Pure Ketoprofen Research Articles

Ketoprofen-Tromethamine: Binary Phase Diagram of Multicomponent Crystal, Dissolution Rate, and Analgesic Activity Evaluation

Ketoprofen is a non-steroidal anti-inflammatory drug (NSAID) whose formulation options are limited due to its low dissolution rate in aqueous media. This research aimed to enhance the solubility of ketoprofen in distilled water and to compare the anti-inflammatory and analgesic effects of its resulting multicomponent crystal with tromethamine. The binary phase diagram of ketoprofen-tromethamine was created across molar ratios ranging from 1:9 to 9:1. The multicomponent crystal comprising ketoprofen and tromethamine in the selected ratio was synthesized using a solvent drop grinding method and subjected to further characterization for thermal properties, crystallinity, chemical groups, and morphology. The dissolution rate assessments were evaluated in CO2-free distilled water. Pharmacological analyses examined the anti-inflammatory and analgesic effects of the multicomponent crystal. The binary phase analysis identified the 5:5 (1:1) molar ratio as optimal in forming a multicomponent crystal. Thermograms and diffractograms revealed crystalline alterations attributed to a new crystalline phase. The new multicomponent crystal exhibited approximately 2.7 times higher dissolution rate after 30 minutes, outperforming pure ketoprofen. Pharmacological assessments demonstrated superior analgesic effects of the multicomponent crystal. In summary, the ketoprofen-tromethamine cocrystal in 1:1 molar ratio offers enhanced dissolution rate and provides better analgesic activity than ketoprofen alone.

In Silico Analysis and Experimental Evaluation of Ester Prodrugs of Ketoprofen for Oral Delivery: With a View to Reduce Toxicity

The present research aimed to synthesize ketoprofen prodrugs and to demonstrate their potentiality for oral treatment to treat chronic inflammation by reducing its hepatotoxicity and gastrointestinal irritation. Methyl 2-(3-benzoyl phenyl) propanoate, ethyl 2-(3-benzoyl phenyl) propanoate and propyl 2-(3-benzoyl phenyl) propanoate was synthesized by esterification and identified by nuclear magnetic resonance (1HNMR) and infrared (IR) spectrometric analysis. In silico SwissADME and ProTox-II analysis stated methyl derivative as ideal candidate for oral absorption, having a >30-fold LD50 value compared to ketoprofen with no hepatotoxicity. Moreover, in vivo hepatotoxicity study demonstrates that these ester prodrugs have significantly lower effects on liver toxicity compared to pure ketoprofen. Furthermore, ex vivo intestinal permeation enhancement ratio was statistically significant (* p < 0.05) compared to ketoprofen. Likewise, the prodrugs were found to exhibit not only remarkable in vitro anti-proteolytic and lysosomal membrane stabilization potentials, but also significant efficiency to alleviate pain induced by inflammation, as well as central and peripheral stimulus in mice model in vivo. These outcomes recommend that ketoprofen ester prodrugs, especially methyl derivative, can be a cost-effective candidate for prolonged treatment of chronic inflammatory diseases.

Thermal Behavior of Cocrystal: A Case Study of Ketoprofen-Malonic Acid and Ketoprofen-Nicotinamide Cocrystals

Thermal properties are essential parameters in transformations of solid state. It is useful for estimating physicalchemical interactions that occur specifically in a multicomponent system as cocrystal. However, there is still minimum information about determining the thermal properties of cocrystal in literature. In this study, the investigation of thermal behavior of cocrystal was determined in non-isothermal conditions based on the Kissinger method. The ketoprofen-malonic acid (KMA) and ketoprofen-nicotinamide (KN) cocrystal used as model were prepared using solvent evaporation method, while the characterization was performed by powder x-ray diffraction (PXRD), differential scanning calorimetry (DSC), and Fourier-transform infrared (FTIR). From the experimental results, the activation energy (Ea ) of pure ketoprofen, KMA cocrystal, and KN cocrystal are 264.38, 384.77, and 116.64 kJ mol-1, while the enthalpy of activation (ΔH*) are 261.31, 381.78, and 113.76 kJ mol-1, respectively. The calculated values of entropy of activation (ΔS*) for pure ketoprofen, KMA cocrystal, and KN cocrystal are 465.22, 809.77, and 84.34 J K-1 mol-1 and the free energy of activation (ΔG*) of pure ketoprofen, KMA cocrystal, and KN cocrystal obtained by general thermodynamic equation are 89.53, 90.87, and 84.62 kJ mol-1, respectively. Experimental results of the thermodynamic parameters showed cocrystals to have a positive value of ΔS*, indicating the formation of cocrystals was a nonspontaneous process. Also, the KMA cocrystal had greater free energy of activation (ΔG*) than the KN cocrystal which indicated the formation of the crystal lattice involving greater binding energy than KN cocrystal.

