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Contents lists available at ScienceDirect

European Journal of Pharmaceutical Sciences journal homepage: www.elsevier.com/locate/ejps 5 6

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Solubility and modeling acid–base properties of adrenaline in NaCl aqueous solutions at different ionic strengths and temperatures

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Clemente Bretti, Rosalia Maria Cigala, Francesco Crea ⇑, Concetta De Stefano, Giuseppina Vianelli

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Dipartimento di Scienze Chimiche, Università di Messina, viale Ferdinando Stagno d’Alcontres, 31, I-98166 Messina (Vill. S. Agata), Italy

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9 10 1 2 2 5 13 14 15 16 17 18 19 20 21 22 23 24

a r t i c l e

i n f o

Article history: Received 9 April 2015 Received in revised form 22 June 2015 Accepted 26 June 2015 Available online xxxx Keywords: Adrenaline Acid–base properties Total and intrinsic solubility SIT parameters Activity coefficients

a b s t r a c t Solubility and acid–base properties of adrenaline were studied in NaCl aqueous solutions at different ionic strengths (0 < I/mol L1 < 3.0) and temperatures (T = 298.15 and 310.15 K), by means of different techniques: potentiometry, UV-spectrophotometry and spectrofluorimetry. The intrinsic solubility of the ligand was calculated from simple mass balance equations, by using the free hydrogen concentration and the protonation constants of the ligand determined in the same experimental conditions of the solubility measurements. The salting-In or Out parameters and the activity coefficient of the neutral species were calculated by means of the Setschenow equation. The dependence of the protonation constants on the ionic strength was modeled by means of the Debye–Hückel type equation and of the SIT (Specific ion Interaction Theory) approach. The specific interaction parameters of the ion pairs were also reported. For the protonation constants, the following thermodynamic values at infinite dilution were obtained: T = 298.15 K, log KH0 1 = 10.674 ± 0.018 and H0 H0 log KH0 2 = 8.954 ± 0.022; T = 310.15 K, log K1 = 10.355 ± 0.018 and log K2 = 8.749 ± 0.030. Ó 2015 Published by Elsevier B.V.

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1. Introduction

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Adrenaline (4-[1-hydroxy-2-(methylamino)ethyl]benzene-1,2 diol, also known as epinephrine), is a catecholamine synthesized in the adrenal gland by an enzymatic process that converts tyrosine into a series of intermediates and ultimately adrenaline. Adrenaline is an important hormone and neurotransmitter, that acts on nearly all body tissues and increases heart rate, the force of heart contractions, facilitates blood flow to the muscles and the brain. Adrenaline relaxes smooth muscle and helps the conversion of glycogen to glucose in liver, increasing the blood sugar level; it also causes acceleration of breathing and is used in medicine in the treatments of the cardiac arrest, asthma and glaucoma. Adrenaline released in response to stress, enhances memory in a variety of tasks and the human memory (Cahill and Alkire, 2003); moreover it interacts with the level of arousal at the time of memory encoding (Flint et al., 2007) and has resulted in improvement of low arousing object recognition in rats (Jurado-Berbel et al., 2010). The knowledge of the thermodynamic aqueous properties of this molecule is a very important task for pharmaceutical product design, because they affect the drug efficacy, its future

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⇑ Corresponding author.

development and formulation efforts and also influence the pharmacokinetics, such as the release, transport and the degree of absorption in the organism. The literature reports some papers (Antikainen and Witikainen, 1973; Aydin, 2007; Bonhomme et al., 1990; Campuzano et al., 1975; Gao et al., 1999; Grgas-Kuznar et al., 1974; Martell and Smith, 1997; Pettit and Powell, 1997) where the thermodynamic properties in aqueous solution of adrenaline were investigated. As already reported in a previous paper (Bretti et al., 2013), the behavior of catecholamines in aqueous solution depends on many parameters, such as pH, temperature, ionic medium, ionic strength and on the exposure to the light and to the oxygen, since they tend to oxidize quickly (Adeniyi and Wright, 2009; Bonhomme et al., 1990; Campuzano et al., 1975; Grant et al., 1994; Grunert and Wollmann, 1982; Nagy and Takacs-Novak, 2004; Szulczewski et al., 1978). Even if the literature reports some interesting data on the chemistry of adrenaline, the lack of information on its aqueous properties, such as solubility, is evident (Florey, 1978; Freier, 1976; Yalkowsky et al., 2010). For this reason, we decided to investigate the acid–base properties and the solubility (total and intrinsic solubility) in NaCl aqueous solutions in a quite high range of experimental conditions in order to calculate by means of the Long and McDevit equation (Long and McDevit, 1952), the Setschenow parameter (Setschenow, 1889) and the activity coefficients of the ligand neutral species. The investigations were carried

E-mail address: [email protected] (F. Crea). http://dx.doi.org/10.1016/j.ejps.2015.06.025 0928-0987/Ó 2015 Published by Elsevier B.V.

Please cite this article in press as: Bretti, C., et al. Solubility and modeling acid–base properties of adrenaline in NaCl aqueous solutions at different ionic strengths and temperatures. Eur. J. Pharm. Sci. (2015), http://dx.doi.org/10.1016/j.ejps.2015.06.025

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out by means of different instrumental techniques (ISE-[H+] potentiometry, UV-spectrophotometry and spectrofluorimetry) at ionic strength values ranging from 0 to 3.0 I/mol L1 at T = 298.15 and 310.15 K. The dependence of the protonation constants on the ionic strength was studied by means of the Debye–Hückel type equation (Bretti et al., 2008c; Crea et al., 2004a,b) and SIT (Specific ion Interaction Theory) (Brønsted, 1922; Ciavatta, 1980; Guggenheim and Turgeon, 1955; Scatchard, 1936) approach that gave us the possibility to calculate the specific interaction coefficients. The protonation constants at different temperatures allowed us to estimate rough enthalpy change values for each ligand protonation step. The information obtained from the speciation studies can be useful to model the behavior of such molecules in quite different experimental conditions simulating the natural or biological fluids.

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2. Material and methods

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2.1. Chemical

106

Adrenaline was purchased from Fluka and the solutions were prepared by weighing the ligand without further purification. The purity was checked potentiometrically by alkalimetric titrations and resulted to be >99%. Sodium chloride aqueous solutions were prepared by weighing pure salt (Fluka, p.a.) previously dried in an oven at T = 383.15 K for 2 h. Sodium hydroxide and hydrochloric acid solutions were prepared from concentrated ampoules (Fluka puriss. electrochemical grade) and standardized against potassium biphthalate and sodium carbonate, respectively. All solutions were preserved from atmospheric CO2 by means of soda lime traps. Grade A glassware and twice distilled water were employed in the preparation of all the solutions.

