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Preliminary thermoluminescence and optically stimulated luminescence investigation of commercial pharmaceutical preparations towards the drug sterilization dosimetry
Applied Radiation and Isotopes 91 (2014) 79–91
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Preliminary thermoluminescence and optically stimulated luminescence investigation of commercial pharmaceutical preparations towards the drug sterilization dosimetry Nikolaos A. Kazakis a,b,n, Nestor C. Tsirliganis b, George Kitis a a b
Nuclear Physics Laboratory, Physics Department, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece Department of Archaeometry and Physicochemical Measurements, R.C. ‘Athena’, PO Box 159, Kimmeria University Campus, 67100 Xanthi, Greece
H I G H L I G H T S
A study of the potential use of certain drugs in post-sterilization dosimetry with TL and OSL is conducted. All investigated drugs exhibit detectable OSL and TL signals in a dose range of 20–1400 Gy. Presence of slow components in the OSL signals is probable. Dose response data can be fitted with a second order polynomial or a power function. Preliminary results are promising and a more thorough study is imperative.
art ic l e i nf o
a b s t r a c t
Article history: Received 17 March 2014 Accepted 15 May 2014 Available online 24 May 2014
Drug sterilization with ionizing radiation is a well-established technology and is gaining ground the last decades due to its numerous advantages. Identification of irradiated drugs would be interesting and, in this respect, the present work aims, for the first time to the authors’ best knowledge, to explore whether OSL and TL can be employed as methods for post-sterilization dosimetry on commercial drugs, i.e., as tools for the detection of irradiated drugs. Five widely used drugs, i.e., Daktarins, Aspirins, Panadols, Brufens and Procefs, are used for this purpose. Preliminary findings are very promising towards the post-sterilization dosimetry and the use of commercial drugs for normal and/or accidental dosimetry. & 2014 Elsevier Ltd. All rights reserved.
Keywords: Sterilization Drugs Thermoluminescence Optically stimulated luminescence Infrared stimulated luminescence Aspirin
1. Introduction Sterilization with gamma irradiation is gaining ground the last decades and this method is being applied extensively to more fields day by day. Due to its high penetrating power this method is also applied for the easy, efficient and almost heat-free sterilization of heat-sensitive pharmaceutical preparations while being packed in the final product package (Abuhanoglu and Ozer, 2010; Frohnsdorff, 1981; Silindir and Ozer, 2009). Exposure of drugs to ionizing radiation may be accompanied by several chemical and molecular changes of the product which can ultimately lead to its degradation and result in a toxicological hazard. Consequently, any change in the drug induced by irradiation can put in risk the health and safety of the consumer (Onori et n Corresponding author at: Nuclear Physics Laboratory, Physics Department, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece. Tel.: þ 302541078787; fax: þ 302541063656. E-mail addresses: [email protected], [email protected] (N.A. Kazakis).
http://dx.doi.org/10.1016/j.apradiso.2014.05.012 0969-8043/& 2014 Elsevier Ltd. All rights reserved.
al., 1996). The above, in conjunction with the fact that sterilization with ionizing radiation is not allowed in all countries unless the manufacturer proves that no product degradation has taken place and authorization has been obtained from the appropriate health authorities, makes the capability of identifying irradiated drugs a necessity (Prem Anand, 2011). In any case, similarly to food, it would be of great interest to be able to verify whether a drug has been irradiated or not (Raffi et al., 2002a). In addition, such a method which would not only distinguish between irradiated and non-irradiated drugs, but could also give a measure of the dose applied, would be of great value for the manufacturers as well for in-house-use, since they would be able to evaluate, in-situ, the radiation sterilization process and the actual radiation absorbed by each preparation through a mass of packed products. Towards this respect, several studies have been conducted (e.g. Onori et al., 1996; Raffi et al., 2002a, 2002b; Aleksieva and Yordanov, 2012; Cozar et al., 1997; Damian, 2003; Gibella et al., 2000; Juárez-Calderón et al., 2009; Polat and Korkmaz, 2006;
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Basly et al., 1997). However, all of them use electron paramagnetic resonance (EPR) or electron spin resonance (ESR) spectroscopy as an investigative tool for the detection of irradiated solid-state drugs based on the study of the radicals formed in drugs. In the above works the main goal was to identify the various changes in the formed radicals with the dose and to explore the time stability of the radicals. According to Raffi et al. (2002a) the ultimate scope is to develop general detection protocols as in case of foodstuffs (Raffi, 1998). To the authors’ best knowledge, less than a handful of studies have been conducted employing Thermoluminescence (TL) for the detection of irradiated drugs (e.g. Stocker et al., 1999; Raffi et al., 2002b), probably due to the high heat-sensitivity of the drugs. For example, Stocker et al. (1999) have reported thermoluminescence signals from ionized ampicillin and accentuate that the method can be employed for the detection of radiated drugs even two years after radiolysis. Similarly, no study was found in the literature regarding the use of optically stimulated luminescence (OSL) for the same purpose, which could be promising since it does not involve heat application. According to the above, the scope of the present preliminary study is twofold. First to explore whether OSL and TL can be employed as methods for post-sterilization dosimetry on commercial drugs, i.e., as tools for the detection of irradiated drugs and second, to investigate the luminescent properties of drugs and determine whether they exhibit the attributes of a good dosimetric material and thus can be potential candidates for normal and/or accidental dosimetry. To accomplish the above preliminary studies relatively low – compared to those used for sterilization – doses are employed due to the limited access presently to large-scale irradiation facilities, which, however, shall be remedied in the future in view of promising preliminary results.
2. Drug composition It is known that a drug product is not composed merely of the active ingredient (organic compound), but it also contains several inactive ingredients (organic or inorganic compounds) which do not influence the therapeutic action of the active ingredient and have no pharmacological effect. For this reason they are also commonly referred to as inert ingredients or excipients and they are added during the manufacturing process of pharmaceutical products and act as binding materials, dyes, preservatives, flavoring and/or drug efficacy enhancing agents etc (Katdare and Chaubal, 2006).
3. Experimental procedure 3.1. Drug selection and details Selection of the commercial pharmaceutical preparations to be studied was based on their “reputation” and availability in the drug market. This means that it was desirable to identify commercial drugs which satisfy two requirements: first, they are commonly and extensively used worldwide and second, they are manufactured and exported by the same company. The former is indicative of the widespread availability of those drugs in stores and houses all over the world, while the latter ensures that the recipe (specifications and concentrations of excipients and active ingredients) of the under-study drugs is exactly the same in the international market, enhancing the significance of the present study and the applicability range of its findings. Commercial drugs selected for the present study with details about their composition are given in Table 1. All drugs were kindly supplied from a pharmacy in closed boxes and before their expiration date as suggested by the manufacturer.
Table 1 Pharmaceutical preparations under investigation. Drug
Classification-type of action
Active ingredient/concentration
Excipients (according to manufacturer)
DAKTARINs (powder)
Antifungal
Miconazole Nitrate/2% w/w
Talc Zinc oxide Silicon dioxide colloidal
ASPIRINs (tablet)
Anti-inflammatory & Analgesic
Acetylsalicylic acid/500 mg/tablet
Cellulose powder Maize starch
PANADOLs (tablet)
Analgesic
Paracetamol/500 mg/tablet
Pregelatinised starch Calcium carbonate Alginic acid Crospovidone Povidone (K-25) Magnesium stearate Colloidal anhydrous silica Parahydroxybenzoates: sodium methyl parahydroxybenzoate (E219) sodium ethyl parahydroxybenzoate (E215) sodium propyl parahydroxybenzoate (E217)
BRUFENs (tablet)
Anti-inflammatory & Analgesic
Ibuprofen/600 mg/tablet
Tricalcium Phosphate Cellulose microcrystalline Povidone (plasdone K29–32) Croscarmellose sodium type A Stearic acid
PROCEFs (tablet)
Antibiotic (penicillin based-2nd generation cephalosporin type)
Cefprozil/500 mg/tablet
Titanium Dioxide Magnesium stearate Macrogol 400 Polysorbate 80, Hypromellose, Sodium starch glucolate, Antifoam C emulsion, Avicel
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At this point, it should be noted that, according to their specifications, almost in all pharmaceutical preparations studied, both the active ingredients and the majority of the excipients are crystalline, thus making promising the presence of luminescent properties. 3.2. Sample preparation In all cases, drugs were used with no further chemical treatment due to their sensitive nature (such as high solubility). Daktarin was
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used in its initial form with no additional grinding, since it is already in a powder form with particle size less than 10 μm (e.g. AIC, 2013). The rest of the drugs, which all are in tablet form, were gently smashed and grinded in a mortar. It should be noted that in the case of Procef, Brufen and Panadol removal of the coating film with a scalpel preceded their grinding, since its chemical composition (excipients, mainly used as binders) is different than the main core of the tablet and in some cases it was unknown. The final size of the grains in all drugs was less than 20 μm and consequently no further sieving was required.
Table 2 OSL measurement conditions.
