On the Correlation of Effective Terahertz Refractive Index and Average ...

J Infrared Milli Terahz Waves DOI 10.1007/s10762-016-0262-0

On the Correlation of Effective Terahertz Refractive Index and Average Surface Roughness of Pharmaceutical Tablets Mousumi Chakraborty 1 & Prince Bawuah 1 & Nicholas Tan 2 & Tuomas Ervasti 3 & Pertti Pääkkönen 1 & J. Axel Zeitler 2 & Jarkko Ketolainen 3 & Kai-Erik Peiponen 1

Received: 14 December 2015 / Accepted: 25 February 2016 # Springer Science+Business Media New York 2016

Abstract In this paper, we have studied terahertz (THz) pulse time delay of porous pharmaceutical microcrystalline compacts and also pharmaceutical tablets that contain indomethacin (painkiller) as an active pharmaceutical ingredient (API) and microcrystalline cellulose as the matrix of the tablet. The porosity of a pharmaceutical tablet is important because it affects the release of drug substance. In addition, surface roughness of the tablet has much importance regarding dissolution of the tablet and hence the rate of drug release. Here, we show, using a training set of tablets containing API and with a priori known tablet’s quality parameters, that the effective refractive index (obtained from THz time delay data) of such porous tablets correlates with the average surface roughness of a tablet. Hence, THz pulse time delay measurement in the transmission mode provides information on both porosity and the average surface roughness of a compact. This is demonstrated for two different sets of pharmaceutical tablets having different porosity and average surface roughness values. Keywords Terahertz pulse . Refractive index . Average surface roughness . Porosity . Pharmaceutical compact

* Mousumi Chakraborty [email protected] * Prince Bawuah [email protected]

1

Institute of Photonics, University of Eastern Finland, P.O. Box 111, FI-80101 Joensuu, Finland

2

Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 3RA, UK

3

School of Pharmacy, Promis Centre, University of Eastern Finland, P. O. Box 1617, FI-70211 Kuopio, Finland

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1 Introduction In modern industrial manufacturing, non-invasive real-time measurement techniques have been applied to monitor the quality of raw materials all the way through to the end product for several decades. Depending on the properties of the object under measurement, different sensor solutions have been realized. For example, in paper mills, the thickness of the paper web is measured in real time using radioactive radiation whereas the moisture of the paper web is detected using NIR radiation [1] at a web speed of about 2 km/min and a width of several metres. However, the utilization of such methodology is a relatively new concept in the pharmaceutical industry where conventional end product testing has traditionally dominated and real-time quality monitoring is rarely exploited. More recently, the high costs of the development of new drugs have led the pharmaceutical industry to find savings, and one option for savings is by enhancing production efficiency. This is one strong argument for moving from conventional batch processing to continuous manufacturing. To achieve the full benefit of continuous manufacturing, process monitoring tools are needed to measure the critical quality parameters of intermediate and end products in real time. The US Food and Drug Administration (FDA) has also noted the importance of process monitoring, and they launched a process analytical technology (PAT) initiative, with the intention to encourage industry to voluntarily develop PAT tools to enhance not only efficiency but also the quality of the products [2]. For example, the non-contact measurement of pharmaceutical materials using Raman spectroscopy was shown to be a useful PAT tool [3]. Indeed, sensing technologies that utilize electromagnetic radiation opens opportunities for non-invasive and non-destructive methods for inspecting raw materials and end products. During the last decade, the use of terahertz (THz) radiation for the inspection of pharmaceutical excipients and tablets has proven to be another powerful tool [4] and THz gap plays an important PAT role in the characterization of physical and chemical state of the active pharmaceutical ingredient (API) of pharmaceutical compacts [5, 6]. Important quality attributes of a pharmaceutical tablet are the porosity, tensile strength and the dissolution rate [7]. For the purpose of PAT, the inspection of the tablet should be very fast. For example, if the production speed would be half a million tablet per hour, then the time for inspection of one tablet would be about 7 ms. While this is a relatively short time, commercially available detectors for electromagnetic radiation can achieve response times of picoseconds. Our aim is to develop both optical and THz-sensing technologies as a PAT tool for the pharmaceutical industry. Here, we study the correlation between the effective refractive index obtained from THz pulse time delay measurements, optically measured surface roughness and the porosity of pharmaceutical tablets with API. The interest to carry out this study was partly kindled by the recent work of Halenius et al., which investigated the tensile strength of tablets using 3D image analysis [8]. Halenius et al. observed that, surprisingly, surface roughness of a tablet is a good indicator of its tensile strength when compressing compacts from pure sodium halides. Based on this observation, we also show that, surprisingly, there exists a linear correlation between the average surface roughness and the effective refractive index of a real pharmaceutical tablet. As far as we know, this promising observed linear relation, which can be used for the inspection of pharmaceutical tablets, has not yet been reported. Due to the porosity of a tablet, which is constituted of a solid material Bskeleton^ and air voids, there will also be Bsurface porosity of the tablet^ which can be detected as the surface roughness of the tablet. Surface roughness of a tablet can play a critical role in the release and absorption of a drug substance.

