MicroED empowered smaller crystal structure determination of pharmaceutical solids

The atomic-level crystal structure is crucial in determining the physicochemical characteristics of pharmaceutical solids; therefore, accurate crystal structure determination is essential for pharmaceutical development. Many active pharmaceutical ingredients (APIs) and multi-component systems exist only as micro or nanocrystalline material, which limits the applicability of conventional single-crystal X-ray diffraction. Co-crystals, which offer a multitude of pharmaceutical and biopharmaceutical upper edge are a major part of these multi-component systems and face the issue that they are obtained in micron-sized crystals. Recent progress in three-dimensional electron diffraction (3DED) has addressed this challenge by enabling structure determination from tiny crystals. This review delves into the relationship between atomic-level structure and physicochemical properties of pharmaceuticals, highlighting how MicroED (Microcrystal Electron Diffraction) enables atomic-resolution structure determination from sub-micron crystals. Primary applications include polymorph identification and characterization, structural analysis of pharmaceutical co-crystals, and the detection of trace or hidden crystallinity in materials previously classified as amorphous. In addition, this review features representative case studies demonstrating the successful application of MicroED to pharmaceutical solids and emphasizes its integration with complementary analytical methods such as Raman spectroscopy, Solid-state NMR, and Powder X-ray diffraction (PXRD). The authors have discussed in detail how MicroED is an effective approach for solid-state characterisation, supporting early-stage decision-making, quality control, and systematic solid form development in pharmaceuticals. Authors have emphasized and provide detailed explanation how MicroED is going to be a game changer once it becomes easily accessible to pharmaceutical scientists.