On a micron or sub-micron scale, solid multi-component samples such as blends for tablets or capsules, compressed tablets or cast films typically exhibit non-homogeneous distribution of components. This results in regions that are disproportionately more concentrated in individual components, which can have a major impact on drug product stability, release rate, and other physical properties. SSCI’s powerful analytical techniques provide a wealth of chemical and physical information on specific microscopic regions of solid samples. Some of the most prominent techniques are:
- Fourier Transform Infrared (FTIR) spectroscopy
- Raman Spectroscopy
- Near infrared (NIR) spectroscopy
- X-ray powder diffraction (XRPD)
- Energy Dispersive X-Ray (EDX) Spectroscopy
- Optical Microscopy (OM)
While traditional application of these techniques involves examination of a single location in the sample and subsequent collection of the chemical or physical information from only that isolated area, new imaging techniques involve automated data collection from multiple locations over a large area of the sample. This allows visualization of qualitative distribution, identification of majority or trace components, or more accurate quantitative analysis.
Imaging is a general term for collection (usually automated) and analysis of data from a large number of locations on a sample. Collection of the data array can be accomplished in several ways. The two most common methods of collecting data are use of an array detector, where data for the entire image are collected simultaneously, and automated mapping, in which analysis is carried out on a number of discrete points. SSCI makes use of both methods of data collection. SSCI scientists can carry out distribution analyses where each measurement represents an area as small as from 50 µm to 1 Å depending on the technique. Small particles or domains can be observed that would not be resolved with single analysis of the entire area. Distribution of a single component is easily visualized. Investigation of interfacial interactions is possible by observing differences between adjacent pixels. The array can be processed repeatedly, observing different chemical or physical signatures. Use of these techniques can produce any number of diagnostic presentations of the total sample area.
Imaging over a large area provides a more representative analysis of the sample for quantitative applications. Each pixel of the image provides a full spectrum that can be compared to spectral databases of known compounds for specific identification. Trace particles as small as a single pixel can provide a pure spectrum of a contaminant that would be undetectable in a single analysis of the entire sample area. Individual spectra from each pixel allow quantitative distribution within the area analyzed. Reprocessing provides a more accurate quantitative analysis of the bulk material.
FTIR is well accepted as a methodology for chemical and structural analysis of organic products, providing a unique “fingerprint” spectrum of each molecule. The resulting spectrum is also diagnostic for subtle changes in the chemical or physical properties of the sample. Each FTIR spectrum represents an area of the sample as small as 10 µm, and distribution of a single component is easily visualized. With proper selection of conditions, FTIR can overcome limitations of Raman and NIR. FTIR is often limited by the presence of water or the need to sample through glass, either of which produces significant spectral interferences.
SSCI scientists have extensive experience analyzing solid-state composition in both drug product intermediates and final dosage forms.
As with FTIR, Raman spectra are unique, allowing for unambiguous chemical identification. Raman is sensitive to the local molecular environment such as changes in crystal structure or subtle chemical modifications and as such can be used to understand both chemical and physical changes in the drug product. Raman spectroscopy occasionally suffers from interference due to fluorescence, a sample-dependent spectral interference, but does not have the material limitations inherent to infrared spectroscopies since both glass and water have minimal Raman spectral interferences. Each Raman spectral map can represent an area as small as 1 µm.
Near infrared spectroscopy offers many of the advantages of FTIR and Raman, but overcomes some of the limitations. NIR offers the same advantage over FTIR as Raman, in that neither glass nor water interferes with the analysis and may also allow for in-situ sampling in a number of packaging configurations. NIR spectra result from absorption of overtones and combination bands from the mid infrared region, therefore, chemical or physical differences detected by FTIR also affect NIR data. NIR occasionally suffers from a lack of spectral specificity that is available with FTIR or Raman. Each NIR spectrum represents an area as small as 10 µm.
X-Ray Powder Diffraction Mapping
X-ray diffraction addresses an entirely different aspect of solid analysis and provides highly reliable analysis of the solid-state form of a material. An XRPD mapping study can, for example, provide information about the solid form composition at different regions in a tablet or identify the presence of a trace amount of a particular solid form. Each diffractogram represents an area as small as 50 µm. XRPD offers limited chemical information as compared to FTIR, Raman or NIR.
Energy dispersive spectrometry (EDS) combines the advantages of scanning electron microscopy (SEM) and elemental analysis. Samples interrogated by SEM can be analyzed for elemental content by EDS under similar conditions of magnification and sampling environment. Each point represents an area as small as 1 Å.
Often overlooked in the current set of modern analytical characterization techniques, characterization by an expert in OM can often be critical to understanding physical changes that are occurring in the drug product. We have used OM as both a qualitative and quantitative tool for understanding crystallization kinetics in drug products such as tablets, soft gels, and topical patches. Our in-house experts have more than 20+ years of industrial experience analyzing materials by OM and solving pharmaceutical problems.