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In other words, surface roughness can serve as a quality parameter for controlling and optimizing the release of drug from a tablet. Effective refractive index is an optical property that is used to model a pharmaceutical tablet as an effective medium; thus, a pharmaceutical tablet contains solid matrix and air voids. In a case where the fill fraction (porosity) of air voids in a tablet is increasing, the effective refractive index of the tablet will be decreasing. One typical effective medium model to describe the effective refractive index of a medium, in the case of weak scattering of the incident electromagnetic radiation, is the Bruggeman model which we have used in a previous study [9]. In that study, we demonstrated a linear correlation between surface roughness and porosity of microcrystalline cellulose (MCC) compacts (by a compact, we mean a tablet that is not suitable for medication) [9], where we observed that an increase of porosity induced an increase in average surface roughness of a tablet. This observation of Ref. [9] cannot be considered to hold generally. Therefore, in the present study, we deal with a more realistic and more general case than the MCC compacts (or sodium halides compacts of Ref. [8]). Herein, we investigate real pharmaceutical tablets, which we compacted using a compression cycle that is exploited in pharmaceutical industry. Furthermore, to get a more general picture of the validity of the measurement technique and method of analysis, we study pharmaceutical tablet sets that have a wider porosity and surface roughness ranges than the compacts used in the study of Ref. [9].

2 Materials and Methods Three flat-faced tablet sets, A, B and C, were prepared and analysed. Tablets in set A were compacted from microcrystalline cellulose (MCC, Avicell PH-200, FMC Biopolymer, Cork, Ireland) while in sets B and C, a different grade of MCC (Avicell PH101, FMC BioPolymer, Philadelphia, USA) was used. Avicell PH101 has a nominal particle size of 50 μm and a true density of 1.55 g cm−3 whereas the size and true density of Avicell PH200 are 180 μm and 1.64 g cm−3, respectively. The detailed tableting process of these samples was described previously [9, 10]. This MCC is a typical hydrophilic excipient that is widely used in pharmaceutical tablets. The tablets in set A were compressed using a triangle-wave compaction profile for the upper punch while the lower punch was kept stationary. Sets B and C were compressed using a sine compaction profiles for both punches, similar to a real tablet compression profile in a rotation press. The tablets were compressed using a compaction simulator (PuuMan, Kuopio, Finland). Using this facility, it is possible to adjust and control the value of porosity and height of the pharmaceutical tablet. Furthermore, it is possible to choose different compression cycles of lower and upper punches and the magnitude of the compression force by making use of options available on the compaction simulator. Indomethacin (Hangzhou Dayangchem Co. Ltd., Hangzhou, China), in its crystalline gamma polymorph, was used as the API in sets B and C with API concentration spanning the range of 9–11 wt%. Indomethacin is relatively weakly absorbing at THz frequencies [5, 11], between 0.1 and 3.0 THz, where crystalline APIs can experience very strong absorption of the THz radiation. In such a case for THz transmission measurement, a typical procedure is to prepare a sample pellet with low concentration of API. By doing so, the sample is not a pharmaceutical compact. Various properties of the tablet sets A–C are shown in Tables 1, 2 and 3. For each tablet sets, errors in the calculations made for the nominal porosities are as follows: diameter ± 0.008 mm, height ± 0.005 mm (standard deviation of the sample mean), weight ± 0.01 mg (readability of the scale) and porosity ± 0.2 % (calculated using the error propagation law).

