Navigating the Waters of Unconventional Crystalline Hydrates

Abstract

Elucidating the crystal structures, transformations, and thermodynamics of the two zwitterionic hydrates (Hy2 and HyA) of 3-(4-dibenzo[b,f][1,4]oxepin-11-yl-piperazin-1-yl)-2,2-dimethylpropanoic acid (DB7) rationalizes the complex interplay of temperature, water activity, and pH on the solid form stability and transformation pathways to three neutral anhydrate polymorphs (Forms I, II°, and III). HyA contains 1.29 to 1.95 molecules of water per DB7 zwitterion (DB7z). Removal of the essential water stabilizing HyA causes it to collapse to an amorphous phase, frequently concomitantly nucleating the stable anhydrate Forms I and II°. Hy2 is a stoichiometric dihydrate and the only known precursor to Form III, a high energy disordered anhydrate, with the level of disorder depending on the drying conditions. X-ray crystallography, solid state NMR, and H/D exchange experiments on highly crystalline phase pure samples obtained by exquisite control over crystallization, filtration, and drying conditions, along with computational modeling, provided a molecular level understanding of this system. The slow rates of many transformations and sensitivity of equilibria to exact conditions, arising from its varying static and dynamic disorder and water mobility in different phases, meant that characterizing DB7 hydration in terms of simplified hydrate classifications was inappropriate for developing this pharmaceutical.

The potential of computed crystal energy landscapes to aid solid-form development

“…Despite the increasingly comprehensive exploration of crystallization conditions and development of advanced analytical tools to detect and characterize solid-state forms, two challenges in generating solid form landscapes remain: finding experimental conditions which will induce a crystal form to nucleate for the first time and identifying bonafide crystal forms amidst materials that are frequently poorly crystalline, disordered or mixtures of phases. In the CSP study of 5-HT2a agonist DB7, a metastable polymorph, Form III, could only be obtained in polycrystalline form by desolvating the zwitterionic dehydrate [49] (Figure 1).…”

“…Conversely, all possible hydrates have to be extensively studied and characterized because of the impossibility of rigorously excluding water from the production processes. Solvates can include multiple solvents, sometimes in variable ratios, and the distinction between surface absorbed water, stoichiometric and nonstoichiometric hydrates is both critical for process design and difficult to establish [49].…”

The solid state forms of the sex hormone 17-β-estradiol

“…This can be particularly demanding for hydrates, as water is difficult to exclude from a process but simple hydrate classifications can be inappropriate for pharmaceutical devel-opment. 5 The control of production of crystalline products, which may be very sensitive to water activity in crystallization, filtration and drying processes, is essential in order to manufacture pharmaceutical material fit for purpose. 6 The studied estrogen, 17-β-estradiol (BES), is a white, odourless powder that is a primary female sex hormone associated with the female reproductive system.…”

An Appreciation of Organic Solid‐State Chemistry and Challenges in the Field of “Molecules, Materials, Medicines”

“…Their sobering conclusion is that “it can never be stated that the most stable form has been found; at best it can be determined which of the known forms is the most stable” (my italics). When coupled with possible competing hydrate and solvate forms appearing during solution crystallisation (and their different stoichiometry as well as polymorphs of the same stoichiometry), it is fair to conclude that this topic still has much to be explored …”