Measurement of the Surface Area Changes During the Dissolution of Poorly Soluble Drugs using a Wide Angle Photosedimentometer

Abstract

Using a Wide Angle Photosedimentometer, surface area changes during the dissolution of suspended particles of frusemide, glibenclamide and bendrofluazide have been measured. The method consisted of recording the change in optical density that occurs whilst the drugs are agitated in water in a 4cm square photosedimentometer cell. It was found that initially a high surface area was recorded which diminished exponentially with time and obeyed first order kinetics. From the surface area measurements, graphs of percentage drug dissolved against time were calculated and plotted and these profiles were found to correlate with similar plots of dissolution rate produced by analysing the amount dissolved spectrophotometrically. It was concluded that the surface area method offers an alternative technique for the measurement of the dissolution rate of poorly water soluble drugs, particularly when no adequate method exists for analysing the dissolved fraction.     

Increasing Dissolution Rates of Poorly Soluble Drugs by Adsorption to Montnorillonith

The surface adsorption of griseofulvin, indomethacin and prednisone to colloidal magnesium aluminum silicate was shown to markedly improve the dissolution rates of there hydrophobic and party soluble drugs. The rapid release of drug from the surface of the clay was due to the weak physical bonding between the two materials and to the swelling of the clay in aqueous media. The hydrophilic and swelling properties of the montmorillonite clay in aqueous media also helped to facilitate the wetting of hydro-phobic drug substances. The equilibrating solvents employed in the preparation of the griseofulvin-clay adsorbates caused a significant variance in the dissolution profiles of griseofulvin. This did not occur with indomethacin. Dramatic increases in dissolution rates were seen with the prednisone adsorbates and 100 percent of the drug was present in solution from the 1:4 ad-sorbate after four minutes.     

Nanoparticle Engineering Processes for Enhancing the Dissolution Rates of Poorly Water Soluble Drugs

Poor water solubility is an industry wide issue, especially for pharmaceutical scientists in drug discovery and drug development. In recent years, nanoparticle engineering processes have become promising approaches for the enhancement of dissolution rates of poorly water soluble drugs. Nanoparticle engineering enables manufacturing of poorly water soluble drugs into nanoparticles alone, or incorporation with a combination of pharmaceutical excipients. The use of these processes has dramatically improved in vitro dissolution rates and in vivo bioavailabilities of many poorly water soluble drugs. This review highlights several commercially or potentially commercially available nanoparticle engineering processes recently reported in the literature for increasing the dissolution properties of poorly water soluble drugs.     

Improved Dissolution Rate of Poorly Soluble Drug by Incorporation of Buffers

This study focused on comparing dissolution rates of indomethacin after cocompressing with three different buffers (calcium carbonate, sodium carbonate, and sodium citrate) at pH 2 and 7. Factors affecting the dissolution rate were also examined, such as type and particle size of buffer and weight-to-weight ratio of drug to buffer. It was found that, at pH 7, the release rates of indomethacin with sodium carbonate (<74 μm, all proportions) and sodium citrate (<74 μm, 75% loading) at a 20-min test time were about 10-fold and 6-fold greater, respectively, than that of indomethacin alone. When the drug and buffer were compressed into tablets using a tableting machine, the release rates of indomethacin for the control, sodium carbonate incorporated (25% and 75% buffer loading), and sodium citrate incorporated (75% buffer loading) at a 15-min test time were 50%, 90%, 66%, and 67%, respectively.     

Characterization of the Precipitates of Poorly Water Soluble Drugs and Determination of the Solubilities in Human Gastro-Intestinal Fluids by Microsopy

Gastrointestinal (GI) fluids were collected from 5 volunteers, and the pH of each fluid measured. Solutions of poorly water soluble sompounds in polyethylene glycol 400 (PEG-400) and absolute ethanol were introduced in measured aliqouts, to 2 mL portions of the GI fluids that were preheated to 37 C. The fluids were examined microscopically after each addition to determine the solubility of the drugs in those fluids and what type of precipitate would result. Melting temperatures of the compounds ranged from 40 C to 200 C. In all cases, the precipitate formed oily droplets in the GI fluids when the solubility limit was exceeded. Oily droplet formation was independent of molecular structure, melting temperature, and fluid pH. Compounds of low water solubility would be expected to form oily droplets in biological fluids, which would enhance absorption regardless of pH. GI fluid pH values were found to vary widely among individual samples from 1.49 to 7.08 (gastric) and 2.18 to 7.06 (intestinal).     