3.3. Instruments and methods Drug
DAKTARINs ASPIRINs PANADOLs BRUFENs PROCEFs
Test dose (Gy) 100 350 200 200 100
Stimulation time (s) CW-BSL
Stimulation time (s) LM-BSL
150 150 150 100 50
213 213 213 142 71
Stimulation time (s) CWIRSL 150 150 150 100 50
Initially, micro-XRF analysis was performed in all drugs in order to examine their chemical composition and to gain an insight into the inorganic elements present which are indicative of the variety of substances used as excipients. A portable and compact micro-XRF spectrometer (SPECTRO, COPRA model) was employed for the micro-XRF measurements. This instrument comprises a side-window X-ray tube with Mo anode (Series
Fig. 1. micro-XRF spectra of the under-study drugs: (a) Daktarin, (b) Aspirin, (c) Panadol, (d) Brufen, (e) Procef.
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5011 XTF, Oxford Instruments) with maximum voltage and current of 50 kV and 1 mA respectively, together with a Peltier-cooled solid state Silicon Drift Detector (SDD) X-ray detector (8 μm Be window, 3.5 mm2 active area, 300 μm nominal thickness and resolution 149–166 eV at the Mn Ka energy). More details about the micro-XRF instrument can be found elsewhere (e.g. Sakalis et al., 2013). The operating conditions during the micro-XRF analyses are 35 kV applied potential, 0.9 mA current and 6.0 min acquisition real time. Three independent micro-XRF measurements were performed in a point scan mode on several points on the tablet in its initial form for each sample in order to achieve a representative elemental qualitative characterization. In the case of Daktarin, powder was confined into a special low mass container to facilitate its handling during the micro-XRF measurements. Various luminescence measurements were conducted regarding the stimulation technique employed. More specifically, all solid-state pharmaceutical preparations were studied with both OSL and TL. Effect of the wavelength of the light stimulation was also studied using
both blue light (BSL) and infra-red stimulation (IRSL), while both continuous wave (CW-OSL) and linearly modulated (LM-OSL) BSL experiments were conducted. For the above measurements a Riso TL/OSL reader (model TL/OSLDA-15) was recruited, equipped with a 90Sr/90Y beta particle source capable of delivering a nominal dose rate of about 3.62 Gy/min at the time of the measurements. The system is also equipped with blue LEDs emitting at 470 nm arranged in six clusters each containing seven individual LEDs (maximum total power 40 mW/cm2 at the sample) and a 1.0 W (delivering 400 mW/cm2 at the sample) solid state IR-laser diode emitting at 830 nm (Botter-Jensen et al., 2000). A 9235QA photomultiplier tube with a combination of the appropriate filters, as described below, was used for light detection. The filters used were: ▪ BSL measurements: a Hoya U-340 with maximum transmittance at approximately 340 nm and full width at half maximum (FWHM) about 80 nm. ▪ IRSL: a Schott BG 39 combined with a Corning 7-59 with transmission window at 340–480 nm. ▪ TL measurements: a Corning 7–59 (320–480 nm) with a heat absorbing Pilkington HA-3 filter. 3.4. Experimental conditions All OSL measurements were performed in room temperature. Measurement conditions (test dose and stimulation times) are presented in Table 2. These values were selected after preliminary measurements for all drugs of the present study. In the same respect, all TL measurements were performed in a nitrogen atmosphere with a constant heating rate of 5 1C/s up to a maximum temperature of 450 1C/s. It must also be noted that in all cases a background signal was also acquired and subsequently subtracted from the original signal of the main measurement. 4. Results and discussion 4.1. micro-XRF measurements Fig. 1 illustrates the micro-XRF spectra of all drugs studied. At this point, it must be pointed that Argon (Ar) present in all spectra
Fig. 2. Decay curves of unirradiated samples (natural) for: (a) Daktarin, (b) Aspirin and Panadol.
Fig. 3. Normalized response of 1st channel and total (inset) counts for all drugs studied for six consecutive cycles of radiation (100 Gy) and BSL on the same sample.
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stems from the atmosphere since micro-XRF measurements are conducted in an open-air environment, which, in addition, makes the detection of light elements (lighter than Si) impossible. It is obvious that Daktarin has the “richest” variety of elements in its chemical composition compared to all other drugs, which was actually expected due to the excipients it contains (Table 1). On the other hand, Aspirin seems to be completely free of heavy elements, while in the rest of the under-study drugs presence of several elements is evident which comply with the composition of few of their excipients (Table 1). However, it seems that the majority of the excipients used in these drugs are of organic nature. In any case, some of these inorganic excipients render these drugs promising candidates for exhibiting interesting luminescence behavior. For example, according to the manufacturer, ZnO and SiO2 are two of Daktarin’s inert ingredients (Table 1), whose luminescent properties have been extensively studied in the literature. 4.2. Natural BSL signal The term “natural signal” in the present study refers to the original signal obtained by the samples prior to any given test dose. Decay curves for the unirradiated samples (natural BSL signal) of Daktarin and Aspirin along with Panadol are presented in Fig. 2a and b respectively. It must be noted that Daktarin is the only drug of the present study which presents a detectable OSL signal without being irradiated in the laboratory. The presence of an intense luminescence signal for Daktarin may partially be attributed to its chemical composition, since two of the used excipients are ZnO and SiO2, with known luminescent properties. In addition, existence of populated traps and centers without artificial radiation can be ascribed to sunlight-UV irradiation or it is an indication that Daktarin has been sterilized by means of radiation after its manufacture. The latter would be of major significance if it is valid as elucidated below. Since the shelf life of Daktarin is three years (e.g. Irish Medicines Board, 2012) and the expiration date of the product used in the present work is 01/2016, this implies that it was manufactured and, thus, possibly sterilized in 01/2013, which is one year prior to the current measurements. Consequently, if this is the case, Daktarin can store radiation at least up to one year. Of course further experiments are needed to verify the above. As seen in Fig. 2a, the Daktarin natural signal decays very fast in the first seconds of stimulation and about 110 s of stimulation are adequate to empty traps responsible for the luminescence signal, since the signal reaches the background signal.
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On the other hand, the rest of the drugs exhibit no natural luminescence and thus the recorded signal corresponds to the respective background. Fig. 2b illustrates the two acquired signals for Aspirin and Panadol which is typical for Brufen and Procef as well. It is obvious that the two background signals are not comparable regarding the OSL intensity, with Aspirin exhibiting an approximately four times higher background than that of Panadol. At this point, it should be noted that Daktarin exhibits a background of similar intensity with that of Aspirin, while Brufen’s and Procef’s backgrounds are comparable to that of Panadol. The above is further evidence that composition of drugs is very dissimilar and plays a determinant role in their luminescence behaviour. 4.3. Sensitization BSL measurements In order to investigate the potential sensitization of the understudy drugs due to stimulation light, one sample of each drug was subjected to six consecutive cycles of radiation and subsequent BSL. All samples were irradiated with a dose of 100 Gy, while stimulation lasted 300 s. Results are depicted in Fig. 3 concerning the counts of the 1st channel (first 0.1 s of stimulation), while total
Fig. 4. Decay curves for three different samples of equal mass for Procef after irradiation with 100 Gy; only the first 5 s of stimulation are presented for clarity reasons.
Table 3 Statistics indicative for measurement precision for all drugs (background has been subtracted). Drug
Sample
Total counts (a.u.)
Mean value (a.u.)
Standard deviation (a.u.)
Standard deviation/mean 100
DAKTARIN
1 2 3
147,902 171,315 142,682
153,966
15,249
9.9
ASPIRIN
1 2 3
18,616 18,596 26,112
21,108
4,334
20.5
PANADOL
1 2 3
21,582 15,546 10,581
15,903
5,509
34.6
BRUFEN
1 2 3
5,783 3,530 9,636
6,316
3,088
48.9
PROCEF
1 2 3
4,018 15,700 6,218
8,645
6,208
71.8
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counts during the whole stimulation time for the various cycles are also given in the inset of Fig. 3. It must be noted that all data were normalized with respect to the data of the first cycle and that in all cases the respective background signal was subtracted from the original signal for each drug. If only the counts of the 1st channel are taken into account it seems that no sensitization is observed in almost all drugs during the six consecutive radiation-stimulation cycles. Daktarin is the only one which exhibits a relatively continuous increase in the 1st channel counts during the successive cycles, demonstrating an
increase of about 15% after the 6th cycle. It should be stated that results are similar if integration over the first second of the stimulation is considered (10 first channels). The above trend seems to change when the total counts of the decay curve are considered (inset of Fig. 3), namely integration over the total stimulation time for each drug. Procef presents a very stable behavior, with the total counts remaining relatively constant during the six cycles of radiation-stimulation. However, a desensitization of the luminescence yield of Brufen seems to occur exhibiting a total decrease of about 17%. On the other hand, the
Fig. 5. CW-BSL decay curves (semi-log scale) for all drugs after being irradiated with the corresponding test dose: (a) Daktarin, (b) Aspirin, (c) Panadol, (d) Brufen, (e) Procef.
