Search

This study shows that the partial control of fluid inclusion numbers and overall volumes is possible. This is achieved by the addition of antisolvents. Antisolvent addition in this case produced RD...

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...

Sodium chlorate (NaClO3) is an achiral compound exhibiting supramolecular chirality at the solid state. It is historically the model compound used by Viedma to report his discovery of the symmetry breaking phenomenon now called Viedma ripening. In this paper, a temperature cycling induced deracemization (TCID) process – recently described as particularly efficient for organic compound deracemization – was developed for NaClO3 and the results were compared to the well-known Viedma ripening process. While the presence of chiral impurities usually improve of the efficacy of chiral compounds TCID, we observed that the voluntary addition of an inorganic impurity (sodium dithionate, Na2S2O6) had an opposite effect on the TCID process of NaClO3. Indeed, the process was strongly delayed by the presence of Na2S2O6. This phenomenon was explained by a suitable combination of crystal growth rate and secondary nucleation rate evaluations.

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. However, when PZA is cospray dried with 1,3-dimethylurea (DMU), it has been reported to remain in its γ form for several years. Scanning electron microscopy (SEM) images reveal that the phase transition from γ-PZA to the low temperature forms involves a vapor-mediated recrystallization, while the reverse phase transition upon heating is a nucleation-and-growth solid–solid phase transition. The lifetime-extending effect of DMU on spray-dried PZA has been investigated in more detail and compared with high-energy ball milling of sublimation-grown γ-PZA crystals. Co-ball milling of PZA and DMU is found to extend the lifetime of the high temperature form of PZA to a few months, while separate ball milling leads to an extension of merely a few weeks. DMU acts as an additive that most likely stabilizes the surface of γ-PZA, which would reduce the vapor pressure of PZA, thereby reducing the transition rate. Alternatively, DMU could prevent nucleation of low temperature forms of PZA., Co-spray drying of pyrazinamide (PZA) with 1,3-dimethylurea (DMU) has been reported to extend the lifetime of the high temperature γ form of PZA from several days to several years. The lifetime-extending effect of DMU and the phase transition mechanisms of PZA have been investigated in more detail and compared with high-energy ball milling of sublimation-grown γ-PZA crystals.

The present study aimed at screening conglomerate derivatives of racemic chlocyphos (4-(2-chlorophenyl)-5,5-dimethyl-2-hydroxy-1,3,2-dioxaphosphorinane 2-oxide) and to perform enantiomeric separati...

An improved process for the deracemization of a racemic conglomerate suspension of enantiomorphs has been created based on principles developed in an earlier method using temperature fluctuations. The method consists of circulating the suspension between two vessels, each controlled at a specific temperature in order to make the process more effective and faster to achieve a homochiral solid state. Crystals in the suspension were partially dissolved in the hot vessel, and the remaining crystals were regrown in the cold vessel. The crystals in the cold vessel have a longer residence time than those in the hot vessel to allow more time for the crystal growth process. The results show that complete deracemization can be achieved via this process far more rapidly than by using the previous temperature cycling (one-vessel) process. Moreover, the new process could easily be scaled up to an industrial scale. The current process can be an effective alternative to currently used enantiopurification methods, with s...

Crystals belonging to P1 and P21 space groups are fascinating research targets because of their potential applications in various fields by taking advantage of their chirality and polarity. However, molecules intrinsically prefer symmetric, achiral nonpolar space groups due to canceling out of dipole moments and close packing in crystalline states. Therefore, it remains difficult to selectively obtain the P1 and P21 crystals, especially from achiral molecules. Here we achieve construction of the chiral P1 and P21 crystals from achiral molecules based on stacking control of chiral two-dimensional hydrogen-bonded layers by halogen bonds (XBs). Precise investigations and theoretical calculations of their crystal structures revealed that space group selectivity among the chiral P1, P21, and achiral space groups is the result of a subtle balance between the stronger interaction: charge-assisted hydrogen bonds and the weaker interactions: van der Waals interaction of alkyl chains and the bonding involving halog...

