Profen Drugs Research Articles

Introduction of the Trifluoropropionate Moiety into Aromatic Rings via Rhodium-Catalyzed Coupling of Arylboronic Acids with Diazoesters.

A catalytic method for the introduction of pharmaceutically meaningful fluorinated propionic acid side chains into aromatic compounds is presented. In the presence of rhodium catalyst [RhCp*Cl2]2, various arylboronic acids are efficiently coupled with an easy-to-access diazoester reagent to give perfluorinated derivatives of phenylpropionic acids, including top-selling profen drugs. The key advantage of this approach is that the pharmacophore is introduced as a whole and is compatible with various functionalities and drug discovery.

Enantiomeric resolution of three profen drugs using direct thin-layer chromatographic method

Enantiomeric resolution of three profen drugs using direct thin-layer chromatographic method

Dynamic kinetic asymmetric arylation and alkenylation of ketones.

Despite the importance of enantioenriched alcohols in medicinal chemistry, total synthesis, and materials science, the efficient and selective construction of enantioenriched tertiary alcohols bearing two contiguous stereocenters has remained a substantial challenge. We report a platform for their preparation through the enantioconvergent, nickel-catalyzed addition of organoboronates to racemic, nonactivated ketones. We prepared several important classes of α,β-chiral tertiary alcohols in a single step with high levels of diastereo- and enantioselectivity through a dynamic kinetic asymmetric addition of aryl and alkenyl nucleophiles. We applied this protocol to modify several profen drugs and to rapidly synthesize biologically relevant molecules. We expect this nickel-catalyzed, base-free ketone racemization process to be a widely applicable strategy for the development of dynamic kinetic processes.

Silver Nanoparticles Embedded within a Silicon Photocathode for Photoelectrochemical Fixation of CO2 to Synthesize Intermediates of Profen Drugs

Photoelectrochemical (PEC) fixation of carbon dioxide (CO2) into intermediates of Profen drugs, a kind of nonsteroidal antiinflammatory drug, is a useful and important technology for the utilization of CO2. In this work, we successfully designed and prepared a silver nanoparticles (AgNPs)-embedded silicon photocathode for PEC-fixating CO2 to synthesize intermediates of Profen drugs with high efficiency and stability. AgNPs endow the photocathode with extremely high catalytic activity, the Schottky junction between Ag and Si promotes the separation and transfer of photogenerated carriers, the AgNPs-embedded structure greatly improves the stability of the photocathode, and the nanohole structure improves light absorption.

CHARACTERIZATION OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS IN TABLETS BY DIRECT ANALYSIS IN REAL TIME/TIME OF FLIGHT/MASS SPECTROMETRY (DART/TOF/MS) WITHOUT SAMPLE PREPARATION

This powerful mass spectrometric technique was used to investigate four profen drugs which are widely used as non-steroidal anti-inflammatory drugs for treating pain, fever and inflammation: Ibuprofen (M = 206), Flurbiprofen (M = 244), Naproxen (M = 230) and Ketoprofen (M = 254). The DART ion source was operated in positive ion mode with helium as the ionizing medium heated to 250°C. A solution containing a mixture of poly (ethylene glycol) standards PEG 600 and PEG 200 was used for mass calibration. A standard solution of each pure standard was manually introduced by using a small glass rod. The high resolution mass spectra of Ibuprofen, Flurbiprofen, Naproxen and Ketoprofen showed the presence of an intense protonated molecular ion [M + H]+ at 207.13860, 245.09776, 231.10632 and 255.09966 Da, respectively. Moreover, a non-protonated molecular ion M+ was also observed except for Ketoprofen. On the other hand, an intense adduct ion [M + H2O]+ was also present in the four mass spectra. Since these profens are 2-arylpropionic acid derivatives they have a known tendency to form dimers; indeed, an intense protonated ion corresponding to this dimer [2M + H]+ was present in the spectrum of Ibuprofen, Flurbiprofen, Naproxen and Ketoprofen at 413.27102, 489.19944, 461.19266 and 509.19662 Da, respectively. The presence of profens as active ingredients was then investigated in various pharmaceutical tablets collected from the local market. A small piece of each solid tablet was submitted to the DART ion source without any sample preparation. The obtained mass spectrum showed the characteristic peaks corresponding to each profen as active principle, as well as the other ingredients of the tablet.

Amorphisation of Free Acid Ibuprofen and Other Profens in Mixtures with Nanocellulose: Dry Powder Formulation Strategy for Enhanced Solubility.

