The Effect of Mixing Variables on the Dissolution Properties of Direct Compression Formulations of Furosemide

The particles of a number of poorly water soluble drugs, for instance furosemide, tend to agglonierate spontaneously and as a result decrease the drug's dissolution properties. This phenomena is undesirable when the drug is to be formulated in a direct compressible formulation. Interactive or ordered mixing with a filler usually rectifies this problem but the drug load is limited to a maxirnuni of ± 5% of the mixture. This is well below the formulation requirements of hrosemide (25 %) and below the maximum drug load which can be handled in dircct compression formulations (± 35 %). The effect of two types of mixers, the mixing time and drug load were investigated for a direct compression formulation of furosemide tablets. A Turbula and a V mixer, both with a volume of 720 ml, were used. The drug was formulated with Ludipress (a commercial direct compression filler, BASF, Germany) at two drug loadings of 20 and 25 %. Magnesium stearate (1 %) was added as a lubricant. A mixture was prepared for each experimental condition. After mixing the whole mixture (120 gram) was tabletted on a Korsch single punch machine producing ± 500 tablets. The crushing strength, mass and disintegration time of ten tablets and the dissolution of six tablets were measured. Dissolutions were donc according to the USP XXII - method 2¹ - in 0, 1 M HCI and a phosphate buffer with pH = 5.8. The intrinsic dissolution rates of some of the mixtures were also deterniined in the two dissolution media. The dissolution properties of the formulations were compared with the properties of Lasix®, a commercially available furoseniide product. which is not manufactured by dircct compression. The dissolution rates of the formulations mixed in the Turbula mixer were significantly higher than those mixed in the V miser. The area under the dissolution curves increased as a function of niixing time for both mixers. The best dissolution results were obtained for formulations with a 20 % drug load and mixed for 120 minutes in the Turbula miser. The dissolution curves for these formulations compared well with the curves for the commercial tablets. Intrinsic dissolution rates were also a hnction of niising time, which indicates that the increase in dissolution properties is probably a result of the deagglomeration of the agglomerated furosemide particles. The Turbula mixer, which can develop more shear force, breaks the agglomerates quicker and to a larger extend than the V mixer. It can be concluded that the type of mixer, mixing time and drug load control the dissolution properties of direct compression formulations of poorly water soluble drugs in which the drug particles form agglomerates.     

The Effect of Mixing Variables on the Dissolution Properties of Direct Compression Formulations of Furosemide

Abstract

The particles of a number of poorly water soluble drugs, for instance furosemide, tend to agglonierate spontaneously and as a result decrease the drug's dissolution properties. This phenomena is undesirable when the drug is to be formulated in a direct compressible formulation. Interactive or ordered mixing with a filler usually rectifies this problem but the drug load is limited to a maxirnuni of ± 5% of the mixture. This is well below the formulation requirements of hrosemide (25 %) and below the maximum drug load which can be handled in dircct compression formulations (± 35 %). The effect of two types of mixers, the mixing time and drug load were investigated for a direct compression formulation of furosemide tablets. A Turbula and a V mixer, both with a volume of 720 ml, were used. The drug was formulated with Ludipress (a commercial direct compression filler, BASF, Germany) at two drug loadings of 20 and 25 %. Magnesium stearate (1 %) was added as a lubricant. A mixture was prepared for each experimental condition. After mixing the whole mixture (120 gram) was tabletted on a Korsch single punch machine producing ± 500 tablets. The crushing strength, mass and disintegration time of ten tablets and the dissolution of six tablets were measured. Dissolutions were donc according to the USP XXII - method 2¹ - in 0, 1 M HCI and a phosphate buffer with pH = 5.8. The intrinsic dissolution rates of some of the mixtures were also deterniined in the two dissolution media. The dissolution properties of the formulations were compared with the properties of Lasix®, a commercially available furoseniide product. which is not manufactured by dircct compression. The dissolution rates of the formulations mixed in the Turbula mixer were significantly higher than those mixed in the V miser. The area under the dissolution curves increased as a function of niixing time for both mixers. The best dissolution results were obtained for formulations with a 20 % drug load and mixed for 120 minutes in the Turbula miser. The dissolution curves for these formulations compared well with the curves for the commercial tablets. Intrinsic dissolution rates were also a hnction of niising time, which indicates that the increase in dissolution properties is probably a result of the deagglomeration of the agglomerated furosemide particles. The Turbula mixer, which can develop more shear force, breaks the agglomerates quicker and to a larger extend than the V mixer. It can be concluded that the type of mixer, mixing time and drug load control the dissolution properties of direct compression formulations of poorly water soluble drugs in which the drug particles form agglomerates.     

