Spectroscopic characteristics and thermal properties of divalent metal complexes of diclofenac

www.elsevier.nl/locate/poly Polyhedron 19 (2000) 2515– 2520

Spectroscopic characteristics and thermal properties of divalent metal complexes of diclofenac R. Bucci a, A.D. Magrı` a, A.L. Magrı` a,*, A. Napoli b a b

Dipartimento di Chimica, Uni6ersita` di Roma ‘La Sapienza’, 00185 Rome, Italy Dipartimento di Scienze Ambientali, Uni6ersita` della Tuscia, 01100 Viterbo, Italy

Abstract The spectroscopic characteristics (IR and diffuse reflectance) and the thermal properties (TG, DTG and DSC) of the solid compounds obtained by the reaction of diclofenac (DH) with manganese(II), iron(II), cobalt(II), nickel(II), copper(II) and zinc(II) are reported and discussed. The complexes agreed with the empirical formula MeD2·(H2O)x and the metal ions are co-ordinated through the carboxylate group of the ligand. The furnace atmosphere (N2 or O2) greatly influences the thermal decomposition trend of the complexes, less their thermal stability. On the contrary, the initial decomposition temperature depends on the co-ordinated metal ion, especially in the case of iron(II) and copper(II) compounds, which are much less stable than other complexes. © 2000 Elsevier Science B.V. All rights reserved. Keywords: Diclofenac; Metal(II) compounds; Spectroscopic properties; Thermal properties

1. Introduction Diclofenac (DS), sodium salt of [2-[(2,6-dichlorophenyl)amino]phenyl] acetic acid, is a potent nonsteroidal anti-inflammatory agent for the treatment of rheumatoid arthritis. The pharmacological effects of this drug are thought to be related to the inhibition of the conversion of arachidonic acid to prostaglandins, which are the mediators of the inflammatory process [1 – 3]. The literature reports several methods for determination of diclofenac [4 – 19] but only few data on the complexing ability of this drug with metal ions [20 –26]. In a previous paper [27] we reported the main results of an extensive investigation on chemical, spectroscopic and thermoanalytical behaviour of DS and proposed new methods for its determination in pharmaceutical formulations. Since it is well-known that the interaction of the metal ions may influence the biological activity of drugs administered for therapeutic reasons, because many drugs act via chelation or by inhibiting the activity of metal-enzymes, in the present paper we extend the above study on the reaction of diclofenac * Corresponding author. Tel: +39-06-499-13371. E-mail address: [email protected] (A.L. Magrı`).

with the Irving and Williams series of divalent metal ions: manganese(II), iron(II), cobalt(II), nickel(II), copper(II) and zinc(II).

2. Experimental

2.1. Apparatus UV –Vis spectra were acquired with 1 cm quartz cells on a Perkin –Elmer 320 UV –Vis spectrophotometer connected to a model 3600 Data Station equipped with software packages ‘IF-320’, for instrument control. The scan speed was adjusted at 30 nm min − 1, slit width=1 nm, response time=0.5 s. The spectrophotometer was connected with a ‘Colora’ ultra-thermostat (25.09 0.1°C). IR and diffuse reflectance spectra were recorded using a Perkin –Elmer 1600 FT-IR and a Beckman DGB spectroreflectometer. The thermal measurements were carried out using a Perkin –Elmer TGS-2 thermal analyser, connected to a model 3600 Data Station, and a 1020 series DSC-7 thermal analysis system equipped with a multitasking software for instrument control and data analysis. Unless specified otherwise, thermogravimetry and differen-

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tial scanning calorimetry runs were made on sample of about 1–2 mg (TG) and 0.3 – 0.5 mg (DSC) in a stream of nitrogen or oxygen (flow rate, 50 ml min − 1, heating rate 10°C min − 1). The acidity of the aqueous solutions was checked with an Orion EA 940 pH-meter with an Orion 81-02 Ross combination pH electrode. Millipore filtering apparatus fitted with 0.45 mm membrane discs.

3. Results and discussion The main data of the spectroscopic and thermoanalytical investigation are summarised in Tables 1 and 2. Because all the complexes showed similar spectroscopic characteristics and thermal behaviour, for the sake of brevity, we give below, as an example, a more detailed discussion of the first compound of the series and only a short presentation of the related studies of other complexes underlining its peculiar features.

