Rev Min Research Articles

Can the USP paddle method be used to represent in-vivo hydrodynamics?

Experiments in-vitro and in dogs were conducted to find in-vitro hydrodynamic conditions that can be used to represent gastrointestinal motility patterns. Specifically, the dissolution performance of micronised and coarse-grade felodipine (a poorly soluble, neutral, lipophilic drug) was studied in a biorelevant medium in the USP paddle apparatus at various paddle speeds. Ratios of percentage dissolved (slower:faster rev min(-1)) were calculated pairwise. These ratios were then compared with AUC ratios obtained in a corresponding pharmacokinetic study in Labradors, in which the absorption of both the micronised and coarse-grade felodipine had been compared under two gastrointestinal hydrodynamic conditions. Using a paddle speed combination of 75 and 125 rev min(-1) to represent the motility patterns in response to administration of normal saline and 5% glucose, respectively, the in-vitro ratios (75:125 rev min(-1) dissolution ratio was 91% for the micronised and 46% for the coarse-grade powder) showed good agreement with the pharmacokinetic data (saline-to-glucose absorption ratio was 98% for the micronised and 46% for the coarse-grade powder). It was concluded that, provided an appropriate composition is chosen for the dissolution test, the USP paddle apparatus can be used to reflect variations in hydrodynamic conditions in the upper gastrointestinal tract.

Improved drug dissolution and product characterization using a crescent-shaped spindle.

Drug release characteristics of two amoxicillin capsule products, 250 and 500 mg strength each, have been described using USP Paddle and crescent-shaped spindles. Using the same spindles, dissolution experiments were conducted with USP disintegrating (prednisone) and non-disintegrating (salicylic acid) calibrator tablets. Dissolution tests were conducted at 50 and 25 rev min(-1) using USP Paddle and crescent-shaped spindles, respectively. In all cases, even with the higher 50 rev min(-1), lower percent drug release results were observed with the Paddle spindle than with the crescent-shaped spindle, which was operated at 25 rev min(-1). The observed lower dissolution for amoxicillin capsule products (< 36 vs > 87% at 30 min) and USP prednisone calibrator tablets (45.5 vs 99.8% at 30 min) with Paddle spindles appeared to occur because of the accumulation of the disintegrated material (cone formation) at the bottom, thus restricting product-medium interaction. Crescent-shaped spindles did not allow any accumulation of the product and provided improved interaction by mixing and stirring, and thus appeared to provide true drug dissolution characteristics of the products. On the other hand, in the case of non-disintegrating USP salicylic acid tablets (18.5 vs 24.4% at 30 min), lower results with Paddle spindles appeared to be because of stagnation of the tablets, which provided poor product-medium interaction for the surface touching the vessel surface. In this case, the crescent-shaped spindles moved the tablets at the base of the vessel, providing improved and efficient product-medium interaction, thus appearing to reflect truer dissolution characteristics of the tablets. The results highlight the possible artifacts of the USP Paddle spindle, which could lead to inaccurate characterization of drug release properties of test products. As reported previously, the artifacts of high variability in results and lack of relevance to product properties appeared to be related to poor mixing and variable hydrodynamics within a dissolution vessel. Results from this study provide further evidence that these artifacts might be addressed adequately using the crescent-shaped spindle, thus resulting in improved drug release as well as better product characterization.

Crystallization conditions and formation of orthorhombic paracetamol from ethanolic solution.

Orthorhombic paracetamol exhibits far better tabletability than the monoclinic form and its bulk crystallization from solution attracts much interest. In this study, temperature changes in supersaturated ethanolic solution have been recorded after seeding with orthorhombic crystals under different cooling temperatures (Tc) and agitation rates (AR). Average cooling rate (CR), time for maximum temperature deviation (tmax) and area confined between curves of measured and reference temperature plots (AUC) were calculated and correlated with crystal yield (Y). The micromeritic (size and shape) and the compression properties, the density and the orthorhombic content of the crystalline product were evaluated and related to the main crystallization conditions applied (Tc and AR). Conditions for optimal crystal yield and orthorhombic content were elucidated. It was found that crystal yield (Y) increased with AR and decreased with Tc. The ratio tmax/CR provided good prediction of crystal yield (Y = 58.92-1.386 tmax/CR, r2 = 0.964 and P = 0.0001). Tc and AR linearly affected crystal size and the size distribution, probably due to alterations in supersaturation, but they did not affect the crystal shape significantly. Density and compression properties (yield pressure and elastic recovery) were determined by the content of the orthorhombic form, which increased linearly with AR (P = 0.009) and with Tc (P = 0.039) when agitation was between 300 and 500 rev min(-1), while tmax decreased. At 700 rev min(-1) orthorhombic content was maximized and became independent to Tc. Higher orthorhombic content and crystal yield was expected for lower Tc and for lower tmax, which corresponded to higher AR and might have also been affected by alteration of seeding and harvesting procedure.

