Equilibrium solubility measurement of ionizable drugs – consensus recommendations for improving data quality

Abstract

This commentary addresses data quality in equilibrium solubility measurement in aqueous solution. Broadly discussed is the "gold standard" shake-flask (SF)

Dissolution rate of ciprofloxacin and its cocrystal with resorcinol

“…CIP is positively charged at low pH values, and its ionization degree decreases as pH increases. The maximum percentage of zwitterionic form and neutral forms exist at pH 7.3, where CIP has a log S 0 around -3.7 (-3.62 [18], -3.72 [19], and -3.76 measured in this work by the shake-flask method according to [20]). At higher pH values, ionization degree rises again due to the deprotonation of the basic group.…”

Harmonizing solubility measurement to lower inter-laboratory variance – progress of consortium of biopharmaceutical tools (CoBiTo) in Japan

“…Incubation time. The incubation time should be set to > 24 h to achieve equilibrium [28,[41][42][43]. If possible, the concentration should be measured over time to ensure achieving equilibrium, for example at 1, 6, and 24 h [24].…”

Solubility-pH profiles of a free base and its salt: sibutramine as a case study

“…The solubility-pH profiles of sibutramine (free base) and its hydrochloride salt have been determined at 25 o C in the pH range between 2.0 and 9.5 by means of the shake-flask method using the recommended protocol [2]. Briefly, a mass spectrometry-friendly minimalist universal buffer (MS-MUB) consisting of 25 mM acetic acid, 25 mM ethylenediamine, and 75 mM trifluoroacetic acid (TFA) was used, incubation was carried out for 48 h (24 h stirring and 24 h sedimentation), pH was measured after 4 h of stirring and readjusted if necessary with sodium hydroxide or hydrochloric acid, and finally the pH was measured again before the phase separation by centrifugation.…”