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We report the first case of mechanochemical deracemization by using liquid-assisted abrasive grinding. The target molecule is a precursor of Paclobutrazol, an important fungicide and plant growth inhibitor. Using mechanochemical deracemization, we are even able to transform a 10 % ee scalemic mixture of this latter in an enantioenriched product of 97 % ee in a couple of hours. This is substantially shorter compared to solution-based deracemization methodologies. The present paper thus introduces an efficient and greener process to enantiopure material.

International audience; Oxychalcogenides are promising candidates for the design of IR nonlinear optical materials. Here, we prepared the first oxysulfide in the polar Fresnoite mineral type, Ba2SnSSi2O7 , and show that it has rare tin square pyramids, SnO4S, with apical Sn-S bond. These units and the Si2O7 groups are corner-shared to form the SnSSi2O7 layer with their Sn-S and apical Si-O bonds pointed along the polar c axis. Second harmonic generation measurements reveal that Ba2SnSSi2O7 is an IR NLO compound. Formally, Ba2SnSSi2O7 results from the mineral Fresnoite, Ba2TiOSi2O7 , by replacing the TiO5 square pyramid with the SnO4S square pyramid. This substitution increases the apical/the equatorial bond ratio of the square pyramid, namely, Ti-Oap /Ti-Oeq = 1.66/2.00 = 0.83 in TiO5 , and Sn-S/Sn-O = 2.03/2.31 = 0.88 in SnO4S. This change has a major impact on the cleavage along the stacking polar c-axis and on the second harmonic generation response, which decreases from Ba2TiOSi2O7 to Ba2SnSSi2O7 by a factor greater than two. The atom response theory analyses based on the density functional theory calculations reveal a remarkable difference between Ba2TiOSi2O7 and Ba2SnSSi2O7 ; the second harmonic generation is positive for the Ti4+ ion of Ba2TiOSi2O7 , but negative for the Sn4+ ion of Ba2SnSSi2O7. A Tauc plot analysis for Ba2SnSSi2O7 assuming indirect and direct transitions led to the optical band gaps of 2.4 and 2.7 eV, respectively.

International audience; The crystal structure of (S)-(+)-p-synephrine was refined at 296 K from X-ray powder diffraction. The compound crystallizes in the orthorhombic systemP2(1)2(1)2(1)with four molecules per unit cell and Z ' = 1. The cell parameters are equal toa= 6.5925(12) angstrom,b= 7.9915(14) angstrom, andc= 17.035(4) angstrom. The melting characteristics of the enantiomers were determined at high DSC scan rates. The pure enantiomers melt at T-fus= 176.6 +/- 0.9 degrees C with a melting enthalpy equal to 234.2 +/- 3.9 J g(-1). Coupling DSC and crystallographic analysis, a stable binary phase diagram between these chiral molecules was established taking into account the racemic compound. Two symmetrical eutectic invariants at: 172.7 +/- 0.5 degrees C for x = 0.05 and x = 0.95 were found pretty close to the melting temperature of the enantiomers. Additionally, the equimolar mechanical mixture of the two enantiomers led to a metastable conglomerate whose melting temperature was estimated to be 149 degrees C, thanks to the Schroder-van Laar relation. The activation energy of the transition from the metastable conglomerate toward the racemic compound was estimated to be E-a = 145 kJ mol(-1)by a nonlinear optical method. This new isothermal second harmonic generation application performed at different temperatures is of general applicability for the assessment of the activation energy associated with the irreversible heterogeneous reaction: + -> .

In this study, co-crystals for Praziquantel (PZQ), an anthelmintic drug used to treat schistosomiasis, are predicted with network-based link prediction. Single crystals of twelve co-crystal indications were grown and subjected to a structural analysis with single-crystal X-ray diffraction.

Mixed-anion compounds are among the most promising systems to design functional materials with enhanced properties. In particular, heteroleptic environments around transition metals allow tuning of the polarity or band-gap engineering for instance. We present the original oxysulfide Ba

Mixed-anion compounds are among the most promising systems to design functional materials with enhanced properties. In particular, heteroleptic environments around transition metals allow tuning of the polarity or band-gap engineering for instance. We present the original oxysulfide Ba5(VO2S2)2(S2)2, the fifth member in the quaternary system Ba–V–S–O. It exhibits the mixed-anion building units V5+O2S2 and isolated disulfide pairs (S2)2–. The structure is solved by combining single-crystal and powder X-ray diffraction and transmission electron microscopy. First-principles calculations were combined in order to highlight the anion roles. In particular, our density functional theory study shows that the 3p states of the disulfide pairs dictate the band gap. In this study, we point out anionic tools for band-gap engineering that can be useful for the design of phases for numerous applications. Finally, third harmonic generation (THG) was measured and compared to the large THG observed for Cu2O, which reveals the potential for nonlinear-optical properties that should be further investigated. 59;9