Solubility and Dissolution Rate Enhancement of Ketoprofen by Nanoparticles

Reduction in particles size cause increase in effected surface area of drug particle. So as dissolutionoccurred at the surface of solute, rapid increase in dissolution rate due to large surface area. Ketoprofenbelong to class II according Biopharmaceutics Classification System in which has low solubility and highpermeability.the aim of study was to enhance solubility as well as dissolution rate of Ketoprofen whenpreparation of Ketoprofen nanoparticles by solvent evaporation method. Different formula of Ketoprofennanoparticles were prepared using different type of polymers (pvpk15,HPMCK15, MCA4C,and CMC 30) .All of the prepared Ketoprofen nanoparticles formulas showed a particle size result within nano-range withentrapment efficiency ranged from (85.7% to 98.3 %). The average particle size of Ketoprofen nanoparticleswas observed from (55 nm to 995 nm). The selected formula was investigation for DSC, PXRD, FTIR,SEM, entrapment efficiency and invitro drug release. The invitro dissolution study showed a significant(p<0.01) enhancement in dissolution rate of nanoparticles formula as compared to pure Ketoprofen (drug alone) and physical mixture(drug and stabilizer), at 10 min. 75.7% of drug release from nanoparticles, whileonly 15.2%, 22.7% for pure ketoprofen and PM(drug: stabilizer), respectively.

Effects of the preparation technique on the physicochemical characteristics and dissolution improvement of ketoprofen-SBE7-β-CD binary inclusion complexes

Ketoprofen (KTF) is classified as a biopharmaceutics classification system (BCS) class II drug owing to low aqueous solubility. To improve the solubility and dissolution profile of pure ketoprofen its inclusion complexes with sulfobutylether7-beta-cyclodextrin (SBE7-β-CD) were prepared by kneading (KD) and freeze-drying (FD) technique. The effects of the preparation technique on the physicochemical characteristics and dissolution improvement of binary inclusion complexes were investigated by comparing with pure ketoprofen and drug-polymer physical mixture. The phase solubility studies of ketoprofen with the carrier revealed the existence of the AL-type phase solubility profile. The characterization of the formed binary systems was carried out through Fourier transform-infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and powder X-ray diffractometry (PXRD). Scanning electron microscope (SEM) used to determine the morphology of the binary systems prepared by different techniques revealed that the rectangular crystalline morphology of ketoprofen was absent and further approve the realization of inclusion complexes. The dissolution profiles of inclusion complexes were estimated and compared with those of pure ketoprofen. The marked dissolution improvement of ketoprofen was observed in freeze-dried binary systems (∼99 % release in 120 min) rather than the kneaded systems. Percentage dissolution efficiency of the inclusion complexes followed the following order: FD-1:5 > FD-1:3 > FD-1:1 > KD-1:5 > KD-1:3 > KD-1:1. Therefore, it can be concluded that the preparation technique played significant roles in the dissolution improvement of the prepared binary systems. In conclusion, the negative docking energy (-4.4 kcal/mol) obtained in the molecular docking study suggests the formation of a stable configuration of the drug-polymer conjugate. Finally, we can suggest that SBE7-β-CD can be an efficient alternative for enhancing the solubility of ketoprofen by the formation of an inclusion complex.

