Microencapsulation of a hydrophilic drug into a hydrophobic matrix using a salting-out procedure. II. Effects of adsorbents on microsphere properties

Wax microspheres of the hydrophilic drug guaifenesin were prepared by the congealable disperse-phase method using a salting-out procedure. In order to improve the particle properties of the microspheres, adsorbents (colloidal silica, magnesium stearate, and talc) were used during preparation. The effects of adsorbents on microsphere properties such as the angle of repose (AR), compressibility index (CI), geometric mean diameter (GMD), loading efficiency (LE), and in vitro drug release (DR) were determined. The AR, CI, and GMD of the microspheres were significantly reduced in the presence of the adsorbents. Increase in the concentrations of colloidal silica and magnesium stearate led to lower LE and faster DR, while talc showed no effect, which could be due to the particle diameter and specific surface area of the adsorbents. The microspheres prepared with colloidal silica were chosen to be compressed into tablets since they were smaller, more uniform, and had better flow properties than those made with magnesium stearate and talc. The in vitro drug release profile of the microsphere tablets was compared with that of commercially available Mucinex®, sustained release guaifenesin matrix tablets. Similar release profiles were observed between the two tablets. Scanning electronic microscopy (SEM) studies of the broken tablets revealed that the deformation of the microspheres caused by compression was minimal.     

Investigation of the biopharmaceutical behavior of theophylline hydrophilic matrix tablets using USP methods and an artificial digestive system

This work aimed to investigate the biopharmaceutical behavior of hydrophilic matrix tablets of theophylline using different in vitro methods: USP II, USP IV, and a novel in vitro system simulating the gastrointestinal tract in man called the artificial digestive system (ADS). The potentiality of each method was evaluated by establishing in vitro/in vivo correlation. Using USP methods, the drug release was pH-independent and dependent on agitation intensity. Level A IVIVCs could be established using the different in vitro methods but one to one correlation was established only when the ADS method was used. For the prediction of in vivo drug dosage form behavior based on in vitro methods, the ADS showed a high predictability when compared to USP in vitro methods.     

Application of hot-melt extrusion in the complexation of naringenin with cyclodextrin using hydrophilic polymers

The complexation of cyclodextrin ranks among the best methods of overcoming the unfavorable pharmacokinetic properties of naringenin (NAR). This work proposes obtaining NAR complexes with hydroxypropyl-β-cyclodextrin (HPβCD) using hot-melt extrusion (HME), a solvent-free, continuous manufacturing process. To that end, the miscibility and stability of NAR in different hydrophilic polymeric matrices were tested using thermal, morphological, and spectroscopic assays, after which inclusion complexes were prepared via HME using different plasticizers. While the cellulosic polymers showed a limited ability to dissolve NAR, Plasdone® S-630 was chemically incompatible with the drug under shearing and heating. By contrast, polyvinyl alcohol and Soluplus® demonstrated compatibility and a high capacity to interact with NAR. The polyvinyl alcohol extrudates accelerated NAR’s dissolution, especially in systems containing HPβCD, which suggests high levels of the inclusion complex’s formation and nearly instantaneous dissolution (28 mg/mL in 15 min) superior to other technological approaches described in the literature. Meanwhile, samples extruded with Soluplus® delayed NAR’s dissolution, with rates modulated according to the drug–cyclodextrin interaction. Thus, HME proved to be a valuable, versatile method of producing cyclodextrin complexes of NAR able to support immediate and prolonged drug delivery systems depending on the formulation parameters. Many industrial advantages, including being eco-friendly and easy to scale up, make HME a promising method for exploring NAR’s remarkable medical potential.     

Separation of neutral saccharide mixtures with capillary electrochromatography using hydrophilic monolithic columns

While developing a combination of capillary electrochromatography (CEC) with tandem mass spectrometry (MS) for the benefit of characterizing complex oligosaccharide mixtures, we needed highly efficient CEC columns operating in an "MS-friendly" mode. We demonstrate here novel types of polar, monolithic CEC columns that separate effectively complex mixtures of saccharides with the use of mobile phases containing acetonitrile/dilute ammonium formate buffers. Using the positive-ion mode of detection for neutral saccharides, the detection conditions were optimized down to the low-femtomole sensitivities with the use of an ion trap mass spectrometer. This column technology provides a nearly universal system that can separate a wide range of carbohydrates: mono- and oligosaccharides with the intact reducing end, as well as saccharide alditols. Even the anomers formed due to mutarotation could be resolved with a high content of organic phase.     

