Pharmaceutical Applications of Terahertz Spectroscopy and Imaging

MY NOTE: THIS IS OLD NEWS TO MOST OF YOU, BUT THz WILL CHANGE THE NATURE OF QUALITY CONTROL FOR MOST PHARMACEUTICAL COMPANIES IN THE NEXT FEW YEARS. THE ONLY REAL QUESTION IS HOW SOON?

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Recent research has focused primarily on the systematic exploration of applications of terahertz radiation for the characterisation of pharmaceutical materials. Because the potential of the terahertz spectral range has only begun to be exploited recently, there is a lack of understanding of the interaction between terahertz light and organic molecular crystals, such as pharmaceutical drugs. Over the past three years we have been particularly interested in how most of the information in a terahertz spectrum reflects information directly originating from the crystal structure, and thus in physical rather than chemical properties of the materials.

Solid state characterisation

Drug polymorphism, where materials exhibit a different crystal structure while the chemical composition remains unchanged, is a very important phenomenon with a large number of economical and therapeutic implications for pharmaceutics. Familiar examples of polymorphic materials are diamond and graphite, which are both polymorphs of carbon. But while these polymorphs differ greatly, for instance in colour and hardness, others are not always that easy to distinguish. It is often difficult to differentiate between pharmaceutical polymorphs, where sometimes the only reliable technique is x-ray crystallography. However, not only is this method rather slow using a laboratory instrument but it is also potentially hazardous due to the ionising nature of x-ray radiation. We have found terahertz spectroscopy to be a technique with enormous potential, which could provide a rapid and intrinsically safe alternative for polymorph identification [1].

Examples of terahertz spectra of different pharmaceutically relevant polymorphs. Different forms of carbamazepine (top) and enalapril (bottom)

Five different polymorphs of sulfathiazole.

Quantitation

We have started to investigate the potential of terahertz radiation in comparison to other more established techniques, such as X-ray powder diffraction (XRPD), thermal analysis and different vibrational spectroscopy techniques in the infrared. We have looked into the quantification of small amounts of one polymorphic form mixed with another, as well as the determination of crystalline impurities in an amorphous matrix [2].

Quantification of physical mixtures of two polymorphic forms of carbamazepine by multivariate analysis (PLS) of their terahertz spectra.

Phase transitions

Terahertz spectroscopy is an excellent technique for this purpose; even though high accuracy and precision can be achieved using other techniques, the speed of terahertz measurements is unparalleled. Using the advantage of very fast measurements we characterised the transition from one polymorphic form to another in real time, [3]. We found that time-resolved terahertz spectroscopy allows to study in detail the mechanism and kinetics during a solid-state phase transition. We were able to confirm earlier findings of the mechanism of the particular phase transition for the material in question, which was thought to be a two-step process based on thermal analysis. This had never been observed in a spectroscopic measurement or quantified before [4].

Solid state conversion of carbamazepine form III to form I below the melting point of form III at 433 K

a) Kinetics of the solid state conversion of carbamazepine form III to form I. b) Amount of sublimated carbamazepine in the gas phase during the conversion process

Assignment of spectral features

To address the lack of theoretical understanding of terahertz spectra we have started to collaborate with Dr Graeme Day, a theoretical chemist from the Department of Chemistry at Cambridge University. In order to compare theory and experiment it is important to acquire spectral data at temperatures as low as possible, because nearly all computational methods available assume vibrational transitions from the ground state into the first excited state under harmonic conditions. We developed an experimental setup to measure terahertz spectra at 4 K and Dr Day developed a first approach to calculate the molecular vibrations at terahertz frequencies. The results of our collaboration were very promising, but as yet tentative [5]. We are currently trying to improve these calculations using first principles electronic structure calculations in crystalline environments. These more advanced calculations are computationally much more expensive, and our approach proved to be an excellent preliminary study to justify the resources required for such studies.

Further examples of pharmaceutical THz-TDS

Parallel to these investigations, we have looked at sulfathiazole. Sulfathiazole is one of the most complex polymorphic systems described in pharmaceutical literature and some of its forms are extremely difficult to differentiate. In conjunction with a novel high speed thermal analysis approach, we have been able to unambiguously identify the polymorphic forms and characterise the transformation processes between the forms [6]. Furthermore, we have investigated how low frequency Raman spectroscopy compares to terahertz spectroscopy over the same frequency range. The results indicated that Raman spectroscopy can be used equally well to distinguish the different polymorphic forms. However, we found that the measurement on the Raman system is far more elaborate, much slower to perform, and that the signal acquisition is often hindered by strong fluorescence.

With hydrate forms, we have applied terahertz spectroscopy to a further area of high practical significance. As hydration and dehydration processes are very common during the manufacture of pharmaceutical tablets, it is important to understand these phenomena on a molecular level prior to the design of the manufacturing process. The drug molecule can become less soluble or unstable due to hydration or dehydration: thus, once again, numerous implications arise on the therapeutic and processing level. Terahertz spectroscopy proved to be very well suited to study such systems [7, 8]. In contrast to other standard spectroscopic methods, terahertz spectroscopy has the additional advantage that evaporating hydrate water can be easily identified due to its very different spectrum compared to water still attached to the crystal. This is potentially very useful for the detailed mechanistic study of dehydration processes.

Terahertz Pulsed Imaging - coating characterisation in solid dosage forms

Besides its application for spectroscopy, terahertz radiation can also be used for structural imaging. We have been exploring potential applications of non-destructive terahertz imaging for different types of tablet coatings, controlled release tablets and capsules with a new instrumental setup that is designed specifically for the analysis of pharmaceutical dosage forms [9]. We evaluated the potential applications of an imaging instrument that is able to perform a fully automated measurement of a tablet of any shape. Using a robot arm, the whole surface of the tablet can be seamlessly scanned and a three-dimensional model of the internal structure of the tablet can be reconstructed from the terahertz data. The findings were validated by optical microscopy after preparing destructive cross-sections [10]. We have compared the coating quality parameters derived from the terahertz imaging experiment to the product performance in a dissolution study of different batches of tablets coated with a sustained release coating. While all tablets showed a similar weight gain, and thus appeared indistinguishable, the information from the terahertz imaging experiment allowed the measurement of coating thickness and density, which in turn allowed us to predict the performance of the tablets during dissolution testing [11].

Further Reading

[1] J.A. Zeitler et al., J. Pharm. Pharmacol. 59, 209 (2007).
[2] C.J. Strachan et al., J. Pharm. Sci. 94, 837 (2005).
[3] J.A. Zeitler et al., Thermochim. Acta 436, 71 (2005).
[4] J.A. Zeitler et al., ChemPhysChem 8, 1924 (2007).
[5] G.M. Day et al., J. Phys. Chem. B 110, 447 (2006).
[6] J.A. Zeitler et al., J. Pharm. Sci. 95, 2486 (2006).
[7] J.A. Zeitler et al., Int. J. Pharm. 334, 78 (2007).
[8] K. Kogermann et al., Appl. Spectrosc. in press (2007).
[9] J.A. Zeitler et al., J. Pharm. Sci. 96, 330 (2007).
[10] L. Ho et al., J. Control. Release 119, 253 (2007).
[11] L. Ho et al., J. Control. Release submitted (2007).
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