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Characterizations of the Calamine tablets by terahertz time-domain spectroscopy
Optik - International Journal for Light and Electron Optics 187 (2019) 278–284
Contents lists available at ScienceDirect
Optik journal homepage: www.elsevier.com/locate/ijleo
Characterizations of the Calamine tablets by terahertz time-domain spectroscopy
T
Sibo Haoa, Haochong Huanga, , Yuanyuan Maa, Shangjian Liub, Zili Zhanga, ⁎ Zhiyuan Zhenga, ⁎
a b
School of Science, China University of Geosciences (Beijing), Beijing, 100083, China Beijing University of Chinese Medicine Dongzhimen Hospital, Beijing, 100700, China
ARTICLE INFO
ABSTRACT
Keywords: Calamine THz-TDS Wedge-tablet design Echo signal Particle size
Terahertz time-domain spectroscopy (THz-TDS) is an attractive technique that is capable of nondestructive penetrating and probing pharmaceutical tablets conveniently. It can provide sufficient optical information of crystalline and polymorphic pharmaceuticals with high signal-tonoise ratio (SNR). These merits make the application of THz-TDS within pharmaceutical industry increase rapidly. Meanwhile, the advancements of the in-line monitoring accuracy and dependence of THz-TDS are highly urgent because of the rigorous pharmaceutical quality control. There, it is the first time to characterize the optical constants of Calamine tablets using THz-TDS. The experimental results prove that THz-TDS can be employed to classify Calamine tablets with different masses. In addition, the issue of existing echo signal has been resolved with enhanced SNR by a novel wedge-tablet design within a minor wedge angle. Furthermore, the relationship between the particle sizes composed the Calamine tablets and the scattering absorption obtained from terahertz spectra is revealed. This research highlights the character of THz-TDS in distinguishing the Calamine tablets composed with different configurations, as well as further deepening the interpretation of in-line monitoring in the pharmaceutic industry.
1. Introduction The in-line quality control of pharmaceutical industry has always been a puzzle, especially for mineral Chinese medicines with multi-component and complicated structure [1–3]. These mineral Chinese medicines have been widely investigated by a bulk of research methods, such as powder X-ray diffraction (PXRD) [4], Thermogravimetric analysis (TG) [5], Near-infrared spectroscopy (NIRS) [6] and Electron probe microanalysis (EPMA) [7]. Calamine, as a kind of carbonate mineral of calcite groups, is a typical mineral Chinese medicine. It belongs to smithsonite, with pink or gray color generally, and has significant effects on detoxifying and relieving itching [8]. The above characterizing methods cannot meet the quality controlling requirements of Calamine increasingly. Terahertz time-domain spectroscopy (THz-TDS), as a newly inherent non-invasive technique with high signal-to-noise ratio (SNR), can penetrate an entire pharmaceutical tablet deeply and allow its optical constants to be determined as a function of frequency [9–11]. Frequency-dependent absorption coefficients and refractive index can be applied for medicine identification and classification. Consequently, THz-TDS can be employed as a unique tool to provide sufficient information for the characterizations of Calamine. Moreover, powder is the most common status for mineral Chinese medicine to deliver active pharmaceutical ingredients to the patient. However, during the modern production process of pharmaceuticals, there are many circumstances in which the ⁎
Corresponding authors. E-mail addresses: [email protected] (H. Huang), [email protected] (Z. Zheng).
https://doi.org/10.1016/j.ijleo.2019.03.102 Received 1 February 2019; Accepted 19 March 2019 0030-4026/ © 2019 Elsevier GmbH. All rights reserved.
Optik - International Journal for Light and Electron Optics 187 (2019) 278–284
S. Hao, et al.
powdered pharmaceutical is required to be fabricated into a tablet composed two flat faces with a thickness of several millimeters to satisfy the demands in terms of drug load, physical stability, and marketing requirements [12]. Under these conditions, echo signal will be introduced by the tablets screened by THz-TDS. The observable echo signal is the result of multiple transmissions caused by multiple backward and forward reflections (Fabry-P´erot effect) within tablets. The appearance of the echo signal will reduce the SNR, interfere with the dependence and accuracy of the spectral data [13], and therefore influence the effective monitoring. Due to such reasons, on the one hand, a tedious algorithm is performed in theory [14,15]. On the other hand, to efficiently separate the echo signal from the main signal, artificial and independent values will be unavoidably induced in the data process. Hence, a method with high sensitivity in terahertz detection is required in pharmaceutical applications. In the present research, definite terahertz spectra assignments of Calamine tablets with different masses were determined by THzTDS. Furthermore, a skillful wedge rather than a flat-faced tablet has been proposed and investigated using THz-TDS to eliminate the echo signal and improve the detecting sensitivity. It is found that the echo signal in Calamine temporal files can be decomposed completely and SNR of the spectra is enhanced as well. The absorption coefficients are optimized substantially without changing the algorithm regime. In addition, terahertz spectra present a high correlation between the wedge angle and the spectral resolution. And the effect of sizes of the particles composed the tablet has also been investigated. All these results indicate that THz-TDS is a feasible and efficient technique to characterize the Calamine, even provide novel insights into other various mineral medicines. 