Chiral Nonsteroidal Anti-inflammatory Drug Research Articles

Loaded of Etodolac on Zinc Oxide Nanoparticles

Etodolac, a chiral nonsteroidal anti-inflammatory drug (NSAID), is widely used for pain management and arthritis treatment. However, it suffers from various side effects, including gastrotoxicity and cardiovascular risks. This study investigated the potential of zinc oxide nanoparticles (ZnO NPs) as a delivery platform for etodolac to improve its efficacy and mitigate these adverse effects. ZnO NPs possess several attractive properties for drug delivery applications, including low toxicity, biodegradability, and the ability to target specific tissues. In this study, etodolac was successfully loaded onto ZnO NPs, and the resulting nanocomposites were characterized using Fourier-transform infrared spectroscopy (FT-IR) and scanning electron microscopy (SEM). FT-IR analysis confirmed the successful loading of etodolac onto the ZnO NPs. Additionally, SEM images revealed morphological changes on the surface of the nanocomposites compared to pure ZnO NPs, further indicating successful drug loading. These findings demonstrate the feasibility of developing etodolac-loaded ZnO NPs as a promising approach for targeted drug delivery. Further studies are warranted to investigate the vivo efficacy and safety of these nanocomposites, paving the way for their potential clinical application.

Designing Powerful Biindole-Based Inherently Chiral Selectors: Enhancing Enantiodiscrimination by Core Functionalization with Additional Coordination Elements.

Among inherently chiral selectors of axial stereogenicity, usually resulting in very good enantiodiscrimination performances, the biindole-based family has the additional advantage of very easy functionalization of the two nitrogen atoms with a variety of substituents with desirable properties. Aiming to evaluate the possibility of exploiting such feature to enhance the enantiodiscrimination ability of the archetype structure, a series of three inherently chiral monomers were designed and synthesized, characterised by a 2,2'-biindole atropisomeric core conjugated to bithiophene wings enabling fast and regular electrooligomerization, and functionalised at the nitrogen atoms with an ethyl, a methoxyethyl, or a hydroxyethyl substituent. Nitrogen alkylation was also exploited to obtain for the first time the chemical resolution of the biindole selectors without employing chiral HPLC. The enantiodiscrimination ability of the selector series was comparatively evaluated in proof-of-concept chiral voltammetry experiments with a "benchmark" chiral ferrocenyl probe as well as with chiral non-steroidal anti-inflammatory drugs naproxen and ketoprofen. The large enantiomer potential differences for all probes increased in the ethyl < methoxyethyl ≪ hydroxyethyl sequence of selector substituents, supporting our assumption on the beneficial role of an additional coordination element. The powerful hydroxyethyl selector was also applied to ketoprofen in a commercial drug matrix.

Innovative insight into the mechanism of enantioselective skin permeation for chiral drugs

ABSTRACT Objectives A profound comprehension of the molecular mechanisms underpinning the enantioselective transdermal permeation of chiral drugs is critical in the design and assessment of transdermal preparations. The primary objective of this study is to investigate the distinct skin permeation behaviors exhibited by enantiomers of non-steroidal anti-inflammatory drugs (NSAIDs) and elucidate the intricate molecular mechanism at play. Methods In vitro and in vivo transdermal permeation studies of chiral NSAIDs were performed using transdermal patch and solution system. Chiral interaction between NSAIDs enantiomers and synthesized chiral ceramide present in the skin was characterized to clarify the different transdermal behaviors. Results The S-enantiomers of NSAIDs exhibited higher permeability through the skin than R-enantiomer in vitro (1.5-fold) and in vivo (2.0-fold), which was attributed to a stronger interaction between S-enantiomer and ceramide caused by more favorable spatial conformations. S-enantiomer required lower activation energy (24.4 kJ/mol) and Gibbs energy (43.3 kJ/mol), which was favorable in forming the H-bond with ceramide in the skin, resulting in more permeation. Conclusion This research furnished an innovative comprehension of the molecular underpinnings governing the enantioselective permeation of drug enantiomers through the skin, fostering the minimization of undesired enantiomer ingestion (distomers) and amplifying therapeutic efficiency.

