Solid amorphous formulations for enhancing solubility and inhibiting Erlotinib crystallization during gastric-to-intestinal transfer.

The objective of this study was to improve the solubility and inhibit the crystallisation during the gastric-to-intestinal transfer of Erlotinib (ERL), a small molecule kinase inhibitor (smKI) compound class, which is classified as class II drug in the Biopharmaceutical Classification System (BCS). A screening approach combining different parameters (solubility in aqueous media, inhibitory effect of drug crystallisation from supersaturated drug solutions) was applied to selected polymers for the development of solid amorphous dispersions of ERL. ERL solid amorphous dispersions formulations were then prepared with 3 different polymers (Soluplus®, HPMC-AS-L, HPMC-AS-H) at a fixed drug: polymer ratio (1:4) by two different production methods (spray drying and hot melt extrusion). The spray-dried particles and cryo-milled extrudates were characterized by thermal properties, shape and particle size, solubility and dissolution behavior in aqueous media. The influence of the manufacturing process on these solid characteristics was also identified during this study. Based on the obtained results, it is concluded that the cryo-milled extrudates of HPMC-AS-L displayed better performance (enhanced solubility, reduced ERL crystallization during the simulated gastric-to-intestinal transfer) and represents a promising amorphous solid dispersion formulation for oral administration of ERL.

Near ground horizontal high resolution Cn2 profiling from Shack-Hartmann slopeand scintillation data.

Coupled slope and scintillation detection and ranging (CO-SLIDAR) is a very promising technique for the metrology of near ground Cn2 profiles. It exploits both phase and scintillation measurements obtained with a dedicated wavefront sensor and allows profiling on the full line of sight between pupil and sources. This technique is applied to an associated instrument based on a mid-IR Shack-Hartmann wavefront sensor coupled to a 0.35 m telescope, which observes two cooperative sources. This paper presents what we believe is the first comprehensive description of the CO-SLIDAR method in the context of near-ground optical turbulence metrology. It includes the presentation of the physics principles underlying the measurements of our unsupervised Cn2 profile reconstruction strategy together with the error bar estimation on the reconstructed values. The application to data acquired in a heterogeneous rural landscape during an experimental campaign in Lannemezan, France, demonstrates the ability to obtain profiles with a sampling pitch of about 220 m over a 2.7 km line of sight. The retrieved Cn2 profiles are presented and their variability in space and time is discussed.

Optimal sparse apertures for phased-array imaging.

A key issue in a sparse-aperture imaging system is the relative arrangement of apertures, or aperture configuration. Transposing previous works into a discrete setting, we perform a systematic search for maximal-resolution configurations with 9 to 21 apertures. From the catalog of found solutions, we derive a procedure to simply optimize the main free parameters of the aperture from high-level constraints, such as the sought resolution and the minimum MTF level or the fill-factor.

Large amplitude tip/tilt estimation by geometric diversity for multiple-aperture telescopes.

A novel method nicknamed ELASTIC is proposed for the alignment of multiple-aperture telescopes, in particular segmented telescopes. It only needs the acquisition of two diversity images of an unresolved source, and is based on the computation of a modified, frequency-shifted, cross-spectrum. It provides a polychromatic large-range tip/tilt estimation with the existing hardware and an inexpensive noniterative unsupervised algorithm. Its performance is studied and optimized by means of simulations. They show that with 5000 photoelectrons/subaperture/frame and 1024×1024 pixel images, residues are within the capture range of interferometric phasing algorithms such as phase diversity. The closed-loop alignment of a 6-subaperture mirror provides an experimental demonstration of the effectiveness of the method.

High-order myopic coronagraphic phase diversity (COFFEE) for wave-front control in high-contrast imaging systems.

