INTRODUCTION:

Cambridge (UK) – 3rd February 2010 – Tera View, along with its partners Oystar Manesty, Liverpool University and Cambridge University have successfully demonstrated the ability to measure in-line the coating thickness,

In recent years, Terahertz Pulsed Imaging (TPI) has aroused interest in the pharmaceutical sciences as a technique to nondestructively measure coating thickness distributions of both, external and buried layers, over the entire tablet surface.

Terahertz pulsed imaging (TPI) is a powerful tool for nondestructive and quantitative characterization of pharmaceutical tablet coatings wavelet-based method can be used to characterize the tablet coating with a thickness

Fig 1: Coating Integrity by Terahertz Spectroscopy

The past 10 years have seen a revolution in terahertz systems of particular significance is the development and commercialization of terahertz pulsed spectroscopy (TPS) and terahertz pulsed imaging (TPI) systems. The core technology is essentially the same between the spectroscopy set-up and the imaging set-up, as both utilize ultrafast femtosecond laser to generate and detect short pulses of broadband terahertz radiation.^[2]

There are three main advantages of using pulsed terahertz radiation Firstly, this technology directly measures the transient electric field, not simply the intensity of the terahertz radiation. This yields terahertz spectrum with far better sensitivity and dynamic range as compared with Fourier transform infrared (FTIR) method, High-quality terahertz spectra are now routinely obtained in less than 20 ms without the need for cryogen cooled bolometer, making terahertz spectroscopy more easily and widely accessible. Secondly, because of this time-gated coherent detection technology used, the extraneous ambient noise (originated from the incoherent blackbody radiation from the sample and its surroundings) is minimized. This allows for the first time the use of terahertz spectroscopy for characterizing heated samples under extreme conditions and for in situ studies of phase transitions of pharmaceutical solids. Thirdly the use of pulsed radiation and the associated coherent detection scheme preserves the time-gated phase information, upon which terahertz imaging has been developed for quantitatively characterizing inner structures of a sample non-destructively. The enormous inherent potential of the terahertz technology led to a rapid development of terahertz systems, and the availability of commercial terahertz products has opened up many exciting opportunities in pharmaceutical sector.^[2]

PRINCIPLE:

When THz radiation interacts with molecules, it may stimulate many resonances such as molecular vibrations, phonons and/or other resonances in the system, resulting in the THz photons being affected by a specific interaction or event. The change in energy and/or frequency yields information about the molecular nature of the interaction. Infrared and Raman spectroscopy, for example, yield similar information but are not capable of detecting as many resonant states as can be detected with THz because terahertz photons are sensitive to the vibrational states of the entire molecule, not just a bond or charge state. Molecular vibrations can range from the simple coupled motion of the two atoms in a diatomic molecule to the much more complex motion of each atom in a large poly functional molecule. In general, each atom will have 6 degrees of freedom (with restrictions in some cases); thus, a molecule composed of N atoms will have 6N vibrational states. Such structures are easily probed by terahertz spectrum.^[1]

· Terahertz pulsed spectroscopy (TPS) and terahertz pulsed imaging (TPI) are two novel techniques.

· Used for the physical characterization of pharmaceutical drug materials and final solid dosage forms

INSTRUMENTATION:

Fig. 2: Schematic diagram of THz spectroscopy instrument.BS: beam splitter; M1: metallic mirror; OEM1–OEM2: off-axis elliptic mirrors.

Fig. shows the schematic diagram of a typical transmission THz instrument. Terahertz generation and detection was achieved using an ultrafast laser such as a Ti: sapphire laser. A beam splitter separated the laser light into two beams an excitation beam and a probe beam. Terahertz pulses were generated by optical excitation of a biased photoconductive antenna. The terahertz pulses emitted from the antenna were collimated and focused onto the sample by an off-axis elliptic mirror. The transmitted terahertz pulses were then collected and focused using another off-axis elliptic mirror onto the surface of an unbiased photoconductive antenna for detection. In THz measurements, the transient terahertz electric field was recorded as a function of the time-delay between the terahertz pulse and the probe pulse using a variable delay stage. The spectral resolution of the measurement was determined by the overall time delay scanned. Most commercial instruments are able to provide a spectral resolution of better than 1 cm−1by scanning a time-delay distance of greater than 5 mm. A waveguide configuration could be used to obtain sharper spectral signature. Usually the sample chamber is either purged with dry nitrogen gas or evacuated throughout the measurement to reduce the effects of water vapor absorption.