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rest of the studied drugs, namely Daktarin, Aspirin and Panadol demonstrate a different behavior. After each cycle the luminescence yield of Daktarin and Panadol constantly increases up to about 35% and 31% respectively. Finally, in the case of Aspirin the total counts of the decay curve increase up to 30% after the first three cycles and remains constant for the next three cycles, which would imply a possible sensitization of slow components. 4.4. Measurement precision-Sample handling In order to examine the precision of the measurements on all drugs of the current work, direct BSL measurements were
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conducted for three different samples of each drug after irradiation with 100 Gy. It must be noted that all samples had exactly the same mass (17.20 70.02 mg) weighed with a 4-digit accuracy scale. Unfortunately, precision was not satisfactory, except for Daktarin. In Table 3 the total counts of all CW-BSL decay curves for all samples of each drug are presented along with the corresponding mean value and standard deviation. Daktarin samples exhibit relatively similar luminescence decay curves, since the standard deviation of the total counts is less than 10% of the mean value. However, the rest of the drugs demonstrate different behavior with the standard deviation varying from 20% (Aspirin) to 72% (Procef) of the mean value. The above results are
Fig. 6. LM-BSL decay curves for all drugs after being irradiated with the corresponding test dose: (a) Daktarin, (b) Aspirin, (c) Panadol, (d) Brufen, (e) Procef.
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independent of the stimulation time over which the signal is integrated for the calculations of Table 3. Fig. 4 also illustrates the decay of signal intensities for Procef samples. It should be noted that similar trend was observed during LM-BSL experiments for the same samples. The above deviation in the decay curves between samples of the same drug may be attributed to the different surface of each sample exposed to the stimulation light, since this is the most important factor affecting the OSL measurements rather than the sample weight. Consequently, special handling of the samples is imperative before the measurements to assure precision in OSL experiments in case of multiple aliquots experiments.
4.5. CW-BSL normal sensitivity measurements Fig. 5 illustrates the CW-OSL decay curves for all drugs after being irradiated with the corresponding test dose (Table 2) and stimulated with blue light. In all cases the luminescence signals present similar features. They consist of one initial and quickly decaying part in the first seconds of stimulation which is followed by a second slow decaying part. In addition, comparing the decay curves of Brufen with the one of Panadol (same test dose) and Procef with Daktarin (same test dose) (Fig. 5), one can readily observe that in the case of Brufen and Procef, the decay curves reach the background level very fast, i.e., in time less than 15 s
Fig. 7. IRSL decay curves (semi-log scale) for all drugs after being irradiated with the corresponding test dose: (a) Daktarin, (b) Aspirin, (c) Panadol, (d) Brufen, (e) Procef.
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which would be an indication of the depth of the traps for the above drugs and the kinetics involved. 4.6. LM-BSL normal sensitivity measurements Fig. 6 illustrates the LM-OSL decay curves for all drugs after being irradiated with the corresponding test dose (Table 2) and stimulated with blue light. Stimulation time seems to be inadequate for Daktarin, since the rate of decay of the curve is relatively slow after the first 120 s and more time is needed to empty the traps and reach the background level. On the other hand, the above is not valid for the rest of the drugs and the selected stimulation time (LMtime ¼√2 CWtime) is satisfactory. 4.7. IRSL normal sensitivity measurements Fig. 7 presents the IRSL decay curves for all drugs after being irradiated with the corresponding test dose (Table 2) and stimulated with infra-red light. Luminescence curves obtained after stimulation with light of longer wavelength (compared to the blue LEDs) are of similar shape as the ones acquired with CW-BSL. As previously discussed, it seems that in the case of Daktarin and Aspirin slow components are involved in the decay process which need further investigation.
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the estimation of the absorbed dose in radiation-processed food and in radio-sterilization of pharmaceuticals (Tepe et al., 2009): ▪ ▪ ▪ ▪
linear regression quadratic fit power function exponential function
Functions studied along with the numerical results of the fitting are given in Table 4. It should be noted that no attempt was made to force the regression through zero. According to Table 4, second order polynomial and power function describe best the intensity data obtained for all drugs studied. The above findings are in agreement with the observations of Tepe et al (2009) and Polat and Korkmaz (2006) who studied the dosimetric features of sultamicillin tosylate and paracetamol respectively by means of ESR. They also found that the experimental intensity data can best be fitted with a power function or a second order polynomial, respectively.
4.8. OSL dose response Fig. 8 illustrates the decay curves for various doses applied in the case of Aspirin. It should be noted that the observed behavior is typical for the other drugs as well. In higher doses more stimulation time is required to empty all traps. It seems that a very slowly decaying OSL component of quite large lifetime is present and its effect becomes more pronounced as the applied dose is increased, due to the enhanced population of deep traps. Dose response for all drugs is depicted in Fig. 9. Very interesting is the fact that, for all drugs, the illustrated dose response is similar even when only the 1st channel counts (0.1 s) or the 1st second of the decay curve are taken into consideration. An attempt was made to fit the data of the dose response for all drugs using four different functions which have been employed for
Fig. 8. Decay curves (semi-log scale) for Aspirin after being irradiated with several doses.
Fig. 9. Dose response for all drugs: (a) Daktarin and Panadol, (b) Aspirin, Brufen and Procef.
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Of course, in order to use the above functions for the absorbed dose estimation in drug sterilization they have to be validated in much higher doses (at least up to 25 kGy). Nevertheless, these fittings in relatively low doses (up to 1.4 kGy) can also be helpful in the frame of the general characterization of the under-study drugs and the examination of their dosimetric and luminescent properties. 4.9. Short-term decay of OSL yield at room temperature Preliminary room-temperature short-term stability studies have also been carried out for all drugs of the present work after irradiation with the test dose (Table 2). Besides the BSL experiment directly after irradiation, OSL measurement with blue light stimulation took place also 24 h after irradiation. Table 5 presents the % reduction in both the total intensity and the 1st channel intensity for all drugs. A first observation is that the choice of the stimulation time over which the signal is integrated for the fading calculations is of major importance, especially for Daktarin and Aspirin. In parallel, only Procef and Panadol exhibit a fairly small decrease in the OSL intensity, namely 13.8% and 7.3% respectively, while the rest of the studied drugs present a rather high reduction in the total luminescence yield 24 h after irradiation. Of course, fading must be tested for longer time periods to get a representative picture of the intensity decrease rate for all drugs.
measurements at five different constant temperatures in the range 25–45 1C with a step of 5 1C were also conducted after irradiation of the samples with the corresponding test dose. In order to gain a quantitative insight into the effect of the studied phenomenon, a BSL measurement after the sample was cooled, was subsequently taken to record the residual luminescence signal after each constant temperature TL experiment. Fig. 10 illustrates the constant temperature TL measurements along with the residual BSL measurements (insets) for all temperatures studied in the case of Daktarin. It should be noted that the depicted behaviour is typical for all drugs of the present study. From Fig. 10, one can observe that as the temperature gradually increases, the TL signal presents slightly higher intensity at the first seconds of the signal and then gradually decays. In parallel, the shape of the experimental residual OSL decay curve remains exactly the same for all temperatures studied. Although the 1st channel counts of the residual OSL slightly decrease as the temperature of the preceding TL increases, integration over the total signal is practically unchanged. This might be an indication of phosphorescence involved, yet of extremely low extent, which releases merely a minor portion of electrons in relatively shallow traps. It seems that in all drugs of the present study luminescence signals are complex and are the result of the recombination of electrons originating from rather deep traps.
4.10. Phosphorescence decay measurements
4.11. Thermoluminescence measurements
Phosphorescence is the decay of thermally stimulated luminescence as a function of time at a constant temperature and it is always associated with trapping of the carriers at rather shallow traps and their subsequent thermal release prior to their radiative recombination (Chen and McKeever, 1997). In this respect, TL
Thermoluminescence measurements were also conducted for the drugs studied and the corresponding glow-curves are illustrated in Fig. 11. These curves are indicative of the various components that contribute to the luminescence signal in each drug, since their shapes are quite dissimilar to each other.
