Polyethylene Glycol Esters Research Articles

Enzymatic Synthesis and Evaluation of Surface Active Properties of Di-Basic Acid Esters of Poly-ethylene Glycols

The present work has synthesized two polyethylene glycol (PEG) esters with two di-basic acids by bioesterification process and has investigated the interface properties like interfacial tension, surface excess concentration, minimum surface area per mole and as well as the Gibbs adsorption and thermodynamic behavior of micelle formation for the PEG-400 esters of the two acids. The esterification reaction was carried out by agitating the reactants in different molar ratios with Mucor miehei (RMIM) lipase enzyme at 70-75°C for 7 hours and 2 mm of Hg pressure. The conversion of PEG to esters ranged from 40-64% depending on the molecular size of di-basic acids.

Krafft Points and Cloud Points of Polyoxyethylated Nonionic Surfactants

Abstract The solubility of polyoxyethylated nonionic surfactants (POSs) in water is limited by an upper and a lower critical temperature. The former, called cloud point (CP), is the temperature at which POSs precipitate from solution on heating because of excessive dehydration of their polyoxyethylene (POE) moieties. The latter, called Krafft point (KP), is the temperature at which POSs crystallize from solution on cooling because of increased alignment and attraction between their hydrocarbon chains. It occurs less frequently: Even if the POSs were capable of crystallizing, ice often crystallizes first. Aqueous solutions of over 100 POSs were examined by obtaining their CPs and ascertaining whether they exhibit KPs. KPs were found in polyoxyethylated primary alcohols and fatty acid amides and in polyethylene glycol esters of fatty acids. Only surfactants with strictly linear hydrocarbon chains crystallize, exhibiting KPs. Any branching, including that in polyoxyethylated linear secondary alcohols, prevents crystallization. Crystallization only occurs when the number mof carbon atoms in the hydrocarbon chains equals or exceeds 12. The KPs are then proportional to m. In homologous series, the surfactants most prone to crystallizing are those with borderline solubility, which possess just enough oxyethylene groups to promote solubility in cold water. Large POE moieties depress or eliminate KPs.

Self‐Assembly of PEG and Diester Copolymers: Effect of PEG Length, Linker, Concentration and Temperature

The formation of micelles in a solvent that is selective for one of the blocks is one of the most important and useful properties of block copolymers. Recently, we have synthesized copolymers of polyethylene glycol and various dimethyl esters, which self‐assemble into nano micellar aggregates in aqueous media. These nano micelles are very effective in solubilizing otherwise insoluble drugs. The structure, interaction and size of these nano micelles are very important and critical to design an efficient drug delivery system. In the present work, we have studied the effect of hydrophilic block, PEG length, linker, concentration and temperature on these nano micellar structures and interactions by static light scattering techniques.

Anti-tumor Activity of Paclitaxel Prodrug Conjugated with Polyethylene Glycol

The purpose of this study was to develop a method for increasing the solubility of paclitaxel in water to reduce its toxicity and make the drug more feasible for chemotherapy. A series of highly water soluble paclitaxel polyethylene glycol (PEG) esters were synthesized and evaluated for their anti-tumor activity and toxicity. The solubility of 7-polyethylene glycol paclitaxel carbonate 5 was 840 mg/mL and the acute toxicity (<TEX>$LD_{50}$</TEX>) was 286 mg/kg. Because of its reduced toxicity, compound 5 showed a dramatic reduction of tumor volume without any loss of animals in long-term treatment (daily consecutive injections for 15 days).

Hydration of an amphiphilic excipient, Gelucire ® 44/14

The incorporation of drugs into Gelucires has been reported to increase the dissolution rate of poorly soluble drugs, often leading to improved drug bioavailability. In pharmaceutical applications, it is important to know how the excipient interacts with the drug, and how the mixture behaves during manufacturing, storage as well as during administration. The uptake of water by an amphiphilic excipient, Gelucire ® 44/14, has been investigated in two ways: storage in humid air and addition of liquid water. During exposure to humid air, the uptake goes in stages that correspond to the dissolution of the components of the excipient, starting with the most hydrophilic ones: glycerol, then polyethylene glycol (PEG), PEG esters (PEG monolaurate and PEG dilaurate), and finally glycerides (trilaurin). At each stage, the remaining crystals are in equilibrium with an interstitial solution made of water and the dissolved components. In this range of hydrations, the total uptake is close to the sum of the equilibrium hydrations of the components. In the pharmaceutical formulation, the active ingredient could dissolve in the liquid phase. At larger hydrations, obtained through addition of liquid water, the state of Gelucire ® 44/14 differs from those of its components. Gelucire ® 44/14 forms a lamellar phase and this phase melts at 30 °C whereas the pure PEG esters form hexagonal and cubic mesophases. The cubic mesophases do not melt until the temperature exceeds 40 °C. At body temperature, all crystals in Gelucire ® 44/14 melt to an isotropic fluid as soon as the total water content exceeds 5%. Therefore the formulation of amphiphilic excipients can be optimized to avoid the formation of mesophases that impede dissolution of the excipient at body temperature.