The Effects of Inclusions on the Properties of Polymer Films,Granules and Compacts

Abstract

Polymer films have been prepared using four tablet binders, lactose, sodium lauryl sulphate and polyethylene glycol 600 have been used as inclusions in the films. The films have been tested to failure in tension and stress/strain diagrams have been prepared for each system examined. Granules and compacts have been prepared using the polymers as binders with, and without, the inclusions. The substrate for the granules was sand to eliminate the effects of solubility. Granules have been examined for size, friability and strength; compacts have been made when possible and tested for strength. The strength of bonds, between glass plates, has been measured using a butt-joint test.

The inclusions resulted in a reduction of the ultimate tensile strength of all the binder films. PEG 600 had little plasticising effect, sodium lauryl sulphate and lactose both made some films of PVP and Starch too brittle to test. Effects on bond strengths varied with film/inclusion combination.

The inclusions weakened the granules but had little effect on friability. Compact strengths were reduced by the inclusions except for lactose combined with either gelatin or starch.     

Compression of Indomethacin Coprecipitates with Polymer Mixtures: Effect of Preparation Methodology

The objective of this study was to prepare, characterize, formulate and compare coprecipitates, solid dispersions and physical mixtures of indomethacin with Eudragit polymer mixtures, RS100 and L100. Coprecipitates, solid dispersions (melting-solvent method) and physical mixtures were prepared with a drug : polymer ratio of 12.6: 1.0 respectively. Biconvex tablets of 7 mm diameter were compressed. Response variables studied were cumulative percent released and T₅₀. Dissolution was performed by exposing the tablets to SGF (PH 1.2) for 1 hour followed by pH 7.2 phosphate buffer for 24 hours. T₅₀ values obtained were 7.5 hours for coprecipitates, 4.5 hours for solid dispersions and 17 hours for physical mixtures. The drug loading for all the three formulations did not show significant difference. The formulations were characterized by X-ray diffraction (qualitative and quantitative) and IR. IR data did not indicate any significant difference between the pure drug and the formulations. However, significant differences were seen in X-ray diffractograms. The crystallinity did not change for physical mixtures, was reduced for coprecipitates and solid dispersions. Also the diffraction patterns for solid dispersions and coprecipitates were similar. The coprecipitates and physical mixture followed the Higuchi's square-root-of-time equation suggesting a matrix effect. These results suggest that compression of coprecipitates offer most efficient release as compared to solid dispersions and physical mixtures.     

Optimization of Direct Compression Tablet Formulations for Use in Tropical Countries

Abstract

With the aid of a combined mixture- and factorial- design, 2 standard tablet formulations were selected suitable for use in tropical countries. The formulations were based on native ingredients or ingredients that are available worldwide. The selection of the standard formulations was based on both the initial tablet properties of the formulations one day after preparation as well as the physical stability after storage under tropical conditions.

The selected formulations were evaluated by adding model drugs (diazepam, 2 mg per tablet or hydrochlorthiazide, 100 mg per tablet) and measuring tablet properties, not only one day after preparation, but also after storage under tropical conditions. Both selected tablet formulations were suitable standard formulations for tablets prepared by direct compression for use in tropical countries.     

Optimization of Direct Compression Tablet Formulations for Use in Tropical Countries

With the aid of a combined mixture- and factorial- design, 2 standard tablet formulations were selected suitable for use in tropical countries. The formulations were based on native ingredients or ingredients that are available worldwide. The selection of the standard formulations was based on both the initial tablet properties of the formulations one day after preparation as well as the physical stability after storage under tropical conditions.

The selected formulations were evaluated by adding model drugs (diazepam, 2 mg per tablet or hydrochlorthiazide, 100 mg per tablet) and measuring tablet properties, not only one day after preparation, but also after storage under tropical conditions. Both selected tablet formulations were suitable standard formulations for tablets prepared by direct compression for use in tropical countries.     

Pressure Effect on Hall Coefficient in Multilayered High-T c Cuprates

Temperature dependence of the Hall coefficient and the resistivity in Tl₂Ba₂CaCu₂O _y (TL-2212), Tl₂Ba₂Ca₂Cu₃O _y (Tl-2223) and Cu_0.7C_0.3Ba₂Ca₃Cu₄O _y (Cu-1234) have been measured under high pressure up to 6 GPa. The values of the intrinsic T _c enhancement not related to charge transfer by applied pressure were estimated to be 0.8K/GPa for the Tl system and 1.1K/GPa for Cu-1234.     