Table 4 Mathematical functions used and parameters calculated from curve fitting. Function
DAKTARINs
ASPIRINs
PANADOLs
BRUFENs
PROCEFs
I¼a þb D
a¼ 72,8007 12,020 b¼ 1,747.30 7 24.82 (R2 ¼ 0.9994)
a ¼49,148 7 12,825 b ¼ 174.56 7 16.51 (R2 ¼0.9655)
a¼ 27,738.0 7 9,990.1 b¼ 401.30 7 16.16 (R2 ¼ 0.9936)
a¼ 5,199.4 7 1,282.1 b ¼30.647 2.07 (R2 ¼ 0.9820)
a¼ 17,078.074,197.6 b¼ 88.89 7 9.34 (R2 ¼ 0.9577)
I¼a þb Dþ c D2
a¼ 58,077.0 7 7,807.3 b¼ 1,920.30 7 57.77 c ¼ 0.1697 0.055 (R2 ¼ 0.9999)
a ¼21,167.0 7 5,694.3 b ¼ 305.80 720.57 c ¼ 0.089 7 0.014 (R2 ¼ 0.9978)
a¼ 10,430.07 7,409.2 b¼ 519.88 736.47 c ¼ 0.0977 0.029 (R2 ¼ 0.9986)
a¼ 2,791.7 7 560.7 b ¼47.147 2.76 c ¼ 0.0137 0.002 (R2 ¼ 0.9987)
a¼ 9,655.9 72,251.0 b¼ 163.26 715.87 c ¼ 0.072 70.015 (R2 ¼ 0.9952)
I¼a [1 e D/b]
a¼ 4.83 106 7 1.70 106 b¼ 2,136.60 7 928.22 (R2 ¼ 0.9971)
a ¼3.18 105 713,614 b ¼ 730.197 61.82 (R2 ¼ 0.9967)
a¼ 9.67 105 7 1.41 105 b¼ 1,680.4 7 327.75 (R2 ¼ 0.9977)
a¼ 49,321.0 7 4,039.9 b ¼747.83 7 111.67 (R2 ¼ 0.9936)
a¼ 1.10 105 7 10,267 b¼ 426.617 82.91 (R2 ¼ 0.9780)
I¼a Db
a¼ 4,720.5 7 866.9 b¼ 0.8617 0.027 (R2 ¼ 0.9990)
a ¼3,113.0 7 669.7 b ¼ 0.622 70.031 (R2 ¼ 0.9940)
a¼ 1,402.17 322.9 b¼ 0.829 7 0.034 (R2 ¼ 0.9970)
a¼ 359.17 36.5 b ¼0.666 70.015 (R2 ¼ 0.9989)
a¼ 2,025.9 7219.0 b¼ 0.56770.017 (R2 ¼ 0.9977)
Note: I: total OSL intensity during stimulation time in arbitrary units (a.u.); D: dose applied in Gy; Point corresponding to dose of 200 Gy in Daktarin dose response curve dose was excluded from all calculations.
Table 5 OSL intensity reduction 24 h after irradiation (fading results). Total counts (a.u.) Drug s
DAKTARIN ASPIRINs PANADOLs BRUFENs PROCEFs
1st channel counts (a.u.) Directly after irradiation
24 h after irradiation
(%) decrease
Directly after irradiation
24 h after irradiation
(%) decrease
255,572 125,072 102,241 12,399 29,468
188,987 61,684 88,084 6,729 27,314
26.1 50.7 13.8 45.7 7.3
18,528 2,697 9,377 1,422 10,784
7,800 2,190 7,174 940 9,505
57.9 18.8 23.5 33.9 11.9
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According to Fig. 11, Daktarin exhibits at least seven peaks (Tmax 105 1C, 205 1C, 220 1C, 255 1C, 340 1C, 380 1C, 425 1C), Aspirin two (Tmax 100 1C, 195 1C), Panadol two (Tmax 140 1C, 250 1C) and Brufen three (Tmax 130 1C, 225 1C, 300 1C), while no TL signal was obtained for Procef as clarified below. At this point, it must be noted that, although a relatively high heating rate was adopted for the TL measurements, heating of the samples caused their degradation or destruction. Daktarin proved
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to exhibit the highest heat resistance and heating caused only marginal changes of its colour (from white to yellowish). On the other hand, heat on the rest of the drugs caused a severe degradation of their texture, colour and general form. In fact, they were scorched and in some cases completely destructed and/or sublimated. The above could probably explain the fact that no glow-curve was recorded for Procef. It seems that its heat resistance is so low that even in relatively low temperatures (o100 1C) significant degradation takes place.
Fig. 10. Constant temperature TL decay curves (phosphorescence decay) for Daktarin at: (a) 25 1C, (b) 30 1C, (c) 35 1C, (d) 40 1C, (e) 45 1C.
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Aspirin, Panadol and Brufen samples seem to have higher heat tolerance permitting the recording of TL glow curves. Yet, due to their final destruction, as described above, the credibility and completeness of the glow curves can be put into question, since losses of the signal above a threshold temperature (apparently different for each drug) are very probable. For this purpose, future experiments and analysis should probably focus only on the Daktarin glow-curve(s).
5. Conclusions Basic preliminary optically stimulated luminescence (CW-OSL, LM-OSL, IRSL) and thermoluminescence experiments were conducted on five commonly and extensively used commercial drugs to identify their potential luminescent properties which would allow the detection of radiation during their sterilization and/or their use as dosimeters. In most cases light sensitization is not observed when integration over the first second of the signal is considered. CW-OSL and IRSL decay curves are of similar shape, namely they consist of one initial and quickly decaying part in the first seconds of stimulation which is followed by a second slow decaying part. In the case of Daktarin and Aspirin, the presence of extremely slow components is very probable and further investigation is required, since these components can be attributed to deeper traps and are expected to be enhanced at higher doses such as used in the sterilization
process. LM-OSL signals were also acquired for all drugs which need further analysis to allow the extraction of valuable information about their components. Interesting were the results of the signal response in several doses applied in the range of 20–1400 Gy. Experimental data can successfully be fitted with a second order polynomial or a power function, which is in accordance with the findings of published studies on other drugs by means of ESR. Loss of OSL signal 24 h after irradiation is rather imperceptible for Panadol and Procef, while a relatively high reduction in the total signal intensity is evident for the rest of the drugs. Phosphorescence decay experiments (TL under constant temperature) reveal a negligible presence of phosphorescence in all drugs and a rather complex pattern in the luminescence signals probably attributed to the recombination of electrons originating from rather deep traps. Thermoluminescence measurements with heating of the samples up to 450 1C led to interesting glow-curves for all drugs, especially for Daktarin. Unfortunately, this kind of measurements with heating involved proves to be completely destructive for all drugs except for Daktarin due to their low heatresistance. Thus, their acquired TL signals are questioned for their credibility and completeness. On the contrary, Daktarin’s relatively high heat-resistance is evident rendering its full characterization promising. According to the above, preliminary findings are very optimistic towards the post-sterilization dosimetry and the use of commercial drugs for normal and/or accidental dosimetry. In this
Fig. 11. TL glow curves corresponding to the test dose for: (a) Daktarin, (b) Aspirin, (c) Panadol, (d) Brufen.
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respect, further analysis and experiments are required, and are currently in progress, employing higher doses and longer storage periods which would elucidate the luminescent properties of the drugs studied and potentially shed light on the role of the active ingredient and of each excipient on the luminescence signal separately. Acknowledgements Authors would like to thank Anastasia Tsetine, Medical Doctor, for the valuable discussions about drug structure, composition and properties and Ioanna Tsetine, Pharmacist, for kindly providing all commercial drugs studied in the present work. References Abuhanoglu, G., Ozer, Y.A., 2010. Radiation effects on pharmaceuticals. FABAD J. Pharm. Sci. 35 (4), 203–217. AIC (2013). Miconazole Nitrate USP Micronized.: Specification Sheet. chttp://www. aicma.com/products/Miconazole%20Nitrate%20USP%20Micronized% 20MCNJCM.pdf. Accessed 10 February 2014. Aleksieva, K., Yordanov, N.D., 2012. EPR investigation of some gamma-irradiated excipients. Radiat. Eff. Defects Solids 167 (9), 685–689. Basly, J.P., Longy, I., Bernard, M., 1997. Radiation effects of Dopamine and Norepinephrine. Pharm. Res. 14 (9), 1192–1196. Botter-Jensen, L., Bulur, E., Duller, G.A.T., Murray, A.S., 2000. Advances in luminescence instrument systems. Radiat. Meas. 32 (5-6), 523–528. Chen, R., McKeever, S.W.S., 1997. Theory of Thermoluminescence and Related Phenomena. World Scientific Publishing Co. Pte. Ltd, Singapore. Cozar, O., Chis, V., David, L., Damian, G., Barbur, I., 1997. ESR investigation of gamma-irradiated Aspirin. J. Radioanal. Nucl. Chem. 220 (2), 241–244. Damian, G., 2003. EPR investigation of γ-irradiated anti-emetic drugs. Talanta 60 (5), 923–927. Frohnsdorff, R.S.M., 1981. Sterilization of medical products in Europe. Radiat. Phys. Chem. 17 (2), 95–106.
