Pharmaceutical performance of solid dispersions containing poly(ethylene) glycol 6000 and diazepam or temazepamInfluence of grinding

The effect of grinding on the physical properties and pharmaceutical performance of solid dispersions made of poly(ethylene) glycol 6000 (PEG6000) and temazepam or diazepam was studied using differential scanning calorimetry (DSC), X-ray powder diffraction and dissolution experiments. DSC-analysis of flash-cooled dispersions revealed that amorphous PEG present immediately after grinding crystallised upon aging mainly into the twice folded modification and to a small extent into the extended form. DSC-analysis of dispersions kept in the slab form for 1 month and subsequently ground, revealed that in the abscence of the grinding impulse crystallisation of PEG6000 takes place in the same way as in dispersions ground immediately after preparation and then aged for 1 month. Grinding solid dispersions immediately after preparation resulted in superior dissolution properties compared with solid dispersions kept in the monolith-slab form and subsequently ground. This difference in dissolution properties was found to be attributed to the drug and not to the polymer, more precisely, it was suggested that the drug particle size in ground dispersions was smaller than in dispersions kept in the slab form and subsequently ground. These findings suggest that grinding of solid dispersions immediately after preparation is the preparation method of choice instead of liquid filling of hard gelatin capsules resulting in monoliths. This revised version was published online in July 2006 with corrections to the Cover Date.     

Pharmaceutical performance of solid dispersions containing poly(ethylene glycol) 6000 and diazepam or temazepam

Differential scanning calorimetry (DSC) data showed that the crystallinity of poly(ethylene glycol) 6000 in solid dispersions containing and diazepam or temazepam only slightly increased upon aging and that the twice folded modification of the polymer unfolded into the once folded modification during aging, while the once folded modification did not unfold. This unfolding was found to be time and temperature dependent. X-ray powder diffraction data revealed that the drug crystallinity in the solid dispersions slightly increased upon aging. The dissolution profiles of aged and non-aged solid dispersions were comparable. It was concluded that polymer unfolding did not have an impact on the pharmaceutical performance of the investigated dispersions. This revised version was published online in July 2006 with corrections to the Cover Date.     

Thermal characterization of polyethylene glycols applied in the pharmaceutical technology using differential scanning calorimetry and hot stage microscopy

In the present study, the effect of the molecular weight and thermal treatments on commercial polyethylene glycols (PEG) samples used in the pharmaceutical processing technology, has been analyzed using DSC and HSM. The molecular weight of these polymers range from 1500 to 200000. Thermal investigations on the melting behavior of original PEG samples (as received from the manufacturer) showed only one single melting DSC endotherm effect before 373 K. This fact was associated to the presence of only one type of polymeric chain. Using standard conditions, PEG samples were solidified from the melt at 373 K, either by flash cooling (using liquid nitrogen and an ice bath) and by slow cooling, soaked and by slow cooling at room temperature. They were further studied by DSC. It was found that after cooling, PEG with molecular weight 1500 and 15000 showed DSC thermograms with a single endothermic peak. However, thermograms for PEG 4000 and 6000 produced a splitted melting endotherm. This fact was attributed to the presence of two types of chains, that are the folded and extended chains.Ageing time influences also the shape of the DSC endothermal effects. It was concluded that the endotherms obtained after heating these PEG indicate that the thermal history determine the structure (extended or folded chain type forms) and the degree of crystallinity, as evidenced by changes in heat of fusion values, melting points and structures after crystallization. The relationships between melting enthalpies and melting points, as deduced from DSC diagrams, with molecular weight of the polymers are also presented.     