2.2. Reagents Diclofenac sodium salt ‘Sigma’ was used without further purification. Purity of dry material, checked by potentiometric titration, was 99.8% (Sr =0.05%, N= 5). The metal ions were in the form of perchlorate ‘Aldrich’. Distilled, deionised and, if necessary, O2 and/or CO2free water was used. All other chemicals were of analytical-reagent grade.

2.3. Preparation of the solid compounds The following general procedure was applied: 20 cm3 of 0.01 mol dm − 3 aqueous solution of the metal ion were added to 40 cm3 of 0.01 mol dm − 3 aqueous solution of the ligand (CL/CM =2), maintaining the pH of the mixture in the range from 5.5 to 6, by the addition of small quantities of NaOH solution. The mixture was stirred for about 2 h, at room temperature, and then the precipitate was filtered off, washed with water and dried in vacuo, over silica gel, for at least 48 h. The analysis of all the solid compounds agreed with the empirical formula MD2·(H2O)x [where M and D are, respectively the metal and the diclofenate ions and x =0 for M =Fe(II), x = 1 for M=Mn(II), Co(II), Ni(II), x =3 for Cu(II) and x =4 for Zn(II)]. The compounds were prepared also in hot aqueous solution [23] achieving the same results.

3.1. Bis(dichlorophenylaminophenylacetato)manganese(II) This compound, a pale pink powder, has the empirical formula Mn(C14H10Cl2NO2)2 (H2O). It is slightly soluble in water, but soluble in ethanol and this solution exhibits a spectrum with two maxima at u= 445 nm and u=370 nm. The diffuse-reflectance spectrum, which shows only a weak band at about 21 300 cm − 1, does not give a sure proof of the stereochemistry of the complex, because of the interference of the ligand absorption which mask the d–d bands. The IR spectrum (Fig. 1) shows a strong band at 3570 cm − 1 attributed to the presence of co-ordinated water. In fact, this band is absent in the anhydrous compound obtained by heating the sample at 150°C (see TG curves). The single band at 3320 cm − 1 (wNH), similar to that found for diclofenac in the protonated form [27], instead of the two strong bands at 3388 cm − 1 (wNH) and 3260 cm − 1 (wNH···O due to intramolecular hydrogen bonding), which appears in DS [22], proves the co-ordination of the metal ion through the carboxylate groups, but it can’t exclude that there is an interaction between NH group and the metal ion. This hypothesis is confirmed by the was COO− and ws COO− bands. The difference Dw = (1554 –1420=)134 cm − 1 is less than that of the DS free ion [Dw = (1572 –1402=) 170 cm − 1] as expected for bidentate co-ordination.

Table 1 Spectroscopic data from visible, diffuse reflectance and infrared spectra of bis(dichlorophenylaminophenylacetato)metal(II) compounds Compound

Colour

Visible a (nm) DH (C14H11Cl2NO2) DS (C14H10Cl2NO2Na) Mn(C14H10Cl2NO2)2·(H2O) Fe(C14H10Cl2NO2)2 Co(C14H10Cl2NO2)2·(H2O) Ni(C14H10Cl2NO2)2·(H2O) Cu(C14H10Cl2NO2)2·(H2O)4 Zn(C14H10Cl2NO2)2·(H2O)3 a b

In ethanol solution. KBr disc.

white white pale pink bronze blue pale green green white

Diagnostic IR b bands (cm−1)

Absorption maximum

370–445 350–528 403–675–750 725

Diffuse reflectance (cm−1)

21 300 11 100–21 300 7700–17 400–18 900 8500–13 500–15 100–25 000 14 500–25 600

was COO−

ws COO−

1694 1572 1554 1578 1578 1578 1616–1558 1560

1304 1402 1420 1400 1400 1400 1415–1394 1432

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Table 2 Thermogravimetric data for the analysed compounds in the temperature range 30–850°C Compound

Mn(C14H10Cl2NO2)2·(H2O)

