Analysis of anisotropic pore structures using terahertz spectroscopy and imaging

This study demonstrates the analysis of anisotropic pore structures of highly porous pharmaceutical powder compacts by combining terahertz time-domain spectroscopy and in-situ measurements of the liquid penetration using terahertz pulsed imaging

On the role of API in determining porosity, pore structure and bulk modulus of the skeletal material in pharmaceutical tablets formed with MCC as sole excipient

The physical properties and mechanical integrity of pharmaceutical tablets are of major importance when loading with active pharmaceutical ingredient(s) (API) in order to ensure ease of processing, control of dosage and stability during transportation and handling prior to patient consumption. The interaction between API and excipient, acting as functional extender and binder, however, is little understood in this context. The API indomethacin is combined in this study with microcrystalline cellulose (MCC) at increasing loading levels. Tablets from the defined API/MCC ratios are made under conditions of controlled porosity and tablet thickness, resulting from different compression conditions, and thus compaction levels. Mercury intrusion porosimetry is used to establish the accessible pore volume, pore size distribution and, adopting the observed region of elastic intrusion-extrusion at high pressure, an elastic bulk modulus of the skeletal material is recorded. Porosity values are compared to previously published values derived from terahertz (THz) refractive index data obtained from exactly the same tablet sample sets. It is shown that the elastic bulk modulus is dependent on API wt% loading under constant tablet preparation conditions delivering equal dimensions and porosity. The findings are considered of novel value in respect to establishing consistency of tablet production and optimisation of physical properties

Simultaneous investigation of the liquid transport and swelling performance during tablet disintegration.

Fast disintegrating tablets have commonly been used for fast oral drug delivery to patients with swallowing difficulties. The different characteristics of the pore structure of such formulations influence the liquid transport through the tablet and hence affect the disintegration time and the release of the drug in the body. In this work, terahertz time-domain spectroscopy and terahertz pulsed imaging were used as promising analytical techniques to quantitatively analyse the impact of the structural properties on the liquid uptake and swelling rates upon contact with the dissolution medium. Both the impact of porosity and formulation were investigated for theophylline and paracetamol based tablets. The drug substances were either formulated with functionalised calcium carbonate (FCC) with porosities of 45% and 60% or with microcrystalline cellulose (MCC) with porosities of 10% and 25%. The terahertz results reveal that the rate of liquid uptake is clearly influenced by the porosity of the tablets with a faster liquid transport observed for tablets with higher porosity, indicating that the samples exhibit structural similarity in respect to pore connectivity and pore size distribution characteristics in respect to permeability. The swelling of the FCC based tablets is fully controlled by the amount of disintegrant, whereas the liquid uptake is driven by the FCC material and the interparticle pores created during compaction. The MCC based formulations are more complex as the MCC significantly contributes to the overall tablet swelling. An increase in swelling with increasing porosity is observed in these tablets, which indicates that such formulations are performance-limited by their ability to take up liquid. Investigating the effect of the microstructure characteristics on the liquid transport and swelling kinetics is of great importance for reaching the next level of understanding of the drug delivery, and, depending on the surface nature of the pore carrier function, in turn controlling the performance of the drug mainly in respect to dissolution in the body

Investigating elastic relaxation effects on the optical properties of functionalised calcium carbonate compacts using optics-based Heckel analysis

Heckel analysis is a widely used method for the characterisation of the compression behaviour of pharmaceutical samples during the preparation of solid dosage formulations. The present study introduces an optical version of the Heckel equation that is based on a combination of the conventional Heckel equation together with the linear relationship defined between the effective terahertz (THz) refractive index and the porosity of pharmaceutical tablets. The proposed optical Heckel equation allows us to, firstly, calculate the zero-porosity refractive index, and, secondly, predict the in-die development of the effective refractive index as a function of the compressive pressure during tablet compression. This was demonstrated for five batches of highly porous functionalised calcium carbonate (FCC) excipient compacts. The close match observed between the estimated in-die effective refractive index and the measured/out-of-die effective THz refractive index supports the validity of the proposed form of the equation. By comparing the measured and estimated in-die tablet properties, a clear change in the porosity and hence, the effective refractive index, due to post-compression elastic relaxation of the FCC compacts, has been observed. We have, therefore, proposed a THz-based compaction setup that will permit in-line monitoring of processes during tablet compression. We envisage that this new approach in tracking powder properties introduced in this preliminary study will lead to the onset of further extensive and detailed future studies

Fast and non-destructive pore structure analysis using terahertz time-domain spectroscopy.

Pharmaceutical tablets are typically manufactured by the uni-axial compaction of powder that is confined radially by a rigid die. The directional nature of the compaction process yields not only anisotropic mechanical properties (e.g. tensile strength) but also directional properties of the pore structure in the porous compact. This study derives a new quantitative parameter, Sa, to describe the anisotropy in pore structure of pharmaceutical tablets based on terahertz time-domain spectroscopy measurements. The Sa parameter analysis was applied to three different data sets including tablets with only one excipient (functionalised calcium carbonate), samples with one excipient (microcrystalline cellulose) and one drug (indomethacin), and a complex formulation (granulated product comprising several excipients and one drug). The overall porosity, tablet thickness, initial particle size distribution as well as the granule density were all found to affect the significant structural anisotropies that were observed in all investigated tablets. The Sa parameter provides new insights into the microstructure of a tablet and its potential was particularly demonstrated for the analysis of formulations comprising several components. The results clearly indicate that material attributes, such as particle size and granule density, cause a change of the pore structure, which, therefore, directly impacts the liquid imbibition that is part of the disintegration process. We show, for the first time, how the granule density impacts the pore structure, which will also affect the performance of the tablet. It is thus of great importance to gain a better understanding of the relationship of the physical properties of material attributes (e.g. intragranular porosity, particle shape), the compaction process and the microstructure of the finished product

Improved Interpretation of Mercury Intrusion and Soil Water Retention Percolation Characteristics by Inverse Modelling and Void Cluster Analysis

This work addresses two continuing fallacies in the interpretation of percolation characteristics of porous solids. The first is that the first derivative (slope) of the intrusion characteristic of the non-wetting fluid or drainage characteristic of the wetting fluid corresponds to the void size distribution, and the second is that the sizes of all voids can be measured. The fallacies are illustrated with the aid of the PoreXpert® inversemodelling package.Anewvoid analysis method is then described, which is an add-on to the inverse modelling package and addresses the second fallacy. It is applied to three widely contrasting and challenging porous media. The first comprises two fine-grain graphites for use in the next-generation nuclear reactors. Their larger void sizes were measured by mercury intrusion, and the smallest by using a grand canonical Monte Carlo interpretation of surface area measurement down to nanometre scale. The second application is to the mercury intrusion of a series of mixtures of ground calcium carbonate with powdered microporous calcium carbonate known as functionalised calcium carbonate (FCC). The third is the water retention/drainage characteristic of a soil sample which undergoes naturally occurring hydrophilic/hydrophobic transitions. The first-derivative approximation is shown to be reasonable in the interpretation of the mercury intrusion porosimetry of the two graphites, which differ only at low mercury intrusion pressures, but false for FCC and the transiently hydrophobic soil. The findings are supported by other experimental characterisations, in particular electron and atomic force microscopy

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie