Aqueous solubility is among the most fundamental molecular properties. Evaluation of a compound's behavior in various aqueous media is part of a pre-formulation study, and may be undertaken as part of lead selection and optimization work, such as the discovery formulation screen offered by WLI. Knowledge of a compound's aqueous solubility can lead to a better understanding of its pharmacokinetics, as well as an appropriate means of formulation. Solubility of organic compounds in water or buffer has become increasingly important for studies of oral absorption of potential pharmaceuticals. As part of in vitro ADME services we offer two methods to determine compound solubility depending on client needs.
This approach is a rapid and practical approach to determine if the test compound is indeed soluble at the concentrations used for biological assay development and screening. Test compound stock solution is prepared in DMSO or another suitable solvent. The stock solution is diluted in PBS buffer and/or in other vehicles of interest to an experimental relevant concentration. The diluted solution is centrifuged to remove any insoluble material and the supernatant analyzed and quantified relative to the DMSO stock solution.
Thermodynamic solubility provides an industry standard approach that may be used to compare test compound solubility relative to other compounds found in the literature. Solubility measurement is performed under equilibrium conditions at pH 7.4. A saturated solution of the drug is prepared and this solution is shaken for 24h to ensure that equilibrium is reached. The solution is then centrifuged to remove the insoluble fraction and the concentration of the compound in solution is determined using a solvent standard calibration curve.
Discovery formulation screening is a useful precursor to rigorous formulation development and is applicable to pre-nomination stage research and development work. We devised the discovery formulation approach to serve clients who wish to rank-order a series of analogues on the basis of solubility properties in a set of vehicles. Alternately, a discovery formulation screen may be used to rapidly and cost-effectively produce a discovery formulation for early pre-nomination animal studies. The discovery formulation is not a substitute for rigorous formulation development but is an effective tool for moving a drug development program from late discovery stage to a nominated development candidate.