Gas

N2

O2

Fe(C14H10Cl2NO2)2

N2

O2

Co(C14H10Cl2NO2)2·(H2O)

N2

O2

Ni(C14H10Cl2NO2)2·(H2O)

N2

O2

Cu(C14H10Cl2NO2)2·(H2O)4

N2

O2

Zn(C14H10Cl2NO2)2·(H2O)3

N2

O2

t range a (°C)

105–125 223–280 280–440 440–700 223–280 280–390 390–585 165–260 260–680 680–800 140–165 165–305 305–390 390–520 30–100 227–280 280–400 400–680 227–287 287–405 405–490 490–615 30–120 228–310 310–700 228–340 340–410 410–565 55–100 154–185 185–280 280–850 154–185 185–356 356–665 70–100 245–286 286–600 245–286 286–372 372–520

(tmax) b (°C)

Weight loss (%)

Residue

Calculated c

Found

(115) (250)

2.74 [H2O]

(630) (236, 247)

5.89 [CO1.66]

2.7 78.3 1.6 5.6 20.0 3.0 62.5 73.6 9.0 5.5 8.3 41.7 4.2 33.6 2.8 78.5 1.0 5.9 64.6 1.3 7.0 11.1 2.8 66.0 20.1 36.1 4.9 44.4 9.4 2.4 38.9 29.2 2.4 28.5 48.9 7.7 75.3 5.9 72.2 2.9 6.0

(485, 520) (230) (738) (148) (240) (490) (60) (253) (600) (259) (470) (572) (72) (265)

5.57 [CO1.5]

2.70 [H2O]

5.78 [CO1.66]

2.70 [H2O]

(268) (525) (75) (175) (234) (175) (234) (493,604) (78) (272) (520) (272)

9.92 [4H2O]

7.61 [3H2O] 6.20 [CO2]

(470)

Calculated c

17.50 [MnCO3]

11.61 [Mn3O4] 17.92 [FeCO3]

12.36 [Fe2O3]

17.82 [CoCO3]

12.03 [Co3O4]

11.20 [NiO]

10.96 [CuO] 17.67 [ZnCO3]

11.6 [ZnO]

Found 97.3 19.0 17.4 11.8 77.3 74.3 11.8 26.4 17.4 11.9 91.7 50.0 45.8 12.2 97.2 18.7 17.7 11.8 32.6 31.3 24.3 13.2 97.2 31.2 11.1 61.1 56.2 11.8 90.6 88.2 49.3 20.1 88.2 59.7 10.8 92.3 17.0 11.1 20.1 17.2 11.2

a

Decomposition temperature range (water loss in O2 occurs as in N2 and it is not reported). tmax is the temperature of the maximum decomposition rate (by DTG analysis of TG curves). c Volatile products and supposed residues are reported in brackets. b

The thermal decomposition trend of this complex is greatly conditioned by the furnace atmosphere. According to thermogravimetry in O2 (Fig. 2, curve a) this compound loss its water molecule in the temperature range from 105 to 125°C (Anal. Calc.: 2.74, Found: 2.7%) and the anhydrous is stable up to about 223°C. The first decomposition process takes place between 223 and 280°C, with about 20% weight loss, and it is a two-step overlapped process (tmax =236 and 247°C). Upon further heating the sample slowly loses mass up to about 390°C, then the decomposition speeds up

suddenly with a new two-step partly overlapped process (tmax = 485 and 520°C). At 585°C the residue consists mainly of Mn3O4 (Anal. Calc.: 11.61, Found: 11.8%) or a mixture of different oxides. In N2 atmosphere (Fig. 2, curve b) the thermal behaviour is similar to that in O2 only up to 223°C, then the decomposition rate increases (tmax = 250°C) and, with an apparent one-step process, at 280°C the residue is about 19% (Anal. Calc. for MnCO3: 17.50%). This residue slowly loses mass (about 1.6% up to 440°C) then, between 440 and 700°C, it changes into the final metal oxide. DSC curves (Fig. 3,

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curves a and b) confirm the influence of the furnace atmosphere on the decomposition mechanism of the complex showing exo- and/or endothermic peaks connected with the weight losses in TG. An endothermic process accompanies the water evolution (tp =120°C; DH = 46 kJ mol − 1) both in O2 and N2 atmosphere. Then, several exothermic reactions characterise the oxidative thermal decomposition of the complex, whereas, in N2, the initial decomposition stage occurs with an exothermic reaction partly neutralised by the overlapped endothermic one. Another wick endothermic peak appears up to 500°C.