Porous polyimide films prepared by thermolysis of porogens with hyperbranched structure

AbstractTwo hyperbranched molecules, benzenetricarboxylic acid dendritic benzyl ether ester (BTRC–BE) and benzenetricarboxylic acid polyethylene glycol ester (BTRC–PEG), were prepared and tested as pore‐generating agents (porogens) for the preparation of porous polyimide. The hyperbranched molecules were thermally stable during the imidization process and completely decomposed well below the degradation temperature of polyimides, indicating that they possessed desirable thermal decomposition characteristics as porogens for the porous polyimide. From the SEM analysis dispersed domains were observed in the poly(amic acid) films containing BTRC–BE, whereas no phase separation was observed in the poly(amic acid) films containing BTRC–PEG. This may be attributable to the different polarities of the porogens because the hydrophobic BTRC–BE was phase‐separated in the hydrophilic poly(amic acid) matrix but BTRC–PEG was well mixed with poly(amic acid). The morphology developed in the poly(amic acid) film was retained after imidization and decomposition of the porogens; thus only BTRC–BE produced the porous polyimide. As the content of BTRC–BE decreased from 20 to 5 wt %, the pore size decreased from 390 ± 100 to 90 ± 50 nm and the pore density also decreased. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 93: 1711–1718, 2004

The preparation of agglomerates containing solid dispersions of diazepam by melt agglomeration in a high shear mixer

The aim of this study was to prepare by melt agglomeration agglomerates containing solid dispersions of diazepam as poorly water-soluble model drug in order to evaluate the possibility of improving the dissolution rate. Lactose monohydrate was melt agglomerated with polyethylene glycol (PEG) 3000 or Gelucire ® 50/13 (mixture of glycerides and PEG esters of fatty acids) as meltable binders in a high shear mixer. The binders were added either as a mixture of melted binder and diazepam by a pump-on procedure or by a melt-in procedure of solid binder particles. Different drug concentrations, maximum manufacturing temperatures, and cooling rates were investigated. It was found to be possible to increase the dissolution rate of diazepam by melt agglomeration. A higher dissolution rate was obtained with a lower drug concentration. Admixing the binders by the melt-in procedure resulted in similar dissolution rates as the pump-on procedure. The different maximum manufacturing temperatures and cooling rates were found to have complex effects on the dissolution rate for formulations containing PEG 3000, whereas only minor effects of the cooling procedure were found with Gelucire 50/13. Gelucire 50/13 resulted in faster dissolution rates compared to PEG 3000.

A simple method for the selection of a suitable emulsifier based on color difference.

The purpose of this study was to establish a simple and rapid method for selecting a nonionic surfactant to prepare an emulsion that can maintain a stable emulsification phase. As an index of the degree of emulsification, the white chromaticity of the prepared sample was measured using a color difference meter. When liquid paraffin was used as an oil, the color difference (dE(H)) was shown as a change in a V-shaped curve depending on changes in the hydrophile-lipophile balance (HLB) number of sorbitan ester, polyoxyethylene sorbitan ester, or polyethyleneglycol ester. Although there was a difference in the minimal value of dE(H) in these experiments, the dE(H) was similar to the required HLB of liquid paraffin (HLB=10). On the other hand, no relationship was found between the HLB number and color difference when polyglycerol ester was used. It seems that there was possibility of the effect by the lowering of apparent HLB with a collapse of the hydration. These results indicate that color difference could be utilized for the selection of surfactants, except for polyglycerol ester.