甘草酸的新型提取与精制方法概述

对近年来发展的新型甘草酸提取技术(连续提取、超声辅助提取、微波提取和多级逆流提取)和精制方法(溶剂提取法、大孔树脂吸附法和双水相萃取法)进行了归纳和总结,期望可为甘草酸的实验研究和生产实践提供有价值的参考依据和方法。     

甘草酸的新型提取与精制方法概述

对近年来发展的新型甘草酸提取技术(连续提取、超声辅助提取、微波提取和多级逆流提取)和精制方法(溶剂提取法,大孔树脂吸附法和双水相萃取法)进行了归纳和总结．期望可为甘草酸的实验研究和生产实践提供有价值的参考依据和方法。     

Micro-contact printing of polydiacetylene liposomes using hydrophilic stamps

Micron-sized polydiacetylene (PDA) liposome patterns have been fabricated on titanium (Ti) substrates using a micro-contact printing (micro-CP) technique. Two types of stamps (PDMS and agarose) and inking methods ("soaking" and "dropping") are used for micro-CP, and we compare their effect on the morphology of the PDA patterns. The size and morphology of the patterned PDA liposomes are analysized by optical and fluorescence microscopies and atomic force microscopy (AFM). When the agarose stamp is inked by the "dropping" method, PDA patterns are most efficiently transferred to the Ti substrate. However, the thickness of the transferred PDA patterns is not homogeneous, with the edge of the transferred pattern being thicker than its center. In contrast, when the PDMS stamp is used for micro-CP, the center of the pattern is thicker than the edge. Red fluorescence patterns are readily obtained by heat treatment of the PDA-immobilized solid substrate. The intensity of the fluorescence of the samples is consistent with the results of optical microscopy and AFM experiments.     

室温条件下乙腈为溶剂炭气凝胶的制备与机理分析

与传统炭气凝胶制备不同,在室温条件下以乙腈为溶剂,间苯二酚和甲醛为前驱体,盐酸为催化剂,采用溶胶-凝胶、超临界干燥结合高温炭化工艺制备炭气凝胶(密度低至约50 mg.cm-3)。红外光谱、比表面积和孔径分布、扫描电子显微镜(SEM)和X射线衍射等测试表明,所制炭气凝胶是一种类石墨结构的非晶态材料,具有纳米骨架网络结构,比表面积达1 300 m2.g-1。对比不同配比气凝胶的SEM发现,气凝胶的颗粒尺寸为40 nm～70 nm。分析溶胶-凝胶过程中的温度变化和乙腈在凝胶化中作用得知,由于盐酸的催化和反应放热共同作用,实现了室温下间苯二酚和甲醛的加成和缩聚反应,并最终形成凝胶;乙腈在反应中起着一种分散剂的作用。     

Recovery of nitrotoluenes from wastewater by solvent extraction enhanced with salting-out effect

Toluene extraction enhanced by salting-out effect was employed to recover dinitrotoluene isomers and 2,4,6-trinitrotoluene (2,4,6-TNT) from wastewater of toluene nitration processes (e.g. dinitration or trinitration). The batchwise experiments were conducted to elucidate the influence of various operating variables on the extracting performance, including concentrations and species of inorganic salts, such as NaCl, KCl, Na(2)SO(4), K(2)SO(4) and MgSO4, acidity of wastewater, volume ratios of solvent versus wastewater and extraction stages in existence of inorganic salts. It was found that recovery of total organic compounds (TOC) was significantly elevated with increasing concentrations of salts, whose promoting effects were in the following order: NaCl>Na(2)SO(4)>K(2)SO(4)>MgSO4>KCl on the weight basis of wastewater. Besides, high volume ratio of toluene/wastewater (ca. 2.0) was more suitable for recovery of TOC from wastewater with or without addition of NaCl, of which extractable priority was as follows: 2,6-DNT>2,4-DNT>2,4,6-TNT. It is remarkable that TOC in wastewater would be almost completely recovered by sequential four stages toluene extraction, promoted continuously by salting-out effect.     