Physical–chemical characterization studies of ketoprofen for orodispersible tablets

The development of orodispersible tablets containing ketoprofen (KTP) offers versatility in administration to patients with swallowing difficulties. The rational development of a medication requires characterization studies for the solid state of the active ingredient and compatibility with excipients to thus ensure a high-quality, safe and effective pharmaceutical form. Therefore, compatibility studies were performed by differential scanning calorimetry (DSC) and thermogravimetry/derivative thermogravimetry (TG/DTG), spectroscopy techniques (DRIFT, DRX, Raman), and morphological analysis by scanning electron microscopy in order to obtain thermal characterization of the drug. The DSC curve demonstrated an endothermic, symmetrical and evident fusion event (Tpeak = 96.37 °C, ΔH = −120.92 J g−1) and the TG/DTG curve showed mass loss of Δm = 92.45% relative decomposition. For stability analysis, the non-isothermal kinetic study was carried out. The granulate KTP showed higher Ea = 77.30 ± 0.25 kJ mol−1, hence being more stable than pure KTP (Ea = 54.69 ± 1.53 kJ mol−1). Regarding the compatibility study, a displacement of the drug’s melting point to lower temperatures was observed. However, a more significant interaction was evident with magnesium stearate. Further studies were performed using spectroscopic techniques of DRIFT, Raman, X-ray diffraction and by scanning electron microscopy, which demonstrated that there was no change in physicochemical properties of pure KTP. Therefore, through this study it is possible to produce orodispersible tablets by compression and freeze-drying methods containing ketoprofen.

A combined approach using differential scanning calorimetry with polarized light thermomicroscopy in the investigation of ketoprofen and nicotinamide cocrystal

A screening of ketoprofen cocrystal with nicotinamide as a coformer was performed using the Kofler contact method and mechanochemistry. The crystallization of KET (with cocrystal formation) can occur during the heating process. However, although it is thermodynamically favorable, it was found that the kinetic reactions were slow, since the KET crystallization took about 30days. The compounds obtained were analysed by differential scanning calorimetry (DSC), polarized light thermomicroscopy (PLTM), Fourier transform infrared spectroscopy (FTIR), and X-ray powder diffraction (XRPD). Cocrystal formation between ketoprofen and nicotinamide has great interest because the nicotinamide has FDA/GRAS status. At the adopted conditions, the achievement of cocrystal between ketoprofen and nicotinamide was not possible by mechanochemical methods However, experiments conducted by the Kofler method confirmed that ketoprofen interacted, under determined conditions, with nicotinamide giving rise to a new cocrystal. Furthermore, biological tests revealed that the KET+NA (1:1) eutectic system obtained by grinding had a greater anti-inflammatory action when compared to pure ketoprofen.

Studies on Control of Erratic Release of Ketoprofen from Commercial Patches for Sustained Pain-Relief Using Silica Microparticles

Sustained release of pharmaceutical drug has been a challenge to medical practitioners for a very long time. This is a requirement of anaesthetists, endoscopic surgeons and even dentists. Though commercial bandages are already available for pain and inflammation control, their drug release mechanism is mostly unknown, and is predominantly erratic. This poses a dilemma for medical practitioners, due to which, even if it is recommended to keep patch adhered to skin for 6 hours, it is often replaced in couple of hours or many a times a good amount of undelivered drug remains in the patch and gets wasted. Combining this need for systematic release of drug through such commercial patches and the property of sustained release of drug molecules through mesoporous silica particles, led to an idea for using a coat of Silica Microparticles (SiMPs) on to these patches to achieve controlled and sustained release of drug, mainly Ketoprofen (KP) (a pain-relieving commercial drug). SiMPs were synthesised and coated with pure KP drug on one hand and on another a thin layer of SiMPs was coated on the commercial KP patch. The sustained release studies were done for duration of 6-8 hours. The structural chemistry and the interaction chemistry of the silica-trapped-KP showed that the carboxylic acidic group of hydrogen from KP makes partial bond with silica through weak van-der-Waal forces interaction and efficiency of 75 % of drug loading. The commercial KP patch showed initial burst and later erratic release. However, KP patches upon coating with SiMPs showed controlled release of drug, with the initial burst release and subsequent sustained release in the agar platform-based drug release study. Loose conjugational chemistry, with good bio-availability of SiMPs provides a fine control over the release mechanism, which probably forms a fine mesh-matrix through which the drug slowly percolates. Further, since the particles are not too small, the passage of these particles through the skin-barrier is also less-probable, thereby imparting a facilitative effect for drug passage, in a controlled fashion. Hence a simple strategy is proposed to achieve better medicinal patches for pain-control and better drug efficacy.