In-vitro and in-vivo correlation for two gliclazide extended-release tablets

The aim of this study was to perform an in-vitro-in-vivo correlation (IVIVC) for two 60-mg gliclazide extended-release formulations (Fast and Slow release) given once a day and to compare their plasma concentrations over time. In-vitro release rate data were obtained for each formulation using the USP apparatus II, paddle stirrer at 50 and 100 rev min(-1) in 0.1 M HCl and pH 7.4 phosphate buffer. The similarity factor (f2) was used to analyse the dissolution data. Eighteen healthy subjects participated in the study, conducted according to a completely randomized, two-way crossover design. The formulations were compared using area under the plasma concentration-time curve, AUC(0-infinity), time to reach peak plasma concentration, Tmax, and peak plasma concentration Cmax, while correlation was determined between in-vitro release and in-vivo absorption. A linear correlation model was developed using percent absorbed data versus percent dissolved data from the two formulations. Predicted gliclazide concentrations were obtained by use of a curve fitting equation. Prediction errors were estimated for Cmax and area under the curve AUC(0-infinity) to determine the validity of the correlation. 0.1 M HCl at 50 rev min(-1) was found to be the most discriminating dissolution method. Linear regression analysis of the mean percentage of dose absorbed versus the mean percentage of in-vitro release resulted in a significant correlation (r2 > 0.98) for the two formulations. An average percent prediction error for Cmax was 4.15% for Fast release and 3.99% for Slow release formulation whereas for AUC(0-infinity) it was 6.36% and 4.66% for Fast release and Slow release formulation, respectively.

A dissolution test for a pressure-controlled colon delivery capsule: rotating beads method.

The rotating beads method is a new in-vitro dissolution test proposed for drugs formulated as pressure-controlled colon delivery capsules (PCDCs). The apparatus consisted of a glass vessel (500 mL) containing 4-mm (i.d.) glass beads (5000, 10000 or 15000) and dissolution medium (0-067 M phosphate buffer, pH 7; 25, 50 or 100 mL) containing polyvinyl alcohol (PVA; 5, 10 or 20 w/v%) to simulate the viscosity of the colon. The vessel was rotated at 5, 10 or 25 rev min(-1) and the temperature was maintained at 37 degrees C. Fluorescein was used as a model drug to explore the optimized conditions under which differences in the drug dissolution rate are detected between colon delivery systems. Fluorescein was formulated in four types of colon delivery systems. One was a tablet coated with an enteric polymer, Eudragit S-100, and the other three were PCDCs prepared with different thicknesses of ethylcellulose coating membrane (type I, II, III). The dissolution behaviour of fluorescein from the PCDC formulation was significantly different from that of the Eudragit S-100-coated tablets, when the dissolution conditions were as follows: rotation speed, 10 rev min(-1); bead number, 10000; dissolution medium, 50mL with 10% PVA. This dissolution method was applied to acetaminophen sustained-release tablets and two other drugs having low solubility in the colon, tegafur and 5-aminosalicylic acid. Similarly, significant differences in the dissolution rates of drugs from the PCDC formulation and the enteric tablet were detected. There was good correlation between the in-vitro dissolution rates and in-vivo absorption rates using T50 (the time for half of the amount of drug to be released from the preparation) and Cmax/Tmax (enteric tablet) or Cmax/(Tmax-Ti) (PCDC), where Ti is the first appearance time in the systemic circulation. The rotating beads method is a valuable technique for evaluating the dissolution rate of drugs formulated in PCDC.

