Radovan Cerny

Preparation and characterization of sterile sub-200 nm meso-tetra(4-hydroxylphenyl)porphyrin-loaded nanoparticles for photodynamic therapy

A photosensitizer, meso-tetra(4-hydroxyphenyl)porphyrin, was incorporated into sub-150 nm nanoparticles using the emulsification-diffusion technique in order to perform sterilization by filtration using 0.22 microm membranes. The three selected polyesters (poly(D,L-lactide-co-glycolide), (50:50 PLGA, 75:25 PLGA) and poly(D,L-lactide (PLA)) for the nanoparticle production were all amorphous in nature and have similar molecular weights but different copolymer molar ratios. The influence of the copolymer molar ratio and the theoretical drug loading was investigated in terms of particle size, drug loading, entrapment efficiency and surface characteristics. With all the polymers used, sub-150 nm nanoparticles were produced with good reproducibility and narrow size distributions irrespective of both the polymer nature and the theoretical drug loading. After purification by cross-flow filtration, the nanoparticle suspensions were sterilized by membrane filtration and freeze-dried in the presence of a lyoprotectant (trehalose). For all types of nanoparticles, complete redispersion in various media could be obtained. All final freeze-dried products were refiltrable on a 0.22 microm membrane and were stable in terms of mean particle size and drug loading over a period up to 6 months. The effective drug loading increased at higher theoretical drug loading, the entrapment efficiency was however decreased. The same trend was observed with the three polyesters. The sterility of the final freeze-dried nanoparticles was confirmed by the results of the sterility testing which showed no bacterial contamination.

A better FOX: using flexible modelling and maximum likelihood to improve direct-space ab initio structure determination from powder diffraction

Abstract Ab initio structure determination using direct-space methods, although relying on an essentially brute-force approach, can be greatly improved through smarter algorithms. The most basic improvement involves the use of prior information to reduce the number of configurations evaluated to find the structure solution. It is however vitally important that the parametrization used to incorporate this prior information does not reduce the efficiency with which the configuration space is explored. We will show that this can be achieved by defining molecules and polyhedra through a set of restraints associated to dedicated random changes, allowing to solve structures up to three times as fast as with the ‘standard’ approach where atomic positions are parametrized directly from bond lengths, bond angles and dihedral angles. To further enhance the efficiency of the algorithm, it is also possible to ‘tune’ the convergence criterion used to compare the structural model to the observed diffraction data (usually χ2 or Rwp). By using Maximum Likelihood principles, it is shown that incorporating the fact that the model is approximate in the χ2 evaluation can improve the algorithm convergence towards the structure solution.

Thermal Polymorphism and Decomposition of Y(BH4)(3)

The structure and thermal decomposition of Y(BH(4))(3) is studied by in situ synchrotron radiation powder X-ray diffraction (SR-PXD), (11)B MAS NMR spectroscopy, and thermal analysis (thermogravimetric analysis/differential scanning calorimetry). The samples were prepared via a metathesis reaction between LiBH(4) and YCl(3) in different molar ratios mediated by ball milling. A new high temperature polymorph of Y(BH(4))(3), denoted beta-Y(BH(4))(3), is discovered besides the Y(BH(4))(3) polymorph previously reported, denoted alpha-Y(BH(4))(3). beta-Y(BH(4))(3) has a cubic crystal structure and crystallizes with the space group symmetry Pm3m and a bisected a-axis, a = 5.4547(8) A, as compared to alpha-Y(BH(4))(3), a = 10.7445(4) A (Pa3). Beta-Y(BH(4))(3) crystallizes with a regular ReO(3)-type structure, hence the Y(3+) cations form cubes with BH(4)(-) anions located on the edges. This arrangement is a regular variant of the distorted Y(3+) cube observed in alpha-Y(BH(4))(3), which is similar to the high pressure phase of ReO(3). The new phase, beta-Y(BH(4))(3) is formed in small amounts during ball milling; however, larger amounts are formed under moderate hydrogen pressure via a phase transition from alpha- to beta-Y(BH(4))(3), at approximately 180 degrees C. Upon further heating, beta-Y(BH(4))(3) decomposes at approximately 190 degrees C to YH(3), which transforms to YH(2) at 270 degrees C. An unidentified compound is observed in the temperature range 215-280 degrees C, which may be a new Y-B-H containing decomposition product. The final decomposition product is YB(4). These results show that boron remains in the solid phase when Y(BH(4))(3) decomposes in a hydrogen atmosphere and that Y(BH(4))(3) may store hydrogen reversibly.

