Comparing and Quantifying the Efficiency of Cocrystal Screening Methods for Praziquantel.

Pharmaceutical cocrystals are highly interesting due to their effect on physicochemical properties and their role in separation technologies, particularly for chiral molecules. Detection of new cocrystals is a challenge, and robust screening methods are required. As numerous techniques exist that differ in their crystallization mechanisms, their efficiencies depend on the coformers investigated.

Combining Viedma Ripening and Temperature Cycling Deracemization.

While much data are available for the Viedma ripening and temperature cycling deracemization processes, not much is known about the advantages (or disadvantages) of a combination of the two. We here try to elucidate what happens when Viedma ripening is used in combination with temperature cycling by comparing not only the deracemization times but also the change in the sizes of the crystals. We found that, in the case of NMPA (-(2-methylbenzylidene)-phenylglycine amide) as a model compound, combined experiments significantly increase the deracemization time.

Influence of Ostwald's Rule of Stages in the Deracemization of a Compound Using a Racemic Resolving Agent.

The stereoisomeric system of -2-phenylglycinamide (PGA) and --acetyl tryptophan (NAT) is significant in the application of chiral resolution because it has been shown that this system can be used for enantioseparation of PGA and/or NAT using a novel deracemization route of the conglomerate salt formed. However, it was also found that the conglomerate salt eventually converted into different crystal forms that limited the time available for the separation. Herein, we try to understand the phase conversion occurring in this system using DSC, PXRD, and SC-XRD.

Cocrystals of Praziquantel: Discovery by Network-Based Link Prediction.

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.

Co-crystal Prediction by Artificial Neural Networks*.

A significant amount of attention has been given to the design and synthesis of co-crystals by both industry and academia because of its potential to change a molecule's physicochemical properties. Yet, difficulties arise when searching for adequate combinations of molecules (or coformers) to form co-crystals, hampering the efficient exploration of the target's solid-state landscape. This paper reports on the application of a data-driven co-crystal prediction method based on two types of artificial neural network models and co-crystal data present in the Cambridge Structural Database.

On the mechanism of solid-state phase transitions in molecular crystals - the role of cooperative motion in (quasi)racemic linear amino acids.

During single-crystal-to-single-crystal (SCSC) phase transitions, a polymorph of a compound can transform to a more stable form while remaining in the solid state. By understanding the mechanism of these transitions, strategies can be developed to control this phenomenon. This is particularly important in the pharmaceutical industry, but also relevant for other industries such as the food and agrochemical industries.

Deracemization in a Complex Quaternary System with a Second-Order Asymmetric Transformation by Using Phase Diagram Studies.

Invited for the cover of this issue is the group of Gérard Coquerel at Université de Rouen Normandie. The image depicts a pyramid-like tetrahedron of the quaternary phase diagram showing where symmetry breaking can take place. Read the full text of the article at 10.

Photoracemization-Based Viedma Ripening of a BINOL Derivative.

Viedma ripening is a deracemization process that has been used to deracemize a range of chiral molecules. The method has two major requirements: the compound needs to crystallize as a conglomerate and it needs to be racemizable under the crystallization conditions. Although conglomerate formation can be induced in different ways, the number of racemization methods is still rather limited.

Deracemization in a Complex Quaternary System with a Second-Order Asymmetric Transformation by Using Phase Diagram Studies.

A productive deracemization process based on a quaternary phase diagram study of a naphthamide derivative is reported. New racemic compounds of an atropisomeric naphthamide derivative have been discovered, and a quaternary phase diagram has been constructed that indicated that four solids are stable in a methanol/H O solution. Based on the results of a heterogeneous equilibria study showing the stable domain of the conglomerate, a second-order asymmetric transformation was achieved with up to 97 % ee.

Racemization and Deracemization through Intermolecular Redox Behaviour.

Chiral molecules exhibiting a quinone and/or hydroquinone moiety are ubiquitous in natural products and small molecule drugs. Herein, we describe a chiral quinone-hydroquinone molecule that racemizes through a reversible redox reaction. Using a combined computational and experimental approach, we show that this racemization proceeds via an intermolecular reaction mechanism.

Cocrystals in the Cambridge Structural Database: a network approach.

To obtain a better understanding of which coformers to combine for the successful formation of a cocrystal, techniques from data mining and network science are used to analyze the data contained in the Cambridge Structural Database (CSD). A network of coformers is constructed based on cocrystal entries present in the CSD and its properties are analyzed. From this network, clusters of coformers with a similar tendency to form cocrystals are extracted.

The Rich Solid-State Phase Behavior of l-Phenylalanine: Disappearing Polymorphs and High Temperature Forms.

After years of controversy over the solid state structure of the essential amino acid l-phenylalanine, four different polymorphic forms were published recently. The common form I has symmetry 2 with four molecules in the asymmetric unit (' = 4), similar to form III, but with a different arrangement of molecular bilayers. Form II, obtained from the hydrate at very low humidity, is unrelated to forms I and III, as is the high-density form IV.

Attrition-Enhanced Deracemization of the Antimalaria Drug Mefloquine.

Mefloquine is an important drug for prevention and treatment of malaria. It is commercially available as a racemic mixture, wherein only one enantiomer is active against malaria, while the other one causes severe psychotropic effects. By converting the drug into a compound that crystallizes as a racemizable racemic conglomerate, the deracemization of mefloquine into the desired enantiomer was achieved.

Role of Additives during Deracemization Using Temperature Cycling.