2. Experiments The THz-TDS measurements were performed based on a conventional transmission configuration of which the detailed principle was depicted in reference [16]. The spectrometer was purged with nitrogen to exclude the negative influence of vapors. The experimental measurements were conducted at room temperature. The particle size of the powdered Calamine was determined by different purpose sieves. All samples compressed into tablets have the diameter of 13 mm. The diagrams of different kinds of tablets in experiments are displayed in Fig. 1. For flat-faced tablet, the terahertz waves were perpendicular to the surface as shown in Fig. 1(a). Normally flat-faced Calamine tablets were formed with different masses ranging from 0.10 to 0.30 g. For wedge shape tablet, the terahertz waves were incident to the flat surface and inclined surface as shown in Fig. 1(b) and (c). And the values of wedge angle θ are about 4°, 9°, and 13°, respectively. In order to compare the differences between the wedge and the flat-faced, the center positions of the wedge and flat-faced tablets have the same thickness as the dashed line shown in Fig. 1. 3. Results and discussions 3.1. Analyses of terahertz spectra The transmission terahertz temporal signals of normally flat-faced Calamine tablets with different masses are shown in Fig. 2(a), where the tablets masses are 0.10, 0.15, 0.20, 0.25, 0.30 g, respectively. The results in Fig. 2(a) illustrate that a heavier weight is equivalent to a more thickness with the same diameter resulting in the more delay time of terahertz signal, as well as the corresponding phase differences shown in Fig. 2(b). Τhe phase differences augment with the increasing of the frequency for all tablets. Ιn Fig. 2(a), there are three obvious echo signals at 10.56, 12.85, 15.73 ps corresponding to tablets of 0.10, 0.15, 0.20 g. However, no echo signals are observed in the curves of the masses of 0.25 and 0.30 g. There are two possible explanations here, one is that the amplitude of the echo signal absorbed by tablets is too weak to be detected, the other is that its location may occur outside the detection coverage of the main signal. In addition, the delay time of the echo signal between the main signal and the echo signal increases from 8.65 to 11.02 ps with the mass increasing from 0.15 to 0.20 g. The delay time of the echo signal is extended corresponding to the mass variation. Consequently, the terahertz spectra presented in Fig. 2 can be employed as a standard to rapidly classify the masses of pharmaceutical tablets. As above discussed in Fig. 2, it is known that the terahertz wave has various responses to the Calamine tablets with different masses in THz-TDS. Moreover, terahertz frequency-domain spectra (THz-FDS) can be calculated from the recorded data by a numerical fast Fourier transform (FFT). Τhe frequency-dependent absorption coefficients and refractive index of each Calamine tablet can be both obtained based on the terahertz spectral information mentioned above. The THz-FDS of the reference signal and the Calamine tablets with different masses are shown in Fig. 3(a). Frequency-dependent refractive indexes and absorption coefficients of
Fig. 1. Different patterns of the terahertz wave incident to the tablets. θ represents the wedge angle. (a) Flat-faced tablet, (b) and (c) are the wedgetablet Calamine. 279
Optik - International Journal for Light and Electron Optics 187 (2019) 278–284
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Fig. 2. Transmission terahertz time-domain signals (a) and frequency-dependent phase differences (b) of Calamine tablets with different masses ranging from 0.10 to 0.30 g.
Fig. 3. The THz-FDS of a reference and the Calamine tablets with different masses (a). Frequency-dependent refractive indexes (b) and absorption coefficients (c) with different tablet masses.
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Fig. 4. Transmission terahertz time-domain signals (a) and absorption coefficients of flat-faced (0°) and wedge-tablet Calamine with wedge angles of 4°, 9°, and 13°, respectively (b).
the Calamine tablets with different masses are presented in Fig. 3(b) and (c). The refractive indexes of 0.25 and 0.30 g are basically a same constant about 2.05 and there is no characteristic peak in the absorption coefficients indicating that Calamine does not seem to have specific absorption bands that could be attributed to any features at terahertz frequencies between 0.2 and 1.6 THz. The oscillations of Calamine tablets (0.10, 0.15 and 0.20 g) caused by echo signals are observed in the THz-FDS, interfering the effective monitoring by THz-TDS. The corresponding refractive indexes and absorption coefficients are clearly distorted by the effect of the echo signal. Based on such a viewpoint, the echo signals should be eliminated as possible. 3.2. The elimination of echo signals Fig. 4 demonstrates the comparisons of terahertz temporal signals and absorption coefficients of the flat-faced and the wedge tablets with wedge angles of 4°, 9°, and 13°. Compared to that of 0°, there is little change of time delay of 4° and 9° in time-domain spectra, as shown in Fig. 4(a). This is mainly due to almost the same optical path the terahertz wave passing through. The time delay is not sensitive to the wedge angle within a range, although it is determined by the tablet thickness (mass), as shown in Fig. 2. In particular, little change of time delay of 4° and 9° promises the un-distortion of the detected transmission terahertz time-domain signal. The corresponding results of the absorption coefficients are illustrated in Fig. 4(b). The absorption coefficients of 0° oscillate unsteadily arising from the effect of the echo. With the wedge angle increasing to 4°, the oscillation has become weaker. There is almost no oscillation observed for 9°. For 13°, the detected transmission terahertz signal has been distorted because of the oversized wedge angle although the elimination of the echo signal has also been realized. And the absorption coefficients have an obvious diverge with that of other angles. Moreover, for 0°, 4° and 9°, the amplitude of the echo signal is the function of the wedge angle. And the improvements of the amplitudes indicate that a higher SNR of the THz-TDS can be obtained by this wedge-tablet shape. It can be seen from the inset in Fig. 4(a) that the amplitude of the echo signal of 0° is the strongest and a weaker for 4°. While the echo signal has been eliminated under the condition of 9°. This interesting phenomenon can be explained by the diagrams of Fig. 5. Under the assumption of normal incidence, ignoring reflections and refractions between the tablet surface and the air, the tablet interior multiple-reflection and transmission pathways are shown in the drawing. With the increasing of the wedge angle, the 281
