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Spectroscopic analytical instrumentation uses molecular vibrations to provide feedback in the form of a spectrum that identifies a material, or flags an unknown compound such as a contaminant or inclusion. Near-infrared spectroscopy can be used for inline monitoring of the extrusion process.
Near-infrared spectroscopy offers several additional benefits to pharmaceutical production. Raman spectroscopy offers the additional benefit of microscopic sampling and imaging, and can map whole areas of a sample such as a tablet to screen for component distribution or contaminations. Rheology offers critical information about the flow properties of the extrusion process, including feedback regarding polymer melt and flow, the effect of additives and the analysis of extrudates.
Near-infrared spectroscopy for PAT monitoring
In drug manufacturing with extruders, specific characteristics such as a precise shear rate and a precise temperature govern the formulation of a wide range of drug molecules. For bioavailability enhancement, where inside the extruder the drug is converted into its amorphous form and molecular level dispersion into a glassy solution, precise control of temperature and shear stress allows for precise conversion of drug molecules from one crystalline modification into another crystalline modification. Residence time distribution of the material processed must also be well controlled.
The process is operated normally in a continuous mode allowing high flexibility in targeted product size. By implementation of near-infrared spectroscopy (NIRS) as process analytical tool (PAT), product quality attributes can be monitored in real-time, ensuring a constant desired product quality.
To guarantee product quality, the quality by design (QBD) concept of operating the process in a pre-determined parameter window can be applied and replace the traditional process operation. Features include:
- Near-infrared monitoring for PAT
- Online monitoring of blend uniformity
- Online monitoring of moisture content
- Online monitoring and control of compounding process
- Final product compliance
- Scalable from lab experiment to production
NIRS extruder probes
In order to adopt continuous process monitoring with NIRS, fiber optic probes connect the spectrometer to the extruder die. Rugged jacketed fiber lines use an industry-standard SMA905 connector. The stainless steel probe body is designed for easy cleaning. Several interfaces are available for NIRS measures using diffuse reflection or transmission modes.
NIRS extruder probes enable easy implementation of continuous monitoring, eliminating offline sampling, the use of reagents or disposables. Chemical and physical information is available in real-time from a single NIR spectrum.
Raman micro-spectroscopy provides a detailed evaluation of component distributions in compounded drug formulations. It can identify and verify the presence of different components and contaminants in various formulations and also provides detailed information on molecular structure and chemical environment. This data can reveal subtle differences in the structure and orientation of molecules. Polymorphs and solvates can be differentiated as well as the physical properties of materials such as stress or degree of crystalline.
Chemical imaging with Raman spectroscopy
Single point Raman analysis is a powerful tool for examining materials but Raman imaging opens up a new way of looking at samples. Imaging provides views of the spatial distributions of components and the variation of physical properties throughout the sample.
Pharmaceutical formulations are typically complex mixtures involving multiple components. The components go through different processing steps from raw material to the finished product.
Raman imaging enables users to identify and verify known components within the product, and identify impurities and contaminants. In some case it is also necessary to be able to monitor the molecular state of the components to make sure that nothing unforeseen has changed during the processing steps.
Raman imaging is able to look at the spatial distribution of components and determine things like particle size and homogeneity.
Optimizing process conditions in polymer-based drug delivery systems such as melt temperature and flow behavior typically requires the investigation of additives in both lab and pilot scales. The flow behavior during extrusion can be monitored using a lab scale extruder with rheological devices. The effect of different modifiers and their concentration on the characteristics of the melt can be measured quantitatively. After the extrusion process, the polymer material may be collected for further rheological characterization.
Simultaneous rheometry and polarization microscopy using a hot stage microscope with heating/cooling capability allows studying the melting behavior of crystals in the heating run, to investigate whether a re-crystallization occurs in the cooling run and derive suitable processing parameters for compounding and extrusion.
This combined method allows investigating pure polymers, pure APIs and mixtures of those with plasticizers and additives and reveals whether an amorphous solid dispersion or a crystalline solid dispersion is obtained during heating and whether it is stable during cooling or storage. Rheometry married together with microscopy, provides well defined heating and cooling rates. It is a highly efficient screening tool delivering parameters which are traditionally collected with several methods parallel to each other using different equipment.