Interaction of Tapentadol with Selected Metal Ions Studied by UV-Vis and FTIR Spectroscopy

Understanding the interaction between drug-metal complexes is important to find out the pharmacological characteristics of a drug. In this work, one of the μ-opioid analgesic type of drug, tapentadol has been used to study the interaction of tapentadol with several metal ions such as Ca (II), K (I) Cr (III), Cu (II), Fe (III), Co (II), and Ni (II) using UV-Vis and FTIR spectroscopy. It was found that tapentadol forms drug-metal complexes with transition metals like Fe (III) and Ni (II) only in acidic conditions. Whereas Cu (II) can interact with tapentadol both in acidic and basic conditions. This study may help to understand the interactions of μ-opioid drugs with the metal ions which ultimately help to develop new drugs of this class with more efficacy.


Introduction
The study of the interaction and complexation of drugs with metal ions is very important in the field of chemical, biochemical, medicinal, and pharmaceuticals for drug design and development.Transition metals like copper, iron, and manganese, etc., and some s-block elements like calcium, and potassium are typically found in the active sites of different biologically active proteins and enzymes engaged in a variety of biological reactions, including electron transfer, catalysis, and structural roles [1].These essential metals and/or metal ions are necessary at a minute amount in the human body but in a strictly regulated form.Disruptions in the control of these vital metals during typical biochemical reactions are linked to the emergence of numerous pathological conditions, for example, deficiency of certain ions for long term like iron, zinc, and copper can cause oncogenesis [2][3].For example, iron deficiency leads to pernicious anemia, insufficient dietary zinc leads to growth retardation, and copper deficiency results in heart disease in infants.On the other hand, if these vital metals are taken excessively into the human body, they can cause different adverse effects due to the toxicity of some metal ions.However, drug-metal complexes are a possible solution to avoid toxicity as well as remove the deficiency of metal ions in the human body [4].After being coordinated to a metal, a drug metal complex can significantly alter the pharmacological mechanism and efficacy of established medications.Previously, Insulin-IOP Publishing doi:10.1088/1757-899X/1305/1/012006 2 mimetic or boosting effects have been found for chromium (III) [5], molybdenum (VI) [6], copper (II) [6,7], cobalt (II) [9], zinc (II) [10], and vanadium (IV) ions [10,11].Metal-based medications are also utilized to treat several disorders, including diabetes, rheumatoid arthritis, inflammatory and cardiovascular diseases, and as diagnostic agents [12,13].The pro-drugs resulting from drug-metal complexation have various physical and physiological features that allow the drug to be released in a regulated manner or at a specific location.For example, complexing nonsteroidal anti-inflammatory medications (NSAIDs) with copper alleviates some of its gastrointestinal adverse effects, and salicylate's Cu (II) complex has been discovered to be around 30 times more effective than aspirin for the reduction of inflammation [14].Previous studies show that NSAID ibuprofen when complexed with metal ions such as copper ibuprofenate (a copper and ibuprofen chelating agent), shows fewer gastrointestinal adverse effects [14][15][16].It has also been studied that NSAID pain killer isoxicam and its Cu-complex can form an inclusion complex [18].On the other hand, tapentadol which is a µ-opioid type analgesic drug is a centrally-acting painkiller with a dual mode of action [19].In this study, tapentadol is used because it is a good analgesic painkiller treating acute, chronic, and neuropathic pain from adults to children [20].Previous studies on tapentadol have been carried out on the synergic interaction between tapentadol and flupirtine in the rat orofacial formalin test [21].Another study shows tapentadol's potential for drug-drug interactions in human liver microsomes and fresh human hepatocytes [22].It has been found that tapentadol, like morphine or oxycodone, also provides good pain relief for those suffering from moderate to severe cancer pain when taken orally [23].As the formation of the drug-metal complex can increase the efficiency of the drug, the investigation of possible interaction between tapentadol and metal ions is required.Hence, in this study, the complexation of tapentadol with metal ions of s-block and transition metals has been investigated using UV-vis and FTIR spectroscopy.

Preparation of sample
The drug-metal complexes were prepared by mixing the tapentadol and metal salts/oxides as the sources of metal ions in a 1:1 weight ratio in the solid phase followed by dissolving in 50 mL methanol (conc.8.8 × 10 -5 M).The pH of the as-prepared complexes was adjusted by adding HCl and NaOH.Then the drug-metal complex solutions were shaken for about 3 hours at 60˚C temperature to mix up properly.The solutions were cooled down to room temperature by natural cooling and then the UV-Vis and IR spectra were recorded.Standard solutions of tapentadol were prepared using a similar experimental protocol without the metal salts (conc.4 × 10 -5 M) [24].

Spectroscopic measurement
Shimadzu UV-1800 UV-Vis Scanning Spectrophotometer was used to record the UV-Vis spectra in the range of 200-400 nm wavelength after dissolving the sample and the standard in CH3OH.Comparing the UV-Vis spectrum of the standard drug solution with the drug-metal ion solutions, the interacting drug-metal solutions were isolated.Then the solvent of interacting drug-metal solutions was evaporated and subjected to IR spectroscopic analysis.To record IR spectra, Shimadzu FTIR 8400S, a Spectrophotometer in the range 4000-400 cm - 1 was used.An appropriate quantity of KBr and the samples (in the ratio of 100:1) were mixed by grinding in an agate mortar.Pellets were made with about 100 mg mixture.The spectra were recorded in the resolution of 2 cm -1 and the number of scans took 30 minutes.