Optik - International Journal for Light and Electron Optics 187 (2019) 278–284
S. Hao, et al.
Fig. 5. The diagrams of multiple-reflection and transmission pathways of the terahertz wave passing through the flat-faced tablets (a), patterns of the terahertz wave incident to the wedge-tablet Calamine with the angle of 4° from the plane surface (b) and the wedge surface (c).
directions of the terahertz wave transmission and multiple-reflection will be changed, exceeding the detecting range, as shown in Fig. 5(b) and (c). With regards to the algorithmic, in the case of normal incidence, all the transmission (reflection) paths overlap with lengths l. the transmitted wave reads [17]
Et ( ) =
l ·exp [ jn^s ( ) ]·FP ( ) ·E0 ( ) c
(1)
E0 ( ) is the incident wave, n^s is the refractive of the tablet. = 2/(1 + n^s ) is the complex transmission coefficient for the wave incident from free space. = 2n^s /(1 + n^s ) is the transmission coefficient for the wave incident in the tablet. In analogy to the total transmitted wave, the total reflected wave can be expressed as Er ( ) = E0 ( ) + Likewise, = (1 and is given as
FP ( )= 1 +
· exp [ 2 jn^s ( )
n^s )/(1 + n^s ) and
2 exp
2 jn^s
l c
+
l ]·FP ( )·E0 ( ) c
(2)
= (n^s
1)/(n^s + 1) are the reflection coefficients. FP(ω) represents the Fabry-P´erot effect,
4 exp
4 jn^s ( )
l c
+
· E0 ( ) = 1
2 exp
2 jn^s ( )
l c
1
(3)
It can be seen from Eq. (3) that FP(ω) is decreasing with the increasing of the thickness (mass) l. In the wedge tablet considered optically thick, the thickness l beam passes through each time is longer than before. Meanwhile, the intensity of the signal is getting weaker sharply after the initial transmission, the thickness l is becoming infinitely longer as seen in the later. This means that Eqs. (1) and (2) are necessary to be solved with FP(ω) = 1. Under this case, FP term can be neglected. In a word, the moderate compatible wedge angle to remove the echo signal of Calamine is 9° in the experiments. Meanwhile, the wedge-tablet design can be extended easily to other substances under transmission measurements using THz-TDS. 3.3. The scattering effect of particle sizes In order to investigate the effect of the incident patterns as shown in Fig. 1, the different incident patterns of 4° are shown in Fig. 6. It demonstrates in Fig. 6(a) that for 4°, the phase delay and the echo of the terahertz transmission signal (inset in Fig. 6) do not relate to the different incident patterns. Likewise, the results of Fig. 6 also apply to the wedge angle of 9°. In addition, it is intriguing to find that the plane and wedge surface of 4° become to diverge above 1.1 THz gradually in Fig. 6(b). This is mainly caused by the scattering effect. According to the Mie scattering theory, scattering effect will get stronger when the particle size approaches to the wavelength [18]. The particle size of the tablets employed in Fig. 6 is less than 300 μm, which closes to the terahertz wavelength at 1.1 THz. Under this case, the scattering effect becomes intense. Theoretical analyses of scattering from spherical particles have contributed to dealing with the scattering problem [19]. But as a part of the absorption, scattering absorption is the absorption caused by obstacles scattering to the propagation of terahertz waves. It is difficult to distinguish with absorptions of the Calamine tablet in the experiments. The scattering absorption is mainly determined by the particle sizes of the tablet. Fig. 7 displays the effect of the particle size of wedge tablets on terahertz spectra. In order to compare, one Calamine tablet is composed by less than 75 μm particle size (which is determined by a 200-purpose sieve) and the other is less than 300 μm (which is determined by a 50-purpose sieve). It can be observed from Fig. 7(a) that the amplitude of 75 μm is higher than that of 300 μm. The corresponding absorption coefficients of 300 μm is higher than that of 75 μm over all frequencies as shown in Fig. 7(b), especially at high frequency. This suggests that the scattering absorption has become intense when the wavelength of the terahertz wave is comparable to the particle size. Notably, controlling the different particle sizes of the tablets is essential during the in-line THz-TDS sensing since it affects the mechanical stability, dissolution and drug releasing rate of the tablets [20]. And the results in Fig. 7 suggest that THz-TDS has unique advantages in distinguishing the tablets with different particle sizes. 282
Optik - International Journal for Light and Electron Optics 187 (2019) 278–284
S. Hao, et al.
Fig. 6. Transmission terahertz time-domain signals (a), absorption coefficients (b) of different incident patterns of the wedge-tablet Calamine with the angle of 4°.
Fig. 7. Transmission terahertz time-domain signals (a) and absorption coefficients of tablets composed by different particle sizes (b). One curve is less than 75 μm and the other is less than 300 μm.
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S. Hao, et al.