Slow release pesticides

Controlled release of crop pesticides could make them safer and more cost-effective to use, according to researchers at Naples University, Italy (Chemweb.com, 1 October). Maria Immacolate La Rotunda and coworkers encapsulated a model pesticide (carbaryl) in microspheres prepared from mono-, di- and –triglycerides and polyethylene glycol esters of fatty acids, and found that the rate of pesticide release could be controlled by the microsphere formulation. Soil run-off loss was also reduced, and thus the environmental impact of pesticides could be controlled. MJD

Analysis of some commercial polysorbate formulations using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

Analyses of polysorbate formulations (Tween 20, Tween 40, Tween 60, and Tween 80) by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) reveal a complex mixture of oligomers that include polyethylene glycols, polyethylene glycol esters, isosorbide polyethoxylates, sorbitan polyethoxylates, polysorbate monoesters, polysorbate diesters, and sorbitol polyethoxylate esters. The MALDI-TOF mass spectra for these formulations show the presence of sodiated molecules in which the major signals are attributed to the presence of polyethylene glycols, isosorbide polyethoxylates, and sorbitan polyethoxylates. Additionally, the complexity of the spectra was correlated to the constituent fatty acid moieties in the polysorbate formulations. Thus Tween 20 showed the presence of polysorbate monolaurates, polysorbate monomyristates, and polysorbate monopalmitates. Tween 40 contained polysorbate mono- and dipalmitates. Tween 60 contained polysorbate monopalmitates and polysorbate monostearates. For the Tween 80, mass assignment for polysorbate monooleates and polysorbate dioleates was equivocal, because both of these oligomeric series have the same molecular weight as the sorbitan polyethoxylates, and thus the Tween 80 MALDI-TOF spectrum appeared to be the least complicated of the four commercial polysorbate formulations.

Final Report on the Safety Assessment of Propylene Glycol (PG) Dicaprylate, PG Dicaprylate/Dicaprate, PG Dicocoate, PG Dipelargonate, PG Isostearate, PG Laurate, PG Myristate, PG Oleate, PG Oleate SE, PG Dioleate, PG Dicaprate, PG Diisostearate, and PG Dilaurate

The Propylene Glycol Dicaprylate family of ingredients includes several esters and diesters of Propylene Glycol and fatty acids. These ingredients are used in cosmetic formulations as skin conditioning agents, viscosity increasing agents, and surfactants. Two skin irritation studies (minimal to no irritation) and a comedogenicity study (insignificant comedogen) on Propylene Glycol Dicaprylate/Dicaprate and a skin irritation study (slight) and an acute oral toxicity study (nontoxic) on Propylene Glycol Laurate were available. Available data were also found indicating that Propylene Glycol Dicaprylate/Dicaprate and Propylene Glycol Dipelargonate may enhance the skin penetration of other chemicals. Because of the ability of these Polyethylene Glycol esters and diesters to enhance penetration of other agents, it was recommended that care be taken in using these and other Polyethylene Glycol esters and diesters in cosmetic products. Previous Cosmetic Ingredient Review safety assessments of related ingredients, including Polyethylene Glycol, Polyethylene Glycol Stearate, Coconut Oils and Acids, Isostearic Acid, Lauric Acid, Myristic Acid, Oleic Acid, and Caprylic/Capric Triglyceride, were summarized. Included were mutagenicity, chronic toxicity, and skin irritation and sensitization data. Based in part on the limited data available on the ingredients included in the report, but more so on the previous reviews of chemically similar moieties, it was concluded that Propylene Glycol Dicaprylate, Propylene Glycol Dicaprylate/Dicaprate, Propylene Glycol Dicocoate, Propylene Glycol Dipelargonate, Propylene Glycol Isostearate, Propylene Glycol Laurate, Propylene Glycol Myristate, Propylene Glycol Oleate, Propylene Glycol Oleate SE, Propylene Glycol Dioleate, Propylene Glycol Dicaprate, Propylene Glycol Diisostearate, and Propylene Glycol Dilaurate are safe for use as cosmetic ingredients in the present practices of use.

The in vitro evaluation of polyethylene glycol esters of hydrocortisone 21-succinate as ocular prodrugs

The rate of hydrolysis of polyethylene glycol esters of hydrocortisone 21-succinate (H-PEGs) by a commercial esterase and by enzymes from ovine cornea was studied. Both the commercial esterase and the corneal enzymes rapidly hydrolysed the H-PEGs. Both lipophilicity and the PEG chain length had an influence on the rate of enzymatic hydrolysis, a significant decrease in enzymatic hydrolysis rate being associated with an increase in the polymer chain length. The in vitro penetration of H-PEGs across ovine cornea and sclera was assessed. In corneal penetration studies no prodrug was detected in the receiver phase while in the sclera penetration study both drug and prodrug were detected. Results from in vitro corneal and scleral absorption studies showed that the use of H-PEG400 increased the rate at which hydrocortisone diffused through excised ovine cornea compared to the use of hydrocortisone itself, particularly when the donor phase was removed after 15 min in order to mimic the situation in vivo. In addition, H-PEG200, H-PEG400, H-PEG600, H-PEG900 and H-PEG2000 gave a significant increase in the rate of diffusion of hydrocortisone+H-PEG through the sclera compared to hydrocortisone itself. Our results on ovine eye show that the rate of diffusion of hydrocortisone across the sclera is about six times higher than that in cornea and for the H-PEGs the scleral diffusion was 10–100 times higher than that observed in the cornea.