107 108 109 110 111 112 113 114 115 116 117

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2.2. Apparatus

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2.2.1. Potentiometric apparatus The acid–base properties and solubility of adrenaline were studied potentiometrically by means of an apparatus consisting of a 809 model Metrohm Titrando system from Metrohm connected to a half cell glass 8101 model Ross Orion electrode, coupled with a standard calomel electrode. The system was connected to a personal computer and the automatic titrations were performed through Metrohm TiAMO 1.2 computer program. The system allows to control the titrant delivery and to record the e.m.f. of the solution under investigation when the equilibrium state was reached after the addition of aliquots of the titrant. Estimated accuracy was ±0.15 mV and ±0.003 mL for e.m.f and titrant volume readings, respectively. The measurements were carried out in termostatted cells at T = 298.15 and 310.15 ± 0.1 K by means of water circulation in the outer chamber of the titration cell from a thermocryostat (model D1-G Haake) and maintained under magnetic stirring. Purified N2(g) was bubbled into the solutions in order to exclude the presence of CO2(g) and O2(g). In the case of the determination of the protonation constants, the solutions under investigation contained different amounts of adrenaline and background salt to reach the pre-establish ionic strength values. For each experiment, independent titrations of strong acid (HCl) solutions with carbonate free NaOH solutions were carried out under the same experimental conditions of the systems investigated, with the aim to determine the electrode potential (E0) and the acidic junction potential (Ej = ja [H+]). In this way, the pH scale used was the free concentration scale, pH  log10[H+], where [H+] is the free proton concentration (not activity). The reliability of the

120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146

calibration in the alkaline range was checked by calculating the ionic product of water (pKw).

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2.2.2. Spectrophotometric apparatus The spectrophotometric measurements, carried out at T = 298.15 ± 0.1 and 310.15 ± 0.1 K, were performed by a Varian Cary 50 UV–VIS spectrophotometer equipped with an optic fiber probe with a fixed 1 cm path length. The wavelength range from k = 200–450 nm was investigated. The spectrophotometer was connected to a PC and the Varian Cary WinUV (3.00 version) software was used for the data acquisition, absorbance (A) vs. wavelength (k/nm). During these measurements, a 602 Biotrode combined metro-sensor glass electrode (from Metrohm) was inserted in the thermostatted measurement cell (total volume of 25 or 50 mL). The electrode was connected to a 713 model Metrohm potentiometer and the addition of titrant was carried out by a 665 model Metrohm automatic burette. This shrewdness allowed us to record simultaneously the couple of data absorbance (A) vs. wavelength (knnm) from the spectrophotometric apparatus, and the couple e.m.f. (mV) vs. volume of titrant (mL), from the potentiometric apparatus. The solutions under investigation contained different amounts of adrenaline and background salt to reach the pre-establish ionic strength values. The homogeneity of the solution during the titration was performed with a magnetic stirring bar and, before each experiment, N2(g) was bubbled in the solution for at least 5 min in order to exclude the presence of CO2(g) and O2(g).

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2.2.3. Spectrofluorimetric apparatus The spectrofluorimetric apparatus consists of a FluoroMax-4 spectrofluorometer by Horiba Jobin–Yvon equipped with an F-3006 Autotitration Injector with two Hamilton Syringes (mods. Gastight 1725 and 1001 TLLX, 250 lL and 1 mL capacity, respectively). The resolutions of wavelength selectors and titrant additions were 0.3 nm and 0.25 lL, respectively. In order to perform measurements at controlled temperature, the instrument was also equipped with a Peltier Sample Cooler (mod. F-3004) controlled by a Peltier Thermoelectric Temperature Controller model LFI-3751 (5 A – 40 W). The titrations were conducted directly in a Hellma type 101-OS precision cell (Light Path 10 mm), into which a magnetic stirrer, the ISE-H+ microelectrode (6.0224.100 model biotrode purchased from Metrohm) and the anti-diffusion burette tip were inserted. The burette tip and the ISE-H+ electrode were placed in a position that would not interfere with the light beam. The automatic data acquisition (fluorescence intensity vs. wavelength (k/nm) for each titrant addition) was performed using the FluorEssence 2.1 software by Horiba Jobin–Yvon. All the experimental conditions were determined through preliminary evaluations in which several parameters, such as equilibration time, scan rate, scan range and integration time, wavelengths of excitation and of emission, were systematically varied to select the values giving the best signal/noise ratio. In the case of adrenaline the wavelengths of excitation is 284 nm and the range of emission investigated is 300–400 nm. The solutions under investigation contained different amounts of adrenaline and background salt to reach the pre-establish ionic strength values, as already reported for the UV–Vis. spectrophotometric measurements.

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2.3. Calculations

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The BSTAC computer program was used for the refinement of all the parameters (protonation constants, analytical concentration of reagents, formal electrode potential) of the alkalimetric titrations. The least squares computer program LIANA that refines the parameters of a generic y = f(x) linear or non-linear equation was

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150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172

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The parameters k(c,m)0 and k(c,m)1 are valid for mNaCl ? 0 and mNaCl ? 1, respectively, both for the molar (c) and the molal (m) concentration scales. This equation was applied with success to many different classes of ligands in several previous papers (Bretti et al., 2008a,b, 2012c; Cataldo et al., 2009; Cigala et al., 2012, 2010), resulting in many cases in a significant improvement of the fit of the experimental data.

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2.4.2. Procedures Saturated solutions of adrenaline were prepared by addition of an excess of ligand to pure water or to solutions containing NaCl as supporting electrolytes at a pre-established concentration. These solutions prepared in proper flasks (purified N2 was bubbled for the whole time), were stirred for at least 24 h in a thermostated room maintained in obscurity, at T = 298.15 ± 1.0 and 310.15 ± 1.0 K. The saturated solutions were then centrifuged and filtered through a cellulose membrane filter (Ø = 0.45 m). 25 ml of the filtered solution was titrated with standard NaOH by using the potentiometric apparatus already described, in order to calculate the total hydrogen and ligand concentration. To avoid systematic errors, independent experiments were performed at least three times.

