Application of green chemistry in decreasing adverse effect of (R,S)-ibuprofen

Lipases from Candida rugosa (OF and MY) were tested for their application in the enzymatic kinetic resolution of (R,S)-ibuprofen by enantioselective esterification. In this study, screening of enzymes was performed, and lipase MY was selected as an optimal catalyst, which allows to obtain products with high enantiopurity. Additionally, the influence of reaction time on the enantiomeric ratio and conversion was tested. High values of enantiomeric ratio (E in the range of 40.1–71.3) of the esterification of (R,S)- -ibuprofen were obtained using lipase MY, which has a great significance in the field of pharmaceutical synthesis of drugs. The chiral compounds (substrates and products) were analysed with the use of chiral stationary phases. As a result of the optimization, the reaction performed with the application of lipase MY allowed to achieve less toxic for human health (S)-enantiomer of ibuprofen with the high enantiomeric excess of product eep = 95%. Conversion of the reaction was c = 30.6% and enantioselectivity E = 58.9 after 126 h of incubation

Immobilization of Candida rugosa lipase onto magnetic beads for kinetic resolution of (R,S)-ibuprofen

Two commercially available lipases from Candida rugosa (CRL from Sigma-Aldrich Co. and OF from Meito Sangyo Co.) were immobilized onto glutaraldehyde-activated and EDC/sulfo-NHS-activated amineterminated magnetic beads (MB). In this study a procedure for immobilization of lipase OF using EDC sulfo-NHS onto the surface of magnetic particles was developed. The resulting “OF lipase enzymatic system” yielded good results of enantioselectivity (E=19, eep=83%) and conversion (c=42%) of the kinetic resolution of (R,S)-ibuprofen. Additionally, this procedure provides easy recovery and effective reuse of lipase OF, maintaining the enantioselectivity of the reaction on the same high level after five cycles. It was also demonstrated that the cross-linking reaction of lipases (CRL and OF) via glutaraldehyde onto magnetic support did not result in acceptable levels of conversion and enantioselectivity of the esterification reaction. Based on the results it should be noted that the immobilization technique we studied using EDC and sulfo-NHS onto MB could be potentially important for industrial application of kinetic resolution of non-steroidal anti-inflammatory drugs

Metabolic chiral inversion of 2-arylpropionic acid derivatives (profens)

2-arylpropionic acid derivatives (profens) are one of the most popular anti-inflammatory, analgesic, and antipyretic drugs. They belong to a group of nonsteroidal anti-inflammatory drugs (NSAID) and exhibit metabolic chiral inversion. Enantiomers of these chiral drugs are often characterised by different pharmacological activity. It is estimated that the values of metabolic chiral inversion of (R)-ibuprofen in humans are between 35 and 70%, depending on the condition of the liver and the intake of other medicines, while (R)-flurbiprofen undergoes chiral metabolic inversion to its opposed (S) form only in small range. The described phenomenon in the case of (R)-ketoprofen is limited to a maximum of around 10%. The metabolic chiral inversion is associated with potentially important pharmacotherapeutic and toxicological consequences, and so an attempt was made to analyse this phenomenon for the most commonly used drugs from the profens group

Application of Lipases from Candida rugosa in the Enantioselective Esterification of (R, S)-Ibuprofen

Three commercially available lipases from Candida rugosa (OF and MY from Meito Sangyo Co., and CRL from Sigma-Aldrich Co.) were used for the enantioselective esterification reaction of (R,S)-ibuprofen with 1-propanol and 2-propanol in saturated cyclohexane as reaction medium. All tested lipases preferentially catalysed the esterification of the S-enantiomer of ibuprofen. However, each one of the analysed lipases demonstrated differences in the catalytic activity. Lipase OF showed the highest conversion degree, and the best enantioselectivity was observed for MY and CRL lipases. The influence of temperature, reaction time and addition of N,N’- dicyclohexylcarbodiimide (DCC) on the enantioselectivity and on the conversion degree in the enzymatic esterification was studied and the optimal condition for nantioselective esterification was evaluated. Moreover, the application of new commercial cellulose-based tris(3,5-dimethylphenylcarbamate) HPLC chiral column was demonstrated for effective separation, qualification and quantification of both substrates and products within one chromatographic analysis

