Antisolvent Crystallization of the Polymorphs of l-Histidine as a Function of Supersaturation Ratio and of Solvent Composition

During the antisolvent crystallization of l-histidine from aqueous solution with the antisolvent ethanol, the polymorphic fraction of the metastable polymorph B increased with increasing supersaturation ratio. For supersaturation ratio SA ≤ 2.0, a mixture of the stable polymorph A and the metastable polymorph B was obtained, while for high supersaturation, SA ≥ 2.3, only form B was observed. The supersaturation ratio was increased either by increasing the l-histidine concentration in the aqueous solution or by increasing the ethanol volume fraction. The induction time for the antisolvent crystallization was one to several orders of magnitude smaller than the time to transform the metastable polymorph B into stable polymorph A in solution, indicating that both polymorphs formed simultaneously. Process simulation of the batch antisolvent crystallization of the polymorphs of l-histidine was applied to predict the outcome of the competition between heterogeneous nucleation and polynuclear growth rates for both polymorphs. When the interfacial energy was calculated as a function of the solubility, only the formation of the stable polymorph A was erroneously predicted. By modification of the relative interfacial energy and the relative step free energy, the predicted polymorphic fraction could be directed toward the observed polymorphic fraction.