The influence of moisture content on the consolidation properties of hydroxypropylmethylcellulose K4M (HPMC 2208)

The effect of moisture content, compression speed and compression force on the compaction properties of HPMC K4M has been evaluated. As the moisture content increased from 0 to 14.9% w/w, the thickness of HPMC K4M compacts increased at constant compression force and speed. This increase in moisture content also resulted in a marked increase in the tensile strength of the tablets. At a speed of 15 mm s-1 and force of 10 kN, as the moisture content increased from 0 to 14.9% w/w, the tensile strengths increased from 1.34 to 8.54 Mpa. Equivalent tensile strengths could be obtained with less compression force as the moisture content in the polymer was increased. Increasing the compression speed generally decreased the tensile strength of HPMC K4M tablets. The dependence of tablet porosity and tensile strength on compression speeds showed that HPMC K4M is consolidated by plastic deformation. At all compression speeds, an increase in moisture content reduced the percentage elastic recovery of HPMC compacts due to greater tablet consolidation. The lowest elastic recovery (1.18%) was found for tablets made at 15 mm s-1 and 5 kN, containing 14.9% w/w moisture content.     

Development of an ultracentrifuge technique to determine the adhesion and friction properties between particles and surfaces

The extension of a centrifuge technique to measure adhesion and friction forces to an ultracentrifuge has been described. The equipment and procedure provide many experimental possibilities of which the adhesion of single particles to flat compacted powder surfaces has been used to measure the adhesion and friction force of starch microspheres to microcrystalline cellulose. The equipment used allows the positioning of the adhesion samples in the rotor in such a way that any angle between the centrifugal force vector and the flat sample surface can be obtained, and hence both adhesion and friction forces can be measured. The adhesion strength between starch microspheres and microcrystalline cellulose could initially be increased by applying a higher press-on force. However, a maximum plastic deformation and hence maximum contact area between the spheres and the surfaces was eventually reached, and any further application of press-on force appeared to lead only to more elastic deformation and hence not to an increase in adhesion strength. The friction between the starch microspheres and the compacted microcrystalline cellulose surfaces at a maximum deformation of the spheres is still very low, so that starch microspheres could be used as excipient in mixtures including microcrystalline cellulose for example in tabletting.     

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.     

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.     

Glomerular processing of dextran sulfate during transcapillary transport

The objective of this work was to develop a method to assess the dilution capacity of direct compression excipients based on a technique previously proposed by Minchom and Armstrong (MA). The technique involves the addition of increasing quantities of a poorly compactible (compressible) material to the excipient and measuring the resultant decrease in the AUC of the tensile strength versus compaction force profiles. The AUC of each mixture is divided by the AUC of the "0% mixture" to obtain MA's "work potential," called "area ratios" in the present study. The applicability of this approach was tested using three excipients differing in their deformation mechanisms: microcrystalline cellulose (Avicel PH 101, 102, 200, 301, 302) representing a plastic material; dibasic calcium phosphate (Cal-Star) representing a brittle material, and anhydrous lactose, which exhibits both brittle and plastic properties. Ascorbic acid or acetaminophen was the poorly compactible challenge material. In the first study, the MA method was found to apply only to Avicel PH 101, since the area ratios for mixtures containing different compositions of acetaminophen with either Cal-Star or anhydrous lactose remain constant until a certain percentage of drug is exceeded, after which a decline starts to be observed. Further work carried out on mixtures of different grades of Avicel with ascorbic acid revealed that MA's approach reflects only the ability of the excipient to handle internal stress induced by the drug and does not take into account the intrinsic ability of the drug-free excipient to form strong compacts. A new index was thus proposed, called the dilution capacity index (DCI), which weights the MA index by the AUC of the drug-free excipient. The results suggest that DCI can be used to compare different grades of microcrystalline cellulose and provide in-house quality control for microcrystalline cellulose suppliers.     