Results and Discussion
Fig. 1 shows the UV-Vis spectrum of the standard tapentadol along with drug-metal complexes.From the UV-Vis spectrum of the standard tapentadol solution in CH3OH, the λmax has been found at 274.00 nm.λmax obtained from UV-Vis spectra of all the samples are compared with the λmax of standard tapentadol to find out the possible complexation as shown in Table I.It was found that λmax of the tapentadol-metal solution has been shifted to a lower wavelength for Fe (III).In the case of the basic solution, only λmax of Cu (II) of CuO shifted to a higher wavelength.These changes in λmax suggest that the tapentadol might have interacted with Fe (III), Ni (II), and Cu (II) in acidic conditions and only with Cu (II) in basic conditions which are shown in Fig. 1.

Figure 1. UV-Vis spectra of various tapentadol-metal complexes in methanol
To identify the interacting functional group FTIR spectra of the drug-metal complexes have been taken.Fig. 2 shows the structural formulae and FTIR spectra of drug-metal complexes of Fe (III), Ni (II), and Cu (II).The peaks assigned for the different functional groups are summarized in Table II.It has been found that standard tapentadol gives peaks at 3167.12 cm -1 for stretching and 1176.58cm -1 for bending of the phenolic -OH group.The peaks at 2688.77, 1255.66, and 1217.08 cm -1 have been observed for -CN stretch, -NH stretch, and -NC rocking of the tertiary amine group respectively.At 1597.06 cm -1 single peak has been observed for aromatic -CC stretching.For the methyl group stretching and bending peaks have been found at 2962.66 cm -1 and 1456.90 cm -1 respectively.
In the case of tapentadol with Cu (II) ion (acidic condition), no peak has been observed for tertiary amine.However, a peak has been observed at 1176.58 cm -1 for bending of the phenolic -OH group.Aromatic -CC peak has been observed at 1624.06 cm -1 .The Methyl group has shown peaks at 2924.09 cm -1 for -CH stretching and 1435.04 cm -1 for -CH bending.It indicates that the Cu (II) has interacted with tapentadol through the secondary amine -N(CH3)2 group and a drug-metal complex has been formed.
In the IR spectrum of tapentadol with Fe (III) (acidic condition), no peak has been found for tertiary amine -N(CH3)2.The peak for phenolic -OH bending has been observed at 1103.28 cm -1 .Aromatic -CC stretching peak has been observed at 1627.92 cm .Peaks have been observed for the methyl group at 2927.94 cm -1 for stretching and 1477.47 cm -1 for bending of -CH.This indicates that a strong interaction of Fe (III) and tapentadol has formed by coordinating with the tertiary amine of tapentadol.
In the case of tapentadol with Ni (II) ion, also there is no peak for the tertiary amine and phenolic hydroxide group.Peak has been observed at 1627.92 cm -1 for aromatic -CC stretching.Peaks of methyl groups have appeared at 2922.16 cm -1 for -CH asymmetric stretching and at 1477.47 cm -1 for -CH bending.Accordingly, it can be concluded that drug-metal complexation of tapentadol with Ni (II) has taken place through both tertiary amine and phenolic hydroxide groups.
Similarly, the absence of the tertiary amine group in the IR spectrum of tapentadol with Cu (II) ion (basic condition) indicates the formation coordinate bond between tapentadol and Cu (II).However, the peak observed at 1172.72 cm -1 for bending of phenolic -OH indicates that the -OH group remains intact.The rest of the peaks have been observed in the similar range of the standard sample.This indicates that tapentadol forms a bond with Cu (II) ion by interacting only with the tertiary amine group.The above analysis shows that tapentadol tends to form transition metal complexes as it has reacted only with transition metals Cu (II), Fe (III), and Ni (II).

Conclusion
In this study, an investigation of the interaction of tapentadol with selected metal ions was carried out.It was found that tapentadol and metal ions like Cu (II) and Fe (III) in acidic conditions and Cu (II) in basic conditions form drug-metal complexes by interacting with the -N(CH3)2 functional group of the drug.Whereas Ni (II) forms a complex by interacting with both -N(CH3)2 and -OH groups in basic conditions.This investigation reveals that like tapentadol, other µ-opioid drugs may form a similar drugmetal complex.In the future, the structure and stability of tapentadol-metal complexes are to be investigated to know about the physiological effects and medicinal value of the complexes.

Figure 2 .
Figure 2. (a) Molecular structure of tapentadol, (b) FTIR spectra of various tapentadol-metal complex (recorded data are made offset for clarity).

Table 1 .
λmax of UV-Vis spectrum of likely drug-metal complex in different conditions and their comparison with standard tapentadol (λmax of tapentadol is at 274.00 nm)

Table 2 .
Frequency and their assigned functional groups of tapentadol and tapentadol-metal ion complexes found from FTIR