Enabling Direct Preferential Crystallization in a Stable Racemic Compound System.

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 (ß = 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.

Prenucleation Self-Assembly and Chiral Discrimination Mechanisms during Solution Crystallisation of Racemic Diprophylline.

The crystallisation behaviour of (RS)-diprophylline (DPL) in two different solvents is investigated to assess the incidence of solvated pre-associations on nucleation, crystal growth and chiral discrimination. In the solvated state, Raman spectroscopy shows that dimeric associations similar to those depicted in the crystalline solid solution (ssRII) predominate in isopropanol (IPA), which may account for the systematic spontaneous nucleation of this crystal form from this solvent. By contrast, spontaneous nucleation in DMF yields the stable racemic compound RI, consistently with the distinct features of the Raman spectrum collected in this solvent. A crystal growth study of ssRII in IPA reveals that the crystal habitus is impacted by the solution enantiomeric excess; this is explained by increased competition between homo- and heterochiral pre-associations. This is supported by a molecular modelling study on the enantiomeric selectivity of the DPL crystal lattices. The combination of assessment methods on solution chemistry, nucleation and chiral discrimination provides methodological tools from which the occurrence of solid solutions can be rationalised.

Formation of new polymorphs without any nucleation step. Desolvation of the rimonabant monohydrate: directional crystallisation concomitant to smooth dehydration.

Rimonabant monohydrate can be dehydrated at 100 °C or above with complete loss of structural information; in this case the amorphous material can lead to nucleation and crystal growth. The water molecules can also be removed by a smooth process below Tg (78 °C) of the anhydrous phase. In that latter process there is a structural filiation between the mother phase and the daughter phase. The solvent molecules escape from the mother structure by using a network of specific channels; the new non-solvated material undergoes a relaxation process similar to a directional crystallization. By this soft mode of desolvation inside a material which has a very limited mobility, the nucleation of a non-solvated material can be avoided. The structural information contained in the mother phase is not used as a template for crystal growth but it is more a progressive rearrangement of the new desolvated material towards the nearest well in energy. Thus, a metastable new polymorph of a non-solvated component can be obtained by: (i) the crystallization of the component as a solvate and (ii) a smooth desolvation at T < Tg. Other parameters liable to interfere with that transmission of structural information are discussed.

Impact of molecular flexibility on double polymorphism, solid solutions and chiral discrimination during crystallization of diprophylline enantiomers.

The polymorphic behavior of racemic and enantiopure diprophylline (DPL), a chiral derivative of theophylline marketed as a racemic solid, has been investigated by combining differential scanning calorimetry, powder X-ray diffraction, hot-stage microscopy and single-crystal X-ray experiments. The pure enantiomers were obtained by a chemical synthesis route, and additionally an enantioselective crystallization procedure was developed. The binary phase diagram between the DPL enantiomers was constructed and revealed a double polymorphism (i.e., polymorphism both of the racemic mixture and of the pure enantiomer). The study of the various equilibria in this highly unusual phase diagram revealed a complex situation since mixtures of DPL enantiomers can crystallize either as a stable racemic compound, a metastable conglomerate, or two distinct metastable solid solutions. Crystal structure analysis revealed that the DPL molecules adopt different conformations in the crystal forms suggesting that the conformational degrees of freedom of the substituent that carries the only two H-bond donor groups might be related to the versatile crystallization behavior of DPL. The control of these equilibria and the use of a suitable solvent allowed the design of an efficient protocol for the preparative resolution of racemic DPL via preferential crystallization. Therefore, the resolution of DPL enantiomers despite the existence of a racemic compound stable at any temperature demonstrates that the detection of a stable conglomerate is not mandatory for the implementation of preferential crystallization.

Vitrification of two active pharmaceutical ingredients by fast scanning calorimetry: From structural relaxation to nucleation phenomena.

Cinchonidine and Theophylline vitrification abilities have been investigated by differential and fast scanning calorimetry. These active pharmaceutical compounds are known in the literature to have a very high tendency to crystallize which has been confirmed by classical differential scanning calorimetry. Due to the growing interest in amorphous pharmaceutical compounds, their possible vitrifications have been investigated by fast scanning calorimetry. This work shows the high potential of this advanced thermal analysis technique to investigate the vitrification of active pharmaceutical compounds by melt-quenching protocol. For the first time, glass transitions of Cinchonidine and Theophylline were measured. From Cinchonidine, it has been shown that complete glassy state can be obtained by cooling from the melt at 2000K/s. Crystallization has also been suppressed by cooling down from the melt at 2K/s. However, such rate does not avoid the formation of nuclei. Theophylline crystallization process has been suppressed by a melt-quenching protocol carried out with a cooling rate of 4000K/s. However, the phenomenon of nuclei formation upon cooling seems unavoidable at this cooling rate. For both active pharmaceutical compounds, physical aging has been observed to play a role on the nuclei formation below the glass transition leading to modify the subsequent crystallization.

