Analytical tools for the physicochemical profiling of drug candidates to predict absorption/distribution

Abstract

The measurement of physicochemical properties at an early phase of drug discovery and development is crucial to reduce attrition rates due to poor biopharmaceutical properties. Among these properties, ionization, lipophilicity, solubility and permeability are mandatory to predict the pharmacokinetic behavior of NCEs (new chemical entities). Due to the high number of NCEs, the analytical tools used to measure these properties are automated and progressively adapted to high-throughput technologies. The present review is dedicated to experimental methods applied in the early drug discovery process for the determination of solubility, ionization constants, lipophilicity and permeability of small molecules. The principles and experimental conditions of the different methods are described, and important enhancements in terms of throughput are highlighted.

Physicochemical Profiling in Drug Research and Development

“…The experimental conditions effect the pK a determination such as buffer type and ionic strength, applied voltage, detection method, etc. are discussed as detailed by Henchoz et al [16].…”

“…This book can be considered as the most competent and detailed compilation of advanced knowledge required by physical chemists involved in drug development. Numerous reviews summarized the state-of-the-art of new HT experimental techniques [12][13][14][15], the most recent was published by Y. Henchoz et al [16]. So, various literature sources are available for all who would expand their understanding of physicochemical profiling according to their need.…”

“…Both potentiometric and UV/pH titration methods are strongly supported commercially, and the available automated instruments such as the GLpKa and its follow up the Sirius T3 automated analyzers (Sirius UK) are widely used. In the recent years, capillary electrophoresis (CE) has proved to be a very powerful pK a determination method, being more sensitive and less sample consuming [11,16]. Some other methods such as NMR/pH titration [55], CD/pH titration [56], and chromatographic technique [57] have also been applied for special cases, but so far have not become routine techniques.…”

“…The application of CE for pK a determination has been intensively growing in the past decade as reviewed [7,16,67,68]. The method utilizes the change in electrophoretic mobility of a compound with change in pH.…”

Raman‐mikrospektroskopischer Nachweis für den Metabolismus eines Tyrosinkinase‐Inhibitors, Neratinib, in Krebszellen

“…Diese Messungen sind essenziell, um die derzeitigen hohen Ausfallraten von neuen Arzneimittelkandidaten zu verringern. [30] Die Anwendung von Imaging-Methoden bei der Arzneimittelentdeckung hat eine Perspektive, um präklinische medizinische Chemieoptimierungszyklen zu beschleunigen und eine in vitro zu in vivo Tr anslation von Arzneimittelkandidaten zu verbessern. [31,32] Darüber hinaus erfolgte in den durch LC-MS identifizierten Neratinib-Metaboliten Hydroxylierung,N -Oxidation und Dealkylierung des Chinolinrings (Tabelle S1 und Abbildungen S32-S35).…”