Article pubs.acs.org/Langmuir
Promethazine−Montmorillonite Inclusion Complex To Enhance Drug Photostability Valeria Ambrogi,*,† Morena Nocchetti,† and Loredana Latterini*,‡ †
Dipartimento di Scienze Farmaceutiche and ‡Dipartimento di Chimica, Biologia e Biotecnologie, Università degli Studi di Perugia, 06123 Perugia, Italy ABSTRACT: The capability of montmorillonite as a matrix (MONT) to improve the photostability of photolabile drugs has been recently reported. Herein promethazine (PRO), which was chosen as a model drug because of its photodegradation mechanism, was intercalated into this inorganic matrix, and the effects on drug photoprotection were evaluated as well. The hybrid material (MONT-PRO) was successfully prepared with high drug loading and then was characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and FTIR spectroscopy. The spectrophotometric measurements as a function of light exposure time showed that PRO intercalation into montmorillonite markedly improved the drug photostability because a 5-fold-slower degradation rate was determined compared to that measured for PRO in homogeneous solutions; nanosecond transient absorption measurements highlighted that the interaction with the inorganic matrix made negligible the photoionization process of the drug, and its efficiency in producing singlet oxygen was strongly reduced. The MONTPRO intercalation compound could be easily formulated in gel or ointment media without losing its photostability.
1. INTRODUCTION Recently, some inorganic matrices have been proposed as agents for improving drug, cosmetic ingredient, and dye photostability.1−7 Among them, montmorillonite (MONT) showed interesting effects with respect to the photostabilization of photolabile drug piroxicam.4 Photodegradation is a problem for many drugs because it can be the cause of the short shelf life of medicinal and photosensibility cutaneous reactions as well. Photosensibility is a kind of adverse reaction to drugs administered both systematically and topically, associated with drug degradation upon light exposition. Photoreactions to exogenous agents occur mostly in response to ultraviolet A (UVA) light (315−400 nm) rather than to shorter wavelengths out of the UVB or UVC band and can be divided into two kinds: phototoxicity and photoallergy.8,9 The clinically used phenothiazines are known to cause both phototoxic and photoallergic reactions in the skin and eyes of patients, and investigations showed that these effects could be due to a variety of free radicals, including cation radicals, hydrated electrons, and some active oxygen species that are formed upon phenothiazine light exposure.10−12 Promethazine (PRO) (Figure 1A) is a photolabile phenothiazine drug with antihistaminic activity, used both after systemic administration for the treatment of nausea, vomiting, and motion sickness and topically for insect bites, eritema, and itch. As suggested in the label enclosed in its packaging, during its use, light exposition should be avoided in order to prevent cutaneous photoreactions. Only a few attempts to improve its photostability are reported by means of the use of cyclodextrins13 and bioactive catanionic vesicles.14 Thus, PRO was chosen as a model drug in order to improve its photostability and to expand the © 2014 American Chemical Society
Figure 1. (A) Structural formula of PRO hydrochloride. (B) XRPD of (a) the crystalline PRO salt, (b) MONT-Na, (c) the PRO/MONT-Na physical mixture, and (d) MONT-PRO.
