Water-miscible Cosolvents Research Articles

Synthesis of tetrapeptide Bz-RGDS-NH2 by a combination of chemical and enzymatic methods

The tetrapeptide Bz-Arg-Gly-Asp-Ser-NH(2) (Bz-RGDS-NH(2)) was successfully synthesized by a combination of chemical and enzymatic methods in this study. Firstly, the precursor tripeptide Gly-Asp-Ser-NH(2) (GDS-NH(2)) was synthesized by a novel chemical method in four steps including chloroacetylation of l-aspartic acid, synthesis of chloroacetyl l-aspartic acid anhydride, the synthesis of ClCH(2)COAsp-SerOMe and ammonolysis of ClCH(2)COAsp-SerOMe. Secondly, lipase (PPL) was used to catalyze the formation of Bz-RGDS-NH(2) in aqueous water-miscible organic cosolvent systems using Bz-Arg-OEt as the acyl donor and GDS-NH(2) as the nucleophile. The optimum conditions were Bz-Arg-OEt 50 mM; GDS-NH(2) 400 mM; 10 degrees C, 0.1M phosphate buffer, pH 7.5; 60% DMF or 58% DMSO, PPL: 10 mg ml(-1) with the maximum yields of the tetrapeptide of 73.6% for DMF and 70.4% for DMSO, respectively. The secondary hydrolysis of the tetrapeptide product did not take place due to the absence of amidase activity of lipase.

Rheological, adhesive and release characterisation of semisolid Carbopol/tetraglycol systems

Gels dosage forms are successfully used as drug delivery systems considering their ability to control drug release and to protect medicaments from an hostile environment. This study deals with the gelation properties of Carbopol 971 e 974 polymeric systems in tetraglycol, a water-miscible cosolvent. In this paper, the attention was noted of the thickening properties of the different Carbopol in tetraglycol solvent at increasing temperatures, in order to obtain gels avoiding neutralisation and, at the same time, to make possible the dissolution in these gels of insoluble or poorly soluble water drugs. Samples were prepared by simply dispersing different Carbopols amount (0.5–4%) were added to tetraglycol and different systems were prepared at room temperature and by heating at 70 °C. All these systems were then characterised rheologically. Frequency sweep, creep-recovery, temperature sweep and time sweep analyses outlined that Carbopol 971 and 974 in tetraglycol gave rise after heating to gels with satisfactory rheological behaviour: the elastic modulus was greater than the viscous one and a remarkable elastic character was found to be present. Systems obtained by heating procedure were examined also from a mechanical point of view using a texture profile analysis. Besides, being Carbopols well known mucoadhesive polymers, gels adhesive properties were also studied using the ex vivo method. Texture and adhesion characterisation confirmed rheological results pointing out a certain greater elasticity and adhesiveness of Carbopol 974 systems. Then, the possible cutaneous irritation was also tested using the in vivo method (Draize test). No signs of cutaneous irritation were obtained for all the samples that were analysed. After rheological and mucoadhesive properties were set, paracetamol as a model drug was inserted in the composition of the gels and the release characteristics were defined. Dissolution tests pointed out the greater release control properties of tetraglycol/Carbopol 971 samples. These studies showed tetraglycol/Carbopol systems as a first-rate alternative to traditional water gels when low water-soluble drugs have to be added.

Rheological, mucoadhesive and release properties of Carbopol gels in hydrophilic cosolvents

Carbopol is one of the most common thickening agent for water phases. It is used after neutralisation and its rheological properties in the aqueous medium are well known. The aim of this work was to investigate the gelation properties of Carbopol 971 e 974 polymeric systems in water-miscible cosolvents such as glycerine and PEG 400. Since in these cosolvents, carboxypolymethylene precipitates after neutralisation with a base, then the attention was pointed out of the gelation properties of the different systems at increasing temperature, in order to obtain Carbopols gels avoiding neutralisation and, at the same time, making possible the dissolution in these gels of insoluble or poorly soluble water drugs. Rheological properties of PEG 400 and glycerine samples were compared with similar systems in water by performing oscillatory analyses and measuring the main rheological parameters, G′, G″ and δ. The results obtained showed that Carbopol 971 and 974 in PEG 400 gave rise after heating to gels that show a satisfactory rheological behaviour. The elastic modulus is greater than the viscous one showing a remarkable elastic character of these samples and the performed frequency sweeps show a typical spectrum of a “gel-like” structure. Being Carbopols well-known mucoadhesive polymers, gels adhesive properties were studied using the ex vivo method. Then, the possible cutaneous irritation were also tested using the in vivo method (Draize test). No signs of cutaneous irritation and good mucoadhesive properties were obtained for the PEG 400 and water gels of Carbopol 974 prepared by heating. After rheological and mucoadhesive properties were set, paracetamol as a model drug was then inserted in the composition of the gels and the release characteristics were defined. Dissolution tests pointed out the greater release control properties of PEG 400-Carbopol 971 samples. These studies showed PEG 400-Carbopol systems as a first-rate alternative to traditional water gels.

