Rimonabant dimorphism, much ado about almost nothing

Abstract

Molecular polymorphism is being studied for almost 2 centuries, if the discovery of two solid forms of benzamide in 1832 by Justus Liebig and Friedrich Wohler is taken as the starting point. Even though considerable progress has been made since then the description of classical thermodynamics by Gibbs, its application by Bakhuis-Roozeboom, and much more recently the growing capability to calculate and thus predict energy differences between crystal structures, to mention a few in many cases, one is still taken by surprise, when a polymorphic form is discovered. Moreover, one does not escape a thorough experimental analysis of the polymorphic forms to determine with certainty which of them is the more stable form under the required conditions. Rimonabant, 5-(4-chlorophenyl)-1-(2,4dichlorophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole3-carboxamide) presents such a case study. It used to be an active pharmaceutical ingredient (API), which has been taken from the market due to its side effects. During the development of the drug, a second solid form was discovered and it had been very difficult to establish which of the solid forms is the more stable one. This was mainly due to the small difference in Gibbs energy that exists between the two forms.