Examination of the compaction properties of a 1:1 acetaminophen:microcrystalline cellulose mixture using precompression and main compression

The compaction properties of a 1:1 acetaminophen and microcrystalline cellulose (MCC) mixture have been studied using a compaction simulator to make tablets by single compression and by a combination of precompression and main compression. The tensile strengths of the tablets and the energies involved in the compressions were determined. The tensile strengths of the tablets increased with increases in single compression pressure from 80 to 400 MPa and as the total applied pressure increased from 80 MPa up to around 400 MPa when combinations of precompression and main compression pressures were used. The tablet porosity decreased with increase in main compression pressure while the tablet tensile strengths increased. At minimum tablet porosity, further increase in main compression pressure could no longer result in increase in tablet strengths. Tablets compressed with combinations of precompression and main compression were stronger (2.15 +/- 0.02 to 3.99 +/- 0.1 MPa) than those produced with single compression (0.73 +/- 0.01 to 3.09 +/- 0.05 MPa). The total gross energies of compression increased with an increase in pressure of both the precompression and main compression. The elastic energies during main compression increased with an increase in precompression pressure as the tablet exhibited greater elastic deformation and reduced plasticity on second compression. The increase in elastic energies during main compression may also be because elastic energy is recoverable and is independent of precompression. As the precompression pressure increased, the minimum tablet porosity was attained; hence, the plastic energy during main compression became smaller while the elastic energy increased. Thus, a combination of low precompression and main compression pressures of 160/80 MPa or 80/160 MPa are more advantageous in the tableting of the 1:1 acetaminophen:MCC than a high single compression pressure of 320 or 400 MPa.     

Physical aspects of wet granulations I: distribution kinetics of water

The kinetics of wetting during the process of making tablet granulations were studied; the process progresses through an intermediate (overwetted) nonequilibrium granule to a final, equilibrated granule. In systematic formulation changes, there is an optimum composition from the point of view of hardness and content of equilibrium granules.     

Development of oral dosage form for elderly patients: use of agar as base of rapidly disintegrating oral tablets

Rapidly disintegrating tablets as an oral dosage form for elderly patients with impaired swallowing were investigated using agar powders (AG) or treated agar powders (TAG). When the compression pressure was changed from 0.4 to 2.0 ton/cm2, the disintegration time of AG tablets increased from about 60 to about 160s, and the hardness significantly increased from 3 to 13 kgw. The disintegration time and hardness of the TAG tablets were scarcely affected by the compression pressure: the disintegration time was 5--6s, and the hardness was 2--3 kgw. The rapid disintegration of the TAG tablets seemed due to the rapid water penetration into the tablet resulting from the large pore size and large overall pore volume. It was found that rapidly disintegrating oral tablets with proper hardness can be prepared using TAG.     

Modeling the effects of hydroxypropylcellulose in acetaminophen tablet formulation

The objective of the research described here was to develop a set of predictive models that would be used to show the performance of hydroxypropylcellulose as a pharmaceutical tablet binder. A statistically designed set of experiments was used to relate tablet formulation to functionality. It was found that the binder level affected both hardness and dissolution time. Useful predictive models were generated for tablet hardness and dissolution time as a function of the binder or binder-drug ratio. The optimal formulation can be predicted from this study, and will depend upon the combination of desired hardness and the dissolution time for a particular drug.     

Influence of tablet hardness and hydrophobicity on the adhesive properties of an acrylic resin copolymer

The adhesive properties--including the force of adhesion, elongation at adhesive failure, the modulus of adhesion, and the adhesive toughness--of an acrylic resin copolymer were determined using the butt adhesion technique. Flat-faced tablets containing up to 30% hydrogenated castor oil were coated with an aqueous dispersion of Eudragit L30D-55. Using data obtained from a Chatillon digital force gauge attached to a motorized test stand, force-deflection profiles, similar to stress-strain curves generated in the tensile testing of free films, were constructed. The surface characteristics of the tablets significantly influenced polymer-substrate interaction. The force of adhesion, the elongation at adhesive failure, and the adhesive toughness decreased as the surface of the tablet became more hydrophobic through the addition of wax to the tablet formulation. Lower adhesive properties were found with increasing tablet hardness, due to a decrease in the effective area of contact between the film coating and the tablet surface. Increased polymer loading resulted in stronger adhesion, indicating a relationship between the mechanical and adhesive properties of the polymer. The present study demonstrated that the area under the force-deflection profile in conjunction with the force of adhesion was more representative of the adhesive properties of the polymer.     

