Combined crystal structure prediction and high-pressure crystallization in rational pharmaceutical polymorph screening

Abstract

Organic molecules, such as pharmaceuticals, agro-chemicals and pigments, frequently form several crystal polymorphs with different physicochemical properties. Finding polymorphs has long been a purely experimental game of trial-and-error. Here we utilize in silico polymorph screening in combination with rationally planned crystallization experiments to study the polymorphism of the pharmaceutical compound Dalcetrapib, with 10 torsional degrees of freedom one of the most flexible molecules ever studied computationally. The experimental crystal polymorphs are found at the bottom of the calculated lattice energy landscape, and two predicted structures are identified as candidates for a missing, thermodynamically more stable polymorph. Pressure-dependent stability calculations suggested high pressure as a means to bring these polymorphs into existence. Subsequently, one of them could indeed be crystallized in the 0.02 to 0.50 GPa pressure range and was found to be metastable at ambient pressure, effectively derisking the appearance of a more stable polymorph during late-stage development of Dalcetrapib.

Unusual seeding effect in the liquid-assisted high-pressure polymorphism of chlorpropamide

“…This is reflected in phenomena which were term-coined as "concomitant polymorphism" (several phases co-existing at the same conditions, often in the same batch) [12] , "disappearing polymorphs" (a fast-growing metastable polymorph obtained once can no longer be crystallised after a seed of the stable form has been obtained) [13,14] , "pre-nucleation" (molecular clusters in solution predetermine the structure of a crystalline nucleus formed at later stages) [15] , "seeding-triggered crystallization" (a seed of a phase triggers crystallization of the same phase) [16] , "template crystallization" (molecules or molecular clusters in solution direct crystallization of a certain crystalline form, even if not included in the final crystal structure themselves) [17,18] . Highpressure has been recently proposed as a tool to obtain new polymorphs of pharmaceuticals, which, if preserved on flashdecompression, can be used as seeds for mass-crystallization at ambient conditions [19][20][21][22][23] . However, the control of highpressure polymorphism is not a trivial task [19,[24][25][26][27][28] .…”

Is zeroth order crystal structure prediction (CSP_0) coming to maturity? What should we aim for in an ideal crystal structure prediction code?

“…73 This iterative work where CSP may inspire experiments that nd more forms, versus the problem of over-prediction, really illustrates the need to dene what is required from CSP. Pressure is becoming increasingly important in the discovery of CSP "predicted" forms for pharmaceuticals, 14,74,75 whereas CSP at pressure has long been established as a route to nding new phases of interest to planetary scientists, including changes in bonding, such as ionic ammonia.…”

Structural Elucidation of α-Cyclodextrin-Succinic Acid Pseudo Dodecahydrate: Expanding the Packing Types of α-Cyclodextrin Inclusion Complexes

“…Upon releasing pressure, there was no microscopic evidence for crystallization of either SA or α-CD alone. While our experiments were not comprehensive, the lack of complex formation at high pressure may be ascribed to concentration, the formation of a particularly stable complex in solution stabilized at high pressure and kinetic effects; it is also conceivable that structural disorder is essential for stability of the α-CD¨SA complex (the entropic contributions of structural disorder in molecular compounds have for instance been discussed in [31][32][33][34]) and that high pressure, favoring more dense, and in general more ordered states, hinders the in situ formation of a complex.…”