Application of RPMI 2650 as a cell model to evaluate solid formulations for intranasal delivery of drugs

During the development of intranasal drug delivery systems for local/systemic effect or brain targeting, it is necessary to assess its cytotoxicity and drug transport through nasal epithelium. In order to avoid animal experiments or the use of excised tissues, in vitro cell models, such as RPMI 2650 cells, are being preferred during recent years. Nevertheless, the deposition of solid formulations into nasal cell layers with further transepithelial transport rate of drugs has been poorly studied or reported.Thus, the purpose of this work is to further investigate RPMI 2650 cell line as an effective alternative to animal tissues for solid drug-loaded formulations cytotoxicity and drug permeation studies in order to become an option as a tool for drug discovery. Furthermore, we wanted to determine the extent to which the administration of drugs in particulate forms would differ in relation to the permeability of the same compounds applied as solutions. RPMI 2650 cells were cultured in submersed or at air-liquid interface conditions and characterized regarding transepithelial electrical resistance (TEER) and production of mucus. Pure ketoprofen (used as model compound) and five formulations loaded with same drug, namely solid lipid particles (Gelucire 43/01™), structured lipid particles (Gelucire 43/01™:Glyceryl monooleate) and aerogel microparticles (Alginate, Alginate:Pectin, Alginate:Carrageenan), were evaluated with RPMI 2650 model in terms of cytotoxicity and permeability of drug (applied as solution, dispersion or powder+buffer).RPMI 2650 cells were capable to grow in monolayer and multilayer, showing the same permeability as excised human nasal mucosa for sodium fluorescein (paracellular marker), with analogous TEER values and production of mucus, as referred by other authors. None of the powders showed cytotoxicity when applied to RPMI 2650 cells. Regarding permeation of drug through cell layers, not only the form of application of powders but also their physical and chemical properties affected the final permeation of active pharmaceutical ingredient. Aerogel microparticles administered directly to the cell layer (powder+buffer) exhibited the highest permeation-enhancing effect compared to the pure drug, which can be attributed to the mucoadhesive properties of the materials composing the carriers, proving to be an attractive formulation for nasal drug delivery.According to these results, RPMI 2650 showed to be a promising alternative to ex vivo or in vivo nasal models for cytotoxicity and evaluation of drug permeability of nasal drug-loaded formulations.

Design and In Vivo Anti-Inflammatory Effect of Ketoprofen Delayed Delivery Systems

For the treatment of inflammatory-based diseases affected by circadian rhythms, the development of once-daily dosage forms is required to target early morning symptoms. In this study, Zn-alginate beads containing ketoprofen (K) were developed by a tandem technique prilling/ionotropic gelation. The effect of main critical variables on particles micromeritics, inner structure as well as on drug loading and in vitro drug release was studied. The invivo anti-inflammatory efficacy was evaluated using a modified protocol of carrageenan-induced edema in rat paw administering beads to rats by oral gavage at 0, 3, or 5h before edema induction. Good drug loading and desired particle size and morphology were obtained for the optimized formulation F20. In vitro dissolution studies showed that F20 had a gastroresistant behavior and delayed release of the drug in simulated intestinal fluid. The in vitro delayed release pattern was clearly reflected in the prolonged anti-inflammatory effect invivo of F20, compared to pure ketoprofen; F20, administered 3h before edema induction, showed a significant anti-inflammatory activity, reducing maximum paw volume in response to carrageenan injection, whereas no response was observed for ketoprofen. The designed beads appear a promising platform suitable for a delayed release of anti-inflammatory drugs. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3451-3458, 2015.