Two polytypes of the new oxyvanadate matrix La

International audience; To decide whether an active pharmaceutical ingredient can be used in its amorphous form in drug formulations, often the glass transition is studied in relation to the melting point of the pharmaceutical. If the glass transition temperature is high enough and found relatively close to the melting point, the pharmaceutical is considered to be a good glass former. However, it is obviously important that the observed melting point and glass transition involve exactly the same system, otherwise the two temperatures cannot be compared. Although this may seem trivial, in the case of hydrates, where water may leave the system on heating, the composition of the system may not be evident. Atorvastatin calcium is a case in point, where confusing terminology, absence of a proper an-hydrate form, and loss of water on heating lead to several doubtful conclusions in the literature. However, considering that no anhydrate crystal has ever been observed and that the glass transition of the anhydrous system is found at 144°C, it can be concluded that if the system is kept isolated from water, the chances that atorvastatin calcium crystallises at room temperature is negligible. The paper discusses the various thermal effects of atorvastatin calcium on heating and proposes a tentative binary phase diagram with water.

International audience; Two polytypes of the new oxyvanadate matrix La7O6(VO4)3 were identified and deeply characterized. The crystal structure of the α-polytype was solved using a combination of precession electron diffraction and powder X-ray diffraction (XRD) techniques. It crystallizes in a monoclinic unit cell with space group P21, a = 13.0148(3) Å, b = 19.1566(5) Å, c = 7.0764(17) Å, and β = 99.87(1)°. Its structure is built upon [La7O6]9+ polycationic units at the origin of a porous 3D network, evidencing rectangular channels filled by isolated VO4 tetrahedra. An in situ high-temperature XRD study highlights a number of complex phase transitions assorted with the existence of a β-polytype also refined in a monoclinic unit cell, space group P21/n, a = 13.0713(4) Å, b = 18.1835(6) Å, c = 7.1382(2) Å, and β = 97.31(1)°. Thus, during the transitions, while the polycationic networks are almost identical, the vanadate’s geometry is largely modified. The use of Eu3+ and Sm3+ at different concentrations in the host lattice is possible using solid-state techniques. The photoluminescence (PL), PL excitation (PLE) spectra, and luminescence decay times were recorded and discussed. The phosphors present an emission light, being bright and reddish orange after excitation under UV. This is mainly due to the V–O band and f–f transitions. Whatever the studied polytype, the final luminescence properties are retained during the heating/cooling process.

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.

International audience; An open-framework silicoaluminophosphate (SAPO) material with a composition of Cs2(Al0.875Si0.125)4(P0.875Si0.125O4)4(HPO4) was synthesized in an organic template-free cesium-containing system under hydrothermal conditions. The material was resolved to be isostructural with an open-framework aluminophosphate (AlPO) material AlPO-CJ19, which was previously synthesized using pyridine as the solvent and 2-aminopyridine as the organic template via a solvothermal route. The substitution of organic templates by alkaline cations not only makes the current synthesis protocol more favorable from an environmental point of view but also leads to a significantly improved thermal stability of this structure. The framework is kept completely stable at a temperature of 510 oC. A high-temperature polymorph was discerned at a temperature higher than 540 oC, the structure of which is revealed to crystallize in P1c1 space group. UV-vis results reveal that cobalt and copper cations could be readily incorporated through simple ion-exchange treatment. The conductivity of the material is 1.70*10-4 S cm-1 (293K, 30% relative humidity) as revealed by the Alternating Current (A.C.) impedance spectroscopy analysis. This is the first report of the synthesis of silicon-containing phase with AlPO-CJ19 structure.

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...

International audience; The effect of low molecular weight excipients on drug–excipient interactions, molecular mobility, and propensity to recrystallization of an amorphous active pharmaceutical ingredient is investigated. Two structurally related excipients (α-pentaacetylglucose and β-pentaacetylglucose), five different drug:excipient ratios (1:5, 1:2, 1:1, 2:1, and 5:1, w/w), and three different solid state characterization tools (differential scanning calorimetry, X-ray powder diffraction, and dielectric relaxation spectroscopy) were selected for the present research. Our investigation has shown that the excipient concentration and its molecular structure reveal quasi-identical molecular dynamic behavior of solid dispersions above and below the glass transition temperature. Across to complementary quantum mechanical simulations, we point out a clear indication of a strong interaction between biclotymol and the acetylated saccharides. Moreover, the thermodynamic study on these amorphous solid dispersions highlighted a stabilizing effect of α-pentaacetylglucose regardless of its quantity while an excessive concentration of β-pentaacetylglucose revealed a poor crystallization inhibition. Finally, through long-term stability studies, we also showed the limiting excipient concentration needed to stabilize our amorphous API. Herewith, the developed procedure in this paper appears to be a promising tool for solid-state characterization of complex pharmaceutical formulations.

