New wave of quality control

Terahertz technology is causing interest due to its ability to non-destructively produce 3D images of intact solid dosage forms, allowing structural and chemical mapping of coatings and core formulations Philip Taday, Alessia Portieri and Yaochun Shen of TeraView explain how it works

Three dimensional THz pulsed imaging (3D TPI) enables pharmaceutical manufacturers to accurately determine coating thickness and uniformity and identify cracks, dislocations and delaminations in single and multi-layer cores^1-4. THz spectroscopy provides the ability to elucidate solid state crystalline structure, such as polymorphs^{3, 5-7}, hydrates8 and solvates without concern for thermal effects. These key measurement advantages of the THz spectral region suggest that THz technology could be integrated as core technology into pharmaceutical development and manufacturing operations to enable the following business benefits to be fully realised:

• In depth knowledge of dosage form structure and attributes to accelerate product development
• Enhanced understanding of product quality attributes affecting solid dosage performance enabling right first time process optimization
• Decreased product and process troubleshooting (Root Cause Analysis) efforts
• Reduced non-compliance and product write-off risks

Terahertz radiation has been called the last unexplored frontier of the electromagnetic spectrum. Occupying frequencies ranging from just below the infrared (4 THz or 133 cm^-1) to just above the microwave region (0.04 THz or 1.33 cm^-1), the so-called Terahertz Gap has received relatively little study compared to the microwave, radio and X-ray regions. This is largely due to a lack of effective radiation sources and detectors at these frequencies; as both conventional optical and silicon solutions have proven unsuccessful

The many useful measurement properties of terahertz radiation have, however, prompted considerable research into its potential applications, which include fields as diverse as astronomy, diagnostic medicine, pharmaceuticals, military and security detection^9,10. Absorptions observed in the THz region are commonly associated with the fundamental intermolecular hydrogen-bonding vibrations and crystalline structure lattice vibrations¹¹. Although most common organic and inorganic materials are semi-transparent to terahertz frequencies (including packaging and coating materials), many exhibit distinctive spectral fingerprints in the terahertz region that are suitable for both qualitative and quantitative purposes.

The proprietary pulsed technology used by the company TeraView measures not only the transient electric fields but the phase of radiation as well; this yields signals with excellent signal-to-noise ratio and a high dynamic range, coupled with the ability to independently determine quantities such as absorption and refractive index¹². These latter characteristics are particularly important to the fields of spectroscopy and imaging in the pharmaceutical industry where, a significant portion of the commercial development of terahertz technology has occurred.

By applying recent advances in both ultra-fast pulsed laser technology and new concepts in semiconductor physics, terahertz spectroscopy and imaging systems have been pioneered by TeraView for use in pharmaceutical analysis, including the investigation of new controlled release delivery systems, troubleshooting in pharmaceutical manufacturing and quality control applications.

Pulsed spectroscopy

Terahertz pulsed spectroscopy is a Fourier-transform technique whereby a pulse generated by an ultra-short pulsed laser and semiconductor is detected in the time-domain and fast-Fourier transformed to the frequency-domain to produce a spectral response¹². This provides information on the chemical constituents (spectral fingerprint). This strategy has proven to work well for the detection and quantification of crystalline polymorphs in drug products^6,13.

Pulsed imaging

Terahertz pulsed imaging combines refractive index measurements with TPS measurements to build complete 3D maps of the internal structures of samples in a non-destructive manner^1-4. Similar in concept to a radar system, to construct a 3D image, a terahertz beam is scanned across the sample, illuminating the target, which reflects portions of the beam from the internal layers. The delay of the reflected pulse across the transient electric field is measured in the time-domain, obtaining both the amplitude and phase of the terahertz pulse to provide a measurement of distance to the various surfaces inside an object with high precision^1-4. Sample reconstructions can then be produced in 3D.

By fast-fourier transforming the time-domain data an absorption spectrum for each voxel (i.e., a 3D pixel) can be obtained, and thus in some instances, 3D TPI can be employed to determine both chemical composition and structural features within a solid dosage form^1,2,13.

