Now at a practical size and
price, terahertz spectroscopy is advancing as a nondestructive method of
analysis for solid forms and tablet coatings.
Spectroscopy—the analysis of the properties of substances
based on their interactions (absorption, transmission, reflectance) with
electromagnetic radiation—is a fundamental analytical tool in the
pharmaceutical industry. Commonplace methods, including infrared (IR) and
ultraviolet-visible (UV-vis), and newer methods, such as near-infrared (NIR)
and Raman, spectroscopy, use radiation of different wavelengths (i.e.,
energies) to provide unique information about the structure and electronic
configuration of different compounds. Terahertz spectroscopy is the newest
entrant on the block, and this low-energy technique is attracting a lot of
attention due to its ease-of-use, rapid analysis time, depth of penetration
into solid materials, and its ability to provide a wide range of physical and
material property information.
Terahertz waves fall on the electromagnetic spectrum between
the infrared and millimeter wave regions (i.e., 300 gigahertz to 10 terahertz).
They are transmitted through many types of materials, such as tablets,
capsules, gels, and even liquids and slurries, which enables the analysis of
their internal structure. Notably, the intermolecular vibrations between small
molecules and the intramolecular vibrations of larger molecules (peptides and
proteins) as they fold around themselves occur at this wavelength. Terahertz
spectroscopy can thus be used to determine the chemical composition of
substances, the presence of impurities, and other properties. In addition, by
comparison with a known spectrum, differences between pharmaceutical products
such as tablets can be analyzed nondestructively.
Recently, the cost and size of terahertz instrumentation has
decreased significantly to the point where it is now a practical tool for
industrial applications, including for pharmaceutical development and
manufacturing, according to Ed King, an R&D fellow at Advantest
Corporation. He also points to the increasing number of presentations given at
conferences and papers appearing in the published literature as evidence that
the utility of terahertz spectroscopy is being recognized in the academic
community.
Generating a terahertz wave
Like many other spectroscopes, terahertz instruments generally have an emitter
and a detector. In this case, femtosecond laser pulses are shined on the
detector, causing the emission of energy in the terahertz region. These
sub-picosecond pulse duration emissions are directed at the sample and are transmitted,
reflected or absorbed. A second laser is then used to digitally sample the
waves that are generated after interaction with the substance being analyzed. A
single scan can be processed in various ways (e.g., Fourier transforms,
time-of-flight analysisto generate a useful spectrum in as little as 8
milliseconds.
“The spectrum of a sample is a unique fingerprint of the
interactions (hydrogen bonding, dipole-dipole, and Van der Waals) between small
molecules and within larger molecules, providing, for example, crystal lattice
information,” observes David Heaps, a principal scientist with Advantest.
Most importantly, rapid, nondestructive imaging and analysis
of pharmaceutical samples in the liquid or solid state is possible.
“Crystalline qualities, the characteristics of constituents, and even the
thickness, density, and internal structure of tablet coatings—previously
impossible to analyze nondestructively—may be evaluated and visually rendered
in two or three dimensions,” adds King.
The Advantest system uses a proprietary, in-house-developed
broadband emitter using an optical rectification-type, terahertz-wave
generation scheme to generate spectral coverage from 0.5 to 7 THz. In addition,
spectrometry tailored to various dosage forms—from liquids to solids—and the
analysis of physicochemical properties are made possible by simply exchanging
the measurement module from transmission to reflectance or to attenuated total
reflection, according to senior R&D scientist Mark Sullivan at Advantest.
An advance in spectroscopic methods
Spectroscopy—the analysis of the properties of substances based on their
interactions (absorption, transmission, reflectance) with electromagnetic
radiation—is a fundamental analytical tool in the pharmaceutical industry.
Commonplace methods, including infrared (IR) and ultraviolet-visible (UV-vis),
and newer methods, such as near-infrared (NIR) and Raman, spectroscopy, use
radiation of different wavelengths (i.e., energies) to provide unique
information about the structure and electronic configuration of different
compounds. Terahertz spectroscopy is the newest entrant on the block, and this
low-energy technique is attracting a lot of attention due to its ease-of-use,
rapid analysis time, depth of penetration into solid materials, and its ability
to provide a wide range of physical and material property information.
Terahertz waves fall on the electromagnetic spectrum between
the infrared and millimeter wave regions (i.e., 300 gigahertz to 10 terahertz).
They are transmitted through many types of materials, such as tablets, capsules,
gels, and even liquids and slurries, which enables the analysis of their
internal structure. Notably, the intermolecular vibrations between small
molecules and the intramolecular vibrations of larger molecules (peptides and
proteins) as they fold around themselves occur at this wavelength. Terahertz
spectroscopy can thus be used to determine the chemical composition of
substances, the presence of impurities, and other properties. In addition, by
comparison with a known spectrum, differences between pharmaceutical products
such as tablets can be analyzed nondestructively.
