Photoreactivity of the Non-Steroidal Anti-inflammatory Drug Oxaprozin

 

Waseem Ahmad1*, Harish Chandra Joshi1, Nitika Garg2, Rajesh Kumar3

1Department of Chemistry, Graphic Era Deemed to be University, Dehradun, Uttarakhand, India.

2Department of Chemistry, RKGIT, Ghaziabad, Uttar Pradesh.

3Department of Chemistry, Mewar University, Chittorgarh, Rajasthan, India.

*Corresponding Author E-mail: waseemahmad8@gmail.com

 

ABSTRACT:

Oxaprozin is a phototoxic, non-steroidal anti-inflammatory drug (NSAID) which is generally used in the treatment of inflammation, swelling, stiffness, and joint pain associated with osteoarthritis and rheumatoid arthritis. In addition to these beneficial properties some adverse phototoxic effects are also associated with this drug.  For this reason here in we have investigate the photochemical behavior of selected phototoxic drug Oxaprozin. In the present study the methanolic solution of Oxaprozin was irradiated with UVA light under different experimental conditions such as aerobic and anaerobic conditions. The reaction progress was strictly monitored by using thin layer chromatography which confirms the formation of three photoproducts. The isolation of the photoproduct was done by column chromatography. The structural morphology of the isolated photoproducts was established by various spectroscopic techniques such as IR, NMR, 13C NMR mass spectroscopy and High Resolution Mass Spectrometry (HRMS). On the basis of structure the photoproducts are identified as 2-(4,5diphenyl oxazol-2-yl) acetaldehyde (2), 2-(4,5diphenyl oxazol-2yl) ethanol (3), 2ethyl-4,5diphenyl Oxazole (4) by spectral studies.

 

KEYWORDS: Oxaprozin, Photodegradation, Electron Transfer, Phototoxicity, NSAID Drug.

 

 


INTRODUCTION: 

During the last few decades the interest in photo-initiated reactions of drugs was intensified among the scientific community1-4. This has been basically due to photo biological reasons because the cases of photo induced disorders are increasing rapidly. Photo induced drug disorders draw more attention as most of the phototoxic response depends on the photochemical reactions5. Thus, it is more important to stimulate more chemists to work on drugs bearing different chromophores which are mainly responsible for the photo-initiated reactions6. In recent years several reports have highlighted that some anti inflammatories7-8 and fluoroquinolone9 antibiotics show unusual photochemical behavior. Studies on the photodegradation mechanism of drugs are an essential part in the drug development process, because they play an important role in drug induced adverse photo biological effects10-12.

 

It has also been reported in so many reports that photoproducts of the photolysis of a drug have different biological effects from those of the parent compounds13-15. The photo induced disorders associated with the non steroidal are more often probably because they are the most common drugs which are used to a large extent16-18 NSAIDs are a group of drugs which contain a variety of chromospheres19-20. This group of drugs are commonly used in the treatment of inflammation and other related diseases, in spite of its wide application various adverse effects such as phototoxicity, photosensitivity and photo allergy are associated with this drug21. The reason behind the phototoxicity of this drug is mainly due to its ability to absorb light radiation of the wavelength 310 nm, these lights are able to penetrate the human skin22.

 

Oxaprozin is a very well known nonsteroidal anti-inflammatory drug (NSAID) belongs to the class of propionic acid. Oxaprozin reduces the formation of prostaglandin (PG) precursors from arachidonic acid by inhibiting the cyclo-oxygenase, resulting in decreased prostaglandin biosynthesis and reduced pain and inflammatory responses. Several clinical and pharmacological reports23-24 indicate that the Oxaprozin was found to be associated with adverse photo-biological effects. With this reference our Interest arises to investigate the Photoreactivity of Oxaprozin. Phototoxicity and Photobiological properties of any phototoxic drug is directly and indirectly associated with photoreactivity of drug hence it is very important to evaluate photoreactivity of drugs. On this basis, in this paper, we report our investigation of the photo reactivity of Non-steroidal Anti-inflammatory drug Oxaprozin

 

METHODOLOGY:

Apparatus and chemicals:

Pure Oxaprozin (Figure-1) was obtained from Pfizer India. All chemicals used in this study were of analytical grade. 

