Minimizing Polymorphic Risk through Cooperative Computational and Experimental Exploration

Abstract

We combine state-of-the-art computational crystal structure prediction (CSP) techniques with a wide range of experimental crystallization methods to understand and explore crystal structure in pharmaceuticals and minimize the risk of unanticipated late-appearing polymorphs. Initially, we demonstrate the power of CSP to rationalize the difficulty in obtaining polymorphs of the well-known pharmaceutical isoniazid and show that CSP provides the structure of the recently obtained, but unsolved, Form III of this drug despite there being only a single resolved form for almost 70 years. More dramatically, our blind CSP study predicts a significant risk of polymorphism for the related iproniazid. Employing a wide variety of experimental techniques, including high-pressure experiments, we experimentally obtained the first three known nonsolvated crystal forms of iproniazid, all of which were successfully predicted in the CSP procedure. We demonstrate the power of CSP methods and free energy calculations to rationalize the observed elusiveness of the third form of iproniazid, the success of high-pressure experiments in obtaining it, and the ability of our synergistic computational-experimental approach to “de-risk” solid form landscapes.

Derisking the Polymorph Landscape: The Complex Polymorphism of Mexiletine Hydrochloride

“…The high density and relatively high stability of calculated Form 436 of mexiletine HCl suggests that it may be possible to isolate this additional form at high pressure in a similar way to the recent isolation of the predicted Form 3 of iproniazid . To explore this hypothesis, a single crystal of Form 2 was compressed to 3.56 GPa in a diamond anvil cell.…”

Along the road to crystal structure prediction (CSP) of pharmaceutical-like molecules

“…12 First of these is polymorphic screening, in which CSP can reveal late-appearing polymorphs 13,14 or reduce the risk of such forms occurring at later stages. 15,16 Apart from that, CSP has been used to determine the crystal structure of drugs crystallizing as microcrystalline powders (jointly with experimental methods) 7,17,18 to assess a drug's propensity to form solvates, 19,20 and in some cases even to guide crystallization efforts to obtain elusive solid forms. 21…”

The unexpected discovery of the ninth polymorph of tolfenamic acid

“…5 Modern crystal structure prediction (CSP) calculations 6,7 can assist this often cumbersome task and they are becoming increasingly popular in industry because they have the potential of minimising and guiding the experimental polymorph screening efforts as well as providing an additional characterisation technique for the identification of thermodynamically stable polymorphs. [8][9][10] These methods, however, remain complementary tools to experimental polymorph screenings and their generated landscapes often raise difficult interpretations. For example, sometimes these landscapes can suggest the existence of an unknown more stable crystal polymorph that has never been crystallised before.…”