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Gibella, M., Crucq, A-S., Tilquin, B., Stocker, P., Lesgards, G., Raffi, J., 2000. Electron spin resonance studies of some irradiated Pharmaceuticals. Radiat. Phys. Chem. 58 (1), 69–76. Irish Medicines Board, 2012. Summary of Product Characteristics: Daktarin 2% w/w Cutaneous Powder. Available in: 〈http://www.imb.ie/images/uploaded/swedo cuments/LicenseSPC_PA0823-059-002_27062012120103.pdf〉. Accessed 11 March 2014. Juárez-Calderón, J.M., Negrón-Mendoza, A., Gómez-Vidales, V., Ramos-Bernal, S., 2009. Study of dosimetric properties of acetylsalicylic acid in pharmaceutical preparations by EPR spectroscopy. J. Radioanal. Nucl. Chem. 280 (2), 245–249. Katdare, A., Chaubal, M.V., 2006. Excipient Development for Pharmaceutical, Biotechnology and Drug Delivery Systems. Informa Healthcare USA, New York, USA. Onori, S., Pantaloni, M., Fattibene, P., Ciranni Signoretti, E., Valvo, L., Santucci, M.M., 1996. ESR identification of irradiated antibiotics: Cephalosporins. Appl. Radiat. Isot. 47 (11-12), 1569–1572. Polat, M., Korkmaz, M., 2006. Effect of radiation on solid paracetamol: ESR identification and dosimetric features of γ -irradiated paracetamol. Radiat. Eff. Defects Solids 161 (1), 51–62. Prem Anand, N., 2011. Hospital Sterilization. Jaypee Brothers Medical Publications, New Delhi, India. Raffi, J., 1998. Identifying irradiated foods. Trends Anal. Chem. 17 (4), 226–233. Raffi, J., Gelly, S., Barral, L., Burger, F., Piccerelle, P., Prinderre, P., Baron, M., Chamayou, A., 2002a. Electron paramagnetic resonance of radicals induced in drugs and excipients by radiation or mechanical treatments. Spectrochim. Acta, Part A 58 (6), 1313–1320. Raffi, J., Gelly, S., Piccerelle, P., Prinderre, P., Chamayou, A., Baron, M., 2002b. Electron spin resonance-thermoluminescence studies on irradiated drugs and excipients. Radiat. Phys. Chem. 63 (3), 705–707. Sakalis, A.J., Kazakis, N.A., Merousis, N., Tsirliganis, N.C., 2013. Study of Neolithic pottery from Polyplatanos (Imathia) using micro X-ray fluorescence spectroscopy, stereoscopic microscopy and multivariate statistical analysis. J. Cult. Heritage 14 (6), 485–498. Silindir, M., Ozer, A.Y., 2009. Sterilization Methods and the Comparison of E-Beam Sterilization with Gamma Radiation Sterilization. FABAD J. Pharm. Sci. 34 (1), 43–53. Stocker, P., Gibella, M., Crucq, A.-S., Tilquin, B., Lesgards, G., Raffi, J., 1999. Thermoluminescence de quelques médicaments ionisés. J. Chim. Phys. Phys.Chim. Biol. 96 (1), 174–177. Tepe, S., Polat, M., Korkmaz, M., 2009. Radiation sensitivity and dosimetric features of sultamicillin tosylate: an electron spin resonance study. Radiat. Eff. Defects Solids 164 (2), 90–100.
Contents lists available at ScienceDirect
Applied Radiation and Isotopes journal homepage: www.elsevier.com/locate/apradiso
Preliminary thermoluminescence and optically stimulated luminescence investigation of commercial pharmaceutical preparations towards the drug sterilization dosimetry Nikolaos A. Kazakis a,b,n, Nestor C. Tsirliganis b, George Kitis a a b
Nuclear Physics Laboratory, Physics Department, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece Department of Archaeometry and Physicochemical Measurements, R.C. ‘Athena’, PO Box 159, Kimmeria University Campus, 67100 Xanthi, Greece
H I G H L I G H T S
A study of the potential use of certain drugs in post-sterilization dosimetry with TL and OSL is conducted. All investigated drugs exhibit detectable OSL and TL signals in a dose range of 20–1400 Gy. Presence of slow components in the OSL signals is probable. Dose response data can be fitted with a second order polynomial or a power function. Preliminary results are promising and a more thorough study is imperative.
art ic l e i nf o
a b s t r a c t
Article history: Received 17 March 2014 Accepted 15 May 2014 Available online 24 May 2014
Drug sterilization with ionizing radiation is a well-established technology and is gaining ground the last decades due to its numerous advantages. Identification of irradiated drugs would be interesting and, in this respect, the present work aims, for the first time to the authors’ best knowledge, to explore whether OSL and TL can be employed as methods for post-sterilization dosimetry on commercial drugs, i.e., as tools for the detection of irradiated drugs. Five widely used drugs, i.e., Daktarins, Aspirins, Panadols, Brufens and Procefs, are used for this purpose. Preliminary findings are very promising towards the post-sterilization dosimetry and the use of commercial drugs for normal and/or accidental dosimetry. & 2014 Elsevier Ltd. All rights reserved.
Keywords: Sterilization Drugs Thermoluminescence Optically stimulated luminescence Infrared stimulated luminescence Aspirin
1. Introduction Sterilization with gamma irradiation is gaining ground the last decades and this method is being applied extensively to more fields day by day. Due to its high penetrating power this method is also applied for the easy, efficient and almost heat-free sterilization of heat-sensitive pharmaceutical preparations while being packed in the final product package (Abuhanoglu and Ozer, 2010; Frohnsdorff, 1981; Silindir and Ozer, 2009). Exposure of drugs to ionizing radiation may be accompanied by several chemical and molecular changes of the product which can ultimately lead to its degradation and result in a toxicological hazard. Consequently, any change in the drug induced by irradiation can put in risk the health and safety of the consumer (Onori et n Corresponding author at: Nuclear Physics Laboratory, Physics Department, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece. Tel.: þ 302541078787; fax: þ 302541063656. E-mail addresses: [email protected], [email protected] (N.A. Kazakis).
http://dx.doi.org/10.1016/j.apradiso.2014.05.012 0969-8043/& 2014 Elsevier Ltd. All rights reserved.
al., 1996). The above, in conjunction with the fact that sterilization with ionizing radiation is not allowed in all countries unless the manufacturer proves that no product degradation has taken place and authorization has been obtained from the appropriate health authorities, makes the capability of identifying irradiated drugs a necessity (Prem Anand, 2011). In any case, similarly to food, it would be of great interest to be able to verify whether a drug has been irradiated or not (Raffi et al., 2002a). In addition, such a method which would not only distinguish between irradiated and non-irradiated drugs, but could also give a measure of the dose applied, would be of great value for the manufacturers as well for in-house-use, since they would be able to evaluate, in-situ, the radiation sterilization process and the actual radiation absorbed by each preparation through a mass of packed products. Towards this respect, several studies have been conducted (e.g. Onori et al., 1996; Raffi et al., 2002a, 2002b; Aleksieva and Yordanov, 2012; Cozar et al., 1997; Damian, 2003; Gibella et al., 2000; Juárez-Calderón et al., 2009; Polat and Korkmaz, 2006;
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Basly et al., 1997). However, all of them use electron paramagnetic resonance (EPR) or electron spin resonance (ESR) spectroscopy as an investigative tool for the detection of irradiated solid-state drugs based on the study of the radicals formed in drugs. In the above works the main goal was to identify the various changes in the formed radicals with the dose and to explore the time stability of the radicals. According to Raffi et al. (2002a) the ultimate scope is to develop general detection protocols as in case of foodstuffs (Raffi, 1998). To the authors’ best knowledge, less than a handful of studies have been conducted employing Thermoluminescence (TL) for the detection of irradiated drugs (e.g. Stocker et al., 1999; Raffi et al., 2002b), probably due to the high heat-sensitivity of the drugs. For example, Stocker et al. (1999) have reported thermoluminescence signals from ionized ampicillin and accentuate that the method can be employed for the detection of radiated drugs even two years after radiolysis. Similarly, no study was found in the literature regarding the use of optically stimulated luminescence (OSL) for the same purpose, which could be promising since it does not involve heat application. According to the above, the scope of the present preliminary study is twofold. First to explore whether OSL and TL can be employed as methods for post-sterilization dosimetry on commercial drugs, i.e., as tools for the detection of irradiated drugs and second, to investigate the luminescent properties of drugs and determine whether they exhibit the attributes of a good dosimetric material and thus can be potential candidates for normal and/or accidental dosimetry. To accomplish the above preliminary studies relatively low – compared to those used for sterilization – doses are employed due to the limited access presently to large-scale irradiation facilities, which, however, shall be remedied in the future in view of promising preliminary results.
2. Drug composition It is known that a drug product is not composed merely of the active ingredient (organic compound), but it also contains several inactive ingredients (organic or inorganic compounds) which do not influence the therapeutic action of the active ingredient and have no pharmacological effect. For this reason they are also commonly referred to as inert ingredients or excipients and they are added during the manufacturing process of pharmaceutical products and act as binding materials, dyes, preservatives, flavoring and/or drug efficacy enhancing agents etc (Katdare and Chaubal, 2006).