A deracemization technique using periodic temperature fluctuations on a conglomerate forming system undergoing a swift racemization in solution is demonstrated. The method uses heating and cooling periods of the suspension in order to create cycles of partial dissolution of the crystal phase followed by crystal regrowth: this enables symmetry breaking in the solid phase. The technique is an effective, simple, and cheap operation, and can promote understanding of the effects of dissolution and recrystallization on chiral symmetry breaking in the solid phase. The heating period leads to the decrease of the size of crystals and the destruction of small crystals; the surviving crystals can then grow during the cooling period. A succession of such cycles allows the autocatalytic transformation from a racemic suspension into pure enantiomer, with an enantiomeric excess (ee) > 99% within a few days. The results demonstrate a possible mechanism for the emergence of homochirality of molecules of biological signifi...

(±)-Bis-tetralone (BisT) crystallizes as a stable conglomerate that can be resolved by preferential crystallization. This preferential crystallization was performed by autoseeded polythermic programmed preferential crystallization (AS3PC) and autoseeded preferential crystallization induced by solvent evaporation (ASPreCISE) variants in dimethylformamide and dichloromethane. Prior to performance of these resolutions, an extensive purification was necessary because the presence of impurities had a strong negative impact on the stereoselective crystal growth. Moreover, the presence of multiepitaxy phenomena required a vigorous stirring during the preferential crystallization in order to avoid a poor optical purity of the crops. Several preferential crystallization attempts demonstrate that ASPreCISE is recommended when there is an unfavorable variation of solubility versus temperature or when chemical degradation occurs on heating.

Crystals of three organic compounds grown several decades ago have been retrieved from a cellar of the Faculte de Pharmacie of Paris. The presence of liquid inclusions in these large particles has provided a unique opportunity to investigate the effects of aging on these macroscopic defects. Beside their evolution toward a shape of negative crystals, it appeared that all liquid inclusions contain a (sometimes large) gaseous bubble in equilibrium with the saturated solution. Hot-stage microscopy analyses revealed that bubbles disappear upon heating, and form back on cooling with hysteresis. Furthermore, it could be established from the combination of structural, crystal growth, and morphological studies with detailed physical characterizations that the formation of inclusions is probably due to a local growth inhibition during the development of faces situated at the extremities of elongated particles, possibly involving in some cases a structural disorder. Our results also suggest that adhesion and/or het...

During the crystallization of the monohydrated disodium salt of hydroxydimethylallyl pyrophosphonate (C-HDMAPP·Na2·H2O) induced by addition of ethanol to an aqueous solution, a synthesis impurity (C-ethylPP2−) can be incorporated into the crystal lattice. Owing to the chemical similarity between the two anionic molecular entities, a solid solution of substitution type is produced and has been characterized by X-ray powder diffraction (XRPD), thermal analysis, and dynamic vapor sorption (DVS). Besides the incidence of the solid solution on diffraction peak positions caused by expansion/contraction of the lattice, XRPD revealed that a distinct crystalline phase is obtained when the proportion of impurity is higher than ca. 20 wt %. The crystal structure of both C-HDMAPP·Na2·H2O and C-ethylPP·Na2 phases were determined, which allowed molecular modeling investigations. A mechanism has been proposed to explain the substitution at a molecular level and is consistent with the correlation observed between the act...

