Pharmaceutical cocrystals: A review of preparations, physicochemical properties and applications.

In this paper, we identified a cocrystal conglomerate of mandelic acid using a drug compound as a coformer. We then developed a chiral resolution process based on preferential cocrystallization. Se...

Chiral Resolution of Mandelic Acid through Preferential Cocrystallization with Nefiracetam

Resolution by Preferential Crystallization of Proxyphylline by using its Salicylic Acid Monohydrate Co‐crystal

Cocrystallization has been promoted as an attractive early development tool as it can change the physicochemical properties of a target compound and possibly enable the purification of single enantiomers from racemic compounds. In general, the identification of adequate cocrystallization candidates (or coformers) is troublesome and hampers the exploration of the solid-state landscape. For this reason, several computational tools have been introduced over the last two decades. In this study, cocrystals of Praziquantel (PZQ), an anthelmintic drug used to treat schistosomiasis, are predicted with network-based link prediction and experimentally explored. Single crystals of 12 experimental cocrystal indications were grown and subjected to a structural analysis with single-crystal X-ray diffraction. This case study illustrates the power of the link-prediction approach and its ability to suggest a diverse set of new coformer candidates for a target compound when starting from only a limited number of known cocrystals.

Cocrystals of Praziquantel: Discovery by Network-Based Link Prediction

We tap into an unexplored area of preferential crystallization, being the first to develop simultaneous chiral resolution of two racemic compounds by preferential cocrystallization. We highlight how the two racemic compounds RS-mandelic acid (MAN) and RS-etiracetam (ETI) can be combined together as enantiospecific R-MAN⋅R-ETI and S-MAN⋅S-ETI cocrystals forming a stable conglomerate system and subsequently develop a cyclic preferential crystallization allowing to simultaneous resolve both compounds. The developed process leads to excellent enantiopurity both for etiracetam (ee>98 %) and mandelic acid (ee≈95 %) enantiomers.

Simultaneous Chiral Resolution of Two Racemic Compounds by Preferential Cocrystallization

The preparative resolution by preferential crystallization (PC) of proxyphylline has been achieved despite the existence of a stable racemic compound. This is enabled through the careful selection of a solvent in which both the racemic compound and the metastable conglomerate possess a low nucleation rate. Induction time measurements in isobutyl alcohol show that a highly supersaturated solution (β = 2.3) remains clear for almost 1 h at 20 mL scale, revealing a slow nucleation rate. Seeding the supersaturated solution with the pure enantiomer triggered its crystallization both isothermal and polythermic modes of PC were successfully implemented. Alongside the reported case of diprophylline, this study opens opportunities to broaden the application of PC toward slowly crystallizing racemic compounds.

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Enabling Direct Preferential Crystallization in a Stable Racemic Compound System.

A cocrystal screening of the chiral drug “proxyphylline” (PXL) and achiral coformers was performed using dry or solvent as-sisted grinding and evaporation methods, yielding 10 different original so...

Discovery of New Proxyphylline-Based Chiral Cocrystals: Solid State Landscape and Dehydration Mechanism

Nucleation of DL- and L-histidine is examined using induction time measurements and their nucleation rates have been deduced. Results indicate a much slower nucleation for the racemic form compared to the pure enantiomer form. The effect of temperature and supersaturation on the nucleation rate is also described. Classical nucleation theory (CNT) is used to determine the interfacial energy, the nucleation energy barrier, and the nucleus size for both compounds. The large difference between the nucleation rates for the pure enantiomer and the racemic compound have so far not led to satisfactory preferential crystallization; however second harmonic generation analysis demonstrates the presence of non-centrosymmetric domains embedded within the racemic crystals implying that improving control over the nucleation conditions may lead to more efficient preferential crystallisation and symmetry breaking.

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Lina C. Harfouche

Papers

Resolution by Preferential Crystallization of Proxyphylline by using its Salicylic Acid Monohydrate Co‐crystal

Enabling Direct Preferential Crystallization in a Stable Racemic Compound System.

Discovery of New Proxyphylline-Based Chiral Cocrystals: Solid State Landscape and Dehydration Mechanism

Nucleation behaviour of racemic and enantiopure histidine