Final Report on the Safety Assessment of Propylene Glycol (PG) Dicaprylate, PG Dicaprylate/Dicaprate, PG Dicocoate, PG Dipelargonate, PG Isostearate, PG Laurate, PG Myristate, PG Oleate, PG Oleate SE, PG Dioleate, PG Dicaprate, PG Diisostearate, and PG Dilaurate

The Propylene Glycol Dicaprylate family of ingredients includes several esters and diesters of Propylene Glycol and fatty acids. These ingredients are used in cosmetic formulations as skin conditioning agents, viscosity increasing agents, and surfactants. Two skin irritation studies (minimal to no irritation) and a comedogenicity study (insignificant comedogen) on Propylene Glycol Dicaprylate/Dicaprate and a skin irritation study (slight) and an acute oral toxicity study (nontoxic) on Propylene Glycol Laurate were available. Available data were also found indicating that Propylene Glycol Dicaprylate/Dicaprate and Propylene Glycol Dipelargonate may enhance the skin penetration of other chemicals. Because of the ability of these Polyethylene Glycol esters and diesters to enhance penetration of other agents, it was recommended that care be taken in using these and other Polyethylene Glycol esters and diesters in cosmetic products. Previous Cosmetic Ingredient Review safety assessments of related ingredients, including Polyethylene Glycol, Polyethylene Glycol Stearate, Coconut Oils and Acids, Isostearic Acid, Lauric Acid, Myristic Acid, Oleic Acid, and Caprylic/Capric Triglyceride, were summarized. Included were mutagenicity, chronic toxicity, and skin irritation and sensitization data. Based in part on the limited data available on the ingredients included in the report, but more so on the previous reviews of chemically similar moieties, it was concluded that Propylene Glycol Dicaprylate, Propylene Glycol Dicaprylate/Dicaprate, Propylene Glycol Dicocoate, Propylene Glycol Dipelargonate, Propylene Glycol Isostearate, Propylene Glycol Laurate, Propylene Glycol Myristate, Propylene Glycol Oleate, Propylene Glycol Oleate SE, Propylene Glycol Dioleate, Propylene Glycol Dicaprate, Propylene Glycol Diisostearate, and Propylene Glycol Dilaurate are safe for use as cosmetic ingredients in the present practices of use.

Enzymatic preparation of polyethylene glycol esters of castor oil fatty acids and their surface‐active properties

AbstractThis study concerns the preparation and evaluation of nonionic surfactants prepared from polyethylene glycol (PEG) esters of castor oil fatty acid, a source of hydroxy fatty acid. A lipase‐catalyzed esterification reaction has been employed to prepare PEG esters of hydroxy acid to overcome problems associated with chemical processes. Castor oil fatty acid (85% ricinoleic acid) was mixed with PEG of different molecular weight. Rhizomucor miehei lipase was added as catalyst (10% level) and the reaction was continued at 60°C under 2 mm Hg pressure for 360 min. Conversion of PEG to esters was in the range of 86–94%, depending on the molecular size of PEG. The products were isolated and examined for surface activity by surface tension measurement. Surface tension values measured at 25°C were about 36–37 dynes/cm.

Comparison of Results of Various Methods Used to Determine the Extent of Modification of Methoxy Polyethylene Glycol 5000-Modified Bovine Cupri-Zinc Superoxide Dismutase

The protein bovine cupri-zinc superoxide dismutase (SOD) was modified by the reaction of lysine residues with an active ester of methoxy polyethylene glycol 5000 (PEG). The extent of modification was determined by capillary zone electrophoresis, matrix-assisted laser desorption/ionization mass spectrometry, Fourier-transform infrared spectroscopy, and Raman spectroscopy and after removing PEG by alkaline hydrolysis of the linkages to SOD followed by quantification of the released PEG using gel-permeation chromatography. There was generally good agreement among the results obtained by these techniques on a typical sample of the PEG-modified protein. The results, extent of protein modification, determined by the preceding methods were compared to that found from the classical trinitrobenzene sulfonic acid (TNBS) procedure. In addition to providing alternatives to the TNBS procedure, results from the described methodologies strongly suggest that the extent of modification determined from the TNBS procedure is overestimated.