The enantioselective enhancing effect and mechanistic insights of chiral enhancers in transdermal drug delivery

Overlook of chiral consideration in transdermal drug delivery increases administrated dose and risk of side effects, decreasing therapeutical effects. To improve the transdermal delivery efficiency of eutomer, this work focused on investigating the law and mechanism of enantioselective enhancing effects of chiral permeation enhancers on drug enantiomers. Chiral nonsteroidal anti-inflammatory drugs and terpene permeation enhancers were selected as model drug and enhancers. The results indicated that the L-isomer of permeation enhancers increased the skin absorption of S-enantiomer of drug and D-isomer improve the permeation of R-enantiomer, in which the enhancement effect (ER) of L-menthol on S-enantiomer (ER = 3.23) was higher than that on R-enantiomer (ER = 1.49). According to the pharmacokinetics results, L-menthol tended to enhance the permeation of S-enantiomer better than R-enantiomer (2.56 fold), and showed excellent in vitro/in vivo correlations. The mechanism study showed that L-isomer of permeation enhancers improved the permeation of S-enantiomer by increasing the retention, but the D-isomer by improving partition for better permeation. Enantioselective mechanism indicated that the weaker chiral H-bond interaction between drug-chiral enhancers was caused by the enantiomeric conformation. Additionally, stronger chiral enhancers-skin interaction between L-isomer and S-conformation of ceramide produced better enhancing effects. In conclusion, enantioselective interaction of chiral drug-chiral enhancers and chiral enhancers-chiral skin played a critical role in transdermal drug delivery, rational utilization of which contributed to improving the uptake of eutomer and inhibiting distomers to decrease a half of dose and side effects, increasing transdermal therapeutical efficiency.

Structural investigations of stereoselective profen binding by equine and leporine serum albumins.

Serum albumin, the most abundant transport protein of mammalian blood, interacts with various nonsteroidal anti-inflammatory drugs (NSAIDs) affecting their disposition, metabolism, and excretion. A big group of chiral NSAIDs transported by albumin, profens, is created by derivatives of 2-arylpropionic acid. The chiral center in the structures of profens is adjacent to the carboxylate moiety and often determines different pharmacological properties of profen enantiomers. This study describes crystal structures of two albumins, isolated from equine and leporine serum, in complexes with three profens: ibuprofen, ketoprofen, and suprofen. Based on three-dimensional structures, the stereoselectivity of albumin is discussed and referred to the previously published albumin complexes with drugs. Drug Site 2 (DS2) of albumin, the bulky hydrophobic pocket of subdomain IIIA with a patch of polar residues, preferentially binds (S)-enantiomers of all investigated profens. Almost identical binding mode of all these drugs clearly indicates the stereoselectivity of DS2 towards (S)-profens in different albumin species. Also, the affinity studies show that DS2 is the major site that presents high affinity towards investigated drugs. Additionally, crystallographic data reveal the secondary binding sites of ketoprofen in leporine serum albumin and ibuprofen in equine serum albumin, both overlapping with previously identified naproxen binding sites: the cleft formed between subdomains IIIA and IIIB close to the fatty acid binding site 5 and the niche created between subdomains IIA and IIIA, called fatty acid site 6.

Simultaneous enantiomeric analysis of chiral non-steroidal anti-inflammatory drugs in water, river sediment, and sludge using chiral liquid chromatography-tandem mass spectrometry

A sensitive and reliable analytical method for the simultaneous enantiomeric analysis of chiral non-steroidal anti-inflammatory drugs in water, river sediment, and sludge was established.