A designer's polymer as an oral drug carrier (tablet) with pseudo-zero-order release kinetics

A new synthetic polymeric material has been investigated as an oral controlled-release system. The water soluble polymer consists of a non-cross-linked, ionic polymer possessing sulfonate functional groups: poly(sulfopropyl methacrylate potassium-co- methyl methacrylate) (PSPMK/MMA). Drug-resin complexes were obtained by preparing an aqueous solution of the polymer to which propranolol HCl as a model drug was added. Using either dextrose or microcrystalline cellulose as a tablet binder did not cause any problems in fabricating a compact drug-resinate tablet. The release of propranolol HCl from drug-resinate tablets (2.5 mm x 9.0 mm, 10% dextrose) was pseudo-zero-order kinetics from the beginning to the end for over 21 h. This was due to the greater contribution of drug release from the edge of the tablets. However, zero-order release tablets were obtained by increasing the radius to thickness ratio of the tablet to greater than 3.13. A mathematical model describing release kinetics from drug-resinate tablets predicted the effects of drug loading and the physical dimensions of the tablets by a heterogeneous dissociation/erosion-controlled mechanism. As the content of dextrose in the tablets increased, the dissociation/erosion rate constant (K0) increased due to the greater influx of water into the tablets along with counterions. As expected, the release rate was decreased as the stirring rate decreased from 100 to 50 rpm, resulting in the dissociation/erosion rate constant of 2.62-2.04 mg/cm2h, respectively. Therefore, this system has been proven to release drugs independent of the pH of simulated gastric/intestinal fluids (1.2 and 7.5) as well as the compression force of the tablet, which ranged from 1500 to 4400 lbs.     

Short- and long-term outcome of patients treated with cyclosporin for severe acute ulcerative colitis

The effect of core material properties on the process of compression and physical properties of compression-coated tablets were investigated using microcrystalline cellulose as the coating material (mantle). Three model core materials: borosilicate glass, silicone rubber, and steel, each of different Young's modulus, were selected to give a range of core mechanical properties. Coated tablets were prepared using a single-punch press, with facilities for monitoring the compression cycle and analysis of data using the Heckel (1) equation. This analysis showed a considerable effect of different core materials on the compression process, (i) as an unanchored core, and (ii) due to core material type with differing Young's modulus.     

Preparation and evaluation of a compressed tablet rapidly disintegrating in the oral cavity

In order to make a compressed tablet which can rapidly disintegrate in the oral cavity, microcrystalline cellulose and low-substituted hydroxypropylcellulose were used as disintegrants, and ethenzamide and ascorbic acid were chosen as poorly and easily water soluble model drugs, respectively. The mixture of microcrystalline cellulose and low-substituted hydroxypropylcellulose was compressed at 100--500 kgf in the absence of an active ingredient. The properties of these tablets, such as hardness, porosity, the time required for complete wetting of a tested tablet (wetting time), water uptake and disintegration time determined by a new disintegration apparatus, were investigated to elucidate the wetting and disintegration characteristics of these tablets, When the MCC/L-HPC ratio was in the range of 8:2 to 9:1, the shortest disintegration time was observed. The disintegration of tablets containing ethenzamide or ascorbic acid was examined next. Tablet disintegration time in the oral cavity was also tested, and good correlation between the disintegration behaviors in vitro and in the oral cavity was recognized.     

Effect of intragranular and extragranular disintegrating agents on particle size of disintegrated tablets

Five materials were compared for their effectiveness as disintegrating agents: maize starch, sodium calcium alginate, alginic acid, microcrystalline cellulose, and a colloidal aluminum silicate. The effect of the proportion of the agent present and the position with respect to the granule, intra- and extragranular, was examined. The extragranular formulations disintegrated much more rapidly than the intragranular ones, but the latter gave a much finer dispersion of particles. A combination of intra- and extragranular disintegrating agents gave the best compromise; of those tested, the alginates appeared to effect the breakdown to the smallest particles when placed intragranularly. A method of assessing the effectiveness of disintegrating agents for uncoated tablets is suggested, but the resulting weight mean particle size is the more important criterion for tablets complying with a pharmacopoeial disintegration test. The porosity and crushing strength of tablets are useful as guides to disintegration only when a given formulation is used.     