1,2-Naphthoquinone-2-semicarbazone (i.e., naftazone) has been characterized by structural analysis (single-crystal X-ray diffraction, powder X-ray diffraction) and by thermal analysis (differential scanning calorimetry, DSC). Although this molecule has no chiral center, the two forms crystallize in chiral space groups: the stable form I (P212121, Z = 4, a = 5.1187(7) A, b = 5.6092(7) A, c = 34.847(5) A; V = 1000.5(2) A3) and the metastable form II (P21, Z = 2, a = 6.3349(1) A, b = 3.9263(1) A, c = 19.790(5) A, β = 92.424(4)°; V = 491.8(2) A3). At high concentration (c = 30 g·L−1), the pure stable form I crystallizes regardless of the antisolvent (water) addition rate. At low concentration (c = 15 g·L−1), the pure metastable form II crystallizes at low water addition rate (ψ = 100 mL·h−1); however, the structurally pure form I is also obtained with a high water addition rate (ψ = 72 × 103 mL·h−1). Concomitant polymorphs crystallize at intermediate antisolvent addition rate and concentration. Therefore in t...

Different types of defects observed inside single crystals of ciclopirox (obtained by recrystallization in ethyl acetate) are characterized. Confocal Raman spectroscopy and optical microscopy analyses revealed the coexistence of three types of defects: (i) liquid inclusions containing saturated solution with or without gas bubbles inside these inclusions, (ii) open cavities with the shape of channels, (iii) isolated gas bubbles inside the crystal matrix. It seems that the two first types of defects originate from the trapping of mother solution during crystal growth. The trapped supersaturated solution continues to crystallize inside the defect, until the formation of a negative crystal (liquid inclusion having the shape of a single crystal). This crystallization is associated with a decrease in volume, responsible in some cases for the formation of a gas bubble. However, if the liquid pocket is not sealed when the crystal is extracted from the mother solution, it produces open channels by evaporation of the solvent. The formation of isolated gas bubbles seems to result from another mechanism.

Detection of conglomerates by using second harmonic generation (SHG) effect is comprehensively reviewed. The fundamentals together with the possibilities and the limitations are detailed. An experimental set up is described and the application of this high throughput prescreening technique is exemplified using (±)-trans-1,2-diaminocyclohexane salts.

The present paper reports a study on the chiral discrimination at the solid state of methyl 2-(diphenylmethylsulfinyl)acetate (hereafter, DMSAM) as a key intermediate in the synthesis of an acetamide derivative (modafinil). A partial solid solution (i.e., stable “racemic conglomerate” with partial miscibility at the solid state) between enantiomers was characterized by X-ray single crystal analyses and high performance liquid chromatography (HPLC). Binary and ternary phase diagrams of DMSAM were investigated by HPLC measurements, differential scanning calorimetry (DSC), discontinuous isoperibolic thermal analysis (DITA), and Raman spectroscopy. Finally, the distribution of the two enantiomers inside single crystals was studied by dissolution and Raman microspectroscopy.

Form I (HT) and form III (LT) of pleconaril are enantiotropically related with a calculated temperature of transition Tτ = 35.7 °C (supposing an ideal behavior). Structural data obtained from single crystal X-ray diffraction at 100 K and room temperature show that (i) form I (HT) can be described as a network of dimers and form III can be described as a three-dimensional weakly H-bonded network of monomers. (ii) These two varieties contradict the density rule. (iii) The solid−solid transition (not observed) could only occur via a destructive−reconstructive mechanism. Investigations on the pleconaril−ethanol binary system show that the conversion form I ⇔ form III at Tτ = 31 ± 2 °C is only possible when mediated by a solvent. A favorable set of thermodynamical and kinetic conditions allows quantification of form I in form III down to 0.1% by using differential scanning calorimetry. To assess the structural purity, this method could be applied to other compounds fulfilling five restrictive conditions.

Polymorphic forms I and III of (±) modafinil have been studied. In contrast to the structure of form I which could be solved by using conventional single crystal X-ray diffraction, the crystal structure of form III could not be elucidated due to the shape and the size of the single crystals resulting from the high supersaturation under which this phase is obtained. To bypass the problem, the derived crystal packing (DCP) model has been successfully applied by recombining the slice (002)A extracted from form I. The calculated XRPD pattern of form III fits well with the experimental data. The extensive similarities between the two crystal structures are carefully detailed.