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3. Results and discussion

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3.1. Solubility

294 295

where only two functional groups were taken into account. The first one is a phenolic group and the second the secondary –NH+2 group. The other phenolic groups in the molecules were neglected since as reported in the literature (Aydin, 2007; Pettit and Powell, 1997), they are very weak acids with pKa value higher than 13. According to Long and McDevit (1952), it is possible to model the variation of the neutral species solubility (S0) respect to the salt concentration by means of the Eq. (2), where km is the Setschenow parameter (Setschenow, 1889) and c and c0 are the activity coefficients of the neutral species expressed in the molal concentration

As previously reported in other sections, the solubility of adrenaline was investigated at two temperatures, T = 298.15 K and T = 310.15 K, in NaCl aqueous solutions and at different ionic strengths (T = 298.15 K 0 < I/mol L1 < 3.0 and T = 310.15 K 0 < I/mol L1 < 1.0). The total and intrinsic or neutral species solubility in the studied experimental conditions are reported in Table 1, together with the pH of the saturated solutions. In the same table, both the total and intrinsic solubility are also expressed as molar fraction of the ligand. At T = 310.15 K, the solubility is systematically higher than the corresponding value at T = 298.15 K. The pH of the saturated solutions determined both by means of the BSTAC computer program and measured experimentally with an ISE-[H+] electrode resulted to be inclusive between 9.3 and 9.9, in dependence on the temperature and ionic strength investigated. These pH values are consistent with the acid–base properties of the molecule and with the solubility (Abraham and Le, 1999).

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scale in the saline solution and pure water, respectively; S00 is the solubility of the neutral species in pure water:

3.2. Protonation constants

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256

c S0 log ¼ log 00 ¼ km  mNaCl c0 S

During our investigations, adrenaline was considered as a simple bi-dentate ligand. In the literature it is possible to find some studies (Aydin, 2007; Martell et al., 2004) where a third protonation constant, with a pKa 13 associated to the second phenolic group was reported and a value of pKa 13.5–14 was attributed to the hydroxyl group of the alkyl chain. In our investigation, this protonation constant was neglected owing to the fact that the alkalimetric titrations were performed up to pH 10.5, since at higher pH values the oxidation of adrenaline may occurs (Bonhomme et al., 1990; Szulczewski et al., 1978). The protonation constants were determined by means of different analytical techniques, namely, potentiometry, spectrophotometry and spectrofluorimetry. Spectrophotometric and spectrofluorimetric measurements were carried out at T = 298.15 K and 310.15 K in NaCl aqueous solutions at different ionic strength values (0.01 < I/mol L1 < 3.0). The protonation constants were determined by means of potentiometric titrations

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209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238

239

used to fit the Debye–Hückel, SIT and Setschenow parameters. Details for the BSTAC and LIANA computer programs are described in reference (De Stefano et al., 1997). UV and spectrofluorimetric spectra were analyzed by the Hyperquad 2008 (Gans et al., 1996) computer program, which allows the calculation of the stability constants and the molar absorbance/emission spectrum of each absorbing/emitting species, by using experimental absorbances/fluorescence intensity, analytical concentration of reagents and the proposed chemical model as input. The advantage of this program is that for aqueous solutions containing few components, it allows to treat simultaneously the potentiometric and spectrophotometric data. The ES4ECI program (De Stefano et al., 1997) is useful for the calculation of the formation percentages of the species present in solution at the equilibrium; the program allows by means of the stability constants and of the analytical concentration of the components, to draw the speciation diagrams in different conditions. Along the manuscript, if not differently reported, the errors associated to the solubility and protonation constant values are expressed as 95% confidence interval (C.I.).

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2.4. Solubility measurements and activity coefficient of the neutral species 2.4.1. Theory In our previous works we already described the theoretical aspect of the total and intrinsic solubility of different classes of organic ligands (Battaglia et al., 2008; Bretti et al., 2008a, 2013, 2012a,c, 2005, 2006a; Cataldo et al., 2009; Cigala et al., 2012, 2010; Crea et al., 2012). Dealing with a ligand containing different functional groups, such as adrenaline, the following equation can be used: T

0

S ¼S 241 242 243 244 245 246 247 248 249 250 251 252

254

257 258 259 260 261 262 263 264 265 266 267 268

269 271

1þ

1 K H1 ½Hþ 

! þ

K H2 ½Hþ 

ð1Þ

ð2Þ

This assumption is valid when the total solubility is low (S < 0.05 mol L1) and in the absence of self-interactions; this model can be also applied for the molar concentration scale. Long and McDevit observed that for apolar organic compounds, the solubility tends to vary linearly with respect to the salt concentration, whilst in many cases, for acid–base non-electrolytes, this variation is not linear (Battaglia et al., 2008; Bretti et al., 2008a, 2012a,c, 2005, 2006a; Cataldo et al., 2009; Cigala et al., 2012, 2010; Crea et al., 2012) and a significant deviation from the ideal behavior was obtained. In these cases, a modified version of the Long and McDevit equation was applied, where the Setschenow parameter is in turn dependent on the salt concentration (c,m)NaCl,:

kðc;mÞ ¼ kðc;mÞ1 þ

kðc;mÞ0  kðc;mÞ1 ðc; mÞNaCl þ 1

ð3Þ

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280 281 282 283 284 285 286 287 288 289 290 291 292

296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312

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Table 1 Total and intrinsic solubility of adrenaline in NaCl aqueous solution at different ionic strengths and temperatures. I/mol L1

log ST

T = 298.15 K 0 2.265 ± 0.058b 0 2.302 ± 0.058 0 2.267 ± 0.058 0.177 1.959 ± 0.052 0.177 1.921 ± 0.052 0.594 1.938 ± 0.044 0.594 1.985 ± 0.044 0.594 1.973 ± 0.044 1.384 1.886 ± 0.048 1.384 1.893 ± 0.048 1.916 1.871 ± 0.060 1.916 1.874 ± 0.060 2.894 1.915 ± 0.096 2.894 1.909 ± 0.096 a b

332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352

log S0

v aa

pH Exp.

pH Calc.

0.978 0.898 0.973 1.972 2.152 2.054 1.843 1.895 2.283 2.247 2.341 2.325 2.081 2.109

2.371 ± 0.028 2.408 ± 0.039 2.373 ± 0.068 2.127 ± 0.044 2.085 ± 0.065 2.084 ± 0.047 2.139 ± 0.044 2.123 ± 0.051 2.035 ± 0.038 2.052 ± 0.073 2.023 ± 0.096 2.030 ± 0.047 2.052 ± 0.096 2.065 ± 0.096

0.766 0.704 0.763 1.450 1.582 1.470 1.328 1.365 1.642 1.615 1.699 1.687 1.543 1.564

9.76

9.78 9.79 9.79 9.39 9.42 9.46 9.46 9.52 9.58 9.63 9.64 9.66 9.66 9.74

9.50 9.35

9.54 9.67 9.89

I/mol L1

log ST

vaa

log S0

v aa

pH Exp.

pH Calc.