3.2. Other complexes All the complexes are fairly soluble in water and soluble in ethanol.

The diffuse reflectance spectra suggest an octahedral geometry around the metal ion for cobalt(II), nickel(II) and copper(II) complexes [23,28] whereas in the case of iron(II) and zinc(II) as reported for manganese(II) compound, the ligand interference is enough to mask the d–d bands. A comparison of the IR spectra, in the range from 1700 to 1300 cm − 1, with those of the ligand in sodium (DS) and protonated (DH) form suggests the carboxylic group is involved in the metal ions complexation and the formed oxygen-metal bond has a different degree of covalent character: in the Fe(II), Co(II) and Ni(II) complexes the bonding is primarily ionic whereas in Cu(II) complex it is primarily covalent [29]. The Cu(II), Ni(II) and Zn(II) complexes show a strong absorption at 3550 cm − 1 attributed to OH stretching of co-ordinated water molecules.

Fig. 1. IR spectra (KBr disc) of bis(dichlorophenylaminophenylacetato)manganese(II).

Fig. 2. TG of bis(dichlorophenylaminophenylacetato)manganese(II) in O2 (curve a) and in N2 (curve b) atmosphere.

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Fig. 3. DSC of bis(dichlorophenylaminophenylacetato)manganese(II) in O2 (curve a) and in N2 (curve b) atmosphere.

According to the thermograms (TG) in a dynamic O2 atmosphere, the water content of the complexes departs at temperature up to about 125°C. The anhydrous compounds are more stable than DH (td =140°C) but less than DS (td =265°C) [27]. The thermal decomposition occurs through a multi-step process, so conclusion is drawn that the partial reactions take place consecutively, partly overlapping one another. At about 650°C the residues consist mainly of the metal oxides. In a dynamic N2 atmosphere the first decomposition step occurs at the same temperature than in O2 but with a more quick and a higher mass loss. An exception is the thermal behaviour of the iron(II) complex. The decomposition delay observed in N2 can be explained by the inhibition of the oxidative decomposition of the complex, which probably occurs through iron(II) to iron(III) transition. In fact, in O2, the decomposition begins with an exothermic peak at 145°C whereas DSC in N2 shows an endothermic peak at about 175°C.

4. Conclusions This study enriches the knowledge of diclofenac with some aspects of its complexing ability and, although the reaction medium is very different from the biological environment, however the obtained results enable to suppose that the administration of this drug for long time could decrease the bioavailability of some important metal ions. In fact diclofenac reacts with divalent metal ions forming 1:2 (metal to ligand ratio) very slightly water-soluble complexes, so much so that the stability constants were not determined. The spectroscopic analysis of the solid compounds proved the carboxylate group of the ligand is involved in the complexation reaction with different degree of

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covalency in the formed metal(II) –oxygen bonds and, with regard to cobalt(II), nickel(II) and copper(II) complexes, an octahedral geometry around the metal ion. The thermal analysis evidenced a great dependence of the thermal decomposition trend of these complexes by the furnace atmosphere. It was found that, in nitrogen, the decomposition occurs through the MeCO3 intermediate (this mechanism was particularly evident in TG curves of manganese(II), iron(II), cobalt(II) and zinc(II) compounds). The kind of the bonded metal ion influenced the thermal stability order that, calculated by the initial decomposition temperature (td) of the anhydrous compounds (in N2), resulted Zn\ Ni ] Co ]Mn  Fe \ Cu. It does not agree fully with that expected for analogous series of metal(II) complexes [30] leading to suppose different structures and/or inter –intramolecular interactions. In particular we emphasise the thermal behaviour of iron(II) complex, the only one precipitated in anhydrous form. This compound, as found in a precedent case [31], is more stable than copper(II) complex only and, in O2 atmosphere, it becomes the least stable of all the analysed complexes. This behaviour could be justified by the initial oxidation reaction of iron(II) to iron(III) that favours the thermal decomposition of the compound.