 

 

Figure-1: Chemical Structure of Oxaprozin

 

The IR spectrum of isolated photoproducts was recorded by using the Thermo scientific Nicolet Summit LITE iD1. 1H NMR (400 MHZ, CDCl3) and 13C NMR (75 MHz, CDCl3) of the isolated product was taken by using JEOL JNM- Nuclear Magnetic Resonance Spectrometer. We use tetra methyl silane and CDCl3 as an internal standard in the recording of 1H NMR and 13C NMR. Fragmentation pattern of the isolated products was determined by using mass spectrometry. For this purpose we use the SCIEX Triple TOF 5600 spectrometer. F254 plates was used to run TLC and in column chromatography we use Merck silica gel

 

Photo irradiation procedure:

In order to carry out the photo irradiation procedure first we prepare the 300mL methanolic solution of our selected drug (265mg). The concentration of the prepared reaction mixture is 3mM. The whole photo-irradiation procedure was carried out in a Rayonet photochemical reactor. Thin layer chromatography is used to check the progress of the reaction. Dichloromethane and methanol is used as a developing solvent in the chromatographic process. Photo-irradiation procedure was performed under both aerobic and anaerobic conditions. Thin layer chromatography of the reaction mixture indicates the formation of the number of photoproducts. The Photoproducts was isolated by using column chromatography and in column chromatography we use dichloromethane and ethyl acetate as eluting solvent25. The photoproducts were identified as 2, 3 (under aerobic condition) and 4(under anaerobic condition) from their spectral properties (figure-2). The product is isolated by using column chromatography and their purity was checked by TLC.

 

2-(4,5diphenyl oxazol-2-yl) acetaldehyde (2):

Yield 65 mg (24.5%);  HRMS calcd. for (M+) C17H13NO2 263.0946 found 263.0938; IR (KBr) 3100, 2947, 2919, 2857, 1725, 1680.5 (H-C=O), 1606,14 cm-1; 1H-NMR(CDCl3) d  9.8 (s,1H,CHO), 7.4-7.2 (m,10H,aromatic) 3.5 (d, 2H, CH2); 13C-NMR (CDCl3) d 199.5 (CO,CHO), 156.5, 136.5 and 125.3 (C-2, C-5and C-4 of oxazole moiety), 133.1 C-1(Phenyl moiety) C-2 & C6-127.4 (phenyl moiety),129.3 C-3 & C-5 (Phenyl moiety), 44.1 (C-2 of aldehyde), FAB-MSm/z: 264 [C17H13NO2+H]+, 221 [C15H10NO+H] +

 

2-(4,5diphenyl oxazol-2yl) ethanol (3):

Yield 54 mg (20.3%); HRMS calcd. for (M+) C17H15NO2 265.1103 found 265.1100; IR(KBr) 3512, 3410, 3100, 2947, 2919, 2857cm-1, 1H-NMR (CDCl3)d 7.45-7.21 (m,10H,aromatic), 3.79 (m,2H,H-1) 2.75 (m,2H,H-2) 13C-NMR(CDCl3) d 154.5, 136.5 and 125.3 (C-2, C-5 and C-4 of oxazole moiety) 133.1 C-1(Phenyl moity) C-2 & C6-127.4 (phenyl moiety),129.3 C-3 & C-5 (Phenyl moiety),60.3 (C-1), 33.3 (C-2), FAB-MS:m/z: 266 [C17H15NO2+H]+,249 [C17H14NO+H]+ ,221[C15H10NO+H]+

 

2ethyl-4,5diphenyl Oxazole (4):

Yield 58 mg (21.8%); HRMS calcd.for (M+) C17H15NO 249.3071 found249.3068 IR(KBr) 3100, 2947, 2919, 2857cm-1, 1H-NMR(CDCl3) d 7.48-7.22 (m, 10H, aromatic) 2.59 (m, 2H, H-2), 1.24(m,3H,H-1), 13C-NMR (CDCl3) d 154.5, 136.6 and 128.5 (C-2,C-5andC-4 of oxazole moiety) 133.1 C-1(Phenyl moiety) C-2 & C6-127.4 (phenyl moiety),129.3 C-3 & C-5 (Phenyl),21.3(C-2) 14.3(C-1), FAB-MS :m/z:250 [C17H15NO+H]+, 221 [C15H9NO+H]+.