3. Experimental procedure 3.1. Drug selection and details Selection of the commercial pharmaceutical preparations to be studied was based on their “reputation” and availability in the drug market. This means that it was desirable to identify commercial drugs which satisfy two requirements: first, they are commonly and extensively used worldwide and second, they are manufactured and exported by the same company. The former is indicative of the widespread availability of those drugs in stores and houses all over the world, while the latter ensures that the recipe (specifications and concentrations of excipients and active ingredients) of the under-study drugs is exactly the same in the international market, enhancing the significance of the present study and the applicability range of its findings. Commercial drugs selected for the present study with details about their composition are given in Table 1. All drugs were kindly supplied from a pharmacy in closed boxes and before their expiration date as suggested by the manufacturer.
Table 1 Pharmaceutical preparations under investigation. Drug
Classification-type of action
Active ingredient/concentration
Excipients (according to manufacturer)
DAKTARINs (powder)
Antifungal
Miconazole Nitrate/2% w/w
Talc Zinc oxide Silicon dioxide colloidal
ASPIRINs (tablet)
Anti-inflammatory & Analgesic
Acetylsalicylic acid/500 mg/tablet
Cellulose powder Maize starch
PANADOLs (tablet)
Analgesic
Paracetamol/500 mg/tablet
Pregelatinised starch Calcium carbonate Alginic acid Crospovidone Povidone (K-25) Magnesium stearate Colloidal anhydrous silica Parahydroxybenzoates: sodium methyl parahydroxybenzoate (E219) sodium ethyl parahydroxybenzoate (E215) sodium propyl parahydroxybenzoate (E217)
BRUFENs (tablet)
Anti-inflammatory & Analgesic
Ibuprofen/600 mg/tablet
Tricalcium Phosphate Cellulose microcrystalline Povidone (plasdone K29–32) Croscarmellose sodium type A Stearic acid
PROCEFs (tablet)
Antibiotic (penicillin based-2nd generation cephalosporin type)
Cefprozil/500 mg/tablet
Titanium Dioxide Magnesium stearate Macrogol 400 Polysorbate 80, Hypromellose, Sodium starch glucolate, Antifoam C emulsion, Avicel
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At this point, it should be noted that, according to their specifications, almost in all pharmaceutical preparations studied, both the active ingredients and the majority of the excipients are crystalline, thus making promising the presence of luminescent properties. 3.2. Sample preparation In all cases, drugs were used with no further chemical treatment due to their sensitive nature (such as high solubility). Daktarin was
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used in its initial form with no additional grinding, since it is already in a powder form with particle size less than 10 μm (e.g. AIC, 2013). The rest of the drugs, which all are in tablet form, were gently smashed and grinded in a mortar. It should be noted that in the case of Procef, Brufen and Panadol removal of the coating film with a scalpel preceded their grinding, since its chemical composition (excipients, mainly used as binders) is different than the main core of the tablet and in some cases it was unknown. The final size of the grains in all drugs was less than 20 μm and consequently no further sieving was required.
Table 2 OSL measurement conditions.
3.3. Instruments and methods Drug
DAKTARINs ASPIRINs PANADOLs BRUFENs PROCEFs
Test dose (Gy) 100 350 200 200 100
Stimulation time (s) CW-BSL
Stimulation time (s) LM-BSL
150 150 150 100 50
213 213 213 142 71
Stimulation time (s) CWIRSL 150 150 150 100 50
Initially, micro-XRF analysis was performed in all drugs in order to examine their chemical composition and to gain an insight into the inorganic elements present which are indicative of the variety of substances used as excipients. A portable and compact micro-XRF spectrometer (SPECTRO, COPRA model) was employed for the micro-XRF measurements. This instrument comprises a side-window X-ray tube with Mo anode (Series
Fig. 1. micro-XRF spectra of the under-study drugs: (a) Daktarin, (b) Aspirin, (c) Panadol, (d) Brufen, (e) Procef.
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5011 XTF, Oxford Instruments) with maximum voltage and current of 50 kV and 1 mA respectively, together with a Peltier-cooled solid state Silicon Drift Detector (SDD) X-ray detector (8 μm Be window, 3.5 mm2 active area, 300 μm nominal thickness and resolution 149–166 eV at the Mn Ka energy). More details about the micro-XRF instrument can be found elsewhere (e.g. Sakalis et al., 2013). The operating conditions during the micro-XRF analyses are 35 kV applied potential, 0.9 mA current and 6.0 min acquisition real time. Three independent micro-XRF measurements were performed in a point scan mode on several points on the tablet in its initial form for each sample in order to achieve a representative elemental qualitative characterization. In the case of Daktarin, powder was confined into a special low mass container to facilitate its handling during the micro-XRF measurements. Various luminescence measurements were conducted regarding the stimulation technique employed. More specifically, all solid-state pharmaceutical preparations were studied with both OSL and TL. Effect of the wavelength of the light stimulation was also studied using
both blue light (BSL) and infra-red stimulation (IRSL), while both continuous wave (CW-OSL) and linearly modulated (LM-OSL) BSL experiments were conducted. For the above measurements a Riso TL/OSL reader (model TL/OSLDA-15) was recruited, equipped with a 90Sr/90Y beta particle source capable of delivering a nominal dose rate of about 3.62 Gy/min at the time of the measurements. The system is also equipped with blue LEDs emitting at 470 nm arranged in six clusters each containing seven individual LEDs (maximum total power 40 mW/cm2 at the sample) and a 1.0 W (delivering 400 mW/cm2 at the sample) solid state IR-laser diode emitting at 830 nm (Botter-Jensen et al., 2000). A 9235QA photomultiplier tube with a combination of the appropriate filters, as described below, was used for light detection. The filters used were: ▪ BSL measurements: a Hoya U-340 with maximum transmittance at approximately 340 nm and full width at half maximum (FWHM) about 80 nm. ▪ IRSL: a Schott BG 39 combined with a Corning 7-59 with transmission window at 340–480 nm. ▪ TL measurements: a Corning 7–59 (320–480 nm) with a heat absorbing Pilkington HA-3 filter. 3.4. Experimental conditions All OSL measurements were performed in room temperature. Measurement conditions (test dose and stimulation times) are presented in Table 2. These values were selected after preliminary measurements for all drugs of the present study. In the same respect, all TL measurements were performed in a nitrogen atmosphere with a constant heating rate of 5 1C/s up to a maximum temperature of 450 1C/s. It must also be noted that in all cases a background signal was also acquired and subsequently subtracted from the original signal of the main measurement. 4. Results and discussion 4.1. micro-XRF measurements Fig. 1 illustrates the micro-XRF spectra of all drugs studied. At this point, it must be pointed that Argon (Ar) present in all spectra
Fig. 2. Decay curves of unirradiated samples (natural) for: (a) Daktarin, (b) Aspirin and Panadol.
Fig. 3. Normalized response of 1st channel and total (inset) counts for all drugs studied for six consecutive cycles of radiation (100 Gy) and BSL on the same sample.
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stems from the atmosphere since micro-XRF measurements are conducted in an open-air environment, which, in addition, makes the detection of light elements (lighter than Si) impossible. It is obvious that Daktarin has the “richest” variety of elements in its chemical composition compared to all other drugs, which was actually expected due to the excipients it contains (Table 1). On the other hand, Aspirin seems to be completely free of heavy elements, while in the rest of the under-study drugs presence of several elements is evident which comply with the composition of few of their excipients (Table 1). However, it seems that the majority of the excipients used in these drugs are of organic nature. In any case, some of these inorganic excipients render these drugs promising candidates for exhibiting interesting luminescence behavior. For example, according to the manufacturer, ZnO and SiO2 are two of Daktarin’s inert ingredients (Table 1), whose luminescent properties have been extensively studied in the literature. 4.2. Natural BSL signal The term “natural signal” in the present study refers to the original signal obtained by the samples prior to any given test dose. Decay curves for the unirradiated samples (natural BSL signal) of Daktarin and Aspirin along with Panadol are presented in Fig. 2a and b respectively. It must be noted that Daktarin is the only drug of the present study which presents a detectable OSL signal without being irradiated in the laboratory. The presence of an intense luminescence signal for Daktarin may partially be attributed to its chemical composition, since two of the used excipients are ZnO and SiO2, with known luminescent properties. In addition, existence of populated traps and centers without artificial radiation can be ascribed to sunlight-UV irradiation or it is an indication that Daktarin has been sterilized by means of radiation after its manufacture. The latter would be of major significance if it is valid as elucidated below. Since the shelf life of Daktarin is three years (e.g. Irish Medicines Board, 2012) and the expiration date of the product used in the present work is 01/2016, this implies that it was manufactured and, thus, possibly sterilized in 01/2013, which is one year prior to the current measurements. Consequently, if this is the case, Daktarin can store radiation at least up to one year. Of course further experiments are needed to verify the above. As seen in Fig. 2a, the Daktarin natural signal decays very fast in the first seconds of stimulation and about 110 s of stimulation are adequate to empty traps responsible for the luminescence signal, since the signal reaches the background signal.
