Dalcetrapib
High-pressure crystallization confirms a predicted, more stable polymorph of dalcetrapib before late-stage development (Nat Commun 2015)
Original title: Combined crystal structure prediction and high-pressure crystallization in rational pharmaceutical polymorph screening
Researchers combined crystal structure prediction with high-pressure crystallization experiments to study the polymorphism of dalcetrapib, one of the most conformationally flexible molecules ever studied computationally, with 10 torsional degrees of freedom. The known experimental crystal polymorphs sat at the bottom of the calculated lattice energy landscape, and two predicted structures were identified as candidates for a missing, thermodynamically more stable polymorph. Pressure-dependent stability calculations suggested high pressure could bring these polymorphs into existence, and one was successfully crystallized in the 0.02 to 0.50 GPa range, found to be metastable at ambient pressure. The approach effectively derisked the late-stage appearance of a more stable polymorph of dalcetrapib.
Original 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.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.