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PANEL10The same compound can crystallize with more than one structure. It is the same molecule but it stacks in space in various different forms, creating different crystalline structures. They are called polymorphs, and the phenomenon is known as polymorphism. It is of vital importance. Each one of these polymorphs has their own diffraction pattern: they each have a different identity card. And what is yet more important, their physical and chemical properties are different. We are talking about graphite and diamond, aragonite and calcite, but also about chocolates and drugs.

The same molecule can crystallize in various different forms. A simple example will help you understand. Let’s make a crystal whose unit cells are coins. We can do so in two different ways. In other words, with two different structures:


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A square structure (on the right) and a hexagonal structure (on the left). The different structures that the same chemical compound can crystallize into are called polymorphs. Despite having the same composition – in this case coins – they have different properties. To the naked eye we can observe that the hexagonal structure is denser (the coins leave smaller gaps in between each other) than the square structure.

Graphite and Diamond

In the world of real crystals, this structural difference is highly important. For example, carbon crystallizes into two polymorphs that the whole world knows: the diamond, which has a cubic structure, and graphite, a layered hexagonal structure.

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Structure of diamond. Structure of graphite.

The properties of both crystals are very different. Diamond has all the carbon atoms interlinked by covalent crystals, which makes it an extremely hard material, the hardest known. Graphite, however, has a layered structure. The bonds within the layers are identical to those in the diamond. Nevertheless, the bonds between the carbon atoms between the layers are much weaker. This makes graphite a soft material, because when we press it, for example onto paper, the layers separate and stick to the paper. Obviously you know that this is why the lead of a pencil is actually graphite.


The main component of chocolate is cocoa butter, the fatty acid of cacao, crystallized. The molecules of the cacao fatty acid can crystallize into six different structures – six polymorphs. Each cacao fatty acid polymorph has a different melting point:


Chocolates with polymorphs from I to IV, with lower melting points, melt very easily, making it difficult to remove them from their packaging and they stain our fingers when holding them. Chocolate crystallized from polymorph VI has the aspect of that whitish crystalline powder that with time “blooms” when the chocolate is exposed to sudden changes of temperature – it recrystallizes. Polymorph V, with a melting point of 33.8, is the one that must be obtained so that the chocolate melts slowly and pleasantly in the mouth.

Polymorphism is of extraordinary importance to the pharmaceutical industry. In many cases, the same drug crystallizes with different structures, in different polymorphs. For example, at least 67% of steroids, 40% of sulphonamides, and 63% of barbiturates form polymorphs.

The molecule, which is the active compound, is the same in the different polymorphs, and when we take a drug it dissolves. So why is polymorphism an issue? Because, as you already know, the properties of each polymorph are different. Stability, solubility, dissolving speed and bioavailability depend on the polymorph into which the drug crystallizes. Controlling polymorphic crystallization is crucial for every pharmaceutical company.

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A typical example of this problem is the case of Norvir, a drug (on the left) for treating patients infected with human immunodeficiency virus type 1, which acts by inhibiting the protease (on the right). Crystallized with a structure that was believed unique, after several years on the market some batches did not pass the solubility tests. It was discovered that during the production process the drug had crystallized with a more stable structure that dissolved more slowly. The product had to be withdrawn from the market, new formulas re-patented, the crystallization studied and the whole production process redesigned, which meant losses of millions for the company.

Sometimes the consequences of a polymorphic transition can be catastrophic, such as in the case of the polymorphic transformations of ammonium nitrate. Or they can be economically important, as in the case of calcium carbonate or of gypsum. For we still do not know how to control polymorphic crystallization, whether that of ritonavir, ammonium nitrate, calcium carbonate or many other compounds.

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However, life itself knows how to do so with enviable precision. Bird eggshells are always made of calcite, a polymorph of calcium carbonate. Reptile eggshells are always aragonite, another polymorph of calcium carbonate. Furthermore, in mollusc shells like those of Haliotis (abalone), life knows how to precipitate nacre (mother-of-pearl) with an aragonite structure just a few microns from the outer layers of calcite.





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