Development of ketoprofen loaded proliposomal powders for improved gastric absorption and gastric tolerance: in vitro and in situ evaluation

The aim of the current investigation was to improve dissolution rate, gastric absorption and tolerance of a water insoluble non-steroidal anti-inflammatory drug ketoprofen by developing proliposomal powders. Ketoprofen proliposomal powders were prepared by solvent evaporation method with varying ratios of hydrogenated soyphosphatidyl choline (HSPC) and cholesterol. The prepared proliposomal powders were characterized for vesicle size, micromeritics, entrapment efficiency and in vitro dissolution behavior. Proliposomal powder (KPL3) composed of equimolar ratios of HSPC and cholesterol loaded on pearlitol SD 200 was selected as optimized formulation as it produced smaller liposomes (5.24 ± 1.35 μm) upon hydration with highest entrapment efficiency (53.16 ± 0.06%). All proliposomal powders showed improved dissolution characteristics than pure drug, however dissolution of drug from KPL3 was found to be highest (91.17 ± 6.3) and which is about 24 times higher than pure ketoprofen within 5 min. The transformation of crystalline ketoprofen to amorphous form was confirmed by solid state characterization. The absorption rate per hour for pure ketoprofen and proliposomal formulation (KPL3) was assessed in the stomach by conducting in situ gastric absorption studies in Wistar rats and was found to be 27 ± 1.22 and 36.98 ± 1.95%, respectively. In conclusion, enhanced dissolution and gastric absorption rate of ketoprofen from proliposomal powders suggest them as potential candidate for oral bioavailability improvement of ketoprofen.

Synthesis and SEM Analysis of Ketoprofen-Hidroxipropil-β-Cyclodextrin Microparticles for Medical Applications as Drug-Release System with a High Bioavailability

Drug-release systems are studied lately for increasing absorption in the body and improve the therapeutic effectiveness is key objective. Whatever form it may take a drug release system: tablet, implant, injectable suspension or transdermal system, the basic unit on which effective therapeutic drug particle. Knowledge of particle size distribution in a disperse system is of great importance in pharmaceutical technology. The size, surface area and volume-surface particle may be relevant to the physical, chemical and pharmacological drug toxicities. Stability and speed of dissolution of ketoprofen are much reduced in pure and coupled with a solubility promoter, enhances the bioavailability and particle size distribution depends. In order to improve absorption properties of ketoprofen were synthesized drug microparticles containing ketoprofen and hydroxypropyl beta cyclodextrin. Drug microparticles were studied by SEM microscopy and the results correlated with solubility properties. It was found that microparticles obtained are more easily soluble than pure ketoprofen and small size increases bioavailability.

PVA-Ketoprofen Nanofibers Manufacturing Using Electrospinning Method for Dissolution Improvement of Ketoprofen

Background and purpose: Ketoprofen is an NSAIDs agent which has analgesic and anti inflammation effects. Ketoprofen is classified into class II in the biopharmaceutical classification system that has a high permeability but low solubility. Hence, the absorption rate of this substance is governed by its dissolution rate. Electrospinning is a method that combine solid dispersion technology and nanotechnology. This method can be selected to enhance the dissolution rate of active substances. The aim of this research is to improve the dissolution rate of ketoprofen through the preparation of polymeric nanofiber polivinyl alcohol (PVA) containing ketoprofen using electrospinning process. Methods: Preparation of nanofibers with various of PVA-ketoprofen ratio, flow rate, and PVA concentration in the solution were accomplished using electrospinning instrument. Casting solid dispersion film were also prepared by solvent evaporation method and used as a reference. The rates of dissolution of ketoprofen from each of nanofibers, casting films, and pure ketoprofen were conducted in HCl pH 1.2 medium at 37oC. Characterization of nanofibers was carried out using Scanning Electron Microscope (SEM) and X-ray Diffraction (XRD). Results: Nanofibers which contained of PVA-ketoprofen 1:1 in ratio w/w showed a significant improvement in dissolution (p<0.05) compared to the pure ketoprofen. Meanwhile, nanofibers obtained from a solution containing 7.5 % PVA (w/v) and 4 ml/h in flow rate showed the best dissolution rate improvement and significantly different (p<0.05) with either the casting film or the pure ketoprofen. The improvement of ketoprofen dissolution was due to the increasing of surface area of nanofiber and the change of ketoprofen from crystalline into amorphous form. Conclusion: Electrospinning technique can be used to improve the dissolution rate of ketoprofen through the PVA-ketoprofen nanofiber formation by choosing the appropriate polymer concentration and manufacturing process.