Characterization of the Precipitates of Poorly Water Soluble Drugs and Determination of the Solubilities in Human Gastro-Intestinal Fluids by Microsopy

Gastrointestinal (GI) fluids were collected from 5 volunteers, and the pH of each fluid measured. Solutions of poorly water soluble sompounds in polyethylene glycol 400 (PEG-400) and absolute ethanol were introduced in measured aliqouts, to 2 mL portions of the GI fluids that were preheated to 37 C. The fluids were examined microscopically after each addition to determine the solubility of the drugs in those fluids and what type of precipitate would result. Melting temperatures of the compounds ranged from 40 C to 200 C. In all cases, the precipitate formed oily droplets in the GI fluids when the solubility limit was exceeded. Oily droplet formation was independent of molecular structure, melting temperature, and fluid pH. Compounds of low water solubility would be expected to form oily droplets in biological fluids, which would enhance absorption regardless of pH. GI fluid pH values were found to vary widely among individual samples from 1.49 to 7.08 (gastric) and 2.18 to 7.06 (intestinal).     

Binding Efficiencies of Strach N. F. and Modified Starches in Formulations of Poorly Water Soluble Drugs

Active and excipient ingredients were granulated in planetary and high intensity mixers. Compression properties of single and multi-drug formulations were evaluated with an insturmented single punch tablet press interfaced with a digitial computer. Dissolution rates were measured using the USP Apparatus #I. Binding efficiency was found directly proportional to granule coarseness for equally well-lubricated granulations. Some differences were observed between the starches, in the manner of their incorporation (dry or as slurry) and between the single and multi-drug formulations. The fromulations containing the pregelatinized starches allowed faster release of a poorly water soluble drug than did those containing starch, N.F.     

Dissolution Rate A Measurement of the Deaggregation of Furosemide Agglomerates During An Interactive Mixing Process

Abstract

Agglomerates of drug particles must be broken down and single particles attached to the carrier to ensure a completely random interactive mixture. Here it was found that the dissolution rates of samples from interactive mixtures compared to suspended furosemide was an indication of the deaggregation of furosemide agglomerates during an interactive mixing process. Deaggregation depended on the forces generated during mixing and was quicker when a high density carrier such as sodium chloride was used.     

Dissolution Rate A Measurement of the Deaggregation of Furosemide Agglomerates During An Interactive Mixing Process

Agglomerates of drug particles must be broken down and single particles attached to the carrier to ensure a completely random interactive mixture. Here it was found that the dissolution rates of samples from interactive mixtures compared to suspended furosemide was an indication of the deaggregation of furosemide agglomerates during an interactive mixing process. Deaggregation depended on the forces generated during mixing and was quicker when a high density carrier such as sodium chloride was used.     

纳米TATB在比表面积测试中的预处理条件研究

由于制备工艺的差异,纳米TATB产品与常规亚微米TATB产品的表面特性不同,在比表面积分析中需采用不同的预处理条件.用低温氮气吸附法测试纳米TATB经不同顶处理条件处理后的表面特性参数,比较总结了纳米TATB的比表面积最佳预处理条件,研究表明,用50℃和1h预处理纳米TATB,可获得最佳的测试结果.用亚微米TATB的预处理条件处理纳米TATB.所得结果与研究所得的最佳预处理条件比较,比表面积测试结果相差-39%.另外,比较了预处理温度和预处理时间对样品测试结果的影响,实验表明.预处理温度对纳米TATB测试结果的影响比预处理时间大得多.     

