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Synthesis and Structural Studies of Bismuth-piroxicam Complex

AYESHA KANWAL1, MUHAMMAD IMRAN1, ZAFAR IQBAL1,2, SUMMIA REHMAN1, ZEESHAN DANISH3, NAYAB BATOOL1,LIVIU MITU4*

1Institute of Chemistry, University of the Punjab, Lahore, Pakistan2Department of Chemistry, SSE, Lahore University of Management Sciences, Lahore 54000, Pakistan3College of pharmacy, University of the Punjab, Lahore, Pakistan4University of Pitesti, Department of Nature Sciences, 1 Targu din Vale,110040, Pitesti, Romania

Piroxicam [4-hydroxy-2-methyl-N-2-(pyridyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide] is aneffective antiinflammatory analgesic drug. In the present work, piroxicam has been chemically modifiedinto its bismuth complex by reacting it with bismuth nitrate at ambient conditions and optimizedstoichiometric ratio. The synthesis of the complex has been monitored by TLC and characterized well byFourier Transform Infrared (FTIR), UV-Vis, ICP, TGA, XRD and SEM. The luminescent behavior of this complexhas also been studied which determined its photoluminescent property.

Keywords: Piroxicam, bismuth, fluorescence, TGA, complex

Piroxicam [4-hydroxy-2-methyl-N-2-(pyridyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide] is a veryeffective antiinflammatory drug and biologically active asan analgesic, antipyretic, hypoglycemic and anti-hypertensive [1]. Chemo preventive and chemosuppressive effects in different cancers i.e colon, lung andbreast cancers have also been studied [2]. This importantmember of oxicam class is a strong chelator for d-blockdivalent metal ions of the periodic table, via nitrogen atomsfrom the pyridyl the amide oxygen atom or thiazolyl rings[3]. It is well established that metal ions play crucial rolesin biological systems and the ligand functionality can beraised when chelated with metal ions [4]. For instance,the antibacterial activity of ciprofloxacin has been reportedto be increased by complexing it with trasition metal ions[5]. Similarly, the efficacy of the parent drug (benzofuranand coumarin) as an antiinflammatory agent and also asan anticancer agent is known to be enhanced by combiningwith Cu(II) and other transition metals with drugs [6]. Highlyphotosensitizing properties, exhibited by the metabolicproduct of piroxicam in the biological system has beenreported [7]. Moreover, DFT study for stability contants ofCu-Piroxicam complexes have been reported by Ledesmaet al., 2016 [8]. Meloxicam and piroxicam complexes withOs and Ru have also been recently studied by Aman et al.,2017 [9]. Pharmaceutical, photosentizing properties ofpiroxicam and less toxicity, stability, easy handling,inexpensive nature of bismuth attracted us to combinethem together which according to accessible literature hasnot been yet reported. The structural as well as luminescentstudies of this complex are part of this manuscript. In-vitroand in-vivo biological properties of this complex are underprogress and will be communicated separately.

Experimental partMaterials

Piroxicam (Apex; m.p: 198oC), ethanol (b.p: 78°C),Bi(NO3)3

.5H2O (Aldrich), NaOH were used without furtherpurification. All the glass apparatus was made up of pyrexand was dried in oven before using. Melting point weredetermined on Gallon Kamp apparatus thrice and reportedas average. Metal contents were determined by inductivelycoupled plasma emission spectrophotometer model

* email: ktm7ro@yahoo.com; Phone: 0040/725160304

Perkin Elmer Optima 2100 DV and by Atomic absorptionspectrophotometer model Perkin Elmer AA Analyst 100.FT-IR spectra were measured on Perkin Elmer IRSpectrometer. UV-visible and fluorescent spectra wererecorded by Perkin Elmer multimode plate reader, SEMimage was taken by Nova Nano 450-SEM ûeld emissionscanning electron microscope (FESEM), TGA by SDT-Q600and Phase analysis was done by using XRD D2 Phaseanalyzer.

Synthesis Synthesis of Bi-complex was carried out according to

previously reported procedure with minor modifications[2]. Na-piroxicam was made by adding 0.001 g of NaOH inethanolic solution of piroxicam (0.09 g, 0.3 mmol). Theresulting solution was then added drop wise withcontinuous stirring to an ethanolic solution ofBi(NO3)3.5H2O (0.07 g, 0.15 m mol). The stirring wascontinued at room temperature for 40-50 min that resultedprecipitates, which were then filtered, washed with ethanoland dried at room temperature.

Results and discussions The synthesis of bismuth complex was obtained in a

good yield (79 %) at room temperature by reacting sodiumsalt of piroxicam (in-situ produced) with bismuth nitrate(scheme 1).

The bismuth complex is a white solid and stable towardsair and moisture. The bismuth complex has moderate togood solubility in common solvents like DMSO, DMF,CH3OH, etc (table 1).