Physicochemical characterization and in vitro dissolution studies of solid dispersions of ketoprofen with PVP K30 and d-mannitol

Aim of the present study was to improve the solubility and dissolution rate of poorly water soluble, BCS class-II drug Ketoprofen (KETO) by solid-dispersion approach. Solid dispersions were prepared by using polyvinylpyrrolidone K30 (PVP K30) and d-mannitol in different drugs to carrier ratios. Dispersions with PVP K30 were prepared by kneading and solvent evaporation techniques, whereas solid dispersions containing d-mannitol were prepared by kneading and melting techniques. These formulations were characterized in the liquid state by phase-solubility studies and in the solid state by Differential Scanning Calorimetry (DSC), Fourier Transform Infrared (FTIR) spectroscopy, X-ray diffraction (XRD) and Scanning Electron Microscopy (SEM). The aqueous solubility of KETO was favored by the presence of both carriers. The negative values of Gibbs free energy illustrate the spontaneous transfer from pure water to the aqueous polymer environment. Solid state characterization indicated KETO was present as fine particles in d-mannitol solid dispersions and entrapped in carrier matrix of PVP K30 solid dispersions. In contrast to the very slow dissolution rate of pure KETO, dispersions of drug in carriers considerably improved the dissolution rate. This can be attributed to increased wettability and dispersibility, as well as decreased crystallinity and increase in amorphous fraction of drug. Solid dispersions prepared with PVP K30 showed the highest improvement in dissolution rate of KETO. Even physical mixtures of KETO prepared with both carriers also showed better dissolution profiles than those of pure KETO.

Polymer-based nanoparticulate solid dispersions prepared by a modified electrospraying process

A modified electrospraying process is exploited to enhance the dissolution profiles of a poorly water-soluble drug. With polyvinylpyrrolidone (PVP) as a hydrophilic polymer matrix and ketoprofen (KET) as a model drug, polymer-drug composites in the form of nanoparticles were prepared and characterized. The surface morphologies, the physical status of the drug, and the drug-polymer interactions were studied using FESEM, DSC, XRD, and ATR-FTIR. FESEM observations demonstrated that the nanoparticles gradually decreased in size from 640 ± 350, to 530 ± 320, 460 ± 200 and 320 ± 160 nm as the KET content increased from 0, to 9.1%, 16.7% and 33.3% w/w, respectively. Results from DSC and XRD suggested that KET was distributed in the PVP matrix in an amorphous manner at the molecular level. This is thought to be due to their compatibility, arising through hydrogen bonding as demonstrated by ATR- FTIR spectra. In vitro dissolution tests showed that the nanoparticles released the incorporated KET within 1 min, evidencing markedly improved dissolution over pure KET and a KET-PVP physical mixture. Electrospraying can hence offer a facile route to develop new polymer composites for biomedical applications, in particular for improving dissolution rate of poorly water-soluble drugs.

Role of bicontinuous microemulsion in the rapid enzymatic hydrolysis of ( R,S)-ketoprofen ethyl ester in a micro-reactor

Bicontinuous microemulsion was employed as the medium for enzymatic hydrolysis of ( R,S)-ketoprofen ethyl ester in the presence of esterase for the first time. In addition, a methodology for the separation of optically pure ketoprofen from the microemulsion system for analysis by gas chromatography was developed. Various factors influencing the enzymatic hydrolysis of ( R,S)-ketoprofen ethyl ester such as temperature, enzyme concentration and reaction time were optimized experimentally. The enzymatic hydrolysis in a bicontinuous microemulsion system showed a final conversion of 84.6% after 50 h of reaction, while hydrolysis in Tris–HCl buffer solution resulted in only 26.9% conversion after 150 h without completing the reaction. A comparison of the rate of the enzymatic hydrolysis reaction with rates of reaction in other biphasic media revealed that the bicontinuous microemulsion system was faster and more advantageous. The extremely large interfacial area of the latter fluid likely facilitated the contact between the catalyst and the substrate. Because the enzyme applied was not selective, formation of ( R)-ketoprofen was also observed. Therefore, application of an enzyme with higher selectivity would provide better results.