冷模压制Ti-6Al-4V粉末的修正Drucker-Prager Cap本构模型

通过单轴压缩实验、径向压缩（巴西圆盘）实验和冷模模压实验建立了基于密度相关修正Drucker-Prager Cap（DPC）的Ti-6Al-4V粉末压制本构模型,利用ABAQUS有限元仿真软件的二次开发用户子程序USDFLD对该本构模型进行了模拟验证。综合考虑压制过程中实验装置变形对实验数据的影响,通过空压校正实验控制实验误差,建立了更加准确的修正DPC模型。结果表明:修正DPC本构模型可很好地应用于Ti-6Al-4V粉末压制过程的仿真模拟;当上模冲压力较小时（< 50 MPa）,模壁摩擦系数随上模冲压力的增加逐渐减小,当上模冲压力较大时（>50 MPa）,模壁摩擦系数随上模冲压力的增加而基本趋于稳定。     

Effect of hypertonic saline on leukocyte activity after spinal cord injury

STUDY DESIGN: The effect of intravenous administration of hypertonic saline on leukocyte adhesion after compression injury of the spinal cord was evaluated. OBJECTIVES: To investigate changes in leukocyte adhesion after spinal cord injury and to evaluate the effect of hypertonic saline on this process. SUMMARY OF BACKGROUND DATA: Leukocytes have been thought to exacerbate tissue injury after ischemia-reperfusion. Downregulating and reducing the number of circulating leukocytes has attenuated tissue damage in various models of cerebral ischemia. Recently, investigators have reported that leukocytes exacerbate injury in the spinal cord after trauma. Other recent findings have indicated that hypertonic saline may play a role in decreasing leukocyte adhesion and activation. METHODS: Sprague-Dawley rats were anesthetized, and a C3-C5 laminectomy was performed. Injury was caused by 35 g of compression applied to the cord for 10 minutes. Animals were divided into three groups: sham treated, untreated, and treated. The treated animals received 7.5% hypertonic saline (5 mL/kg, intravenously) 5 minutes after the injury. Sticking leukocytes and shear rate were measured using fluorescence microscopy. RESULTS: Administration of 7.5% hypertonic saline after injury significantly decreased the number of sticking leukocytes in the venules and arterioles. Shear rate was unchanged between the groups. CONCLUSIONS: The results show that an increase in leukocyte adhesion after a compressive injury is attenuated by the administration of 7.5% hypertonic saline. The decrease in adhesion cannot be attributed to changes in the shearing forces, because no significant change was observed in the shear rate. Hypertonic saline may interfere with leukocytes directly by interfering with their ability to swell and thus may prevent activation.     

Nitrergic relaxation of the horse corpus cavernosum. Role of cGMP

A rotatable central composite design is used to evaluate the effects of lubricants and compression force on the physical characteristics of effervescent tablets. Effervescent tablets lubricated with a combination of spray dried L-leucine and polyethylene glycol 6000 are prepared by direct compression and examined. Residual force, crushing strength and disintegration time are considered as response variables and related to the L-leucine and polyethylene glycol concentrations and to the compression force. The calculated models are used to assess the influence of the production factors on tablet properties. As increasing amounts of L-leucine, showing good lubricating properties, reduce the crushing strength and prolong tablet disintegration, the L-leucine concentration is kept at a low level. An optimum tablet formulation contains 2% L-leucine and 3% polyethylene glycol 6000. The tablets have a tensile strength of 0.47 MPa and disintegrate in less than 2 min. Predicted and experimental results are in agreement within a 95% CI.     