Effect of crystallization behavior of polyethylene glycol 6000 on the properties of granules prepared by fluidized hot-melt granulation (FHMG)

The objective of this study was to investigate the effect of the crystallization behavior of Macrogol 6000 (polyethylene glycol 6000; PEG 6000), used as a binder, during the solidification process on the properties of mononucleic granules prepared by the fluidized hot-melt granulation (FHMG) technique. Crystallization of PEG 6000 from molten liquid was investigated using differential scanning calorimetry (DSC) and hot stage microscopy. The results obtained from the measurement of isothermal crystallization demonstrated that crystallization of PEG 6000 was either slow or rapid. Analysis based on solid-state decomposition showed that slow crystallization was due to the two-dimensional growth of nuclei mechanism, while rapid crystallization was due to the three-dimensional growth of nuclei mechanism. Observation of the crystallization of PEG 6000 by hot stage microscopy supported the existence of two different crystallization mechanisms. Granules containing PEG 6000 that underwent rapid crystallization during FHMG showed a significantly higher fraction powder under 150 microm in diameter. This was caused by the loss of powder particles from the surface of mononucleic granules during the solidification process, because many cracks were observed after crystallization of PEG 6000 with a short isothermal crystallization time (ICT) due to the reduced of sticking of particles. The results of this study suggested that the crystallization behavior of the binder during the solidification process of FHMG can influence the properties of the resultant granules, such as particle size distribution, content uniformity or taste masking. It was also indicated that measuring the ICT using DSC was a useful method to classify PEG 6000.     

Dissolution Enhancement and Characterization of Nimodipine Solid Dispersions with Poloxamer 407 or PEG 6000

The solid dispersion approach is an alternative to increase drug solubility. Many carriers have been studied, but there is few information about poloxamer 407 (P407). Consequently, the objective of this study was to evaluate P407 as a carrier for nimodipine solid dispersions and to compare its solubility and dissolution rates with those from polyethylene glycol (PEG 6000). The solid dispersions were prepared by the hot melting and solvent methods and they were characterized by FTIR, DSC, solubility, and dissolution tests. The results indicated a three-fold increase in solid dispersions solubility in the presence with P407 than those prepared with PEG.     

Nimesulide/cyclodextrin/PEG 6000 ternary complexes: physico-chemical characterization, dissolution studies and bioavailability in rats

Purpose Ternary solid dispersions were prepared in order to estimate the effect of a double hydrophilization by cyclodextrins and PEG 6000 on nimesulide apparent characteristics. Ternary solid dispersions of nimesulide, cyclodextrins and PEG 6000 were characterized using DSC, FT-IR, dissolution studies and evaluating the bioavailability in rats. Methods Ternary solid dispersions were prepared either using native powders or using a preformed inclusion complex of nimesulide and cyclodextrin. Inclusion complexes and pure drug were used as references. Circulating nimesulide was measured out in rat plasma after orally administration of our different products (ternary solid dispersions, inclusion complexes and pure drug). Results An improvement of the nimesulide dissolution rate was obtained with inclusion complexes and ternary solid dispersion. In rat plasma, inclusion complexes and ternary solid dispersion improved T _max. Conclusions A second hydrophilization of inclusion complexes by PEG 6000 does not allow to achieve better results concerning nimesulide concentration in rat plasma or in dissolution studies than with inclusion complexes alone.     

Physicochemical characterization of finasteride:PEG 6000 and finasteride:Kollidon K25 solid dispersions, and finasteride: ��-cyclodextrin inclusion complexes

Finasteride is a practically insoluble in water drug that belongs to the Class II of the BCS (poor solubility and high permeability). Solid dispersions are solid products consisting of at least two different components, generally a hydrophilic matrix and a hydrophobic drug. Solid dispersions are a successful strategy to improve drug release of poorly water-soluble drugs such as finasteride. Natural cyclodextrins are doughnut-shaped molecules with an internal hydrophobic cavity and a hydrophilic external surface. The lipophilic cavity enables cyclodextrins to form non-covalent inclusion complexes with a wide variety of poorly water-soluble drugs such as finasteride. The aim of this study was to investigate the formation of finasteride:PEG 6000 and finasteride:Kollidon K25 solid dispersions and finasteride:??-cyclodextrin inclusion complexes by solvent evaporation method using a mixture of water:ethanol (1:1). The formation of finasteride:PEG 6000 and finasteride:Kollidon K25 solid dispersions and finasteride:??-cyclodextrin inclusion complexes was investigated and characterized by differential scanning calorimetry (DSC), infrared (IR) spectroscopy, and dissolution studies from capsules containing a quantity equivalent to 5 mg of finasteride. The DSC thermograms revealed the transformation of finasteride into the amorphous state in solid dispersions with PEG 6000 and Kollidon K25, and in inclusion complexes with ??-cyclodextrin. The IR spectra demonstrated molecular interaction in solid dispersions of finasteride with PEG 6000, and in inclusion complexes with ??-cyclodextrin. Dissolution rate of solid dispersions and inclusion complexes was significantly greater than that of corresponding physical mixtures and pure drug, indicating that the formation of solid dispersions and inclusion complexes increased the solubility of the poorly soluble drug, finasteride.     

