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 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
[7] because these techniques at the most suggest a different crystal structure but are unable to specify one however, given the recent advances in XRPD, it is perfectly feasible to obtain the structure of a polymorph of a drug, even if there is no single crystal available for that polymorphic form. 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.
[8], fine structural details were given by Bond et al.
[9] 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
