Impact of a Partial Solid Solution and Water Molecules on the Formation of Fibrous Crystals and Fluid Inclusions

Abstract

Resolution of (±)ibuprofen using S-α-Methylbenzylamine in pure ethanol leads to the enriched S-IBU/S-αMBA diastereomeric salt which crystallizes as very fine needles. In order to improve the filterability and processability of the solid phase, water can be added to the medium and lead to more equant particles that are still elongated. A high fraction of the resulting platelets display on both ends a fluid inclusion containing both liquid and a large bubble of gas. A detailed analysis of the particles reveals that they are not really single crystals but more an ordered association of fibers defined as fibrous crystal. A domain of partial solid solution is evidenced near the pure less soluble diastereomer and its impact on the formation of fibrous crystals is demonstrated. When pure S-IBU/S-αMBA diastereomeric salt is recrystallized in the same medium (e.g., ethanol–water) the crystallinity is improved, but fluid inclusions can still be observed.

Green and Strategic Approach for Chiral Resolution by Diastereomeric Salt Formation: The Study of Racemic Ibuprofen

“…When more R salt tends to remain in the solution due to its higher solubility, a diastereomeric mixture can be resolved by the crystallization of the more insoluble S salt. We also attempted to predict the %de by calculations of the solubility data (Figures S2 and S3) but failed due to the existence of a partial solid solution . It was reported that the solid solution contains a certain amount of R -IBU- S -MBA (i.e., the diastereomeric R salt) versus temperature, for example, χ R ‑IBU‑ S ‑MBA = 0.17 (i.e., 66%de) at a eutectic temperature of around 145 °C and χ R ‑IBU‑ S ‑MBA = 0.13 (i.e., 74%de) at 20 °C .…”

“…We also attempted to predict the %de by calculations of the solubility data (Figures S2 and S3) but failed due to the existence of a partial solid solution . It was reported that the solid solution contains a certain amount of R -IBU- S -MBA (i.e., the diastereomeric R salt) versus temperature, for example, χ R ‑IBU‑ S ‑MBA = 0.17 (i.e., 66%de) at a eutectic temperature of around 145 °C and χ R ‑IBU‑ S ‑MBA = 0.13 (i.e., 74%de) at 20 °C . The revised binary phase diagram between S -IBU- S -MBA and R -IBU- S -MBA has been determined by DSC measurements in sealed pans and represented by a Tammann graph, while no solid solution existing was claimed previously .…”

“…For the case with a partial solid solution, it is impossible to achieve 100%de from a racemic compound in a single step of crystallization. Unfortunately, both the diastereomers and enantiomers of IBU show partial solid solution behavior causing difficulty in diastereomeric and enantiomeric resolutions based on their recently revised phase diagrams. , Accordingly, the selection of a suitable solvent is very important, especially when a number of crystallization steps are required.…”

“…47 It was reported that the solid solution contains a certain amount of R-IBU-S-MBA (i.e., the diastereomeric R salt) versus temperature, for example, χ R-IBU-S-MBA = 0.17 (i.e., 66%de) at a eutectic temperature of around 145 °C and χ R-IBU-S-MBA = 0.13 (i.e., 74%de) at 20 °C. 47 The revised binary phase diagram between S-IBU-S-MBA and R-IBU-S-MBA has been determined by DSC measurements in sealed pans and represented by a Tammann graph, 48 while no solid solution existing was claimed previously. 49 Accordingly, it is almost impossible to reach 100%de (i.e., the pure S-IBU-S-MBA) in a single step of diastereomeric crystallization.…”

Double Trouble: A Peculiar Case of Solid Solution Cocrystals Involving Two Chiral Compounds

“…Solid solution cocrystals involving chiral compounds often occur due to a change in the enantiomeric ratio of the chiral compound . If the counter enantiomers are partially miscible, the term partial solid solution − is used, whereas a complete solid solution is obtained if substitution occurs over the whole range of enantiomeric ratios. − Cappuccino et al investigated such systems looking into the cocrystallization of praziquantel with malic acid and tartaric acid . In their study racemic praziquantel and an equivalent amount of malic acid and/or tartaric acid formed complete solid-solution cocrystals with a freely varying enantiomeric ratio of tartaric acid or malic acid.…”