The formulation of arylpropionic acid derivatives (profens), which are poorly soluble Biopharmaceutical Classification System (BCS) Type II drugs, has a strong impact on their therapeutic action. This article shows that heat-treated powder mixtures of free acid profens with high surface area Cladophora cellulose induces drug amorphization and results in enhanced solubility and bioavailability. Similar mixtures produced using conventional low surface area cellulose, i.e., microcrystalline cellulose, does not produce the same effect. The concept is thoroughly described and links the solid-state characterization data, such as differential scanning calorimetry, X-ray powder diffraction, and Fourier-transform infra-red spectroscopy, with in vitro dissolution in biorelevant media and in vivo pharmacokinetic analysis in rats. The concept is demonstrated for several substances from the profens group, including ibuprofen (main model drug), ketoprofen, flurbiprofen, and naproxen. The presented approach opens new ways to produce solid dosage forms of profen drugs in their free acidic form as alternatives to existing analogues, e.g., drug-salt conjugates or soft gel liquid capsules.

Cyclosporin A-sensitive cytotoxicity of flurbiprofen non-stereoselectively mediated by cytochrome P450 metabolism in three-dimensional cultured rat hepatocytes

2-Arylpropionic acid (profen) drugs are associated with severe hepatotoxicity; however, risk factors are still poorly understood. Acyl-coenzyme A (acyl-CoA) thioesters of profen drugs play a more important role in the covalent binding to rat hepatocyte proteins than the respective acyl-glucuronides. Therefore, we examined whether acyl-glucuronides, acyl-CoA thioesters and oxidative metabolites of profen drugs stereoselectively participated in liver damage. Cytotoxicity was determined by measuring lactate dehydrogenase (LDH) leakage from three-dimensional cultured rat hepatocytes. LDH leakage was not induced by R-2-phenylpropionic acid and R-ibuprofen greatly forming acyl-CoA thioesters. S-Naproxen metabolized mainly by Uridine 5'-diphosphate (UDP)-glucuronosyl-transferase did not enhance LDH leakage. However, flurbiprofen (FLP) induced LDH leakage. A selective cytochrome P450 (CYP) 2C11 inhibitor suppressed 40-50% of the R-FLP and S-FLP-induced cytotoxicity. Borneol non-stereoselectively accelerated the FLP-induced cytotoxicity. The R-FLP-induced cytotoxicity decreased intracellular adenosine triphosphate (ATP) levels to 50% of untreated hepatocytes. An inhibitor of mitochondrial permeability transition pore, cyclosporin A (Cys A), rescued ATP levels and LDH leakage back to control levels. The reactive acyl-CoA thioesters and acyl-glucuronides were not associated with liver damage, denying one of the leading hypotheses. CYP metabolism of FLP non-stereoselectively participated in Cys A-sensitive cytotoxicity, suggesting mitochondrial injury.

In Silico Prediction of Interactions between Site II on Human Serum Albumin and Profen Drugs

Since binding of a drug molecule to human serum albumin (HSA) significantly affects the pharmacokinetics of the drug, it is highly desirable to predict the binding affinity of the drug. Profen drugs are a widely used class of nonsteroidal anti-inflammatory drugs and it has been reported that several members of the profen class specifically bind to one of the main binding sites named site II. The actual binding mode of only ibuprofen has been directly confirmed by X-ray crystallography. Therefore, it is of interest whether other profen drugs are site II binders. Docking simulations using multiple template structures of HSA from three crystal structures of complexes between drugs and HSA have demonstrated that most of the currently available profen drugs should be site II binders.

Polarimetric Detection in HPLC of R(-)-Naproxen: Features and Intrinsic Weakness

Polarimetric detection in high-performance liquid chromatography (HPLC) might seem like a matter of course, especially in areas such as control of the optical purity of drugs or fingerprinting of herbal extracts. However, there are well founded reasons for the relatively low popularity of polarimetric detection in HPLC. Such reasons include, for example, the insufficient sensitivity of this type of detector when compared with photodiode array detection or evaporative light-scattering detection, or the economic factors. This paper, regarding an example of R(-)-naproxen, discusses physical phenomena (i.e., gelation of organic solvents by small organic molecules, the effect of molecular rotors and oscillatory interconversion of chiral analytes) that might obstruct the quantification of profen drugs (more generally, of chiral low molecular carboxylic acids) with the use of HPLC with polarimetric detection. The discussed (or analogous) phenomena are even more general, which hamper the widespread application of polarimetric detection in HPLC.