Conductometric measurement indicated conductancevalue (15.84µS) of this complex revealing its non-electrolytic nature and is in agreement with the relatedcomplexes of piroxicam [3]. The calculated and theobserved values of metal content (on the basis of ICP) inthe complex are given (table 1) and indicate M/L ratio 1:3,thus proposing octahedral geometry of this complex. Theother elemental analyses also favour the proposedoctahedral geometry (table 1). Each ligand is monoanionicbidentate as elucidated from FT-IR (detail below in FT-IRsection).

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UV-Visible SpectroscopyUV-Visible absorption spectrum of piroxicam and

bismuth complex was recorded in DMF at wavelengthrange 200-500 nm. It shows that piroxicam gives threebands at 325, 270 and 220 nm (table 1). The peaks forpiroxicam complex were shifted towards bathochromicregion. This shift indicates the involvement of piroxicam inthe chelation with Bi(III) ion [3].

IR-Spectroscopy The well-defined peaks of piroxicam and its metal

complex was obtained in FT-IR spectra and compared.The distinct peaks at 3335s and 3392s cm-1 in spectrum ofpiroxicam are referred to the v(N-H) and v(O-H) vibrationsrespectively. The disappearance of band at 3392s cm-1

supports the deprotonation of enol group and itscoordination with bismuth ions [10]. Similarly, shifting ofthe v(C=O) stretching mode is seen from 1630 cm-1

(piroxicam) to 1621 cm-1 in bismuth complex suggestingcoordination from this moiety (fig. 1, table 2).

Fluorescence Analysis The photoluminescence studies of Bi-complex with

piroxicam were made by dissolving it in methanol through

Scheme 1. Synthesis route to Bi(L)3

Table 1PHYSICO ANALYTICAL DATA OF PIROXICAM AND ITS

BISMUTH COMPLEX

Fig. 1. Infrared spectra of (a) piroxicam (b) Bi-piroxicam complex

Table 2IR ASSIGNMENT OF PIROXICAM AND

ITS BISMUTH COMPLEX (cm-1)

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sonication. Excitation of the sample was made at 320 nmand then measured the emission intensity. The emissionspectrum of the complex (fig. 2) shows emission peaks at390-400 nm and 500-530 nm, these peaks are assigned toπ-π* fluorescence. The UV-Visible spectrum of the ligandshows maximum absorption at 270 and 325 nm which isdue to aromaticity of the ligand or the lone pairs present init, as more the aromaticity more will be fluorescenceemission. Furthermore, it can be attributed to high spinorbital coupling (SOC) of bismuth [11, 12]. The observedvalue of emission fluorescence of Bi(III) complex iscomparable with previously reported complexes inliterature [13-15].

Thermogravimetric AnalysisThermogravimetric analysis was carried for bismuth

complex and is represented in (fig. 3). The obtained dataindicates that piroxicam complex is thermally stable andthe initial weight loss (around 100°C) is by the loss of wateror moisture [16]. The decomposition of complex, especiallyits organic part occurred in two steps that are very close,the first estimated temperature range was 170-430oC andcalculated % age weight loss was 60 % and that of secondtemperature range was 430-520oC (% age weight loss is32.22 %). Further decomposition, i.e above 520oC can beattributed to metal oxide formation. The curves obtainedare all in harmony with the previous one, mentioned inliterature for related metal complexes [7]. Moreover, TGAweight loss and associated DTA exotherm can occuranywhere in the range 400 to 700oC.

radiation (λ = 1.54 Å) operated at 30 kV. The XRD patternof bismuth complex (fig. 4), reveals that the complex hasenough crystallinity and all the diffracted peaks aredifferent than piroxicam reported peaks [3, 17, 18].

SEMThe morphology of the sample was done by Nova Nano

450-SEM ueld emission scanning electron microscope(FESEM). SEM image at various resolutions was done toconfirm the morphology of the system. It has been foundthat morphology is perfectly crystalline which is alsoconfirmed by XRD study. Cavities in the system reveal thatit may be used for any drug loading electrostatically due toits unique morphology (fig. 5).

Fig. 2. Fluorescence spectrum of Bi-piroxicam

Fig. 3. TGA curve for Bi-Piroxicam complex

XRD AnalysisCrystal structure of the bismuth complex was identified

using XRD in the 2theta range of 20-70° with Cu-K α

Fig. 4. XRD pattern of Bi-Piroxicam

Fig. 5. Sanningelectron

microscopy (SEM)of Bi-piroxicam

ConclusionsIt was concluded from this study that piroxicam behaved

in a monoanionic bidentate manner and found to be apotential candidate for complexation toward bismuth ions.The resulting bismuth complex possessed appreciableluminiscence activity.

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Manuscript received: 6.06.2017