Solving issues

THz spectroscopy and imaging are both important tools for realising the pharmaceutical industry's initiatives to accelerate drug development and improve process control and production consistency - reinforced by the US Food & Drug Administration's (FDA) Process Analytical Technology (PAT) and Quality by Design (QbD) initiatives. PAT initiatives seek to optimise process operations through effective measurement and efficient analysis, to eliminate out-of-spec and out-of-range product. QbD initiatives seek to ensure that the design and function of new solid dosage form delivery systems are optimised during pharmaceutical development process to de-risk process scale-up and eliminate conventional root cause analysis.

Solid dosage forms

Tablet coatings are a key route to regulating the release of active pharmaceutical ingredients (APIs) in controlled or sustained release formats. Non-uniformity in the coating can lead to serious consequences affecting safety and efficacy, making it vital for pharmaceutical companies to be able to assess coating thickness and uniformity as a quality control measure, both by batch and on an individual tablet basis. Complex multi-layer tablet cores are another avenue used in sustained or controlled release (SR or CR) technologies. Terahertz technology can probe coating integrity and thickness as well as the interface between the substrate and coating, and can be used to monitor these quantities during product development, process scale-up and manufacture, as well as in a root cause troubleshooting for current operations.

As the majority of pharmaceutical tablet coating and core materials are semi-transparent to terahertz photons, the technology manages to penetrate to depths not achieved by other methods of analysis and it achieves impressive thickness resolution of less than 40 microns with high precision (less than a few microns)^1,4.

Polymorph Identification

The THz spectral region provides unique insight into the formation, structure, and phase transitions of polymorphs^{3,5,6,11,13,15}, hydrate8, and solvate forms. The recognition of a drug's polymorphic forms is vital for pharmaceutical manufacturers, as different polymorphs can significantly affect factors such as the solubility, stability and bioavailability of the drug. It is also imperative for manufacturers to detect their product's polymorphs for patenting purposes.

While the detection of polymorphs can often be determined visually through their crystalline formation or distinct colourings, more complex forms can be detected through a variety of sophisticated techniques. Each method developed for polymorph analysis has unique advantages, however, when employed in the pharmaceutical industry many lose specificity as they are either destructive to the tablet or cannot be deployed rapidly enough for effective process optimisation. In contrast,TPS and TPI are non-destructive techniques that can provide rapid analysis for ready implementation during the manufacturing process and quality assessment.

Changes occurring during processing, where alterations to the solid-state form may occur, and during stability testing and storage, where tablets are subject to challenging temperature and humidity regimes, must be monitored as key areas where TPS can be deployed.

Conventional solid dosage form and drug substance analysis today relies on wet chemical and destructive procedures. The potential of Terahertz imaging and spectroscopy is that critical quality attributes can be directly probed without modifying or destroying the sample. Terahertz radiation thus has enormous potential as a tool yielding new design information and quality assurance capabilities alongside conventional techniques.

TPS is a complimentary technique which affords the opportunity to probe fundamental intermolecular structure to yield information about the solid state properties of chemical moieties. In particular, it provides this measurement opportunity with non-ionizing radiation, while avoiding concern of thermal effects, common with alternative technique such as Raman.

TPS manages to overcome the difficulties of these conventional methods to provide clear, timely and uncompromised polymorphic identification. Due to the different spectra produced by the variance in intermolecular interactions^{11, 13, 15}, TPS can also be used to identify solid state forms for the investigation of active ingredients in finished tablets3. A significant advantage of this system is that intact or complete tablets can be analysed requiring little or no sample preparation.

In the area of imaging, TPI has the ability to non-destructively and quickly assess structural features such as, coating thickness, core integrity, API or excipient irregularities, at depths of 1 mm or more below that of the tablet surface. Existing techniques such as Infrared, Near-Infrared and Raman imaging are practically limited to 2D imaging only as they can probe depths to only 200 - 300 µm below the tablet surface. X-Ray and MRI lack chemical sensitivity, are difficult to implement, and involve complex and time-consuming spectral image reconstruction.

The ability of Terahertz techniques to uncover and monitor chemical and structural features in pharmaceutical products leads to important business benefits in manufacturing for solid dosage form design, manufacture and quality control.