J Infrared Milli Terahz Waves Table 1 Data of tablets set A. The values of the diameter d, height H, weight W, porosity f, effective refractive index neff and average surface roughness Ra for set A tablets are shown W (mg)

f (%)

neff

Ra (μm)

Sample

d (mm)

H (mm)

1

13.080

3.00

396.52

40.1

1.237

2.401

2

13.084

2.99

407.11

38.3

1.243

2.566

3

13.074

3.00

416.73

36.9

1.247

2.540

4

13.072

2.99

426.84

35.1

1.251

2.458

5

13.070

2.98

436.42

33.4

1.258

2.316

6

13.074

3.00

446.81

32.4

1.266

2.212

7

13.069

3.00

457.86

30.7

1.273

2.074

8 9

13.059 13.058

3.01 3.00

467.26 476.24

29.3 27.8

1.282 1.287

1.996 1.892

10

13.055

3.02

486.37

26.7

1.288

1.932

11

13.050

3.02

494.17

25.5

1.292

1.745

12

13.048

3.03

503.86

24.1

1.297

1.557

13

13.045

3.04

511.88

23.2

1.304

1.724

2.1 THz Measurement of Effective Refractive Index Terahertz time-domain spectroscopy (THz-TDS) is a non-destructive tool which has already been used to inspect pharmaceutical compacts in production environments [4]. For a description of a setup of THz-TDS, see Ref. [10]. The setup is based on the well-known THz time delay measurement configuration using a femtosecond laser for the generation of radiation in the THz gap 0.1–3 THz and using a collimated probe beam. The measurements were performed in controlled laboratory conditions. This means that the tablets were placed in the same position in the sample compartment of the spectrometer. One key quantity that can be measured using THz-TDS is the refractive index of the medium. In this context, the refractive index is termed Beffective^ due to the various components such as air, excipients and API of a tablet. The absolute measurement error of effective refractive index is ca. ±0.002 and the porosity ca. ±0.5 % [10]. Here, we do not consider spectral properties but instead deal with the time delay data because conducting the time delay measurement is relatively fast and can meet the measurement demands in a real pharmaceutical tablet production line. Table 2 Data of tablet set B. The mean values of the diameter d, height H, weight W, porosity f, effective refractive index neff and average surface roughness Ra for set B tablets are shown Sample

d (mm)

H (mm)

W (mg)

f (%)

neff

1

13.130

3.034

343.18

46

1.444

3.9058

2 3

13.121 13.166

3.049 3.021

357.65 370.67

44 41

1.464 1.484

3.7776 3.5727

4

13.105

3.004

384.34

38

1.506

3.0847

5

13.097

2.998

398.46

36

1.527

2.7681

Ra (μm)

J Infrared Milli Terahz Waves Table 3 Data of tablet set C. The values of the diameter d, height H, weight W, porosity f, effective refractive index neff, average surface roughness Ra and API concentration for set C tablets are shown Sample

d (mm)

H (mm)

W (mg)

f (%)

neff

Ra (μm)

API (wt%)

1

13.076

3.955

404.02

50

1.405

5.2907

11.0

2

13.075

3.642

403.64

46

1.441

4.5800

10.5

3

13.094

3.273

405.67

40

1.498

3.6882

10.0

4

13.093

2.971

404.23

34

1.551

2.7175

9.5

5

13.081

2.734

406.20

28

1.602

2.2079

9.0

If H and neff are the height and effective refractive index of the tablets, respectively, and c is the speed of light in a vacuum, the THz pulse time delay Δt can be obtained from Δt ¼

H ðneff − 1Þ c

ð1Þ

In Eq. (1), it is assumed that the effective refractive index has the same value all over the tablet. If the porosity of a tablet would change as a function of the tablet height, then one has to deal with an integral to calculate the optical path length. Such a situation could happen but is rare because in the production lines of pharmaceutical tablets, uniform quality of tablet products is crucial. In practical measurement, if we wish to exploit THz pulse transmission and Eq. (1), we have to detect the time of flight of the THz pulse for a reference and the sample, and Δt is obtained by subtracting the time of flight of the reference pulse from the sample pulse. The good property is that the position of the tablet on the optic axis is not crucial because the same time delay is expected to be measured. Usually, the tablet makers’ desire is to obtain a priori known constant height for all tablets in a batch to be able to fit into a blister with fixed dimensions during packaging. Since THz pulse constitutes a band of frequencies, the effective refractive index in Eq. (1) is considered to be given at a virtual frequency. The advantage of working with the single THz pulse time-domain measurement is that less time is consumed in order to get the value of the effective refractive index. If we wish to do signal analysis in the frequency domain, then it is necessary to measure the amplitude of the THz field using a delay line to scan the THz pulse with a chosen step of time, and utilize Fourier transform. This procedure involves temporal delay caused by spatial displacement of a mirror (see the measurement system for transmission spectroscopy illustrated in Ref. [12]) which is usually time consuming. Yet, high-quality terahertz spectra can be currently measured in less than 20 ms [13]. We have also investigated the frequency-dependent refractive index of the present samples and observed that the refractive index was, practically speaking, constant over the THz spectral range used namely 0.1–1.5 THz (results to be presented elsewhere). This means that dispersion has a negligible role in the propagation of the transmitted THz pulse. In a more general case, the presence of dispersion due to API and/or excipients is possible due to their crystalline nature. Usually, crystallinity means the presence of absorption and hence hinders the detection of a transmitted signal from a relatively thick pharmaceutical tablet. However, for high-absorbing tablets, it is usually possible to find an appropriate measurement window in THz spectral range where absorption is weak. In other words, the window is chosen from the wings of an absorption band.

