Paddle Stirrer Research Articles

Enhancement of Solubility of Lamotrigine by Solid Dispersion and Development of Orally Disintegrating Tablets Using 3(2) Full Factorial Design.

Present investigation deals with the preparation and evaluation of orally disintegrating tablets (ODTs) of lamotrigine using β-cyclodextrin and PVP-K30 as polymers for the preparation of solid dispersion which help in enhancement of aqueous solubility of this BCS CLASS-II drug and sodium starch glycolate (SSG) and crospovidone as a superdisintegrating agent, to reduce disintegration time. The ODTs were prepared by direct compression method. Nine formulations were developed with different ratios of superdisintegrating agents. All the formulations were evaluated for disintegration time, weight variation, hardness, friability, drug content uniformity, wetting time, and in vitro drug release study. In vitro drug release study was performed using United States Pharmacopoeia (USP) type 2 dissolution test apparatus employing paddle stirrer at 50 rpm using 900 mL of 0.1 N HCl maintained at 37°C ± 0.5°C as the dissolution medium. On the basis of evaluation parameters formulations were prepared using β-CD 1 : 1 solid dispersion. Then 32 full factorial design was applied using SSG and crospovidone in different ratios suggested by using design expert 8.0.7.1 and optimized formulation was prepared using amount of SSG and crospovidone as suggested by the software. The optimized formulation prepared had disintegrating time of 15 s, wetting time of 24 s, and % friability of 0.55.

The effect of shear rate on aggregate size distribution and structure at steady state: a comparison between a Taylor–Couette reactor and a mixing tank

The paper deals with the dependence of aggregate properties on the shear rate ( G ) at steady state. Aggregation of natural raw water and ferric sulphate was carried out in a laboratory Taylor–Couette reactor (TC) and continuous flow mixing tank (MT) with a paddle stirrer. Shear rates in the range of 20–350 s −1 were used. Methods of image and fractal analyses were used to determine the aggregate size and structure, respectively. It was found that the aggregate size decreased with increasing shear rate. There was a small difference in sizes of aggregates formed in TC and MT at G −1 , but at higher shear rates, almost no difference between TC and MT was observed. The D 2 fractal dimension increased with increasing shear rate indicating that aggregates became less porous and more compact. Moreover, a very close match in D 2 values was attained for both mixing devices. The D pf fractal dimension decreased with increasing shear rate meaning that aggregates were more regular at higher shear rates, but jagged on the surface with irregular shape at lower shear rates. In contrast to D 2 , aggregates formed in MT were much more irregular (jagged) than those formed in TC.

Preparation of Pickering Emulsions and Colloidosomes with Relatively Narrow Size Distributions by Stirred Cell Membrane Emulsification

Stirred cell membrane emulsification has been used to prepare Pickering emulsions and covalently cross-linked colloidosomes using poly(glycerol monomethacrylate) stabilized polystyrene particles as the sole emulsifier. Pickering emulsions of 44-269 μm in size can be prepared with coefficients of variation as low as 25%, by varying the emulsification parameters. The cell membranes consisted of 5 μm pores with a pore-to-pore spacing of 200 μm. Significantly more uniform emulsions are produced when these open pores are restricted to a narrow ring around the membrane surface. Increasing the oil flux rate through this annular ring membrane increases both the size and polydispersity of the resulting emulsion droplets. There was no evidence for a "push off" force contributing to droplet detachment over the oil flux range investigated. Increasing the paddle stirrer speed from 500 to 1500 rpm reduces the average droplet diameter from 269 to 51 μm while simultaneously decreasing the coefficient of variation from 47% to 25%. Any further increase in surface shear led to droplet breakup within the dispersion cell and resulted in a significantly more polydisperse emulsion. The Pickering emulsions reported here have much narrower droplet size distributions than those prepared in control experiments by conventional homogenization (25% vs 74% coefficients of variation). Finally, low polydispersity colloidosomes can be conveniently prepared by the addition of an oil soluble polymeric cross-linker to the dispersed phase to react with the stabilizer chains.

