Pharmaceuticals physicochemical profiling

Physicochemical profiling at the early discovery stage is important in the pharmaceutical industry because poor bioavailability is a leading factor in compound attrition. The ability to rapidly measure absorption properties such as solubility, log P, and log D allows promising compounds to quickly pass into exploratory development. 

Jia, Z. (2005) Physicochemical profiling by capillary electrophoresis. Current Pharmaceutical Analysis, 1, 41-56. 

Studies on drug stability have a central role in physicochemical profiling [1-6]. It is important to know (i) how long the substrate maintains its chemical identity in various environments carrying out its therapeutic action and (ii) the pathway followed when it degrades. Both sets of information are vitally important issues in the pharmaceutical industry. The first is necessary to decide whether to continue to investigate the molecule of interest or not An unstable drug can reduce its efficiency... 

In the case of drug products, developmental pharmaceutics (which include physicochemical profiles and excipient interaction studies) provide similar information that is needed to determine edges of failure and reliable end values. Stability studies and behavior of various lots of clinical supplies also contribute insight to drag product end value design. 

Kerns, E. (2001) High throughput physicochemical profiling for drug discovery. Journal of Pharmaceutical Sciences, 90 (11), 1838-1858. 

The majority of pharmaceutical compounds are either acidic or basic and are therefore ionizable. Other physicochemical properties, such as lipophilicity and solubility, are p Ta dependent therefore, pATa is one of the fundamental parameters of a drug molecule. The pATa determination of acids and bases by CE is based on measuring the electrophoretic mobility of charged species associated with the acid-base equilibria as a function of pH. The detailed theory of pATa and log Pow measurements is beyond the scope of this chapter and readers are referred to a review by Jia [221], which describes in more detail the theoretical aspects of physicochemical profiling by CE methods including FSCE, NACE, MEKC, and MEEKC. 

In this chapter we want to review the main technologies available for physicochemical profiling in the pharmaceutical industry, with focus on strengths and limitations of the currently available approaches, and then to give practical hints how to use the different technologies to derive experimental parameters of sufficient quality. 

Valko, K., Reynolds, D. P. High-throughput physicochemical and in vitro ADMET screening a role in pharmaceutical profiling. Am. J. Drug Deliv. 2005, 3, 83-100. 

Theoretical calculations can also provide physicochemical data, which can be used as an input for 3D-QSAR correlation studies [134,141]. There is a current trend in the area of lead-finding in the pharmaceutical industry to use calculations to set up computer search profiles to be used in the screening of large structural databases, such as the chemical suppliers databases and the internal company databases. 

Among physicochemical properties, the stability of drug candidates is receiving increasing attention. Unfortunately, its evaluation very often requires a lot of experimental time and profiling of many molecules would be nearly impossible without new, computer-aided methods. Any effort useful to facilitate this first part of pharmaceutical investigation is appreciated because it can be converted to a considerable lowering of the research cost. 

A compromise between large unbiased and small focused libraries has become popular, especially for pharmaceutical applications. These biased-targeted libraries are not inspired by a precise structural information, but rather by general information regarding similar classes of targets (e.g., kinases or 7-transmembrane receptors) or by the desired activity-unrelated profile that a drug must possess (e.g., the molecular weight, the partition coefficient, the water solubihty, and other physicochemical properties). Their main properties are fisted in Fig. 5.6. 

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