Acknowledgements The authors acknowledge the National Research Council of Italy (CNR) for the financial support.

References [1] Martindale, The Extrapharmacopeia, 29th ed., The Pharmac. Press, London, 1980. [2] P.A. Todd, E.M. Sorkin, Drugs 35 (1988) 244. [3] P. Moser, A. Sallmann, I. Wiesemberg, J. Med. Chem. 33 (1990) 2358. [4] A. Shumaker, H.E. Geissler, E. Mutschler, J. Chromatogr. 181 (1980) 512. [5] W. Schneider, P.H. Degen, J. Chromatogr. 217 (1981) 263. [6] K.K.H. Chan, K.H. Vyas, K. Wnuck, Anal. Lett. 15 (1982) 1649. [7] J. Godbilon, S. Gauron, J.P. Metayer, J. Chromatogr. 338 (1985) 151. [8] C. Sarbu, J. Chromatogr. 367 (1986) 286. [9] B. Henning, A. Steup, R. Benecke, Pharmazie 42 (1987) 861. [10] D. Grandjean, J.C. Beolor, M.T. Quincon, E. Savel, J. Pharm. Sci. 78 (1989) 247. [11] M.R. Borenstein, Y. Xue, S. Cooper, T. Tzeng, J. Chromatogr. B 685 (1996) 59. [12] C.S. Sastry, A.R.M. Rao, T.N.V. Prasad, Anal. Lett. 20 (1987) 349. [13] C.S.P. Sastry, A.S.R.P. Tipirneni, M.V. Suryanarayana, Analyst 114 (1989) 513. [14] B.V. Kamath, K. Shivram, Indian J. Pharm. Sci 54 (1992) 81. [15] B.V. Kamath, K. Shivram, G.P. Oza, S. Vangani, Anal. Lett 26 (1993) 665.

2520

R. Bucci et al. / Polyhedron 19 (2000) 2515–2520

[16] B.V. Kamath, K. Shivram, Anal. Lett 26 (1993) 903. [17] H. Fabre, S.W. Sun, B. Mandrou, H. Maillols, Analyst 118 (1993) 1061. [18] J.C. Botello, G. Perez-Caballero, Talanta 42 (1995) 105. [19] I. Kramancheva, I. Dobrev, L. Brakalov, A. Andreeva, Anal. Lett. 30 (1997) 2235. [20] S.A. Abdel Fattah, S.Z. El-Khateeb, S.A. Abdel Razeg, M. Tawakkol, Spect. Lett. 21 (1988) 533. [21] S.A. Kustrin, L. Zivanovic, D. Radulovic, M. Vasiljevic, Analyst 116 (1991) 753. [22] D. Kovala-Demertzi, D. Mentzafos, A. Terzis, Polyhedron 12 (1993) 1361. [23] R. Kesharwani, P. Singh, J. Indian Chem. Soc. 72 (1995) 803. [24] A. Fini, G. Feroci, G. Fazio, M.J. Fernandez-Hervas,

.

[25] [26] [27] [28] [29] [30] [31]

M.A. Olgado, A.M. Rabasco, Int. J. Pharm. Adv. 1 (1996) 269. S. Agatonovic-Kustrin, L. Zivanovic, M. Zecevic, D. Radulovic, J. Pharm. Biomed. Anal. 16 (1997) 147. C. Castellari, G. Feroci, S. Ottani, Acta Crystallogr., Sect. C 55 (1999) 907. R. Bucci, A.D. Magrı`, A.L. Magrı`, Fresenius J. Anal. Chem. 362 (1998) 577. A.B.P. Lever, Inorganic Electronic Spectroscopy, Elsevier, Amsterdam, 1968. R.E. Sievers, J.C. Bailer, Jr, Inorg. Chem. 1 (1962) 174. A.L. Magrı`, A.D. Magrı`, F. Balestrieri, E. Cardarelli, G. D’Ascenzo, Thermochim. Acta 38 (1980) 225. R. Bucci, A.D. Magrı`, A.L. Magrı`, A. Napoli, Thermochim. Acta 217 (1993) 213.