Chiral discrimination in host-guest supramolecular complexes. Understanding enantioselectivity and solid solution behaviors by using spectroscopic methods and chemical sensors.

Diastereomeric host-guest associations formed between permethylated-beta-cyclodextrin (TMbeta-Cd) and the two enantiomers of p-bromophenylethanol (pBrPE) were characterized in aqueous solution by NMR spectroscopy, revealing similar inclusion geometries and weak binding constants, whatever the guest configuration. These features were confirmed by hydrogenation experiments, and do not allow to account for the ability of TMbeta-Cd to resolve racemic pBrPE by successive crystallizations [Grandeury, A.; Petit, S.; Gouhier, G.; Agasse, V.; Coquerel, G. Tetrahedron: Asymmetry 2003, 14, 2143-2152]. The analysis, by means of solid-state NMR, oxidation experiments, and solubility measurements, of the two crystalline phases containing known proportions of guest enantiomers revealed identical inclusion geometries in a given phase, irrespective of the enantiomeric composition. The corresponding solid solutions were further characterized by the determination of an isothermal section (40 degrees C) in the relevant ternary phase diagram. It appears from all these data that chiral resolution mechanisms in this system can only be envisaged in terms of nucleation conditions of each crystal form (with its specific inclusion geometry) and enantiomeric recognition at crystal solution interfaces during the growth of each crystal packing.

Molecular Mobility of an Amorphous Chiral Pharmaceutical Compound: Impact of Chirality and Chemical Purity.

A dielectric relaxation spectroscopy (DRS) study was performed to investigate the molecular mobility of amorphous chiral diprophylline (DPL). For this purpose, both racemic DPL and a single enantiomer of DPL were considered. After fast cooling from the melt at very low temperature (-140 °C), progressive heating below and above the glass transition (Tg ≈ 37 °C) induces two secondary relaxations (γ- and δ-) and primary relaxations (α-) for both enantiomeric compositions. After chemical purification of our samples by means of cooling recrystallization, no γ-process could be detected by DRS. Hence, it was highlighted that the molecular mobility in the glassy state is influenced by the presence of theophylline (TPH), the main impurity in DPL samples. We also proved that the dynamic behavior of a single enantiomer and the racemic mixture of the same purified compound are quasi-identical. This study demonstrates that the relative stability and the molecular mobility of chiral amorphous drugs are strongly sensitive to chemical purity.

Structural Aspects of Solid Solutions of Enantiomers.

A mixture of two enantiomers can crystallize according to three types of heterogeneous equilibria: a racemic compound (a 1:1 stoichiometric compound), a conglomerate (a physical mixture of particles with opposite chirality) or, more rarely, as a solid solution (a crystalline architecture exhibiting a lack of chiral discrimination with respect to the two enantiomers). Due to the scarce occurrence of solid solutions, only a few examples of such behavior are known, and even fewer systems have been investigated by means of single crystal X-ray diffraction. Yet, preliminary work performed in the 1970s by several research teams revealed that structural investigations of solid solutions could provide valuable insights into chiral discrimination mechanisms at the crystal lattice scale. In the present paper, our aim is to review published cases of enantiomeric solid solutions for which both melting phase diagrams and crystal structures are available in order to analyze the lack of chiral discrimination associated to these phases. Our methodology consists in considering both the molecular and crystallographic aspects of stereoselectivity with the final aim of identifying structural criteria responsible for the occurrence of solid solutions. The experimental conditions allowing access to solid solutions will also be considered in light of these structural criteria.

New synthesis of (Z,E)-2,7-bis(4-cyanobenzylidene)cycloheptan-1-one under stereospecific constraints induced by host-guest interactions.

A selective, efficient, and fast access to (Z,E)-2,7-bis(4-cyanobenzylidene)cycloheptan-1-one (BCBCH), precursor of the synthetic antagonist of tissue-plasminogen activator (t-PA), is reported using a solid/solid aldolisation-crotonisation reaction on a supramolecular complex under microwave irradiation. The underlying mechanism is investigated from the crystal structure of the intermediate host-guest complex formed between permethylated gamma-cyclodextrin and (Z)-2-(4-cyanobenzylidene)cycloheptan-1-one.