Powder diffraction methods for studies of borohydride-based energy storage materials

Abstract The world today is facing increasing energy demands and a simultaneous demand for cleaner and more environmentally friendly energy technologies. Hydrogen is recognized as a possible renewable energy carrier, but its large-scale utilization is mainly hampered by insufficient hydrogen storage capabilities. In this scenario, powder diffraction has a central position as the most informative and versatile technique available in materials science. This is illustrated in the present review by synthesis, physical, chemical and structural characterisation of novel boron based hydrides for hydrogen storage. Numerous novel BH4– based materials have been investigated during the past few years and this class of materials has a fascinating structural chemistry. The experimental methods presented can be applied to a variety of other materials.

Direct space methods of structure determination from powder diffraction: principles, guidelines and perspectives

In the last twenty five years structure determination from powder diffraction has evolved from a complex, time-consuming method to one easily usable. While the use of direct methods is restricted to samples well crystallized (sharp peaks, high resolution diffraction), structure solution using global optimization in direct space have become extremely popular, using either publicly or commercially available software. In this article we present a short history of direct space methods of structure determination from powder diffraction, and a list of available software. We then give an overview of frequent issues when solving structures in direct space, as well as how algorithms are currently evolving to solve more complex structures.

Rietveld refinement for indium nitride in the 105–295 K range

Results of Rietveld refinement for indium nitride data collected in the temperature range 105–295 K are presented. Acicular microcrystals of indium nitride prepared by reaction of liquid indium with nitrogen plasma were studied by X-ray diffraction. The diffraction measurements were carried out at the Swiss-Norwegian Beamline SNBL (ESRF) using a MAR345 image-plate detector. Excellent counting statistics allowed for refinement of the lattice parameters of InN as well as those of the metallic indium secondary phase. In the studied temperature range, the InN lattice parameters show a smooth increase that can be approximated by a linear function. Lattice-parameter dependencies confirm the trends indicated earlier by data measured using a conventional equipment. The relative change of both the a and c lattice parameters with increasing the temperature in the studied range is about 0.05%. The axial ratio slightly decreases with rising temperature. The experimental value of the free structural parameter, u=0.3769(14), is reported for InN for the first time. Its temperature variation is found to be considerably smaller than the experimental error. The thermal-expansion coefficients (TECs), derived from the linearly approximated lattice-parameter dependencies, are aa=3.09(14)x10-6 K-1 and ac=2.79(16)x10-6 K-1. The evaluated TECs are generally consistent with the earlier data. For the present dataset, the accuracy is apparently higher for both, the lattice parameters and thermal-expansion coefficients, than for the earlier results. The refined lattice parameter cIn of the indium secondary phase exhibits the known strongly nonlinear behavior; a shift (∆T equal about -50 K) of the maximum in cIn(T) dependence is observed with respect to the literature data..

pH-Dependent dissolving nano- and microparticles for improved peroral delivery of a highly lipophilic compound in dogs.