Ionic Liquids: A New Strategy in Pharmaceutical Synthesis

The industrial synthesis of pharmaceutical compounds often involves the use of organic solvents. Unfortunately, these reaction media are responsible for organic contaminations in the final product. In recent years, ionic liquids (ILs) have become the “green alternatives” of volatile organic solvents. Thus, the application of ILs instead of conventional reagents offer a new opportunity to solve problems of environmentally harmful solvents. This mini-review discusses a new application of ILs in laboratory-scale pharmaceutical synthesis

Lipase B from Candida antarctica — the wide applicable biocatalyst in obtaining pharmaceutical compounds

Lipases are commonly applied in the pharmaceutical and chemical industry, especially in immobilizedform. The use of immobilized lipases facilitates the design of reactors and control of reactions, for example,fast stopping the reaction. The immobilization procedure should increase the stability of the lipaseand its activity, as well as be simple and efficient. Lipase B from Candida antarctica (CAL-B) is an enzymefrom the lipase group, isolated from the Candida antarctica species. CAL-B has the highest activity innon-polar organic solvents, such as hexane and toluene, and the lowest in polar solvents, e.g. acetonitrile.Due to its hydrolytic properties, this enzyme degrades triglycerides of fatty acids to free fatty acids (FFA)and glycerol. Described lipase is often immobilized, in the aim to increase enantioselective and lipolyticactivity. The kinetic and dynamic resolution with the application of lipase is one of the ways in obtainingan enantiopure form of the drugs, which usually are more effective and safer for the patient. The CAL-Bcould be also applied in the kinetic resolution of compounds being building blocks, derivates of drugs orconjugated forms. Furthermore, the CAL-B is used in the reactions in receiving of organic compounds,which are the natural origin, especially vegetable. Based on the presented data, it can be concluded, thatCAL-B is an enzyme with a wide application in the biosynthesis of compounds with therapeutic activity

1-ALKYL-3-METHYLIMIDAZOLIUM TETRAFLUOROBORATE AS AN ALTERNATIVE MOBILE PHASE ADDITIVES FOR DETERMINATION OF HALOPERIDOL IN PHARMACEUTICAL FORMULATION BY HPTLC UV DENSITOMETRIC METHOD

An alternative thin-layer chromatography (TLC) method for the determination of haloperidol in pharmaceutical formulation against the method proposed by European Pharmacopeia (7.0) has been compared and described. The proposed method uses a mobile phase composed of acetonitrile/ water, 60:40, with the addition of 1.5% (v/v) 1-ethyl-3-methylimidazolium tetrafluoroborate ionic liquid. The ionic liquid modifiers of a mobile phase have been shown to be suitable suppressor of silanol ionization in the TLC of basic drugs. Besides the silanol-suppressing potency of the 1-ethyl-3-methylimidazolium tetrafluoroborate, the lack of interaction and interference with UV densitometric detection was observed. These properties open a new possibilities in the application of alky-imidazolium-based ionic liquids in chromatographic techniques

Evaluation of Designed Immobilized Catalytic Systems: Activity Enhancement of Lipase B from Candida antarctica

Publisher's version (útgefin grein)Immobilized enzymatic catalysts are widely used in the chemical and pharmaceutical industries. As Candida antarctica lipase B (CALB) is one of the more commonly used biocatalysts, we attempted to design an optimal lipase-catalytic system. In order to do that, we investigated the enantioselectivity and lipolytic activity of CALB immobilized on 12 different supports. Immobilization of lipase on IB-D152 allowed us to achieve hyperactivation (178%) in lipolytic activity tests. Moreover, the conversion in enantioselective esterification increased 43-fold, when proceeding with lipase-immobilized on IB-S861. The immobilized form exhibited a constant high catalytic activity in the temperature range of 25 to 55°C. Additionally, the lipase immobilized on IBD152 exhibited a higher lipolytic activity in the pH range of 6 to 9 compared with the native form. Interestingly, our investigations showed that IB-S500 and IB-S60S offered a possibility of application in catalysis in both organic and aqueous solvents. A significant link between the reaction media, the substrates, the supports and the lipase was confirmed. In our enzymatic investigations, highperformance liquid chromatography (HPLC) and the titrimetric method, as well as the Bradford method were employed.This work was supported by the National Science Centre Poland grant DEC-2013/09/N/NZ7/03557.Peer Reviewe