Structure-Binding Effects: Comparative Binding of 2-Anilino-6-naphthalenesulfonate by a Series of Alkyl- and Hydroxyalkyl-Substituted ß-Cyclodextrins.

Cyclodextrins (CDs) are the most widely used organic hosts for the inclusion of guest molecules. CDs can be readily modified through substitutions of the hydroxyl groups, and these modified CDs can have different host binding properties compared to those of parent CDs. However, only relatively few systematic studies of the effects of chemical substitution on CD binding ability have been reported thus far. In this paper, we report the study of the binding properties of five different analytically pure modified ß-cyclodextrin (ß-CD) hosts (substituted with alkyl and/or hydroxyalkyl groups) with 2-anilino-6-naphthalenesulfonate (2,6-ANS) as guest. Binding constants for the formation of the inclusion complex between 2,6-ANS and each CD were determined using both fluorescence spectroscopy and capillary electrophoresis. Addition of modified CDs to an aqueous solution of 2,6-ANS resulted in significant enhancement of the fluorescence intensity of 2,6-ANS, as well as a significant spectral blue shift, indicative of inclusion. Inclusion of 2,6-ANS within the CD cavity was confirmed by NMR spectroscopy. Substitution at position 3 decreased the magnitude of the binding constants, while alkyl or hydroxylalkyl substitution of the primary hydroxyl at position 6 increased the magnitude of the binding constant in all cases, in relation with increasing length of the alkyl chain linker. In addition, binding constants decreased with solvent polarity when increasing amounts of methanol were added. Structure-binding correlations for CDs based on these binding constant results are presented and discussed.

A hybrid mechanism in chiral discrimination induced by crystallization of supramolecular compounds.

Host-guest complexes formed in aqueous medium between permethylated ß-cyclodextrin (TMß-CD) and racemic 1-(p-fluorophenyl)ethanol (p-F-PE) are studied. The crystalline complexes are characterized and their crystal structures are determined, revealing two sets of solid phases with specific abilities for chiral discrimination: on the one hand, a stable complete solid solution with two independent complexes per asymmetric unit exhibits a limited chiral recognition, and on the other hand, two metastable partial solid solutions with unusual 1:2 host-guest stoichiometries behave as diastereomeric complexes. The structural features of the 1:2 complexes and their study by means of molecular modeling show that these solid phases, described as cocrystals formed between one host-guest inclusion complex and one non-engulfed p-F-PE molecule, present a significant chiral discrimination occurring both inside the cyclodextrin and outside the macrocycle in a crystal lattice cavity. Therefore, the enantioselectivity observed in this system results from an interplay between molecular inclusion in the cyclodextrin and lattice inclusion. To our knowledge, it is the first report of such a hybrid mechanism. An overview of the crystal structures of the literature containing TMß-CD is also achieved and allows their classification in four structural groups in relation to their crystal packing features.

Polarizing a hydrophobic cavity for the efficient binding of organic guests: the case of calix[6]tren, a highly efficient and versatile receptor for neutral or cationic species.

The host-guest properties of calix[6]tren 1 have been evaluated. The receptor is based on a calix[6]arene that is covalently capped at the narrow rim by a tren unit. As a result, the system presents a concave hydrophobic cavity with, at its bottom, a grid-like nitrogenous core. Despite its well-defined cavity and opening to the outside at the large rim, 1 did not behave as a good receptor for neutral molecules in chloroform. However, it exhibited efficient endo-complexation of ammonium guests. By contrast, the per-protonated host, 1.4H(+), behaved as a remarkable receptor for small organic molecules. The complexation is driven by a strong charge-dipole interaction and hydrogen bonds between the polar guest and the tetracationic cap of the calixarene. Finally, coordination of Zn(2+) to the tren core led to the asymmetrization of calixarene cavity and to the strong but selective endo-binding of neutral ligands. This study emphasizes the efficiency of a receptor presenting a concave hydrophobic cavity that is polarized at its bottom. The resulting combination of charge-dipole, hydrogen bonding, CH-pi, and van der Waals interactions highly stabilizes the supramolecular architectures. Also, importantly, the tren cap allows the tuning of the polarization, offering either a basic (1), a highly charged and acidic (1.4H(+)), or a coordination (1.Zn(2+)) site. As a result, the system proved to be highly versatile, tunable, and interconvertible in solution by simple addition of protons, bases, or metal ions.