knowledge of the effects of MONT on drug photostability. In fact, very little information is known about the mechanism of photostabilization provided by this inorganic material. MONT is a natural silicate with unique hydration, swelling, and adsorption properties. It is composed of silica tetrahedral sheets layered between one aluminia octahedral sheet.15 Because of the isomorphic substitution of some Al with Mg ions, the clay Received: August 26, 2014 Revised: November 6, 2014 Published: November 19, 2014 14612
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centrifuged (4000 rpm, 10 min). The sediment was washed with deionized water (4 × 25 mL), dried at 40 °C for 24 h, and triturated into fine powder that was maintained in a desiccator with CaCl2. PRO intercalation was performed to protect the drug from the light. 2.6. Drug-Loading Determination. PRO loading was determined by UV spectrophotometry (Spectrophotometer Agilent 8453) after the suspension of a well-known amount of the intercalated compound (10 mg) with aqueous 5 mol L−1 HCl (100 mL) under stirring for 24 h (λmax = 249.0 nm). The PRO content was also evaluated by TG analysis considering the exothermic weight loss in the temperature range of 150−700 °C. PRO loading as a percentage in the hybrid was furnished as a medium. 2.7. Preparation of MONT-PRO Formulations. The hydrophilic ointment was obtained according to Italian Pharmacopoeia (F.U. XII) by melting poly(ethylene glycol) 4000 (60 g) in a steam bath and adding to this melt poly(ethylene glycol) 400 (40 g) under continuous stirring. The melt was removed from the heating source, and the stirring was continued until the melt cooled. PRO salt or the intercalated compound (both in an amount so that PRO concentration in formulations was 1.8%) was pulverized in a mortar and then was properly incorporated into the base at room temperature. The gel was obtained by dispersing sodium carboxymethylcellulose (5%) in glycerin (10%) with stirring, and then distilled water (85%) was added under continuous stirring to obtain a uniform dispersion. This preparation was kept overnight so that the gel became uniform in texture and appearance and the air bubbles could escape. PRO salt was added by dissolving it in water. The intercalated compound was properly added using a pestle and mortar. In both gels, the PRO concentration was 1.8%. 2.8. In Vitro Release Studies. In vitro PRO release from all formulations was carried out for 8 h with a Franz diffusion cell (PermeGear, Inc., Bethlehem, PA, diameter 20 mm) consisting of a water-jacketed receptor chamber (15 mL) and a donator chamber. Phosphate buffer at pH 5.5 (F.U. XII) was used as a receptor phase. The test was performed at 32 °C under stirring (600 rpm). The two chambers were separated by a cellulose filter membrane (Whatman 41 filter paper, 20−25 μm, Whatman GmbH, Dassel, Germany). Each formulation (200 mg) was loaded onto the upper donor chamber, and then 1 mL of phosphate buffer was added and the top was successively sealed with parafilm. At regular time intervals, samples of the receiving phase were withdrawn and replaced by the same volume of fresh dissolution medium. The PRO content was spectrophotometrically determined at λmax 249.0 nm by using a UV−vis spectrophotometer (Agilent model 8453). The experiments were carried out under sink conditions, and the data are reported as an average of three measurements. 2.9. Photophysical Studies and Investigation of Drug Photostability. The drug photostability studies in solutions were performed through UV−vis absorption spectra, which were recorded with a PerkinElmer Lambda 800 spectrophotometer in air-equilibrated solutions. The optical behavior of the solid samples was investigated through spectrophotometric measurements; the spectra were recorded with a Varian (Cary 4000) spectrophotometer equipped with a 150 mm integration sphere, and a barium sulfate tablet was used as a reference. The recorded spectra were analyzed with the Kubelka-Munk equation in order to make the comparison possible. (The experimental errors in the absorbance values were about 7%.) The transient behavior of the samples was investigated using a flash photolysis setup previously described,27,28 which is based on a Nd:YAG Continuum laser (Surelite II, third harmonics, λexc = 355 nm, pulse width ca. 7 ns, and energy ca.1 mJ pulse). The transient spectra were obtained by monitoring the optical density changes every 5−10 nm over the 300−800 nm range and averaging at least 10 decays at each wavelength. The kinetic analysis of the signals at selected wavelengths allowed the transient decay time to be determined. The calibration of the experimental setup, for quantum yield determinations, was carried out with an optically matched solution of benzophenone in acetonitrile (triplet quantum yield, ΦT = 1 and εT = 6500 M−1 cm−1).29 The experimental errors in the transient decay
sheets have a negative surface charge and are naturally found stacked on top of each other, with positively charged ions intercalated between the layers. These cations are also exchangeable with larger cations. MONT is largely used as a reologic agent for cosmetic and pharmaceutical semisolid systems,16 and recently, because of its property of intercalating ions, MONT has been proposed as a carrier for drugs, vitamins, and amino acids that are intercalated between the inorganic layers and can be released in a modified manner under the proper conditions.17−27 Thus, in this article PRO was intercalated into MONT layers, and the photochemical behavior of the drug before and after intercalation into MONT was evaluated. Finally, proper topical formulations were realized, and the drug photochemical behavior and release were evaluated as well.
