The seventh blind test of crystal structure prediction: structure generation methods.

A seventh blind test of crystal structure prediction was organized by the Cambridge Crystallographic Data Centre featuring seven target systems of varying complexity: a silicon and iodine-containing molecule, a copper coordination complex, a near-rigid molecule, a cocrystal, a polymorphic small agrochemical, a highly flexible polymorphic drug candidate, and a polymorphic morpholine salt. In this first of two parts focusing on structure generation methods, many crystal structure prediction (CSP) methods performed well for the small but flexible agrochemical compound, successfully reproducing the experimentally observed crystal structures, while few groups were successful for the systems of higher complexity. A powder X-ray diffraction (PXRD) assisted exercise demonstrated the use of CSP in successfully determining a crystal structure from a low-quality PXRD pattern.

Cocrystal Synthesis through Crystal Structure Prediction.

Crystal structure prediction (CSP) is an invaluable tool in the pharmaceutical industry because it allows to predict all the possible crystalline solid forms of small-molecule active pharmaceutical ingredients. We have used a CSP-based cocrystal prediction method to rank ten potential cocrystal coformers by the energy of the cocrystallization reaction with an antiviral drug candidate, MK-8876, and a triol process intermediate, 2-ethynylglyclerol. For MK-8876, the CSP-based cocrystal prediction was performed retrospectively and successfully predicted the maleic acid cocrystal as the most likely cocrystal to be observed.

Absolute Configuration Determination of Chiral API Molecules by MicroED Analysis of Cocrystal Powders Formed Based on Cocrystal Propensity Prediction Calculations.

Establishing the absolute configuration of chiral active pharmaceutical ingredients (APIs) is of great importance. Single crystal X-ray diffraction (scXRD) has traditionally been the method of choice for such analysis, but scXRD requires the growth of large crystals, which can be challenging. Here, we present a method for determining absolute configuration that does not rely on the growth of large crystals.

Selecting a stable solid form of remdesivir using microcrystal electron diffraction and crystal structure prediction.

Therapeutic options in response to the coronavirus disease 2019 (COVID-19) outbreak are urgently needed. In this communication, we demonstrate how to support selection of a stable solid form of an antiviral drug remdesivir in quick time using the microcrystal electron diffraction (MicroED) technique and a cloud-based and artificial intelligence implemented crystal structure prediction platform. We present the MicroED structures of remdesivir forms II and IV and conclude that form II is more stable than form IV at ambient temperature in agreement with experimental observations.

Virtual Coformer Screening by Crystal Structure Predictions: Crucial Role of Crystallinity in Pharmaceutical Cocrystallization.

One of the most popular strategies of the optimization of drug properties in the pharmaceutical industry appears to be a solid form changing into a cocrystalline form. A number of virtual screening approaches have been previously developed to allow a selection of the most promising cocrystal formers (coformers) for an experimental follow-up. A significant drawback of those methods is related to the lack of accounting for the crystallinity contribution to cocrystal formation.

Helium in-plane migration behavior on 〈1 0 0〉 symmetric tilt grain boundaries in tungsten.

We present the results of an atomistic modeling study of small helium cluster migration in the plane of symmetric tilt grain boundaries. The relevant migration pathways and energies were determined by way of temperature accelerated dynamics and the nudged elastic band method. We find that small helium clusters show much higher migration energies when bound to the grain boundary than in the bulk for all types of grain boundaries, indicating strongly-impeded helium transport behavior.