The estimation and compensation of quasi-static aberrations is mandatory to reach the ultimate performance of high-contrast imaging systems. COFFEE is a focal plane wave-front sensing method that consists in the extension of phase diversity to high-contrast imaging systems. Based on a Bayesian approach, it estimates the quasi-static aberrations from two focal plane images recorded from the scientific camera itself. In this paper, we present COFFEE's extension which allows an estimation of low and high order aberrations with nanometric precision for any coronagraphic device. The performance is evaluated by realistic simulations, performed in the SPHERE instrument framework. We develop a myopic estimation that allows us to take into account an imperfect knowledge on the used diversity phase. Lastly, we evaluate COFFEE's performance in a compensation process, to optimize the contrast on the detector, and show it allows one to reach the 10(-6) contrast required by SPHERE at a few resolution elements from the star. Notably, we present a non-linear energy minimization method which can be used to reach very high contrast levels (better than 10(7) in a SPHERE-like context).

Coronagraphic phase diversity: a simple focal plane sensor for high-contrast imaging.

Exoplanet direct imaging is a challenging goal of today's astronomical instrumentation. Several high-contrast imaging instruments dedicated to this task are currently being integrated; they are ultimately limited by the presence of quasi-static speckles in the imaging focal plane. These speckles originate in residual quasi-static optical aberrations, which must be measured and compensated for, typically at a nanometric level. We present a novel focal plane wavefront sensor (WFS) designed for this particular application. It is an extension of the phase diversity technique to coronagraphic imaging. This sensor requires no dedicated hardware and uses only two scientific images differing from a known aberration, which can be conveniently introduced by the adaptive optics subsystem. The aberrations are therefore calibrated all the way down to the scientific camera, without any differential aberrations between the sensor and the scientific camera. We show the potential of this WFS by means of simulations, and we perform a preliminary experimental validation.

Marginal blind deconvolution of adaptive optics retinal images.

Adaptive Optics corrected flood imaging of the retina has been in use for more than a decade and is now a well-developed technique. Nevertheless, raw AO flood images are usually of poor contrast because of the three-dimensional nature of the imaging, meaning that the image contains information coming from both the in-focus plane and the out-of-focus planes of the object, which also leads to a loss in resolution. Interpretation of such images is therefore difficult without an appropriate post-processing, which typically includes image deconvolution. The deconvolution of retina images is difficult because the point spread function (PSF) is not well known, a problem known as blind deconvolution. We present an image model for dealing with the problem of imaging a 3D object with a 2D conventional imager in which the recorded 2D image is a convolution of an invariant 2D object with a linear combination of 2D PSFs. The blind deconvolution problem boils down to estimating the coefficients of the PSF linear combination. We show that the conventional method of joint estimation fails even for a small number of coefficients. We derive a marginal estimation of the unknown parameters (PSF coefficients, object Power Spectral Density and noise level) followed by a MAP estimation of the object. We show that the marginal estimation has good statistical convergence properties and we present results on simulated and experimental data.

Analytical expression of long-exposure adaptive-optics-corrected coronagraphic image. First application to exoplanet detection.

In this paper we derive an analytical model of a long-exposure star image for an adaptive-optics(AO)-corrected coronagraphic imaging system. This expression accounts for static aberrations upstream and downstream of the coronagraphic mask as well as turbulence residuals. It is based on the perfect coronagraph model. The analytical model is validated by means of simulations using the design and parameters of the SPHERE instrument. The analytical model is also compared to a simulated four-quadrant phase-mask coronagraph. Then, its sensitivity to a miscalibration of structure function and upstream static aberrations is studied, and the impact on exoplanet detectability is quantified. Last, a first inversion method is presented for a simulation case using a single monochromatic image with no reference. The obtained result shows a planet detectability increase by two orders of magnitude with respect to the raw image. This analytical model presents numerous potential applications in coronographic imaging, such as exoplanet direct detection, and circumstellar disk observation.

On-line long-exposure phase diversity: a powerful tool for sensing quasi-static aberrations of extreme adaptive optics imaging systems.