On ups and downs by analysis of profen drugs. A mini review

Summary Drug analysis is among the most sensitive areas of chemical analysis, simply because of its relevance to human health. Profens make the most important group of nonsteroidal anti-inflammatory drugs (NSAIDs), and in many countries some of them are freely sold over the counter. The in vitro liquid chromatographic analysis of profen drugs faces certain not commonly recognized yet acute and often impassable problems, due to the specific physicochemical properties of these compounds. In this mini review, we share our experience on the practical failures with the enantioseparation of profen drugs both by means of chiral planar and column chromatography. By use of such analytical techniques as polarimetry, 1H and 13C NMR spectroscopy, and mass spectrometry, we point out objectively the reasons that make liquid chromatographic enantioseparation of profens an almost impossible task. These compounds have an inherent ability (both in aqueous and nonaqueous solutions) to undergo oscillatory chiral conversion and oscillatory condensation, combined with a highly pronounced gelating ability. In our view, the oscillatory chiral conversion of profens questions the credibility of widespread claims on the superiority of the curative potential with the (+)-profens over that of the respective (−)-antimers (although the rightfulness of such claims cannot be dismissed, as the in vivo and in vitro behavior of many drugs are known to sometimes fundamentally differ). Moreover, it seems highly probable that, due to their highly pronounced gelating property, profen drugs can easily clog the blood vessels and thereby jeopardize living organisms.

On simple experimental evidence confirmed by HPLC data of supramolecular aggregation and aggregate mobility withS(+)-naproxen in aqueous ethanol solution

Summary In our earlier studies performed with the use of thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), polarimetry, and several other instrumental techniques, we have provided abundant experimental evidence for the oscillatory chiral conversion and the oscillatory condensation of the low-molecular-weight carboxylic acids from the groups of profen drugs, amino acids, and hydroxy acids. We have also proposed several kinetic-diffusive models aimed at elucidation of these striking phenomena, which in the diffusive term assumed contribution from the density inhomogeneity of the investigated liquid systems. Moreover, each model laid special emphasis on the importance of cyclic H-bonded carboxylic acid homodimers of the SS and RR type. In this paper, we introduce a simple experimental approach enabling convenient registration of the density inhomogeneity in the S(+)-naproxen solution prepared in 70% aqueous ethanol. To this effect, we use a zooming scanner that is able to scan this solution in a Petri dish placed in UV light (λ = 254 nm). Scanning in the selected time intervals allows tracing the dynamics of supramolecular aggregation of the investigated profen drugs. The mobility of these aggregates can probably result from the energy released in the process of chemical polycondensation. The obtained results seem to correlate well with those originating from HPLC, and the relevant conclusions are drawn. It seems possible that the zooming scanner can prove helpful in monitoring some other interesting chemical processes as well, thus contributing to the studies on the mechanism and kinetics of the nonlinear organic reactions.

Condensation oscillations in the condensation of mandelic acid

Summary In our earlier studies, we were the first to discover a spontaneous chiral conversion of the low-molecular-weight carboxylic acids dissolved in aqueous media, running in vitro. The investigated chiral carboxylic acids belong to the classes of profen drugs, amino acids, and hydroxy acids. Then, the spontaneous chiral conversion running in vitro and accompanied by the spontaneous condensation of the discussed compounds was discovered. From the literature, we learnt that spontaneous condensation of certain chiral compounds sometimes can be oscillatory in nature. Thus, we considered it noteworthy to check if spontaneous condensation of the chiral low-molecular-weight carboxylic acids follows a linear or a nonlinear dynamic pattern. In this paper, we present the results of our studies on the dynamics of condensation of S-, R-, and rac-mandelic acid, carried out with the aid of the high-performance liquid chromatography with the diode-array detection (HPLC-DAD), and with the aid of mass spectrometry (MS). The obtained data furnish reliable evidence that condensation of mandelic acid is oscillatory in nature. Finally, a theoretical model is recalled, which jointly describes the oscillatory chiral conversion and the oscillatory condensation with S-, R-, and rac-mandelic acid.