Nanosizing of sodium ibuprofen by SAS method

The micro/nanosizing of drug particles has been identified as a potentially effective and broadly applicable approach. Sodium ibuprofen is a chiral nonsteroidal anti-inflammatory drug. This work aimed to recrystallize particles of sodium ibuprofen, reducing its particle size, using a Supercritical Anti-solvent (SAS) technique performed in a modified supercritical fluid extraction unit. For this purpose, the phase equilibrium of the system sodium ibuprofen+acetone+CO2 was also investigated at temperatures ranging from 35 to 55°C. Phase equilibrium data exhibited solid–vapor–liquid and vapor–liquid transitions. The average particle sizes of the SAS-precipitated ibuprofen were below 380±84nm for all the SAS conditions tested, reducing the original dimension of the samples from micrometric to nanometric order. The best SAS operational conditions, in order to produce the lowest estimated particle size and higher crystallinity were, respectively, using 0.5 and 1.0mgibuprofen/mL, and 1mLsolution/min, 1kgCO2/h, 110bar and 35°C. The DSC results indicated that, besides reducing the ibuprofen particle size, the SAS process appears to have changed the original sodium ibuprofen to the acid form. The PXRD and RAMAN results indicated that the SAS process at 1mgibuprofen/mL, 1mLsolution/min, 1kgCO2/h, 110bar and 35°C is the best condition to obtain ibuprofen particles with higher crystallinity.

SAT0427 S- and R-flurbiprofen pharmacokinetics following repeated transdermal medication to healthy subjects

BackgroundFlurbiprofen (fbp) is a chiral non-steroidal anti-inflammatory drug (NSAID) used as racemate in the treatment of rheumatism & non-arthritic pain. Topical formulations of NSAIDs have become popular for treatment of...

Development of Novel Methods for Preparing Chiral Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) by Asymmetric Esterification

A novel and efficient method for preparing chiral 2-arylalkanoic acid derivatives, including non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, ketoprofen, fenoprofen, flurbiprofen, and naproxen, and their esters by asymmetric esterification is presented in this paper. A variety of optically active carboxylic esters are produced by the kinetic resolution of racemic 2-arylalkanoic acids with achiral alcohols, using carboxylic anhydrides in the presence of chiral acyl-transfer catalysts. It was found that the combination of the modified benzotetramisole-type catalyst, (S)-β-Np-BTM, and a newly designed nucleophile, di(α-naphthyl)methanol, in the presence of a carboxylic anhydride, p-methoxybenzoic anhydride (PMBA) or pivalic anhydride (Piv₂O), is most suitable for producing the corresponding chiral esters from 2-arylpropionic acid derivatives, with high enantiomeric excess under very mild reaction conditions. Using this new chiral acylation system, fairly broad substrate scope could be realized despite the multi-functional groups on the aromatic ring of the substrate. It was also revealed that ortho-substituted aromatic compounds, especially, 2,5-disubstituted aromatic ones were the most suitable compounds for providing a high selectivity.

Non-enzymatic dynamic kinetic resolution of racemic α-arylalkanoic acids: an advanced asymmetric synthesis of chiral nonsteroidal anti-inflammatory drugs (NSAIDs)

An efficient protocol was developed to produce chiral 2-arylalkanoic esters in high yields (up to 99%) from racemic carboxylic acids utilizing the racemization of the mixed-anhydrides generated from acid components with pivalic anhydride in the presence of an acyl-transfer catalyst. The present DKR involves the enantio-discriminating esterification of the racemic 2-arylalkanoic acids and the rapid racemization of the chiral 2-arylalkanoic acids under suitable reaction conditions using pivalic anhydride, diisopropylethylamine, and benzotetramisole (BTM) in a polar solvent, and this method was successfully applied for the preparation of pharmacodynamically active (S)-enantiomers of nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen.

Stereoselective flunoxaprofen-S-acyl-glutathione thioester formation mediated by acyl-CoA formation in rat hepatocytes.