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CaTeO3(H2O) was obtained from microwave-assisted hydrothermal synthesis as a polycrystalline sample material. The dehydration reaction was followed by thermal analysis (thermogravimetric/differential scanning calorimetry) and temperature-dependent powder X-ray diffraction and leads to a new δ-CaTeO3 polymorph. The crystal structures of CaTeO3(H2O) and δ-CaTeO3 were solved ab initio from PXRD data. CaTeO3(H2O) is non-centrosymmetric: P21cn; Z = 8; a = 14.785 49(4) Å; b = 6.791 94(3) Å; c = 8.062 62(3) Å. This layered structure is related to the ones of MTeO3(H2O) (M = Sr, Ba) with layers built of edge-sharing [CaO6(H2O)] polyhedra and are capped of each side by [Te(IV)O3E] units. Adjacent layers are stacked along the a-axis and are held together by H-bonds via the water molecules. The dehydration reaction starts above 120 °C. The transformation of CaTeO3(H2O) into δ-CaTeO3 (P21ca; Z = 8; a = 13.3647(6) Å; b = 6.5330(3) Å; c = 8.1896(3) Å) results from topotactic process with layer condensation along the a-axis and the 1/2b⃗ translation of intermediate layers. Thus, δ-CaTeO3 stays non-centrosymmetric. The characteristic layers of CaTeO3(H2O) are also maintained in δ-CaTeO3 but held together via van der Waals bonds instead of H-bonds through water molecules. Electron localization function and dipole moment calculations were also performed. For both structures and over each unit cell, the dipole moments are aligned antiparallel with net dipole moments of 3.94 and 0.47 D for CaTeO3(H2O) and δ-CaTeO3, respectively. The temperature-resolved second harmonic generation (TR-SHG) measurements, between 30 and 400 °C, show the decreasing of the SHG intensity response from 0.39 to 0.06 × quartz for CaTeO3(H2O) and δ-CaTeO3, respectively.

The application of powder second harmonic generation (P-SHG), temperature-resolved SHG (TR-SHG), and SHG microscopy (SHGM) in the characterization of bulk crystalline samples is illustrated. P-SHG applied to powder samples can be an extremely sensitive approach to detect the absence of an inversion center in crystalline structures, TR-SHG serves to monitor temperature-induced phase transitions, and SHGM is used in the detection of non-centrosymmetric zones inside a heterogeneous material. These methods are of great relevance, e.g., in the pharmaceutical industry where crystalline active pharmaceutical ingredients are often made of a single enantiomer and are therefore non-centrosymmetric. Herein, several examples are provided to describe how a given SHG signal should be interpreted. A general procedure to carry out a P-SHG experiment is illustrated in detail.

The present study focuses on the ability of excipients to induce the crystallization of a specific polymorphic form of pyrazinamide (PZA) and more interestingly, to block the irreversible solid–solid transition of the metastable forms of the PZA to the stable form at room temperature. We outline an experimental protocol for the production of a structurally pure γ form of PZA by means of spray drying. Without any particular treatment, phase transition to δ form was detected after 14 days of storage under ambient conditions. In order to prevent this irreversible phase transition, different excipients were co-spray dried with PZA. By co-spray drying 5% in mass of 1,3-dimethylurea (DMU) with PZA, we noticed its ability in preventing phase transitions and thus to maintain PZA under its γ form up to 12 months of storage at room temperature. Raman spectroscopy evidenced how DMU crystals surround particles of γ PZA which suggest that DMU might interact with the surface of PZA particles, thus blocking the phase transition. On the other hand, the co-spray drying of PZA with the polymerpolyvinylpyrrolidone (PVP) resulted in the crystallization of δ form of PZA. The physical mixture was intact over 12 months of storage at room temperature.