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On the other hand, the rest of the drugs exhibit no natural luminescence and thus the recorded signal corresponds to the respective background. Fig. 2b illustrates the two acquired signals for Aspirin and Panadol which is typical for Brufen and Procef as well. It is obvious that the two background signals are not comparable regarding the OSL intensity, with Aspirin exhibiting an approximately four times higher background than that of Panadol. At this point, it should be noted that Daktarin exhibits a background of similar intensity with that of Aspirin, while Brufen’s and Procef’s backgrounds are comparable to that of Panadol. The above is further evidence that composition of drugs is very dissimilar and plays a determinant role in their luminescence behaviour. 4.3. Sensitization BSL measurements In order to investigate the potential sensitization of the understudy drugs due to stimulation light, one sample of each drug was subjected to six consecutive cycles of radiation and subsequent BSL. All samples were irradiated with a dose of 100 Gy, while stimulation lasted 300 s. Results are depicted in Fig. 3 concerning the counts of the 1st channel (first 0.1 s of stimulation), while total
Fig. 4. Decay curves for three different samples of equal mass for Procef after irradiation with 100 Gy; only the first 5 s of stimulation are presented for clarity reasons.
Table 3 Statistics indicative for measurement precision for all drugs (background has been subtracted). Drug
Sample
Total counts (a.u.)
Mean value (a.u.)
Standard deviation (a.u.)
Standard deviation/mean 100
DAKTARIN
1 2 3
147,902 171,315 142,682
153,966
15,249
9.9
ASPIRIN
1 2 3
18,616 18,596 26,112
21,108
4,334
20.5
PANADOL
1 2 3
21,582 15,546 10,581
15,903
5,509
34.6
BRUFEN
1 2 3
5,783 3,530 9,636
6,316
3,088
48.9
PROCEF
1 2 3
4,018 15,700 6,218
8,645
6,208
71.8
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counts during the whole stimulation time for the various cycles are also given in the inset of Fig. 3. It must be noted that all data were normalized with respect to the data of the first cycle and that in all cases the respective background signal was subtracted from the original signal for each drug. If only the counts of the 1st channel are taken into account it seems that no sensitization is observed in almost all drugs during the six consecutive radiation-stimulation cycles. Daktarin is the only one which exhibits a relatively continuous increase in the 1st channel counts during the successive cycles, demonstrating an
increase of about 15% after the 6th cycle. It should be stated that results are similar if integration over the first second of the stimulation is considered (10 first channels). The above trend seems to change when the total counts of the decay curve are considered (inset of Fig. 3), namely integration over the total stimulation time for each drug. Procef presents a very stable behavior, with the total counts remaining relatively constant during the six cycles of radiation-stimulation. However, a desensitization of the luminescence yield of Brufen seems to occur exhibiting a total decrease of about 17%. On the other hand, the
Fig. 5. CW-BSL decay curves (semi-log scale) for all drugs after being irradiated with the corresponding test dose: (a) Daktarin, (b) Aspirin, (c) Panadol, (d) Brufen, (e) Procef.
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rest of the studied drugs, namely Daktarin, Aspirin and Panadol demonstrate a different behavior. After each cycle the luminescence yield of Daktarin and Panadol constantly increases up to about 35% and 31% respectively. Finally, in the case of Aspirin the total counts of the decay curve increase up to 30% after the first three cycles and remains constant for the next three cycles, which would imply a possible sensitization of slow components. 4.4. Measurement precision-Sample handling In order to examine the precision of the measurements on all drugs of the current work, direct BSL measurements were
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conducted for three different samples of each drug after irradiation with 100 Gy. It must be noted that all samples had exactly the same mass (17.20 70.02 mg) weighed with a 4-digit accuracy scale. Unfortunately, precision was not satisfactory, except for Daktarin. In Table 3 the total counts of all CW-BSL decay curves for all samples of each drug are presented along with the corresponding mean value and standard deviation. Daktarin samples exhibit relatively similar luminescence decay curves, since the standard deviation of the total counts is less than 10% of the mean value. However, the rest of the drugs demonstrate different behavior with the standard deviation varying from 20% (Aspirin) to 72% (Procef) of the mean value. The above results are
Fig. 6. LM-BSL decay curves for all drugs after being irradiated with the corresponding test dose: (a) Daktarin, (b) Aspirin, (c) Panadol, (d) Brufen, (e) Procef.
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independent of the stimulation time over which the signal is integrated for the calculations of Table 3. Fig. 4 also illustrates the decay of signal intensities for Procef samples. It should be noted that similar trend was observed during LM-BSL experiments for the same samples. The above deviation in the decay curves between samples of the same drug may be attributed to the different surface of each sample exposed to the stimulation light, since this is the most important factor affecting the OSL measurements rather than the sample weight. Consequently, special handling of the samples is imperative before the measurements to assure precision in OSL experiments in case of multiple aliquots experiments.
4.5. CW-BSL normal sensitivity measurements Fig. 5 illustrates the CW-OSL decay curves for all drugs after being irradiated with the corresponding test dose (Table 2) and stimulated with blue light. In all cases the luminescence signals present similar features. They consist of one initial and quickly decaying part in the first seconds of stimulation which is followed by a second slow decaying part. In addition, comparing the decay curves of Brufen with the one of Panadol (same test dose) and Procef with Daktarin (same test dose) (Fig. 5), one can readily observe that in the case of Brufen and Procef, the decay curves reach the background level very fast, i.e., in time less than 15 s
Fig. 7. IRSL decay curves (semi-log scale) for all drugs after being irradiated with the corresponding test dose: (a) Daktarin, (b) Aspirin, (c) Panadol, (d) Brufen, (e) Procef.
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which would be an indication of the depth of the traps for the above drugs and the kinetics involved. 4.6. LM-BSL normal sensitivity measurements Fig. 6 illustrates the LM-OSL decay curves for all drugs after being irradiated with the corresponding test dose (Table 2) and stimulated with blue light. Stimulation time seems to be inadequate for Daktarin, since the rate of decay of the curve is relatively slow after the first 120 s and more time is needed to empty the traps and reach the background level. On the other hand, the above is not valid for the rest of the drugs and the selected stimulation time (LMtime ¼√2 CWtime) is satisfactory. 4.7. IRSL normal sensitivity measurements Fig. 7 presents the IRSL decay curves for all drugs after being irradiated with the corresponding test dose (Table 2) and stimulated with infra-red light. Luminescence curves obtained after stimulation with light of longer wavelength (compared to the blue LEDs) are of similar shape as the ones acquired with CW-BSL. As previously discussed, it seems that in the case of Daktarin and Aspirin slow components are involved in the decay process which need further investigation.
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the estimation of the absorbed dose in radiation-processed food and in radio-sterilization of pharmaceuticals (Tepe et al., 2009): ▪ ▪ ▪ ▪
linear regression quadratic fit power function exponential function
Functions studied along with the numerical results of the fitting are given in Table 4. It should be noted that no attempt was made to force the regression through zero. According to Table 4, second order polynomial and power function describe best the intensity data obtained for all drugs studied. The above findings are in agreement with the observations of Tepe et al (2009) and Polat and Korkmaz (2006) who studied the dosimetric features of sultamicillin tosylate and paracetamol respectively by means of ESR. They also found that the experimental intensity data can best be fitted with a power function or a second order polynomial, respectively.
4.8. OSL dose response Fig. 8 illustrates the decay curves for various doses applied in the case of Aspirin. It should be noted that the observed behavior is typical for the other drugs as well. In higher doses more stimulation time is required to empty all traps. It seems that a very slowly decaying OSL component of quite large lifetime is present and its effect becomes more pronounced as the applied dose is increased, due to the enhanced population of deep traps. Dose response for all drugs is depicted in Fig. 9. Very interesting is the fact that, for all drugs, the illustrated dose response is similar even when only the 1st channel counts (0.1 s) or the 1st second of the decay curve are taken into consideration. An attempt was made to fit the data of the dose response for all drugs using four different functions which have been employed for
Fig. 8. Decay curves (semi-log scale) for Aspirin after being irradiated with several doses.
Fig. 9. Dose response for all drugs: (a) Daktarin and Panadol, (b) Aspirin, Brufen and Procef.