4. Conclusions Finally, the conclusion gives a brief illustration of the work and findings. The frequency-dependent refractive indexes and absorption coefficients of Calamine with masses ranging from 0.10 to 0.30 g were determined by THz-TDS. Furthermore, the echo signal in terahertz time-domain spectra of Calamine has been eliminated using a kind of design wedge-tablet. Within a minor wedge angle of 9°, the echo signal can be eliminated completely with the efficient enhanced absorption coefficients. Under the case of 13°, the raw data has been distorted. Temporal spectra and absorption coefficients of Calamine also relate with the particle size composed the tablet, especially when the particle size is comparable to the terahertz wavelength. In summary, THz-TDS can be served as an effective tool for in-line pharmaceutical tablets monitoring. This work supplies an optimization in the sensing accuracy and reliability, as well as the optical parameter extraction of Calamine. It is not only of benefits in characterizing Calamine and other mineral medicines, but also to be expected to play a key role in characterization methods of the pharmaceutic industry. Acknowledgments This project supported by the National Natural Science Foundation of China (61805214), Fundamental Research Funds for the Central Universities (2652017142). References [1] L. Chen, J. Ming, M.Y. Yuan, Y.M. Liu, B.S. Huang, K.L. Chen, Construction of a systematic identification method for mineral Chinese medicine, Chin. Pharm. 19 (2016) 351–356. [2] J. Liang, Q.J. Guo, T.Y. Chang, K. Li, H.L. Cui, Reliable origin identification of Scutellaria baicalensis based on terahertz time-domain spectroscopy and pattern recognition, Optik 174 (2018) 7–14. [3] H. Zhang, Z. Li, Terahertz spectroscopy applied to quantitative determination of harmful additives in medicinal herbs, Optik 156 (2018) 834–840. [4] L.J. Zhou, L. Zhang, C.Z. Lu, A.W. Ding, Market sales calcined calamine composition analysis and quality evaluation, China Pharm. 27 (2010) 2534–2536. [5] X.L. Meng, J.N. Ma, N.N. Cui, Y.H. Ping, K. Li, S.S. Zhang, Calamine calcination based on thermal analysis, Chin. J. Trad. Chin. Med. 38 (2013) 4303–4308. [6] M. Le, L. Chen, B.S. Huang, K.L. Chen, M.Y. Yuan, Identification of 7 sulfate minerals by near infrared spectroscopy, World Sci. Technol.-Modern. Trad. Chin. Med. 11 (2014) 2385–2389. [7] L.J. Yang, Z.J. Zhang, R. Li, X.F. Feng, J.Y. Yang, Analysis of the composition of calamine in traditional Chinese medicine, Chin. J. Trad. Chin. Med. 37 (2012) 331–334. [8] X. Zhang, L. Chen, Y. Sun, Y. Bai, B. Huang, K. Chen, Determination of zinc oxide content of mineral medicine calamine using near-infrared spectroscopy based on MIV and BP-ANN algorithm, Spectrochim. Acta A. Mol. Biomol. Spectrosc. 193 (2018) 133–140. [9] B. Ferguson, X.C. Zhang, Materials for terahertz science and technology, Nat. Mater. 1 (2002) 26–33. [10] H.C. Huang, D.Y. Wang, L. Rong, S. Panezai, D.L. Zhang, P.Y. Qiu, L. Gao, H. Gao, H.K. Zheng, Z.Y. Zheng, Continuous-wave off-axis and in-line terahertz digital holography with phase unwrapping and phase autofocusing, Opt. Commun. 426 (2018) 612–622. [11] H.C. Huang, D.Y. Wang, W.H. Li, L. Rong, Z.-D. Taylor, Q.H. Deng, B. Li, Y.X. Wang, W.D. Wu, S. Panezai, Continuous-wave terahertz multi-plane in-line digital holography, Opt. Laser Eng. 94 (2017) 76–81. [12] P. Bawuah, P. Silfsten, T. Ervasti, J. Ketolainen, J.A. Zeitler, K.E. Peiponen, Non-contact weight measurement of flat-faced pharmaceutical tablets using terahertz transmission pulse delay measurements, Int. J. Pharm. 476 (2014) 16–22. [13] L. Duvillaret, F. Garet, J.-L. Coutaz, Highly precise determination of optical constants and sample thickness in terahertz time-domain spectroscopy, Appl. Optics 38 (1999) 409. [14] L. Duvillaret, F. Garet, J.L. Coutaz, A reliable method for extraction of material parameters in terahertz time-domain spectroscopy, IEEE J. Sel. Top. Quant. 2 (1996) 739–746. [15] T.D. Dorney, R.G. Baraniuk, D.M. Mittleman, Material parameter estimation with terahertz time-domain spectroscopy, J. Opt. Soc. Am. A 18 (2001) 1562. [16] W.C. Tang, Z.L. Zhang, K. Xiao, C.C. Zhao, Z.Y. Zheng, Terahertz frequency characterization of anisotropic structure of tourmaline, Front. Optoelectron. 10 (2017) 409–413. [17] W. Withayachumnankul, M. Naftaly, Fundamentals of measurement in terahertz time-domain spectroscopy, J. Infrared Millim. Terahertz 35 (2013) 610–637. [18] G. Mie, Beiträge zur Optik trüber Medien, speziell kolloidaler Metallösungen, Ann. Phys. 25 (1908) 377–445. [19] M. Kaushik, W.H. Ng, B.M. Fischer, D. Abbott, Terahertz fingerprinting in presence of quasi-ballistic scattering, Appl. Phys. Lett. 101 (2012) 48–57. [20] T. Bonakdar, M. Ghadiri, Analysis of pin milling of pharmaceutical materials, Int. J. Pharm. 552 (2018) 394–400.