Surfactants – the application in pharmaceutical biocatalysis

Biocatalysis is one of the most commonly applied processes using enzymes. The modulation of biocatalytic reactions often requires the addition of molecules with various tendencies to behave in aqueous and/or non-aqueous media. Surfactants, as compounds containing both hydrophilic and hydrophobic groups in their structure, seem to be extremely useful in biotechnological, chemical, and pharmaceutical industries. Surfactants can be divided based on their e.g. electrical charge (cationic, anionic, amphoteric, non-ionic) and/or chemical structure (cyclic, acyclic). These compounds were applied especially in reactions catalyzed by lipases, the enzymes characterized by high activity and stability. Thus, lipases, due to their unique properties (interfacial activation), are widely used in reactions with pharmaceutical significance. This review aimed to show the effect of surfactants on lipase activity, especially in various pharmaceutical reactions such as obtaining drugs or their building blocks. The participation of surfactants in the reactions catalyzed by 12 various lipases – lipase from Candida rugosa (CRL), lipase B from Candida antarctica (CALB), lipase from Burkholderia cepacia (BCL), Thermomyces lanuginosus (TLL), Pseudomonas fluorescens (PFL), Pseudomonas aeruginosa (PAL), Pseudomonas stutzeri (PSL), Aspergillus oryzae (AOL), Aspergillus niger (ANL), Yarrowia lipolytica (YLL), Rhizomucor miehei (RML) and Fusarium oxysporum (FOL), has been described. The literature data showed the effect of applied surfactants on lipase activity. The positive effect of non-ionic Tween (20, 80) on the activity of most used lipases (CRL, CALB, BCL, PAL, PSL, AOL, ANL) has been presented. The application of non-ionic Triton X-100 in the reaction mixture has also beneficial impact on lipase activity (CALB, BCL, TLL, PFL, PSL, AOL, RML, FOL). On the other hand, ionic surfactants such as sodium dodecyl sulfate (anionic, SDS) showed various effects – the increase of RML activity, and decrease in CALB, TLL, PFL, and PSL activity have been observed. In turn, the cetyltrimethylammonium bromide (cationic, CTAB/CTABr) positively influenced BCL, AOL, and ANL and negatively on CRL, TLL, PFL, PSL, and RML lipase activity. The effect of surfactant on lipase activity was dependent on the detergent structure and concentration and reaction conditions e.g. pH, and temperature. Therefore, surfactants are considered important components in developing catalytic systems

The occurrence of cardiovascular risk factors and functioning in chronic illness in the Polish population of EUROASPIRE V

Background: The aim of this study was to assess the impact of cardiovascular risk on the functioning of patients without a history of atherosclerotic cardiovascular disease. Methods: Two hundred patients diagnosed with arterial hypertension, hypercholesterolemia, or diabetes were enrolled in the study. The median age was 52.0 years (interquartile range [IQR] 43.0–60.0). The following risk factors were assessed: blood pressure, body mass index, waist circumference, physical activity, smoking, LDL-cholesterol, triglycerides, and fasting plasma glucose concentration. Total cardiovascular risk was determined as the number of uncontrolled risk factors, and with the Systemic Coronary Risk Evaluation Score (SCORE). The Functioning in the Chronic Illness Scale (FCIS) was applied to assess the physical and mental functioning of patients. Results: The median number of measures of cardiovascular risk factors was 4.0 (IQR 3.0–5.0). The median of SCORE for the whole study population was 2.0 (IQR 1.0–3.0). Patients with lower total cardiovascular risk as defined by SCORE and number of uncontrolled risk factors had better functioning as reflected by higher FCIS (R = –0.315, p < 0.0001; R = –0.336, p < 0.0001, respectively). Multivariate logistic regression analysis identified abnormal blood pressure, abnormal waist circumference, tobacco smoking, and lack of regular physical activity to be negative predictors of functioning. Lack of regular physical activity was the only predictor of low FCIS total score (odds ratio 9.26, 95% confidence interval 1.19–71.77, p = 0.03). Conclusions: The functioning of patients worsens as the total cardiovascular risk increases. Each of the risk factors affects the functioning of subjects without coronary artery disease with different strength, with physical activity being the strongest determinant of patient functioning