Enantiospecific pharmacokinetic studies on ketoprofen in tablet formulation using indirect chiral HPLC analysis

The present study was undertaken to evaluate the possibility of chiral discrimination in the release of enantiomers of ketoprofen (KT) in tablet form and, in turn, the bioavailability of the individual enantiomers, using the rabbit as a model. The enantiomeric concentration of KT in plasma was determined using a customized chiral HPLC analysis. First the plasma concentration-time profile was established for pure (±) KT in order to assess the extent of chiral discrimination. Subsequently the tablet formulation (Rhofenid-100mg) was administered, at a dose equivalent to 10 mg/kg, to assess the enantiospecific bioavailability of KT enantiomers in the rabbit following the same protocol as followed for the pure KT. In vivo studies revealed that the bioavailability of S-KT is higher than that of the R-enantiomer, after oral dosing with both KT-tablet and KT-pure. But the degree of chiral discrimination is more pronounced and more statistically significant in the case KT formulation as reflected by the enantioselective pharmacokinetic data. The observations presented in this article further emphasize the significance of differentiating between enantiomers of chiral drugs when assessing bioavailability and correlating efficiency with drug concentration. The study opens up a new avenue to the design of stereoselective dosage forms.

Ketoprofen nanoparticle gels formed by evaporative precipitation into aqueous solution

AbstractAqueous nanoparticle gels of a poorly‐water soluble drug, ketoprofen, were produced by evaporative precipitation into aqueous solution (EPAS). Liquid droplets of surfactant stabilized ketoprofen containing residual solvent were dispersed in water from 60 to 90°C below the melting point of pure ketoprofen. The carboxylic acid group in ketoprofen dissociates in pure water, providing electrostatic stabilization of the droplets to complement steric stabilization. Stable amorphous ketoprofen particles with a mean size of 135 nm, measured by dynamic light scattering, were formed with only 0.1% w/v poloxamer 407, resulting in an exceptionally high drug‐to‐surfactant ratio of 10:1. For 5% w/v poloxamer 407, interactions with ketoprofen produced a bluish, transparent gel composed of ∼50 nm particles. In 2 min, 98% of the ketoprofen in the gel nanoparticles dissolved. The favorable interactions between the ketoprofen and poloxamer 407, along with the electrostatic and steric stabilization, lead to gelation, which further stabilizes the unusually small particles. The rapidly dissolving wet gels with extremely small particle sizes, one month stability, and relatively low viscosities, are of interest in transdermal and parenteral delivery; furthermore, the gels may be dried for oral delivery. © 2006 American Institute of Chemical Engineers AIChE J, 2006

Dendrimers as potential drug carriers. Part II. Prolonged delivery of ketoprofen by in vitro and in vivo studies

Ketoprofen, a non-steroidal anti-inflammatory drug with well-known anti-inflammatory, antipyretic and analgesic properties, has low solubility in water and causes local or systemic disturbance in the gastrointestinal tract. In the present study we investigated the potential of polyamidoamine (PAMAM) dendrimers as drug carriers of ketoprofen by in vitro and in vivo studies. The in vitro release of ketoprofen from the drug–dendrimer complex is significantly slower compared to pure ketoprofen. Anti-nociceptive studies using the acetic acid-induced writhing model in mice showed a prolonged pharmacodynamic behavior for the ketoprofen–PAMAM dendrimer complex. Also, the blood level studies were investigated. We concluded that PAMAM dendrimers might be considered as a potential drug carrier of ketoprofen with a sustained release behavior under suitable conditions.

Current technologies for the production of ( S)-ketoprofen: Process perspective

Ketoprofen (2-(3-benzoylphenyl)-propionic acid), belongs to the family of 2-arylpropionic acids (profens), is one of the nonstreroidal anti-inflammatory drugs. The production of single enantiomer of ketoprofen is expected to grow due to its enantiomer displaying better pharmacologic activities and benefits. Kinetic resolution is the most widely used method in the production of enantiomer pure ketoprofen. However, the process has a number of limitations, which are yet to be overcome. These limitations call for an innovative approach where two processes (enantioselective esterification and dynamic kinetic resolution) can be combined and operated under a single operating enzymatic membrane reactor system. The technology is more economical, more enantiomerically benign and has a potential maximum yield more than 50%. This paper will highlight the current technology in the production of biologically active ( S)-ketoprofen, the limitations associated with the production and solutions to overcome these limitations.