Towards the determination of the solubilities of the two enantiotropically related crystallographic forms of etiracetam in methanol

This contribution focuses on the presentation and the comparison of five experimental methods for the determination of the solubilities of the two enantiotropically related crystallographic forms of etiracetam (racemic intermediate to the synthesis of leviteracetam, Keppra, UCB Pharma) in methanol. The five experimental methods can be divided into two sets of methods, depending on whether the method is isothermal or whether the temperature varies during the experiment. The results show that the most accurate and reliable determination of the solubility curves of the two crystallographic forms is obtained when combining the different methods. Using a single method limits the amount of information gained, does not allow for a verification of the obtained data, and can even limit the range for which solubility data can be experimentally determined. The results allow distinguishing the solubilities of the stable and the metastable forms and hence confirming the enantiotropic relationship of the two crystallographic forms. The transition temperature is determined to be equal to 30 °C, which confirms previous findings. © 2011 American Chemical Society.