Nonisothermal crystallization behavior, and morphology of poly(trimethylene terephthalate)/polyethylene glycol copolymers

Poly(trimethylene terephthalate)/polyethylene glycol (PTT/PEG) copolymers, with PEG content ranging from 27.2 to 47.4 wt%, were synthesized by melt copolycondensation. Wide-Angle X-ray diffractometer revealed that all copolymers had the same crystal structure of homo-PTT at room temperature. All copolymers could form ring-banded spherulites, and band spacing increased with increasing PEG content at a given crystallization temperature. Nonisothermal crystallization morphology of copolymers was greatly influenced by cooling rate. When the cooling rate was 2.5 °C/min or lower, banded patterns were absent, whereas when the cooling rate was 20 °C/min or higher, a novel crystal morphology composed of non-banded spherulites (central part) and ring-banded spherulites with decreasing band spacing along the radial growth direction was observed. Moreover, the size of the non-banded spherulitic part decreased with increasing cooling rate. Finally, the nonisothermal crystallization kinetics of copolymers were analyzed and only the Mo method was satisfactory to accurately describe this system.     

Sorption and transport behavior of gasoline components in polyethylene glycol membranes

Desulphurization mechanism of polyethylene glycol (PEG) membranes has been investigated by the study of solubility and diffusion behavior of typical gasoline components through PEG membranes with various crosslinking degrees. The sorption, diffusion and permeation coefficients were calculated by the systematic studies of dynamic sorption curves of gasoline components such as thiophene, n-heptane, cyclohexane, cyclohexene and toluene in PEG membranes. Furthermore, the temperature dependence of diffusion and solubility coefficients and the influence of crosslinking degree on sorption and diffusion behaviors were conducted to elucidate the mass-transfer mechanism. According to the discussions on dynamic sorption curves, transport mode, activation energy and thermodynamic parameters, thiophene species were the preferential permeation components. Crosslinking is an effective modification way to improve the overall performance of PEG membranes applied in gasoline desulphurization. The pervaporation (PV) and gas chromatography (GC) experiments results corresponded to the conclusions. All these investigations will provide helpful suggestions for the newly emerged membrane desulphurization technology and complex organic mixture separation by pervaporation.     

Simply and effectively preparing high-purity phosvitin using polyethylene glycol and anion-exchange chromatography

An attempt was made to develop a new protocol for preparing phosvitin that could be easy scaled up using polyethylene glycol (PEG6000). Influence of PEG6000 concentration and pH of sample solution on phosvitin isolation was investigated. Phosvitin of high purity (99%) was obtained in good yield (47%) with the optimal condition of pH 4.0 and 3% PEG6000 precipitation. In addition, through evaluating different anion-exchange chromatography methods, the DEAE procedure at pH 7.5 was finally selected as the best procedure to obtain metal-free phosvitin that lost the least protein. Furthermore, it is observed that the purity and characterizations of prepared phosvitin were similar to those of the standard phosvitin from Sigma, and the random coil of phosvitin converted into more compact structure after removing metal ion. In conclusion, the developed method was simple and suitable for scaled up preparation of phosvitin.     

