Continuous Mixing Technology: Characterization of a Vertical Mixer Using Residence Time Distribution.

Continuous powder mixing technology (CMT) application during continuous direct compression has emerged as a leading technology used in the development and manufacture of solid oral dosage forms. The critical quality attributes of the final product are heavily dependent on the performance of the mixing step as the quality of mixing directly influences the drug product quality attributes. This study investigates the impact of blend material properties (bulk density, API particle size distribution) and process parameters (process throughput, hold up mass and impeller speed) on the mixing performance. Mixing of the blend was characterized using the Residence Time Distribution (RTD) of the process by trending the outlet stream of the mixer using a near-infrared (NIR) probe after the injection of a small mass of tracer at the inlet stream. The outcomes of this study show that the RTDs of the mixer with throughput ranging between 15 and 30 kg/h; impeller speed ranging between 400 and 600 rpm and hold up mass (HUM) ranging between 500 and 850 g can be described by a series of two ideal Continuous Stirred Tank Reactors (CSTRs) with different volumes, and correspondingly, different mean residence times. It is also observed that the mixing is mainly occurring in the lower chamber of the CMT and the normalized RTDs of the mixer are similar across the range of process conditions and material attributes studied. The results also showed that the formulation blend with different API particle sizes and bulk properties, like bulk density and flowability, provide insignificant impact on the mixing performance. The CMT allows independent selection of target set points for HUM, impeller rotational speed and line throughput and it shows great robustness and flexibility for continuous blending in solid oral dose manufacturing.

Spectroscopic imaging of biomaterials and biological systems with FTIR microscopy or with quantum cascade lasers.

Spectroscopic imaging of biomaterials and biological systems has received increased interest within the last decade because of its potential to aid in the detection of disease using biomaterials/biopsy samples and to probe the states of live cells in a label-free manner. The factors behind this increased attention include the availability of improved infrared microscopes and systems that do not require the use of a synchrotron as a light source, as well as the decreasing costs of these systems. This article highlights the current technical challenges and future directions of mid-infrared spectroscopic imaging within this field. Specifically, these are improvements in spatial resolution and spectral quality through the use of novel added lenses and computational algorithms, as well as quantum cascade laser imaging systems, which offer advantages over traditional Fourier transform infrared systems with respect to the speed of acquisition and field of view. Overcoming these challenges will push forward spectroscopic imaging as a viable tool for disease diagnostics and medical research. Graphical abstract Absorbance images of a biopsy obtained using an FTIR imaging microscope with and without an added lens, and also using a QCL microscope with high-NA objective.

FTIR spectroscopic imaging and mapping with correcting lenses for studies of biological cells and tissues.

Histopathology of tissue samples is used to determine the progression of cancer usually by staining and visual analysis. It is recognised that disease progression from healthy tissue to cancerous is accompanied by spectral signature changes in the mid-infrared range. In this work, FTIR spectroscopic imaging in transmission mode using a focal plane array (96 × 96 pixels) has been applied to the characterisation of Barrett's oesophageal adenocarcinoma. To correct optical aberrations, infrared transparent lenses were used of the same material (CaF2) as the slide on which biopsies were fixed. The lenses acted as an immersion objective, reducing scattering and improving spatial resolution. A novel mapping approach using a sliding lens is presented where spectral images obtained with added lenses are stitched together such that the dataset contained a representative section of the oesophageal tissue. Images were also acquired in transmission mode using high-magnification optics for enhanced spatial resolution, as well as with a germanium micro-ATR objective. The reduction of scattering was assessed using k-means clustering. The same tissue section map, which contained a region of high grade dysplasia, was analysed using hierarchical clustering analysis. A reduction of the trough at 1077 cm(-1) in the second derivative spectra was identified as an indicator of high grade dysplasia. In addition, the spatial resolution obtained with the lens using high-magnification optics was assessed by measurements of a sharp interface of polymer laminate, which was also compared with that achieved with micro ATR-FTIR imaging. In transmission mode using the lens, it was determined to be 8.5 µm and using micro-ATR imaging, the resolution was 3 µm for the band at a wavelength of ca. 3 µm. The spatial resolution was also assessed with and without the added lens, in normal and high-magnification modes using a USAF target. Spectroscopic images of cells in transmission mode using two lenses are also presented, which are necessary for correcting chromatic aberration and refraction in both the condenser and objective. The use of lenses is shown to be necessary for obtaining high-quality spectroscopic images of cells in transmission mode and proves the applicability of the pseudo hemisphere approach for this and other microfluidic systems.