Cosolvent effects of phenanthrene sorption‐desorption on a freshwater sediment

This study evaluated the effects of the water-miscible cosolvent methanol on the sorption-desorption of phenanthrene by the natural organic matter (NOM) of a freshwater sediment. A biphasic pattern was observed in the relationship between the log of the carbon-normalized sorption distribution coefficient (Koc) and the volumetric fraction of water-miscible cosolvent (fc), in this case methanol, that was accounted for with phenanthrene solubility data. Results also indicated that methanol elicited additional effects on phenanthrene sorption beyond the solution phase effects. The level off, was observed to have a significant effect on sorption-desorption hysteresis, with hysteresis being greater for treatments where phenanthrene and sediment were equilibrated with methanol-phenanthrene solutions but desorbed with aqueous solutions. These results are discussed in light of the deformable pore network of the rubbery/glassy NOM polymer construct.

Enzyme-Based Vinyl Polymerization

In vitro enzyme-mediated polymerization of vinyl monomers is reviewed. Oxidoreductase enzymes have been used for the polymerization of styrene, derivatives of styrene, acrylates, and acrylamide in water and water-miscible co-solvents. Kinetic and mechanistic studies revealed that a ternary system (horseradish peroxidase, H2O2, initiator, or β-diketone) is required for efficient polymerization and the initiator controls the polymer characteristics.

Solubilization of rapamycin

The solubilization of rapamycin, a poorly water soluble investigational immunosuppressive drug, by facilitated hydrotropy is presented. Partially water-miscible aromatic solutes (such as benzyl alcohol, benzoate, or benzoic acid) can be solubilized by water-miscible cosolvents, such as ethanol and propylene glycol. Once solubilized, the partially miscible aromatic solute becomes a solubilizing agent. This technique yielded a dramatic (>1000-fold) increase in the aqueous solubility of rapamycin.

Removal of PAHs from highly contaminated soils found at prior manufactured gas operations

Removal of PAHs from highly contaminated soil found at a manufactured gas site was evaluated using solvent washing with mixed solvents. The following solvents were considered as water miscible co-solvents in mixed solvents: ethanol, 2-propanol, acetone, and 1-pentanol. In batch solvent extraction of soil, ethanol and 2-propanol were selected as primary components of mixed solvents in addition to 1-pentanol. Using ternary solutions containing either ethanol or 2-propanol with a volume fraction of 1-pentanol ranging from 5 to 25% and a water volume fraction ranging from 5 to 30%, ethanol was more effective than 2-propanol in extracting PAHs from soil. A solvent mixture of 5% 1-pentanol, 10% water and 85% ethanol was selected as the extraction solvent. Using a 1 g:4 ml soil:solvent extraction ratio, extraction kinetics showed that from 65 to 90% of the extractable PAHs were removed within an hour of contact between soil and solvent. Using this 1 g:4 ml extraction ratio, PAHs were removed in a three-stage cross-current solvent washing process where the same batch of soil was extracted with clean solvent for 1 h in each stage. PAH removals in three-stage cross-current solvent washing were comparable to PAH removals obtained with Soxhlet extraction.