Determination of folates in human plasma using hydrophilic interaction chromatography-tandem mass spectrometry

Folic acid is an essential nutrient, and folate deficiency is associated with a variety of disorders including neural tube defects (during pregnancy) and heart disease. A fast, sensitive, and robust HPLC-tandem mass spectrometry (LC-MS-MS) method was developed for the quantification of free folic acid, tetrahydrofolate, 5'-methyltetrahydrofolate, and 5'-formyltetrahydrofolate in human plasma. Sample preparation required only acetonitrile precipitation of proteins followed by filtration instead of solid-phase extraction or solvent-solvent extraction as in other methods. The rapid and streamlined sample handling procedure minimized degradation of the highly unstable folate species. Hydrophilic interaction chromatography was used for additional sample cleanup on-line, and baseline separation and detection of all four folate species was achieved in less than 30 min. The folate species were detected using negative ion electrospray-tandem mass spectrometry with multiple reaction monitoring of the diagnostic fragment ions of each deprotonated molecule. The predominately organic (hydrophobic) solvent system combined with the microbore flow rate (50 microL/min) used for the chromatography resulted in enhanced electrospray signal response compared to reversed-phase HPLC using a wider bore column. The recovery of all folate species (from spiked plasma) was >97% over a concentration range from 300 pg/L to 12 mg/L with intraday precision (RSD, n = 5) of 3.7-6.5%. Stability studies were carried out for spiked samples in order to define storage and handling conditions. The folic acid limit of quantification (LOQ) in human plasma was 80 pmol/L +/- 10%, and the limit of detection (LOD) was 37.5 pmol/L. The LOQ and LOD for tetrahydrofolate, 5'-methyltetrahydrofolate, and 5'-formyltetrahydrofolate were 1250, 400, and 360 pmol/L of plasma and 425, 165, and 140 pmol/L of plasma, respectively.     

Fluidized Bed Medium Separation (FBMS) using the particles with different hydrophilic and hydrophobic properties

Three kinds of particles with different hydrophilic and hydrophobic properties were used as fluidized particles of Fluidized Bed Medium Separation (FBMS). A minimum fluidization velocity, an apparent specific gravity of fluidized bed and floating-sinking behaviors of dry and wet coals were measured in the range of relative humidity from 50% to 80%. In a hydrophilic particle, the fluidization became unstable with increasing relative humidity because particle aggregation took place at a high humidity, and hence floating-sinking behaviors depend on changes in a relative humidity. On the other hand, in a highly hydrophobic particle, the fluidization was stable and floating-sinking behaviors based on the specific gravity difference were obtained even for wet coals and at a high relative humidity. Therefore, the FBMS using a highly hydrophobic particle is applicable at a high relative humidity without a control device of relative humidity.     

Investigation of the connectivity of hydrophilic domains in Nafion using electrochemical pore-directed nanolithography

A method of determining the connectivity of ion-conducting hydrophilic channels within the Nafion polymer electrolyte membrane by way of pore-directed nanolithography has been developed. Electrochemical etching of a silicon surface is performed through a Nafion-membrane mask. The resulting silicon surface imaged by tapping-mode atomic force microscopy (TMAFM) provides a footprint of the hydrophilic channels at the Nafion-silicon interface. In a similar fashion, a TMAFM phase-contrast image of the top surface of the Nafion mask prior to etching reveals the spatial distribution of hydrophilic domains at the surface of the polymer membrane. Collectively, these images provide detailed information about the structure of the hydrophilic channels at the top and bottom surfaces of the Nafion membrane. Autocorrelation statistical analysis of these two sets of images shows that only 48% of hydrophilic channels beginning at the Nafion surface connect to the silicon-Nafion interface.     

Enhanced oral bioavailability and intestinal lymphatic transport of a hydrophilic drug using liposomes

A liposome system was evaluated for oral delivery of a poorly bioavailable hydrophilic drug. The system was prepared from proliposome, which consisted of negatively charged phosphatidylcholine, whereas cefotaxime was chosen as the model drug. An in vivo study was carried out on nine rats according to a three-way crossover design to compare the oral bioavailability of cefotaxime from the liposomal formulation with that of an aqueous drug solution and a physical mixture of cefotaxime with blank liposomes. The results indicated that the extent of bioavailability of cefotaxime was increased approximately 2.7 and 2.3 times compared with that of the aqueous solution and the physical mixture, respectively. In a separate study, simultaneous determination of cefotaxime in intestinal lymph (collected from the mesenteric lymph duct) and in plasma (collected from the tail vein) revealed that its concentration was consistently higher in the lymph than in the plasma when administered via the liposomal formulation, whereas the reverse was observed with the aqueous solution. Thus, the results indicated that the liposomes system has the potential of increasing the oral bioavailability of poorly bioavailable hydrophilic drugs and also promote their lymphatic transport in the intestinal lymph.     