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Of course, in order to use the above functions for the absorbed dose estimation in drug sterilization they have to be validated in much higher doses (at least up to 25 kGy). Nevertheless, these fittings in relatively low doses (up to 1.4 kGy) can also be helpful in the frame of the general characterization of the under-study drugs and the examination of their dosimetric and luminescent properties. 4.9. Short-term decay of OSL yield at room temperature Preliminary room-temperature short-term stability studies have also been carried out for all drugs of the present work after irradiation with the test dose (Table 2). Besides the BSL experiment directly after irradiation, OSL measurement with blue light stimulation took place also 24 h after irradiation. Table 5 presents the % reduction in both the total intensity and the 1st channel intensity for all drugs. A first observation is that the choice of the stimulation time over which the signal is integrated for the fading calculations is of major importance, especially for Daktarin and Aspirin. In parallel, only Procef and Panadol exhibit a fairly small decrease in the OSL intensity, namely 13.8% and 7.3% respectively, while the rest of the studied drugs present a rather high reduction in the total luminescence yield 24 h after irradiation. Of course, fading must be tested for longer time periods to get a representative picture of the intensity decrease rate for all drugs.
measurements at five different constant temperatures in the range 25–45 1C with a step of 5 1C were also conducted after irradiation of the samples with the corresponding test dose. In order to gain a quantitative insight into the effect of the studied phenomenon, a BSL measurement after the sample was cooled, was subsequently taken to record the residual luminescence signal after each constant temperature TL experiment. Fig. 10 illustrates the constant temperature TL measurements along with the residual BSL measurements (insets) for all temperatures studied in the case of Daktarin. It should be noted that the depicted behaviour is typical for all drugs of the present study. From Fig. 10, one can observe that as the temperature gradually increases, the TL signal presents slightly higher intensity at the first seconds of the signal and then gradually decays. In parallel, the shape of the experimental residual OSL decay curve remains exactly the same for all temperatures studied. Although the 1st channel counts of the residual OSL slightly decrease as the temperature of the preceding TL increases, integration over the total signal is practically unchanged. This might be an indication of phosphorescence involved, yet of extremely low extent, which releases merely a minor portion of electrons in relatively shallow traps. It seems that in all drugs of the present study luminescence signals are complex and are the result of the recombination of electrons originating from rather deep traps.
4.10. Phosphorescence decay measurements
4.11. Thermoluminescence measurements
Phosphorescence is the decay of thermally stimulated luminescence as a function of time at a constant temperature and it is always associated with trapping of the carriers at rather shallow traps and their subsequent thermal release prior to their radiative recombination (Chen and McKeever, 1997). In this respect, TL
Thermoluminescence measurements were also conducted for the drugs studied and the corresponding glow-curves are illustrated in Fig. 11. These curves are indicative of the various components that contribute to the luminescence signal in each drug, since their shapes are quite dissimilar to each other.
Table 4 Mathematical functions used and parameters calculated from curve fitting. Function
DAKTARINs
ASPIRINs
PANADOLs
BRUFENs
PROCEFs
I¼a þb D
a¼ 72,8007 12,020 b¼ 1,747.30 7 24.82 (R2 ¼ 0.9994)
a ¼49,148 7 12,825 b ¼ 174.56 7 16.51 (R2 ¼0.9655)
a¼ 27,738.0 7 9,990.1 b¼ 401.30 7 16.16 (R2 ¼ 0.9936)
a¼ 5,199.4 7 1,282.1 b ¼30.647 2.07 (R2 ¼ 0.9820)
a¼ 17,078.074,197.6 b¼ 88.89 7 9.34 (R2 ¼ 0.9577)
I¼a þb Dþ c D2
a¼ 58,077.0 7 7,807.3 b¼ 1,920.30 7 57.77 c ¼ 0.1697 0.055 (R2 ¼ 0.9999)
a ¼21,167.0 7 5,694.3 b ¼ 305.80 720.57 c ¼ 0.089 7 0.014 (R2 ¼ 0.9978)
a¼ 10,430.07 7,409.2 b¼ 519.88 736.47 c ¼ 0.0977 0.029 (R2 ¼ 0.9986)
a¼ 2,791.7 7 560.7 b ¼47.147 2.76 c ¼ 0.0137 0.002 (R2 ¼ 0.9987)
a¼ 9,655.9 72,251.0 b¼ 163.26 715.87 c ¼ 0.072 70.015 (R2 ¼ 0.9952)
I¼a [1 e D/b]
a¼ 4.83 106 7 1.70 106 b¼ 2,136.60 7 928.22 (R2 ¼ 0.9971)
a ¼3.18 105 713,614 b ¼ 730.197 61.82 (R2 ¼ 0.9967)
a¼ 9.67 105 7 1.41 105 b¼ 1,680.4 7 327.75 (R2 ¼ 0.9977)
a¼ 49,321.0 7 4,039.9 b ¼747.83 7 111.67 (R2 ¼ 0.9936)
a¼ 1.10 105 7 10,267 b¼ 426.617 82.91 (R2 ¼ 0.9780)
I¼a Db
a¼ 4,720.5 7 866.9 b¼ 0.8617 0.027 (R2 ¼ 0.9990)
a ¼3,113.0 7 669.7 b ¼ 0.622 70.031 (R2 ¼ 0.9940)
a¼ 1,402.17 322.9 b¼ 0.829 7 0.034 (R2 ¼ 0.9970)
a¼ 359.17 36.5 b ¼0.666 70.015 (R2 ¼ 0.9989)
a¼ 2,025.9 7219.0 b¼ 0.56770.017 (R2 ¼ 0.9977)
Note: I: total OSL intensity during stimulation time in arbitrary units (a.u.); D: dose applied in Gy; Point corresponding to dose of 200 Gy in Daktarin dose response curve dose was excluded from all calculations.
Table 5 OSL intensity reduction 24 h after irradiation (fading results). Total counts (a.u.) Drug s
DAKTARIN ASPIRINs PANADOLs BRUFENs PROCEFs
1st channel counts (a.u.) Directly after irradiation
24 h after irradiation
(%) decrease
Directly after irradiation
24 h after irradiation
(%) decrease
255,572 125,072 102,241 12,399 29,468
188,987 61,684 88,084 6,729 27,314
26.1 50.7 13.8 45.7 7.3
18,528 2,697 9,377 1,422 10,784
7,800 2,190 7,174 940 9,505
57.9 18.8 23.5 33.9 11.9
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According to Fig. 11, Daktarin exhibits at least seven peaks (Tmax 105 1C, 205 1C, 220 1C, 255 1C, 340 1C, 380 1C, 425 1C), Aspirin two (Tmax 100 1C, 195 1C), Panadol two (Tmax 140 1C, 250 1C) and Brufen three (Tmax 130 1C, 225 1C, 300 1C), while no TL signal was obtained for Procef as clarified below. At this point, it must be noted that, although a relatively high heating rate was adopted for the TL measurements, heating of the samples caused their degradation or destruction. Daktarin proved
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to exhibit the highest heat resistance and heating caused only marginal changes of its colour (from white to yellowish). On the other hand, heat on the rest of the drugs caused a severe degradation of their texture, colour and general form. In fact, they were scorched and in some cases completely destructed and/or sublimated. The above could probably explain the fact that no glow-curve was recorded for Procef. It seems that its heat resistance is so low that even in relatively low temperatures (o100 1C) significant degradation takes place.
Fig. 10. Constant temperature TL decay curves (phosphorescence decay) for Daktarin at: (a) 25 1C, (b) 30 1C, (c) 35 1C, (d) 40 1C, (e) 45 1C.
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Aspirin, Panadol and Brufen samples seem to have higher heat tolerance permitting the recording of TL glow curves. Yet, due to their final destruction, as described above, the credibility and completeness of the glow curves can be put into question, since losses of the signal above a threshold temperature (apparently different for each drug) are very probable. For this purpose, future experiments and analysis should probably focus only on the Daktarin glow-curve(s).
5. Conclusions Basic preliminary optically stimulated luminescence (CW-OSL, LM-OSL, IRSL) and thermoluminescence experiments were conducted on five commonly and extensively used commercial drugs to identify their potential luminescent properties which would allow the detection of radiation during their sterilization and/or their use as dosimeters. In most cases light sensitization is not observed when integration over the first second of the signal is considered. CW-OSL and IRSL decay curves are of similar shape, namely they consist of one initial and quickly decaying part in the first seconds of stimulation which is followed by a second slow decaying part. In the case of Daktarin and Aspirin, the presence of extremely slow components is very probable and further investigation is required, since these components can be attributed to deeper traps and are expected to be enhanced at higher doses such as used in the sterilization
process. LM-OSL signals were also acquired for all drugs which need further analysis to allow the extraction of valuable information about their components. Interesting were the results of the signal response in several doses applied in the range of 20–1400 Gy. Experimental data can successfully be fitted with a second order polynomial or a power function, which is in accordance with the findings of published studies on other drugs by means of ESR. Loss of OSL signal 24 h after irradiation is rather imperceptible for Panadol and Procef, while a relatively high reduction in the total signal intensity is evident for the rest of the drugs. Phosphorescence decay experiments (TL under constant temperature) reveal a negligible presence of phosphorescence in all drugs and a rather complex pattern in the luminescence signals probably attributed to the recombination of electrons originating from rather deep traps. Thermoluminescence measurements with heating of the samples up to 450 1C led to interesting glow-curves for all drugs, especially for Daktarin. Unfortunately, this kind of measurements with heating involved proves to be completely destructive for all drugs except for Daktarin due to their low heatresistance. Thus, their acquired TL signals are questioned for their credibility and completeness. On the contrary, Daktarin’s relatively high heat-resistance is evident rendering its full characterization promising. According to the above, preliminary findings are very optimistic towards the post-sterilization dosimetry and the use of commercial drugs for normal and/or accidental dosimetry. In this
Fig. 11. TL glow curves corresponding to the test dose for: (a) Daktarin, (b) Aspirin, (c) Panadol, (d) Brufen.
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