Flunoxaprofen (FLX) is a chiral nonsteroidal anti-inflammatory drug that was withdrawn from clinical use because of concerns of potential hepatotoxicity. FLX undergoes highly stereoselective chiral inversion mediated through the FLX-S-acyl-CoA thioester (FLX-CoA) in favor of the (R)-(-)-isomer. Acyl-CoA thioester derivatives of acidic drugs are chemically reactive species that are known to transacylate protein nucleophiles and glutathione (GSH). In this study, we investigated the relationship between the stereoselective metabolism of (R)-(-)- and (S)-(+)-FLX to FLX-CoA and the subsequent transacylation of GSH forming FLX-S-acyl-glutathione (FLX-SG) in incubations with rat hepatocytes in suspension. Thus, when hepatocytes (2 million cells/ml) were treated with (R)-(-)- or (S)-(+)-FLX (100 microM), both FLX-CoA and FLX-SG were detected by sensitive liquid chromatography-tandem mass spectrometry techniques. However, these derivatives were observed primarily from (R)-(-)-FLX incubation extracts, for which the formation rates of FLX-CoA and FLX-SG were rapid, reaching maximum concentrations of 42 and 2.8 nM, respectively, after 6 min of incubation. Incubations with (S)-(+)-FLX over 60 min displayed 8.1 and 2.7% as much FLX-CoA and FLX-SG area under the concentration versus time curves, respectively, compared with corresponding incubations with (R)-(-)-FLX. Coincubation of lauric acid (1000 microM) with (R)-(-)-FLX (10 microM) led to the complete inhibition of FLX-CoA formation and a 98% inhibition of FLX-SG formation. Reaction of authentic (R,S)-FLX-CoA (2 microM) with GSH (10 mM) in buffer (pH 7.4, 37 degrees C) showed the quantitative formation of FLX-SG after 3 h of incubation. Together, these results demonstrate the stereoselective transacylation of GSH in hepatocyte incubations containing (R)-(-)-FLX, which is consistent with bioactivation by stereoselective (R)-FLX-CoA formation.

Ibuprofen–arginine generates nitric oxide and has enhanced anti-inflammatory effects

Ibuprofen, a chiral non-steroidal anti-inflammatory drug chemically related to fenoprofen and naproxen, has moderate but definite anti-inflammatory, analgesic and antipyretic properties, with considerably less gastrointestinal adverse effect than other drugs in the same family. Currently available in the market are preparations in which bioavailability of ibuprofen is increased by salification with various salts. We have investigated the pharmacological properties of one such salt, ibuprofen–arginine, of biological interest because l-arginine acts as substrate of the nitric oxide (NO) synthesising enzymes. Using epithelial HeLa cells expressing the endothelial NO synthase we show that ibuprofen–arginine releases NO and that this NO protects against the cytotoxic apoptogenic effects of staurosporine. We also found that ibuprofen–arginine is endowed with enhanced anti-inflammatory effects with respect to ibuprofen, as shown by reduced hind paw oedema, neutrophil infiltration and chondrocyte apoptosis in collagen-induced mouse arthritis, a model of chronic inflammation. NO has pleiotropic beneficial effects that may contribute to limit inflammation and anti-inflammatory compounds able to release NO display higher efficacy than the parent drugs in defined clinical settings. Our results open the possibility that NO generation contributes to the enhanced anti-inflammatory effects of ibuprofen–arginine vs. ibuprofen, suggesting co-administration of anti-inflammatory drugs and arginine as an additional way to exploit the beneficial effects of NO.

Modulatory effect of chiral nonsteroidal anti‐inflammatory drugs on apoptosis of human neutrophils

