Noninvasive Characterization of Pharmaceutical Solids by Diode Laser Oxygen Spectroscopy (2007)

Characterization of solid pharmaceuticals, ranging from monitoring of solid-state reactions to understanding tablet dissolution, is of great interest for pharmaceutical science. The quality of the finished product highly depends on knowledge about the pharmaceutical materials used and the different unit operations involved in manufacturing of pharmaceuticals. Thus, availability of appropriate and reliable tools for measurements of physical and chemical properties of drug materials in situ during chemical and physical processing is a key for optimized processing. In early stages of pharmaceutical development a whole range of techniques for characterization of the solid state is available, addressing, for example, particle size and shape, density, porosity, calorimetry, thermo-mechanical properties, specific area, and crystallinity. However, most of these techniques are slow and not well suited for fast laboratory-based or process applications. Process analytical technology (PAT) is a term describing a holistic approach to pharmaceutical manufacturing based on in-depth understanding through advanced process sensors and modeling tools. In order to succeed with this, new tools are needed, e.g., with capability to directly measure physico-chemical attributes in situ of the mechanical process. In this context, tools based on spectroscopic techniques offer obvious advantages owing to their speed, compactness, versatility, and ability to perform noninvasive analysis. By employing the spectroscopic technique referred to as gas in scattering media absorption spectroscopy (GASMAS), it is possible to extract information related to gas dispersed within highly scattering (turbid) materials. In our case, the key is contrast between the sharp (GHz) absorption features of molecular oxygen located around 760 nm and the broad absorption features related to tablet bulk material. The technique is based on high-resolution diode laser absorption spectroscopy, and its main principle is illustrated in Fig. 1. Light is injected into a highly scattering sample, often utilizing optical fibers. The actual path length distribution of transmitted photons will depend on the scattering properties of the sample. Due to significant multiple scattering, the average photon path length greatly exceeds sample dimensions. For example, the average path length of photons that have traveled through a pharmaceutical tablet typically exceeds 10 cm. During passages through air-filled pores, photons in resonance with an absorption line in the A-band of molecular oxygen can be absorbed. Oxygen absorption can be distinguished from bulk absorption due to the extremely narrow absorption features (GHz) exhibited by free gases. To resolve such narrow features, high-resolution spectroscopy must be employed. The resulting absorption signal depends on both the oxygen content and the scattering properties (photons path lengths) of the sample. Indirectly, it is thus related to mechanical properties such as porosity and particle size. The GASMAS technique has previously been used to study the gas content in, for example, polystyrene foam, wheat flour, granulated salt, wood materials, fruit, and human sinuses. Gas exchange dynamics has been studied by placing samples of wood and fruit in nitrogen atmospheres and monitoring the re-invasion of oxygen. In this paper we show the potential of using GASMAS for determination of physical and structural parameters of pharmaceutical solids. We present results from a study of pharmaceutical tablets made from two different sieve fractions (particle size distributions) and with different compression forces. In addition, the prospects of a broader use of this technique for pharmaceutical analysis are discussed.