284
Contents lists available at ScienceDirect
Optik journal homepage: www.elsevier.com/locate/ijleo
Characterizations of the Calamine tablets by terahertz time-domain spectroscopy
T
Sibo Haoa, Haochong Huanga, , Yuanyuan Maa, Shangjian Liub, Zili Zhanga, ⁎ Zhiyuan Zhenga, ⁎
a b
School of Science, China University of Geosciences (Beijing), Beijing, 100083, China Beijing University of Chinese Medicine Dongzhimen Hospital, Beijing, 100700, China
ARTICLE INFO
ABSTRACT
Keywords: Calamine THz-TDS Wedge-tablet design Echo signal Particle size
Terahertz time-domain spectroscopy (THz-TDS) is an attractive technique that is capable of nondestructive penetrating and probing pharmaceutical tablets conveniently. It can provide sufficient optical information of crystalline and polymorphic pharmaceuticals with high signal-tonoise ratio (SNR). These merits make the application of THz-TDS within pharmaceutical industry increase rapidly. Meanwhile, the advancements of the in-line monitoring accuracy and dependence of THz-TDS are highly urgent because of the rigorous pharmaceutical quality control. There, it is the first time to characterize the optical constants of Calamine tablets using THz-TDS. The experimental results prove that THz-TDS can be employed to classify Calamine tablets with different masses. In addition, the issue of existing echo signal has been resolved with enhanced SNR by a novel wedge-tablet design within a minor wedge angle. Furthermore, the relationship between the particle sizes composed the Calamine tablets and the scattering absorption obtained from terahertz spectra is revealed. This research highlights the character of THz-TDS in distinguishing the Calamine tablets composed with different configurations, as well as further deepening the interpretation of in-line monitoring in the pharmaceutic industry.
1. Introduction The in-line quality control of pharmaceutical industry has always been a puzzle, especially for mineral Chinese medicines with multi-component and complicated structure [1–3]. These mineral Chinese medicines have been widely investigated by a bulk of research methods, such as powder X-ray diffraction (PXRD) [4], Thermogravimetric analysis (TG) [5], Near-infrared spectroscopy (NIRS) [6] and Electron probe microanalysis (EPMA) [7]. Calamine, as a kind of carbonate mineral of calcite groups, is a typical mineral Chinese medicine. It belongs to smithsonite, with pink or gray color generally, and has significant effects on detoxifying and relieving itching [8]. The above characterizing methods cannot meet the quality controlling requirements of Calamine increasingly. Terahertz time-domain spectroscopy (THz-TDS), as a newly inherent non-invasive technique with high signal-to-noise ratio (SNR), can penetrate an entire pharmaceutical tablet deeply and allow its optical constants to be determined as a function of frequency [9–11]. Frequency-dependent absorption coefficients and refractive index can be applied for medicine identification and classification. Consequently, THz-TDS can be employed as a unique tool to provide sufficient information for the characterizations of Calamine. Moreover, powder is the most common status for mineral Chinese medicine to deliver active pharmaceutical ingredients to the patient. However, during the modern production process of pharmaceuticals, there are many circumstances in which the ⁎
Corresponding authors. E-mail addresses: [email protected] (H. Huang), [email protected] (Z. Zheng).
https://doi.org/10.1016/j.ijleo.2019.03.102 Received 1 February 2019; Accepted 19 March 2019 0030-4026/ © 2019 Elsevier GmbH. All rights reserved.
Optik - International Journal for Light and Electron Optics 187 (2019) 278–284
S. Hao, et al.
powdered pharmaceutical is required to be fabricated into a tablet composed two flat faces with a thickness of several millimeters to satisfy the demands in terms of drug load, physical stability, and marketing requirements [12]. Under these conditions, echo signal will be introduced by the tablets screened by THz-TDS. The observable echo signal is the result of multiple transmissions caused by multiple backward and forward reflections (Fabry-P´erot effect) within tablets. The appearance of the echo signal will reduce the SNR, interfere with the dependence and accuracy of the spectral data [13], and therefore influence the effective monitoring. Due to such reasons, on the one hand, a tedious algorithm is performed in theory [14,15]. On the other hand, to efficiently separate the echo signal from the main signal, artificial and independent values will be unavoidably induced in the data process. Hence, a method with high sensitivity in terahertz detection is required in pharmaceutical applications. In the present research, definite terahertz spectra assignments of Calamine tablets with different masses were determined by THzTDS. Furthermore, a skillful wedge rather than a flat-faced tablet has been proposed and investigated using THz-TDS to eliminate the echo signal and improve the detecting sensitivity. It is found that the echo signal in Calamine temporal files can be decomposed completely and SNR of the spectra is enhanced as well. The absorption coefficients are optimized substantially without changing the algorithm regime. In addition, terahertz spectra present a high correlation between the wedge angle and the spectral resolution. And the effect of sizes of the particles composed the tablet has also been investigated. All these results indicate that THz-TDS is a feasible and efficient technique to characterize the Calamine, even provide novel insights into other various mineral medicines. 2. Experiments The THz-TDS measurements were performed based on a conventional transmission configuration of which the detailed principle was depicted in reference [16]. The spectrometer was purged with nitrogen to exclude the negative influence of vapors. The experimental measurements were conducted at room temperature. The particle size of the powdered Calamine was determined by different purpose sieves. All samples compressed into tablets have the diameter of 13 mm. The diagrams of different kinds of tablets in experiments are displayed in Fig. 1. For flat-faced tablet, the terahertz waves were perpendicular to the surface as shown in Fig. 1(a). Normally flat-faced Calamine tablets were formed with different masses ranging from 0.10 to 0.30 g. For wedge shape tablet, the terahertz waves were incident to the flat surface and inclined surface as shown in Fig. 1(b) and (c). And the values of wedge angle θ are about 4°, 9°, and 13°, respectively. In order to compare the differences between the wedge and the flat-faced, the center positions of the wedge and flat-faced tablets have the same thickness as the dashed line shown in Fig. 1. 