Membrane Emulsification with Oscillating and Stationary Membranes

Membrane emulsification of sunflower oil in aqueous solutions of 2% (v/v) Tween 20 was performed using a stationary disk membrane with a rotating paddle stirrer and, for comparison, a tubular membrane oscillating normal to the direction of oil flow in an otherwise stationary continuous phase. The oscillation frequency ranged from 10 to 90 Hz. The oil was injected through a sieve-type membrane with a 10 μm pore size and 180 μm between pore spacing at low flux rates to minimize any droplet interference. Using the same membrane material under identical peak shear conditions in both systems, smaller and more uniform drops (30−50 μm median sizes) were produced in the oscillating system. In oscillation, the drop size was modeled by a force balance, including a correction for neck formation at the pore surface, but in the rotating paddle system, neck formation did not appear to be relevant. Drop size was not found to be frequency of oscillation dependent, apart from its influence on the shear stress at the membr...

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.

In-situ observation of a dendrite growth in an aqueous condition and a uranium deposition into a liquid cadmium cathode in an electrowinning system

A zinc–gallium system was setup to observe the growth process of dendrites and to compare the performance of the stirrers which would prevent a dendrite formation. In a no-stirring condition, zinc was easily deposited on a liquid gallium cathode in the form of dendrites. It was difficult for a paddle stirrer to directly fracture the zinc dendrites to fine particles. However, a harrow stirrer was observed to fracture the dendrite to some extent at high speeds. Not only their rotation speed but also the length of their blades needed to be properly adjusted to enhance their performance. In the uranium–cadmium experiment, the diffusion coefficient of the uranium species was obtained by the cyclic voltammetry method, which is around 1 × 10 −5 cm 2/s. In a no-stirring condition, most of the uranium deposited at the current densities of 35, 100 and 200 mA/cm 2 did not sink into the liquid cadmium cathode.

Membrane emulsification using membranes of regular pore spacing: Droplet size and uniformity in the presence of surface shear

During membrane emulsification it is shown that the size of the drops formed at the membrane surface may increase with increasing dispersed phase injection rate through the membrane, or it may decrease, depending on the prevailing conditions. This is illustrated using a paddle stirrer positioned above flat disc membranes with regular arrays of pores of 20 μm diameter and spacing between the pores of 80 and 200 μm. In the former case an additional mechanism for drop detachment is the push-off force, which is determined by the geometry of the drops as they deform at the membrane surface. When dispersing sunflower oil in to aqueous solutions containing Tween 20, drop sizes between 60 and 200 μm were produced, and in the case of the membrane when the push-off force was working the Coefficient of Variation of the drops formed was below 10%. The push-off force may be added to the shear-drag force to predict drop detachment. For the 200 μm pore spaced membrane this force is much less prominent than the 80 μm spaced membrane. The capillary-shear model has been modified to include this push-off force. The experimental study required the use of very low dispersed phase injection rates as well as very high rates. Hence, two different types of pumps were used to provide these: a peristaltic and syringe pumps. A small study comparing the drop size, and size distributions, showed that the pump type did not influence the drops produced by the membrane emulsification process.

Extended Release Dosage Form of Glipizide: Development and Validation of a Level A in Vitro-in Vivo Correlation

Defining a quantitative and reliable relationship between in vitro drug release and in vivo absorption is highly desired for rational development, optimization, and evaluation of controlled-release dosage forms and manufacturing process. During the development of once daily extended-release (ER) tablet of glipizide, a predictive in vitro drug release method was designed and statistically evaluated using three formulations with varying release rates. In order to establish internally and externally validated level A in vitro-in vivo correlation (IVIVC), a total of three different ER formulations of glipizide were used to evaluate a linear IVIVC model based on the in vitro test method. For internal validation, a single-dose four-way cross over study (n=6) was performed using fast-, moderate-, and slow-releasing ER formulations and an immediate-release (IR) of glipizide as reference. In vitro release rate data were obtained for each formulation using the United States Pharmacopeia (USP) apparatus II, paddle stirrer at 50 and 100 rev. min(-1) in 0.1 M hydrochloric acid (HCl) and pH 6.8 phosphate buffer. The f(2) metric (similarity factor) was used to analyze the dissolution data. The formulations were compared using area under the plasma concentration-time curve, AUC(0-infinity), time to reach peak plasma concentration, T(max), and peak plasma concentration, C(max), 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 from the three formulations. Predicted glipizide concentrations were obtained by convolution of the in vivo absorption rates. Prediction errors were estimated for C(max) and AUC(0-infinity) to determine the validity of the correlation. Apparatus II, pH 6.8 at 100 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 (r(2)>or=0.9) for the three formulations.