We study the physicochemical transformations of crystalline quinidine upon high-energy milling. The investigations have been achieved by classical, high performance, and fast scanning calorimetry combined with broadband dielectric spectroscopy and X-ray powder diffraction. As evolution of crystalline quinidine with time of milling revealed a prominent sub-Tg cold-crystallization phenomenon, independent and complementary analytical techniques were implemented. Fast scanning calorimetry was performed for the first time on a milled pharmaceutical compound to postpone the crystallization event to higher temperatures. These fast thermal analyses allowed one to spotlight a genuine glass transition event. In addition, an aging experiment on the milled powder revealed a clear structural relaxation testifying to the presence of a glassy fraction in the milled sample. Last, dielectric analysis of milled quinidine disclosed the presence of localized and delocalized molecular mobility characteristics of glasses. Resu...

Particularly relevant in the context of polymorphism is understanding how structural, thermodynamic, and kinetic factors dictate the stability domains of polymorphs, their tendency to interconvert through phase transitions, or their possibility to exist in metastable states. These three aspects were investigated here for two 4′-hydroxyacetophenone (HAP) polymorphs, differing in crystal system, space group, and number and conformation of molecules in the asymmetric unit. The results led to a ΔfGm°-T phase diagram highlighting the enantiotropic nature of the system and the fact that the Z′ = 1 polymorph is not necessarily more stable than its Z′ = 2 counterpart. It was also shown that the form II → form I transition is entropy driven and is likely to occur through a nucleation and growth mechanism, which does not involve intermediate phases, and is characterized by a high activation energy. Finally, although it has been noted that conflicts between hydrogen bond formation and close packing are usually behin...

The crystallization behavior and morphological features of particles obtained from amorphous diprophylline (DPL) are reported. After fast cooling of the melt, progressive heating above the glass transition (Tg ≈ 37 °C) induces the nucleation and growth of well-shaped crystals: PC for primary crystals. The combination of differential scanning calorimetry, hot stage optical microscopy, powder X-ray diffraction, and Raman spectroscopy revealed that these PC are kinetically favored and can form spontaneously in the supercooled melt whatever the enantiomeric composition, although their development and relative stability are influenced by the presence of theophylline, the main impurity in DPL samples. Specific crystal surfaces of the PC act as favorable areas and support for the subsequent formation of previously known metastable crystal forms consisting of solid solutions of the two DPL enantiomers. This study demonstrates the complex multistep mechanism that can occur during the temperature-induced crystalliz...

International audience; In this article, we conduct a comprehensive molecular relaxation study of amorphous Quinidine above and below the glass-transition temperature (Tg) through broadband dielectric relaxation spectroscopy (BDS) experiments and theoretical density functional theory (DFT) calculations, as one major issue with the amorphous state of pharmaceuticals is life expectancy. These techniques enabled us to determine what kind of molecular motions are responsible, or not, for the devitrification of Quinidine. Parameters describing the complex molecular dynamics of amorphous Quinidine, such as Tg, the width of the α relaxation (βKWW), the temperature dependence of α-relaxation times (τα), the fragility index (m), and the apparent activation energy of secondary γ relaxation (Ea-γ), were characterized. Above Tg (> 60 °C), a medium degree of nonexponentiality (βKWW = 0.5) was evidenced. An intermediate value of the fragility index (m = 86) enabled us to consider Quinidine as a glass former of medium fragility. Below Tg (< 60 °C), one well-defined secondary γ relaxation, with an apparent activation energy of Ea-γ = 53.8 kJ/mol, was reported. From theoretical DFT calculations, we identified the most reactive part of Quinidine moieties through exploration of the potential energy surface. We evidenced that the clearly visible γ process has an intramolecular origin coming from the rotation of the CH(OH)C9H14N end group. An excess wing observed in amorphous Quinidine was found to be an unresolved Johari–Goldstein relaxation. These studies were supplemented by sub-Tg experimental evaluations of the life expectancy of amorphous Quinidine by X-ray powder diffraction and differential scanning calorimetry. We show that the difference between Tg and the onset temperature for crystallization, Tc, which is 30 K, is sufficiently large to avoid recrystallization of amorphous Quinidine during 16 months of storage under ambient conditions.

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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...

Even if (±)-trans-1,2-diaminocyclohexane crystallizes as a conglomerate, its low melting point (−10 °C) and its sensitivity to light, CO2, O2, and moisture make this molecule difficult to resolve. It has been shown that the citrate monohydrate of this compound crystallizes as a stable conglomerate with a high thermal stability (up to 163 °C) with no drawbacks as to those listed above for the pure diamine. The crystal structure of this salt, resolved by single crystal X-ray diffraction, reveals structural features consistent with the thermal stability of this phase. Several preferential crystallization attempts (AS3PC) have been performed at a 100 ml scale and at a one liter scale in water with and without additives. Finally a productivity of 40 g per batch per liter of solvent per hour was achieved with a crude enantiomeric purity better than 90%. A simple recrystallization of the crude crops gives quantitatively the crystalline compound with an ee >99% proving the absence of partial solid solution at room temperature.