T = 310.15 K 0 0 0 0.049 0.049 0.049 0.155 0.498 0.498 0.498 0.749 0.749 0.749 1.032

2.188 ± 0.024 2.178 ± 0.024 2.208 ± 0.024 2.120 ± 0.024 2.065 ± 0.024 2.030 ± 0.024 2.098 ± 0.020 1.899 ± 0.020 1.901 ± 0.020 1.890 ± 0.020 2.018 ± 0.028 2.034 ± 0.028 1.989 ± 0.028 1.903 ± 0.040

1.168 1.195 1.115 1.364 1.548 1.678 1.432 2.251 2.240 2.298 1.704 1.642 1.821 2.209

2.307 ± 0.033 2.297 ± 0.043 2.327 ± 0.060 2.292 ± 0.021 2.229 ± 0.055 2.135 ± 0.026 2.236 ± 0.024 2.051 ± 0.060 2.052 ± 0.032 2.041 ± 0.072 2.169 ± 0.011 2.190 ± 0.072 2.129 ± 0.026 2.082 ± 0.044

0.888 0.908 0.848 0.980 1.112 1.206 1.001 1.684 1.494 1.532 1.110 1.072 1.189 1.413

9.51

9.54 9.54 9.54 8.90 8.92 9.15 9.38 9.27 9.34 9.33 9.39 9.19 9.45 9.16

9.03

9.38 9.32

9.30

9.17

Molar fraction * 10,000. 95% C.I.

(2 < cL/mmol L1 < 10) of solutions obtained from solubility measurements or from fresh solutions obtained dissolving a known amounts of adrenaline in NaCl aqueous solutions at different ionic strengths (an aliquot of HCl was added to start measurements at low pH values). Successively, other investigations were made by UV–Vis spectrophotometric titrations at lower ligand concentrations (0.06 < cL/mmol L1 < 0.12), and by spectrofluorimetric titrations (0.06 < cL/mmol L1 < 0.10), but in this case only at T = 310.15 K. In Fig. 1, a spectrophotometric titration diagram at different pHs is reported, where it is possible to observe a shift of the absorption band at higher wavelength values when pH increases and with a significant increase of the absorbance. From the data collected by means of the different techniques, it was possible to calculate the protonation constants in the experimental conditions studied, as reported in Tables 2 and 3, at T = 298.15 and 310.15 K, respectively, where the first protonation step refers to the protonation of the secondary amine group and the second one to the protonation of the phenolic group of the aromatic ring (Antikainen and Witikainen, 1973; Nagy and Takacs-Novak, 2004; Szulczewski et al., 1978). These data were then processed altogether by means of the LIANA computer program in order to model the dependence of

Table 2 Experimental protonation constants of the adrenaline in NaCl aqueous solutions at different ionic strengths and at T = 298.15 K (molar concentration scale).

a b c

0.8 5

0.6

Absorbance

331

vaa

4

0.4 3

0.2 1

0.0

250

2

300

350

400

450

λ /nm 1

Fig. 1. Spectrophotometric titration profile of adrenaline (cL = 0.11 mmol L ) in NaCl aqueous solution at I = 0.15 mol L1 and T = 298.15 K at different pH values. 1. pH = 3.5; 2. pH = 7.6; 3. pH = 8.5; 4. pH = 9.5; 5. pH = 10.6.

I/mol L1

log KH 1

log KH 2

0.055b 0.110b 0.163b 0.177c 0.177c 0.252c 0.493c 0.508b 0.594c 0.594c 0.594c 0.764c 0.990c 0.999b 1.384c 1.384c 1.916c 1.916c 2.894c 2.894c

10.344 ± 0.050a 10.466 ± 0.010 10.215 ± 0.046 10.019 ± 0.010 10.058 ± 0.040 10.079 ± 0.016 10.255 ± 0.044 10.115 ± 0.036 10.161 ± 0.030 10.131 ± 0.060 10.207 ± 0.060 10.128 ± 0.024 10.202 ± 0.018 10.522 ± 0.008 10.277 ± 0.060 10.294 ± 0.080 10.330 ± 0.120 10.330 ± 0.100 10.395 ± 0.020 10.410 ± 0.100

8.683 ± 0.0014a 8.632 ± 0.016 8.613 ± 0.016 8.763 ± 0.100 8.780 ± 0.040 8.715 ± 0.018 8.746 ± 0.052 9.250 ± 0.030 8.763 ± 0.040 8.787 ± 0.060 8.836 ± 0.020 8.810 ± 0.028 8.847 ± 0.020 8.673 ± 0.016 8.898 ± 0.080 8.982 ± 0.080 8.970 ± 0.120 9.000 ± 0.100 8.928 ± 0.080 9.080 ± 0.100

95% C.I. From spectrophotometric measurements. From potentiometric measurements.

the protonation constants on the ionic strength, using a Debye–Hückel type equation. This procedure allowed us to obtain the calculated protonation constants, both at T = 298.15 K and T = 310.15 K, and at the desired ionic strength values. The calculated protonation constants, in the molal concentration scale, are reported in the Table 4 for the two temperatures considered. The conversion of the ionic strength and of the protonation constants from the molar concentration scale to the molal one was made by using procedures already reported in previous papers (Bretti et al., 2012a; Crea et al., 2006). The equation used is: c/m = d0 + a1c + a2c2, where d0 is the density (g cm3) of pure water and a1 and a2 are empirical parameters; as an example at T = 298.15 K and in NaCl, a1 = 0.017765 and a2 = 6.525  104. The density of water at the two temperatures was taken from literature (Harned and Owen, 1964). The calculated protonation constants expressed in the molar concentration scale are reported in Tables 1S and 2S of the Supplementary Information. The log KHi values reported in the Table 4 for the molal concentration scale (but this is also valid for the data reported in the

Please cite this article in press as: Bretti, C., et al. Solubility and modeling acid–base properties of adrenaline in NaCl aqueous solutions at different ionic strengths and temperatures. Eur. J. Pharm. Sci. (2015), http://dx.doi.org/10.1016/j.ejps.2015.06.025

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C. Bretti et al. / European Journal of Pharmaceutical Sciences xxx (2015) xxx–xxx Table 3 Experimental protonation constants of adrenaline in NaCl aqueous solutions at different ionic strengths and at T = 310.15 K (molar concentration scale).

a b c d

373 374 375 376 377 378

I/mol L1

log KH 1

log KH 2

0.049b 0.049b 0.099c 0.149c 0.150d 0.498b 0.498b 0.498b 0.500d 0.500d 0.745c 0.749b 0.749b 0.749b 0.993c 1.000d 1.000d 1.032b 2.000d 2.000d 3.000d 3.000d 3.000d