The association of aqueous phenolic resin with polyethylene oxide and poly(acrylamide-co-ethylene glycol)

Comb copolymers formed from acrylamide and poly(ethylene-glycol) methacrylate macro-monomer (PAM-co-PEG) were compared to poly(ethylene oxide) (PEO) with respect to hydrogen bond complex formation with water-borne phenolic resins. The behaviors of the two types of high molecular weight polyethers were similar. Complex formation gave a transient increase in viscosity followed by precipitation. Copolymers with pendant PEG chain lengths ≥ 9 formed complexes with phenolic resin whereas PEG homopolymer with a molecular weight of 2000 did not form a complex. For both copolymer and high molecular weight PEO, the tendency of the complex to precipitate increased when the pH was decreased from 7 to 4. Acridine orange, a cationic dye, bound to the phenolic resin and, after the addition of PEO, yielded visible complex gels with diameters about 20 μm. © 1995 John Wiley & Sons, Inc.     

Comparison of polyethylene glycol adsorption to nanocellulose versus fumed silica in water

The recent intensification of industrially produced cellulose nanocrystals (CNCs) and cellulose nanofibrils has positioned nanocelluloses as promising materials for many water-based products and applications. However, for nanocelluloses to move beyond solely an academic interest, a thorough understanding of their interaction with water-soluble polymers is needed. In this work, we address a conflicting trend in literature that suggests polyethylene glycol (PEG) adsorbs to CNC surfaces by comparing the adsorption behaviour of PEG with CNCs versus fumed silica. While PEG is known to have strong hydrogen bonding tendencies and holds water tightly, it is sometimes (we believe erroneously) presumed that PEG binds to cellulose through hydrogen bonding in aqueous media. To test this assumption, the adsorption of PEG to CNCs and fumed silica (both in the form of particle films and in aqueous dispersions) was examined using quartz crystal microbalance with dissipation, isothermal titration calorimetry, rheology and dynamic light scattering. For all PEG molecular weights (300–10,000 g/mol) and concentrations (100–10,000 ppm) tested, strong rapid adsorption was found with fumed silica, whereas no adsorption to CNCs was observed. We conclude that unlike silanols, the hydroxyl groups on the surface of CNCs do not readily hydrogen bond with the ether oxygen in the PEG backbone. As such, this work along with previous papermaking literature supports the opinion that PEG does not adsorb to cellulose surfaces.     

Two-phase channel structures based on alpha-cyclodextrin-polyethylene glycol inclusion complexes

Wide-angle X-ray scattering observations of alpha-cyclodextrin (CD)-poly(ethylene glycol) (PEG) inclusion complexes (ICs) have shown for the first time that two crystalline columnar modifications (forms I and II) are produced in the process of their formation. This was made possible by precise azimuthal X-ray diffraction scanning of oriented IC samples. Form I is characterized by CDs threaded onto PEG chains and arranged along channels in the order head-to-head/tail-to-tail, while form II is formed by unbound CDs also arranged into columns in a head-to-tail and also possibly a head-to-head/tail-to-tail manner, probably as a result of template crystallization on the form I IC crystals. It was shown that similar structural peculiarities are inherent for channel structures based on ICs obtained with PEG with a wide range of molecular weights (MWs). The characteristic feature of ICs based on PEG, especially with MW > 8000, is the presence of unbound polymer in the composition of the complex. The amount of unbound PEG was shown to rise with increasing MW of PEG, resulting in greater imperfections in the IC crystalline structure. The polyblock structure of ICs based on alpha-CD and PEG was therefore proposed.     

Improvement of the dissolution rate of silymarin by means of solid dispersions

Solid dispersions of silymarin were prepared by the fusion method with the intention of improving the dissolution properties of silymarin. Polyethylene glycol 6000 (PEG 6000) was used as the inert hydrophilic matrix. The dissolution studies of the solid dispersions were performed in vitro. And the results obtained showed that the dissolution rate of silymarin was considerably improved when formulated in solid dispersions with PEG 6000 as compared to original drug, and the increased dissolution rate might be favorable for further oral absorption.     