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.

This study investigates for the first time the thermodynamic changes of Biclotymol upon high-energy milling at various levels of temperature above and below its glass transition temperature (Tg). Investigations have been carried out by temperature modulated differential scanning calorimetry (TM-DSC) and X-ray powder diffraction (XRPD). Results indicate that Biclotymol undergoes a solid-state amorphization upon milling at Tg-45 °C. It is shown that recrystallization of amorphous milled Biclotymol occurs below the glass transition temperature of Biclotymol (Tg=20 °C). This displays molecular mobility differences between milled Biclotymol and quenched liquid. A systematic study at several milling temperatures is performed and the implication of Tg in the solid-state transformations generally observed upon milling is discussed. Influence of analysis temperature with respect to interpretation of results was investigated. Finally, it is shown that co-milling Biclotymol with only 20 wt% of amorphous PVP allows a stable amorphous dispersion during at least 5 months of storage.

Dehydration of trehalose dihydrate implemented by slow heating (1 K min−1), has been monitored by Raman microspectroscopy from 25 to 110°C directly on single crystals. Between 90 and 120°C, gas initially trapped in irregular macroscopic defects, reorganizes to form spherical vacuoles. The Raman analysis of these vacuoles highlights that the areas in vicinity of the defects are the first affected by the dehydration mechanisms. Indeed, the progressive amorphization of the crystal starts around these defects.

CaTeO3(H2O) is prepared by microwave-assisted hydrothermal reaction of Ca(NO3)2, TeO2, NaOH, and H2O (microwave furnace, autoclave, 185 °C, 1 h).

The present case study focuses on the crystallization kinetics and molecular mobility of an amorphous mouth and throat drug namely Biclotymol, through differential scanning calorimetry (DSC), temperature resolved X-ray powder diffraction (TR-XRPD) and hot stage microscopy (HSM). Kinetics of crystallization above the glass transition through isothermal and non-isothermal cold crystallization were considered. Avrami model was used for isothermal crystallization process. Non-isothermal cold crystallization was investigated through Augis and Bennett model. Differences between crystallization processes have been ascribed to a site-saturated nucleation mechanism of the metastable form, confirmed by optical microscopy images. Regarding molecular mobility, a feature of molecular dynamics in glass-forming liquids as thermodynamic fragility index m was determined through calorimetric measurements. It turned out to be around m=100, describing Biclotymol as a fragile glass-former for Angell's classification. Relatively long-term stability of amorphous Biclotymol above Tg was analyzed indirectly by calorimetric monitoring to evaluate thermodynamic parameters and crystallization behavior of glassy Biclotymol. Within eight months of storage above Tg (T=Tg+2°C), amorphous Biclotymol does not show a strong inclination to crystallize and forms a relatively stable glass. This case study, involving a multidisciplinary approach, points out the importance of continuing looking for stability predictors.

International audience; Polyelectrolyte multilayers are now a well established concept with numerous potential applications in particular as biomaterial coatings. To timely control the biological activity of cells in contact with a substrate, multicompartment films made of different polyelectrolyte multilayers deposited sequentially on the solid substrate constitute a promising new approach. In a first paper (Langmuir 2004, 20, 7298) we showed that such multicompartment films can be designed by alternating exponentially growing polyelectrolyte multilayers acting as reservoirs and linearly growing ones acting as barriers. In the present study, we first demonstrate however that these barriers composed of synthetic polyelectrolytes are not degraded despite the presence of phagocytic cells. We propose an alternative approach where exponentially growing poly-(L-lysine)/hyaluronic acid (PLL/HA) multilayers, used as reservoirs, are alternated with biodegradable polymer layers consisting in poly(lactic-co-glycolic acid) (PLGA) and acting as barriers for PLL chains that diffuse within the PLL/HA reservoirs. We first show that these PLGA layers can be deposited alternatively with PLL/HA multilayers leading to polyelectrolyte multilayer/hydrolyzable polymeric layer films and acting as a reservoirs/barriers system. Bone marrow cells seeded on these films ending by a PLL/HA reservoir rapidly degrade it and internalize the PLL chains confined in this reservoir. Then the cells degraded locally the PLGA barrier and internalize the PLL localized in a lower (PLL/HA) compartment after 5 days of seeding. By changing the thickness of the PLGA layer, we hope to be able to tune the time delay of degradation. Such mixed architectures made of polyelectrolyte multilayers and hydrolyzable polymeric layers could act as coatings allowing us to induce a time scheduled cascade of biological activities. We are currently working on the use of comparable films with compartments filled by proteins or peptides and in which the degradation of the barriers results from a hydrolysis over tunable time scales.