9.513 ± 0.088a 9.563 ± 0.140 10.015 ± 0.018 9.990 ± 0.012 10.113 ± 0.016 9.953 ± 0.012 10.022 ± 0.044 10.011 ± 0.038 9.764 ± 0.010 9.744 ± 0.008 9.395 ± 0.008 10.079 ± 0.048 9.862 ± 0.034 10.179 ± 0.030 9.077 ± 0.020 9.790 ± 0.208 9.780 ± 0.212 9.759 ± 0.018 9.677 ± 0.020 9.680 ± 0.016 9.689 ± 0.016 9.968 ± 0.012 9.972 ± 0.012

8.284 ± 0.110a 8.282 ± 0.196 8.285 ± 0.014 8.520 ± 0.008 8.656 ± 0.054 8.599 ± 0.014 8.656 ± 0.054 8.646 ± 0.046 8.519 ± 0.034 8.427 ± 0.020 8.580 ± 0.006 8.713 ± 0.060 8.530 ± 0.042 8.738 ± 0.036 8.727 ± 0.006 8.416 ± 0.260 8.403 ± 0.270 8.574 ± 0.022 9.239 ± 0.024 9.166 ± 0.020 9.138 ± 0.024 9.239 ± 0.020 9.187 ± 0.022

95% C.I. From potentiometric data. From spectrofluorimetric/ISE H+ data. From UV–Vis spectrophotometric/ISE H+.

Tables 1S and 2S) refer to the protonation constants obtained processing separately the data collected from each technique (columns 1–6). It is possible to observe in some cases at T = 310.15 K, a significant differences in the values of the log KHi, especially for the log KH 1 , whilst for the data at T = 298.15 K, a better agreement between the different sets of data was observed.

By analysing altogether the different sets of data, the log KHi reported in the columns 7–8 of Table 4, were obtained. Independently of the ionic strength value and of the temperature, low errors associated to the protonation constants are observed. The absence of similar data in the literature, gives us the possibility to consider this log KHi as suggested values. By using the spectrophotometric measurements, the molar absorptivity (e/mol1 L cm1) of each species was calculated by means of deconvolution procedures of the experimental data. As an example Fig. 2 reports the corresponding values at I = 0.15 mol L1 and T = 298.15 K, over the whole wavelength range investigated. The distribution of the adrenaline species as a function of the temperatures (T = 298.15 and 310.15 K), at a given ionic strength value (I = 0.15 mol L1), was determined by means of the ES4ECI program, as reported in Fig. 3. Taking into account the same species, it is possible to observe that increasing the temperature, the molar fraction of the species is shifted at lower pH values, as a clear dependence of the protonation constants on the temperature (see Scheme 1). By using similar procedures, the dependence of the protonation constants on the ionic strength was also investigated; Fig. 4 reports the distribution of the species at I = 0.15, 0.50 and 1.0 mol L1, and at T = 310.15 K. The dependence of the protonation constants on the ionic strength can be explained, as already reported in many works, namely in terms of weak ion pairs formation, between the charged ligand species and the ions of the supporting electrolytes (Bretti et al., 2012a; Daniele et al., 2008).

379

3.3. Setschenow and activity coefficients

407

By following the usual procedures already reported in several papers (Battaglia et al., 2008; Bretti et al., 2008a, 2013, 2012b, 2012c, 2005, 2006a; Crea et al., 2012), the Setschenow coefficients were calculated both in the molar and the molal concentration

408

Table 4 Calculated protonation constants of adrenaline in NaCl aqueous solutions at different ionic strengths and at T = 298.15 and 310.15 K, using different analytical techniques (molal concentration scale). I/mol kg1 T = 310.15 K 0 0.05 0.10 0.15 0.25 0.50 0.75 1.00 1.50 2.00 3.00 T = 298.15 K 0 0.05 0.10 0.15 0.25 0.50 0.75 1.00 1.50 2.00 3.00 a b c d e

a log KH 1

a log KH 2

10.232 ± 0.016e 9.933 ± 0.014 9.881 ± 0.014 9.862 ± 0.014 9.875 ± 0.018 9.964 ± 0.032 10.112 ± 0.048 10.281 ± 0.064

8.737 ± 0.020 8.592 ± 0.018 8.569 ± 0.016 8.562 ± 0.014 8.570 ± 0.012 8.635 ± 0.010 8.724 ± 0.014 8.823 ± 0.020

e

10.421 ± 0.056 10.087 ± 0.056 9.998 ± 0.054 9.943 ± 0.052 9.876 ± 0.050 9.796 ± 0.044 9.765 ± 0.038 9.755 ± 0.036 9.765 ± 0.034 9.797 ± 0.042 9.889 ± 0.070

e

8.701 ± 0.026 8.545 ± 0.050 8.512 ± 0.050 8.495 ± 0.050 8.483 ± 0.048 8.499 ± 0.042 8.538 ± 0.040 8.589 ± 0.036 8.704 ± 0.026 8.830 ± 0.020 9.097 ± 0.010

e

9.004 ± 0.022 8.843 ± 0.020 8.805 ± 0.020 8.783 ± 0.020 8.762 ± 0.018 8.754 ± 0.016 8.770 ± 0.016 8.796 ± 0.016 8.865 ± 0.024 8.943 ± 0.032 9.115 ± 0.052

e

10.704 ± 0.056 10.374 ± 0.048 10.289 ± 0.044 10.238 ± 0.040 10.177 ± 0.034 10.116 ± 0.030 10.103 ± 0.042 10.111 ± 0.064

e

8.854 ± 0.044 8.690 ± 0.040 8.650 ± 0.038 8.626 ± 0.038 8.598 ± 0.020 8.575 ± 0.030 8.577 ± 0.090 8.589 ± 0.124

e

10.682 ± 0.052 10.353 ± 0.050 10.270 ± 0.014 10.221 ± 0.016 10.164 ± 0.018 10.113 ± 0.032 10.110 ± 0.048 10.127 ± 0.066 10.194 ± 0.034 10.281 ± 0.046 10.485 ± 0.076

e

b log KH 1

b log KH 2

c log KH 1

10.516 ± 0.080 10.146 ± 0.076 10.021 ± 0.072 9.931 ± 0.066 9.791 ± 0.062 9.532 ± 0.066 9.321 ± 0.090 9.132 ± 0.124

c log KH 2

e

8.537 ± 0.138 8.395 ± 0.132 8.375 ± 0.124 8.373 ± 0.118 8.389 ± 0.102 8.478 ± 0.070 8.583 ± 0.044 8.703 ± 0.040

