Abstract: The problem of obtaining multi-component crystals as co-crystals (with neutral molecules) rather than salts (with charged cations and anions) attracts much attention. This is not merely a scientific challenge, but is often important for issues related to intellectual property in the pharmaceutical industry. Until now, examples have been documented when control over co-crystal – salt state has been achieved by modifying either chemical components (co-formers) or temperature. Serendipitously we recently obtained, for the first time, a co-crystal and a salt of the same chemical composition – β-alanine and DL-tartaric acid - crystallizing stochastically at the same temperature from the same solution (Acta Cryst. (2018). C74, 177-185; https://doi.org/10.1107/S2053229617017909). Here we report the possibility to obtain reproducibly the crystals of either of the two forms, the stable co-crystal (II), or a metastable salt (III), depending on the crystallization protocol. These observations are rationalized in terms of control over nucleation and nuclei growth of the two phases, Ostwald’s rule of stages and “disappearing polymorphs”. We report the results of using slow evaporation, fast and slow anti-solvent crystallization, and co-grinding with variable amount of added water, as well as of “slurry experiments”. The thermodynamically stable co-crystal (II) can be obtained as a pure phase on liquid-assisted grinding, and on crystallization from solution if seeds of it are already present in solution. The metastable molecular salt (III) is formed as a pure phase on “dry” co-grinding without any water added specially (although in humid atmosphere), fast anti-solvent crystallization, or in slow anti-solvent crystallization experiments before any seeds of the co-crystal (II) become available. After the co-crystal (II) has been formed once, even introducing a seed of the molecular salt (III) does not help to crystallize the salt from solution. The salt (III) is thus a typical “disappearing polymorph”. For comparison, we describe the co-crystallization of DL-tartaric acid with other amino acids of the same homological series. It gives the same products under all of the tested crystallization conditions – salts for larger γ- and α- aminobutyric acids (GABA (IV) and AABA (V), respectively) and a cocrystal for smaller glycine (I). The findings shed light on the mechanism of the alternative precipitation of co-crystals or salts of zwitter-ionic compounds from their aqueous solutions.

Cite: Losev E.A. , Boldyreva E.V.
A Salt or a co-Crystal – when Crystallization Protocol Matters
CrystEngComm. 2018. V.20. N16. P.2299-2305. DOI: 10.1039/c7ce02204b WOS Scopus РИНЦ AN OpenAlex

Dates:

Submitted:	Dec 21, 2017
Accepted:	Mar 23, 2018
Published online:	Mar 26, 2018
Published print:	Apr 28, 2018

Identifiers:

Web of science:	WOS:000430709700014
Scopus:	2-s2.0-85045905728
Elibrary:	35491943
Chemical Abstracts:	2018:588182
OpenAlex:	W2790656614

Citing:

DB	Citing
Web of science	32
Scopus	33
OpenAlex	33

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