Fatigue and Compression Characteristics of Al 6061–B 4 c Composite Materials

Aluminum matrix composites reinforced with boron carbide are a kind of materials that are widely used because of high strength, low density, and improved tribological properties. In this study, mechanical properties of Al 6061–B4C composites reinforced with B4C of three different particle sizes were investigated. In the Al 6061–B4C composite materials, produced by the powder metallurgy methods (extrusion of billets obtained by sintering at temperature of 550°C under pressure of 450 MPa), the change of mechanical properties such as hardness, compressive strength, and fatigue life, related to B4C particle size and the applied heat treatment mode (aging at 180°C for 5 h), were investigated. The hardness of the materials is increased with B4C grain size and the heat treatment. After the heat treatment, the fatigue life of Al 6061–B4C (3 μm) material increases slightly, while that of the composite materials decreases with larger size of B4C reinforcement. The fatigue life of the composite materials reinforced with a larger grain size B4C is reduced by heat treatment. While the compression test data of untreated composite materials were similar to each other, the heat treatment increased these values in all samples. The highest increase in the compression strength was observed in the composite reinforced with 17 μm sized B4C. The addition of graphite reduces the deformation ability of the composites.     

Pharmaceutical granulation and tablet formulation using neural networks

Current-day pharmaceutical formulation may be trial and error in nature due to the absence of a clear relationship between the formulation characteristics (output variables) and the material and process variables (input variables). Neural networks are networks of adaptable nodes, which through a process of learning from task examples, store experiential knowledge and make it available for prediction. Prediction of a model granulation and tablet system characteristics from the knowledge of material and process variables utilizing neural networks is the basis of this presentation. The formulation design contained the following variables: granulation equipment, diluent, method of binder addition, and the binder concentration. The material, process, granulation evaluation, and tablet evaluation data of the formulations were used as the data set for training and testing of the neural network models. A comparison of the neural network prediction performance with that of regression models was also done. Both the granulation model and the tablet model converged fairly rapidly in the training step. In the testing step, the predictions for all granulation model variables (geometric mean particle size, flow value, bulk density, and tap density) were satisfactory. In the tablet model, the predictions for disintegration and thickness were also satisfactory. The predictions for hardness and friability were less than satisfactory. Two situations where the neural network may not perform adequately are discussed. The neural network prediction is better or comparable for all the predicted variables in this study compared to regression methods. The results clearly show the applicability of neural networks to formulation modeling.     

Bioavailability of morphine after administration of a new bioadhesive buccal tablet

A new bioadhesive buccal morphine tablet was developed for controlled release delivery of drug and improved bioavailability compared with oral controlled release tablet. In order to characterize the pharmacokinetic properties of this bioadhesive buccal formulation, a bioavailability study was performed in 12 healthy volunteers who received: a 30 mg oral controlled release tablet (A); a 20 mg aqueous solution retained in the mouth for 10 min (B); and the 60 mg bioadhesive buccal tablet placed between the lower gum and lip for 6 h (C). The mean amount of morphine absorbed from the solution was very low, only 2 mg of the 20 mg dose. After administration of forms A and C, plasma levels exhibit typical sustained release concentration-time curves. The mean amount of drug recovered from the residual bioadhesive buccal tablet after 6 h indicated that approximately 50% of the dose was released from the bioadhesive buccal tablet. The relative bioavailability of the buccal tablet (corrected for residual unabsorbed dose) compared with the controlled-release tablet was 98% based on the morphine AUC values. Good correlations between the AUC and the Cmax of the bioadhesive tablet for the drug and metabolite plotted versus the amount of morphine absorbed were found.     

