In this work we show the feasibility of resolving a racemic drug substance with a second chiral drug. Via enantiospecific cocrystallization a dual-drug cocrystal is obtained. Such a method can be useful not only for chiral resolution but also for the parallel creation of dual-drug formulations. Here, racemic ibuprofen is resolved using levetiracetam through the formation of an enantiospecific cocrystal. Cocrystallization is utilized as a resolution tool for (in this case) (S)-ibuprofen, the active enantiomer. To find the right conditions to resolve the system, the appropriate ternary and quaternary phase diagrams were constructed. Since these diagrams are governed by thermodynamics, where the kinetic forms are prevented via seeding, the system is robust under scale-up conditions and is an interesting alternative to chiral chromatography or enantioselective synthesis for the pharmaceutical industry.

Spontaneous symmetry breaking and chiral amplification by means of Viedma ripening by definition should result in complete deracemization of a racemic conglomerate into either one of the enantiomers with equal probability. In practice, however, chiral impurities influence Viedma ripening and one enantiomer is obtained in preference over the other. Here, we show that by increasing the attrition intensity during Viedma ripening, the effect of chiral impurities is suppressed and deracemization does yield either enantiomer with equal probability. The reason for this is that the resulting smaller crystals lead to such a low surface density of chiral impurities that they no longer inhibit the crystal growth sufficiently to determine the chiral outcome. Furthermore, we show that even for low attrition intensities, the effect of chiral impurities can be canceled by using the right amount (10 ppm) of chiral additives.

A new process methodology to obtain enantiopure (S)-Ibuprofen has been designed. Starting from racemic Ibuprofen, co-crystallization with Levetiracetam is used as a resolution tool to obtain only the target enantiomer, (S)-Ibuprofen, in the solid state. The resulting mother liquor, enriched in (R)-Ibuprofen, is recovered and submitted to a racemization cycle, after which another co-crystallization step is introduced. Levetiracetam can be recovered from the co-crystal phase and reused, resulting in an economical use of the resolution agent. Overall, a novel approach to transform a racemic compound into enantiopure material has been developed.

Deterioration of crystal surfaces during removal from solution prior to observation poses a problem for ex situ (atomic force) microscopy studies. We use potash alum (KAl(SO 4 ) 2 •12H 2 O) crystals as a model system and investigate the variation of the following parameters: size, orientation, lifting rate, humidity, airflow, rinsing, and pollution. A model to describe the effects occurring during removal is developed and implications for other systems are presented to minimize the discrepancy between in situ and ex situ surfaces. This discrepancy is minimized for potash alum when a crystal is lifted slowly from its solution in a vertical position at a humidity below room humidity and in the absence of air flow.

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