A picture tells a thousand words…
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The successful development and commercialization of an active pharmaceutical ingredient (API) requires not only adequate bioavailability and stability but also ´processability´.  Traditionally the focus in drug discovery and development has been on potency and toxicity whilst physical properties have taken less of a priority.  Since the turn of the century there is, however, a growing awareness that poor physical and material properties can be a significant contributor to the failure of new drug products.

Today it is common practice to study the physical form of an API in relation to its biopharmaceutical performance and to do so early on in development.  Researchers evaluate crystalline versus amorphous states and complexes such as salts, co-crystals and hydrates against the free form of the compound in relation to the bioavailability and safety profile of the drug substance.  These experiments have to do with the transition of the drug from its inactive solid state into the biologically active molecular dissolved state.  A lack of attention on the physical properties of a molecule and its formulation and production possibilities (and limitations) early on in development leaves the development company with potential fatal flaws at a later stage.

The study and characterization of polymorphs uses a plethora of analytical techniques.  Most of these techniques, such as thermal analysis (DSC and TGA), spectroscopic characterizations (IR, Raman, solution and solid state NMR) and X-ray crystallography investigate inter and intra molecular interactions.  Only few techniques are available that investigate the particles at a macro scale.  In general, equidimensional crystals are preferred as they have better handling and processing characteristics such as flowability and compactability (tabletting).

Hot Stage Microscopy and Polarized Light Microscopy (Figure 1) shed some light on specific thermal events and crystal shape and habit and the latter has a profound impact on the processability and formulation properties of a pharmaceutical compound.

Figure 1. Polarized light microscopy image of needle like shaped crystals of an API

In contrast to the light microscopy which provides limited information, Scanning Electron Microscopy (SEM) is an accessible and affordable technique which provides quick and detailed results on properties such as particle size, shape and habit.  Different polymorphs often display a different habit which results in a significantly different particle shape.  As demonstrated in Figure 2, light microscopy may not provide enough detail to clearly demonstrate the differences.  The differences between both forms of the same API become very clear in the SEM images.  Not only can various polymorphs or pseudo polymorph result in different particle habit, but also, the same polymorph obtained from different crystallization solvents may lead to differences, as demonstrated in Figure 3.

Figure 2. Comparison of light microscopy and SEM images of the anhydrous and hydrated forms of the same API.  Top pictures show the anhydrous form with the light microscopy image on the left and the SEM image on the right.  The bottom pictures are the monohydrated form with light microscopy image on the left and SEM image on the right

Figure 3. Comparison of SEM images taken from material crystallized from anisole (top) and butyl acetate/tetrahydrofuran (bottom).  XRPD analysis of the material confirmed that both solids represented Form 1 and were non-solvated and anhydrous

Solid form investigations are usually initiated at the start of the pre-clinical development phase.  SEM images taken at this stage provides important information which together with other physical chemical properties enable an informed decision on which form is most suited to proceed with.