Development of a multiparticulate drug delivery system for in situ amorphisation

In the current study, the concept of multiparticulate drug delivery systems (MDDS) was applied to tablets intended for the amorphisation of supersaturated granular ASDs in situ, i.e. amorphisation within the final dosage form by microwave irradiation. The MDDS concept was hypothesised to ensure geometric and structural stability of the dosage form and to improve the in vitro disintegration and dissolution characteristics. Granules were prepared in two sizes (small and large) containing the crystalline drug celecoxib (CCX) and polyvinylpyrrolidone/vinyl acetate copolymer (PVP/VA) at a 50 % w/w drug load as well as sodium dihydrogen phosphate monohydrate as the microwave absorbing excipient. The granules were subsequently embedded in an extra-granular tablet phase composed of either the filler microcrystalline cellulose (MCC) or mannitol (MAN), as well as the disintegrant crospovidone and the lubricant magnesium stearate. The tensile strength and disintegration time were investigated prior to and after 10 min of microwave irradiation (800 and 1000 W) and the formed ASDs were characterised by X-ray powder diffraction and modulated differential scanning calorimetry. Additionally, the internal structure was elucidated by X-ray micro-Computed Tomography (XµCT) and, finally, the dissolution performance of selected tablets was investigated. The MDDS tablets displayed no geometrical changes after microwave irradiation, however, the tensile strength and disintegration time generally increased. Complete amorphisation of CCX was achieved only for the MCC-based tablets at a power input of 1000 W, while MAN-based tablets displayed partial amorphisation independent of power input. The complete amorphisation of CCX was associated with the fusion of individual ASD granules within the tablets, which negatively impacted the subsequent disintegration and dissolution performance. For these tablets, supersaturation was only observed after 60 min. On the other hand, the partially amorphised MDDS tablets displayed complete disintegration during the dissolution experiments, resulting in a fast onset of supersaturation within 5 min and an approx. 3.5-fold degree of supersaturation within the experimental timeframe (3 h). Overall, the MDDS concept was shown to potentially be a feasible dosage form for in situ amorphisation, however, there is still room for improvement to obtain a both fully amorphous and disintegrating system

Tablet disintegration studied by high-resolution real-time magnetic resonance imaging.

The present work employs recent advances in high-resolution real-time magnetic resonance imaging (MRI) to investigate the disintegration process of tablets containing disintegrants. A temporal resolution of 75 ms and a spatial resolution of 80 x 80 m with a section thickness of only 600 m were achieved. The histograms of MRI videos were quantitatively analyzed with MATLAB. The mechanisms of action of six commercially available disintegrants, the influence of relative tablet density, and the impact of disintegrant concentration were examined. Crospovidone seems to be the only disintegrant acting by a shape memory effect, whereas the others mainly swell. A higher relative density of tablets containing croscarmellose sodium leads to a more even distribution of water within the tablet matrix but hardly impacts the disintegration kinetics. Increasing the polacrilin potassium disintegrant concentration leads to a quicker and more thorough disintegration process. Real-time MRI emerges as valuable tool to visualize and investigate the process of tablet disintegration

Assessment of disintegrant efficacy with fractal dimensions from real-time MRI.

An efficient disintegrant is capable of breaking up a tablet in the smallest possible particles in the shortest time. Until now, comparative data on the efficacy of different disintegrants is based on dissolution studies or the disintegration time. Extending these approaches, this study introduces a method, which defines the evolution of fractal dimensions of tablets as surrogate parameter for the available surface area. Fractal dimensions are a measure for the tortuosity of a line, in this case the upper surface of a disintegrating tablet. High-resolution real-time MRI was used to record videos of disintegrating tablets. The acquired video images were processed to depict the upper surface of the tablets and a box-counting algorithm was used to estimate the fractal dimensions. The influence of six different disintegrants, of different relative tablet density, and increasing disintegrant concentration was investigated to evaluate the performance of the novel method. Changing relative densities hardly affect the progression of fractal dimensions, whereas an increase in disintegrant concentration causes increasing fractal dimensions during disintegration, which are also reached quicker. Different disintegrants display only minor differences in the maximal fractal dimension, yet the kinetic in which the maximum is reached allows a differentiation and classification of disintegrants

Development of a multiparticulate drug delivery system for in situ amorphisation

In the current study, the concept of multiparticulate drug delivery systems (MDDS) was applied to tablets intended for the amorphisation of supersaturated granular ASDs in situ, i.e. amorphisation within the final dosage form by microwave irradiation. The MDDS concept was hypothesised to ensure geometric and structural stability of the dosage form and to improve the in vitro disintegration and dissolution characteristics. Granules were prepared in two sizes (small and large) containing the crystalline drug celecoxib (CCX) and polyvinylpyrrolidone/vinyl acetate copolymer (PVP/VA) at a 50 % w/w drug load as well as sodium dihydrogen phosphate monohydrate as the microwave absorbing excipient. The granules were subsequently embedded in an extra-granular tablet phase composed of either the filler microcrystalline cellulose (MCC) or mannitol (MAN), as well as the disintegrant crospovidone and the lubricant magnesium stearate. The tensile strength and disintegration time were investigated prior to and after 10 min of microwave irradiation (800 and 1000 W) and the formed ASDs were characterised by X-ray powder diffraction and modulated differential scanning calorimetry. Additionally, the internal structure was elucidated by X-ray micro-Computed Tomography (XµCT) and, finally, the dissolution performance of selected tablets was investigated. The MDDS tablets displayed no geometrical changes after microwave irradiation, however, the tensile strength and disintegration time generally increased. Complete amorphisation of CCX was achieved only for the MCC-based tablets at a power input of 1000 W, while MAN-based tablets displayed partial amorphisation independent of power input. The complete amorphisation of CCX was associated with the fusion of individual ASD granules within the tablets, which negatively impacted the subsequent disintegration and dissolution performance. For these tablets, supersaturation was only observed after 60 min. On the other hand, the partially amorphised MDDS tablets displayed complete disintegration during the dissolution experiments, resulting in a fast onset of supersaturation within 5 min and an approx. 3.5-fold degree of supersaturation within the experimental timeframe (3 h). Overall, the MDDS concept was shown to potentially be a feasible dosage form for in situ amorphisation, however, there is still room for improvement to obtain a both fully amorphous and disintegrating system

Air-Con Metal-Organic Frameworks in Binder Composites for Water Adsorption Heat Transformation Systems

Metal–organic frameworks (MOFs) currently receive high interest for cycling water adsorption applications like adsorption heat transformation for air-conditioning purposes. For practical use in adsorption heat pumps (AHPs), the microcrystalline powders must be formulated such that their high porosity and pore accessibility are retained. In this work, the preparation of millimeter-scaled pellets of MIL-160(Al), Al-fumarate (Basolite A520), UiO-66(Zr), and Zr-fumarate (MOF-801) is reported by applying the freeze granulation method. The use of poly(vinyl alcohol) (PVA) as a binder reproducibly resulted in highly stable, uniformly shaped PVA/MOF pellets with 80 wt % MOF loading, with essentially unchanged MOF porosity properties after shaping. The shaped pellets were analyzed for the application in AHPs by water adsorption isotherms, over 1000 water adsorption/desorption cycles, and thermal and mechanical stability tests. Furthermore, the Al-fum pellets were applied in a fixed-bed, full-scale heat exchanger, yielding specific cooling powers from 349 up to 431 W/kg (adsorbent), which outperforms the current commercially used silica gel grains in AHPs under comparable operating conditions