Thermal study of the polyethyleneglycol 6000-triamterene system

This paper examines binary polyethyleneglycol (molecular weight 6000)-Triamterene (PEG 6000-T) solid dispersions (5–40 w/w% of T) prepared by the fusion carrier method, and physical mixtures (5–90 w/w% of T) are studied using DSC and Hot Stage Microscopy (HSM). The use of these combined techniques allows to explain the thermal behaviour on the basis of dissolution of T in the liquid carrier according to the progressive disappearance of the original crystals over a wide range of temperatures (ca. 100°C). The above fact, and possibly the sublimation of T, also could explain that at low T content (<- 30 w/w%), DSC curves exhibited only a single endothermic peak and/or weak endothermic peaks. On the basis of DSC data, a tentative phase diagram of this system is proposed.     

Quaternary ammonium bromide functionalized polyethylene glycol: a highly efficient and recyclable catalyst for selective synthesis of 5-aryl-2-oxazolidinones from carbon dioxide and aziridines under solvent-free conditions

A quaternary ammonium bromide covalently bound to polyethylene glycol (PEG, MW = 6000), i.e., PEG(6000-)(NBu(3)Br)2, was found to be an efficient and recyclable catalyst for the cycloaddition reaction of aziridines to CO(2) under mild conditions without utilization of additional organic solvents or cocatalysts. As a result, 5-aryl-2-oxazolidinone was obtained in high yield with excellent regioselectivity. The catalyst worked well for a wide variety of 1-alkyl-2-arylaziridines. Besides, the catalyst could be recovered by centrifugation and reused without significant loss of catalytic activity and selectivity.     

Ungewöhnliche Phasendiagramme der Polyethylenglykole 6000 und 4000 mit Harnstoff

The binary systems of urea with polyethylene glycols 6000 and 4000 show inclusion compounds with higher melting points than the two components (m.p. 143 and 142.5°C resp.). From the melt unstable forms crystallize beside the stable crystal modifications. These have also been identified by FTIR microscopy and X-ray powder diffractometry. The phase diagrams are uncommon in so far as the inclusion compounds do not form eutectics but monotectics with both components. The inclusion compounds of the two polyethylene glycols with urea are isomorphous and form a series of mixed crystals following the Roozeboom I type of diagram.     

Improvement of dissolution and bioavailability for mebendazole, an agent for human echinococcosis, by preparing solid dispersion with polyethylene glycol.

The solid dispersion of mebendazole was prepared with polyethylene glycol (PEG) to enhance the dissolution rate of mebendazole, an agent for the chemotherapy of human echinococcosis. The dissolution rate of the solid dispersion increased compared with the physical mixture, and also increased with the incorporation of an increasing amount of PEG-6000. An extensive improvement of the dissolution rate was observed when the ratio of the solid dispersion of mebendazole to PEG-6000 was more than 1: 2. Furthermore, greater bioavailability in rabbits was obtained after oral administration of the solid dispersion compared with the physical mixture.     

聚乙二醇二丁二酸酯的合成

聚乙二醇在药物合成上有很广泛的用途,但其端羟基的活性相对较低,直接应用受到限制.若将羟基活化为羧基则可以扩大其应用范围;尤其是在合成二聚物时,将疏水链换成亲水的聚乙二醇二丁二酸酯链可以增加桥链的亲水性.为此,以聚乙二醇、丁二酸酐为反应物,以吡啶为溶剂,分别合成了一缩二乙二醇二丁二酸酯、二缩三乙二醇二丁二酸酯、三缩四乙二...     

Polymorphism of progesterone

Solid dispersions are used in pharmaceutical technology in order to improve solubility and/or dissolution kinetics of poorly water soluble drugs [1, 2, 3]. A preliminary study concerning progesterone structure after melting revealed the existence of a drug polymorphism after cooling, and gave the opportunity to specify the manufacturing conditions in order to obtain the stable form of this hormone [4]. In this work, two different types of progesterone solid dispersion have been compared. The first one is obtained by a slow cooling rate of the drug in the presence of polyoxyethylene glycol 6000 and the second one after quenching in the presence of saccharose distearate. DSC and radiocrystallographic studies of the solid dispersions served to specify the nature of the compounds obtained and to characterize the physical structure of the hormone in the solidified melts.