2. EXPERIMENTAL SECTION 2.1. Materials. Nanofil 116 (MONT-Na), used as sodium montmorillonite (MONT-Na), was kindly furnished by Rockwood Clay Additives GmbH (Moosburg, Germany). Promethazine hydrochloride (PRO salt), glycerin, sodium carmellose, poly(ethylene oxide) 400, and poly(ethylene oxide) 4000 were purchased from A.C.E.F. s.p.a. (Fiorenzuola D’Arda, Piacenza, Italy). Deionized water was obtained by a reverse-osmosis process with a Milli-Q system (Millipore, Rome, Italy). Other reagents and solvents were of reagent grade and were used without further purification. 2.2. Experimental Techniques. XRPD patterns were taken using a computer-controlled PW 1710 Philips diffractometer (Lelyweg, The Netherlands) with Ni-filtered Cu Kα radiation. DSC analyses were performed using an automatic thermal analyzer (Mettler Toledo DSC821e). Temperature calibrations were achieved by using an indium standard. Holed aluminum pans were employed for all samples, and an empty pan, prepared in the same way, was used as reference. Samples of 3−6 mg were loaded directly into the aluminum pans, and thermal analyses were conducted in air flow at a heating rate of 10 °C min−1 from 25 to 300 °C. FTIR spectra were recorded in air at room temperature on a Jasco FT/IR-410, 420 Herschel series (Jasco Corporation Tokyo, Japan) in a KBr dispersion using the EasiDiff diffuse reflectance accessory. Samples were prepared by gently grounding the powders with KBr. The data region was 4000−400 cm−1. The PRO content of the solids was determined by coupled thermogravimetric (TG) and differential thermal (DTA) analyses performed with a Netzsch STA 449 C apparatus in air flow at a heating rate of 10 °C min−1. The sodium content was determined by an inductively coupled plasma-optical emission spectrometry (ICP-OES) Varian, Inc. 710-ES series. 2.3. Determination of MONT-Na Ion-Exchange Capacity of MONT-Na. MONT-Na (100 mg) was added to a 1 mol L−1 aqueous ammonium acetate solution (30 mL). The mixture was stirred at room temperature overnight and centrifuged (4000 rpm, 5 min), and the sediment was washed with ethanol (3 × 10 mL). Then a 10% sodium chloride solution (30 mL) was added, and the mixture was stirred overnight and centrifuged (4000 rpm, 10 min). The sediment was washed with deionized water. After the sediment was dry, a known amount of this was stirred overnight at room temperature with a 1 M aqueous ammonium acetate solution (20 mL) and centrifuged, and sodium ions in the supernatant were determined by ICP. 2.4. Preparation of PRO Salt and MONT-Na Physical Mixture. The physical mixture was prepared by mixing crystalline PRO salt and the inorganic matrix in a proper weight ratio with a spatula. 2.5. PRO Intercalation into MONT-Na. MONT-Na (1 g) was dispersed in 40 mL of deionized water by vigorous stirring for 24 h at room temperature. Then an aqueous solution (5 mL) of PRO salt (PRO/MONT-Na molar ratio 1.3) was added, and the pH of the mixture was adjusted to 7.2 with a 1 M NaOH solution. The mixture was kept at room temperature under stirring for 24 h and then was 14613
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Figure 2. Thermal profile of (a) crystalline PRO salt, (b) MONT-Na, (c) PRO/MONT-Na physical mixture, and (d) MONT-PRO. time values were estimated to be about 10% whereas those in the quantum yields were about 15%. The measurements on MONT-PRO samples were carried out in aqueous suspensions that were spectrophometrically prepared. All of the measurements were performed in air-equilibrated samples. The singlet oxygen yields (ϕΔ) were determined by measuring the phosphorescence intensity of O2 (1Δg) with a germanium diode detector in air-equilibrated solutions and by using phenalenone (0.97) as a reference.10
melting, in accordance with XRPD analysis in which no peak of crystalline PRO was found. The physical mixture showed the PRO salt melting peak at a lower temperature than the crystalline drug probably as a result of interactions between PRO and the MONT-Na surface. The PRO salt FTIR spectrum (Figure 3) showed characteristic large absorption bands at 2385 cm−1 (stretching of the
