Equilibrium solubility measurement of compounds with low dissolution rate by Higuchi's Facilitated Dissolution Method. A validation study

K. Takács-Novák, Maria Urac, P. Horváth, Gergely Völgyi, Bradley D. Anderson, Alex Avdeef

Research output: Article

8 Citations (Scopus)


Incubation time plays a critical role in the accurate measurement of equilibrium solubility of compounds. Substances which dissolve very slowly generally need long incubation times (days or weeks) to reach equilibrium. However, long times may pose several problems, such as decomposition of solute, molding of buffer, and drifting of pH. Higuchi in 1979 proposed the Facilitated Dissolution Method (FDM) to dramatically reduce incubation time. It employs a small volume of water-immiscible organic solvent to partly solubilize the sample and thereby increase the surface area available for dissolution. The method has been used only rarely. In this study we performed a systematic validation of FDM using progesterone as model compound. The reference solubility value, 7.95 ± 0.21 μg/mL (p < 0.05, n = 5), was determined in Britton-Robinson buffer solution (pH 7.4) at 25.0 °C by the standardized protocol of Saturation Shake-Flask (SSF) method. Also, the solubility was measured by the FDM approach under varied experimental conditions (e.g., type and volume of organic solvent, time of agitation, and amount of solid excess), and compared to the reference value. It was demonstrated that the small amount of organic solvent used in the FDM does not impact the measured solubility, compared to the reference value. Additionally, four compounds of low dissolution rate (dexamethasone, digoxin, haloperidol and cosalane) were used to demonstrate that FDM can reduce the long equilibration time to the standardized 24 h (6 h stirring and 18 h sedimentation). The time dependence of solubility equilibrium was measured by SSF, and the results were compared with those obtained by FDM. Our study, based on > 200 solubility experiments, supports the validity of Higuchi's method. In this study we propose a standardized protocol for the FDM, where 1% v/v of organic solvent is used. Octane (or isooctane) was found to be suitable for highly hydrophobic compounds. Alternatively, octanol or 1,2-dichloroethane can be used for less lipophilic compounds.

Original languageEnglish
Pages (from-to)133-141
Number of pages9
JournalEuropean Journal of Pharmaceutical Sciences
Publication statusPublished - aug. 30 2017

ASJC Scopus subject areas

  • Pharmaceutical Science

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