RESUMEN
We review the use of transmission electron microscopy (TEM) and associated techniques for the analysis of beam-sensitive materials and complex, multiphase systems in-situ or close to their native state. We focus on materials prone to damage by radiolysis and explain that this process cannot be eliminated or switched off, requiring TEM analysis to be done within a dose budget to achieve an optimum dose-limited resolution. We highlight the importance of determining the damage sensitivity of a particular system in terms of characteristic changes that occur on irradiation under both an electron fluence and flux by presenting results from a series of molecular crystals. We discuss the choice of electron beam accelerating voltage and detectors for optimizing resolution and outline the different strategies employed for low-dose microscopy in relation to the damage processes in operation. In particular, we discuss the use of scanning TEM (STEM) techniques for maximizing information content from high-resolution imaging and spectroscopy of minerals and molecular crystals. We suggest how this understanding can then be carried forward for in-situ analysis of samples interacting with liquids and gases, provided any electron beam-induced alteration of a specimen is controlled or used to drive a chosen reaction. Finally, we demonstrate that cryo-TEM of nanoparticle samples snap-frozen in vitreous ice can play a significant role in benchmarking dynamic processes at higher resolution. This article is part of a discussion meeting issue 'Dynamic in situ microscopy relating structure and function'.
RESUMEN
Crystal engineering has advanced the strategies for design and synthesis of organic solids with the main focus being on customising the properties of the materials. Research in this area has a significant impact on large-scale manufacturing, as industrial processes may lead to the deterioration of such properties due to stress-induced transformations and breakage. In this work, we investigate the mechanical properties of structurally related labile multicomponent solids of carbamazepine (CBZ), namely the dihydrate (CBZ·2H2O), a cocrystal of CBZ with 1,4-benzoquinone (2CBZ·BZQ) and the solvates with formamide and 1,4-dioxane (CBZ·FORM and 2CBZ·DIOX, respectively). The effect of factors that are external (e.g. impact stressing) and/or internal (e.g. phase transformations and thermal motion) to the crystals are evaluated. In comparison to the other CBZ multicomponent crystal forms, CBZ·2H2O crystals tolerate less stress and are more susceptible to breakage. It is shown that this poor resistance to fracture may be a consequence of the packing of CBZ molecules and the orientation of the principal molecular axes in the structure relative to the cleavage plane. It is concluded, however, that the CBZ lattice alone is not accountable for the formation of cracks in the crystals of CBZ·2H2O. The strength and the temperature-dependence of electrostatic interactions, such as hydrogen bonds between CBZ and coformer, appear to influence the levels of stress to which the crystals are subjected that lead to fracture. Our findings show that the appropriate selection of coformer in multicomponent crystal forms, targetting superior mechanical properties, needs to account for the intrinsic stress generated by molecular vibrations and not solely by crystal anisotropy. Structural defects within the crystal lattice, although highly influenced by the crystallisation conditions and which are especially difficult to control in organic solids, may also affect breakage.
RESUMEN
In the pharmaceutical industry, it is important to determine the effects of crystallisation and processes, such as milling, on the generation of crystalline defects in formulated products. Conventional transmission electron microscopy and scanning transmission electron microscopy (STEM) can be used to obtain information on length scales unobtainable by other techniques, however, organic crystals are extremely susceptible to electron beam damage. This work demonstrates a bright field (BF) STEM method that can increase the information content per unit specimen damage by the use of scanning moiré fringes (SMFs). SMF imaging essentially provides a magnification of the crystal lattice through the interference between closely aligned lattice fringes and a scanning lattice of similar spacing. The generation of SMFs is shown for three different organic crystals with varying electron beam sensitivity, theophylline, furosemide and felodipine. The electron fluence used to acquire the BF-STEM for the most sensitive material, felodipine was approximately 3.5â¯e-/Å2. After one additional scan of felodipine (total fluence of approximately 7.0â¯e-/Å2), the SMFs were no longer visible due to extensive damage caused to the crystal. Irregularity in the SMFs suggested the presence of defects in all the organic crystals. Further effort is required to improve the data analysis and interpretation of the resulting SMF images, allowing more information regarding the crystal structure and defects to be extracted.