Polymorphonuclear neutrophils (PMNs) are short-lived leukocytes that die by apoptosis. Although PMNs are crucial in the defense against infection, they have been implicated in the pathogenesis of tissue injury observed in inflammatory diseases. The induction or prevention of PMN apoptosis is currently discussed as a key event in the control of inflammation. Caspase-3 activation is the first step in the execution phase of apoptosis. In the study, effect of racemic mixtures and enantiomers of 2-arylpropionic acid derivatives: ketoprofen, flurbiprofen (FBP), and (+)-S-naproxen and 2-arylbutyric acid: indobufen on apoptosis activation via caspase-3 and phosphatidylserine (PS) translocation (annexin-V binding) in human neutrophils in vitro has been investigated. Caspase-3 activation was detected by Western blotting, fluorometric assay of DEVD-AMC cleavage, and flow cytometry with carboxyfluorescein (FAM) labeled caspase inhibitor. PMNs were isolated and cultured up to 24 h. The chiral nonsteroidal anti-inflammatory drugs (NSAIDs) were found to modulate human PMN apoptosis in a dose- and time-dependent manner. The greater activation of caspase was found at 75-150 microg/ml concentration of racemates as well enantiomers, especially for FBP, whereas NSAIDs at smaller quantities (15 microg/ml) were inactive. At concentration of 75 microg/ml, NSAIDs increased the rate of PS externalization in PMA-stimulated and non-stimulated neutrophils. Additionally, no cytotoxic effect of the NSAIDs was observed at concentration up to 75 microg/ml that induce apoptosis. Regulation of caspase activity by NSAIDs may represent a potent target to trigger apoptosis and resolve inflammatory disorders.

Stereodifferentiating Drug−Biomolecule Interactions in the Triplet Excited State: Studies on Supramolecular Carprofen/Protein Systems and on Carprofen−Tryptophan Model Dyads

Stereoselective interaction between a chiral nonsteroidal antiinflammatory drug, namely carprofen (CP), and human serum albumin (HSA) was studied, and the results were compared with those obtained with model dyads. In the presence of albumin the same triplet-triplet transition was detected for both CP stereoisomers; however, time-resolved measurements revealed a remarkable stereodifferentiation in the CP/HSA interaction. For each stereoisomer, the decay dynamics evidenced the presence of two components with different lifetimes that can be correlated with complexation of CP to the two possible albumin binding sites (site I and site II). This assignment was confirmed by using ibuprofen, a site II displacer. Thus, the shorter lived components, for which stereodifferentiation was more important (tauR/tauS ca. 4), were ascribed to the CP triplet state in site I; the lifetime shortening can be attributed to electron-transfer quenching by the only tryptophan (Trp) of the protein. Laser flash photolysis of model dyads containing covalently linked CP and Trp revealed formation of the expected Trp radical cation, providing support for such a mechanism. Moreover, significant stereodifferentiation was observed between the (R)- and (S)-CP-Trp dyads. In the case of CP/HSA complexes, as well as in the model compounds, the stereodifferentiation detected in the decays is in good agreement with that observed in the formation of the only CP photoproduct, resulting from a photodehalogenation process. Moreover, stereodifferentiation was also found to occur for the photobinding of CP to the protein.

The pharmacokinetics of vedaprofen and its enantiomers in dogs after single and multiple dosing

Vedaprofen is a chiral nonsteroidal anti-inflammatory drug that has been developed as a gel formulation for oral administration to dogs and horses. The pharmacokinetics of vedaprofen and its enantiomers were studied in beagle dogs after single (intravenous solution and oral gel) and multiple (oral gel) dosing at a dosage of 0.5 mg/kg body weight. Plasma concentrations of vedaprofen and its enantiomers were analysed by HPLC. The plasma protein binding of vedaprofen was studied by ultrafiltration. The absorption of vedaprofen was rapid (tmax 0.63 +/- 0.14 h) and almost complete after oral administration (bioavailability 86 +/- 7%). The terminal half-lives after intravenous and oral administration, 16.8 +/- 2.2 and 12.7 +/- 1.7 h respectively, were of the same order of magnitude. Enantioselective analysis showed that the R(-) enantiomer predominated in plasma. The change in the plasma time course of the plasma R(-)/S(+) enantiomer concentration ratio over time was similar after single intravenous and oral dosing, with R(-)/S(+) ratios in the AUC of 1.7 +/- 0.5 and 1.9 +/- 0.2 respectively. Plasma protein binding of vedaprofen and its enantiomers was high (> 99.5%). Vedaprofen is absorbed rapidly from the gastrointestinal tract, has a high bioavailability and does not accumulate in plasma in dogs following repeated oral administration.

