Near-Infrared Chemical Imaging and the PAT Initiative NIR-CI Adds a Completely New Dimension to Conventional NIR Spectroscopy
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Molecular Spectroscopy Workbench Near-infrared Chemical Imaging and the PAT Initiative NIR-CI adds a completely new dimension to conventional NIR spectroscopy. E. Neil Lewis, Joe Schoppelrei, and Eunah Lee Dear and gentle readers, this month I present an important other manufacturing steps have on the final dosage form? To tool in the process analytical technologies (PAT) initiative: encourage the PAT initiative FDA is streamlining the mecha- Near-infrared chemical imaging (NIR-CI). You might wonder nism for adopting new technologies in pharmaceutical manu- why I am seemingly concentrating on IR and NIR. The an- facturing. swer is quite simple: I need all the heat I can get, here in New York. Seriously, E. Neil Lewis, Joe Schoppelrei, and The Role of Near-infrared Chemical Imaging (NIR-CI) Eunah Lee of Spectral Dimensions (Olney, MD) have put to- A typical tablet is not just a pressed block of a single material, gether an excellent explanation of what NIR-CI is and what but rather a complex matrix containing one or more active its part in PAT is and will be. For those of you who do not pharmaceutical ingredients (APIs), fillers, binders, disinte- know Neil Lewis, he is one of the pioneers in IR and NIR im- grants, lubricants, and other materials. A basic problem in aging. He has won numerous awards for his research at the pharmaceutical manufacturing is that a relatively simple for- National Institutes of Health (NIH) and subsequent accom- mulation with identical ingredients can produce widely vary- plishments. It is truly exciting to have this paper in my hum- ing therapeutic performance depending upon how the ingre- ble column and I know you will find it informative and enter- dients are distributed in the final matrix. More potent APIs taining. can be formulated at dosages of 5 mg or less, but the finished tablet still must be large enough for convenient handling. In he US Food and Drug Administration (FDA) recently this case, maintaining content uniformity is even more cru- released a new guideline strongly advocating the use cial. Pharmaceutical makers also are developing advanced Tand development of new measurement technologies in tablets for drug dosage management, which can provide pharmaceutical manufacturing (1). The process analytical longer, flatter, or sometimes complex bloodstream profiles. technology (PAT) initiative, as it is known, promotes the use Approaches include the use of barrier layers, cored tablets, se- of techniques that enable the monitoring of critical process lective-release microspheres, and even osmotic pumps. These parameters during pharmaceutical manufacturing. The goal is tablets essentially are highly engineered drug delivery systems to not only enable process measurement but, more impor- in which the physical structure is as critical as the chemical tantly, to enable process understanding and ultimately process composition. optimization. Although FDA historically has focused on pu- Existing analytical techniques such as high performance rity and potency as its yardstick of product quality, in the fu- liquid chromatography (HPLC) and mass spectrometry (MS) ture more time will be spent trying to address issues dealing often are used to accurately determine the gross composition with physical processes. For example, what effects, if any, do of a dosage form, but they provide no information about the small changes in the blending, drying, pressing, coating, or distribution of the individual components. The manner and duration of component release is examined through dissolu- tion testing. However, this provides no insight into the cause Emil W. Ciurczak of the profiles obtained. All of these techniques require de- works as a consultant with Integrated struction of the sample, making it difficult or impossible to Technical Solutions, 77 Park Road, Goldens trace the sources of failures or anomalies. Bridge, NY 10526. He can be reached via e- Spectroscopic techniques enable rapid, nondestructive mail at: [email protected]. analysis of samples and can be employed at a number of points in the pharmaceutical development and manufactur- ing process. In particular, NIR spectroscopy quickly is becom- ing a workhorse technique for the industry due to its high in- 26 Spectroscopy 19(4) April 2004 www.spectroscopyonline.com Molecular Spectroscopy Workbench formation content and flexibility of im- around, and reducing time-to-market. sample. This is the fundamental concept plementation. It is used widely for the of chemical imaging: a rapid analytical characterization of raw materials, and Chemical Imaging Principles method that simultaneously delivers also has been used in applications such Conventional