This work illustrates the use of powder second harmonic generation (powder SHG), temperature-resolved second harmonic generation (TR-SHG), and second harmonic generation microscopy (SHGM) in monoph...

We show the detection of an order–disorder like transition by temperature-resolved second harmonic generation (TR-SHG) in a series of triazoyl ketone (X-TAK derivatives). These compounds have the particularity to exhibit a disorder on the tert-butyl (t-Bu) group that was highlighted by single crystal X-Ray diffraction (SC-XRD). TR-SHG confirms the nature of this disorder as a dynamic disorder and allows to determine the freezing temperature of the t-Bu motion.

We present a polarization-independent double phase conjugate mirror (DPCM) working at telecommunication wavelength 1.32 μm. To do this, InP:Fe photorefractive crystals are used. A 2Z-DPCM configuration is realized in order to eliminate conical diffraction and to reduce the instabilities. With this device, the conjugation efficiency remains almost unchanged when the polarization state of the incident beam varies. Dynamic measurements demonstrate that the device is well-adapted to relatively slow variations of the polarization, induced by thermal variations for example.

The design of molecule-based systems combining magnetic, chiroptical and second-order optical nonlinear properties is still very rare. We report an unusually unsymmetric diiron(III) complex 1, in which three bulky chiral carboranylpyridinealkoxide ligands (oCBhmp-) bridge both metal ions and the complex shows the above-mentioned properties. The introduction of o-carborane into the 2-(hydroxymethyl)pyridine (hmpH) architecture significantly alters the coordination of the simple or aryl-substituted 2-hmpH. The unusual architecture observed in 1 seems to be triggered by the poor nucleophilicity of our alkoxide ligand (oCBhmp-). A very rare case of spontaneous resolution takes place on precipitation or exposure to solvent vapor for the bulk compound, as confirmed by a combination of single-crystal and powder X-ray diffraction, second-harmonic generation, and circular dichroism. The corresponding enantiopure complexes (+)1 and (-)1 have also been synthesized and fully characterized. This research provides a new building block with unique geometry and electronics to construct coordination complexes with multifunctional properties. Fil: Di Salvo, Florencia. Consejo Superior de Investigaciones Científicas. Instituto de Ciencia de Los Materiales de Barcelona; España. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina Fil: Tsang, Min Ying. Consejo Superior de Investigaciones Científicas. Instituto de Ciencia de Los Materiales de Barcelona; España Fil: Teixidor, Francesc. Consejo Superior de Investigaciones Científicas. Instituto de Ciencia de Los Materiales de Barcelona; España Fil: Viñas, Clara. Consejo Superior de Investigaciones Científicas. Instituto de Ciencia de Los Materiales de Barcelona; España Fil: Planas, José Giner. Consejo Superior de Investigaciones Científicas. Instituto de Ciencia de Los Materiales de Barcelona; España Fil: Crassous, Jeanne. Universite de Rennes I; Francia Fil: Vanthuyne, Nicolas. Aix Marseille Université; Francia Fil: Aliaga Alcalde, Núria. Consejo Superior de Investigaciones Científicas. Instituto de Ciencia de Los Materiales de Barcelona; España Fil: Ruiz, Eliseo. Universidad Central de Barcelona; España Fil: Coquerel, Gerard. Universite de Rouen; Francia Fil: Clevers, Simon. Universite de Rouen; Francia Fil: Dupray, Valerie. Universite de Rouen; Francia Fil: Choquesillo Lazarte, Duane. Consejo Superior de Investigaciones Científicas; España Fil: Light, Mark E.. University of Southampton; Reino Unido Fil: Hursthouse, Michael B.. University of Southampton; Reino Unido

Temperature-resolved second harmonic generation (TR-SHG) and SHG microscopy were used to study under normal pressure the solid–solid transition mechanism occurring between the two monotropically related polymorphic forms (metastable Pna21 and stable P21/n) of 3-hydroxybenzoic acid (MHBA). The activation energy Ea (as a measure of the barrier energy) of the irreversible transition was determined via isothermal TR-SHG (137–144 kJ·mol–1). It fits well with that determined from differential scanning calorimetry (139 kJ·mol–1). Regarding the two crystal structures, optical microscopy observations, and kinetics parameters from TR-SHG, a destructive/reconstructive mechanism is proposed for the solid–solid transition. The present study clearly demonstrates that TR-SHG is a relevant and accurate technique for monitoring solid–solid phase transitions.