The influence of aggregate microenvironment on the dissolution of oxazepam in ternary surfactant interactive mixtures.

The purpose of this research was to test the hypothesis that the dissolution rate of oxazepam in interactive mixtures was dependent on the influence of surfactant within the microenvironment of mixed oxazepam-surfactant aggegrates produced during dissolution. The studies utilised both powder and intrinsic dissolution methodology; spectrophotometric assays were developed and validated and dissolution data were modelled using multi-exponential equations and dissolution rate constants estimated using non-linear least squares algorithms. For a series of water-soluble ternary additives to the oxazepam interactive mixture, sodium lauryl sulfate and cetrimide were shown not only to decrease aggregation through enhanced dispersion, but also to increase the dissolution rate constant. Such an increase in dissolution rate constant was observed in the intrinsic dissolution studies when surfactant concentrations exceeded the critical micelle concentration and the oxazepam solubility increased. Laser diffraction particle sizing during the dissolution process confirmed the presence of dispersed particles and aggregates and demonstrated that the presence of surfactant improved the state of dispersion. The results of studies using different rotational speeds produced unexpected increases in aggregation and decreases in dissolution rate constants at about 150 rev min(-1), consistent with the transient formation of loose aggregates containing dissolved surfactant.

Development of a robust once-a-day glipizide matrix system

The robustness of a new hydroxypropylmethylcellulose (HPMC) based modified release glipizide (10 mg) formulation was studied. The tablet formulations were prepared by dry blending the ingredients and direct compression, incorporating a range of release modifying agents up to +/-20% w/w relative to an optimized formulation. The dissolution was assessed in 900 mL pH 6.8 buffer at 75 rev min(-1) paddle speed. Calculated difference and similarity factors (f(1) and f(2)) and results of analysis of variance suggest that the overall release profiles were similar. Compositional changes up to +/-20% w/w and a reduction of drug dose to half did not change the general release pattern of this low dose/pH-dependent drug in a significant way. It is concluded that the drug release from the developed matrix systems is highly dependent on the kinetics of hydration and erosion, and that the proposed compositional changes within +/-20% w/w did not alter this relationship. The particulate systems used were characterized by determining the Carr index, Hausner ratio and the rheological properties using a texture analyser. Results indicate that the release is reproducible and the system has potential for successful scale-up operation, while complying with recommended Food and Drug Administration guidelines "Scale Up and Post Approval Changes".

An investigation into the erosion behaviour of a high drug-load (85%) particulate system designed for an extended-release matrix tablet. Analysis of erosion kinetics in conjunction with variations in lubrication, porosity and compaction rate.

The effects of the amounts of lubricants (magnesium stearate 0-5% and talc 0-3%) and changes in compaction rate and tablet porosity on the mechanism of drug release from high drug-load controlled-release theophylline tablets have been examined. Drug release was satisfactorily described by a surface-erosion model that takes into account the geometry of the tablet, differential radial and axial erosion rates, and the initial burst effect (r2 > 0.99 for all formulations). The axial and radial erosion rate constants were inversely proportional to the amount of magnesium stearate in the formulation (P < 0.0001). The most dramatic reductions in erosion rate occurred between 0 and 1% magnesium stearate content. For magnesium stearate concentrations > or =2.5% the ratio of radial to axial erosion rate constants was essentially constant at 3 (approx.); however, for formulations with magnesium stearate < or =1% the ratio tended toward unity. Reducing matrix porosity over the range 26 to 14% resulted in reduced erosion rates. However, a threshold of 17% (approx.) porosity was identified below which further reductions in porosity resulted in only incremental changes in release rates. The rate of erosion and drug release was insensitive to changes in machine speed over the range 20 to 100 rev min(-1). For highly loaded matrix tablets containing sparingly soluble drugs, such as theophylline, magnesium stearate at appropriate levels can modulate the erosion rate constants and act as an effective release-controlling excipient. Drug-release profiles are predictable and relatively robust in terms of changes in compaction rate and applied force routinely encountered in large-scale tablet manufacturing.

