Computational and Experimental Screening Approaches to Aripiprazole Salt Crystallization

Abstract

Introduction: The screening of multicomponent crystal system (MCC) is a key method for improving physicochemical properties of active pharmaceutical ingredients (APIs). The challenges associated with experimental salt screening include a large number of potential counterions and solvent systems and tendency to undergo disproportionation to produce free form during crystallization. These challenges may be mitigated by a combination of experimental and computational approaches to salt screening. The goal of this study is to evaluate performance of the counterion screening methods and propose and validate novel approaches to virtual solvent screening for MCC crystallization.

Methods: The actual performance of the ΔpK_a > 3 rule for counterion selection was validated using multiple screenings reports. Novel computational models for virtual solvent screening to avoid MCC incongruent crystallization were proposed. Using the ΔpK_a rule, 10 acid counterions were selected for experimental aripiprazole (APZ) salt screening using 10 organic solvents. The experimental results were used to validate the proposed novel virtual solvent screen models.

Results: Experimental APZ salt screening resulted in a total of eight MCCs which included glucuronate, mesylate, oxalate, tartrate, salicylate and mandelate. The new model to virtually screen solvents provided a general agreement with APZ experimental findings in terms of selecting the optimal solvent for MCC crystallization.

Conclusion: The rational selection of counterions and organic solvents for MCC crystallization was presented using combined novel computational model as well as experimental studies. The current virtual solvent screen model was successfully implemented and validated which can be easily applied to newly discovered APIs.

Keywords: crystallization; modeling; multicomponent crystals; salt screening; virtual screening.