3. Results and discussions 3.1. Analyses of terahertz spectra The transmission terahertz temporal signals of normally flat-faced Calamine tablets with different masses are shown in Fig. 2(a), where the tablets masses are 0.10, 0.15, 0.20, 0.25, 0.30 g, respectively. The results in Fig. 2(a) illustrate that a heavier weight is equivalent to a more thickness with the same diameter resulting in the more delay time of terahertz signal, as well as the corresponding phase differences shown in Fig. 2(b). Τhe phase differences augment with the increasing of the frequency for all tablets. Ιn Fig. 2(a), there are three obvious echo signals at 10.56, 12.85, 15.73 ps corresponding to tablets of 0.10, 0.15, 0.20 g. However, no echo signals are observed in the curves of the masses of 0.25 and 0.30 g. There are two possible explanations here, one is that the amplitude of the echo signal absorbed by tablets is too weak to be detected, the other is that its location may occur outside the detection coverage of the main signal. In addition, the delay time of the echo signal between the main signal and the echo signal increases from 8.65 to 11.02 ps with the mass increasing from 0.15 to 0.20 g. The delay time of the echo signal is extended corresponding to the mass variation. Consequently, the terahertz spectra presented in Fig. 2 can be employed as a standard to rapidly classify the masses of pharmaceutical tablets. As above discussed in Fig. 2, it is known that the terahertz wave has various responses to the Calamine tablets with different masses in THz-TDS. Moreover, terahertz frequency-domain spectra (THz-FDS) can be calculated from the recorded data by a numerical fast Fourier transform (FFT). Τhe frequency-dependent absorption coefficients and refractive index of each Calamine tablet can be both obtained based on the terahertz spectral information mentioned above. The THz-FDS of the reference signal and the Calamine tablets with different masses are shown in Fig. 3(a). Frequency-dependent refractive indexes and absorption coefficients of
Fig. 1. Different patterns of the terahertz wave incident to the tablets. θ represents the wedge angle. (a) Flat-faced tablet, (b) and (c) are the wedgetablet Calamine. 279
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Fig. 2. Transmission terahertz time-domain signals (a) and frequency-dependent phase differences (b) of Calamine tablets with different masses ranging from 0.10 to 0.30 g.
Fig. 3. The THz-FDS of a reference and the Calamine tablets with different masses (a). Frequency-dependent refractive indexes (b) and absorption coefficients (c) with different tablet masses.
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Fig. 4. Transmission terahertz time-domain signals (a) and absorption coefficients of flat-faced (0°) and wedge-tablet Calamine with wedge angles of 4°, 9°, and 13°, respectively (b).
the Calamine tablets with different masses are presented in Fig. 3(b) and (c). The refractive indexes of 0.25 and 0.30 g are basically a same constant about 2.05 and there is no characteristic peak in the absorption coefficients indicating that Calamine does not seem to have specific absorption bands that could be attributed to any features at terahertz frequencies between 0.2 and 1.6 THz. The oscillations of Calamine tablets (0.10, 0.15 and 0.20 g) caused by echo signals are observed in the THz-FDS, interfering the effective monitoring by THz-TDS. The corresponding refractive indexes and absorption coefficients are clearly distorted by the effect of the echo signal. Based on such a viewpoint, the echo signals should be eliminated as possible. 3.2. The elimination of echo signals Fig. 4 demonstrates the comparisons of terahertz temporal signals and absorption coefficients of the flat-faced and the wedge tablets with wedge angles of 4°, 9°, and 13°. Compared to that of 0°, there is little change of time delay of 4° and 9° in time-domain spectra, as shown in Fig. 4(a). This is mainly due to almost the same optical path the terahertz wave passing through. The time delay is not sensitive to the wedge angle within a range, although it is determined by the tablet thickness (mass), as shown in Fig. 2. In particular, little change of time delay of 4° and 9° promises the un-distortion of the detected transmission terahertz time-domain signal. The corresponding results of the absorption coefficients are illustrated in Fig. 4(b). The absorption coefficients of 0° oscillate unsteadily arising from the effect of the echo. With the wedge angle increasing to 4°, the oscillation has become weaker. There is almost no oscillation observed for 9°. For 13°, the detected transmission terahertz signal has been distorted because of the oversized wedge angle although the elimination of the echo signal has also been realized. And the absorption coefficients have an obvious diverge with that of other angles. Moreover, for 0°, 4° and 9°, the amplitude of the echo signal is the function of the wedge angle. And the improvements of the amplitudes indicate that a higher SNR of the THz-TDS can be obtained by this wedge-tablet shape. It can be seen from the inset in Fig. 4(a) that the amplitude of the echo signal of 0° is the strongest and a weaker for 4°. While the echo signal has been eliminated under the condition of 9°. This interesting phenomenon can be explained by the diagrams of Fig. 5. Under the assumption of normal incidence, ignoring reflections and refractions between the tablet surface and the air, the tablet interior multiple-reflection and transmission pathways are shown in the drawing. With the increasing of the wedge angle, the 281
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Fig. 5. The diagrams of multiple-reflection and transmission pathways of the terahertz wave passing through the flat-faced tablets (a), patterns of the terahertz wave incident to the wedge-tablet Calamine with the angle of 4° from the plane surface (b) and the wedge surface (c).