Study on combustion stability of DI-HCCI engine fuelled with dimethyl ether

<title/>Characteristics of direct injection (DI) combustion, direct injection-homogeneous charge compression ignition (DI-HCCI) combustion and HCCI combustion in an engine fuelled with dimethyl ether are investigated. The combustion stabilities of three combustion modes are compared, and the effects of premixed ratio, speed and load on them are given. The analysis shows that the maximum values of pressure, heat release rate, pressure rise rate and acceleration of DI combustion are lower than those of HCCI combustion and their phases are retarded. The combustion duration of DI combustion is shorter than that of HCCI combustion. In DI-HCCI combustion, with increasing premixed ratio, the maximum values of pressure, pressure rise rate and acceleration increase, and their phases advance respectively, and the combustion duration shortens evidently. The coefficient of variation (COV) of maximum pressure of DI combustion is much larger than that of HCCI combustion at 1100 and 1500 rev min−1. In DI-HCCI combustion, the COV first decreases with increasing premixed ratio, and then changes little at 1100 rev min−1. The COV with large premixed ratio was lower in comparison to that with small premixed ratio at various Loads. At 1500 rev min−1, premixed ratio has few effects on COV, no matter with large or small premixed ratio; COV is maintained at a relatively small value at various Loads. The pressure fluctuation results are consistent with those of the COV analysis.

Experimental investigation of regulated and unregulated emissions from a diesel engine fueled with Euro V diesel fuel and fumigation methanol

Experiments were conducted on a four-cylinder direct-injection diesel engine with part of the engine load taken up by fumigation methanol injected into the air intake of each cylinder to investigate the regulated and unregulated gaseous emissions and particulate emission of the engine under five engine loads at an engine speed of 1920 rev min −1. The fumigation methanol was injected to top up 10%, 20% and 30% of the engine load under different engine operating conditions. The experimental results show that at low engine loads, the brake thermal efficiency (BTE) decreases with increase in fumigation methanol; but at high engine loads, the BTE is not significantly affected by fumigation methanol. The fumigation methanol results in significant increase in hydrocarbon (HC), carbon monoxide (CO) and nitrogen dioxide (NO 2) emissions, but decrease in nitrogen oxides (NO x). For the unregulated gaseous emissions, unburned methanol, formaldehyde and BTX (benzene, toluene and xylene) emissions increase but ethyne, ethene and 1,3-butadiene emissions decrease. Particulate mass and number concentrations also decrease with increase in fumigation methanol. A diesel oxidation catalyst (DOC) is found to reduce significantly most of the pollutants, including the air toxics, when the exhaust gas temperature is sufficiently high.

Performance of a spark ignition engine under the effect of friction using a gas mixture model

This paper presents the effect of friction on the performance of a spark ignition engine using a gas mixture as the working fluid. The results were compared to a frictionless engine. Engine parameters that were studied include equivalence ratio, engine speed, break mean effective pressure (BMEP), and cycle thermal efficiency. It was found for the frictionless engine operating at 6000 rev min−1 and stoichiometric air–fuel mixture that BMEP and efficiency were about 14 bar and 36% respectively. On the other hand, when friction is included under the same condition BMEP and efficiency were about 10 bar and 27% respectively. However, at lower engine speed and equivalence ratio, the deviations were much smaller. Therefore, it is more realistic to consider the effect of friction using the gas mixture model instead of air as the working fluid for the analysis of spark ignition engines, especially when running at high speeds and/or rich mixtures.

Optimization of exopolysaccharide production fromArmillaria melleain submerged cultures

To study the optimization of submerged culture conditions for exopolysaccharide (EPS) production by Armillaria mellea in shake-flask cultures and also to evaluate the performance of an optimized culture medium in a 5-l stirred tank fermenter. Shake flask cultures for EPS optimal nutritional production contained having the following composition (in g l(-1)): glucose 40, yeast extract 3, KH(2)PO(4) 4 and MgSO(4) 2 at an optimal temperature of 22 degrees C and an initial of pH 4.0. The optimal culture medium was then cultivated in a 5-l stirred tank fermenter at 1 vvm (volume of aeration per volume of bioreactor per min) aeration rate, 150 rev min(-1) agitation speed, controlled pH 4.0 and 22 degrees C. In the optimal culture medium, the maximum EPS production in a 5-l stirred tank fermenter was 588 mg l(-1), c. twice as great as that in the basal medium. The maximum productivity for EPS (Q(p)) and product yield (Y(P/S)) were 42.02 mg l(-1) d(-1) and 26.89 mg g(-1), respectively. The optimal culture conditions we proposed in this study enhanced the EPS production of A. mellea from submerged cultures. The optimal culturing conditions we have found will be a suitable starting point for a scale-up of the fermentation process, helping to develop the production of related medicines and health foods from A. mellea.

