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By Emil W. Ciurczak, Contributing Editor
With its long history in process manufacturing, NIR has the largest variety of hardware and software available for PAT (as well as the most applications published). Explosion-proof NIR instruments, capable of working in any environment, are traditionally lab instruments enclosed in containment chambers.
Figure 6: NIR on a Fluid Bed Dryer. Click for larger image.
Figure 6 shows the NIR viewing a fluid bed dryer. Information about amount of solvents, particle size, and other factors may all be gathered in this manner. Often, it is as important to know where the water molecules lie (hydrate, surface) as how much water is present.
Because the NIR spectra are influenced by hydrogen bonding in the chemical matrix, various physical data may be determined as well as chemical data. NIR spectra vary with particle size (of the same chemical) as baseline offsets, increasing in apparent absorbance with increasing particle size. The physical interaction of optical isomers is apparent in many molecules, due to the intermolecular hydrogen bonding and van der Waal’s repulsions between them. These are most apparent when racemic mixtures are formed. Polymorphic forms of the same substance exhibit spectral differences for the same reasons.
A technique usually associated with NIR but applicable to Raman and MIR spectroscopy is chemical imaging. (See Pharmaceutical Manufacturing, May 2008, NIR-Based Chemical Imaging.) Where standard spectroscopy measures the “average” properties of a sample, chemical imaging (CI) uses multiple pixel imaging to generate a chemical and special image of the sample. That is, the spectra of individual points on a surface are captured in a two-dimensional matrix. This “hyper-spectral cube” of data can then be analyzed for many statistical properties: spatial distribution of chemical moieties (API and excipients), statistical distribution of particle sizes, homogeneity, and so forth. A “snapshot” of roughly 82,000 pixels, each with a full spectrum, may consume over 25 megabytes of space. Figure 7 shows one ranitidine and one acetaminophen tablet. In the former, the two polymorphic forms of the API and the excipient are highlighted through use of PLS functions, and in the latter, the active and excipients are given false colors by wavelength.
Figure 7: Ranitidine and Acetaminophen Tablets by NIR. Click for larger image.
For most of its history, far-infrared was used by crystallographers to measure subtle variations in mor-phology. Based on the rotations of atoms and mainly affected by intra-molecule forces, it is now used to look at interfaces within complex dosage forms. While not an on-line or particularly rapid means of analysis, terahertz can supply information not readily obtainable by other techniques.
While relatively expensive and slower than many other PAT tools, terahertz has a number of unique applications. The source of terahertz absorption is intermolecular, so interfaces between surfaces are the strength of this technique. Figure 8 shows the three interfaces (layer boundaries) of a complex enteric coated tablet; air/tablet surface interface, coating 1/ coating 2 interface, and coating 2/core interface. While limited in application, the data are unique.
Figure 8: Interfaces in Multilayer Tab by Terahertz. Click for larger image.
The Raman Effect was demonstrated by Sir C.V.Raman, an Indian scientist, in 1938. Using sunlight as a source, Dr. Raman first reported results on organic molecules. Later, when lasers became available, Raman spectroscopy became one more tool for characterization in organic synthesis. While actually not an absorption technique (it is based upon scattering of the light), the information gleaned allows it to be paired with infrared. Whereas mid-range IR has its base in non-symmetric bonds (e.g., C-O, C-H, O-H), Raman has its strongest peaks based on symmetric bonds (e.g., O=C=O, C=C, C=C, N=N, etc.). This makes it a perfect companion for MIR.
Raman is quickly making itself known in PAT. In the past few years it has gone from a laboratory novelty to a hardened process tool. Its ability to ignore water allows for aqueous applications even more sensitive than NIR. Since it is based on scattering (in a clear solution), the light may be focused into the container (i.e., glass) and radiation collected nearby, obviating transmission through a fast-moving, curved container. Certainly, Raman is another technique to consider for both raw material and dosage form identification. Handheld instruments are commercially available and are in use in process and off-campus activities.
One limitation of this technique is the difficulty in absolute quantification. Since the intensity of the incident radiation determines the Raman spectrum and there is no “blank” or zero absorption, the standard I/Io (reflected/incident) ratio cannot be calculated, thus eliminating any Beer’s law calculations. Relative intensities, however, are simple to measure and a process may be followed over time (drying, mixing, etc.). A chemical reaction’s progress is shown in Figure 9, where a Grignard reaction proceeds.
Figure 9: In-process Monitoring of a Reaction by Raman. Click for larger image.
The “Raman shift” or spectrum is followed over time. In a case such as this, the starting materials can be seen to disappear while the product appears. When the process is complete, the Raman spectrum stops changing. At this point, compendial analysis may be run.
While PAT and QbD were originally considered small-molecule concepts, they are rapidly being adopted by biopharmaceutical companies. Some of the typical assay techniques in biopharma are even more time-consuming than the chemical assays in pharma. In-line measurements, while not ubiquitous as yet, are becoming more commonplace. Samples that are drawn for conventional tests risk exposing workers to pathogens and the process to contamination. Thus, time and safety concerns are being addressed with PAT.
Knowing when to perform the conventional assay also becomes critical. Probes have been specially built for bioprocess work, wherein the probe may be automatically withdrawn and cleaned, between readings. Typical analyses are for ammonia, mass, glycerin and sugars. Batch-fed fermentations may have nutrients and products followed in real time.
Working with vendors and other resources, a PAT/QbD group can find a spectrometer for nearly every chemical or physical measurement. It is strongly advised that a process be examined, the parameter needed to be measured determined, and then an instrument company approached to ascertain whether or not that particular measurement is feasible.
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