Disappearing polymorphs revisited

Abstract

Nearly twenty years ago, Dunitz and Bernstein described a selection of intriguing cases of polymorphs that disappear. The inability to obtain a crystal form that has previously been prepared is indeed a frustrating and potentially serious problem for solid-state scientists. This Review discusses recent occurrences and examples of disappearing polymorphs (as well as the emergence of elusive crystal forms) to demonstrate the enduring relevance of this troublesome, but always captivating, phenomenon in solid-state research. A number of these instances have been central issues in patent litigations. This Review, therefore, also highlights the complex relationship between crystal chemistry and the law.

Keywords: crystallization; drug formulation; nucleation; polymorphism; solid-state chemistry.

Figure 1

a) Molecular structure of ranitidine hydrochloride. b) Example 32 from patent US 4128658A (“Aminoalkyl furan derivatives”), the apparently straightforward procedure for the preparation of Form 1 of ranitidine hydrochloride. c) Overlay of the ranitidine cation from Form 1 (blue) and Form 2 (red). Form 2 features a disordered nitroethenediamine moiety.

Figure 2

a) Molecular structure of ritonavir. b) Crystal structures of its Form I (left) and Form II (right). c) Formation of the presumed heteronuclear seed of ritonavir Form II through a base-catalyzed reaction.

Figure 3

a) Molecular structure of the paroxetine cation. b) Crystal structure of Form 1 viewed along the crystallographic c axis. c) Crystal structure of Form 2 viewed along the crystallographic b axis. The positions of the water hydrogen atoms in Form 1 were not determined (green spheres: chloride anions; red spheres: water molecules).

Figure 4

a) Molecular structure of rotigotine and b) overlay of rotigotine molecules extracted from the crystal structures of Forms I and II (shown in red and blue, respectively). Only the major occupation site of the disordered thiophene moiety is shown.

Figure 5

Molecular structure of DMP 543.

Figure 6

a) Molecular structure of LAB687, and b) the dimeric urea impurity believed to be responsible for the formation of LAB687 Form D.

Figure 7

a) Molecular structure of sulfathiazole. b) Crystal structures of Form I showing how sulfathiazole builds a three-dimensional hydrogen-bonded network (left) that is interpenetrated by a two-dimensional hydrogen-bonded network (right). The two networks are built from crystallographically independent molecules (colored red and blue). c–f) Crystal structures of Forms II–V showing the formation of two-dimensional hydrogen-bonded networks. The two-dimensional networks in Forms III and V (shown in (d) and (f), respectively) are sustained by two crystallographically independent sulfathiazole molecules (colored red and blue).

Figure 8

a) Molecular structures of progesterone and pregnenolone. b) Crystal structure of Form I of progesterone. c) Crystal structure of Form II of progesterone. d) Crystal structure of the 1:1 progesterone:pregnenolone cocrystal (progesterone blue, pregnenolone red). Crystal structures in (b) and (c) are viewed along the crystallographic a axis.

Figure 9

a) Molecular structures of aspirin and the aspirin anhydrate. Crystal structures of b) Form I and c) Form II. The crystal structures in (b) and (c) are viewed along the crystallographic b axis. The inversion centers are represented with black spheres, while the 2₁ screw axes are depicted using green arrows.

Figure 10

a) Molecular structure of caffeine (caf) and benzoic acid (BA). b) Cocrystals as heteronuclear seeds: cocrystals composed of caffeine (caf), 2-fluorobenzoic acid (2 FBA), and 2,5-difluorobenzoic acid (25 diFBA). c) Predicted lowest-energy crystal structure of (caf)⋅(BA). d) Overlay of the isomorphous lowest-energy predicted and obtained (caf)⋅(BA) cocrystal (red: predicted, blue: observed).