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Although the results reported below are encouraging, one has to realize that tablet production in the laboratory environments is quite different from industrial tablet-producing environments. Moreover, one has to consider, for example, issues related to the location and time consumption of tablet measurement, as well as stability of the measurement conditions. Important motivation for us is that currently, there is no inline real-time measurement method in pharmaceutical industry to detect porosity or surface roughness of pharmaceutical tablets. A traditional method for the measurement of porosity of a tablet is based on mercury porosimetry, which is restricted to laboratory conditions, and mercury is a dangerous medium for human beings.

2.2 Surface Roughness The surface roughness of a tablet is an important factor because it affects the rate of drug release and absorption which are important to know regarding the achievement of correct dose for medical treatment. One of the most widely used surface roughness parameters is the standardized average surface roughness, which is defined as follows: if S is the scanned area, f(x,y) is the surface topography as a function of location in the Cartesian coordinate system and 〈f(x, y)〉 is the mean surface giving the minimum variance, the average surface roughness Ra is defined by Ra ¼

1 S ∫∫ j f ðx; yÞ−h f ðx; yÞij dx dy S 0

ð2Þ

The values of the average surface roughness for tablets of sets A, B and C were measured using an optical interference profilometer WYKO NT9300 (Veeco, NY, USA) by applying the vertical scanning interferometric (VSI) method. This instrument is a non-contact profilometer and capable of rendering fast measurements. The optical layout of the profilometer has been described previously [9]. The vertical measurement resolution is 0.1 nm. The scattering of THz waves due to the surface roughness of lactose compacts, a typical pharmaceutical excipient, has been investigated by the detection of reflected THz pulse [14]. It was observed that relatively rough lactose surfaces with average surface roughness of Ra = 21 and 55 μm significantly weaken the strength of the specular reflected THz radiation, incident at an oblique angle, from a tablet’s surface. However, the compacts of this study are much smoother and therefore THz scattering due to surface roughness is relatively weak.

3 Results and Discussion In Ref. [9], a linear correlation was suggested between porosity data versus average surface roughness. Such a property means that the surface roughness is dependent on the porosity. In other words, the knowledge of the porosity, which is a volume property, can give information on the condition of the surface of the tablet. Herein, we suggest a new approach of data analysis which is based on the correlation between the effective refractive index and the average surface roughness, whose information could be crucial in cases when the porosity of a tablet is not known. In order to find out the porosity with a non-contact THz probe radiation, we have to detect the transmittance to estimate porosity, which is a volumetric property. Unfortunately, there are pharmaceutical tablets that absorb strongly THz radiation and hence

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can be inspected using only reflection measurement mode of a THz pulse. Fortunately, from the reflectance of the reflected THz signal, it is possible to get information on the surface roughness of the tablet by utilization of probability distribution theory of heights of the surface such as in [15, 16]. Before we can claim that a reflection THz signal contains information on pharmaceutical tablet’s surface roughness-dependent porosity, we have to explore a training set of tablets, such as in this study, to learn more about correlation between refractive index, porosity and surface roughness. In Figs. 1, 2 and 3, we have fitted experimental data and propose that in addition to the linear correlation between the average surface roughness and porosity for tablet sets A, B and C, a linear correlation exists between the effective refractive index and average surface roughness of these tablets as well. The data of set A presents the simple case of MCC and air voids. Data for set A are shown only for the sake of comparison with tablets containing API because API can have an effect on the porosity as well as the surface roughness of the tablet. We wish to emphasize that although the data of Figs. 1, 2 and 3 suggest linear relationships, these relationships hold locally. By locally we mean that the surface roughness range corresponds to the a priori known porosity of the tablets. It is possible that pharmaceutical tablets having lower or higher porosity than tablet sets B and C may follow a different and non-linear rule such as in the case of utilizing the Maxwell-Garnett effective medium model for a tablet [17]. Using the data shown in Figs. 1, 2 and 3, it is possible to calibrate the THz measurement device to provide information also on the correlation between effective refractive index and average surface roughness of training sets of pharmaceutical compacts and pharmaceutical tablets. This is an additional advantage because we get information on both porosity and average surface roughness using only one instrument instead of two (i.e. avoiding the use of an optical profilometer). Optical profilometer usually requires steady-state laboratory measurement conditions for surface profile scanning, and therefore it is less practical regarding the real-time surface sensing of pharmaceutical tablets. It is obvious from Figs. 1, 2 and 3 that the effective refractive index (optical property) correlates quite well with porosity (volumetric property as shown in Figs. 1a, 2a and 3a) and the average surface roughness (topographical property as shown in Figs. 1b, 2b and 3b) of the tablet. Since in set A a triangular wave compaction profile was used for the upper punch while the lower punch remained stable, there is a negligible difference of ca. 1 % in the average surface roughness value depending on which side of the tablet was used during the surface roughness measurement. Figures 2 and 3 show encouraging results because regardless of the presence of