We report the use of second harmonic generation (SHG) and temperature resolved second harmonic generation (TR-SHG) for in situ probing and monitoring the structural purification of m-hydroxybenzoic acid (MHBA). Pure and mixtures of the two polymorphic forms of MHBA (metastable Pna21 and stable P21/c) and commercial MHBA were analysed by: DSC, XRPD and SHG. Results obtained with these three techniques are compared and demonstrate for that particular component, the high sensitivity and accuracy of SHG in assessing the polymorphic purity of MHBA. The SHG detection threshold for the metastable polymorph is circa 2 ppm and is several orders of magnitude better than the sensitivity of XRPD (1 wt%) and DSC (only 17 wt%). The proportion of the metastable phase in the commercial MHBA was evaluated to 1 wt% by SHG. Results of TR-SHG measurements performed on commercial MHBA at 5 K min−1 heating rate show that TR-SHG is a good technique for an in situ monitoring of the structural purity. The present study clearly demonstrates that SHG and TR-SHG are relevant and accurate techniques for probing the structural purity and for the monitoring of solid–solid phase transitions provided one of the two varieties crystallizes in a non-centrosymmetric space group.

This work focuses on characterization of chiral organic systems with partial solid solutions. Particularly, behavior of the (R)- and (S)-ethanolammonium 3-chloromandelates (E3ClMA) has been investigated experimentally. Partial solid solutions of the series (R)-E3ClMA–(Rac)-E3ClMA and (S)-E3ClMA–(Rac)-E3ClMA were discovered at the eutectic type of the binary phase diagram by means of systematic differential scanning calorimetry and X-ray powder diffraction measurements. Solubility and metastable zone width were measured for solutions of (R)-E3ClMA, (Rac)-E3ClMA, and their mixtures in ethanol as the solvent. The crystal structure of the pure (R)-E3ClMA was successfully determined by single-crystal X-ray diffraction. Several efforts of single crystals productions from (R, S) solutions were made by means of cooling and evaporation methods. Crystal morphology changes from well-shaped crystals for the pure enantiomer to spherulites for the racemic composition.

An object is considered as “chiral” if it is not superimposable on its mirror image. Due to the presence of asymmetric carbon atoms, numerous molecules are chiral but other stereogenic centers provide the asymmetric character of molecular compound (e.g. sulfoxides). Metalorganic complexes can also be asymmetric even if the ligands do not have any stereogenic center. The equimolar mixture of two enantiomers is the racemic mixture. Except for their rotatory powers which are equal in value but of opposite signs, enantiomers present identical chemical and physical properties in achiral environment. Conversely, their behaviors in chiral environment such as biological systems are often different. In particular, for chiral drugs, the pharmacological and the toxicological effects can be drastically dissimilar.

Using an accurate and rigorous protocol, the crystal growth behavior in solution of the antifungal drug ciclopirox was investigated with the aim to identify the experimental factors responsible for the appearance of macroscopic inclusions of saturated solution. Counterintuitively, these inclusions are produced only when the relative supersaturation is below a critical threshold; simultaneously the crystals exhibit a hexagonal morphology. An increase in the driving force leads to a rod-shaped morphology without inclusion and without any change of the crystal phase, as confirmed by X-ray diffraction. The correlation between this morphological transition and the occurrence of liquid inclusions could be rationalized by considering the associated change of growth rates of {(1 1 1)} and {(1 1 -1)} faces. However, the nature of the solvent, the presence of impurities and diffusion in solution appeared to have no detectable incidence on the formation of liquid inclusions, inducing that the presumed contribution of a chemical adsorption phenomenon—side products or solvents—could not be established.

A homemade setup was designed in order to investigate the influence of gas bubbling on the crystal growth of the active pharmaceutical ingredient ciclopirox. It appears from these experiments perfo...

The resolution of this derivative was optimized at 2-L scale in methanol by using two preferential crystallization modes (auto-seeded polythermic programmed preferential crystallization, hereafter AS3PC, and seeded isothermal preferential crystallization, hereafter SIPC) and by tuning the starting temperature. The results evidenced that the AS3PC mode is more efficient than the SIPC mode, and the higher the starting temperature, the higher the productivity. Despite a careful tuning of the operating conditions and a stable conglomerate offering a full chiral discrimination in the solid state, the enantiomeric excess of the crude solid obtained by preferential crystallization remained lower than 90%. However, this can be improved up to 99% by a single recrystallization of the methanol solvate of the imeglimin-2,4-dichlorophenylacetate since it crystallizes as a stable conglomerate without any detectable partial solid solution.