Enantioselective Pharmacokinetics of Ibuprofen and Involved Mechanisms

Although dexibuprofen (S-ibuprofen) was marketed in Austria and Switzerland, the racemate at various formulations is still extensively used worldwide, and there are no indications that the racemate will be replaced by the single enantiomer. Thus, elucidation of the characteristics and involved mechanisms of the chiral pharmacokinetics of racemic ibuprofen is of special importance for the understanding of the pharmacological and toxicological consequences, and for prediction of the clinically potential drug interactions and influence of the pathological states. Stereoselective pharmacokinetics and metabolism are common features for chiral nonsteroidal antiinflammatory drugs (NSAIDs) and especially for 2-arylpropionic acid derivatives characterized with a chiral center adjacent to the carboxyl group. Although the enantioselective pharmacokinetic characteristics of different NSAIDs should be treated case by case, they share similar mechanisms underlying the protein binding, metabolism and chiral inversion. Ibuprofen was the most extensively researched drug in terms of chiral characteristics and mechanisms. Therefore, elucidation of the mechanisms derived from research on ibuprofen may provide better understanding and prediction of other chiral drugs. This article attempts to elucidate the chiral pharmacokinetics and involved mechanisms of ibuprofen in comparison with other NSAIDs based on recent developments. Topics on history of ibuprofen, enantioselective analysis method, absorption, protein binding, conventional metabolism, metabolic chiral inversion, gene polymorphism, and biochemical developments were included. It is worth mentioning that some underlying biochemical mechanisms, especially for the metabolic chiral inversion and ethnic differences still remain to be seen. Further research is required to develop human-resourced researching model and to provide more evidence concerning the site of inversion, species variation, CYP450 gene polymorphisms, and biochemical mechanisms.

Enantioselective Pharmacokinetics of Ibuprofen and Involved Mechanisms

Although dexibuprofen (S-ibuprofen) was marketed in Austria and Switzerland, the racemate at various formulations is still extensively used worldwide, and there are no indications that the racemate will be replaced by the single enantiomer. Thus, elucidation of the characteristics and involved mechanisms of the chiral pharmacokinetics of racemic ibuprofen is of special importance for the understanding of the pharmacological and toxicological consequences, and for prediction of the clinically potential drug interactions and influence of the pathological states. Stereoselective pharmacokinetics and metabolism are common features for chiral nonsteroidal antiinflammatory drugs (NSAIDs) and especially for 2-arylpropionic acid derivatives characterized with a chiral center adjacent to the carboxyl group. Although the enantioselective pharmacokinetic characteristics of different NSAIDs should be treated case by case, they share similar mechanisms underlying the protein binding, metabolism and chiral inversion. Ibuprofen was the most extensively researched drug in terms of chiral characteristics and mechanisms. Therefore, elucidation of the mechanisms derived from research on ibuprofen may provide better understanding and prediction of other chiral drugs. This article attempts to elucidate the chiral pharmacokinetics and involved mechanisms of ibuprofen in comparison with other NSAIDs based on recent developments. Topics on history of ibuprofen, enantioselective analysis method, absorption, protein binding, conventional metabolism, metabolic chiral inversion, gene polymorphism, and biochemical developments were included. It is worth mentioning that some underlying biochemical mechanisms, especially for the metabolic chiral inversion and ethnic differences still remain to be seen. Further research is required to develop human-resourced researching model and to provide more evidence concerning the site of inversion, species variation, CYP450 gene polymorphisms, and biochemical mechanisms.

