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 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 is 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.
An analogous phenomenon for amorphous materials is polymorphism, 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 do not 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 [1] 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
[2] 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 is not always well understood. In 2006 a new crystal form was discovered of
maleic acid 124 years after the first crystal structure determination [3]. 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 P21/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
Pca21 when the compound was crystallized in the presence of an additive, trisindane. This experiment shows that
additives can induce the appearance of polymorphic forms. [4]
Ostwald's rule
Ostwald's rule or Ostwald's step rule conceived by Wilhelm Ostwald
states that in general it is not the most stable but the least stable polymorph that crystallizes first. See for examples the
aforementioned benzamide, dolomite or phosphorous which on
sublimation first forms the less stable white and then the more stable red allotrope.
Polymorphism in pharmaceuticals
Polymorphism is important in the development of pharmaceutical ingredients. Many
drugs are receiving 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 had 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 importantly only described with basic techniques such as infrared spectroscopy and XRPD, a practise criticised
by in one review [5] 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.
[6], fine structural details were given by Bond et al.
[7] A new crystal type was found after attempted
co-crystallization of aspirin and levetiracetam from hot acetonitrile. The form II is only stable 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. Alternatively, 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.
References
- ^ F. Wöhler, J. Liebig, Ann. Pharm. 1832, 249 – 282.
- ^ Polymorphism in Benzamide: Solving a 175-Year-Old Riddle Jorgen
Thun, Lena Seyfarth, Jorgen Senker, Robert E. Dinnebier, and Josef Breu Angew. Chem. Int.
Ed. 2007, 46, 6729 –6731 doi:10.1002/anie.200701383
- ^ Graeme M. Day, Andrew V. Trask, W. D.
Samuel Motherwell and William Jones (2006). "Investigating the latent polymorphism of maleic acid". Chemical Communications 1: 54 - 56. DOI:10.1039/b513442k.
- ^ Thallapally PK, Jetti RKR, Katz AK (2004).
"Polymorphism of 1,3,5-trinitrobenzene induced by a trisindane additive". Angewandte
Chemie International Edition 43 (9): 1149-1155.
- ^ Polymorphisms and Patent, Market, and Legal Battles: Cefdinir Case
Study Walter Cabri, Paolo Ghetti, Giovanni Pozzi, and Marco Alpegiani Org. Process Res. Dev.; 2007; 11(1) pp 64 - 72;
(Review) doi:10.1021/op0601060
- ^ Peddy Vishweshwar, Jennifer A. McMahon,
Mark Oliveira, Matthew L. Peterson, and Michael J. Zaworotko (2005). "The Predictably Elusive Form II of Aspirin".
J. Am. Chem. Soc. 127 (48): 16802 - 16803.
DOI:10.1021/ja056455b.
- ^ Andrew D. Bond, Roland Boese, Gautam R.
Desiraju (2007). "On the Polymorphism of Aspirin: Crystalline Aspirin as Intergrowths of Two "Polymorphic" Domains".
Angewandte Chemie International Edition 46 (4): 618-622.
DOI:10.1002/anie.200603373.
External links
This entry is from Wikipedia, the leading user-contributed encyclopedia. It may not have been reviewed by professional editors (see full disclaimer)
