Mechanism of Photoinduced Decomposition of Ketoprofen

Abstract

UV-induced decarboxylation of the NSAID ketoprofen, followed by activation of molecular oxygen or formation of a decarboxylated peroxide adduct, is explored using computational quantum chemistry. The excited energy surfaces reveal that the neutral species will not decarboxylate, whereas the deprotonated acid decarboxylates spontaneously in the triplet state, and with an associated 3-5 kcal/mol barrier from several low-lying excited singlet states. The observed long lifetimes of the decarboxylated anion is explained in terms of the high stability of the triplet benzoyl ethyl species with protonated carbonylic oxygen, from which there is no obvious decay channel. Mechanisms for the generation of singlet oxygen and superoxide are discussed in detail. Addition of molecular oxygen to give the corresponding peroxyl radical capable of initiating propagating lipid peroxidation reactions is also explored. The computed data explains all features of the observed experimental observations made to date on the photodegradation of ketoprofen.

Water‐ and Acid‐Mediated Excited‐State Intramolecular Proton Transfer and Decarboxylation Reactions of Ketoprofen in Water‐Rich and Acidic Aqueous Solutions

“…This is consistent with the deprotonation from the triplet state of neutral KP being found to be energetically viable, which may in turn be accompanied by a decarboxylation of anion produced from this reaction. [32] Scaiano and co-workers reported that the strong transient absorption band of carbanion appeared at 650 nm. [25] In the case of the ns-TR 3 experiments for KP in water-rich solutions, the carbanion intermediate cannot be observed when 319.9 nm is used as the probe wavelength.…”

“…BCH species probably undergoes a water-assisted proton shift or acid-assisted proton transfer and then radiationless decay to produce the singlet ground-state 3-ethylbenzophenone product. [32,47] Density functional theory (DFT) computational study of acid-catalyzed decarboxylation of triplet-state KP: Based on the results obtained by the ns-TR 3 experiments, a Brønsted acid (perchloric acid, sulfuric acid, and hydrochloric acid) can catalyze the decarboxylation reaction of 3 [KP] in moderate and strongly acidic solutions. To better understand the decarboxylation reaction of complex (RC n ), transition state (TS n ), and product complex (PC n ) (for which n represents the sequence of reaction steps) obtained from UB3LYP/6-311G** calculations on the 3 [KP] reacting with different acids involved in the reaction system.…”

New nonsteroidal anti‐inflammatory molecules with reduced photodegradation side effects and enhanced COX‐2 selectivity

“…Phototoxic degradation mechanisms of the most commonly used drugs (due to their availability as OTC agents, dispensed in large quantities with or without prescription) ketoprofen (KP), ibuprofen (IBU), naproxen (NP), flurbiprofen (FBP), diclofenac (DF), suprofen (SUP), and tiaprofenic acid (TP) have been extensively studied experimentally and are well documented, e.g., [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. Recently, studies have been performed using computational quantum chemistry techniques (DFT, TD-DFT) to investigate the detailed photodegradation mechanisms of these compounds [39][40][41][42][43][44]. Despite the fact that such a large number of experimental studies have been performed to date; however, to our knowledge, no new or modified drugs have been proposed or dispensed into the market that are considered to reduce or prevent the phototoxicity of this NSAID family.…”

“…[6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]) and our previous theoretical quantum chemical studies [39][40][41][42][43][44], new compounds are herein reported, obtained by modifying the parent NSAIDs with the aim to be more photostable. To investigate their activity and selectivity toward the COX isoforms, molecular modeling studies are also carried out with the help of information available from X-ray diffraction studies.…”

“…The photochemical reactions forming all these species can be experimentally investigated by spectroscopic techniques, of which laser flash photolysis and UV-visible spectrophotometry are particularly common. In this context, KP [39] spontaneously decarboxylates from its deprotonated triplet state (without energy barrier), whereas the corresponding deprotonated (acidic) IBU and NP decarboxylate by passing low-energy barrier of <0.3 and 1 kcal/mol, respectively [40,41]. These low barriers of decarboxylation have been raised through the currently introduced modifications, leading to reduced photodegradation potential and hence safer compounds than the parent drug molecules as discussed below.…”