directions of the terahertz wave transmission and multiple-reflection will be changed, exceeding the detecting range, as shown in Fig. 5(b) and (c). With regards to the algorithmic, in the case of normal incidence, all the transmission (reflection) paths overlap with lengths l. the transmitted wave reads [17]
Et ( ) =
l ·exp [ jn^s ( ) ]·FP ( ) ·E0 ( ) c
(1)
E0 ( ) is the incident wave, n^s is the refractive of the tablet. = 2/(1 + n^s ) is the complex transmission coefficient for the wave incident from free space. = 2n^s /(1 + n^s ) is the transmission coefficient for the wave incident in the tablet. In analogy to the total transmitted wave, the total reflected wave can be expressed as Er ( ) = E0 ( ) + Likewise, = (1 and is given as
FP ( )= 1 +
· exp [ 2 jn^s ( )
n^s )/(1 + n^s ) and
2 exp
2 jn^s
l c
+
l ]·FP ( )·E0 ( ) c
(2)
= (n^s
1)/(n^s + 1) are the reflection coefficients. FP(ω) represents the Fabry-P´erot effect,
4 exp
4 jn^s ( )
l c
+
· E0 ( ) = 1
2 exp
2 jn^s ( )
l c
1
(3)
It can be seen from Eq. (3) that FP(ω) is decreasing with the increasing of the thickness (mass) l. In the wedge tablet considered optically thick, the thickness l beam passes through each time is longer than before. Meanwhile, the intensity of the signal is getting weaker sharply after the initial transmission, the thickness l is becoming infinitely longer as seen in the later. This means that Eqs. (1) and (2) are necessary to be solved with FP(ω) = 1. Under this case, FP term can be neglected. In a word, the moderate compatible wedge angle to remove the echo signal of Calamine is 9° in the experiments. Meanwhile, the wedge-tablet design can be extended easily to other substances under transmission measurements using THz-TDS. 3.3. The scattering effect of particle sizes In order to investigate the effect of the incident patterns as shown in Fig. 1, the different incident patterns of 4° are shown in Fig. 6. It demonstrates in Fig. 6(a) that for 4°, the phase delay and the echo of the terahertz transmission signal (inset in Fig. 6) do not relate to the different incident patterns. Likewise, the results of Fig. 6 also apply to the wedge angle of 9°. In addition, it is intriguing to find that the plane and wedge surface of 4° become to diverge above 1.1 THz gradually in Fig. 6(b). This is mainly caused by the scattering effect. According to the Mie scattering theory, scattering effect will get stronger when the particle size approaches to the wavelength [18]. The particle size of the tablets employed in Fig. 6 is less than 300 μm, which closes to the terahertz wavelength at 1.1 THz. Under this case, the scattering effect becomes intense. Theoretical analyses of scattering from spherical particles have contributed to dealing with the scattering problem [19]. But as a part of the absorption, scattering absorption is the absorption caused by obstacles scattering to the propagation of terahertz waves. It is difficult to distinguish with absorptions of the Calamine tablet in the experiments. The scattering absorption is mainly determined by the particle sizes of the tablet. Fig. 7 displays the effect of the particle size of wedge tablets on terahertz spectra. In order to compare, one Calamine tablet is composed by less than 75 μm particle size (which is determined by a 200-purpose sieve) and the other is less than 300 μm (which is determined by a 50-purpose sieve). It can be observed from Fig. 7(a) that the amplitude of 75 μm is higher than that of 300 μm. The corresponding absorption coefficients of 300 μm is higher than that of 75 μm over all frequencies as shown in Fig. 7(b), especially at high frequency. This suggests that the scattering absorption has become intense when the wavelength of the terahertz wave is comparable to the particle size. Notably, controlling the different particle sizes of the tablets is essential during the in-line THz-TDS sensing since it affects the mechanical stability, dissolution and drug releasing rate of the tablets [20]. And the results in Fig. 7 suggest that THz-TDS has unique advantages in distinguishing the tablets with different particle sizes. 282
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Fig. 6. Transmission terahertz time-domain signals (a), absorption coefficients (b) of different incident patterns of the wedge-tablet Calamine with the angle of 4°.
Fig. 7. Transmission terahertz time-domain signals (a) and absorption coefficients of tablets composed by different particle sizes (b). One curve is less than 75 μm and the other is less than 300 μm.