d log KH 1

e

d log KH 2

10.355 ± 0.018 10.022 ± 0.016 9.935 ± 0.016 9.881 ± 0.016 9.816 ± 0.014 9.742 ± 0.012 9.717 ± 0.012 9.714 ± 0.014 9.736 ± 0.020 9.780 ± 0.028 9.897 ± 0.048

e

8.749 ± 0.030 8.593 ± 0.030 8.559 ± 0.030 8.543 ± 0.028 8.530 ± 0.028 8.545 ± 0.026 8.584 ± 0.024 8.633 ± 0.024 8.747 ± 0.022 8.871 ± 0.026 9.134 ± 0.038

e

10.674 ± 0.018 10.346 ± 0.018 10.264 ± 0.016 10.215 ± 0.016 10.159 ± 0.016 10.108 ± 0.016 10.107 ± 0.018 10.126 ± 0.022 10.195 ± 0.032 10.285 ± 0.044 10.495 ± 0.068

e

8.954 ± 0.022 8.794 ± 0.022 8.757 ± 0.022 8.738 ± 0.020 8.718 ± 0.020 8.716 ± 0.018 8.738 ± 0.018 8.770 ± 0.020 8.851 ± 0.030 8.941 ± 0.040 9.137 ± 0.064

e

From potentiometric measurements. From UV spectrophotometric measurements. From spectrofluorimetric measurements. Processing altogether experimental data. 95% C.I.

Please cite this article in press as: Bretti, C., et al. Solubility and modeling acid–base properties of adrenaline in NaCl aqueous solutions at different ionic strengths and temperatures. Eur. J. Pharm. Sci. (2015), http://dx.doi.org/10.1016/j.ejps.2015.06.025

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7000

log

ε /mol -1 L cm -1

6000

LH

0

4000 3000 +

LH 2

L

-

250

300

350

400

450

λ /nm Fig. 2. Molar absorptivity coefficients of adrenaline vs. k/nm (cL = 0.11 mmol L1) in NaCl aqueous solution at I = 0.15 mol L1 and T = 298.15 K.

412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427

scales, for the two temperatures investigated. The Setschenow coefficients expressed by the one and two parameters model, Eqs. (2) and (3) respectively, are reported in Table 5. In the same table, the solubility of the neutral species at infinite dilution is also reported at T = 298.15 K and 310.15 K. Generally, the use of the two parameters model gives a significant improvement of the standard deviation on the fit and of the errors associated to the k0 and k1 values. In these cases, we can consider the two models equally valid to fit the intrinsic solubility, independent of the temperature and concentration scale used. Table 6 reports the activity coefficients of the ligand neutral species at different ionic strengths and at T = 298.15 K and 310.15 K, calculated only by means of the one parameter model (Eq. (2)). For ionic strength values higher than 0.5 mol kg1, significant differences in the values of activity coefficients were found, as shown in Fig. 5.

 0:51  z

3.4. Dependence of protonation constants on ionic strength

429

The dependence of the protonation constants on ionic strength was studied by means of different approaches, namely the Debye– Hückel type equation and SIT model. The Debye Hückel type equation (Crea et al., 2004a) used is:

432

433

1a

0.8 1b

2b

2a

439

ð5Þ

pffiffi X 0:51 I pffiffi þ log c ¼ z2 e  mi 1 þ 1:5 I

ð6Þ

where ei is the specific interaction coefficient of a generic ionic species, and the sum is extended over all the ions present in solution at the molality mi. In the case of the neutral species, the activity coefficient is given by:

log c ¼ km I

ð7Þ

where km is the Setschenow coefficient (Setschenow, 1889) that accounts for the variation of the activity coefficient of the neutral species with the saline concentration. Using the simple formulation and the molal concentration scale (mol kg1 (H2O)), the SIT approach is identical to Eq. (4):

pffiffi I

pffiffi þ De  I 1 þ 1:5 I

ð8Þ

where C  I ¼ De  I The De parameter can be expressed as a function of the ionic strength by:

ð9Þ

e0  e1

8

9

Iþ1

ð10Þ

10

pH Fig. 3. Distribution diagram of adrenaline fraction vs. pH at different temperatures. Experimental conditions: cL = 3 mmol L1, in NaCl aqueous solution at I = 0.15 mol L1. Species: 1. LH+2; 2. LH0; 3. L; a. T = 298.15 K and b. T = 310.15 K.

440 441 442

445 446 447 448 449 450 451 452 453

454 456 457 458 459 460

461 463 464 465 466 467 468

469 471 472 473 474

477 478 479 480 481

482

3a

7

438

475

De0  De1 De ¼ De1 þ Iþ1

Table 7 reports the De parameters defined by the Eqs. (8) and (9) and the protonation constants at infinite dilution in the molal concentration scale, for the two temperatures investigated. From

0.2

437

443

c0  c1 Iþ1

where c1 and c0 are the parameters for the dependence of protonation constants on ionic strength, valid for I ? 1 and I ? 0, respectively. The data obtained by different analytical techniques and analyzed by the Debye Hückel type equation, are reported in Table 3S of the Supplementary Information. According to the SIT model (Brønsted, 1922; Ciavatta, 1980; Guggenheim and Turgeon, 1955; Scatchard, 1936), the molal activity coefficient ci of an ion of charge z is given by:

e ¼ e1 þ

0.4

435

parameter that accounts for the dependence of the protonation constants on ionic strength. This parameter can be also expressed as a function of the ionic strength by means of the equation (Crea et al., 2004a):

3b

0.6

0.0

ð4Þ

where De = Rereactants  Reproducts; if the specific interactions of the ligand with the ions of the supporting electrolyte are taken into account, we can calculate the specific interaction coefficients e of the single ionic species, by means of the Eqs. (8) or (10)

1.0

eph fraction

431

pffiffi þ C  I 1 þ 1:5 I

436

log K Hi ¼ log K Hi  0:51  z

428

pffiffi I

0

0

430



where K Hi and K H0 refer to the protonation constant at a given i saline concentration and at infinite dilution, respectively, for the P 2 P ith ionic species, z ¼ zchargereact  z2chargeprod and C is an empirical

C ¼ c1 þ

1000 0

¼ log

0 K Hi

0

5000

2000

K Hi

Scheme 1. General formula of adrenaline.

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1.0

1c

1a

eph fraction

0.8

2b

1b

3c

2c

3b

2a

0.6

3a

0.4 0.2 0.0

7

8

9

10

pH Fig. 4. Distribution diagram of adrenaline fraction vs. pH at different ionic strengths (mol L1) in NaCl aqueous solution at T = 310.15 K. Experimental conditions: cL = 3 mmol L1; ionic strength: a. 0.15 mol L1; b. 0.50 mol L1; c. 1.00 mol L1. Species: 1. LH+2; 2. LH0; 3. L.