Preparation and characterization of PLGA particles for subcutaneous controlled drug release by membrane emulsification

Uniformly sized microparticles of poly( d,l-lactic- co-glycolic) (PLGA) acid, with controllable median diameters within the size range 40–140 μm, were successfully prepared by membrane emulsification of an oil phase injected into an aqueous phase, followed by solvent removal. Initially, simple particles were produced as an oil in water emulsion, where dichloromethane (DCM) and PLGA were the oil phase and water with stabiliser was the continuous phase. The oil was injected into the aqueous phase through an array type microporous membrane, which has very regular pores equally spaced apart, and two different pore sizes were used: 20 and 40 μm in diameter. Shear was provided at the membrane surface, causing the drops to detach, by a simple paddle stirrer rotating above the membrane. Further tests involved the production of a primary water in oil emulsion, using a mechanical homogeniser, which was then subsequently injected into a water phase through the microporous membrane to form a water in oil in water emulsion. These tests used a water-soluble model drug (blue dextran) and encapsulation efficiencies of up to 100% were obtained for concentrations of 15% PLGA dissolved in the DCM and injected through a 40 μm membrane. Solidification of the PLGA particles was followed by removal of the DCM through the surrounding aqueous continuous phase. Different PLGA concentrations, particle size and osmotic pressures were considered in order to find their effect on encapsulation efficiency. Osmotic pressure was varied by changing the salt concentration in the external aqueous phase whilst maintaining a constant internal aqueous phase salt concentration. Osmotic pressure was found to be a significant factor on the resulting particle structure, for the tests conducted at lower PLGA concentrations (10% and 5% PLGA). The PLGA concentration and particle size distribution influence the time to complete the solidification stage and a slow solidification, formed by stirring gently overnight, provided the most monosized particles and highest encapsulation efficiency.

Agitation Effects in a Gas-Liquid-Liquid Reactor System: Methyl Ethyl Ketazine Production

Our understanding of gas-liquid–liquid reaction systems is not well developed today despite their widespread use in the process industries. Research work is demanded or inspired in those fields where basic information is either lacking or poorly organized. The field of mixing and agitation in gas-liquid-liquid reaction system is a typical example. Methyl ethyl ketazine formation is a typical case of homogeneous catalyzed gas-liquid-liquid reaction. The parametric study of ketazine formation has been carried out in a semi batch reactor. Agitation effect on methyl ethyl ketazine formation has been studied. Two types of agitators are used - flat paddle stirrer and vaned disk stirrer. The studies show that agitation plays an important role on the reaction. Yield of ketazine improved with degree of agitation, categorizing the reaction as moderately fast. Vaned disk stirrer is found to be more effective compared to flat paddle stirrer. Rate of reaction increases up to 600 rpm indicating diffusion control, beyond 600 rpm there is no appreciable change in the yield, thus favoring kinetics controlled mechanism. This 600 rpm can be thus regarded as "the desired level of agitation."

Stirred Cell Membrane Emulsification and Factors Influencing Dispersion Drop Size and Uniformity

Water-in-oil (w/o) and oil-in-water (o/w) emulsions were generated using 30-μm pore diameter surface membranes to investigate the factors influencing drop size, and the degree of uniformity of drop size distribution, using a stirred cell employing a simple paddle mounted above a circular disc membrane. The importance of the transitional radius, which is the radius at which the vortex around the unbaffled paddle stirrer changes from a forced vortex to a free vortex and the shear stress at the membrane surface below the stirrer is at its greatest, is demonstrated. Monosized emulsions were produced, with drop size distribution coefficient of variation values of 10% for o/w emulsions and 13.5% for w/o emulsions. These tests demonstrated that a membrane of reduced annular operating area (ringed membrane) produced a more monosized o/w emulsion than a membrane where the full area was used to generate the emulsion, without affecting the mean drop size. The improved size distribution was achieved while the transitional radius was located within the ringed annular section of the membrane. The force balance model, applied to drops formed at the surface of the membrane during emulsification, predicted the droplet diameter provided further drop break up within the stirred cell did not occur. Drop break up occurred at Reynolds numbers below 300 for both oil-in-water and water-in-oil dispersions. Therefore, for Reynolds numbers greater than this, an annular radial ring membrane can be designed to produce monosized droplets using the stirred cell at known continuous phase viscosities with predictable mean droplet size. This knowledge can be used as a design tool to produce monosized droplets of a specified size for various applications using simple stirred cell emulsification.