An HPLC-DAD and LC-MS Study of Condensation Oscillations with S(+)-Ketoprofen Dissolved in Acetonitrile

In our earlier studies, a spontaneous chiral conversion of the selected low-molecular-weight carboxylic acids (i.e., amino acids, hydroxy acids, and profen drugs) dissolved in aqueous ethanol medium, running in vitro was described. Then it became clear that this spontaneous chiral conversion is accompanied by the spontaneous condensation of the discussed compounds. With several acids, it was established that this condensation is also oscillatory in nature. The theoretical models were developed aiming to give a rough explanation of the observed non-linear processes. In this paper, the results of these studies on the dynamics of condensation with S(+)-ketoprofen, a very popular profen drug, when stored for certain amount of time dissolved in a non-aqueous medium (i.e., acetonitrile) is presented. These investigations were carried out with the aid of two independent high-performance liquid chromatographic systems with the diode array detection and of a third high-performance liquid chromatographic system equipped with mass spectrometric detection. In one cycle of chromatographic measurements, it was possible to monitor condensation of S(+)-ketoprofen in 25-min intervals for 30 h, thus obtaining kinetic information on the progress of this process. Mass spectrometric detection confirmed the presence of new species in the stored solution with molecular weights much higher than that of S(+)-ketoprofen, which can be attributed to the condensation products. The obtained data show that condensation of S(+)-ketoprofen dissolved in acetonitrile progresses in a rapid manner, and that the observed oscillatory concentration changes with S(+)-ketoprofen and with the main condensation product characterize with an irregularity and shallow amplitudes. A theoretical model was referenced that jointly describes the oscillatory chiral conversion and the oscillatory condensation with the low-molecular-weight chiral carboxylic acids.

Examination of Template Structural Effects on CEC Chiral Separation Performance of Molecule Imprinted Polymers Made by a Generalized Preparation Protocol

Some acidic chiral templates were used to prepare open tubular (OT) molecule imprinted polymer (MIP) capillary columns to explore the effects of molecular structures of templates on chiral recognition capabilities and to verify the feasibility of the general MIP preparation protocol introduced in the previous study. The templates are phenyl carboxylic acids and their derivatives. Optimization was carried out for chiral separation of template enantiomers for each MIP column through varying pH and composition of eluent. It was found that the preparation protocol can be successfully applied for the appropriate templates with functional groups fulfilling the three-points interaction rule. The chiral separation performances were quite satisfactory for MIPs of such templates although they are yet inferior to the separation performances of the MIP columns fabricated with the templates of profen drugs (2-arylpropionic acids with a large substituent on the phenyl ring). Subtle variations of the template molecular structures have been found to be critical to enhance chiral recognition ability of the resultant MIP column.

Liquid Chromatographic Investigation of Spontaneous Oscillatory In Vitro Chiral Conversion and Spontaneous Oscillatory Condensation of Simple Carboxylic Acids in Aqueous and Nonaqueous Media

Oscillatory reactions are a narrow reaction type among the entity of chemical reactions and those involving purely organic compounds make a small contribution to an overall number of all known oscillatory reactions. The most abundant type is purely inorganic and mixed inorganic-organic oxidation-reduction reactions, basically because monitoring them is relatively easy (e.g., with use of potentiometric measurements). Investigation of the organic reactions can be more demanding, and then chromatography is an analytical technique of choice. In this paper, we provide an overview of chromatographic evidence with oscillatory reactions discovered in our laboratory in the course of the last several years that involve the low-molecular-weight carboxylic acids (profen drugs, amino acids, and hydroxy acids). The investigated processes comprise the oscillatory chiral conversion and the oscillatory condensation, spontaneously running in the aqueous and nonaqueous abiotic media, and they were traced with use of TLC and HPLC coupled with different detector types.

Preparation of open tubular molecule imprinted polymer capillary columns with various templates by a generalized procedure and their chiral and non‐chiral separation performance in CEC

A generalized preparation procedure of open tubular (OT) molecule imprinted polymer (MIP) columns is proposed for a number of templates with acidic functionality such as profen drugs and others. The template (S-enantiomer) was mixed with methacrylic acid, ethylene glycol dimethacrylate and 4-styrenesulfonic acid, dissolved in a porogen mixture of ACN/2-propanol (9/1), and incubated in a pretreated and silanized fused silica capillary by the thermal non-covalent polymerization procedure. The whole preparation procedure was exactly the same for all the MIP capillaries except for the selection of template. Nevertheless, the morphologies of the MIP layers were markedly variant depending upon the choice of template. The separation efficiency of each OT-MIP column for chiral separation of R- and S-enantiomers was examined and tuned to obtain the best separation efficiency by changing the chromatographic parameters such as eluent composition and pH. Different optimized conditions were obtained for different OT-MIP columns. Nevertheless, a unified eluent could be used to obtain still quite satisfactory results. Non-chiral separation of the MIP columns were also examined in the unified eluent with two sets of test mixtures, that is, a mixture of alkylbenzenes and a mixture of small polar solutes. The chiral and non-chiral separation of this study resulted in very good separation efficiencies. This work is the very first study for the generalization of preparation of OT-MIP columns for a number of templates.

