Polymorphism

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. The complete morphology of a material is described by polymorphism and 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. 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.


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 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 Fujisawa 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 criticised 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 realised 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 neighbouring molecules instead of one. With respect to the hydrogen bonds formed by the carboxylic acid groups, both polymorphs form identical dimer structures.

Paracetamol powder has poor compression properties:
this poses difficulty in making tablets, so a new polymorph of paracetamol is discovered which is more compressible.

due to differences in solubility of polymorphs, one polymorph may be more active therapeutically than another polymorph of same drug

cortisone acetate exists in at least five different polymorphs, four of which are unstable in water and change to a stable form.

carbamazepine(used in epilepsy and trigeminal neuralgia) beta-polymorph developed from solvent of high dielectric constant ex aliphatic alcohol, whereas alpha polymorph crystallized from solvents of low dielectric constant such as carbon tetrachloride

estrogen and chloroamphenicol also show polymorphism

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