Automated assays for thermodynamic (equilibrium) solubility determination

Abstract

Solubility is a crucial physicochemical property for drug candidates and is important in both drug discovery and development. Poor solubility is detrimental to absorption after oral administration and can mask compound activity in bioassays in various ways. Hence, solubility liabilities should ideally be identified as early as possible in the drug development process. With the increasing number of compounds as potential drug candidates, automated thermodynamic solubility assays for high throughput screening enabling rapid evaluation of a large number of compounds are becoming increasingly important. This review discusses the current status of the most widely used automated assays for thermodynamic solubility, followed by recent high throughput measurements of properties related to solubility (e.g. dissolution rate and supersaturation) and a brief overview of predictive computational methods for thermodynamic solubility reported in the literature.

Electrospun nanofibers: A nanotechnological approach for drug delivery and dissolution optimization in poorly water-soluble drugs

“…Classes II and IV in the BCS have poor solubility due to their complete dose not being possible to dissolve when ingested with a glass of water (250 ml) [140][141][142]. A great majority of new drug molecules and lead compounds are within Class II and IV, and thus present limited oral absorption, slow in vivo dissolution, and low bioavailability [141,[143][144][145].…”

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.…”

“…Thermodynamic solubility is determined by dispensing the relevant buffer (e.g., 1 ml of fasted state simulated intestinal fluid [FaSSIF], fed state simulated intestinal fluid [FeSSIF], simulated gastric fluid [SGF], or simulated lung fluid [SLF]-see Table 1) into a 4 ml glass vial containing circa 1 mg of solid compound. 30 The resulting suspension is shaken at 900 rpm for 4 h at room temperature before residual solid is removed by filtration using a MultiScreen HTS 96-well solubility filter plate (Millipore). The supernatant is quantified by high-performance liquid chromatography-ultraviolet (HPLC-UV), with a dynamic range of typically 1-1000 µg/ml.…”

Automated solubility screening platform using computer vision

“…Recent advances in technology have enabled the development of automated robotic platforms (Burger et al, 2020;Li et al, 2018;MacLeod et al, 2020) that aid in decreasing hands-on experimental time and increasing throughput (Selekman et al, 2017). While effective when applied to solubility screening (Goodwin, 2006;Selekman et al, 2017;Sou and Bergströ m, 2018), most existing systems are only partially automated and still require human intervention and interpretation at many stages of the workflow. In addition, these systems continue to rely on analytical techniques that require time-consuming method development as well as calibration prior to the solubility screen.…”