Recently, the cost and size of terahertz instrumentation has
decreased significantly to the point where it is now a practical tool for
industrial applications, including for pharmaceutical development and
manufacturing, according to Ed King, an R&D fellow at Advantest
Corporation. He also points to the increasing number of presentations given at
conferences and papers appearing in the published literature as evidence that
the utility of terahertz spectroscopy is being recognized in the academic
community.
Generating a terahertz wave
Like many other spectroscopes, terahertz instruments generally have an emitter
and a detector. In this case, femtosecond laser pulses are shined on the detector,
causing the emission of energy in the terahertz region. These sub-picosecond
pulse duration emissions are directed at the sample and are transmitted,
reflected or absorbed. A second laser is then used to digitally sample the
waves that are generated after interaction with the substance being analyzed. A
single scan can be processed in various ways (e.g., Fourier transforms,
time-of-flight analysisto generate a useful spectrum in as little as 8
milliseconds.
“The spectrum of a sample is a unique fingerprint of the
interactions (hydrogen bonding, dipole-dipole, and Van der Waals) between small
molecules and within larger molecules, providing, for example, crystal lattice
information,” observes David Heaps, a principal scientist with Advantest.
Most importantly, rapid, nondestructive imaging and analysis
of pharmaceutical samples in the liquid or solid state is possible.
“Crystalline qualities, the characteristics of constituents, and even the
thickness, density, and internal structure of tablet coatings—previously
impossible to analyze nondestructively—may be evaluated and visually rendered
in two or three dimensions,” adds King.
The Advantest system uses a proprietary, in-house-developed
broadband emitter using an optical rectification-type, terahertz-wave
generation scheme to generate spectral coverage from 0.5 to 7 THz. In addition,
spectrometry tailored to various dosage forms—from liquids to solids—and the
analysis of physicochemical properties are made possible by simply exchanging
the measurement module from transmission to reflectance or to attenuated total
reflection, according to senior R&D scientist Mark Sullivan at Advantest.
Numerous applications
Tablet coatings can be highly complex systems that consist of multiple layers,
contain APIs, and serve a functional purpose (i.e., sustained-release, taste
masking) beyond providing the appearance of the dosage form. As the complexity
of such coatings increases, the uniformity of the thickness and distribution of
active ingredients, interactions between multiple layers and the tablet core,
and coating stability all become critical quality parameters, according to
King.
By analyzing the time-delay and amplitude of terahertz wave
pulses reflected by different coating layers with different refractive indices,
the thickness and density of the layers can be evaluated as can the interfacial
adhesion between the layers and the tablet. Changes in the results obtained
over a period of time can indicate migration of ingredients within the coating
or from the coating to the tablet.
Furthermore, because terahertz waves can penetrate up to a
few millimeters into a solid, the chemical composition of the tablet itself can
be evaluated. In addition to the distribution of ingredients in a tablet, the
density and porosity can be determined. This analysis gives results similar to
those that are obtained using the hardness test, which requires destruction of
the tablet. Terahertz spectroscopy has also been proposed for the evaluation of
the uniformity of the density of ribbons produced by roller compaction.
Analysis of polymorphs is also possible. Terahertz
spectroscopy gives results similar to those obtained using X-ray powder
diffraction, but there are no safety issues associated with low-energy
terahertz radiation, and the results are obtained much more rapidly, according
to Sullivan.
Absorption in the THz frequency range is sensitive to
crystal-lattice vibrations. These absorptions result in a characteristic
spectrum for each crystal form, thus enabling the analysis of polymorphs.
“Rapid evaluation is becoming increasingly important as poorly soluble drugs
begin to be formulated as cocrystals. In solid-form discovery, maybe 10
different pure polymorphs, hydrates, or salts will be screened to select the
best candidates for development. The number of possible forms for cocrystals is
significantly higher, perhaps even comprising a combinatorial library of
possible forms,” he notes.
Terahertz spectroscopy is also useful for the evaluation of
the physical stability of amorphous dispersions of poorly soluble drugs. In all
of these cases, being able to extensively characterize the solid form of APIs
is critical for establishing a strong intellectual property position.
PAT potential
The ability to rapidly acquire spectra makes terahertz spectroscopy suited for
use in process analytical technology (PAT) applications, according to Heaps.
“In many of the aspects of pharmaceutical manufacturing where continuous
processing is being actively explored, there is a great need for vary rapid
analytical techniques that can be used to provide real-time information.
Terahertz spectroscopy is very attractive for this application because it can
be used to monitor multiple different properties very rapidly, and can be used
equally effectively for R&D, pilot plants, and commercial-scale production,”
he adds.
Many advantages
A key advantage of terahertz spectroscopy is that it enables the analysis of
many material properties that traditionally have required the destruction of
the sample. The greater penetration of terahertz waves probes sample depths
that are not obtainable using most spectroscopic techniques, and its high
sensitivity allows for limits of detection of < 1% for minor components in a
sample. In addition, it does not present any safety hazards, unlike X-ray
analysis, and extensive operator training is not required with the
instrumentation available today. Finally, terahertz spectroscopy can be used to
complement FTIR, NIR, Raman, and X-ray powder diffraction, and its speed of
measurement makes it attractive for online measurement