Sources of terahertz radiation are

1. The gyrotron

2. The backward wave oscillator

3. The far infrared laser

4. Cascade laser

5. The free electron laser

6. Synchrotron light sources

7. Photo mixing sources

Terahertz pulsed imaging (TPI) The ability to generate terahertz radiation from a point source coupled with the fact that many pharmaceutical excipients are semitransparent in this region has resulted in the development of imaging systems capable of nondestructive, three-dimensional investigations of solid dosage forms. The core technology is essentially the same between the spectroscopy set-up (fig no 2) and the imaging set-up (fig no 3). Terahertz radiation is generated by pumping a biased photoconductive antenna with an ultra-short laser pulse from a Ti: sapphire laser. The emitted terahertz pulse is collected, collimated, and then focused onto a sample under test. The reflected and backscattered terahertz pulse is then collected and focused onto an unbiased photoconductive antenna for the laser-gated terahertz detection. In a TPI measurement, the terahertz waveform is taken at many points mapped over the surface of a sample, and at each pixel terahertz wave form is recorded as a function of optical time delay. Thus, TPI provides three-dimensional information: the x- and y axis describe vertical and horizontal dimensions of the sample and the z-axis represents the time-delay (depth) dimension. Note that a reflection configuration is more appropriate for terahertz imaging. This not only allows thick sample, which may be opaque to terahertz radiation, to be imaged, but more importantly, this allows the use of the time-of-flight capabilities of the technique^.[4]

Fig. 3: Terahertz pulsed imaging (TPI)

PHARMACEUTICAL APPLICATIONS ^[1,6]:

THz spectroscopy or imaging can be utilized for improving quality and uniformity of pharmaceutical products, such as identifying polymorphic forms, measuring tablet coating thickness, and 3D chemical mapping. These properties contribute greatly to drug dissolution and bioavailability, which are highlighted for specific investigation by the Food and Drug Administration (FDA), the regulatory body for the pharmaceutical industry in the United States.

— To characterize crystalline properties of drugs and excipients.

— Different polymorphic forms of a drug can be readily distinguished and quantified.

— Measurement of coating thickness.

— Uniformity in coated pharmaceutical tablets.

— Structural imaging and 3D chemical imaging of solid dosage.

Polymorphism Many pharmaceutical materials can exist in multiple solid forms. These polymorphic forms have the same chemical composition but different crystalline structures, and therefore exhibit different physiochemical properties such as dissolution and stability. These properties of any pharmaceutical product are required to be well documented and controlled for regulatory purposes in order to achieve an ideal pharmacokinetic profile in the body. Since polymorphic transitions can be triggered during a number of steps in crystallization, manufacturing and storage, it is essential to be able to monitor any transition during each step. THz spectroscopy has clearly distinguished polymorph forms for several compounds, and the temperature dependence of these spectroscopic signatures has helped develop an understanding of the intermolecular interaction or vibration in the molecules.^[1]

3-D Chemical Mapping During the tableting process, the distribution of medicine may be non-uniform or have an incorrect structure, compromising the desired bioavailability and drug release profile. Thus, monitoring the 3D chemical mapping is also an important factor during manufacturing. While measuring the thickness of a tablet, the chemical map can also be obtained by looking at the spectral data set which is derived from the time domain signal with a Fourier transform. The location of the chemicals in the tablet and identification of the chemical can be both obtained by reconstructing a 3D chemical map, whereas the ultrasound imaging lacks the specificity required for chemical mapping and infrared imaging is limited to surface chemical mapping and not a 3D distribution. In the near-IR and mid-IR range, FTIR and Raman spectroscopy have been successfully developed for chemical mapping. However, many pharmaceutical tablet coatings are opaque to IR light, owing to either strong absorption or scattering. Therefore, conventional IR technique is mostly suitable for mapping out the surface distributions of chemicals, and thus is a two-dimensional chemical mapping technique. In addition, near-IR and mid-IR imaging technology would not be able to discriminate between different pharmaceutical polymorphs. Terahertz radiation, on the other hand, can penetrate deep into a tablet sample and is also capable of polymorph discrimination. Therefore, in principle, TPI provides the necessary penetration capability and spectral specificity for non-destructive chemical mapping in a three-dimensional matrix.

Tablet Coating Coatings have a variety of functions in regulating the release of drugs into the human body. Such controlled release alters the bioavailability of coated drugs during certain times and locations within the body. For oral dosage forms, coatings can protect the active ingredients from premature gastric acid degradation before they reach the small intestine and get absorbed. Coatings can also prolong the tablet shelf-life by protecting the coated components from moisture and oxygen degradation. Therefore, it is important to characterize the tablet coating, and to inspect the coating uniformity within a single tablet or an entire batch efficiently.