On the spontaneous condensation of profens, with ketoprofen as an example

Summary In a series of recently published full-length papers and short communications we attempted to gain deeper insight into elementary reactions which might contribute to the non-linear nature of the spontaneous chiral conversion of low-molecular-weight carboxylic acids. Earlier, we succeeded in demonstrating that amino acids and hydroxy acids can undergo spontaneous peptidization and spontaneous esterification (both regarded as condensation), respectively, when dissolved in 70% aqueous ethanol. In this study we provide experimental proof from thin-layer chromatography and 13C NMR spectroscopy of spontaneous condensation of profens, with ketoprofen as an example. It can be expected that other profen drugs undergo an analogous condensation. In the future, an analogy between the ability of amino acids, hydroxy acids, and profens to undergo spontaneous peptidization or condensation (as reported in our papers), and the ability of selected organosilanols to undergo the spontaneous oscillatory condensation (...

Combined use of chiral ionic liquid and cyclodextrin for MEKC: Part I. Simultaneous enantioseparation of anionic profens

The enantiomers of five profen drugs were simultaneously separated by MEKC with the combined use of 2,3,6-tri-O-methyl-beta-cyclodextrin and chiral cationic ionic liquid, N-undecenoxy-carbonyl-L-leucinol bromide, which formed micelles in aqueous buffers. Enantioseparations of these profen drugs were optimized by varying the chain length and concentration of the IL surfactant using a standard recipe containing 35 mM 2,3,6-tri-O-methyl-beta-cyclodextrin, 5 mM sodium acetate at pH 5.0. The batch-to-batch reproducibility of N-undecenoxy-carbonyl-L-leucinol bromide was tested and found to have no significant impact in terms of enantiomeric resolution, efficiency, and migration time. Finally, this method was successfully applied for the quantitative determination of ibuprofen in pharmaceutical tablets.

On the spontaneous condensation of selected hydroxy acids

Summary In a previous study we provided thin-layer chromatographic, polarimetric, and other experimental evidence that phenylglycine can undergo easy spontaneous peptidization in abiotic aqueous media. From our unpublished results it is apparent that this behaviour is also characteristic of some other amino acids (e.g., alanine and phenylalanine). It seems highly probable that this abiotic peptidization of amino acids dissolved in aqueous media is directly linked to their ability to undergo spontaneous oscillatory chiral conversion. In our earlier research it was also shown that spontaneous oscillatory chiral conversion was characteristic not only of amino acids but also of several other classes of carboxylic acid, including profen drugs and hydroxy acids. We therefore decided to check whether selected chiral hydroxy acids — lactic acid and mandelic acid — previously recognized for their ability to undergo spontaneous oscillatory chiral conversion, could also furnish the respective polyacids. Condensation of hydroxy acids can be viewed as a reaction fully analogous with peptidization of amino acids and, hence, it seemed to us highly probable that it also can be triggered by oscillatory chiral conversion. In our study, we used thin-layer chromatography and 13C NMR spectroscopy to check whether formation of polylactic acid and polymandelic acid occurred in stored solutions of lactic and mandelic acids. By means of polarimetry with continuous recording we provided experimental evidence that all three hydroxy acids investigated (i.e. l-(+)-lactic acid, S-(+)-mandelic acid, and R-(−)-mandelic acid) undergo continuous chiral conversion. From the thin-layer chromatographic results obtained it was apparent that — similar to the spontaneous and instantaneous peptidization of amino acids — the hydroxy acids investigated also undergo easy condensation to form the respective polyacids. 13C NMR spectroscopy provided additional experimental confirmation of this.

Long open tubular molecule imprinted polymer capillary columns with excellent separation efficiencies in chiral and non‐chiral separation by capillary electrochromatography

Long open tubular S-ketoprofen molecule imprinted polymer capillary columns (1, 2, and 3 m) with the number of theoretical plates (N) over a million for both chrial and non-chiral CEC separation have been prepared. Chiral separation of racemic ketoprofen and non-chiral separation of other profen drugs have been achieved with excellent efficiency and good selectivity after optimization of the chromatographic conditions. The N value per column was not proportional to the effective column length although it was increased with the column length. This study has shown the outstanding prospect of the strategy to form a porous and rugged open tubular layer in a moderately long (1 m) capillary column in molecule imprinted polymer-CEC studies.