Compression of Microcapsules I: Effect of Excipients and Pressure on Drug Release

Microcapsules containing phenylpropanolamine-resin complexes were compressed with various diluents. Compression of microcapsules produced an increase in the release rate. An average reduction of 0.50 hours was observed when Emdex or Fast Flo Lactose were compared to Avicel at various pressures (35 to 281 MPa). Increasing the amount of microcapsules in the formulation reduced the T50% with all three diluents     

Compression of Microcapsules I: Effect of Excipients and Pressure on Drug Release

Abstract

Microcapsules containing phenylpropanolamine-resin complexes were compressed with various diluents. Compression of microcapsules produced an increase in the release rate. An average reduction of 0.50 hours was observed when Emdex or Fast Flo Lactose were compared to Avicel at various pressures (35 to 281 MPa). Increasing the amount of microcapsules in the formulation reduced the T50% with all three diluents     

“Studies of the Effect of Compaction force on Displacement of Large Compacts Formed from Direct Compression Matrices”

Large compacts (3.93 cm x 4 cm) formed from commercial direct compression bases have been prepared by hydraulic compression and then loaded in axial compression when removed from the die.

Avicel and Sta-Rx formed compacts resistant to shear, and failure in free axial compression was due to induced tensile stresses both radial and circumferential. Paracetamol DC, a direct compression form of paracetamol, behaved as a brittle solid and split axially along its length. Emdex and Encompress formed compacts weak in shear and failed along double shear cones at low axial loading.

Emdex gave force v displacement plots for both axial and radial displacement which suggests that it flows plastically at low loads insufficient to cause failure. The other compacts behaved as elastic solids at low axial loadings.

A method was devised to compare radial pressure at various points along the axial length of the compacts when they were formed or recompressed in the die. Although easily ejeeted, compacts of Avicel and Sta-Rx were the best transmitters of radial pressure. Emdex and Encompress compacts were both difficult to eject. It is suggested that this is due to shear failure and and rebonding along the shear cones demonstrated infreeaxial compression.     

Evaluation of Mujol as a Direct Compression Excipient in Oxytetracycline Hydrochloride Tablet Formulations

Abstract

The physical properties of oxytetracyc1ine hydrochloride tablets compressed with Musol, a new autocompressib1e vehicle obtained by chemical modification of an edible seed polysaccharide were studied, Avice1 PH 101, Fast-f1o lactose and Emcompress were used as basis for comparison.

With the exception of those tablets containing Emcompress, good disintegration and dissolution profiles were obtained in all the batches formulated. The dissolution characteristics of the tablets did not change significantly after storage in the dark at 30°C for 96 weeks.     

不同结构多层膜中巨磁阻抗效应的研究

研究了封闭式和开放式FeSiB/Cu/FeSiB多层膜以及Cu/FeSiB/Cu多层膜中的巨磁阻抗效应。实验结果表明：多层膜的不同结构对巨磁阻抗效应影响很大。改变外加磁场,封闭式FeSiB/Cu/FeSiB多层膜中阻抗变化最大,开放式FeSiB/Cu/FeSiB多层膜次之,而Cu/FeSiB/Cu多层膜中阻抗几乎不变。三组多层膜中不同的阻抗特征可用多层膜的具体结构解释：在封闭式多层膜内,磁路形成密封结构,使泄漏到多层膜外面空间的磁通大大减少;在Cu/FeSiB/Cu多层膜中,上下两铜层在铁磁薄膜内产生的总磁场近似为零,外加磁场的改变不能引起其阻抗发生变化。对于封闭式FeSiB/Cu/FeSiB多层膜,在100kHz到1MHz时就能够出现较大的阻抗变化比值,最大阻抗变化比值出现在3MHz。开放式FeSiB/Cu/FeSiB多层膜阻抗特性与封闭式类似,但比例只是封闭式多层膜的1／3。     

铁磁层/导电层/铁磁层多层膜中巨磁阻抗效应理论*

采用经典电磁理论,对铁磁层／导电层／铁磁层（M／C／M）多层膜中出现的巨磁阻抗效应进行了理论分析。对于单轴横向磁各向异性多层膜,理论计算结果表明：高频阻抗在某一外加磁场（近似等于等效各向异性场）下出现最大值,铁磁层和导电层电阻率相关较大的多层膜中将出现较强的巨磁阻抗效应。多层膜在1MHz附近即可出现远大于单层膜的阻抗变化比。多层膜理论计算与实验结果能够较好地符合。     

Bead Coating: II. Effect of Spheronization Technique on Drug Release from Coated Spheres

The effect of spheronization method on drug release from coated spheres may be evaluated by determining the drug release rate, the critical coating level and the release mechanism. Drug release is faster from pan beads than from marumerizer beads at the same coating level. An equation is proposed which indicates that the critical coating level is inversely proportional to sphere size and sphere density, which in turn results from the different spheronization techniques. From the calculation, the critical coating levels for 14/16 mesh cuts of marumerizer beads and pan beads are 12% and 18%, respectively. Disintegration, pore-control and barrier control are involved in the release mechanisms of drugs from coated pan beads.     

