The Interpretation of Scanning Electron Microscopy for Solid State Application
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Scanning Electron Microscopy (SEM) can be a powerful tool in the study of the physical form of an Active Pharmaceutical Ingredient (API). It can be used to determine the shape of the crystal. Equidimensional crystals usually have better handling and processing characteristics such as flowability and compactability (tabletting). The crystals in Figure 1 are in fact polymorphs of the same API. In this case it would, therefore, be possible to determine which polymorph is formed in the crystallization process. SEM imaging can also reveal when two polymorphs have been crystallized simultaneously and it allows the estimation of the ratio of the polymorphs.

Figure 1.  Two SEM pictures of the same compound crystallized in two different polymorphs with a different crystal habit.


Two different batches of the same API crystallized as the same polymorph are seen in Figure 2. The differences between the two batches are rather obvious. Batch α consisting of well developed crystals with flat faces and sharp angles and the Particle Size Distribution (PSD) appears to be rather narrow when examining the picture. Batch β, on the other hand, appears to have a rather broad PSD, including a large number of very small particles. The PSD was determined by laser diffraction in suspension and the impression given by the SEM images was confirmed. Determination of the PSD using SEM images can be an alternative to the determination of the PSD by laser diffraction in suspension, especially when the analyzed compound has the tendency to form agglomerates in solution.

Figure 2.  SEM images of different batches of the same polymorph. Crystal quality of different batches and PSD can be assessed using SEM. The small pictures show the corresponding PSD distribution of the batches determined by laser diffraction in solution.


The crystal surface contains information about the quality of the crystal and the crystallization process. Picture A of Figure 3 shows etching holes which occur when the crystal was exposed to an undersaturated solution. When crystallization occurs at high supersaturation the surface can be rough and the crystals become round, as seen in picture B. An example of an API crystal is shown in Picture F. The growth steps result in a layered structure of the crystal. Phenomena as the growth steps (C+D) and the growth spiral (E) indicate that the crystal growth happened at conditions allowing the crystal to grow slowly. Slow growth leads, next to visible growth steps and spirals, to well developed crystals consisting of flat faces with sharp angles. Well developed, slowly grown crystals tend to contain less impurities or residual solvent.

Figure 3.  Different patterns that can be found on the crystal surface using SEM imaging. A - etching holes; B - coarsening of a crystal with loss of crystal facets and a rough surface; C - Growth steps on a flat crystal surface; D - trigonal growth step on natural diamond; E - growth spiral on a flat crystal surface; F - Layers and growth steps observed on a API crystal.