Terahertz waves reflected from samples are used to non-destructively analyzes the thickness of film coating on pharmaceutical tablets, as well as their interior structure and film-core interface with the TAS7500IM system ^[4]

Fig. 4: Thickness of film coating on pharmaceutical tablets and their interior structure and film-core interface.

Fig. 5: Terahertz Imaging Instrumentation (TAS7500IM system).

Tablet integrity and performance:

Terahertz image can be optimized for performing 3D analysis on tablets. It can enable determination of coating integrity and thickness, detect and identify localized chemical or physical structure such as cracks or chemical agglomeration within a core and to interrogate embedded layers (such as an interface between two layers) for delamination and integrity.

Terahertz measurements may well become the primary method for the nondestructive determination of coating thickness, requiring little or no calibration for most coatings and substrates. It can reveal the thickness, uniformity, distribution and coverage of simple and complex coating. Terahertz image can also detect embedded layers and localized chemical or physical structural features in the cores of intact tablets to confirm 3D morphology and blend uniformity.

CONCLUSIONS:

This study described the use of TPI as a tool to evaluate critical process parameters for inter-tablet coating uniformity in an active coating process. Preliminary results indicate that terahertz imaging spectroscopy can be used to investigate the geometrical structure of solid dosage forms. It is possible to detect structural defects like delaminations, inclusions, and the presence or absence of inner structures. Moreover, the chemical composition and distribution of the chemical components of solid dosage forms can be analyzed. Tablets have a fingerprint that is unique to the coating, the contents, and potentially the manufacturer. These fingerprints are sensitive to small variances in a product, and every tablet manufactured has a fingerprint that is specific to its physical structure and chemical composition. This fingerprint can be used for quality control or for the detection of counterfeit drugs. However, there still remain several challenges in the application of THz measurement equipment for in-line measurements. The non-flat shape of solid dosage forms is one of the challenges which can be addressed with shape specific optics and handling systems. Future work includes the analysis of a greater variety of prescription drugs.

REFERENCES:

1. Latika M. Ingle ,2013, Terahertz spectroscopy for pharmaceutical applications, International Journal of Pharmacy and Pharmaceutical Science Research, ISSN: 2249-0337.

2. Yao-Chun Shen,2010, Terahertz pulsed spectroscopy and imaging for pharmaceutical applications: A review; International Journal of Pharmaceutics 417 (2011) 48–60.

3. Allis, D.G., Prokhorova, D.A., Korter, T.M., 2006. Solid-state modeling of the terahertz spectrum of the high explosive HMX. J. Phys. Chem. A 110, 1951– 1959.

4. Ho, L., Mueller, R., Krueger, C., Gordon, K.C., Kleinebudde, P., Pepper, M., Rades, T., Shen, Y., Taday, P.F., Zeitler, J.A., 2010. Investigating dissolution performance critical areas on coated tablets: a case study using terahertz pulsed imaging. J. Pharm. Sci. 99, 392–402.

5. Cogdill, R.P., Forcht, R.N., Shen, Y.C., Taday, P.F., Creekmore, J.R., Anderson, C. A., Drennen III, J.K., 2007. Comparison of terahertz pulse imaging and near-infrared spectroscopy for rapid non-destructive analysis of tablet coating thickness and uniformity. J. Pharm. Innov. 2, 29–36

6. file:///E:/data/ravi/project%20m.pharm/recent%20trends/terahertz/2ppt/Pharmaceutical%20Applications.pdf

7. Ikeda, Y., Ishihara, Y., Moriwaki, T., Kato, E., Terada, K., 2010. A novel analytical method for pharmaceutical polymorphs by terahertz spectroscopy and the optimization of crystal form at the discovery stage. Chem. Pharm. Bull. 58, 76–81.

8. M. C. Beard and M. G. Turner and C. A. Schmuttenmaer, "Terahertz Spectroscopy", in Journal of Physical Chemistry, vol. 106, pp 7146-7159, 2002.

9. J. A. Zeitler and P. F. Taday and D. A. Newnham and M. Pepper and K. C. Gordon and T. Rades, "Terahertz pulsed spectroscopy and imaging in the pharmaceutical setting- a review", in Journal of Pharmacy and Pharmacology, vol. 59, pp. 209-223,2007.

10. J. Fitzgerald and B. E. Cole and P. F. Taday, "Nondestructive analysis of tablet coating thickness using terahertz pulsed imaging", in J. Pharm. Sci., vol. 94, pp.177-183, 2005.

Received on 03.07.2020 Modified on 27.07.2020

Research J. Science and Tech. 2020; 12(4):317-322.

DOI: 10.5958/2349-2988.2020.00047.9