 

RESULTS AND DISCUSSION:

Photolysis of Oxaprozin:

The photolysis of Oxaprozin (1) was carried out in a photochemical reactor having a medium pressure mercury vapour lamp. Two different photoproducts were obtained; under aerobic condition 2-(4,5diphenyl oxazol-2-yl) acetaldehyde (2) and 2-(4,5diphenyl oxazol-2yl) ethanol (3) and under anaerobic condition 2ethyl-4, 5 diphenyl oxazole (4) was obtained as major photoproducts. The formation of the different Oxaprozin photoproducts was explained by discussing the photo degradation mechanism of drug as depicted in figure-3 and figure-4

 

Figure 2: Photodegradation Products of Oxaprozin

 

 

Mechanistic Study:

Under aerobic conditions the formation of photoproducts can take place as the excited Oxaprozin transfers an electron to well known electron acceptor CCl4 which is present as reaction medium. As a result of electron transfer Oxaprozin radical cation and carbon tetrachloride radical anion (CCl4.-) was formed. Carbon tetrachloride radical anion CC14.- easily loses a chlorine anion as it was an unstable radical anion. The oxaprozin radical intermediate reacts with oxygen to produce an unstable hydroperoxide intermediate which dissociates to give photoproduct 2 and 3 (Figure-3).

 

 

Figure: 3 Mechanism of the formation of photoproduct 2 & 3

 

Under anaerobic conditions singlet excited states of Oxaprozin show intramolecular electron transfer from carboxylate to heteroaromatic ring after this electron transfer a carbon dioxide molecule was released and a carbanion intermediate was formed. This carbanion reaction intermediate on protonation give a the final photoproduct-4 (figure-4)

 

 

Figure-4 Mechanism the formation of photoproduct-4

 

Product study:

There is no prominent peak at 1650 cm-1 in the IR spectra of different photoproducts clearly establishing the absence of acid group in all photoproducts. A peak appears at 1680.5 cm-1 in the IR spectra of photoproduct 2 indicates the presence of an aldehyde group in the photoproduct 2. In the NMR spectrum of photoproduct 2 signals in the ring A (1st Phenyl ring), B (2nd Phenyl ring) and C (oxazole ring) were found to be unaffected.Spectroscopic analysis of 3, particularly NMR data indicated that the ring 1st Phenyl ring), B (2nd Phenyl ring) and C (oxazole ring) were unaffected and the IR absorption band at 3410 (OH) supported the assigned structure.The NMR of Photoproduct 4 again indicates that during the conversion the ring A (1st Phenyl ring), B (2nd Phenyl ring) and C (oxazole ring) were conserved. In addition a new signal at δ 1.24 in NMR and a signal at 14.3 in 13CNMR suggested the presence of a new methyl group in photoproduct 4.The structure of the isolated photoproducts was also supported by their mass spectrometric study. A peak at m/z 264 associated with the [C17H13NO2+H]+ ion of the photoproduct 2 and band at m/z 221 associated to protonated 4, 5 diphenyl oxazol-2-yl, This fragmentation pattern indicate the loss off acetaldehyde unit. The mass spectrum of the photoproduct 3 shows a prominent peak at at m/z 266 and another peak m/z 249 indicate the loss of hydroxyl group followed by the protonation. The mass spectra of photoproduct 4 show a god peak at m/z 250 and at m/z 221 these two peaks rise due to the splitting of the side chain. The Phototoxicity of any soluble compound can be evaluated by using standard natural red phototoxicity method and this test exhibited that the photoproduct not show any kind of phototoxicity26-27

 

CONCLUSION:

The proposed work demonstrates the different photodegradation mechanism of our selected Non-steroidal anti-inflammatory drug Oxaprozin under aerobic and anaerobic conditions. The three different photoproducts were identified as the main photodegradation product. The significant yield of the isolated photoproducts demonstrates the importance of the suggested route of the photodegradation of oxaprozin. The photosensitized electron transfer can generate a number of radical cations and anions. It is clear from the observations of the present study that electron transfer plays a significant role in the phototoxicity of the drug. The photochemical investigation of pharmaceutical products is of great relevance from various points of view since the formation free radical intermediate during the course photodegradation is one of the main routes for phototoxic responses of these pharmaceutical products hence The present findings of our work is very useful to understand the probable mechanism phototoxic repossess given by our selected drug oxaprozin.

 

CONFLICTS OF INTEREST:

Authors declare that they have no conflicts of interest.

 

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Received on 06.12.2022            Modified on 12.05.2023

Accepted on 06.08.2023           © RJPT All right reserved

Research J. Pharm. and Tech 2024; 17(4):1653-1656.

DOI: 10.52711/0974-360X.2024.00261