Fig. 1 A comparison between the effective refractive index as a function of a porosity (the slope value = 6.60 × 10−4, and correlation coefficient R2 = 0.99) and b average surface roughness (the slope value = 1 × 10−2, and correlation coefficient R2 = 0.92) of set A samples

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Fig. 2 A comparison between the effective refractive index as a function of a porosity (the slope value = 7.96 × 10−3, and correlation coefficient R2 = 0.99) and b average surface roughness (the slope value = 7 × 10−2, and correlation coefficient R2 = 0.96) of set B samples

API in sets B and C, the data of these figures resemble the data of Fig. 1 (i.e. similar linear correlation is observed). The linear relation between the effective refractive index and average surface roughness remains unaffected, but the magnitude of both the effective refractive index and average surface roughness changes due to the presence of API. The average surface roughness of set A falls within a relatively narrow range (ca. 1.7–2.4 μm) and has relatively low value, whereas the range is wider for samples of sets B (ca. 2.7– 3.9 μm) and C (ca. 2.2–5.3 μm). In addition, some tablets in sets B and C have a much higher average roughness than the maximum value of 2.4 μm for samples of the set A. We therefore infer that, although the sample sets under study have different ranges of surface roughness, the linearity between effective refractive index and average surface roughness remains unaffected. With reference to the work of Halenius et al. [8], as already mentioned in the introduction section, we propose that the effective refractive index can also yield information on the tensile strength of a tablet by detecting the THz pulse time delay. A crucial difference between the method suggested in this paper and that in Ref. [8] is that by adopting the THz time delay measurement, we get information on porosity of a tablet which is out of scope regarding the imaging method of Ref. [8].

Fig. 3 A comparison between the effective refractive index as a function of a porosity (the slope value = 8.99 × 10−3, and correlation coefficient R2 = 0.99) and b average surface roughness (the slope value = 6 × 10−2, correlation coefficient R2 = 0.99) of set C samples

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As it can be observed from Figs. 1, 2 and 3 that there is some scattering of the data points with respect to the fitted lines. Probably, this scattering is indicating a well-known phenomenon related to tablet compression, namely relaxation of the tablet after compression. This relaxation can result to the change of the porosity and hence the effective refractive index of the pharmaceutical tablet. The relaxation process can be rather long as it was demonstrated for ibuprofen using a measurement technique, which was based on the detection of dynamic laser speckle pattern [18]. Flat-faced tablets present a special case of pharmaceutical tablets. Commercial tablets take various shapes. We are currently conducting similar studies as reported in this article but using curved tablets. Preliminary results are encouraging, and after finishing the analysis of the THz data obtained from convex tablets, these results will be reported later in another publication. One important issue regarding commercial pharmaceutical tablets is the presence of fakes especially in the developing countries. We have inspected authentic and fake antimalarial tablets by the detection of THz spectra from tablets [19]. One of the parameters that was observed during the screening of original and fake tablets was the difference in their average surface roughness values. In other words, the fake tablets had much higher average surface roughness and also higher porosity. Hence, we believe that the method suggested in this article is suitable also for checking authenticity of pharmaceutical tablets.

4 Conclusions In this article, we studied the correlation between surface and volume properties of pharmaceutical tablets without and with API by means of THz and optical measurement techniques. These properties include the average surface roughness, the porosity and the effective refractive index of the tablet. The interesting observation made is that the effective refractive index linearly correlates with surface roughness of the set of tablets studied, which in turn correlates with the porosity of the tablet. In this study, although we exploited two different grades of MCC and also two different compression profiles of tablets, similar results were obtained regarding the linear relationship between the effective refractive index and the average surface roughness of the tablet. The goal of our future studies is to get detailed information on porosity of pharmaceutical tablets using reflection measurement mode.

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