The biocompatibility of carbon hydroxyapatite/ß-glucan composite for bone tissue engineering studied with Raman and FTIR spectroscopic imaging.

The spectroscopic approaches of FTIR imaging and Raman mapping were applied to the characterisation of a new carbon hydroxyapatite/ß-glucan composite developed for bone tissue engineering. The composite is an artificial bone material with an apatite-forming ability for the bone repair process. Rabbit bone samples were tested with an implanted bioactive material for a period of several months. Using spectroscopic and chemometric methods, we were able to determine the presence of amides and phosphates and the distribution of lipid-rich domains in the bone tissue, providing an assessment of the composite's bioactivity. Samples were also imaged in transmission using an infrared microscope combined with a focal plane array detector. CaF2 lenses were also used on the infrared microscope to improve spectral quality by reducing scattering artefacts, improving chemometric analysis. The presence of collagen and lipids at the bone/composite interface confirmed biocompatibility and demonstrate the suitability of FTIR microscopic imaging with lenses in studying these samples. It confirmed that the composite is a very good background for collagen growth and increases collagen maturity with the time of the bone growth process. The results indicate the bioactive and biocompatible properties of this composite and demonstrate how Raman and FTIR spectroscopic imaging have been used as an effective tool for tissue characterisation.

Analyzing the impact of different excipients on drug release behavior in hot-melt extrusion formulations using FTIR spectroscopic imaging.

The drug release performance of hot-melt extrudate formulations is mainly affected by its composition and interactions between excipients, drug and the dissolution media. For targeted formulation development, it is crucial to understand the role of these interactions on the drug release performance of extrudate formulations. Attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopic imaging was used with an in-situ flow-cell device to analyze the impact of different excipients on drug release from extrudates. The compositions differed in the type of polymer (copovidone and Soluplus®), the salt or acid form of ibuprofen and the addition of sodium carbonate. For comparison, conventional USP (United States Pharmacopeia) Apparatus 2 dissolution studies were performed. FTIR imaging revealed that differences in the drug release rate were mainly due to drug-polymer interactions. Ibuprofen acid showed interactions with the matrix polymer and exhibited a slower drug release compared to non-interacting ibuprofen salt. Addition of sodium carbonate to the ibuprofen acid containing formulations enhanced the drug release rate of these systems by interfering with the drug-polymer interactions. In addition, drug release rates also depended on the polymer type, showing faster drug release rates for extrudate formulations containing copovidone compared to Soluplus®. FTIR imaging revealed that the stronger the drug-polymer interaction in the formulations, the slower the drug release. The addition of sodium carbonate improved release as it reduces drug-polymer interactions and allows for the formation of the more water-soluble ibuprofen salt.

Fast drying and film formation of latex dispersions studied with FTIR spectroscopic imaging.

Drying of thin latex films (∼20 µm) at high drying speeds (of the order of seconds) has been studied by fast chemical imaging. ATR-FTIR spectroscopic imaging combined with a fast "kinetic" mode was used to acquire spectral images without coaddition, enabling the amount of water and homogeneity of the drying film to be studied over time. Drying profiles, constructed from analyzing the water content in each image, show two stages of drying, a fast and a slow region. The formulation of latex dispersions affects the onset of slow drying and the volume fraction of water remaining at the onset of slow drying. In this work, the effect of physical properties, film thickness and glass transition temperature (Tg), were investigated, as well as the effect of monomer composition where two monomoers, 2-ethylhexyl acrylate and n-butyl acrylate, and the amount of hydrophilic comonomer, methyl methacrylate (MMA), were varied. It was found that thicker films produced slower overall drying and that the formulation with a Tg above the minimum film formation temperature did not dry evenly, exhibiting cracking. However, the drying kinetics of high and low Tg films were similar, highlighting the advantage of using a spatially-resolved spectroscopic approach. Formulations containing more MMA dried faster than those with less. This was due to the hydrophilicity of MMA and the increase in Tg of the dispersion from the addition of MMA. Overall, FTIR spectroscopic imaging was shown to be a suitable approach in measuring film drying at high speeds as both chemical changes and chemical distribution could be analyzed over time.