Structure Determination and 3D ED/MicroED-Guided Synthesis of a New (S)-Ibuprofen–l-phenylalanine Co-Crystal

Abstract

Pharmaceutical cocrystals are of interest to the pharmaceutical industry due to their novel potential for improving the physicochemical characteristics of old APIs. However, cocrystal screening and following synthetic optimization consume time and effort. A two-component crystalline phase of (S)-ibuprofen and l-phenylalanine with 2:3 stoichiometry (Ibu-Phe) is reported. High-quality Ibu-Phe cocrystal was synthesized easily by the liquid-assisted grinding (LAG) method, but some impurities remained. The crystal structure of Ibu-Phe can be solved ab initio from 3D ED/MicroED. Furthermore, a nearly pure Ibu-Phe cocrystal sample can be obtained under the guidance of stoichiometry from 3D ED/MicroED following synthesis optimization in a few attempts.