Occurrence of fragmentation during compression of pellets prepared from a 4 to 1 mixture of dicalcium phosphate dihydrate and microcrystalline cellulose

The occurrence of pellet fragmentation during the compression of pellets prepared mainly from a hard pharmaceutical filler material was investigated. The pellets consisted of 4 parts dicalcium phosphate dihydrate (generally considered as a hard material) to 1 part microcrystalline cellulose (used as a pellet forming material). Pellets of two porosities, 36% and 55%, were prepared. Compacts formed at 100 MPa applied pressure were fractured and the fracture surfaces were then visually examined. Lubricated pellets were also compacted in order to obtain tablets which could be easily deaggregated. Pellets retrieved from deaggregated tablets were compared with uncompacted pellets with respect to size and fracture resistance. The results showed that many pellets exposed in the tablet fracture surface were fractured, especially those with higher porosity. However, the lubricated pellets retrieved from deaggregated tablets were similar in size to the uncompacted pellets, i.e. fragmentation of these pellets was minimal. Furthermore, these retrieved pellets were more resistant to fracture than the original uncompacted pellets, indicating that the formation of cracks or flaws in the pellets during compaction was also minimal. It was thus concluded that deformation and probably densification, and not fragmentation, was the dominant compression mechanisms of this pellet formulation.     

Pharmacokinetics and effect of food on the bioavailability of orally administered venlafaxine

Venlafaxine is a unique antidepressant currently under evaluation for treatment of various affective disorders. The pharmacokinetics and relative bioavailability of venlafaxine were evaluated in healthy volunteers after oral administration. The bioavailability of 50 mg of venlafaxine as a tablet relative to a solution was determined in a two-period randomized crossover study. The rate of absorption from the gastrointestinal tract was assessed by the time to peak plasma concentration (tmax), a model-dependent calculation of the first-order absorption rate constant, and a model-independent calculation of mean residence time. The extent of absorption was assessed by peak plasma concentration (Cmax) and area under the concentration-time curve (AUC). No statistically significant differences were observed between the two formulations for either the rate or extent of absorption. Similarly, systemic concentrations of the active O-demethylated metabolite did not significantly differ after administration of the two venlafaxine formulations. AUC ratios indicated that the relative bioavailabilities of the parent drug, and formulation of metabolite were approximately 98% and 92%, respectively, for the tablet versus the solution. A separate study was conducted to examine the influence of food on venlafaxine absorption from the 50-mg tablet. A standard, medium-fat breakfast eaten immediately before drug administration delayed the tmax of venlafaxine but did not affect Cmax or AUC. Therefore the tablet formulation of venlafaxine is bioequivalent to the oral solution, and the presence of food appears to decrease the rate but not the extent of absorption of venlafaxine from the tablet formulation.     

Effect of compression temperature on the consolidation mechanism of chlorpropamide polymorphs

The effect of environmental temperature on the compression mechanism of chlorpropamide (CPM) polymorph, forms A and C, was investigated with an eccentric type tabletting machine with two load cells and a noncontact displacement transducer. The temperature of the die was controlled at 0 and 45 degrees C by a thermocontroller. Sample powders (200 mg), which were also controlled at 0 and 45 degrees C by a thermocontroller, were compressed at almost 230 MPa. The tabletting dynamic processes of CPM forms A and C at 0 and 45 degrees C were evaluated by Cooper and modified Heckel analyses. The results suggest that particle brittleness or plasticity was affected by compression at different temperatures. The higher tablet hardness of form A at 45 degrees C was thought to be caused by the increased plasticity of primary particles, whereas that of form C at 45 degrees C was ascribed to the decreased size of the secondary particles.     

Identification of formulation and manufacturing variables that influence in vitro dissolution and in vivo bioavailability of propranolol hydrochloride tablets

The purpose of this study was to evaluate the effect of formulation and processing changes on the dissolution and bioavailability of propranolol hydrochloride tablets. Directly compressed blends of 6 kg (20,000 units) were prepared by mixing in a 16-qt V blender and tablets were compressed on an instrumented Manesty D3B tablet press. A half-factorial (2(5-1), Resolution V) design was used to study the following variables: filler ratio (lactose/dicalcium phosphate), sodium starch glycolate level, magnesium stearate level, lubricant blend time, and compression force. The levels and ranges of the excipients and processing changes studied represented level 2 or greater changes as indicated by the Scale-up and Post Approval Changes (SUPAC-IR) Guidance. Changes in filler ratio, disintegrant level, and compression force were significant in affecting percent drug released (Q) in 5 min (Q5) and Q10. However, changes in magnesium stearate level and lubricant blend time did not influence Q5 and Q10. Hardness was found to be affected by changes in all of the variables studied. Some interaction effects between the variables studied were also found to be significant. To examine the impact of formulation and processing variables on in vivo absorption, three batches were selected for a bioavailability study based on their dissolution profiles. Thirteen subjects received four propranolol treatments (slow-, medium-, and fast-dissolving formulations and Inderal 80 mg) separated by 1 week washout according to a randomized crossover design. The formulations were found to be bioequivalent with respect to the log Cmax and log AUC0-infinity. The results of this study suggest that (i) bioavailability/bioequivalency studies may not be necessary for propranolol and perhaps other class 1 drugs after level 2 type changes, and (ii) in vitro dissolution tests may be used to show bioequivalence of propranolol formulations with processing or formulation changes within the specified level 2 ranges examined.     