The impact of co-solvents and the composition of experimental formulations on the pump rate of the ALZET® osmotic pump

The water-miscible co-solvents polyethylene glycol 400 (PEG400), N-methyl-2-pyrrolidone (NMP), and N, N-dimethylacetamide (DMA) exhibit the potential to increase the solubility of poorly water-soluble compounds and therefore they represent promising vehicles for compound delivery using osmotic pumps in early discovery experiments. Thus, the selected co-solvents were investigated for their compatibility with the interior of ALZET® osmotic pumps. Moreover, 1-week pumps were filled with mixtures of either the co-solvents with water (60:40, v/v), with neat PEG400, or with PEG400/water mixtures of different concentrations. It was determined whether the composition of an experimental formulation could have an impact on the overall pump rate with 14C-mannitol being used as the model compound. It was found that neat PEG400 was compatible with the reservoir material, whereas NMP and DMA were tolerable only in aqueous solutions up to 60%. PEG400, NMP, and DMA mixtures with water (60:40) resulted in release rates comparable to those of water and PEG400/water mixtures of lower co-solvent concentration. Moreover, as demonstrated using the various PEG400/water mixtures, the amount of co-solvent in the formulation had no significant impact on the overall release profile. By contrast, the use of neat PEG400 resulted in a significant decrease in the pump rate.

The rational design of semisynthetic peroxidases

A semisynthetic peroxidase was designed by exploiting the structural similarity of the active sites of vanadium dependent haloperoxidases and acid phosphatases. Incorporation of vanadate ion into the active site of phytase (E.C. 3.1.3.8), which mediates in vivo the hydrolysis of phosphate esters, leads to the formation of a semisynthetic peroxidase, which catalyzes the enantioselective oxidation of prochiral sulfides with H(2)O(2) affording the S-sulfoxide, e.g. in 66% ee at 100% conversion for thioanisole. Under reaction conditions the semi-synthetic vanadium peroxidase is stable for over 3 days with only a slight decrease in turnover frequency. Polar water-miscible cosolvents, such as methanol, dioxane, and dimethoxyethane, can be used in concentrations of 30% (v/v) at a small penalty in activity and enantioselectivity. Among the transition metal oxoanions that are known to be potent inhibitors, only vanadate resulted in a semisynthetic peroxidase when incorporated into phytase. A number of other acid phosphatases and hydrolases were tested for peroxidase activity, when incorporated with vanadate ion. Phytases from Aspergillus ficuum, A. fumigatus, and A. nidulans, sulfatase from Helix pomatia, and phospholipase D from cabbage catalyzed enantioselective oxygen transfer reactions when incorporated with vanadium. However, phytase from A. ficuum was unique in also catalyzing the enantioselective sulfoxidation, albeit at a lower rate, in the absence of vanadate ion.

The rational design of semisynthetic peroxidases

A semisynthetic peroxidase was designed by exploiting the structural similarity of the active sites of vanadium dependent haloperoxidases and acid phosphatases. Incorporation of vanadate ion into the active site of phytase (E.C. 3.1.3.8), which mediates in vivo the hydrolysis of phosphate esters, leads to the formation of a semisynthetic peroxidase, which catalyzes the enantioselective oxidation of prochiral sulfides with H2O2 affording the S-sulfoxide, e.g. in 66% ee at 100% conversion for thioanisole. Under reaction conditions the semi-synthetic vanadium peroxidase is stable for over 3 days with only a slight decrease in turnover frequency. Polar water-miscible cosolvents, such as methanol, dioxane, and dimethoxyethane, can be used in concentrations of 30% (v/v) at a small penalty in activity and enantioselectivity. Among the transition metal oxoanions that are known to be potent inhibitors, only vanadate resulted in a semisynthetic peroxidase when incorporated into phytase. A number of other acid phosphatases and hydrolases were tested for peroxidase activity, when incorporated with vanadate ion. Phytases from Aspergillus ficuum, A. fumigatus, and A. nidulans, sulfatase from Helix pomatia, and phospholipase D from cabbage catalyzed enantioselective oxygen transfer reactions when incorporated with vanadium. However, phytase from A. ficuum was unique in also catalyzing the enantioselective sulfoxidation, albeit at a lower rate, in the absence of vanadate ion. © 2000 John Wiley & Sons, Inc. Biotechnol Bioeng 67: 87–96, 2000.

The rational design of semisynthetic peroxidases.