Synthesis and characterisation of polyethylene glycol conjugates of hydrocortisone as potential prodrugs for ocular steroid delivery

A method for the synthesis of polyethyleneglycol esters of hydrocortisone 21-hemisuccinate (H-PEGs) as potential ocular prodrugs, was developed using dicylohexylcarbodiimide to promote esterification. The products were purified by semipreparative high performance liquid chromatography (HPLC). The steroid derivatives were, mainly, highly water soluble. The products were characterised by NMR, fast atom bombardment mass spectrometry and elemental analysis. The polyethylene glycol esters were studied with respect to their stability in aqueous solution and their partition coefficients.

Penicillin amidase-catalysed preparative synthesis of cephem - 7- (2-benzoxazolon-3-yl-acetamido)-desacetoxycephalosporanic acid using a non-specific polyethyleneglycol-modified acyl donor

Penicillin amidase (EC 3.5.1.11) catalysed the synthesis of cephem 7-(2-benzoxazolon-3-yl-acetamido)-desacetoxycephalosporanic acid by a kinetically controlled transfer of the non-specific 2-benzoxazolon-3-yl-acetyl moiety from its polyethyleneglycol ester (m.w. 400, nine monomeric units) to the nucleophile 7-aminodesacetoxycephalosporanic acid. Penicillin amidase from E.Coli immobilised in polyacrylamide gel was used as biocatalyst. A high degree of nucleophile conversion (98 %) into the corresponding cephem at biotechnologically relevant concentrations (50 mM) was achieved.

Perspektiven der Fettsäurepolyglykolester als Derivate der Fettsäuremethylester

Fatty acids and their methyl esters, derived from palmoil and coconutoil, have become available in considerable amounts in recent years. They can serve as starting materials for polyethyleneglycol esters. Opportunities for technical applications and uses of these esters are investigated and compared to those of other polyethyleneglycol derivatives, i. e. oxethylates.

α‐sulfonated fatty acid esters: II. Solution behavior of α‐sulfonated fatty acid polyethylene glycol esters

AbstractSodium α‐sulfonated, fatty acid polyethylene glycol monoesters [CmH2m+1CH(SO3Na)COO(C2H4O)nH] and diesters [CmH2m+1CH(SO3Na)COO(C2H4O)nCOCH(SO3Na)CmH2m+1], wherem=10–16 andn=1–35, were prepared by esterification of α‐sulfonated, fatty acids with polyethylene glycols, followed by neutralization with NaOH. Crude products were purified by reversed‐phase column chromatography on an octadecyl‐modified silica gel. Characteristic solution behavior of these α‐sulfonated fatty acid esters was, examined, and the following features were observed. All monoesters prepared in this work had Krafft points below 0°C and also possessed good calcium stabilities. Critical micelle concentrations of the monoesters increased monotonously, as a rule, with an increase in the number of oxyethylene units. These results suggest that the polyethylene glycol residue of the monoester behaves as a hydrophile. On the other hand, diesters possessed high water solubility, low foamability, and critical micelle concentrations that were lower by a factor of ten compared to those of the monoesters.

Quantitation of slow drug release from an implantable and degradable gentamicin conjugate by in vivo magnetic resonance imaging.

A biodegradable model hydrogel containing a covalently bound aminoglycoside in which drug release can be monitored by magnetic resonance imaging (MRI) in vivo was developed. The hydrogel consists of the bishydroxysuccinimide ester of polyethylene glycol disuccinate cross-linked albumin, to which gentamicin and Gd-diethylenetriaminepentaacetic acid are covalently attached in stochiometric quantities. MRI allowed us to depict the three-dimensional structure of implanted gels, to accurately calculate their volumes, and thus to calculate the concentration of hydrogel-bound gentamicin. The correlation coefficient for the concentration of released gentamicin and the hydrogel volume was 0.965. Free and hydrogel-released gentamicin conjugates had similar antibiotic efficacies when tested in microbiological agar diffusion assays. In vivo, hydrogel-released gentamicin had a longer half-life in plasma than unaltered gentamicin (5.6 versus 0.7 h), presumably because of residual bound polyethylene glycol residues. Hydrogel implants into rats resulted in a prolonged (7 to 10 days) release of gentamicin and a decreased 24-h mortality in mice infected with a lethal dose of Pseudomonas aeruginosa. The results indicate the feasibility of imaging and quantitating therapeutic drug concentrations in vivo by MRI.