Active pharmaceutical ingredient product optimization

I hope that this chapter provides a fitting introduction to the complex task of active pharmaceutical ingredient product design through ciystallization, and most importantly that it will stimulate work and encourage further growth in the application of thermodynamic models and optimization techniques in this area. 

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... 

Supercritical fluids are widely used in manufacturing operations, however analytical-scale SFE has had a relatively modest impact on the isolation of pharmaceutical impurities. Pharmaceutical samples usually consist of complex matrices with polar target analytes, which lead to difficult method development and optimization steps for SFE. Nevertheless, novel laboratory research has successfully used supercritical fluids for the isolation of active pharmaceutical ingredients (API) and pharmaceuticals products. 

Fig. 1. Forced stress test. Results of automatic optimization of the separation of an active pharmaceutical ingredient (API) impurities and degradation products are present at concentration levels of 0.01-0.7% relative to the API. Software ChromSword 3.1, ChemStation 10.2. Agilent 1100 HPLC system. Column Inertsil ODS-3, 5 pm, 15 cm x 4.6 mm.

The Negishi coupling allows also the coupling of zincated oxazoles in very good yields (Scheme 5-71). This reaction was optimized to be conducted on larger scale, since this and related products formed are important intermediates in the synthesis of an active pharmaceutical ingredient (API). 

First layers of a 10-pm thin monolithic sihca gel structure with 1- to 2- am macropores and 3- to 4-nm mesopores were manufactured by hydrolytic polycondensation of hquid alkoxysiloxane films coated on glass substrates. Separations were performed for steroids, pesticides, dyestuffs, amino acids, pharmaceutically active ingredients, phenols, and plasticizers [3,4]. Besides this commercially available monohthic UTLC product, which resulted from these studies and was used for several hyphenations to MS [5-10], the sol-gel synthesis process was further improved to provide a high homogeneity, reproducibihty, and mechanical stability of the layer material. Optimized synthesis is still used to build up monolithic stationary phases with new characteristics, and synthetic dyes and food dyes were separated on a 100-pm thin layer [11,12]. 

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