A semisynthetic peroxidase was designed by exploiting the structural similarity of the active sites of vanadium dependent haloperoxidases and acid phosphatases. Incorporation of vanadate ion into the active site of phytase (E.C. 3.1.3.8), which mediates in vivo the hydrolysis of phosphate esters, leads to the formation of a semisynthetic peroxidase, which catalyzes the enantioselective oxidation of prochiral sulfides with H(2)O(2) affording the S-sulfoxide, e.g. in 66% ee at 100% conversion for thioanisole. Under reaction conditions the semi-synthetic vanadium peroxidase is stable for over 3 days with only a slight decrease in turnover frequency. Polar water-miscible cosolvents, such as methanol, dioxane, and dimethoxyethane, can be used in concentrations of 30% (v/v) at a small penalty in activity and enantioselectivity. Among the transition metal oxoanions that are known to be potent inhibitors, only vanadate resulted in a semisynthetic peroxidase when incorporated into phytase. A number of other acid phosphatases and hydrolases were tested for peroxidase activity, when incorporated with vanadate ion. Phytases from Aspergillus ficuum, A. fumigatus, and A. nidulans, sulfatase from Helix pomatia, and phospholipase D from cabbage catalyzed enantioselective oxygen transfer reactions when incorporated with vanadium. However, phytase from A. ficuum was unique in also catalyzing the enantioselective sulfoxidation, albeit at a lower rate, in the absence of vanadate ion.

Enzymatic synthesis of alkylglucosides by amphiphilic phase enzyme reaction

Alkyl-β-glucosides were synthesized with β-glucosidase, from almond, in an amphiphilic phase reaction system using different water-miscible cosolvents. By means of stepwise addition of glucose, we obtained about 1.5 times higher concentration of hexylglucoside than that of normal reaction. Using the same way, octyl-, decyl- and dodecylglucoside were synthesized and their concentrations were 6.64, 5.3 and 4.48 g l−1, respectively.

Interaction of penicillin V acylase with organic solvents:: Catalytic activity modulation on the hydrolysis of penicillin v

The modulation of hydrolytic activity of penicillin V acylase (EC 3.5.1.11) from Streptomyces lavendulae by organic solvents is reported. On one hand, the addition of water-soluble cosolvents increases the catalytic activity up to a critical concentration of the non-aqueous solvents, yet further increase of the latter leads to protein denaturation. For alcohols and aprotic polar solvents, there are linear correlations between the critical concentration of water miscible cosolvent (at which enzyme deactivation does not begin to take place) and the dielectric constant of the cosolvents added. On the other hand, water-immiscible solvents can show activating or inhibitory effects that may be related to interactions between the structure of the solvent and the enzyme.

Predicting Cosolvency. 1. Solubility Ratio and Solute log Kow

The solubility ratio of organic chemicals in an organic solvent and in water, σ, has been found to correlate with the logarithm of the octanol−water partition coefficient (log Kow) of the solutes; i.e., log σ = N + M log Kow. A total of 607 sets of thousands of solubility data were extracted from literature sources. From this database, values of N and M are obtained for 15 completely water-miscible cosolvents which are often used in pharmaceutical and environmental activities. A linear free energy relationship between σ and log Kow is theoretically derived. The deviation of the slope M from the theoretical value of unity seems to originate mainly from the differences in activity coefficients of solute in water-saturated octanol and in pure cosolvent. The effect of dissolved octanol in water in defining Kow may also influence the slope of σ ∼ log Kow regression.

Data-, knowledge- and method-bases in chemical sciences I. BAQOR—database for equilibrium constants in aquo-organic media

BAQOR is a computer readable database for equilibrium constants in presence of different percentages of water miscible cosolvents. The present version with user friendly software in dBase III+ contains 740 records and runs on any IBM compatible PC. The physico-chemical properties of binary and ternary water-cosolvent mixtures, the equilibrium constants of proton– and metal–ligand complexes are retrievable through pop-up menus. Specific searches by metal-, ligand-, solvent-, and stoichiometry-wise and their combinations is possible. Several display modes—monitor, file and hard copy—are available for the numerical fields as well as for literature citation.