Tool design and stir zone grain size in AZ31 friction stir spot welds

The influence of tool design and tool rotational speed variations on the torque, energy output, stir zone temperature and average grain size in the stir zones of AZ31 friction stir spot welds was investigated. The average stir zone grain size decreased by ∼1 μm in AZ31 friction stir spot welds made using a three-flat/threaded tool design and tool rotational speeds of 2250 and 3000 rev min−1. However, there was no statistically significant influence of tool design on the average grain sizes in friction stir spot welds made using tool rotational speeds of 1500 and 1000 rev min−1. There was no evidence of grain growth in the stir zones of AZ31 friction stir spot welds. Similar torque, calculated energy output and stir zone temperature values were found in AZ31 friction stir spot welds made using threaded and three-flat threaded tool designs and tool rotational speeds from 1000 to 3000 rev min−1.

Experimental investigation of particulate emissions from a diesel engine fueled with ultralow-sulfur diesel fuel blended with diglyme

Abstract Experiments are conducted on a 4-cylinder direct-injection diesel engine using ultralow-sulfur diesel as the base fuel and diglyme as the oxygenate component to investigate the particulate emissions of the engine under five engine loads at two engine speeds of 1800 rev min −1 and 2400 rev min −1 . Blended fuels containing 5%, 10.1%, 15.2%, 20.4%, 25.7% and 53% by volume of diglyme, corresponding to 2%, 4%, 6%, 8%, 10% and 20% by mass of oxygen, are studied. The study shows that with the increase of oxygen in the fuel blends, smoke opacity, particulate mass concentration, NO x concentration and brake specific particulate emission are reduced at the two engine speeds. However, the proportion of soluble organic fraction is increased. For each blended fuel, the total particle number concentration is higher while the geometric mean diameter is smaller, compared with that of ultralow-sulfur diesel, though the particle number decreases with the oxygen content of the blended fuel. Furthermore, the blended fuels also increase the number concentrations of particles smaller than 100 nm.

Optimisation of friction stir welding process parameters to weld cast aluminium alloy A413 – an experimental approach

A413 is a high strength eutectic aluminium silicon cast alloy used in the food, chemical, marine, electrical and automotive industries. Fusion welding of these cast alloys can lead to problems such as porosity, microfissuring and hot cracking, etc. However, friction stir welding can be used to weld these cast alloys effectively, without defects. In this investigation, an attempt was made to optimise the friction stir welding process parameters for joining the cast aluminium alloy A413. Joints were made using four levels each of tool rotation speed, welding speed and axial force. The quality of the weld zone was analysed using macrostructure and microstructure analysis. Tensile strength of the joints were evaluated and correlated with the weld zone hardness and microstructure. The joint fabricated using a tool rotation speed of 900 rev min−1, a welding speed of 75 mm min−1 and an axial force of 3 kN showed the best tensile strength.

Thermal Expansion Coefficient and Mechanical Properties of Friction Stir Welded Invar (Fe-36%Ni)

Two high-temperature pin tools, one a polycrystalline cubic BN and the other of W-25%Re, were used to friction stir weld 12.7 mm thick Invar (Fe-36%Ni) plate. Successful welds were produced at a rotational speed of 600 rev min−1 and travel speeds of 76, 102, and 127 mm min−1. The coefficient of thermal expansion, tensile strength, and microhardness of the welds were measured and found to be essentially unchanged from the parent material. The measured elongation was 52% for the parent material and 30 and 37% for welds made with the W-Re and the polycrystalline cubic BN pin tools. Both pin tools produced comparable welds but the W-Re tool exhibited more wear and left small wear remnants in the weld especially at the weld plunge.