Enhanced Oral Bioavailability of a Poorly Water Soluble Drug PNU‐91325 by Supersaturatable Formulations

Supersaturatable cosolvent (S‐cosolvent) and supersaturatable self‐emulsifying drug delivery systems (S‐SEDDS) are designed to incorporate water soluble cellulosic polymers such as hydroxypropyl methylcellulose (HPMC), which may inhibit or retard drug precipitation in vivo. A poorly soluble drug, PNU‐91325, was used as a model drug in this study to illustrate this formulation approach. The comparative in vitro studies indicated that the presence of a small amount HPMC in the formulation was critical to achieve a stabilized supersaturated state of PNU‐91325 upon mixing with water. An in vivo study was conducted in dogs for assessment of the oral bioavailability of four formulations of PNU‐91325. A five‐fold higher bioavailability (～ 60%) was observed from a S‐cosolvent formulation containing propylene glycol (PG) + 20 mg/g HPMC as compared to that (～ 12%) of a neat polyethylene glycol (PEG) 400 formulation. The low bioavailability of the PEG 400 formulation is attributed to the uncontrolled precipitation of PNU‐91325 upon dosing, a commonly observed phenomenon with the cosolvent approach. A S‐SEDDS formulation composed of 30% w/w Cremophor (surfactant), 9% PEG 400, 5% DMA, 18% Pluronic L44, 20% HPMC, and other minor components showed an oral bioavailability of ～ 76%, comparable to that of a neat tween formulation (bioavailability: ～ 68%). The significant improvement of the oral bioavailability of the supersaturatable S‐cosolvent and S‐SEDDS formulations is attributed to a high free drug concentration in vivo as a result of the generation and stabilization of the supersaturated state due to the incorporation of polymeric precipitation inhibitor.     

Tablet-to-Tablet Dissolution Variability and its Relationship to the Homogeneity of a Water Soluble Drug

The homogeneity of a water soluble drug in a tablet granulation was studied by mixing the granulated drug with excipients in a V-shaped tumbling mixer. Samples were withdrawn from five different locations of the mixer for homogeneity and dissolution studies at different mixing times. For dissolution studies, tablets were compressed at a constant compression load. Qualitatively, the coefficient of variation of mixing and dissolution looked similar, suggesting that the mixing homogeneity may have some relationship to the tablet-to-tablet dissolution variability. The addition of magnesium stearate resulted in an increase in the coefficient of variation of mixing and a decrease in the dissolution rate. A large decrease in the dissolution rate occured during the first minute of mixing with the magnesium stearate. The tablet crushing strength continuously decreased during the first 10 minutes of mixing with the magnesium stearate. The results suggested that the formulation in which a major portion of the excipients was not wet granulated with the drug resulted in higher tablet-to-tablet dissolution variability. The addition of sodium starch glycolate or sodium carboxymethyl cellulose to starch for enhancing disintegration neither improved the tablet-to-tablet dissolution variability nor increased the rate of drug dissolution.     

{110} Planes During the Dissolution of AgBr Microcrystals

Etching of silver bromide microcrystals by Na₂S₂0₃, Na2S03, or KCN produced crystal shapes essentially bounded by {110} planes. Regular rhombic dodecahedra were observed during etching of octahedral AgBr crystals while complicated polyhedra with exclusively {110} planes were obtained from cubic AgBr crystals.     

A Four-Component Study for Estimating Solubilities of a Poorly Soluble Compound in Multisolvent Systems Using a Scheffé-Type Model

Abstract

The equilibrium solubility of GF1209184, a poorly soluble compound with potential use as a multidrug resistance (MDR) inhibitor of P-glycoprotein, was studied at 25°C in multisolvent systems containing polyethylene glycol 300, polysorbate 80, ethanol, and water. The objective was to determine the feasibility, with respect to solubility, of formulating a concentrated formulation for product presentation in an ampule or vial. Data were fit to a quadratic Scheffé-type model with excellent correlation between the experimentally determined and fitted equilibrium solubilities (R² = 0.9875, slope = 1.043). Solubilities greater than 4 mg base/mL at 25°C were determined for mixtures in this study, making it feasible, with regard to solubility, to formulate a concentrated vial or ampule formulation. Maximum solubility, however, was dependent on the ability to adjust the apparent pH to ≤3.5 in the cosolvent/surfactant systems studied.     