The phase diversity technique is a useful tool to measure and pre-compensate for quasi-static aberrations, in particular non-common path aberrations, in an adaptive optics corrected imaging system. In this paper, we propose and validate by simulations an extension of the phase diversity technique that uses long exposure adaptive optics corrected images for sensing quasi-static aberrations during the scientific observation, in particular for high-contrast imaging. The principle of the method is that, for a sufficiently long exposure time, the residual turbulence is averaged into a convolutive component of the image and that phase diversity estimates the sole static aberrations of interest. The advantages of such a procedure, compared to the processing of shortexposure image pairs, are that the separation between static aberrations and turbulence-induced ones is performed by the long-exposure itself and not numerically, that only one image pair must be processed, that the estimation benefits from the high SNR of long-exposure images, and that only the static aberrations of interest are to be estimated. Long-exposure phase diversity can also be used as a phasing sensor for a segmented aperture telescope. Thus, it may be particularly useful for future planet finder projects such as EPICS on the European ELT.

Gram-scale purification of aconitine and identification of lappaconitine in Aconitum karacolicum.

Aconitum karacolicum from northern Kyrgyzstan (Alatau area) contains about 0.8-1% aconitine as well as other aconite derivatives that have already been identified. In this paper, we compare several methods for the further purification of an Aconitum karacolicum extract initially containing 80% of aconitine. Reverse-phase flash chromatography, reverse-phase semi-preparative HPLC, centrifugal partition chromatography (CPC) and recrystallization techniques were evaluated regarding first their efficiency to get the highest purity of aconitine (over 96%) and secondly their applicability in a semi-industrial scale purification process (in our case, 150g of plant extract). Even if the CPC technique shows the highest purification yield (63%), the recrystallization remains the method of choice to purify a large amount of aconitine as i) it can be easily carried out in safe conditions; ii) an aprotic solvent is used, avoiding aconitine degradation. Moreover, this study led us to the identification of lappaconitine in Aconitum karacolicum, a well-known alkaloid never found in this Aconitum species.

Image-based adaptive optics for in vivo imaging in the hippocampus.

Adaptive optics is a promising technique for the improvement of microscopy in tissues. A large palette of indirect and direct wavefront sensing methods has been proposed for in vivo imaging in experimental animal models. Application of most of these methods to complex samples suffers from either intrinsic and/or practical difficulties. Here we show a theoretically optimized wavefront correction method for inhomogeneously labeled biological samples. We demonstrate its performance at a depth of 200 µm in brain tissue within a sparsely labeled region such as the pyramidal cell layer of the hippocampus, with cells expressing GCamP6. This method is designed to be sample-independent thanks to an automatic axial locking on objects of interest through the use of an image-based metric that we designed. Using this method, we show an increase of in vivo imaging quality in the hippocampus.

Darwin--a mission to detect and search for life on extrasolar planets.

The discovery of extrasolar planets is one of the greatest achievements of modern astronomy. The detection of planets that vary widely in mass demonstrates that extrasolar planets of low mass exist. In this paper, we describe a mission, called Darwin, whose primary goal is the search for, and characterization of, terrestrial extrasolar planets and the search for life. Accomplishing the mission objectives will require collaborative science across disciplines, including astrophysics, planetary sciences, chemistry, and microbiology. Darwin is designed to detect rocky planets similar to Earth and perform spectroscopic analysis at mid-infrared wavelengths (6-20 mum), where an advantageous contrast ratio between star and planet occurs. The baseline mission is projected to last 5 years and consists of approximately 200 individual target stars. Among these, 25-50 planetary systems can be studied spectroscopically, which will include the search for gases such as CO(2), H(2)O, CH(4), and O(3). Many of the key technologies required for the construction of Darwin have already been demonstrated, and the remainder are estimated to be mature in the near future. Darwin is a mission that will ignite intense interest in both the research community and the wider public.

Conoscopic holography: toward three-dimensional reconstructions of opaque objects.