Temperature cycling, alongside Viedma ripening, has been established as a reliable method for deracemizing racemic mixtures of chiral compounds that crystallize as a conglomerate. Here we report that the speed of temperature cycling can be increased by using chiral additives. We also demonstrate that the chirality of the additive determines the final enantiomeric state of the solid phase.

Solid-Phase Conversion of Four Stereoisomers into a Single Enantiomer.

Viedma ripening is an emerging method for the solid-phase deracemization of mixtures of enantiomers. Up to now, the scope of the method has remained limited to molecules with a single stereocenter. We show here that this method can be extended to obtain a single enantiomer from a mixture of stereoisomers with two different stereocenters.

The Rich Solid-State Phase Behavior of dl-Aminoheptanoic Acid: Five Polymorphic Forms and Their Phase Transitions.

The rich landscape of enantiotropically related polymorphic forms and their solid-state phase transitions of dl-2-aminoheptanoic acid (dl-AHE) has been explored using a range of complementary characterization techniques, and is largely exemplary of the polymorphic behavior of linear aliphatic amino acids. As many as five new polymorphic forms were found, connected by four fully reversible solid-state phase transitions. Two low temperature forms were refined in a high ' crystal structure, which is a new phenomenon for linear aliphatic amino acids.

Inhibition of the Vapor-Mediated Phase Transition of the High Temperature Form of Pyrazinamide.

Tailor-made additives can prove an effective method to prolong the lifetime of metastable forms of pharmaceutical compounds by surface stabilization. Pyrazinamide (PZA) is a pharmaceutical compound with four polymorphic forms. The high temperature γ form, which can be produced by spray drying or sublimation growth, is metastable at room temperature and transforms within days when produced by spray drying, and within several months up to years for single crystals produced by sublimation.

Deracemization of a Racemic Compound by Using Tailor-Made Additives.

Viedma ripening is a process that combines abrasive grinding of a slurry of crystals with solution-phase racemization, resulting in solid-phase deracemization. One of the major disadvantages of Viedma ripening is that the desired compound needs to crystallize as a racemic conglomerate, accounting for only 5-10 % of all chiral molecules. Herein, we show that use of a chiral additive causes deracemization under conditions, in which the compound normally crystallizes as a racemic compound.

Polymorphism and Modulation of Para-Substituted l-Phenylalanine.

The crystal structure of -methyl-l-phenylalanine at 230 K resembles that of the para-fluorinated analogue from the literature but is commensurately modulated with seven molecules in the asymmetric unit (' = 7). At 100 K, the superstructure loses its modulation, leading to a unit cell with ' = 1, with clear disorder in the phenyl ring orientations. The methyl-substituent in -methyl-l-phenylalanine has, in contrast to fluorine, no polar interactions with protons of neighboring molecules, which might allow for the well-defined modulation of the crystal structure at 230 K.

Solid Phase Deracemization of an Atropisomer.

The scope of Viedma ripening and temperature cycling with respect to chiral molecules has remained mostly limited to molecules with a single stereogenic center, while racemization proceeds through inversion at that particular stereocenter. In this article we demonstrate for the first time that atropisomers, chiral rotamers that possess an axis of chirality, can be successfully deracemized in the solid phase by either applying temperature cycling or Viedma ripening.

Deracemization of a Racemic Allylic Sulfoxide Using Viedma Ripening.

Despite the importance of enantiopure chiral sulfoxides, few methods exist that allow for their deracemization. Here, we show that an enantiopure sulfoxide can be produced from the corresponding racemate using Viedma ripening involving rearrangement-induced racemization. The suitable candidate for Viedma ripening was identified from a library of 24 chiral sulfoxides through X-ray structure determination.

Searching for stereoisomerism in crystallographic databases: algorithm, analysis and chiral curiosities.

The automated identification of chiral centres in molecular residues is a non-trivial task. Current tools that allow the user to analyze crystallographic data entries do not identify chiral centres in some of the more complex ring structures, or lack the possibility to determine and compare the chirality of multiple structures. This article presents an approach to identify asymmetric C atoms, which is based on the atomic walk count algorithm presented by Rücker & Rücker [(1993), J.

Speeding up Viedma ripening.

Viedma ripening allows the conversion of a solid state racemate into a single enantiomer. Using the gradual conversion of a metastable racemic compound into the conglomerate, the speed of deracemization for two amino acid derivatives could be considerably increased from several days to a few hours.

Report on the sixth blind test of organic crystal structure prediction methods.

The sixth blind test of organic crystal structure prediction (CSP) methods has been held, with five target systems: a small nearly rigid molecule, a polymorphic former drug candidate, a chloride salt hydrate, a co-crystal and a bulky flexible molecule. This blind test has seen substantial growth in the number of participants, with the broad range of prediction methods giving a unique insight into the state of the art in the field. Significant progress has been seen in treating flexible molecules, usage of hierarchical approaches to ranking structures, the application of density-functional approximations, and the establishment of new workflows and `best practices' for performing CSP calculations.

Viedma ripening: a reliable crystallisation method to reach single chirality.

Crystallisation processes have evolved to practical methods that allow isolation of an enantiopure product in high yield. Viedma ripening in particular enables access to enantiopure products in a reliable way, simply through grinding of crystals in a solution. This tutorial review covers the basic principles behind asymmetric crystallisation processes, with an emphasis on Viedma ripening, and shows that to date many novel organic molecules can be obtained in enantiopure solid form.