Cocrystallization of racemic-compound-forming chiral molecules can result in conglomerate cocrystals or diastereomerically related cocrystals, which enable the application of chiral separation techniques such as preferential crystallization and classic resolution. Here, a systematic method to identify the types and phase diagrams of cocrystals formed by chiral target compounds and candidate coformers in a particular solvent system is presented, which allows the design of suitable chiral resolution processes. The method is based on saturation temperature measurements of specific solution compositions containing both enantiomers of chiral molecules and a coformer. This method is applied to analyze three different systems. For racemic phenylalanine (Phe) in water/ethanol mixtures one of the enantiomers selectively cocrystallizes with the opposite enantiomer of valine (Val), forming the more stable diastereomerically related cocrystal. The racemic compound ibuprofen crystallizes with the nonchiral coformer 1,2-bis(4-pyridyl)ethane (BPN) as racemic compound cocrystals. More interestingly, when it is combined with trans-1-(2-pyridyl)-2-(4-pyridyl)ethylene (BPE), the racemic compound ibuprofen cocrystallizes as a conglomerate, which in principle enables the application of preferential crystallization of this racemic compound. The systematic method shows the benefit of using pseudo-binary phase diagrams. Such pseudo-binary phase diagrams depict the saturation temperature on a very specific route through the quaternary phase diagram, allowing the identification of various cocrystal types as well as the corresponding cocrystallization conditions. The systematic method can be used to identify a suitable solid phase for chiral separation, and the obtained phase diagram information enables the performance of a crystallization-mediated chiral resolution process design. Such a guideline for a chiral resolution process design has never been reported for conglomerate cocrystal systems such as IBU:BPE, presented in this study.

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Salts of chiral molecules, which originally crystallize as racemic compounds, could form conglomerates. The utilization of such conglomerate salts, as intermediates for the deracemization of corresponding racemic compounds, expands the theoretical application range of Viedma Ripening by roughly 10-fold. In the present study, the use of temperature cycling on conglomerate forming salts as an alternative technique for Viedma Ripening was studied. The racemic compound Phenylalanine (Phe) was successfully deracemized via its conglomerate-forming salt with 2,5-xylenesulfonic acid (XSA) by continuous heating-cooling cycles applied to its suspension in glacial acetic acid, coupled with a solution racemization reaction. In addition, the dependence of the deracemization rate on the operational parameters was studied. Enhanced racemization reaction kinetics, either by a larger amount of free amino acid or by a higher concentration of catalyst, was shown to accelerate the deracemization process. It seems to indicate that a concentration difference between the two enantiomers, which could be diminished by a faster racemization rate, behaves as one of the major rate-limiting factors for the deracemization process. A larger mass fraction of solid dissolving and recrystallizing in the heating-cooling cycles, achieved by either a larger temperature swing or a smaller dry mass concentration, also leads to a faster deracemization. A change in cooling rate does not affect the deracemization rate significantly within the range tested, indicating a limited presence of secondary nucleation of the minor enantiomers. The results can be used as a preliminary foundation for process optimization as well as mechanisms investigation. The advantages and disadvantages of temperature cycling and Viedma Ripening, as deracemization methods in an industrial setting, are discussed.

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A survey is given of new types of crystallographic faces and forms occurring on modulated crystals which have to be indexed with four integers (hklm). These faces have so far been found on modulated crystals with an average jS-K2S04 structure which can be grown from an aqueous solution and the mineral crystal calaverite (AuTe2) which can be grown from the melt. Interesting data on crystal growth obtained from in situ observations are presented. Among others, spiral-like patterns can be recognized. The occurrence on quasicrystals of crystal forms to be indexed with six integers (hklmno) is discussed and it is shown that these faces can in principle be explained by a generalization of the Hartman- Perdok theory. Crystal forms (hklm) and (hklmno) occurring on modulated and quasicrystals respectively can be explained by the higher than three-dimensional crystallography of de Wolff, Janner and Janssen where these crystals are considered as threedimensional cuts out of a higher than three-dimensional truly translational invariant structure.@en