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Experiences on equilibrium solubility measurement by saturation shake-flask method

Edit Baka, Department of Pharmaceutical Chemistry, Semmelweis University, Hungary

Various methods have been developed for the measurements of equilibrium (thermodynamic) solubility of drugs, but the basic approach has remained the saturation shake-flask method. Any new solubility method has to be validated compairing with the shake-flask procedure however this later is lack of standardization itself. In this lecture I summary the experiences were obtained during a study of standardization of shake-flask method.

The hydrochlorothiazide was chosen as the model compound for this work, because of its favorable properties. This substance is ionizable, sparingly soluble in water and chemically stable; it has intensive UV absorbance and no polymorphism. During the experiment we modified the following parameters to examine their effect on solubility data:
- composition of the aqueous buffer
- amount of solid excess
- temperature
- saturation time
- sedimentation time
- the method of separation of the phases

My talk presents the experimental results. Some of the examined parameters caused significant variation in solubility data. We observed that the amount of solid excess did not cause any change in the results. However, the thermodynamic solubility is strongly depending on the temperature and the sedimentation time. The other parameters caused only slight variance of the solubility results.

Based on these results a “new protocol” has been suggested for the shake-flask method, which requires shorter experimental time.

Sponsored by ACD/Labs

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Last modified: 28 April 2008