3. RESULTS AND DISCUSSION 3.1. PRO Intercalation Compound Preparation and Its Characterization. Drug intercalation was performed at pH 7.2 on the basis of literature data30 that reported that the maximum adsorption was achieved in the pH range of 7 to 8. The obtained sample was submitted to XRPD in order to verify the drug intercalation. Figure 1B shows the XRPD patterns of sample MONT-PRO, PRO salt, the pristine montmorillonite, and the physical mixture between PRO salt and MONT-Na. MONT-Na had a basal spacing of 1.25 nm.31−33 The XRPD pattern of the MONT-PRO clay hybrid exhibited a first reflection at high diffraction angles corresponding to an interlayer distance of 2.29 nm. Moreover, the lack of reflection for MONT-Na was an indication of a complete exchange between sodium and PRO ions. The interlayer distance was compatible with an arrangement of the phenothiazine group plane tilt with respect to the silicate layers; this arrangement had already been observed in MONT intercalated with organic moieties.4 From UV spectrophotometric and thermogravimetric analyses, PRO loading in the intercalated compounds was 31.5% according to the amount of PRO given. Taking into account the cation exchange capacity (CEC) of MONT-Na (120 mequiv/100 g of clay), we found that complete ion exchange would afford a drug loading of 26.9% (26.9 g of drug/ 100 g of intercalate), suggesting that all of the PRO added is present in the intercalation mixture. It is very likely that all of the sodium cations were exchanged with PRO and that the excess was adsorbed on the MONT surface as an amorphous phase, as also observed by XRPD. In Figure 2, the DSC thermal behavior of intercalated compound MONT-PRO, crystalline PRO salt, and montmorillonite/PRO salt physical mixtures is reported. The PRO salt thermogram showed an endothermic peak at 232 °C due to melting,13 followed by a large exothermic peak. The MONTPRO thermal profile did not show any peak attributable to drug
Figure 3. FTIR spectra of (a) crystalline PRO salt, (b) MONT-Na, (c) PRO salt/MONT-Na physical mixture, and (d) MONT-PRO.
NH+ group of the PRO hydrochloride salts) and 1461, 1591, and 1569 cm−1 (aromatic rings).31 The MONT-Na FTIR spectrum showed the characteristic absorption bands at 3585 cm−1 (OH stretching of silicate), 3400 cm−1 (OH stretching of adsorbed water), 1640 cm−1 (OH bending of adsorbed water), 1051 cm−1 (stretching vibration of silicate Si−O−Si), and 925 cm−1 (from Al−OH−Al deformation of aluminates);34 in the physical mixture spectrum, peaks relative to both MONT-Na and PRO salt were present as well, indicating that the spectrum was the overlap of the two compound spectra. However, in intercalation compound MONT-PRO the lack of a peak at 14614
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2385 cm−1 was proof that the drug was no longer in the hydrochloride form.35 3.2. Formulation and in Vitro Release Studies. When a semisolid topical formulation is applied to the skin, the active agent must be released from the vehicle; then it is in contact with the epidermal surface and is available for its action on the skin or for absorption. Therefore, MONT-PRO was properly formulated, and PRO release was evaluated. Two classical formulations, a hydrophilic ointment and a hydrogel, were prepared, and the release profiles of PRO from these formulations were studied. The formulations containing MONT-PRO were subjected to XRPD with the aim of verifying the preservation of PRO in the intercalated form. With respect to the hydrogel formulation, it has to be highlighted that when MONT-Na is mixed with water, the latter penetrates between the platelets, forcing them further apart. Thus, the exchangeable ions begin to diffuse away from the platelet faces. Further penetration of water between the platelets then happens in an osmotic process until they are completely separated. In general, the speed with which platelet separation occurs is directly related to the amount of energy introduced during hydration, and both mechanical (mixing) and thermal energy (warm water) are used to accelerate hydration. In the hydrophilic gel, water molecules are blocked among the network of a hydrophilic polymer and thus are less disposable for penetrating between the montmorillonite platelets. First, to verify the preservation of the intercalated MONT-PRO after its formulation, the XRPD pattern of the gel containing MONT-PRO (Figure 4) was collected and
presence of PRO between the platelets could be hypothesized but not surely confirmed. This hypothesis was not in contrast with the different behavior of MONT-Na in the gel because PRO is highly affine for the silicate layers, as shown during PRO loading, and thus whereas in the case of MONT-Na the layers could rapidly be moved away from each other, when MONT-PRO was formulated, intercalated PRO did not easily diffuse away from the platelets. The results of PRO release from the MONT-PRO gel are reported in Figure 5A. The same formulations (gel) containing PRO salt and the physical mixture were prepared and tested for comparison. Analyzing the profiles from all formulations in both receptor media, we found that PRO was released faster from the gel containing free PRO salt than from the other gels. In the case of the gel containing free PRO salt, the drug release was due to the drug diffusion