Synthesis of porous titania thin films using carbonatation reaction and its hydrophilic property

Super-hydrophilic porous titania thin films containing mesoscale channels were successfully synthesized by the carbonatation reaction. An amorphous Li-Ti-O film with a smooth surface was prepared on a glass substrate by radio frequency magnetron sputtering using a Li₂TiO₃ target in an Ar atmosphere. The as-deposited films were carbonated at 400 °C for 10 h in CO₂, resulting in the formation of Li₂CO₃ and the development of characteristic through-channels. After dissolution of the Li₂CO₃ in distilled water, porous TiO₂ thin films with mesoscale through-channels were fabricated. The obtained porous films had a large surface area and show a rapid decrease in the water contact angle or excellent super-hydrophilicity.     

Carbon nanotubes with hydrophilic surfaces produced by a wet-mechanochemical reaction with potassium hydroxide using ethanol as solvent

Multi-walled carbon nanotubes (MWCNTs) were treated by a simple wet-mechanochemical reaction with potassium hydroxide using ethanol as solvent to enhance their dispersibility. Fourier transmission infrared spectroscopy measurements show that the non-reactive surfaces of MWCNTs were modified directly by multiple hydroxyl groups. The products, defined as MWCNTols, are highly soluble in water and other polar solvents. Different microstructures of linear, swirl, and ring shapes have been observed in MWCNTol sheets. The formation mechanism has been investigated and MWCNTol length was proposed as the key factor affecting the observed microstructures.     

Enhanced solubility of piperine using hydrophilic carrier-based potent solid dispersion systems

Context: Piperine alkaloid, an important constituent of black pepper, exhibits numerous therapeutic properties, whereas its usage as a drug is limited due to its poor solubility in aqueous medium, which leads to poor bioavailability.

Objective: Herein, a new method has been developed to improve the solubility of this drug based on the development of solid dispersions with improved dissolution rate using hydrophilic carriers such as sorbitol (Sor), polyethylene glycol (PEG) and polyvinyl pyrrolidone K30 (PVP) by solvent method. Physical mixtures of piperine and carriers were also prepared for comparison.

Methods: The physicochemical properties of the prepared solid dispersions were examined using SEM, TEM, DSC, XRD and FT-IR. In vitro dissolution profile of the solid dispersions was recorded and compared with that of the pure piperine and physical mixtures. The effect of these carriers on the aqueous solubility of piperine has been investigated.

Results: The solid dispersions of piperine with Sor, PEG and PVP exhibited superior performance for the dissolution of piperine with a drug release of 70%, 76% and 89%, respectively after 2?h compared to physical mixtures and pure piperine, which could be due to its transformation from crystalline to amorphous form as well as the attachment of hydrophilic carriers to the surface of poorly water-soluble piperine.

Conclusion: Results suggest that the piperine solid dispersions prepared with improved in vitro release exhibit potential advantage in delivering poorly water-soluble piperine as an oral supplement.     

Solid self microemulsification of Atorvastatin using hydrophilic carriers: a design

Context: Atorvastatin has a limited advantage to formulate oral dosage forms.

Objective: To enhance the solubility of Atorvastatin and to design the suitable solid self-microemulsifying drug delivery systems (S-SMEDDS)

Materials and methods: The clear and transparent self-microemulsifying drug delivery system (SMEDDS) were formulated using coconut oil and isopropyl myristate as lipid phases; Tween 80 as surfactant; PEG 400 and glycerin as co-surfactant at 2:1, 3:1, 1:2 and 1:3 ratio. The pseudo ternary phase diagrams were constructed to identify the microemulsion region. The SMEDDS were evaluated for zeta potential, poly dispersity index, globule size, pH, viscosity and drug release. The solid SMEDDS were developed by employing adsorption and melt granulation methods. The S-SMEDDS were evaluated for micromeritics, morphology, solid state property, reconstitution ability, drug release and stability.

Results: The micro formulations formed with particle size of 25?nm had shown a 3-folds rise in drug release. The solid SMEDDS had reconstituted to a good microemulsion rapidly in 1–3?min, with a release of 94.62% at the end of 30?min and behaved as immediate releasing capsules. Their shelf-life was found to be 1.3 years.

Discussion: The 1:3 ratio SMEDDS had shown more drug release owing to their less particle size. The solid SMEDDS had shown an increased dissolution profiles than atorvastatin. The solid state of the drug had changed in formulation inferring their enhanced solubility.

Conclusion: The solid form of atorvastatin liquid SMEDDS had been formulated successfully with enhanced shelf life and solubility.