488 489 490 491 492 493 494

495 497 498 500

the comparison of the standard deviation on the fit, it can be observed that in some cases, the two parameters model gave rather worse values with respect to the one parameter model. Table 8 reports the specific interaction coefficients of the different protonated or/and unprotonated species with the ions of the supporting electrolyte (NaCl). The De values can be expressed by means of the following equations: 

De1 ¼ eðL ; Naþ Þ þ eðHþ ; Cl Þ  km 

ð11Þ



De2 ¼ km þ eðHþ ; Cl Þ  eðLHþ2 ; Cl Þ

ð12Þ +



507

For the specific interaction coefficients of H Cl , values already determined at T = 298.15 K; e(H+; Cl) = 0.21; e1(H+; Cl) = 0.136 and e0(H+; Cl) = 0.0848 were used (Bretti et al., 2006b). The corresponding values at T = 310.15 K, were calculated from the dependence of the specific interaction coefficients on temperature, as already reported in previous works on penicillin derivatives (Crea et al., 2012) and dopamine (Bretti et al., 2013).

508

4. Literature comparison

509

The literature reports some papers (Antikainen and Witikainen, 1973; Aydin, 2007; Bonhomme et al., 1990; Campuzano et al., 1975; Gao et al., 1999; Grgas-Kuznar et al., 1974; Martell and Smith, 1997; Pettit and Powell, 1997) where the stability of adrenaline in aqueous solution was investigated as a function of the light exposure, pH, temperature and in presence or absence of oxygen (Bonhomme et al., 1990; Grant et al., 1994; Grunert and

501 502 503 504 505 506

510 511 512 513 514 515

Wollmann, 1982; Nagy and Takacs-Novak, 2004; Szulczewski et al., 1978). Grunert and Wollmann (1982) performing similar studies on the degradation of adrenaline, reported that the process is catalyzed by light, air, temperature and presence of heavy metals. Adeniyi and Wright (2009) studied the effect of pH and oxygen on the oxidation of adrenaline in aqueous solution. All the results reported by these authors on this topic were taken into account during all the investigations, in order to obtain reliable protonation constant and solubility values. The information about the fluorescence properties of adrenaline are sufficient; the intensity drops slightly between pH 3 and 4. This is followed by a steady rise between pH 4 and 6. The maximum fluorescence intensity is reached at pH = 6, after which it falls rather precipitously to the minimum at pH = 10. This suggests that adrenaline reaction is optimized in acidic solutions; the presence of oxygen reduces fluorescence intensity. The temperature increases adversely affects fluorescence intensity of the adrenaline solution. It is rationalized that increasing temperature increases frequency of molecular collisions, which results in deactivation by vibrational relaxation and internal conversion. Another problem for the study of the behavior of the adrenaline in aqueous solution is bound to the knowledge of deprotonation/protonation sequence, since correct mass balance equations must be used to define correctly the thermodynamic properties of such molecule. In this order, Nagy and Takacs-Novak (2004) proposed the possible sequence of protonation/deprotonation of each ionisable group. Furthermore, in the literature, there are some studies that report the protonation constants at different ionic strength values, in different ionic media and temperatures. Table 9 reports some literature data of adrenaline; it is possible to observe that the third protonation constant is only reported in some cases, from spectrophotometric technique, and generally the log KH 3 values reported by the different authors differ of more than one log unit. No systematic study for the dependence of the protonation constants

Table 6 Activity coefficients of the neutral species at different ionic strengths and temperatures.

a

I/mol kg1

ca T = 298.15 K

T = 310.15 K

0.05 0.10 0.15 0.25 0.5 0.75 1

0.988 0.975 0.963 0.940 0.883 0.830 0.780

0.978 0.956 0.935 0.893 0.798 0.713 0.637

Calculated from Eq. (2).

Table 5 Intrinsic solubility in pure water and Setschenow parameters obtained using Eqs. (2) and (3), at different temperatures. 2-Parametersc

T/K

k(c,m)0

r

k(c,m)

rfite

log S 0 = 2.253 ± 0.019 mol L1 0.082 ± 0.017a mol kg1 0.067 ± 0.015

0.490 ± 0.062a 0.493 ± 0.059

0.075 0.075

0.105 ± 0.017a 0.108 ± 0.016

0.100 0.110

log S00 = 2.268 ± 0.006a,b mol L1 0.563 ± 0.028 mol kg1 0.543 ± 0.021

0.810 ± 0.021 0.822 ± 0.015

0.058 0.059

0.197 ± 0.031 0.217 ± 0.031

0.073 0.073

k(c,m)1 298.15

310.15

a b c d e

1-Parameterd

0

e fit

a,b

95% C.I. Molar concentration scale. Eq. (3). Eq. (2). Std. dev. on the fit of Eqs. (2) and (3).

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1.00 0.95 0.90

γN

0.85 0.80 0.75 0.70 0.65 0.60

0.2

0.4

0.6

0.8

on the ionic strength and temperature is reported, as well as, information about the solubility. Concerning the solubility of adrenaline in aqueous solutions, few available data are published by some authors; these data refer generally to pure water and T = 293.15 K. No study of the dependence of total and intrinsic solubility on the ionic strengths in NaCl aqueous solution is reported. As an example Freier et al. reports at T = 293 K a value of log ST = 3.008 (Freier, 1976; Yalkowsky et al., 2010). Taking into account the different temperatures investigated and the trend of the solubility of epinephrine with respect to the temperature variation, we can consider our values in pure water in fairly good agreement with the one reported in the literature (Florey, 1978; Freier, 1976; Yalkowsky et al., 2010).

551

5. Final remarks

565

The protonation constants, the solubility (total and intrinsic of the neutral species) and the activity coefficients of adrenaline were

566

Fig. 5. Activity coefficients of neutral species at different ionic strengths and temperatures. Legend: s T = 310.15 K and h T = 298.15 K.

Table 7 Protonation constants at infinite dilution and SIT parameters (Eqs. (8) and (9)) at different temperatures.