Validation of a high-performance liquid chromatographic method for the determination of norfloxacin and its application to stability studies (photo-stability study of norfloxacin)

The development and validation study of a sensitive, rapid, reproducible, easy and precise reversed-phase high-performance liquid chromatographic assay for norfloxacin (NFLX) samples from photo-stability of solid dosage forms, without using gradient elution, extraction methods and without using counter-ion has been carried out. The method showed excellent linearity (r2> or =0.999) in the range 1-20 microg ml(-1) using a Lichrosorb-RP-8 column (10 microm, 20 cm x 4.6 mm) and UV-detection (278 nm) at ambient temperature. This method showed good efficiency for the analysis of photodegraded NFLX samples, and was applied to study the photo-stability of NFLX tablets under different conditions (direct sun light, ultraviolet light and fluorescent light). It was proven that the use of a disintegrant can increase the photo-stability of the NFLX in the tablets. This effect was studied in directly compressible tablets with microcrystalline cellulose (MCC) and mannitol for direct compression.     

Influence of hold time on low cycle fatigue behaviour of near alpha titanium alloy IMI 834 at 873K

In the present work, IMI 834, a near α titanium alloy was evaluated for tensile and low cycle fatigue (LCF, with and without hold time) behavior at 873K. Tensile tests were performed at the initial strain rate of 4 × 10^?3 s^?1 at 873K. Fully reversed, total strain control LCF tests were conducted at total strain amplitude of ± 1.0% at constant strain rate of 4 × 10^?3 s^?1 at 873K. For LCF tests with dwell, hold time were imposed in tension, compression and tension — compression mode with varied hold times of 60 sec, 120 sec, 180 secs. In LCF tests without dwell, the Coffin-Manson plot showed dual slope behavior at 873K. In LCF tests with dwell, at 873K, tensile, compressive and tensile — compressive hold time tests have shown lower LCF resistance than that of the tests without hold time. Among the three modes of hold times employed, the tensile hold has exhibited the highest LCF resistance followed by tensile — compressive and compressive hold time tests. In the present study, tensile hold introduces compressive mean stresses while the compressive hold introduces tensile mean stresses. Further, the creep effect of stress relaxation was examined at 873K in order to explain the hold time effects.     

Ibuprofen release kinetics from controlled-release tablets granulated with aqueous polymeric dispersion of ethylcellulose II: influence of several parameters and coexcipients

The objective of this study was to investigate the mechanism of ibuprofen (IBF) release from tablets prepared by wet granulation method, using Surelease as a granulating agent. The influence of certain parameters such as the levels of Surelease solids content (SSC), pH of dissolution media, selected dissolution method, and agitation speed on the release profiles of IBF was investigated. The effect of partial replacement of lactose (primary excipient) by various coexcipients such as microcrystalline cellulose, starch, polyvinylpyrrolidone (PVP), sodium alginate, hydroxypropylmethylcellulose (HPMC), and sodium carboxymethyl cellulose (CMC-Na) was also studied. Tablets prepared with surelease as a granulating agent were non-disintegrating and exhibited prolonged release rates as compared to control tablets. The release of IBF from the tablets appears to occur either via water-filled pores or by diffusion through membrane, depending on the levels of SSC. At higher SSC levels pH independent release profiles for IBF were achieved. Dissolution method and agitation speed exhibited no significant effect on the release profiles. All the coexcipients studied enhanced the release rates, irrespective of whether the coexcipients were water-soluble or water-insoluble.     

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.     

