(488c) Solid Solutions: The Forgotten Sixth Crystal Phase

Anhydrous polymorphs, hydrates, solvates, salts and co-crystals are all well-established and used throughout pharmaceutical industry in DS and DP applications, including crystallization. Crystalline solid solutions (CSS), however, have not rendered the same interest and have largely been omitted from crystallization research of organic compounds in part because of lack of detection. CSS are nevertheless ubiquitous in mineralogy, metallurgy and among inorganic compounds and possess unique and tunable properties that are critical for society. Famous examples include alloys like steel, bronze and solder. The prevalence of CSS in pharmaceutical crystallizations has recently been reported as the predominant mechanism for entrapping impurities[i]. Crystallization in the presence of structurally similar impurities, additives or dopants routinely produce CSS with the product, including the active pharmaceutical ingredient (API), which can dramatically impact its solid-state properties and crystallization performance.

In this presentation is provided an overview of CSS of organic compounds in terms of how they can be detected, their physical and thermodynamic properties and the importance they exert on pharmaceutical crystallization and development. The structural origin and distinction between CSS and the classical stoichiometric crystal forms are highlighted. Their pronounced effect on the solubility of the product is presented through experimental examples that include so-called terminal solid solutions. It is shown how small levels of a second component can dramatically increase the solubility of the product. This effect is also demonstrated to have the potential to change the thermodynamic stability relationships of polymorphs and impact the polymorphic outcome in crystallization. Finally, the impact of CSS-forming impurities on the performance of the crystallization is presented. Examples are showcased demonstrating how the rate of crystallization is affected by the thermodynamic contribution from CSS, which can result in a new type of crystal ripening leading to significant alterations in crystal morphology. This presentation is intended to provide crystallization scientists an overview of a poorly studied field in crystallization, while highlighting the importance of CSS for every-day crystallization development.

[i] Nordstrom, Sirota, Hartmanshenn, Kwok, Paolello, Li, Abeyta, Bramante, Madrigal, Behre, Capellades, accepted for publication in Org. Proc. Res. & Dev.