Enantioselective determination of ibuprofen in plasma by high-performance liquid chromatography–electrospray mass spectrometry

The enantioselective analysis of ibuprofen (IBU), a chiral nonsteroidal anti-inflammatory drug, in human plasma was carried out by high-performance liquid chromatography (HPLC)–mass spectrometry (LC–MS–MS). The plasma samples were prepared by liquid–liquid extraction using hexane:ethyl acetate (8:2, v/v). The HPLC chiral resolution of IBU was obtained using a chiral stationary phase based on a tris-(3,5-dimethylphenylcarbamate) amylose derivative, under reversed phase conditions (CHIRALPAK AD-RH column), using a mobile phase consisting of methanol:water (8:2, v/v), containing 0.1% of an aqueous solution of phosphoric acid at pH 2, at a flow rate of 0.6 ml/min. A make-up liquid of 4.5% (w/v) NH 4OH aqueous solution was used to assure optimum electrospray ionization in the negative mode. The coefficients of variation and deviation from nominal values were lower than 15% for both within- and between-day assays. The quantitation limit was 0.12 μg/ml and the linear range was 0.12–90.0 μg/ml for both enantiomers. The method proved to be suitable for single dose pharmacokinetic studies.

Nonsteroidal antiinflammatory drugs inhibiting prostanoid efflux: as easy as ABC?

Nonsteroidal antiinflammatory drugs (NSAIDs) and prostanoids continue to be fascinating research targets. Humans have been using NSAIDs in one form or another, from folk remedies through to the products of modern pharmaceutical research, for thousands of years. However, we still have not characterized all of the systems through which these drugs produce their beneficial and harmful effects (1, 2). We are certain, from seminal work carried out in the 1960s and early 1970s, that NSAIDs have the common property of inhibiting the activity of cyclooxygenase (COX), the enzyme that initiates the formation of prostanoids (1). An explosion of research in the last decade or so has led us to understand that COX exists in two forms, COX-1 and -2, and that drugs targeted against COX-2 still retain the antiinflammatory properties of traditional NSAIDs (1, 2). Because the traditional NSAIDs generally inhibit both isoforms of COX, it is the ability of NSAIDs to inhibit COX-1 that has become associated with their deleterious side effects, particularly within the gastrointestinal tract. However, this dualist approach, COX-1 = good prostanoids and COX-2 = bad prostanoids, does not appear to supply a full understanding of the effects of NSAIDs in vivo . For that reason, researchers have continued to look for other targets at which NSAIDs may exert effects. For example, NSAIDs have been shown to inhibit factors within inflammatory pathways, such as nuclear factor κ-B (3), and to elevate the production of antiinflammatory adenosine (4). Other researchers have suggested that there could be yet more COX isoforms on which the NSAIDs act (see ref. 2). Experiments with chiral NSAIDs have also shown that enantiomers inactive on COX duplicate some of the therapeutic effects of NSAIDs. For example, whereas for ketoprofen and flurbiprofen only the S- and not the R-enantiomers inhibit COX (5 …

Micronization of Ibuprofen by RESS

Ibuprofen (a chiral nonsteroidal antiinflammatory drug) is micronized via the Rapid Expansion of the Supercritical CO 2 Solution (RESS) process. Experiments are conducted to investigate the effects of extraction pressure (130–170 bar), pre-expansion temperature (76–104 °C), capillary length (8 and 12 mm), spraying distance (20–60 mm), and collision angle (45 and 90°) on the size and morphology of the precipitated Ibuprofen particles. The characterization (size, morphology and crystallinity) of the particles is carried out using scanning electron microscopy (SEM), and X-ray diffraction (XRD) measurements. The average particle size of the original material is 45 μm (±1.51), while the average particle size of Ibuprofen after micronization via the RESS process is between 2.85 μm (±0.31) and 7.48 μm (±0.54) depending upon the experimental conditions used. The degree of crystallinity of Ibuprofen is slightly reduced after processing with the RESS process compared to the original material. No clear dependence of the particle size on the extraction pressure is observed, whereas an increase in the spraying distance increases the particle size. However, increases in the pre-expansion temperature, capillary length, and collision angle have reducing effects on the average size of Ibuprofen particles collected.