Fine Dosage of Antisolvent in the Crystallization of L-Histidine: effect on Polymorphism

In this work, the antisolvent membrane crystallization process has been used to influence the polymorphic composition in the crystallization of L-histidine. When finely dosing the amount of ethanol in the crystallizing solution, by generating the proper trans-membrane flux, the composition of the precipitate shifts regularly from the prevalence of the thermodynamic stable polymorph A toward the predominance of the metastable phase B. Form A crystals are always the first to nucleate, thus following an “anti-Ostwald rule” behavior and in accordance with classical nucleation theory previsions. However, as the antisolvent content exceeds a threshold limit, the number of phase A crystals progressively reduces and the first weak nucleation is followed by a second massive production of a powder of the polymorph B. The elapsed time between the two events reduces as the antisolvent dosing flux increases. This result might be due to a combined effect on the nucleation and growth rates when the amount of ethanol exceeds the critical value. No significant membrane fouling was observed over the duration of the experiments, and stable fluxes were observed. A slight increase in membrane permeability, due to the reduced hydrophobicity when using a high initial amount of ethanol, was observed.