298.15

log KH 1 10.682 ± 0.026 10.704 ± 0.026 10.675 ± 0.009

d e

log KH 2 9.004 ± 0.011 8.854 ± 0.022 8.954 ± 0.021 310.15

a

c d e f g

0.262 ± 0.019 0.222 ± 0.022 0.267 ± 0.013

a

De 0.201 ± 0.011 0.143 ± 0.007 0.225 ± 0.013

De1

rfitb

De0 a

a

0.043 0.008 0.038

0.135 ± 0.024 1.541 ± 0.370 0.156 ± 0.020

0.517 ± 0.188 0.455 ± 0.312 0.473 ± 0.040

0.036 0.039 0.032

rfitb

De1

De0

rfitb

0.321 ± 0.037 0.253 ± 0.222 0.414 ± 0.052

0.016 0.026 0.031

0.022 0.031 0.037

0.139 ± 0.016 0.602 ± 0.278 0.128 ± 0.020

log KH 1

De

rfitb

De1

De0

rfitb

10.234 ± 0.008 c 10.418 ± 0.028 d 10.518 ± 0.041f 10.355 ± 0.012g

0.885 ± 0.035 0.168 ± 0.020 0.577 ± 0.084 0.194 ± 0.012

0.025 0.042 0.027 0.038

0.082 ± 0.286 0.224 ± 0.028 1.181 ± 0.317 0.166 ± 0.027

1.478 ± 0.186 0.020 ± 0.100 0.052 ± 0.360 0.273 ± 0.075

0.020 0.040 0.017 0.043

log KH 2

De

rfitb

De1

De0

rfitb

8.740 ± 0.009 8.694 ± 0.029 8.538 ± 0.070 8.765 ± 0.017 b

rfitb

De a,c

0.511 ± 0.018 0.329 ± 0.010 0.597 ± 0.088 0.317 ± 0.010

0.013 0.052 0.043 0.030

0.131 ± 0.143 0.420 ± 0.034 0.571 ± 0.239 0.265 ± 0.028

0.744 ± 0.137 0.083 ± 0.107 0.617 ± 0.308 0.453 ± 0.088

0.009 0.046 0.043 0.034

95% C.I. std. dev. on the fit. From potentiometric. From spectrophotometric/ISE-[H+] data. From potentiometric and spectrophotometric/ISE-[H+] data: From spectrofluorimetric/ISE-[H+] data. From potentiometric, spectrophotometric/ISE-[H+] and spectrofluorimetric/ISE-[H+] data.

Table 8 Specific interaction coefficients of adrenaline species at different temperatures. SIT parameters T/K 298.15

310.15

c

Species 

Interaction 

+

e1e

ed a

e0e a

1.217 ± 0.055a

L HL0 H2L+

e[L , Na ]

0.055 ± 0.037

0.166 ± 0.065

L HL0 H2L+

e[L, Na+]

0.309 ± 0.027

0.624 ± 0.017a

0.686 ± 0.043a

Km b e[LH+2, Cl]

0.161 ± 0.014

1.109 ± 0.023

1.007 ± 0.062

Km b e[LH+2, Cl]

553 554 555 556 557 558 559 560 561 562 563 564

1.0

I/mol kg -1

T/K

552

0.219 ± 0.014 0.008 ± 0.018

0.252 ± 0.037

Setschenow coefficients determined from solubility measurements at T = 310.15 K. a 95% C.I. b Setschenow coefficients determined from solubility measurements at T = 298.15 K. d Refers to Eq. (6). e Refer to Eq. (10).

Please cite this article in press as: Bretti, C., et al. Solubility and modeling acid–base properties of adrenaline in NaCl aqueous solutions at different ionic strengths and temperatures. Eur. J. Pharm. Sci. (2015), http://dx.doi.org/10.1016/j.ejps.2015.06.025

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C. Bretti et al. / European Journal of Pharmaceutical Sciences xxx (2015) xxx–xxx Table 9 Literature protonation constants of adrenaline. I/mol L1

T/K

log K H 1

log K H 2

log K H 3

Authors

0.1, NaNO3 0.02, Phosphate buffer

293.15 298.15 298.15 293.15 310.15

8.52 8.64 9.46 8.66 9.84 8.45

– 8.60 8.02 – 8.63 –

Grgas-Kuznar et al. (1974) Corona-Avendaño et al. (2007)

0.15, KCl 0.2, KCl 0.15, NaCl

10.04 9.67 10.28 9.96 13.13 9.76

600

determined in NaCl aqueous solutions at different ionic strengths and T = 298.15 and 310.15 K. The analysis of the experimental data allowed us to observe that at the pH range investigated, only to protonation steps are determinable; in fact the most basic protonation steps at pH > 12 were not taken into account, owing to the possible oxidation of the molecule at pH values higher than 10.5. The two log KH values determined by means of potentiometric and spectrophotometric measurements refer to the protonation of the secondary amine group of the lateral chain and to the protonation of one of the two adiacent phenolic groups (probably those in para position with respect to the aliphatic chain containing the alcoholic and amine groups). From the solubility measurements, we observed that adrenaline has a total solubility comparable to other biologically active molecules already studied, such as penicillin derivatives and DL-Tryptophan (Bretti et al., 2012c). By means of the Debye–Hückel and SIT approaches (Brønsted, 1922; Ciavatta, 1980; Crea et al., 2004a; Guggenheim and Turgeon, 1955; Scatchard, 1936) and of the Long and McDevit equation (Long and McDevit, 1952), the parameters for the dependence of the protonation constants and of the intrinsic solubility on the ionic strength were proposed for the first time. From the measurements carried out at different temperatures (T = 298.15 and 310.15 K), it is possible to propose a rough temperature gradient for the protonation steps; for the protonation of the secondary amine group, a DH value of 33 ± 5 kJ mol1 was calculated; this value can be considered in fairly good agreement with values reported in the literature (Martell and Smith, 1977; May and Murray, 2000; Pettit, 1984; Pettit and Powell, 1997). For the DH of the phenolic group, the only information that we can give, is that the lowering of the protonation constant indicates that the process is exothermic in nature.

601

Acknowledgement

602 603

Authors thank University of Messina for the partial financial support.

604

Appendix A. Supplementary data

605 606

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.ejps.2015.06.025.

607

References

608 609 610 611 612 613 614 615 616 617

Abraham, M.H., Le, J., 1999. The correlation and prediction of the solubility of compounds in water using an amended solvation energy relationship. J. Pharm. Sci. 88, 868–880. Adeniyi, W.K., Wright, A.R., 2009. Novel fluorimetric assay of trace analysis of epinephrine in human serum. Spectrochim. Acta Part A Mol. Biomol. Spectrosc. 74, 1001–1004. Antikainen, P.J., Witikainen, U., 1973. A comparative study on the ionization of catechol amines in aqueous solutions. Acta Chem. Scand. 27, 2075–2082. Aydin, R., 2007. Study on the interaction of Yttrium(III) with adrenaline, noradrenaline, and dopamine. J. Chem. Eng. Data 52, 2400–2404.

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