In situ monitoring of powder blending by non-invasive Raman spectrometry with wide area illumination (original) (raw)
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Continuous quantitative monitoring of powder mixing dynamics by near-infrared spectroscopy
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FT-NIR spectroscopy with a fiber optical reflection probe was applied as a process analytical technology tool for the continuous quantitative in-line monitoring of pharmaceutical powder mixing processes in a bladed mixer. Two powders, acetyl salicylic acid as an active pharmaceutical ingredient (API) and α-lactose monohydrate as an excipient were characterized in advance in terms of shear cell tests, flowability tests and particle-size determination to deduce flow properties of the powders. For the quantitative monitoring of the API content, two predictive models were developed with partial-least-squares calibration based on off-line calibration. On the basis of these predictive models, powder agitation and mixing times until blend uniformity were quantitatively monitored. Mixing experiments with systematically varied filling levels and filling protocols showed a strong variation in mixing, but eventually yielded uniform powder blend. Simulation results from the literature were linked to our experimental findings in order to identify and elucidate the effects of convective and diffusive mixing. In accordance to the international conference on harmonization acceptance level of 5% for the nominal API content, UV/Vis reference measurements were performed to verify the blend uniformity as predicted by the NIR measurements.
In-line monitoring of a pharmaceutical blending process using FT-Raman spectroscopy
European Journal of Pharmaceutical Sciences, 2004
FT-Raman spectroscopy (in combination with a fibre optic probe) was evaluated as an in-line tool to monitor a blending process of diltiazem hydrochloride pellets and paraffinic wax beads. The mean square of differences (MSD) between two consecutive spectra was used to identify the time required to obtain a homogeneous mixture. A traditional end-sampling thief probe was used to collect samples, followed by HPLC analysis to verify the Raman data. Large variations were seen in the FT-Raman spectra logged during the initial minutes of the blending process using a binary mixture (ratio: 50/50, w/w) of diltiazem pellets and paraffinic wax beads (particle size: 800-1200 m). The MSD-profiles showed that a homogeneous mixture was obtained after about 15 min blending. HPLC analysis confirmed these observations. The Raman data showed that the mixing kinetics depended on the particle size of the material and on the mixing speed. The results of this study proved that FT-Raman spectroscopy can be successfully implemented as an in-line monitoring tool for blending processes.
Near-infrared spectroscopy and imaging for the monitoring of powder blend homogeneity
Journal of Pharmaceutical Sciences, 2001
In-process testing requirements for adequacy of mixing are established in 21 CFR 211.110(a)(3). Considering also, the U.S. Food and Drug Administration's draft guidance published in 1999 (Guidance for Industry, ANDAs: Blend Uniformity Analysis; http://www.fda.gov/cder/guidance/index.htm), the importance of when and how to perform blend uniformity analysis is obvious. Near-infrared (NIR) spectroscopy was used noninvasively, in this study, to monitor powder blend homogeneity. Powder mixtures consisting of salicylic acid and Fast-Flo lactose were blended in an 8-qt. V-Blender. Optical ports installed at six positions on the blender allowed spectral collection using ®ber optics. A traditional thief probe was used to collect powder samples for ultraviolet (UV) reference analysis. The blender was stopped at preselected time points for collection of NIR and UV data. Several algorithms and sampling protocols were studied to identify an optimum methodology for blend homogeneity determination. The blending process was also monitored with an InSb imaging camera for comparison with the traditional NIR spectroscopy and UV reference data. Data analysis indicates that multiple sampling points were essential for accurate and precise estimation of mixing end points. Moreover, multiple runs of identical blends often display homogeneity at unique end points, thus demonstrating the potential advantage of monitoring every blend. ß
Raman spectroscopy as a PAT for pharmaceutical blending: Advantages and disadvantages
Journal of pharmaceutical and biomedical analysis, 2018
Raman spectroscopy has been positively evaluated as a tool for the in-line and real-time monitoring of powder blending processes and it has been proved to be effective in the determination of the endpoint of the mixing, showing its potential role as process analytical technology (PAT). The aim of this study is to show advantages and disadvantages of Raman spectroscopy with respect to the most traditional HPLC analysis. The spectroscopic results, obtained directly on raw powders, sampled from a two-axis blender in real case conditions, were compared with the chromatographic data obtained on the same samples. The formulation blend used for the experiment consists of active pharmaceutical ingredient (API, concentrations 6.0% and 0.5%), lactose and magnesium stearate (as excipients). The first step of the monitoring process was selecting the appropriate wavenumber region where the Raman signal of API is maximal and interference from the spectral features of excipients is minimal. Blend ...
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Solid form diversity of raw materials can be critical for the performance of the final drug product. In this study, Raman spectroscopy, image analysis and combined Raman and image analysis were utilized to characterize the solid form composition of a particulate raw material. Raman spectroscopy provides chemical information and is complementary to the physical information provided by image analysis. To demonstrate this approach, binary mixtures of two solid forms of carbamazepine with a distinct shape, an anhydrate (prism shaped) and a dihydrate (needle shaped), were characterized at an individual particle level. Partial least squares discriminant analysis classification models were developed and tested with known, gravimetrically mixed test samples, followed by analysis of unknown, commercially supplied carbamazepine raw material samples. Classification of several thousands of particles was performed, and it was observed that with the known binary mixtures, the minimum number of pa...
Journal of pharmaceutical and biomedical analysis, 2017
A new macro-Raman system equipped with a motorized translational sample stage and low-frequency shift capabilities was developed for bulk composition and homogeneity analysis of multi-component pharmaceutical powders. Different sampling methods including single spot and scanning measurement were compared. It was found that increasing sample volumes significantly improved the precision of quantitative composition analysis, especially for poorly mixed powders. The multi-pass cavity of the macro-Raman system increased effective sample volumes by 20 times from the sample volume defined by the collection optics, i.e., from 0.02μL to about 0.4μL. A stochastic model simulating the random sampling process of polydisperse microparticles was used to predict the sampling errors for a specific sample volume. Comparison of fluticasone propionate mass fractions of the commercial products Flixotide(®) 250 and Seretide(®) 500 simulated for different sampling volumes with experimentally measured com...