Microencapsulation of Antimicrobial Ceftiofur Drugs

ABSTRACTPolymeric microparticles containing two ceftiofur salts as antimicrobial agents for intramammary application in dry cows were prepared by modified o/w-solvent evaporation methods (dispersion or cosolvent method) or by a w/o/w-multiple emulsion solvent evaporation method. The microspheres were characterized with respect to drug loading, drug release, and morphological properties. The three methods resulted in high encapsulation efficiencies. The choice of organic solvent/solvent mixture strongly affected the structure of the microparticles; both matrix and reservoir-type structures with different porosities were obtained. Scaling up to larger batch sizes resulted in microspheres with a faster drug release. The addition of water-miscible cosolvents to the water-immiscible polymer solution allowed the preparation of microparticles from a drug solution rather than a drug dispersion. Microparticles prepared by the cosolvent method could be separated after shorter time intervals from the aqueous phase; the microspheres had a denser matrix with finely dispersed drug crystals and a slower drug release when compared with microspheres prepared by the dispersion method, which had a more porous structure with larger embedded drug crystals. The cosolvent and dispersion methods present a simple alternative to the w/o/w-solvent evaporation method for the encapsulation of water-soluble drugs with an external water phase.

Physicochemical properties of a nonpeptide cyclic urea HIV protease inhibitor (DMP 323)

DMP 323 ([4R-(4α, 5α, 6β, 7β)]-hexahydro-5,6-bis(hydroxy)-1,3-bis ([(4-hydroxymethyl)phenyl]methyl)-4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-one), a potent inhibitor of HIV protease and HIV replication, is a white irregular-shaped nonhygroscopic crystalline material. Differential scanning calorimetry revealed a single melt peak at 195.7°C. DMP 323 was practically insoluble in water at 10 µg/ml (pH 8.1) at 25°C. The aqueous solubility was unaffected by changes in pH. The logarithm of the solubility of DMP 323 is a linear function of the percentage of water miscible cosolvents. The highest solubility values of DMP 323 were 272 mg/ml in 95% (v/v) ethanol in water, 160 mg/ml in propylene glycol, 144 mg/ml in polyethylene glycol 400, 65.5 mg/ml in 70% (w/w) polyethylene glycol 1450 in water, 64.2 mg/ml in polyoxyethylene sorbitan monooleate, and 1.61 mg/ml in glycerin. DMP 323 was stable as a function of pH with no loss observed at pH 3, 5, 7, 9 and 12.7 in aqueous buffers containing 5% (v/v) methanol after eight weeks at 40°C. In polyethylene glycol 400 solutions, the degradation of DMP 323 was approximated with apparent first order kinetics at elevated temperatures. Butylated hydroxytoluene and butylated hydroxyanisole were effective antioxidants in reducing the degradation in polyethylene glycol 400 solutions while citric acid afforded no protection from the degradation. Argon flushing was effective at reducing the oxidative degradation in polyethylene glycol 400 solutions stored at room temperature. Consistent with the oxidative degradation, DMP 323 degraded to the mono- and dibenzaldehyde, the monobenzoic acid, and the monobenzaldehyde monobenzoic acid derivatives.

Thermodynamics of Organic Chemical Partition in Soils. 3. Nonlinear Partition from Water-Miscible Cosolvent Solutions

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Synthesis of L-tyrosine glyceryl ester catalyzed by α-chymotrypsin in water-miscible organic solvents: A possible sun-tan accelerator product

The synthesis of L-tyrosine glyceryl ester, from glycerol and L-tyrosine methyl ester, was carried out by a transesterification reaction catalyzed by α-chymotrypsin. Values of 60 % (v/v) for glycerol and 200 mM for L-tyrosine methyl ester were optimal for the transesterification reaction. Additionally to glycerol, several other water miscible cosolvents (acetonitrile, N,N'-dimetyl formamide and tetrahydrofurane) were tested in the reaction media, but their presence did not give an enhancement on the transesterification activity with respect to the glycerol/water medium. However, increasing the hydrophobicity of the cosolvent resulted in a reduction of the enzyme activity, the water:glycerol mixture being the best reaction media.

Aspartame precursor synthesis in water miscible cosolvent catalysed by thermolysin

The synthesis of the dipeptideN-benzyloxycarbonyl-L- aspartyl-phenylalanine methyl ester, aspartame precursor, catalysed by thermolysin in aqueous and aqueous methanolic solutions was studied. Thermolysin with concentration as low as 10 μM in 25% methanol can catalyse the synthetic reaction. The optimum methanol compositions at 4°C and 37°C were 50% and 25% respectively where an increase in peptide yield of 85% was obtained for both conditions as compared to that in water.