Terahertz radiation sheds light on pharmaceutical analysis

Terahertz light resides between the microwave and mid-infrared regions of the electromagnetic spectrum. Radiation from the terahertz region (3–333cm⁻¹ or 100GHz–10THz) is useful for pharmaceutical applications because of its lower frequencies and longer wavelengths relative to mid-infrared radiation. In particular, terahertz radiation is sensitive to vibrations of noncovalent bonds but not to those of discrete bonds. The former correspond to intermolecular vibrations or vibrations of large units in a molecule. When employed in spectroscopic techniques, terahertz radiation affords information on phonons in crystalline semiconductors and in molecular systems. Thus, in the pharmaceutical industry, terahertz technology can be used to identify particular molecules. In addition, longer wavelengths result in little scattering, which, when combined with low absorption in dry solids, renders terahertz radiation important for imaging.

The properties of lower frequencies and longer wavelengths mean that terahertz technology has advantages in both imaging and in spectroscopy. Pharmaceutical scientists can locate physicochemical fingerprints of a particular pharmaceutical compound not previously available using Raman or IR spectroscopic techniques. Furthermore, scientists can nondestructively probe for information up to several millimeters beneath the surface of a dosage form. At TeraView Ltd.¹ in Cambridge, United Kingdom, we have pioneered and developed a terahertz core technology that can be fitted in spectroscopy and 3D imaging systems. Such systems allow rapid data extraction for analysis.

Figure 1. Terahertz spectral features of the drug ranitidine hydrochloride, polymorphic forms I and II. Signature peaks for each form can be identified easily using terahertz spectroscopy.

In the pharmaceutical field, terahertz-pulsed spectroscopy (TPS) is used mostly in solid-state analysis because terahertz light can probe intermolecular changes. The first successes of TPS were in polymorph recognition and quantification, hydrate analysis, and phase transition monitoring. ^2–5 These areas are important in the early stages of research and development, and during manufacturing and storage of a drug product. Changes in crystalline structure of active pharmaceutical ingredients can alter in vivo bioavailability, limit manufacturing procedures, and affect shelf life. Moreover, influences on the patent cycle of a particular pharmaceutical product can be monitored closely and controlled using TPS in conjunction with other analytical techniques.

The use of drug polymorph patents to hinder generic competition is well known. One example involves GlaxoSmithKline's product Zantac^® (ranitidine hydrochloride) for treatment of ulcers. Both polymorphs I and II of ranitidine hydrochloride are therapeutically equivalent. However, form II is manufactured by GlaxoSmithKline for Zantac^® and form I by generic companies, such as Apotex Inc., the manufacturer of Apo-Ranitidine^®. In 1997 Glaxo Wellcome (prior to the merger with SmithKline) could not stop generic companies from manufacturing and selling polymorph I for the same therapeutic purpose. The resulting lawsuit highlighted the importance of polymorph recognition for the purpose of drug patent protection. As a consequence, most pharmaceutical ‘giants’ endeavour to build up extensive polymorphic libraries on their patented drug products to ensure their patent cycles will not be cut short by generic competitors. To see how TPS can protect drug patents, consider the comparisons in Figure 1, which displays the signature peaks of two polymorphic forms of ranitidine hydrochloride. Clearly, the terahertz spectral features for polymorph form I differ from those of form II. This demonstrates that TPS is an ideal tool for determining drug polymorphism.

Figure 2. Black and white terahertz B-scans of a tablet of the painkiller Nurofen^® (top) and a generic tablet (bottom). These B-scans are cross-section terahertz images of the samples.

Another new application is terahertz pulsed imaging (TPI) of solid dosage forms, including tablets, which can be conducted for single-point data acquisition or full scans of the entire surface. Although single-point measurement lends itself towards online analysis—each measurement takes less than 50ms—the option of a full surface scan has exciting prospects as a process analytical tool (PAT). Teraview's TPI^TM imaga 2000 imaging system, developed for tablet inspection, is equipped with a six-axis robotic arm. The arm ensures that the surface of the solid dosage form is always at a normal angle to the incident terahertz beam. This enables fully-automated 3D imaging of the entire surface.

A rapid single-point scan affords accurate measurement of tablet coating layer thickness and resolution of inner coating interfaces. Internal coatings alter the drug release profile of most therapeutically coated tablets, including controlled-release, sustained-release, and enteric-coated tablets. Controlled release of a drug over time or at a specific site can be of vital importance for successful treatment of disease.

We analyzed ibuprofen tablets to demonstrate how singlepoint measurement can help the user differentiate between innovative and generic products. A single-point TPI scan revealed four additional interfaces in the coating structure of a sugar-coated Nurofen^® tablet when compared to a competitor's generic product (see Figure 2).⁸ The generic tablet has not only a less sophisticated coating matrix, but also a thinner coating layer than the Nurofen^®  tablet.

Figure 3. Precise information about a coating defect can be obtained from slides of cross sections in the x, y, and z directions.

Although fast single-point measurement can discriminate between innovative products and generic or counterfeit ones, a complete surface scan can give insight into the integrity of coating structure. Quality control of the integrity of the coating structure is crucial because coating defects can occur during any stage of the coating process. These defects may have life-threatening consequences, such as, dose dumping (when a drug is released all at once into the system). Visible coating defects like blisters and craters can be mapped easily with the 3D imaging process. Reconstructing artificial cross-section slides enables mapping of the exact location, depth, and size of a defect to assess its extent (see Figure 3).⁹ Defects not apparent to the naked eye, such as a bimodal distribution of coating layer thickness and subtle surface roughness, can be detected with a full surface scan. In addition, information on intra-batch or inter-batch coating uniformity and distribution variations can be determined using TPI (see Figure 4).⁹ Besides inspection of tablet coatings during manufacturing, investigation of tablets in blister packs with plastic transparent to terahertz radiation is possible. This means that degradation over time can be monitored in a completely nondestructive manner.¹⁰

Figure 4. Intra-batch variability of coating layer thickness. These four tablets are from the same batch; one side of the tablet surface is presented. Tablet film coating defects are visible as red spots in two of the images on the right. The color scale bar for coating layer thickness is in microns.

A recent US Food and Drug Administration study further suggests that coating layer thickness (determined by TPI) is associated with mean dissolution time. Thus, TPI may be employed to predict dissolution performance of enteric-coated tablets designed to dissolve in the intestine. Moreover, because coating thickness plays a significant role in functional dissolution performance, it should be monitored for better product design.¹¹ A related study of sustained-release tablets monitored the spray-coating process during a scale-up.¹² It found that, when employed for coating quality assessments, terahertz parameters (pulse distance between various refractive interfaces and electric field peak strength) can accurately and rapidly offer information on coating layer thickness and variations in film coating density. Both of these important factors govern the dissolution behavior of sustained-release tablets. Furthermore, correlations of terahertz parameters and dissolution profile were stronger than correlations based on weight gain, the traditional coating quality metric. This suggests that measurement of terahertz parameters gives more reliable insights regarding functional performance of tablets during process scale-up and bioavailability when taken by patients.

Recent advances in terahertz technology are remarkable with respect to physical characterization of solid dosage forms. Although terahertz spectroscopy and imaging afford unique information previously unavailable, we envision new applications, such as solid-state process analytical technology tools, with high throughput and nondestructive characteristics. In the future, manufacturing plants will have arrays of terahertz sensors in various locations with predictive capacity much enhanced by such measurements. In sum, our work demonstrates that terahertz technology can play an important role in the pharmaceutical industry from research to manufacturing and storage. At Teraview, we continue to explore new avenues.