Conoscopic holography is an interferometric technique that permits the recording of three-dimensional objects. A two-step scheme is presented to recover an opaque object's shape from its conoscopic hologram, consisting of a reconstruction algorithm to give a first estimate of the shape and an iterative restoration procedure that uses the object's support information to make the reconstruction more robust. The existence, uniqueness, and stability of the solution, as well as the convergence of the restoration algorithm, are studied. A preliminary experimental result is presented.

On-axis conoscopic holography without a conjugate image.

We present a method for removing the conjugate image in an incoherent-light holographic technique, namely, on-axis conoscopic holography. The point-spread function that we obtain is that of a complex Gabor zone pattern, which thus should allow good-quality reconstructions of objects. Experimental results are also presented, which confirm the validity of this method.

Conoscopic holography: two-dimensional numerical reconstructions.

Conoscopic holography is an incoherent light holographic technique based on the properties of crystal optics. We present experimental results of the numerical reconstruction of a two-dimensional object from its conoscopic hologram.

Efficient phase estimation for large-field-of-view adaptive optics.

We propose a maximum a posteriori-based estimation of the turbulent phase in a large field of view (FOV) to overcome the anisoplanatism limitation in adaptive optics. We show that, whatever the true atmospheric profile, a small number of equivalent layers (two or three) is required for accurate restoration of the phase in the whole FOV. The implications for multiconjugate adaptive optics are discussed in terms of the number and conjugated heights of the deformable mirrors. The number of guide stars required for wave-front measurements in the field is also discussed: three (or even two) guide stars are sufficient to produce good performance.

Myopic deconvolution of adaptive optics images by use of object and point-spread function power spectra.

Adaptive optics systems provide a real-time compensation for atmospheric turbulence. However, the correction is often only partial, and a deconvolution is required for reaching the diffraction limit. The need for a regularized deconvolution is discussed, and such a deconvolution technique is presented. This technique incorporates a positivity constraint and some a priori knowledge of the object (an estimate of its local mean and a model for its power spectral density). This method is then extended to the case of an unknown point-spread function, still taking advantage of similar a priori information on the point-spread function. Deconvolution results are presented for both simulated and experimental data.

Optimal wave-front reconstruction strategies for multiconjugate adaptive optics.

We propose an optimal approach for the phase reconstruction in a large field of view (FOV) for multiconjugate adaptive optics. This optimal approach is based on a minimum-mean-square-error estimator that minimizes the mean residual phase variance in the FOV of interest. It accounts for the C2n profile in order to optimally estimate the correction wave front to be applied to each deformable mirror (DM). This optimal approach also accounts for the fact that the number of DMs will always be smaller than the number of turbulent layers, since the C2n profile is a continuous function of the altitude h. Links between this optimal approach and a tomographic reconstruction of the turbulence volume are established. In particular, it is shown that the optimal approach consists of a full tomographic reconstruction of the turbulence volume followed by a projection onto the DMs accounting for the considered FOV of interest. The case where the turbulent layers are assumed to match the mirror positions [model-approximation (MA) approach], which might be a crude approximation, is also considered for comparison. This MA approach will rely on the notion of equivalent turbulent layers. A comparison between the optimal and MA approaches is proposed. It is shown that the optimal approach provides very good performance even with a small number of DMs (typically, one or two). For instance, good Strehl ratios (greater than 20%) are obtained for a 4-m telescope on a 150-arc sec x 150-arc sec FOV by using only three guide stars and two DMs.

Noise propagation in wave-front sensing with phase diversity.

The phase diversity technique is studied as a wave-front sensor to be implemented with widely extended sources. The wave-front phase expanded on the Zernike polynomials is estimated from a pair of images (in focus and out of focus) by use of a maximum-likelihood approach. The propagation of the photon noise in the images on the estimated phase is derived from a theoretical analysis. The covariance matrix of the phase estimator is calculated, and the optimal distance between the observation planes that minimizes the noise propagation is determined. The phase error is inversely proportional to the number of photons in the images. The noise variance on the Zernike polynomials increases with the order of the polynomial. These results are confirmed with both numerical and experimental validations. The influence of the spectral bandwidth on the phase estimator is also studied with simulations.