The dissolution behaviour of native phosphocaseinate as a function of concentration and temperature using a rheological approach

A simplified method to study native phosphocaseinate dissolution was developed. The method involved dispersing powder in distilled water at a constant shear rate. The use of a Stress Tech Rheometer equipped with a custom-built paddle stirrer permitted the determination of the viscosity during the dissolution. The viscosity profiles obtained highlighted the dissolution stages of the powder including particle wetting, and then swelling followed by a slow disintegration and dissolution of the particles. Using this method, the viscosities of native phosphocaseinate suspensions were followed as a function of protein concentration, temperature and dissolution time. Indeed, the best knowledge of the dissolution properties could be one way to extend the application of this high protein content powder: the principal limitation of this powder being its poor dissolution ability.

Development and validation of an in vitro–in vivo correlation for buspirone hydrochloride extended release tablets

The aim of this study was to develop an in-vitro–in-vivo correlation (IVIVC) for two buspirone hydrochloride extended release formulations and to compare their plasma concentrations over time with the commercially available immediate release (IR) tablets. In vitro release rate data were obtained for each formulation using the USP Apparatus 2, paddle stirrer at 50 and 100 rpm in 0.1 M HCl and pH 6.8 phosphate buffer. A three-way crossover study in 18 healthy subjects studied a 30 mg “Fast” (12 h) and 30 mg “Slow” (24 h) formulation of buspirone hydrochloride given once a day, and 2×15 mg immediate release tablets dosed at a 12 h interval. The similarity factor ( f 2) was used to analyze the dissolution data. A linear correlation model was developed using percent absorbed data and percent dissolved data from the two formulations. Predicted buspirone hydrochloride concentrations were obtained by use of a curve fitting equation for the immediate release data to determine the volume of distribution and fraction absorbed constants. Prediction errors were estimated for C max and area under the curve (AUC) to determine the validity of the correlation. pH 6.8 at 50 rpm was found to be the most discriminating dissolution method. Linear regression analyses of the mean percentage of dose absorbed versus the mean in vitro release resulted in a significant correlation ( r 2>0.95) for the two formulations. An average percent prediction error for C max was −0.16%, but was 16.1%, for the AUCs of the two formulations.

Stirring Characteristics and Performance Evaluation in a Cup-Type Vessel Mixed by Paddles. Numerical Flow analysis of Single Liquid in the Atmosphere.

Cup-mixing system (Cup-type Vessel mixed by paddle) becomes so dominant system in cup-type beverage vending machines that the optimum design procedure for paddle stirrer geometry, its setting location, its revolutions, etc, is strongly required to be quickly specified for different kind of beverage materials. This work aims first at numerically simulating the stirring flow-fields of cup-type mixing vessel, second characterize the stirring flow phenomena by introducing a new standard measure called fluid exchange frequency, and finally at evaluating the stirring characteristics resulting in the optimum condition. The simulation with the sliding mesh method is carried out of water stirring flow in the cup-type vessel, which is mixed by paddles with a revolution of 900 rpm. Based on the verification of the stirring flow simulation with the flow visualization experiment, the fluid exchanging frequency is proved to be helpful to evaluating the stirring performance locally and entirely.

Modeling of hydrazodicarbonamide oxidation by chlorine in a gas–liquid–solid system

The oxidation reaction of solid hydrazodicarbonamide with chlorine in aqueous solution is experimentally studied in a 1 l agitated glass vessel reactor with a four-blade paddle stirrer. Based on the film theory, a model is first developed for this complicated system by taking account of the gas–liquid and solid–liquid mass transfer, solid dissolution, and instantaneous reaction, especially the reduction of solid–liquid mass transfer interfacial area arising from the solid reactant dissolution. The model can reasonably and well describe the experimental data. According to the values of gas–liquid and solid–liquid mass transfer coefficients estimated with the proposed model, it is found that the gas–liquid mass transfer is a rate-controlling step in the majority of the reaction course, but the solid–liquid mass transfer becomes a rate-controlling step when the reaction is close to the final stage of the process.

Dissolution rate limited bioavailability of flutamide, and in vitro – in vivo correlation

Flutamide is due to its properties as a practically water-insoluble, high-dose drug substance a typical representative of a drug with particle size limited dissolution rate and bioavailability. An in vitro dissolution test method comprising of standard paddle stirrer, round-bottomed vessel of 4 l capacity, and 0.1 N hydrochloric acid with 0.5% of sodium lauryl sulphate as dissolution medium, was developed. The dissolution method was shown discriminatory and predictive regarding bioavailability of conventional 250 mg flutamide tablets with different in vitro dissolution rates. Relative bioavailability of flutamide from the tablets, determined as AUC of the active metabolite 2-hydroxyflutamide in healthy male subjects, could be correlated with drug amount dissolved during 45 min in the in vitro test. Also bioavailability data from four different biostudies could be compared utilising the calculated ratios R AUC and R Diss. for the test and reference formulations in the individual studies. It is suggested that the concept of R AUC and R Diss. can also be applied to other orally administered, poorly soluble, high-dose drug substances with dissolution rate limited bioavailability.

