Investigation of the Binary System of Proxyphylline Enantiomers: Structural Resolution and Phase Diagram Determination.

The solid-state landscape of proxyphylline (PXL), a chiral derivative of theophylline crystallizing as a racemic compound, was extensively investigated by means of thermal analyses and diffraction techniques. This study revealed the presence of five distinct polymorphic forms that were characterized: two polymorphs of the racemic mixture and three polymorphs of the pure enantiomer. The nature of each solid phase was confirmed by combining the different analytical techniques, revealing the presence of a thermodynamically stable racemic compound, RI (TFus= 134 °C), in equilibrium with the stable enantiopure crystal form, EI (TFus = 148.3 °C). Additionally, other crystal forms could be evidenced: a polymorph of the racemic compound, RII (TFus= 111.5 °C), as well as two metastable conglomerates, cEI and cEII, and two other polymorphs of the pure enantiomer, EII and EIII. The crystal structures of RI and EI are reported and discussed, highlighting the diversity of molecular conformations that can be adopted by the PXL molecule, which accounts for the versatility of the crystallization behaviors observed in this system. These findings enhance our understanding of the crystallization behavior of chiral pharmaceutical compounds and have implications for optimizing their crystallization processes in the pharmaceutical industry.

A Greener Pathway to Enantiopurity: Mechanochemical Deracemization through Abrasive Grinding.

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.

Critical Influence of Water on the Polymorphism of 1,3-Dimethylurea and Other Heterogeneous Equilibria.

It is shown that the presence of hundreds of ppm of water in 1,3-dimethylurea (DMU) powder led to the large depression of the transition temperature between the two enantiotropically related polymorphic forms of DMU (Form II → Form I) from 58 °C to 25 °C, thus explaining the reported discrepancies on this temperature of transition. Importantly, this case study shows that thermodynamics (through the construction of the DMU-water temperature-composition phase diagram) rather than kinetics is responsible for this significant temperature drop. Furthermore, this work also highlights the existence of a monohydrate of DMU that has never been reported before with a non-congruent fusion at 8 °C. Interestingly, its crystal structure, determined from X-ray powder diffraction data at sub-ambient temperature, consists of a DMU-water hydrogen bonded network totally excluding homo-molecular hydrogen bonds (whereas present in forms I and II of DMU).

Oxysulfide Ba5(VO2S2)2(S2)2 Combining Disulfide Channels and Mixed-Anion Tetrahedra and Its Third-Harmonic-Generation Properties.

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.

Pure and RE3+-Doped La7O6(VO4)3 (RE = Eu, Sm): Polymorphism Stability and Luminescence Properties of a New Oxyvanadate Matrix.

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 ß = 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 ß-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 ß = 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.

Investigation of Drug-Excipient Interactions in Biclotymol Amorphous Solid Dispersions.

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 ß-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 ß-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.

Hydrothermal Synthesis and Dehydration of CaTeO3(H2O): An Original Route to Generate New CaTeO3 Polymorphs.

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.

A racemic and enantiopure unsymmetric diiron(III) complex with a chiral o-carborane-based pyridylalcohol ligand: combined chiroptical, magnetic, and nonlinear optical properties.

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.

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. 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.

Does the trihydrate of atorvastatin calcium possess a melting point?

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 anhydrate 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.

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.

Insights on the Physical State Reached by an Active Pharmaceutical Ingredient upon High-Energy Milling.

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. Results for samples obtained by two distinct amorphization routes, vitrification and high-energy milling, indicate that amorphous fraction in milled quinidine behaves the same way as melt-quenched quinidine. These above-mentioned techniques proved their relevancy and efficiency to characterize milled quinidine, and fast scanning calorimetry in particular appears a promising screening tool for disordered systems.

Biologically active lipid A antagonist embedded in a multilayered polyelectrolyte architecture.

Recently [Jessel N, Schwinte P, Donohue R, Lavalle P, Boulmedais F, Darcy R, et al. Pyridylamino-beta-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 beta-cyclodextrin (CD) with chaperone properties. Here we develop innovative architectures containing a complex made of a charged beta-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 24h.

Transformation of an active pharmaceutical ingredient upon high-energy milling: A process-induced disorder in Biclotymol.

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.

Molecular Relaxations in Supercooled Liquid and Glassy States of Amorphous Quinidine: Dielectric Spectroscopy and Density Functional Theory Approaches.

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 (ßKWW), 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 (ßKWW = 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.

Crystallization kinetics and molecular mobility of an amorphous active pharmaceutical ingredient: A case study with Biclotymol.

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.

Concomitant dehydration mechanisms in single crystals of alpha,alpha-trehalose.

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.

Polyelectrolyte multilayers and degradable polymer layers as multicompartment films.

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.