digital imaging is the spatial, chemical, structural, and func- as blend homogeneity, moisture meas- process of reproducing the spatial infor- tional information. urement, and the analysis of intact mation of a scene onto a two-dimen- The hypercube. Spectral images are tablets (2–4). sional optical detector. The typical visualized as a three-dimensional NIR-CI adds a completely new di- image recorded with a standard digital block of data spanning one wavelength mension (pun intended) to conven- camera or web-cam is collected across a and two spatial dimensions called a tional NIR spectroscopy. It offers the broad range of optical wavelengths, usu- hypercube (Figure 1). The hypercube ability to obtain high fidelity, spatially ally in the visible region, to produce a can be treated as a series of spatially resolved pictures of the chemistry of the grayscale image. Placing relatively resolved spectra (called pixels) or, al- sample. Elucidation of compositional broadband color filters in front of the ternatively, as a series of spectrally re- heterogeneity and structure is invalu- same detector produces a conventional solved images (called image planes or able for both the development and color image. On the other hand, a single channels). Selecting a single pixel will manufacture of solid dosage forms (5, spectral image usually is collected across yield the spectrum recorded at that 6). NIR images can be used to deter- a narrow wavelength range (very often particular spatial location in the sam- mine content uniformity, particle sizes, in the IR or NIR spectral region). It can ple. Similarly, selecting a single image and distributions of all the sample com- be used to reveal the chemical composi- plane will show the intensity response ponents, polymorph distributions, tion of the sample through absorption (typically scaled to color) of the scene moisture content and location, contam- by one or more chemical species within at that one particular wavelength. inants, coating and layer thickness, and the sample of that particular diagnostic Data analysis. The ultimate goal of the a host of other structural details (7–9). wavelength. The result is a spatially re- experiment is to generate highly specific Through the development phases of solved chemical map of the sample. chemical contrast in an image to visual- preformulation and scale-up, NIR-CI Chemical, or hyperspectral, imaging is ize and identify the compositional het- can be used to identify precisely the elu- the acquisition of images across a larger, erogeneity within the sample. Analysis sive critical control parameters that will usually contiguous series of narrow of the hypercube to produce this con- affect the performance of the finished spectral bands comparable to tradi- trast can be accomplished at several dif- product. The technique is fast and non- tional (single-point) spectroscopic tech- ferent levels. In some cases simply se- destructive and can be used independ- niques, thus integrating the complete lecting the image plane at a wavelength ently or in concert with other tech- spatial and chemical information of the of a characteristic band from a species niques, such as dissolution analysis, to rapidly diagnose potential production problems. NIR-CI instrumentation also is rugged and flexible, suitable for both λ the laboratory and the manufacturing environment. Therefore, analysis meth- ods developed in the laboratory often can be tailored for implementation near-line or at-line. NIR-CI also is mas- yψ sively parallel NIR spectroscopy, making the technique well-suited for high λ λ × λ Spectrum: from 1 to k at (x i, y i) Image plane: n m pixels at j throughput at-line and even on-line ap- x x plications. Imaging also can represent significant economic benefits to the pharmaceuti- cal manufacturer. “Blind” manufactur- Single-pixel spectrum ing processes produce products that can be tested only after the fact. Traditional analytical techniques usually are, in Single-channel image many cases, unable to pinpoint the sources of defects and failures in a timely fashion leading to costly delays. NIR-CI provides chemical and physical information at return rates that are Figure 1. Schematic representation of a spectral imaging hypercube showing the relationship faster than those of any other existing between spatial and spectral dimensions. technique, improving testing turn- 28 Spectroscopy 19(4) April 2004 www.spectroscopyonline.com of interest will readily indicate the spa- application of conventional multivariate spectra. In 1988, Harthcock and Atkin tial distribution and abundance of that quantitative methods in which individ- (14) published the first chemical maps material. However, this univariate ap- ual pixel spectra are analyzed using cali- collected with an Fourier-transform IR proach of data interrogating is quite bration data sets and