The hydration behaviour of rennet caseins in calcium chelating salt solution as determined using a rheological approach

Rennet casein is used in the manufacture of Mozzarella cheese analogues. Hot solutions of calcium chelating salts are used to facilitate hydration of the protein which subsequently acts as an emulsifier for the oil phase dispersed in the protein/aqueous phase of the cheese analogue. On cooling, a matrix resembling cheese in texture and other rheological properties is produced. Considerable variations in the functional performance of different rennet caseins during cheese analogue manufacture have been observed. Commercial rennet caseins have been obtained and are being studied to establish the nature and causes of these variations in performance. A simplified model system to study rennet casein hydration was developed. The method involves dispersing rennet caseins in solutions of chelating salt at 55°C with stirring. The changes in viscosity index that occur as the rennet casein hydrated were followed using a controlled shear rate rheometer equipped with a custom designed paddle stirrer. Hydration of the rennet casein particles was found to occur in a number of stages including particle swelling, clumping, network formation and subsequent breakdown of the network. Considerable variations in the times taken for different rennet caseins to swell, clump and reach maximum viscosity index and in the stability of the hydrated protein dispersions were found. The rheological properties of the rennet caseins during hydration were highly dependent on the concentration of the chelating salt in the hydrating solution.

In-vivo/in-vitro correlation of four extended release formulations of pseudoephedrine sulfate

An in-vivo/in-vitro correlation was established for four formulations of pseudoephedrine sulfate modified release tablets exhibiting different in-vivo and in-vitro release rate and absorption characteristics. In-vitro release rate data were obtained for 12 individual tablets of each formulation using the USP Apparatus 2 paddle stirrer at 50 rev min −1 in 1000 ml 0.1 N hydrochloric acid for the first hour followed by 0.1 M phosphate buffer at pH 7.5 for hours 2–16. Inspection of the individual and mean release rate data indicated that the in-vitro release rate of pseudopehedrine sulfate was consistent with the intended design of the four extended release formulations. The in-vivo bioavailability and pharmacokinetics of these formulations were evaluated in 20 healthy volunteers under fasted conditions. Wagner-Nelson analyses of the in-vivo data revealed extended release absorption profies for all four formulations. Linear regression analyses of the mean percentage of dose absorbed versus the mean in-vitro release resulted in statistically significant correlations ( r 2 > 0.99, p < 0.0001) for each formulation. Qualitative rank order correlations were observed among all combinations of in-vivo and in-vitro parameters. These data support a Level A correlation between in-vivo absorption profiles and in-vitro release rates of four pseudoephedrine sulfate extended release formulations determined in fasted healthy volunteers.

Comparison of stirring and vortex mixing for the extraction of available nutrients from soil using a laboratory robot

Abstract We investigated the efficiency with which a laboratory robot is able to extract available nutrients from soil contained in tubes. We have shown that for vortex mixing, the volume of soil and extractant are of critical importance. In cases where the soil/extractant volumes are small (e.g. 2 mL soil: 10 mL extractant), extraction of all the nutrients investigated was good. However, keeping the ratio the same, but increasing the volumes to 6 mL soil:30 mL extractant leads to an overall decrease in extracting efficiency. Using a paddle stirrer to mix the soil and extractant together results in the same extraction efficiency across the range of soil/ extractant volumes.

Stirring‐induced solution crystallization of ultra high molecular weight polyamide 6

AbstractUnstable solutions of ultrahigh molecular weight polyamide 6 have been prepared by adding a nonsolvent to the polymer solution. Crystallization of the polyamide from such a solution proceeds very slowly. It has been found, however, that vigorous stirring of the unstable solutions induces rapid fibrous crystallization of the polymer. The fiber mat consists of irregularly shaped fibers. A low temperature and a high stirring rate are among the conditions necessary to obtain a high yield of fibrous material. The fibers formed upon stirring have a higher molecular weight than the polyamide 6 molecules which remain in the solution. The melting point of the fibers depends on the speed of the paddle stirrer. The differential scanning calorimetry (DSC) thermogram reveals higher melting temperatures of the fibrous material if higher stirring rates have been applied.