Solubility Assay

Solubility is an important physicochemical parameter for drug candidates and is crucial in both drug discovery and development process. Poor solubility is detrimental to absorption after oral administration and may cover compound activity in bioassays in different ways. As such, solubility properties should be ideally identified as soon as possible in the early phase of drug development. With a high reputation in the bio-manufacturing market, Creative Biolabs has introduced high-throughput kinetic and thermodynamic assays in drug discovery to make an estimate of a compound's solubility, which guides our clients the best option to access a potential drug candidate before the clinical stage.

Solubility in Drug Discovery

Compound molecules need to be dissolved to undergo pharmacological processes in vivo (e.g. intestinal absorption) and in vitro (e.g. permeation, metabolism, bioassay, and target binding). The solubility of a compound is dependent on its structure and dissolving conditions (e.g. solution components and physical conditions). Structure decides the lipophilicity, ionizability, hydrogen bonding, molecular volume, and crystal energy, which determine solubility. Dissolving conditions are affected by pH, additives, co-solvents, ionic strength, as well as time and temperature. Numerous drug discovery assays are managed under kinetic solubility conditions. In drug discovery, solubility exerts a great influence on bioassays, formulation for in vivo dosing, and intestinal absorption.

Solubility Assays at Creative Biolabs

Technically, solubility is defined as the concentration of a compound at equilibrium with excess solid (saturated solution) of the most stable crystal structure under specific physical and chemical solution conditions. Low solubility will lead to unpredictable and unreliable results during in vitro testing, thereby increasing the research costs. At the later stage of drug discovery, solubility issues may cause poor bioavailability, undervalued toxicity, and other obstacles, reducing the chances of a drug candidate for success.

Fig.1 Schematic diagram of the recommended workflow for automated high-throughput solubility determination adapted from the SORESOS assay. (Sou, 2018)

The rapid determination of compound solubility is an essential tool for the early drug discovery process, as well as for lead optimization. As a key physical property, it can be measured as either a kinetic or thermodynamic value. At Creative Biolabs, we provide a wide range of methods to accurately determine compound solubility, since good solubility is required not only for obtaining reliable results in early drug discovery but also enabling sufficient concentration of a drug being in circulation to get the optimum exposure. Our precise solubility assays including but not limited to:

• Kinetic Solubility Assays

The kinetic solubility is the maximum solvability of the fastest precipitating species of a compound. It is often measured by a stock solution of the compound dissolved in an organic solvent as the starting material, typically dimethyl sulfoxide (DMSO). This determination is performed in high throughput with shorter incubation times and final high-throughput analyses using plate readers.

Conventional kinetic solubility assays

• Nephelometric assay
• Direct UV assay

Extended kinetic solubility assays

• Solvent evaporation methods - Lyophilisation solubility assay (LYSA)
• Scaled-down shake-flask method
• High-throughput screening (HTS) method - Solubility and residual solid screening (SORESOS) assay
• Complementary and alternative methods - Potentiometric titration methods, dissolution and supersaturation measurements
• Computational approaches
• Thermodynamic Solubility Assays

The thermodynamic solubility is the saturation solvability of a compound at the end of the dissolution process, where the dissolved compound is in equilibrium with the undissolved material in excess. This type of solubility depends on dispensing a solid compound into a solvent. It is normally deemed as the true solubility of a compound and is a critical parameter in formulation development.

Advantages

• Multiple strategies to address drug solubility in drug discovery and development
• A high throughput solubility workflow for drug solubility project
• Obtain reliable in vivo and in vitro assay results in early drug discovery
• Standard protocols and overall monitoring for guaranteed deliverables

The solubility indicates the importance of measuring it for drug discovery compounds. Accurate understanding and control of a compound solubility are beneficial to fruitful drug research and development. As an expert in the bio-manufacturability assessment, Creative Biolabs provides a variety of solubility measurement assays according to the special needs of clients’ respective situations, which ensures their productive drug discovery activities, including structure design for optimizing the solubility, determining effects of solubility on drug discovery assays. For more information, please directly contact us or consult our experts online.

Reference

1. Sou, T.; et al. Automated assays for thermodynamic (equilibrium) solubility determination. Drug Discov Today Technol. 2018, 27: 11-19.

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