmaceutical ingredients (API). Crystallization is the preferred method of isolating commercial API products because it offers a highly efficient means of purification. The crystallization process is also where the physical properties of the drug substance are defined. These properties can have a significant impact on the formulated product and process, and eventually on the drug release profile in the patient. 

The design of crystallization processes for the manufacture of Active Pharmaceutical Ingredients is a significant technical challenge to Process Research and Development groups throughout the Pharmaceutical and related industries. It requires an understanding of both the thermodynamic and kinetic aspects of crystallization, to ensure that the physical properties of the product will consistently meet specification. Failure to address these issues may lead to production problems associated with crystal size, shape and solubility, and to dissolution and bioavailability effects in the formulated product. 

It is a general requirement for an optimal therapeutic effect that the active pharmaceutical ingredient (API) is delivered to the site of action in order to provide effective but not toxic concentration levels. Therefore, studies to measure BA are of great importance in order to support new drug product applications. Thus, data on the BA of orally administered drug products is a general requirement to the development... 

Borman, P. J., Chatfield, M. J., Crowley, E. L., Eckers, C., Elder, D. P., Francey, S. W., Laures, A. M-F., Wolff, J-C. Development, validation and transfer into a factory environment of a liquid chromatography tandem mass spectrometry assay for the highly neurotoxic impurity FMTP (4-(4-flurophenyl)-l-methyl-l,2,3,6-tetrahydropyridine) in paroxetine active pharmaceutical ingredient (API). J. Pharm. Biomed. Anal., 48, 2008, 1082-1089. 

Safety Production of the requisite drug molecule, called the active pharmaceutical ingredient (API) or bulk pharmaceutical chemical (BPC), may involve materials, solvents, or intermediates that are volatile, toxic, or even explosive. The development program has to determine the appropriate manufacturing processes to ensure that safety is not compromised and the API can be produced and purified to remove impurities and toxic residues. 

Table 12 gives an orientation help for CE separations sorted by pharmaceutical substances published in review articles. As this chapter focuses on the technical development of drug substances and products, only drug substances and drug formulations are covered. A useful compendium of CE applications in the pharmaceutical environment can be found in the book Capillary Electrophoresis Methods for Pharmaceutical Analysis written by G. Lunn. The book covers more than 700 active pharmaceutical ingredients and contains short method descriptions, sample preparation steps, and references. 

Jamali, B., and Lehmann, S. (2004). Development and validation of a high-resolution capillary electrophoresis method for multi-analysis of ragaglitazar and arginine in active pharmaceutical ingredients and low-dose tablets. /. Pharm. Biomed. Anal. 34(3), 463—472. 

Jamali, B., and Nielsen, H. M. (2003). Development and validation of a capillary electrophoresis-indirect photometric detection method for the determination of the non-UV-absorbing 1,4-dideoxy-l,4-imino-d-arabinitol in active pharmaceutical ingredients, solutions and tablets using an internal standard. J. Chromatogr. A 996(1—2), 213-223. 

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