The dehydration behaviour of α,α-trehalose (α- d -glucopyranosyl α- d -glucopyranoside) dihydrate single crystals is investigated by thermomicroscopy, Raman microscopy, and differential scanning calorimetry. The results show at a given stage the simultaneous presence of two polymorphic forms, amorphous material, and movement of a fluid phase. The study also underlines that the characterization of the average phase by conventional XRPD and DSC techniques is not sufficient to describe the dehydration mechanisms of α,α-trehalose particles. Moreover, it confirms that the dehydration behaviour is mainly driven by heterogeneities and the rate of water loss.

The dehydration behaviour of alpha,alpha-trehalose (alpha-D-glucopyranosyl alpha-D-glucopyranoside) dihydrate single crystals is investigated by thermomicroscopy, Raman microscopy, and differential scanning calorimetry. The results show at a given stage the simultaneous presence of two polymorphic forms, amorphous material, and movement of a fluid phase. The study also underlines that the characterization of the average phase by conventional XRPD and DSC techniques is not sufficient to describe the dehydration mechanisms of alpha,alpha-trehalose particles. Moreover, it confirms that the dehydration behaviour is mainly driven by heterogeneities and the rate of water loss.

Up to know, the enantiomers of component A (a chiral intermediate schematized in figure 1) have been separated by means of chiral chromatography. A less expensive method applicable to industrial production was requested. The resolution by preferential crystallization, which requires a stable conglomerate, could be one of the alternative routes. In this study, the screening of potential conglomerates was performed by using the Second Harmonic Generation (SHG). Among the 109 crystallization attempts with different counter ions and solvents, 51 crystalline salts were obtained; a single conglomerate-forming system has been detected (with sulfamic acid). Resolution by means of preferential crystallization has been achieved with this salt. This paper underlines the potential of SHG method as a pre high throughput technique for spotting chiral discrimination in the solid state.

International audience; Recently [Jessel N, Schwinte P, Donohue R, Lavalle P, Boulmedais F, Darcy R, et al. Pyridylamino-b-cyclodextrin as a molecular chaperone for lipopolysaccharide embedded in a multilayered polyelectrolyte architecture. Adv Funct Mater 2004;14:963-9], we demonstrated the biological activity of a lipopolysaccharide from Escherichia coli incorporated into layer-by-layer films made of poly (L-lysine) and poly (L-glutamic acid) and containing a polycationic b-cyclodextrin (CD) with chaperone properties. Here we develop innovative architectures containing a complex made of a charged b-cyclodextrin and a lipid A antagonist (LAA) as potential systems for local endotoxin antagonistic activity. We examine the biological activity of these architectures. The CD-LAA complex adsorbed on top, or embedded into the polyelectrolyte films keeps its LPS antagonistic activity on both murine and human macrophages for at least 24 h. r

Two-wave mixing in photorefractive InP:Fe crystals is revisited considering an externally applied dc field combined with the moving grating technique. We show that the disagreement previously observed in the literature between theory and experiments finds an explanation in the influence of both the absorption along the propagation axis and the nonlinearities occurring at relatively large fringe modulations. A finite difference method is used to demonstrate the dependence of these nonlinearities on the average incident intensity.

Double Phase Conjugate Minors (DPCM) are of great interest for the realization of free-space interconnections between single mode optical fibers. However, an alteration of the polarization of the incident beams, which can be easily induced by mechanical constraints on standard fibers, leads to a dramatic reduction of the conjugation efficiency. We present here a polarization-independent DPCM. The polarization insensitive experimental set-up is described in figure 1. A biréfringent calcite crystal is inserted at the output of the monomode fiber. Thus, two orthogonally polarized components are spatially separated. The polarization of the component that would not contribute to the formation of the DPCM in a conventional configuration is rotated in a liquid crystal cell. Both components are then directed into the InP:Fe sample with a lens. The pump beam results from the interference of the two components. Our experiment is performed by manipulating the polarization of only one pump beam to demonstrate the principle of the polarization independent DPCM. Obviously, the other pump beam could be obtained applying the same method. In order to eliminate conical diffraction and instabilities, this elementary set-up was incorporated in a 2Z-DPCM configuration. Experiments were carried out with an InP:Fe photorefractive crystal at the telecommunication wavelength of 1.32 μm. The diffraction efficiency and the depletion rate were measured for different polarization directions of the incident beam labeled A. The results are illustrated in figure 2. The averaged values of the depletion rate and the diffraction efficiency are 50% and 10% respectively. It is worth noting that these results are comparable to those obtained with a classical configuration. The relative variations of the diffraction efficiency are less than 8% when the polarization state of the incident beam varies. Keeping in mind that the relative variations can reach nearly 100% in a conventional DPCM, our device can be considered stable.