Everything about Polymorphism Materials Science totally explained
Polymorphism in
materials science is the ability of a solid material to exist in more than one form or
crystal structure. Polymorphism can potentially be found in any crystalline material including
polymers,
minerals, and
metals, and is related to
allotropy, which refers to
elemental solids. Together with polymorphism the complete morphology of a material is described by other variables such as
crystal habit,
amorphous fraction or
Crystallographic defects. Polymorphism is relevant to the fields of
pharmaceuticals,
agrochemicals,
pigments,
dyestuffs,
foods, and
explosives.
When polymorphism exists as a result of difference in crystal packing, it's called
packing polymorphism. Polymorphism can also result from the existence of different
conformers of the same molecule in
conformational polymorphism. In
pseudopolymorphism the different crystal types are the result of
hydration or
solvation. An example of an organic polymorph is
glycine, which is able to form
monoclinic and
hexagonal crystals.
Silica is known to form many polymorphs, the most important of which are;
α-quartz,
β-quartz,
tridymite,
cristobalite,
coesite, and
stishovite.
An analogous phenomenon for
amorphous materials is
polyamorphism, when a substance can take on several different amorphous modifications.
Background
In terms of thermodynamics, there are two types of polymorphism. For a monotropic system, a plot of the free energy of the various polymorphs against temperature don't cross before all polymorphs melt - in other words, any transition from one polymorph to another will be irreversible. For an enantiotropic system, a plot of the free energy against temperature shows a crossing point before the various melting points, and it may be possible to convert reversibly between the two polymorphs on heating and cooling.
The first observation of this property is attributed to
Friedrich Wöhler and
Justus von Liebig when in 1832 they examined a boiling solution of
benzamide: on cooling the benzamide initially crystallised as silky needles but on standing these were slowly replaced by rhombic crystals. Present-day analysis identifies three polymorphs for benzamide: the least stable one, formed by flash cooling is the
monoclinic form II. This type is followed by the
centrosymmetric form III (observed by Wöhler/Liebig) in which
aromatic stacking is the dominant feature. The most stable form is
monoclinic form I which is optimized for
hydrogen bonding.
Despite the potential implications, polymorphism isn't always well understood. In 2006 a new crystal form was discovered of
maleic acid 124 years after the first crystal form was studied. Maleic acid is a chemical manufactured on a very large scale in the chemical industry and is a salt forming component in medicine. The new crystal type is produced when a
caffeine - maleic acid co-crystal (2:1) is dissolved in
chloroform and when the solvent is allowed to evaporate slowly. Whereas form I has
monoclinic space group P2
1/
c, the new form has space group
Pc. Both polymorphs consist of sheets of molecules connected through
hydrogen bonding of the
carboxylic acid groups; but, in form I, the sheets alternate with respect of the net
dipole moment, whereas, in form II, the sheets are oriented in the same direction.
1,3,5-Trinitrobenzene is more than 125 years old and was used as an explosive before the arrival of the safer
2,4,6-trinitrotoluene. Only one crystal form of 1,3,5-trinitrobenzene has been known in the space group
Pbca. In 2004, a second polymorph was obtained in the space group
Pca2
1 when the compound was crystallized in the presence of an additive, trisindane. This experiment shows that additives can induce the appearance of polymorphic forms.
Ostwald's rule
Ostwald's rule or
Ostwald's step rule
conceived by
Wilhelm Ostwald states that in general it isn't the most stable but the least stable polymorph that crystallizes first. See for examples the aforementioned benzamide,
dolomite or
phosphorus, which on sublimation first forms the less stable white and then the more stable red allotrope.
Ostwald suggested that the solid first formed on crystallization of a solution or a melt would be the least stable polymorph. This can be explained on the basis of irreversible thermodynamics, structural relationships, or a combined consideration of statistical thermodynamics and structural variation with temperature. Ostwald's rule isn't a universal law but is only a possible tendency in nature.
Polymorphism in pharmaceuticals
Polymorphism is important in the development of
pharmaceutical ingredients. Many
drugs receive
regulatory approval for only a single crystal form or polymorph. In a classic
patent case the pharmaceutical company
GlaxoSmithKline defended its patent for the polymorph type II of the active ingredient in
Zantac against competitors while that of the polymorph type I'd already expired. Polymorphism in drugs can also have direct medical implications.
Medicine is often administered orally as a crystalline solid and
dissolution rates depend on the exact crystal form of a polymorph.
Cefdinir is a drug appearing in 11 patents from 5 pharmaceutical companies in which a total of 5 different polymorphs are described. The original inventor
Fuijsawa now
Astellas (with US partner
Abbott) extended the original patent covering a
suspension with a new
anhydrous formulation. Competitors in turn patented
hydrates of the drug with varying water content, which were described with only basic techniques such as
infrared spectroscopy and
XRPD, a practice criticized by in one review because these techniques at the most suggest a different crystal structure but are unable to specify one. These techniques also tend to overlook chemical impurities or even co-components. Abbott researchers realized this the hard way when, in one patent application, it was ignored that their new cefdinir crystal form was, in fact, that of a
pyridinium salt. The review also questioned whether the polymorphs offered any advantages to the existing drug: something clearly demanded in a new patent.
Acetylsalicylic acid elusive 2nd polymorph was first discovered by Vishweshwar et al., fine structural details were given by Bond et al. A new crystal type was found after attempted co-crystallization of aspirin and
levetiracetam from hot
acetonitrile. The form II is stable only at 100
K and reverts back to form I at ambient temperature. In the (unambiguous) form I, two salicylic molecules form centrosymmetric
dimers through the
acetyl groups with the (acidic)
methyl proton to
carbonyl hydrogen bonds, and, in the newly-claimed form II, each salicylic molecule forms the same hydrogen bonds, but then with two neighboring molecules instead of one. With respect to the hydrogen bonds formed by the
carboxylic acid groups, both polymorphs form identical dimer structures.
Trivia
Walter McCrone stated that
every compound has different polymorphic forms, and that, in general, the number of forms known for a given compound is proportional to the time and money spent in research on that compound.
Crystal Polymorphs can disappear. There have been cases of individual laboratories growing one crystal form. They then grow a different crystal form, and are unable to make the first form again. Also, they find that they can make the first form again, but it now converts to the second form over time. The drug
Paroxetine was subject to a law suit that hinged on such a pair of polymorphs (A link to a discussion of cases in Canada and the US has been given below). An example is known when a so-called 'disappeared' polymorph re-appeared after 40 years. These so-called 'disappearing' polymorphs are probably metastable kinetic forms.
Further Information
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