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The advantages of coupling hot melt extrusion technology with online FT-NIR spectroscopy are explained.
How does hot melt extrusion complement Quality by Design?
With an increasing focus on Quality by Design (QbD), pharmaceutical companies need to be able to control and analyse product quality online and in real time throughout the manufacturing process. This will not only lead to more efficient manufacturing, but also ensure better understanding of the processes and a substantially lower risk profile.
One major paradigm in QbD is the shift from batch to continuous processing. Continuous processing spreads risk out over time, without dramatically decreasing throughput, rather than depending on the success of a single, largescale batch. Such processes are also easier to adjust and control effectively in real time.
One continuous processing technology that is receiving considerable attention from the pharma industry is hot melt extrusion (HME). HME combines multiple batched unit operations such as granulation and blending into a single process and, in some cases, may also remove the need for drying materials. HME involves processing polymeric materials above their glass transition temperature (Tg) to effect molecularlevel mixing of thermoplastic binders and/or polymers and actives. The technique is a combination of melting and mechanical granulation, and gives many advantages over batch processes, including highthroughput, dust reduction and high precision. Crucially, it is possible to instantly respond to out of specification results without affecting an entire product run.
Using significantly reduced mixing volumes, HME rapidly homogenises excipients and APIs, while continuously delivering final product. In particular, the technology has been emerging as a way to address poor API stability; it does not create hydrolyic stress during processing and it also negates the need for a drying step. It has also been shown to enhance dissolution properties and bioavailability via preparation of a solid dispersion.1,2 Additionally, it is possible for users to monitor specific HME process parameters such as temperature, the speed of the screws and the gravity feed rate of the component materials, which are all critical to produce a product that is within specification.
How can FT-NIR be used to predict HME component concentrations in real time?
As with many continuous processes, HME can be readily coupled with online Fourier Transform Near Infrared (FT-NIR) spectroscopy. This allows for real time feedback and control (a significant part of PAT and the larger paradigm of QbD) of the chemical composition of the extruded materials, leading to enhanced control of the HME process itself. FTNIR spectroscopy has proven extremely effective as a PAT tool for many applications including tablet content uniformity and online moisture quantification in a fluid bed dryer.3,4 FT-NIR measures the vibrational response of molecules in a sample using a white light source and provides a spectroscopic fingerprint that can be used to distinguish one molecule from another. The innately low absorbances of the technique allows for long pathlength measurements through traditionally infrared-opaque media and NIR light can also be efficiently transmitted through optical fiber, which means the point of analysis can be up to 100 m away from the analyser.
FT-NIR is well suited to monitor and control hot melt extruders as it is rapid without being destructive. FT-NIR also eliminates the need for sample preparation and doesn't require the use of solvents or consumables. It is capable of measuring component concentrations, as well as strict physical properties such as average particle size. It is readily adaptable to any environment through the use of customised probes.
How do I integrate FT-NIR with HME?
The integration of FT-NIR analysers and hot melt extruders is both physical and electronic. The physical aspect involves coupling the analyser to the sampling point, which is done using a low-hydroxide fiber optic cable (the low concentration of hydroxide in the fiber allows the NIR light to pass through unabsorbed) and probes built for reflection or transmission analysis (or both). The cable, either as a bundle or a single fiber, connects to the analyser using a threaded SMA (Surface Mount Assembly) 905 stainless steel connector.
In the case of a hot melt extruder, the probe is screwed into a tapped hole on the extrusion die where the final product is ejected. The probe (which is equipped with a hexagonal feature on the neck that accommodates a standard wrench) is mounted simply by screwing it into the die and will be equipped with a sapphire window that allows the light to bounce off (reflection probe) or go through (transmission probe) the extruding material. The fiber optical cable then guides the light back to the analyser for detection and processing.
The electronic portion of the integration involves systems communications, where the computer controlling the spectrometer is integrated into the manufacturing feedback loop. HME controllers monitor physical information about the process (e.g., temperature across the different zones, screw rate etc.) and then feed the data to a central 'brain' that makes actionable decisions about the operation of the system. Integrating the chemical information about the extrudate itself from the FTNIR analyser also opens the door to process feedback based on the composition of the target product, offering a direct measure of process robustness.
FT-NIR systems can be interfaced with almost any processing equipment, regardless of sample type. Modern spectrometers can also be interfaced to many different control systems, such as Distributed Control Systems or Supervisory Control and Data Acquisition systems to close the loop in process communications. OPC (Object linking and embedding for Process Control) is a standardised ethernetbased approach to process communication that bridges many different input/output systems in a manufacturing facility. OPC travels through ethernet lines and requires an OPC server at the front end (where the information is generated) and an OPC client at the back end (where the information is received). Some FTNIR spectrometers come with an integrated OPC server in the system software; some hot melt extruder controllers also come with OPC clients, which makes the connection between the two relatively simple. Software is also useful to translate OPC to other, older technologies, such as analog, to enable product quality information from the spectrometer PC to be sent almost anywhere in the process area.
Overall, FT-NIR spectroscopy is a rapid, non-destructive vibrational technique that can provide real time feedback of critical chemical information of extruded products. Modern FT-NIR instrumentation can provide this solution by integrating with existing hardware and software via fiber optics, probes and universal process communications methodologies such as OPC.
Jeffrey Hirsch Chief Scientist, Molecular and Microanalysis, at Thermo Fisher Scientific.
1. R. Jayachandra Babu et al., Materials Letters, 63 (30), 2666–2668 (2009).
2. S. Yunzhe et al., Int. J. Pharma., 359(1–2), 114–149 (2008).
3. J. Hirsch and R. De Maesschalck, European Pharmaceutical Review, 1 (2004).
4. M. Kemper and L.M. Luchetta, J. Near Infrared Spectroscopy, 11, 155–174 (2003).