Reduced arterial O2 saturation during supine exercise in highly trained cyclists

As part of a larger effort aimed at optimizing the properties of pellets produced by spheronization of extruded masses, the effect of the moisture content of wet masses on extrusion force and torque was studied. The wet masses were composed of either microcrystalline cellulose (MCC) or mixtures of MCC with lactose or dicalcium phosphate. Based on the force and torque data, a moisture content "window" was defined for consistent extrusion. Moisture exerts a lubricant effect, and a moisture level of 100-120% w/w dry solid seemed necessary for the extrusion of MCC into rod-shaped, discrete pieces. Screen force clearly depended on the moisture content but was relatively insensitive to extruder speed, especially at 80% and 100% moisture content. The physical properties of pellets as a function of spheronization time were studied by sampling the material at known intervals. The percent yield, tapped density, and a two-dimensional sphericity index of an 18/20 mesh fraction of pellets were measured. Maximum yield, tapped density, and sphericity were achieved within 60 sec in the spheronizer. With increasing residence time, the shape and density were unchanged while the yield was severely reduced. Among the formulations studied, pellets with equal amounts of lactose and MCC were superior to those of pure MCC in yield, density, and sphericity. Based on these results, an outline to optimize the endpoint of the spheronization process for formulations containing MCC is suggested.     

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.     

Bioavailability of sulfadiazine in rabbits using tablets prepared by direct compression and fluidized-bed granulation

Experimental sulfadiazine tablets prepared by direct compression, using a commercially available direct compression tablet mass, were compared with experimental sulfadiazine tablets prepared by fluidized-bed granulation and commercially available sulfadiazine tablets USP. The values for friability and the time required to release 10 and 50% of the direct compression tablets were between those of the fluidized-bed tablets and the commercial product. With the commercial tablet as a standard, the extent of bioavailability was determined in rabbits; it was slightly higher for both the direct compression and fluidized-bed tablets. A statistically significant difference was found between the direct compression tablets and the standard with respect to the extent of bioavailability and the time of the peak.     

A mammary epithelial cell line is transiently stimulated towards milk lipid synthesis by lactogenic treatments

The effect of moisture sorption at different relative humidities on the tensile strength and the physical stability of compacts of crystalline and partly amorphous lactose, alone and in binary mixtures with PVP, has been studied. Furthermore, the role of moisture as a plasticizer and its effect on the glass transition temperature, Tg, are related to the compactibiltiy. Samples were conditioned for 2 hr using a climate test chamber at different relative humidities. Moisture sorption was determined, the radial crushing strength for compacts was measured immediately and after storage, and the tensile strength was calculated. The glass transition temperature, Tg, was determined using DSC. The tensile strength of the compacts was found to depend on both the conditioning humidity and the humidity during storage. An increase in humidity to a level at which the glass transition temperature, Tg, fell below the operating temperature, T, resulted in transition from a rigid glassy state to a mobile rubbery state. For compacts of partly amorphous lactose, an increase in the tensile strength was observed during storage of tablets, due to recrystallization of the amorphous regions above Tg. Tablets of mixtures of lactose and PVP exhibit a sharp decrease in tensile strength at humidities above 70% RH, due to the glass-to-rubber transition of PVP.     

The mechanical behavior of LTI carbon dental implants

LTI pyrolytic carbon blade-type dental implants consisting of a graphite substrate and an LTI pyrolytic carbon coating have a strength that increases with the coating thickness. For implants having a coating thickness of about 0.03 in., average fracture loads of about 1500 lb and 230 lb were obtained in axial compressive loading and eccentric loading (e.g., axial compressive loading plus a bending moment), respectively. Depending on the type of loading, the maximum stresses in the graphite substrate were calculated to be very close to its compressive or tensile fracture strength. Also studied was the effect of a variety of defects on the overall strength of the implants.     

固相烧结低钨含量W-Ni-Fe合金的微观结构与力学性能

采用固相烧结工艺(1 300℃保温1 h)制备低钨含量(质量分数为60%~80%)的W-Ni-Fe合金,测定合金的抗拉强度、抗压强度和伸长率,利用金相显微镜观察合金的显微组织,并通过扫描电镜(SEM)观察合金断口形貌,研究钨含量对固相烧结W-Ni-Fe合金力学性能与微观结构的影响。结果表明:随钨含量降低,合金的孔隙率和平均孔径减小,抗拉强度增大,伸长率显著提高,抗压强度变化不大。W含量为60%~80%的W-Ni-Fe合金,其孔隙率为17.8%~21.4%,抗拉强度为231~262 MPa,抗压强度2 450~2 550 MPa,伸长率为0.3%~2.3%,压拉比为9.45~11.04,都能满足易碎型穿甲弹弹芯材料的性能要求。     

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.