High Energy Ordered Mixture for Improving the Dissolution Rate of Sparingly Soluble Compounds

Abstract

Bioavailability of a sparingly soluble drug is often limited by the rate of dissolution of the drug substance. The drug in a micronized form is generally employed to maximize the bioavailability. However, the micronized drugs tend to agglomerates and do not always exhibit an improved dissolution rate. In this study, a simple processing using a high energy mill was demonstrated as an effective means to utilize the entire surface area available for drug release of the micronized drug. An experimental hydrophobic drug in a micronized form was milled with a carrier, hydrous lactose using Micropulverizer to achieve a uniform mixture so-called “high energy ordered mixture”. The high energy ordered mixture provided a contact surface area taking part in dissolution 4-fold greater than the micronized drug agglomerates. Therefore, the dissolution was significantly improved, irrespective of test parameters such as agitation and the presence of surfactant. This high energy ordered mixture provided the advantages over a simple ordered mixture for: (i) complete deaggregation of the micronized drug to fine primary particles, (ii) improving the efficiency of the carrier by increasing contact surface area, and (iii) enhancing the bonding effect between the drug and lactose particles due to free water molecules released from the crystal lattices of hydrous lactose during milling. This procedure could be applied to overcome dissolution problems of sparingly soluble drugs with cohesive nature.     

High Energy Ordered Mixture for Improving the Dissolution Rate of Sparingly Soluble Compounds

Bioavailability of a sparingly soluble drug is often limited by the rate of dissolution of the drug substance. The drug in a micronized form is generally employed to maximize the bioavailability. However, the micronized drugs tend to agglomerates and do not always exhibit an improved dissolution rate. In this study, a simple processing using a high energy mill was demonstrated as an effective means to utilize the entire surface area available for drug release of the micronized drug. An experimental hydrophobic drug in a micronized form was milled with a carrier, hydrous lactose using Micropulverizer to achieve a uniform mixture so-called “high energy ordered mixture”. The high energy ordered mixture provided a contact surface area taking part in dissolution 4-fold greater than the micronized drug agglomerates. Therefore, the dissolution was significantly improved, irrespective of test parameters such as agitation and the presence of surfactant. This high energy ordered mixture provided the advantages over a simple ordered mixture for: (i) complete deaggregation of the micronized drug to fine primary particles, (ii) improving the efficiency of the carrier by increasing contact surface area, and (iii) enhancing the bonding effect between the drug and lactose particles due to free water molecules released from the crystal lattices of hydrous lactose during milling. This procedure could be applied to overcome dissolution problems of sparingly soluble drugs with cohesive nature.     

试论广角镜头在科教电影中的作用

人们在看电影的时候,银幕上有时会出现一张变形的脸或者两个对峙的高楼变成了球形,这种影像看起来十分夸张,究其原因是使用了广角镜头的结果。那什么是广角镜头呢?习惯上把焦距接近或等于画幅对角线的物镜叫做标准镜头。相对于标准镜头,就把焦距短于画幅对角线的物镜就叫做广角镜头。不同画幅尺寸的摄影机其标准镜头的焦距不同。如果是35毫米的摄影机,一般把焦距5 0毫米或4 0毫米的镜头定为标准镜头,而把焦距小于4 0毫米的镜头作为广角镜头;如果是16毫米的摄影机,把焦距2 5毫米的镜头定为标准镜头,则把焦距小于2 5毫米的镜头作为广角镜头。…     

Loads Analysis of Flanges of a Transonic and Supersonic Wind Tunnel Wide Angle Diffuser

Compared with general circular flanges,flanges on conical shells have different configurations.In the Chinese national code GB150,however,there are no related contents about flange design of this kind of type.So,it needs to study loads of flanges of this kind of type.This paper takes the flange connection of a wide angle diffuser in a transonic and supersonic wind tunnel as the background,according to the principles of flange design in Chinese national code GB150,combining the characteristics of flanges of a wide angle diffuser,the loads of flanges have been analyzed,and the equations of loads and their locations have been presented.