Polymorphism (materials science)

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 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 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 ^{[5] [6]} conceived by phosphorous, 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. The Ostwald's rule is not a universal law but is only a possible preferred tendency in the nature.

Polymorphism in pharmaceuticals

Polymorphism is important in the development of dissolution rates depend on the exact crystal form of a polymorph.

XRPD, a practice criticized by in one review ^[7] 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.

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.

References

1. ^ F. Wöhler, J. Liebig, Ann. Pharm. 1832, 249 – 282.
2. ^ 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
3. ^ 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.
4. ^ 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.
5. ^ Ostwald, W. (1897). "Studies upon the forming and changing solid bodies". Zeitschrift fur Physikalische Chemie 22: 289-330.
6. ^ Threlfall, T. (2003). "Structural and thermodynamic explanations of Ostwald's Rule". Organic Process Research and Development 7 (6): 1017-1027. ISSN 1083-6160. Retrieved on 2007-10-30.
7. ^ 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
8. ^ 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.
9. ^ 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.

• "A discussion of crystal form litigation to develop generic versions of Paroxetine "