Ontrolled-Release Theophylline Tablet Formulations Containing Acrylic Resins. I. Dissolution Properties of Tablets

The dissolution properties of controlled-release theophylline tablets containing acrylic resins are presented. Four different resins (Eudragit RSPM, RLPM, Sl00 and Ll00) were incorporated into theophylline tablets by direct compression techniques and the properties of the resulting dosage form were evaluated in dilute acid, buffer media pH 4.0 and simulated intestinal media pH 7.5. Tablets (500 mg) containing 300 mg of theophylline were prepared with each of the four resins and compressed to a hardness level of 6.5 to 7.5 kg. Excellent flow properties, weight uniformity and drug content uniformity were observed with all tablet formulations. Preliminary data suggest that three of the four resins tested showed great promise as a retardant in a matrix controlled drug delivery system. The dissolution properties of three commercially available sustained-release theophylline tablets were also determined. A comparison of profiles from Theodur^R (300 mg) in acid and simulated intestinal media showed a similarity in release properties to those of theophylline in tablets containing the RLPM resin.     

含有助复剂扩散-轧制复合钢板的研究

借鉴了钎焊、瞬间液相扩散焊以及压力焊工艺的原理及特点,运用助复剂来促进碳钢的复合。对浸涂有助复剂的钢板,在小变形扩散-轧制条件下,为使其达到最佳的复合效果,对复合工艺参数进行了研究。结果表明,在小变形范围内,变形量增大有利于复合;为达到好的复合效果,保温时间不宜过长,但也不宜过短;加热温度过高反而影响复合。     

Ontrolled-Release Theophylline Tablet Formulations Containing Acrylic Resins. I. Dissolution Properties of Tablets

Abstract

The dissolution properties of controlled-release theophylline tablets containing acrylic resins are presented. Four different resins (Eudragit RSPM, RLPM, Sl00 and Ll00) were incorporated into theophylline tablets by direct compression techniques and the properties of the resulting dosage form were evaluated in dilute acid, buffer media pH 4.0 and simulated intestinal media pH 7.5. Tablets (500 mg) containing 300 mg of theophylline were prepared with each of the four resins and compressed to a hardness level of 6.5 to 7.5 kg. Excellent flow properties, weight uniformity and drug content uniformity were observed with all tablet formulations. Preliminary data suggest that three of the four resins tested showed great promise as a retardant in a matrix controlled drug delivery system. The dissolution properties of three commercially available sustained-release theophylline tablets were also determined. A comparison of profiles from Theodur^R (300 mg) in acid and simulated intestinal media showed a similarity in release properties to those of theophylline in tablets containing the RLPM resin.     

Bead Coating: II. Effect of Spheronization Technique on Drug Release from Coated Spheres

Abstract

The effect of spheronization method on drug release from coated spheres may be evaluated by determining the drug release rate, the critical coating level and the release mechanism. Drug release is faster from pan beads than from marumerizer beads at the same coating level. An equation is proposed which indicates that the critical coating level is inversely proportional to sphere size and sphere density, which in turn results from the different spheronization techniques. From the calculation, the critical coating levels for 14/16 mesh cuts of marumerizer beads and pan beads are 12% and 18%, respectively. Disintegration, pore-control and barrier control are involved in the release mechanisms of drugs from coated pan beads.     

Optimization of Slow-Release Tablet Formulations: Containing Montmorillonite I. Properties of Tablets

Slow-release tablets containing 20%. sodium sul fathiazole and 30%. magnesium aluminum silicate were prepared by direct compression techniques. Dissolution studies indicated that tablet hardness exerted a negligible influence on drug release from the tablets. During the dissolution process the clay slowly swelled to form a gelatinous hydrated layer around the tablet matrix. At faster stirring speeds, friction between the dissolution basket and the tablet rapidly removed the hydrated boundary region and resulted in a more rapid dissolution rate of the sulfonamide. Faster rates of dissolution were seen in deionized water than in dilute acid since the clay hydrated more readily at the higher pit.     

Studies on Furosemide Tablets I Dissolutions of Commercial Products and Different Formulations

Abstract

Tablet properties of 3 different commercial brands of furosemide tablets from different marufacturers have been investigated. Their dissolution characteristics were determined by using USP rotating basket method and two different pH degrees as the test medium. At pH 4.6 a large variation in the dissolution rate of these brands was observed. The release rate differed from one lot to another.

The effect of methods of tablet processing on furosemide release was also studied. A poor dissolution profile was observed with the tablet prepared by direct compression. The best result was obtained with the wet-granulation and the further study is extended on this process.