across the gel and this explained the faster drug release in comparison to that of other gels. In fact, when PRO was intercalated between the montmorillonite layers, its release was due to the following steps: first, the diffusion of the ions of the receptor medium across the gel, then ionic exchange of PRO with these cations, and finally drug diffusion toward the acceptor medium. Thus, the drug release was slower. To find a kinetic model feasible for describing the process, data analyses were carried out on the basis of diffusion models. One of these, proposed for ionic resins,36 asserts that if the diffusion through the solid particle is the rate-limiting step, then it is enough to check the direct proportionality between log(1 − released fraction) and time0.65. The other model applied is the Higuchi matrix diffusion model37 in which the quantity of drug released at time t is proportional to time0.5. Both models had good correlation coefficients (Table 1), meaning that both could describe the process and that diffusion was the main mechanism responsible for drug release. There was no difference in the release profile from the gel containing MONT-PRO and the physical mixture in the phosphate buffer medium. With respect to the gel containing the physical mixture, a partial intercalation of PRO between the montmorillonite layers cannot be excluded. Moreover, drug diffusion through the gel containing the physical mixture can be slowed down by the increased viscosity of the formulation as a result of montmorillonite thickening properties16 and by the presence of the inorganic layers with negative charge, which can produce electrostatic interactions with the positively charged drug ions. In Figure 6, XRPD patterns of the ointment containing MONT-PRO is reported and compared to those of the neat ointment and to those containing MONT-Na and physical mixture PRO salt/MONT-Na. The ointments containing MONT-Na both without PRO and with PRO showed the lack of the basal spacing of 1.25 nm typical of the sodium montmorillonite form and the presence of a peak relative to an interlayer distance of 1.73 nm typical of the intercalation of poly(ethylene glycol) that is the polymer present in the hydrophilic ointment.38,39 Ointment containing MONT-PRO showed, as observed in the gel (Figure 4d), a shoulder corresponding to the MONT-PRO intercalation compound, meaning that PRO could be still intercalated and that probably only a partial exfoliation of montmorillonite occurred. Results of PRO release from the ointments are reported in Figure 5B. As observed for the gels, PRO was released faster from the ointment containing free PRO salt than from others. The slowest release was observed for the ointment containing
Figure 4. XRPD of (a) crystalline MONT-Na, (b) MONT-PRO, (c) MONT-Na gel, (d) MONT-PRO gel, and (e) neat gel.
compared to those of the neat gel and the gel containing MONT-Na. The latter showed the lack of the basal spacing of 1.25 nm typical of the MONT-Na form, and this was a proof that with just manual dispersion of the MONT-Na in the gel with a pestle and mortar, the inorganic platelets moved away from each other. In the case of gel containing MONT-PRO, the peak relative to the interlayer distance of 2.29 nm was not easily identified because it appeared as a large shoulder. Thus, the 14615
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Figure 5. In vitro release profiles of (A) PRO in phosphate buffer from gel containing (a) PRO salt, (b) MONT-PRO, and (c) the PRO salt/ MONT-Na physical mixture and of (B) ointment containing (a) PRO salt, (b) MONT-PRO, and (c) the PRO/MONT-Na physical mixture.
previously observed. Table 1 shows the fitting of PRO release from MONT-PRO ointment based on Higuchi and Baskar kinetics. As observed for the MONT-PRO gel, both models had good correlation coefficients, meaning that also in this case diffusion was the main mechanism responsible for drug release. 3.3. Photophysical Studies and Investigation of Drug Photostability. PRO is a well-known photolabile compound. The photoproduct analysis indicated that the photodegradation mechanism strongly depends on the media and the presence of oxygen.13,40,41 In aqueous solutions, the photoinduced degradation of the drug was spectrophotometrically monitored (Figure 7). Upon PRO irradiation in water at 300 nm under
Table 1. Kinetics Parameters model kinetics Higuchi Bhaskar
gel in phosphate buffer
ointment in phosphate buffer
equation (r2) y = 0.478x − 1.089 0.9971 y = 0.0008x − 0.00008 0.9977
equation (r2) y = 1.0731x + 7.3182 0.9902 y = 0.0018x + 0.0087 0.9989
Figure 7. Absorption spectra of PRO in water at different irradiation times (0−60 min, λexc = 300 nm) under air-equilibrated conditions.