RR01, a new highly lipophilic drug showing extremely low water solubility and poor oral bioavailability, has been incorporated into pH-dependent dissolving particles made of a poly(methacrylic acid-co-ethylacrylate) copolymer. The physicochemical properties of the particles were determined using laser-light-scattering techniques, scanning electron microscopy, high-performance liquid chromatography, and x-ray powder diffraction. Suspension of the free drug in a solution of hydroxypropylcellulose (reference formulation) and aqueous dispersions of pH-sensitive RR01-loaded nanoparticles or microparticles were administered orally to Beagle dogs according to a 2-block Latin square design (n =6). Plasma samples were obtained over the course of 48 hours and analyzed by gas chromatography/mass spectrometry. The administration of the reference formulation resulted in a particularly high interindividual variability of pharmacokinetic parameters, with low exposure to compound RR01 (AUC0–48h of 6.5 μg.h/mL and coefficient of variation (CV) of 116%) and much higher Tmax, as compared to both pH-sensitive formulations. With respect to exposure and interindividual variability, nanoparticles were superior to microparticles (AUC0–48h of 27.1 μg.h/mL versus 17.7 μg.h/mL with CV of 19% and 40%, respectively), indicating that the particle size may play an important role in the absorption of compound RR01. The performance of pH-sensitive particles is attributed to their ability to release the drug selectively in the upper part of the intestine in a molecular or amorphous form. In conclusion, pH-dependent dissolving particles have a great potential as oral delivery systems for drugs with low water solubility and acceptable permeation properties.

Third structure determination by powder diffractometry round robin "SDPDRR-3…

The results from a third structure determination by powder diffractometry (SDPD) round robin are discussed. From the 175 potential participants having downloaded the powder data, nine sent a total of 12 solutions (8 and 4 for samples 1 and 2, respectively, a tetrahydrated calcium tartrate and a lanthanum tungstate). Participants used seven different computer programs for structure solution (ESPOIR, EXPO, FOX, PSSP, SHELXS, SUPERFLIP, and TOPAS), applying Patterson, direct methods, direct space methods, and charge flipping approach. It is concluded that solving a structure from powder data remains a challenge, at least one order of magnitude more difficult than solving a problem with similar complexity from single-crystal data. Nevertheless, a few more steps in the direction of increasing the SDPD rate of success were accomplished since the two previous round robins: this time, not only the computer program developers were successful but also some users. No result was obtained from crystal structure prediction experts.

FOX : A friendly tool to solve nonmolecular structures from powder diffraction

Structural characterization from powder diffraction of compounds not containing isolated molecules but three-dimensional infinite structure _alloys, intermetallics, framework compounds, extended solids_ by direct space methods has been largely improved in the last 15 years. The success of the method depends very much on a proper modeling of the structure from building blocks. The modeling from larger building blocks improves the convergence of the global optimization algorithm by a factor of up to 10. However, care must be taken about the correctness of the building block, like its rigidity, deformation, bonding distances, and ligand identity. Dynamical occupancy correction implemented in the direct space program FOX has shown to be useful when merging excess atoms, and even larger building blocks like coordination polyhedra. It also allows joining smaller blocks into larger ones in the case when the connectivity was not a priori evident from the structural model. We will show in several examples of nonmolecular structures the effect of the modeling by correct structural units

Novel sodium aluminium borohydride containing the complex anion [Al(BH4,Cl)4]-.

The synthesis of a novel alkali-metal aluminium borohydride NaAl(BH4)xCl4-x from NaBH4 and AlCl3 using a solid state metathesis reaction is described. Structure determination was carried out using synchrotron powder diffraction data and vibrational spectroscopy. An orthorhombic structure (space group Pmn2(1)) is formed which contains Na+ cations and complex [Al(BH4,Cl)4]- anions. Due to the high chlorine content (1 < or = x < or = 1.43) the hydrogen density of the borohydride is only between 2.3 and 3.5 wt.% H2 in contrast to the expected 14.6 wt.% for chlorine free NaAl(BH4)4. The decomposition of NaAl(BH4)xCl4-x is observed in the target range for desorption at about 90 degrees C by differential scanning calorimetry (DSC), in situ Raman spectroscopy and synchrotron powder X-ray diffraction. Thermogravimetric analysis (TG) shows extensive mass loss indicating the loss of H2 and B2H6 at about 90 degrees C followed by extensive weight loss in the form of chloride evaporation.