Effect of tool rotation rate on microstructure and mechanical properties of friction stir welded copper

Defect free copper welds were achieved by friction stir welding (FSW) carried out at a constant welding speed of 100 mm min−1. The influence of tool rotation rate on microstructure, mechanical properties and fracture location was investigated. As the tool rotation rate increased, the grains of nugget zone grew significantly, the thermomechanically affected zone became indistinct and the grain size increased, but the effect of tool rotation rate on the grain size of heat affected zone was limited. Both ultimate tensile strength (UTS) and elongation increased first and then decreased with increasing rotation rate and the UTS achieved a highest value of 282 MPa at the rotation rate of 400 rev min−1 together with the welding speed of 100 mm min−1, which was on the level of the base metal. The fracture occurred at the cavity defect on the advancing side of the joint when the FSW was performed at a low tool rotation rate, while it occurred on the retreating side when the tool rotation rate was relatively high.

Regulated and unregulated emissions from a diesel engine fueled with biodiesel and biodiesel blended with methanol

Experiments were carried out on a diesel engine operating on Euro V diesel fuel, pure biodiesel and biodiesel blended with methanol. The blended fuels contain 5%, 10% and 15% by volume of methanol. Experiments were conducted under five engine loads at a steady speed of 1800 rev min −1 to assess the performance and the emissions of the engine associated with the application of the different fuels. The results indicate an increase of brake specific fuel consumption and brake thermal efficiency when the diesel engine was operated with biodiesel and the blended fuels, compared with the diesel fuel. The blended fuels could lead to higher CO and HC emissions than biodiesel, higher CO emission but lower HC emission than the diesel fuel. There are simultaneous reductions of NO x and PM to a level below those of the diesel fuel. Regarding the unregulated emissions, compared with the diesel fuel, the blended fuels generate higher formaldehyde, acetaldehyde and unburned methanol emissions, lower 1,3-butadiene and benzene emissions, while the toluene and xylene emissions not significantly different.

Effect of friction stir processing tool probe on fabrication of SiC particle reinforced composite on aluminium surface

An investigation has been carried out of the effects of tool probe shape and size on the formation of surface composite by uniformly distributing SiC particles into a surface layer of an A1050-H24 aluminium plate through friction stir processing (FSP). Tool probes of three different diameters (3, 5 and 7 mm) and four different shapes (circular with threads, circular without threads, square and triangular) have been used to fabricate the surface layers at rotation speeds of 1500–2250 rev min−1 and a travelling speed of 1·66 mm s−1. The SiC particles were packed into a groove of 3 mm width and 1·5 mm depth cut on the aluminium plate and covered by an aluminium sheet of 2 mm thickness. A rotating tool was plunged into the plate through the cover sheet so that the tip of the probe reached beyond the bottom of the groove. As a result, it was found that the square probe dispersed the SiC particles homogeneously in the nugget zone compared with other probe shapes regardless of the rotation speeds. Furthermore, the distributed particles and also the aluminium matrix grain size became finer by the use of square probe than those of the other shapes. On the other hand, the wear rates of the square and triangular probes were higher than that of circular shape. The worn iron debris from the tool reacted with aluminium matrix and form fine iron aluminides compound dispersed in the nugget zone. The probe size had limited effects on the homogeneity of the SiC particles distribution in the nugget zone; the distribution of SiC particles obtained by triple FSP passes was less homogeneous when the probe size was smaller. Microhardness of the nugget zone was homogeneously increased to a level as high as 60 HV with tool of square probe shape after three passes to be compared with 23 HV of the aluminium matrix beside the nugget zone.

Novel mechanical alloying method for preparing Cr coating on inner surface of carbon steel tubes

The armoring or reinforcing of the inner surface of a tubular component is an important consideration in improving its performance. In the present work, a novel mechanical alloying method was developed to prepare Cr coating on the inner substrate of carbon steel tubes using a planetary ball mill. The X-ray diffraction, EDX, and SEM results revealed that a highly dense ∼60 μm thick layer of metal Cr and its alloy CrFe4 was deposited on the steel substrate, by setting a bowl rotation speed of 300 rev min–1 and a ball milling time of 10 h. The maximum microhardness of the coating reached 661 HV0·1, which was three times higher than that of the steel substrate. A reasonable mechanism for the formation of the mechanically alloyed coating on the inner surface of a metal tube was also proposed.