Figure 6. XRPD of (a) MONT-Na, (b) MONT-PRO, (c) physical mixture PRO salt/MONT-Na ointment, (d) MONT-Na ointment, (e) MONT-PRO ointment, and (f) neat ointment.
aerobic conditions, remarkable spectral modifications were observed that were attributed to the efficient photodegradation processes on the basis of literature data.40,42 In particular, the structureless spectrum centered at 300 nm with increasing radiation dose progressively intensified and shifted to longer wavelengths, developing a maximum at 380 nm and a clear shoulder at 350 nm. Under anaerobic conditions, the spectral modifications were reduced although still present. In powder form, PRO presented a broad and structurless spectrum in the 200−400 nm region; the broadening of the spectrum can likely be attributed to the molecular packing of
MONT-PRO, and this was in agreement with what was expected because the drug release was due to the diffusion of ions across the ointment matrix, the exchange of these with the intercalated PRO, and finally the drug diffusion across the ointment toward the release medium. The slow drug release observed in the case of the ointment containing the physical mixture was probably due to the presence of the charged layers of montmorillonite, which can be obstacles to the diffusion of ions and to the increase in the formulation viscosity, as 14616
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Figure 8. Absorption spectra of PRO (A) and MONT-PRO (B) solid samples at different irradiation times (λexc = 350 nm) together with the kinetic analysis of PRO (△) and MONT-PRO (☆) of the data (C).
Figure 9. Transient absorption spectra of PRO in water (left, recorded 0.1, 0.7, 2.0, 4.5, 6.0 μs after the laser pulse) and MONT-PRO (right, recorded 1.0 μs after the laser pulse) (λexc = 355 nm).
triplet state of phenothiazine derivatives is able to sensitize singlet oxygen efficiently.10 The photophysical behavior of PRO was investigated though nanosecond-laser flash photolysis experiments. The time-resolved absorption spectra shown in Figure 9 were obtained upon photolysis of air-equilibrated aqueous solutions of PRO. The spectral shape and the kinetic analysis of the signal indicated that three transient species were generated by the laser excitation. The spectral and kinetic properties of the transients detected in water are shown in Table 2, together with the formation quantum efficiency and the yield of singlet oxygen sensitization. On the basis of literature data, the transients were assigned to the lowest triplet state (λmax = 450 nm), the radical cation (λmax = 520 nm), and the solvated electron (λmax = 710 nm), with the latter two formed through the photoionization of the drug, as already observed for similar systems.43 It has to be noted that the radical cation species was formed with remarkable efficiency (0.17) when the drug was free in water. Furthermore, the decay kinetics of the triplet state was strongly affected by the presence of oxygen through a diffusion control process. Indeed, singlet
the chromophore. Upon irradiation at 350 nm, clear spectral modifications were observed for PRO already in early irradiation stages (low radiation dose) and reached almost a 90% decrease after 120 min of irradiation. In particular, the spectra recorded at increasing irradiation times (Figure 8A) showed an absorbance reduction in the 200−350 nm range and an increase in the 350−500 nm region. The absorption spectrum of MONT-PRO showed three maxima in the 200− 400 nm range (220, 270, and 320 nm); the spectral structure observed for MONT-PRO was likely due to the interactions between the chromophore and the matrix, which alter the packing of the chromophore compared to that of the neat solid samples, as previously observed for other drugs.4 Despite the photoinduced degradation, phenothiazine derivatives exhibit phototoxic activity, which has been attributed to the intermediate species formed upon photoexcitation of the drug. For example, it has been demonstrated that phenothiazines induce DNA photocleavage though an electron-transfer process from the drug radical cation to the bases of the biopolymer and specifically to guanine units. Furthermore, the 14617
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ointment. In Figure 10, the relative changes in the absorption intensities as a function of irradiation time are reported for
Table 2. Spectral and Kinetic Parameters of Transient Data Together with Their Formation Quantum Yield and Singlet Oxygen Formation Efficiency samples PRO/H2O
MONT-PRO
λobs (nm)
T (μs)
ϕ
ϕΔ
450 520 710 460 520 710
0.6 t1/2 = 3.0
