Use of Calculated Physicochemical Properties to Enhance Quantitative Response When Using Charged Aerosol Detection

Abstract

Universal quantitative detection without the need for analyte reference standards would offer substantial benefits in many areas of analytical science. The quantitative capability of high-performance liquid chromatography (HPLC) with charged aerosol detection (CAD) was investigated for 50 compounds with a wide range of physical and chemical properties. It is widely believed that CAD is a mass detector. Quantification of the 50 compounds using a generic calibrant and mass calibration achieved an average error of 11.4% relative to 1H NMR. Correction factors are proposed that estimate the relative surface area of particles in the detector, taking into account the effects of the density and charge of analytes. Performing these corrections and quantifying with surface area calibration, rather than mass, shows considerably improved linearity and uniformity of detection, reducing the average error relative to 1H NMR to 7.1%. The accuracy of CAD quantification was most significantly improved for highly dense compounds, with traditional mass calibration showing an average error of 34.7% and the newly proposed surface area calibration showing an average error of 5.8%.

High-throughput screening of the Plasmodium falciparum cGMP-dependent protein kinase identified a thiazole scaffold which kills erythrocytic and sexual stage parasites

“…5 ml of 10 mM DMSO compound solution is diluted to 100 μl with pH7.4 phosphate buffered saline, equilibrated for 1 hour at room temperature and filtered through Millipore Multiscreen HTS -PCF filter plates (MSSL BPC). The filtrate is quantified by suitably calibrated Charged Aerosol Detector 56 . The upper limit of the solubility is 500 µM when working from 10 mM DMSO stock solution.…”

Optimization of a Series of 2,3-Dihydrobenzofurans as Highly Potent, Second Bromodomain (BD2)-Selective, Bromo and Extra-Terminal Domain (BET) Inhibitors

“… Overall, potency and selectivity were generally maintained in all examples ( 6 , ( S )-23 – ( S )-27 , and 46 – 49 ) and an average ChromLogD reduction of 0.2 log units was observed. The cyclopropyl amides ( S )-25 and 48 had similar profiles, but ( S )-25 had improved CAD solubility (≥190 vs 8 μg/mL). − This trend was also observed with the methylcyclopropyl analogues ( S , S , S )-26 and 49 , which also displayed similar potencies and increased solubility with the loss of the CH 2 F group (≥76 from 7 μg/mL). Cyclopropyl amide ( S )-25 also had an encouraging rat hepatocyte in vitro clearance value of 2.0 mL/min/g, akin to that of the preferred DBF 6 , and was therefore progressed for further profiling, which will be discussed subsequently.…”

Using Physicochemical Measurements to Influence Better Compound Design

“…30 Typically, rapid, highthroughput experiments 31 (often using a precipitative method in aqueous buffer from a small volume of 10 mM stock in a carrier solvent such as DMSO) give a kinetic solubility, representing the maximum solubility of the fastest-precipitating species of the compound, often quantified by chemiluminescent nitrogen detection (CLND) 32 or charged aerosol dispersion (CAD). 33 More intensive experiments, run by dissolution of better-characterized solid samples with longer equilibration times, furnish thermodynamic solubility data, 30 whereby the dissolved compound is in equilibrium with the undissolved material (e.g., a stable polymorph) in excess. 29 Table 1 gives examples of commonly used simulated fluids 34 used to estimate solubilities pertinent to drug discovery.…”