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4. Conclusions Finally, the conclusion gives a brief illustration of the work and findings. The frequency-dependent refractive indexes and absorption coefficients of Calamine with masses ranging from 0.10 to 0.30 g were determined by THz-TDS. Furthermore, the echo signal in terahertz time-domain spectra of Calamine has been eliminated using a kind of design wedge-tablet. Within a minor wedge angle of 9°, the echo signal can be eliminated completely with the efficient enhanced absorption coefficients. Under the case of 13°, the raw data has been distorted. Temporal spectra and absorption coefficients of Calamine also relate with the particle size composed the tablet, especially when the particle size is comparable to the terahertz wavelength. In summary, THz-TDS can be served as an effective tool for in-line pharmaceutical tablets monitoring. This work supplies an optimization in the sensing accuracy and reliability, as well as the optical parameter extraction of Calamine. It is not only of benefits in characterizing Calamine and other mineral medicines, but also to be expected to play a key role in characterization methods of the pharmaceutic industry. Acknowledgments This project supported by the National Natural Science Foundation of China (61805214), Fundamental Research Funds for the Central Universities (2652017142). References [1] L. Chen, J. Ming, M.Y. Yuan, Y.M. Liu, B.S. Huang, K.L. Chen, Construction of a systematic identification method for mineral Chinese medicine, Chin. Pharm. 19 (2016) 351–356. [2] J. Liang, Q.J. Guo, T.Y. Chang, K. Li, H.L. Cui, Reliable origin identification of Scutellaria baicalensis based on terahertz time-domain spectroscopy and pattern recognition, Optik 174 (2018) 7–14. [3] H. Zhang, Z. Li, Terahertz spectroscopy applied to quantitative determination of harmful additives in medicinal herbs, Optik 156 (2018) 834–840. [4] L.J. Zhou, L. Zhang, C.Z. Lu, A.W. Ding, Market sales calcined calamine composition analysis and quality evaluation, China Pharm. 27 (2010) 2534–2536. [5] X.L. Meng, J.N. Ma, N.N. Cui, Y.H. Ping, K. Li, S.S. Zhang, Calamine calcination based on thermal analysis, Chin. J. Trad. Chin. Med. 38 (2013) 4303–4308. [6] M. Le, L. Chen, B.S. Huang, K.L. Chen, M.Y. Yuan, Identification of 7 sulfate minerals by near infrared spectroscopy, World Sci. Technol.-Modern. Trad. Chin. Med. 11 (2014) 2385–2389. [7] L.J. Yang, Z.J. Zhang, R. Li, X.F. Feng, J.Y. Yang, Analysis of the composition of calamine in traditional Chinese medicine, Chin. J. Trad. Chin. Med. 37 (2012) 331–334. [8] X. Zhang, L. Chen, Y. Sun, Y. Bai, B. Huang, K. Chen, Determination of zinc oxide content of mineral medicine calamine using near-infrared spectroscopy based on MIV and BP-ANN algorithm, Spectrochim. Acta A. Mol. Biomol. Spectrosc. 193 (2018) 133–140. [9] B. Ferguson, X.C. Zhang, Materials for terahertz science and technology, Nat. Mater. 1 (2002) 26–33. [10] H.C. Huang, D.Y. Wang, L. Rong, S. Panezai, D.L. Zhang, P.Y. Qiu, L. Gao, H. Gao, H.K. Zheng, Z.Y. Zheng, Continuous-wave off-axis and in-line terahertz digital holography with phase unwrapping and phase autofocusing, Opt. Commun. 426 (2018) 612–622. [11] H.C. Huang, D.Y. Wang, W.H. Li, L. Rong, Z.-D. Taylor, Q.H. Deng, B. Li, Y.X. Wang, W.D. Wu, S. Panezai, Continuous-wave terahertz multi-plane in-line digital holography, Opt. Laser Eng. 94 (2017) 76–81. [12] P. Bawuah, P. Silfsten, T. Ervasti, J. Ketolainen, J.A. Zeitler, K.E. Peiponen, Non-contact weight measurement of flat-faced pharmaceutical tablets using terahertz transmission pulse delay measurements, Int. J. Pharm. 476 (2014) 16–22. [13] L. Duvillaret, F. Garet, J.-L. Coutaz, Highly precise determination of optical constants and sample thickness in terahertz time-domain spectroscopy, Appl. Optics 38 (1999) 409. [14] L. Duvillaret, F. Garet, J.L. Coutaz, A reliable method for extraction of material parameters in terahertz time-domain spectroscopy, IEEE J. Sel. Top. Quant. 2 (1996) 739–746. [15] T.D. Dorney, R.G. Baraniuk, D.M. Mittleman, Material parameter estimation with terahertz time-domain spectroscopy, J. Opt. Soc. Am. A 18 (2001) 1562. [16] W.C. Tang, Z.L. Zhang, K. Xiao, C.C. Zhao, Z.Y. Zheng, Terahertz frequency characterization of anisotropic structure of tourmaline, Front. Optoelectron. 10 (2017) 409–413. [17] W. Withayachumnankul, M. Naftaly, Fundamentals of measurement in terahertz time-domain spectroscopy, J. Infrared Millim. Terahertz 35 (2013) 610–637. [18] G. Mie, Beiträge zur Optik trüber Medien, speziell kolloidaler Metallösungen, Ann. Phys. 25 (1908) 377–445. [19] M. Kaushik, W.H. Ng, B.M. Fischer, D. Abbott, Terahertz fingerprinting in presence of quasi-ballistic scattering, Appl. Phys. Lett. 101 (2012) 48–57. [20] T. Bonakdar, M. Ghadiri, Analysis of pin milling of pharmaceutical materials, Int. J. Pharm. 552 (2018) 394–400.
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