Polyethylene glycol as a binder for tablets

Polyethylene glycol 6000 was evaluated as a binder for the direct compression of 11 tablet formulations. Six formulations compressed quite well, and the resulting tablets were satisfactory in all respects. To evaluate stability, actual shelflife studies were considered more appropriate than the accelerated studies. After a shelflife of 3 years, five of the six formulations were stable. The ascorbic acid formulation was stable for up to 18 months.     

Bead compacts. I. Effect of compression on maintenance of polymer coat integrity in multilayered bead formulations

Little information is available on the compactability of beads for oral sustained-release dosage forms. It is known that polymer-coated beads may fuse together to produce a non-disintegrating controlled-release matrix tablet when compressed. This study evaluates the effect of compression on beads with multiple layers of polymer and drug coat, and the effect of cushioning excipients and compaction pressure on drug release from compressed bead formulations. The multilayered beads consist of several alternating layers of acetaminophen (APAP) and polymer coats (Aquacoat) with an outer layer of mannitol as a cushioning excipient. Percent drug release versus time profiles showed that the release of drug decreases from noncompacted beads as the amount and number of coatings increases, with only 43% of drug released in 24 hr for coated beads with 10 layers. It was shown that the compacted multilayered beads will disintegrate in gastrointestinal fluids, providing a useful drug release pattern. It was shown that beads of drug prepared by any method can be spray-layered with excipients such as Avicel and mannitol. Spray-layering of the cushioning excipient onto beads can provide an effective way to circumvent segregation issues associated with mixing of the polymer-coated beads and powdered or spherical/nonspherical cushioning excipients. Spray layering of the cushioning excipient can also provide excellent flow properties of the final formulation as visually observed in our experiments. Triple-layered caplets (TLC) were also prepared with outer layers of Avicel PH-101 or polyethylene oxide (PEO), and a center layer of polymer-coated beads. For TLC, the polymer coating on the beads fractured, and nondisintegrating matrix formulations were obtained with both caplet formulations.     

Laboratory extrusion of Nb3Sn

A study of laboratory direct extrusion of HIP processed Nb₃Sn has been undertaken to assess the effect of hydrostatic pressure on the ductile fracture process that is observed in simple compression above 1400 °C. (Remanent porosity and low melting point microconstituents provide fracture centers; and void growth, linkage, and gross fracture can proceed rather rapidly, with pore linkage being obvious at the specimen surface after a 15 pct reduction in simple compression.) A rather porous, 1200 °C HIP processed material (5 pct porosity and 2.4 pct of low melting point phases) has been successfully extruded at 1650 °C in round bar form to a 51 pct area reduction with neither extensive pore linkage nor gross fracture. The results imply that little porosity development occurs in the presence of hydrostatic pressure of about twice the flow stress. Moreover, in the absence of free surface conditions, effective strains of the order of 0.7 will produce no more than about 10 pct porosity development under hydrostatic pressures of about one-half of the flow stress. Gross porosity development is associated with free surface deformation. Powdered graphite proves to be a poor lubricant, with the bulk of the extrusion pressure reflecting sticking friction.     

应用数控铣镗床TK6920加工转动支架的方法

介绍了应用数控铣镗床TK6920加工三辊铝管穿孔机转动支架滑槽的方法及G代码程序，探讨了应用数控机床加工该类型复杂工件的方法与优点。