Polymorphism and Migratory Chiral Resolution of the Free Base of Venlafaxine. A Remarkable Topotactical Solid State Transition from a Racemate to a Racemic Conglomerate

Abstract

The unique behavior of the active pharmaceutical ingredient Venlafaxine free base, used as an antidepressant, with respect to polymorphism and chiral resolution is reported. Using several complementary techniques, three crystal structures of Venlafaxine were identified and isolated. All three structures are composed of virtually identical enantiomeric pure layers with different stacking modes. In the crystal structure with the highest melting point, the enantiomeric separation is complete, leading to a racemic conglomerate. The conglomerate can be grown from solution or via a solid-solid phase transition of the lowest melting racemic compound. Remarkably, the crystal shape is conserved during the transition. The corresponding chiral resolution is achieved via a local melting process, allowing for a long-range migration of the molecules between layers.

Long-timescale simulations of diffusion in molecular solids

“…Restructuring will occur once the product has formed, where the excess energy can be applied in accommodating the local environment for the newly-formed molecule. These restructuring processes are central to many fields and environments, e.g., ice layers on dust particles in the atmosphere and enantiomer separation 2 . In all cases, understanding the restructuring mechanism will shed light on the nature of the entire system 3 .…”

“…In the present paper, we focus specifically on the formation and evolution of interstellar ices, which is important for questions dealing with star and planet formation and ultimately with the origin of life, specifically concerning the delivery of molecules -like H 2 O, CO 2 and organic molecules -to habitable planets. Molecules that are present in ices on dust particles can become trapped during accretion from dust to planet, or may be transported by comets to existing planets.…”

Limits of the Co-crystal Concept and Beyond

“…[23][24][25][26] These multi-epitaxies between enantiomers create bi-dimensional racemic compounds which, for reasons not yet understood, do not expand in the third dimension. Actually there is no conceptual limit between these repetitive epitaxies and the corresponding racemic co-crystal (Figure 13.10).…”

Propagation of Biochirality: Crossovers and Nonclassical Crystallization Kinetics of Aspartic Acid in Water

“…Statistical analyses demonstrated only about 5 to 10% of the racemates form conglomerates, and aspartic acid falls into the remaining 90% category of a racemic forming system as evidenced by (i) the seeding experiment, and (ii) the solubility test . Several interesting cases such as ( R , S )‐2‐chloromandelic acid, free base of venlafaxine, and disulfide‐based iodoplumbate, whose solid state transition depending on the crystallization conditions can take place either from a racemic compound to a racemic conglomerate or vice versa …”

“…2 Several interesting cases such as (R,S)-2-chloromandelic acid, free base of venlafaxine, and disulfide-based iodoplumbate, whose solid state transition depending on the crystallization conditions can take place either from a racemic compound to a racemic conglomerate or vice versa. [3][4][5] Intriguingly, when aspartic acid was crystallized from solutions inside porous media, racemic conglomerate crystals of d-and l-aspartic acid were always produced. 6 Recently, we have also discovered the unusual molecular association of aspartic acid enantiomers in water forming a "racemic conglomerate solution" (CS).…”