Introduction to Polymorphism

Starring

Andreas Lemmerer and Molecules with Chronic

Multiple Chemical Personality Disorder ☺

Centre for Supramolecular Chemistry Research, University of Cape Town, South Africaand

Institut für Pharmazie, Leopold Franzens Universität Innsbruck, Austria presents

Polymorphism• Definition: A phenomenon which occurs whenever a given chemical compound exists in

more than one structural form or arrangement.• McCrone: A solid crystalline phase of a given compound resulting from the possibility of at

least two different arrangements of molecules of that compound in the solid state.• Examples: Diamond and Graphite are allotropes of the element carbon. Diamond has a

tetrahedral arrangement of carbon atoms, which forms four covalent bonds; whereas graphite has a hexagonal arrangement and forms three covalent bonds.

Concomitant Polymorphs of the Antihyperlipoproteinemic

Bezafibrate

Cl

O

N

O

O O

HH

A. Lemmerer, N. Báthori, C. Esterhuysen, Susan A. Bourne and Mino R. Caira, Crystal Growth & Design, 2009, 2646-2655

Background Information • 2-[4-[2-(4-chlorobenzamide)ethyl]phenoxy]-2-methylpropanoic acid, marketed as

Bezalip®.• Bezafibrate is used to regulate the amount of lipid produced by the body, lowering

the amount of low density lipoprotein (LDL) and triglycerides and raising the amount of high density lipoprotein (HDL), which reduces the risk of heart disease.

• The preparation of bezafibrate is reported in the patent literature (DE-PS 21 49 070 US-PS 4,749,101 and DE-PS 29 20 413).

• Crystals of bezafibrate were grown from acetone or water solutions and were reported to have a melting point of 183°C (US-PS 4,749,101) and 186°C (DE-PS 21 49 070). The habit of bezafibrate crystals thus prepared is needle-like.

• However, working on a large scale with needle-like crystals is complicated by filtration and processability. The crystal habit is an important factor in the large-scale production.

• Patent EP 0 625 504 A17 later described the preparation of a new “b-form”, which crystallizes as block-shaped crystals. The crystals were grown from a mixture of water and a ketone (examples of ketones used are 2-butanone, 3-pentanone and 4-methyl-2-oxopentane), together with a 4-10% v/v addition of an alcohol.

• We prepared the same block-like crystals by adding nicotinamide to the crystallization solution containing 2-butanone.

Structure of Form a

Structure of Form b

Conformational Differences

Overlay of Conformations

Form a: Green and Purple; Form b: Blue

Spectroscopic Differences

Powder Diffraction Differences

Differential Scanning Calorimetry

Variable Temperature Powder Diffraction

Energy-Temperature Diagram