The present disclosure provides methods of collecting electron diffraction patterns from nanocrystals to obtain a three-dimensional structural model of a compound, as well as methods of identifying compounds and methods of determining polymorphic forms. In addition, the present disclosure provides methods of characterizing a first compound from a sample, as well as methods of screening compounds from a sample. The present disclosure also provides systems for characterizing a compound from a sample, which systems include modules for high-performance liquid chromatography, dispensing, and electron microscopy.

Methods and systems for conducting tomographic imaging microscopy of a sample with a high energy charged particle beam include irradiating a first region of the sample in a first angular position with a high energy charged particle beam and detecting emissions resultant from the charged particle beam irradiating the first region. The sample is repositioned into a second angular position such that the second region to be different than the first region, and a second region of the sample is irradiated. Example repositioning may include one or more of a translation of the sample, a helical rotation of the sample, the sample being positioned in a non-eucentric position, or a combination thereof. Emissions resultant from irradiation of the second region are then detected, and a 3D model of a portion of the sample is generated based at least in part on the detected first emissions and detected second emissions.

Molecular structure of a crystal may be solved based on at least two diffraction tilt series acquired from a sample. The two diffraction tilt series include multiple diffraction patterns of at least one crystal of the sample acquired at different electron doses. In some examples, the two diffraction tilt series are acquired at different magnifications.

Crystallographic information of crystalline sample can be determined from one or more three-dimensional diffraction pattern datasets generated based on diffraction patterns collected from multiple crystals. The crystals for diffraction pattern acquisition may be selected based on a sample image. At a location of each selected crystal, multiple diffraction patterns of the crystal are acquired at different angles of incidence by tilting the electron beam, wherein the sample is not rotated while the electron beam is directed at the selected crystal.

A method for correcting distortion in a coherent electron diffraction imaging (CEDI) image induced by a projection lens makes use of a known secondary material that is imaged together with a sample of interest. Reflections generated from the secondary material are located in the image, and these observed reflections are used to approximate a beam center location. Using a known lattice structure of the secondary material, Friedel pairs are located in the image and unit cell vectors are identified. Predicted positions for each of the secondary material reflections are then determined, and the position differences between the observed reflections and the predicted reflections are used to construct a relocation function applicable to the overall image. The relocation function is then used to adjust the position of image components so as to correct for the distortion.

Methods and systems for conducting tomographic imaging microscopy of a sample with a high energy charged particle beam include irradiating a first region of the sample in a first angular position with a high energy charged particle beam and detecting emissions resultant from the charged particle beam irradiating the first region. The sample is repositioned into a second angular position such that the second region to be different than the first region, and a second region of the sample is irradiated. Example repositioning may include one or more of a translation of the sample, a helical rotation of the sample, the sample being positioned in a non-eucentric position, or a combination thereof. Emissions resultant from irradiation of the second region are then detected, and a 3D model of a portion of the sample is generated based at least in part on the detected first emissions and detected second emissions.

Dynamic band contrast image (DBCI) is constructed with scattering patterns acquired at multiple scanning locations of a sample using a charged particle beam. Each pixel of the DBCI is generated by integrating the corresponding scattering pattern along a diffraction band. The DBCI includes charged particle channeling condition and can be used for detecting sample defects.

A method includes accelerating an electron bunch along a direction of propagation to a relativistic energy and partitioning the electron bunch by transmitting the electron bunch through a grating at the relativistic energy. The grating includes a plurality of alternating narrow portions and wide portions. The narrow portions have a first thickness in a direction substantially parallel to the direction of propagation of the electron bunch, and the wide portions have a second thickness in the direction substantially parallel to the direction of propagation of the electron bunch. The second thickness is greater than the first thickness. The method also includes generating a pulse of light using the partitioned electron bunch.

A method includes accelerating an electron bunch along a direction of propagation to a relativistic energy and partitioning the electron bunch by transmitting the electron bunch through a grating at the relativistic energy. The grating includes a plurality of alternating narrow portions and wide portions. The narrow portions have a first thickness in a direction substantially parallel to the direction of propagation of the electron bunch, and the wide portions have a second thickness in the direction substantially parallel to the direction of propagation of the electron bunch. The second thickness is greater than the first thickness. The method also includes generating a pulse of light using the partitioned electron bunch.

Crystallographic information of crystalline sample can be determined from one or more three-dimensional diffraction pattern datasets generated based on diffraction patterns collected from multiple crystals. The crystals for diffraction pattern acquisition may be selected based on a sample image. At a location of each selected crystal, multiple diffraction patterns of the crystal are acquired at different angles of incidence by tilting the electron beam, wherein the sample is not rotated while the electron beam is directed at the selected crystal.