Solubility is one of the most important properties of a compound in new drug research and development, as it must dissolve in a sufficient concentration to be absorbed and to achieve the desired pharmacological effect. There are several terms for solubility, among which thermodynamic solubility is used the most. It describes the solubility of a compound in a saturated solution at equilibrium. The gold standard for its determination is the shake-flask method, where traditional mechanical mixing is used as a means of mixing. In the early stages of drug development, often only a limited amount of the active substance is available and therefore needs to be used sparingly. In order to achieve biopharmaceutically relevant solubility with a low consumption of active substance, the solvent volume must also be small, which can be a challenge with conventional mechanical mixing, because it is only effective down to a certain lower limit of the volume of the medium (~250 μL). As an alternative, ultrasound offers the possibility of effective mixing at even smaller volumes.
As part of the research work, we have therefore developed and evaluated an updated sonic mixing procedure for the thermodynamic solubility determination based on the shake-flask method and compared the results to the reference values obtained by conventional mechanical mixing on a large number of model compounds. The methods were compared by determining the solubility of 34 compounds in three buffers at pH 1,2, 4,5 and 6,8 at a biopharmaceutically relevant temperature of 37 °C. We have showed that the used buffers had a sufficiently high buffer capacity and resisted well the pH change after the addition of the compounds.
We have confirmed that the solubility determination using the method with sonic mixing gives comparable results to the shake-flask method with traditional mechanical mixing. At the same time, we have shown that the use of ultrasound to dissolve compounds does not lead to supersaturation, but only to the equilibrium state. In addition, we have determined the thermodynamic solubility of 34 model compounds at three different pH values at 37 °C, thus creating the largest known collection of experimentally determined biopharmaceutically relevant solubilities of active pharmaceutical ingredients, which can be of help and reference to other researchers.
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