Paddle Speed Research Articles

Bioequivalence of Oral Drug Products in the Healthy and Special Populations: Assessment and Prediction Using a Newly Developed In Vitro System "BE Checker".

In order to assess and predict the bioequivalence (BE) of oral drug products, a new in vitro system “BE checker” was developed, which reproduced the environmental changes in the gastrointestinal (GI) tract by changing the pH, composition, and volume of the medium in a single chamber. The dissolution and membrane permeation profiles of drugs from marketed products were observed in the BE checker under various conditions reflecting the inter-patient variations of the GI physiology. As variable factors, initial gastric pH, gastric emptying time, and GI agitation strength were varied in vitro. Dipyridamole, a basic drug, showed rapid and supersaturated dissolution when the paddle speed in the donor chamber was 200 rpm, which corresponds to the high agitation strength in the stomach. In contrast, supersaturated dissolution disappeared, and the permeated amount decreased under the conditions with a slow paddle speed (100 and 50 rpm) and short gastric emptying time (10 min). In those conditions, disintegration of the formulation was delayed, and the subsequent dissolution of dipyridamole was not completed before the fluid pH was changed to neutral. Similar results were obtained when the initial gastric pH was increased to 3.0, 5.0, and 6.5. To investigate that those factors also affect the BE of oral drug products, dissolution and permeation of naftopidil from its ordinary and orally disintegrating (OD) tablets were observed in the BE checker. Both products showed the similar dissolution profiles when the paddle speed and gastric emptying time were set to 100 rpm and 10 or 20 min, respectively. However, at a low paddle speed (50 rpm), the dissolution of naftopidil from ordinary tablets was slower than that from the OD tablets, and the permeation profiles became dissimilar. These results indicated the possibility of the bioinequivalence of some oral formulations in special patients whose GI physiologies are different from those in the healthy subjects. The BE checker can be a highly capable in vitro tool to assess the BE of oral drug products in various populations.

Residence time and mixing capacity of a rotary tablet press feed frame

Purpose Most rotary tablet presses contain a feed frame to provide a continuous powder flow and to feed powder into the dies. The wide residence time distribution (RTD) of these feed frames is problematic, because it negatively affects material traceability in continuous manufacturing. In a rotary tablet press, different machine settings influence the RTD, which is characterized by the mean and the width of the distribution. This study focused on the effects of the rotational speed of the feed frame paddles and the rotary tablet press throughput on the RTD. Methods An in-line UV/Vis measurement method was developed for determining the RTD in the feed frame. A model based on a plug flow and a continuous stirred tank reactor was adapted to model the experimentally determined RTDs. Finally, the mixing capacity of a feed frame was evaluated and correlated with a model parameter of the RTD. Results Overall, the developed UV/Vis measurement method was suitable and could be used to obtain process information regarding content uniformity in real time. The experimentally-determined RTDs were described well by fitting an inverse mixing and a transport time. In addition, a correlation between the location and the shape of measured RTDs and tablet press throughput was found. In contrast, rotational feed frame paddle speed did not affect the RTDs. Split-feeding experiments indicated the mixing capacity of the rotary tablet press feed frame. Conclusion The inverse mixing time can be used as an initial indicator for estimating the mixing capacity.

Sampling optimization for blend monitoring of a low dose formulation in a tablet press feed frame using spatially resolved near-infrared spectroscopy

In-line measurements of low dose blends in the feed frame of a tablet press were performed for API concentration levels as low as 0.10% w/w. The proposed methodology utilizes the advanced sampling capabilities of a Spatially Resolved Near-Infrared (SR-NIR) probe to develop Partial Least-Squares calibration models. The fast acquisition speed of multipoint spectra allowed the evaluation of different numbers of co-adds and feed frame paddle speeds to establish the optimum conditions of data collection to predict low potency blends. The interaction of the feed frame paddles with the SR-NIR probe was captured with high resolution and allowed the implementation of a spectral data selection criterion to remove the effect of the paddles from the calibration and testing process. The method demonstrated accuracy and robustness when predicting drug concentrations across different feed frame paddle speeds.

Synthesis and characterization of osmotic pump capsules containing polyoxyethylene and pH modifier to control the release of nifedipine

The aim of this study was to formulate osmotic pump capsules (OPCs) to control the release of nifedipine (NP). NP solid dispersion was prepared by solvent evaporation method. The prepared mixture of NP solid dispersion and various excipients were filled into the commercial HPMC hard capsule shells and then coated with cellulose acetate (CA) solution to form NP-OPC. The CA coating solution consisted of CA as semi-permeable membrane, and Poloxamer 188 as pore formers. The impact of addition agents, citric acid and pore formers on in vitro drug release were investigated. Furthermore, the study has highlighted the impact of paddle speed and the pH value of release media, on the release and compared the release with the commercial controlled release tablets. The in vitro drug release study indicated that drug release could reach 95% in 24 h with optimal formulation, and interestingly model fitting showed that the drug release behavior was closely followed to zero-order release kinetics. The pharmacokinetic studies were performed in rabbits with commercial controlled release tablets as reference, both preparations showed a sustained release effect. Compared with traditional preparation methods of OPCs, the new preparation process was simplified without the operation of laser drilling and the sealing process of capsule body and cap, which improved the feasibility of industrial production.

Potential Application of USP Paddle and Basket Dissolution Methods in Discriminating for Portioned Moist Snuff and Snus Smokeless Tobacco Products.

The focus of the study was to develop discriminatory dissolution methods for portioned snus and moist snuff sub-categories of smokeless tobacco products (STPs) using USP basket and paddle apparatuses. Skoal Classic Wintergreen (SCW) and CORESTA CRP1.1 pouches were used as test products. The dissolution was performed at 10, 20, 30, 40, and 50rpm basket or paddle speed in 500ml artificial saliva pH6.8. The products were also characterized for assay, pH, particle size, and loss on drying. The dissolution profiles were evaluated for amount/% of nicotine dissolved, time to reach plateau, and profiles comparison by f2 and f1 factors. The nicotine assay was 13.3 ± 0.2 and 7.6 ± 0.1mg/pouch for SCW and CRP1.1, respectively. The nicotine dissolved in 30min from SCW and CRP1.1 were 38.4-81.8 and 37.6-88.1, and 50.5-64.9 and 72.3-92.1% by paddle and basket methods, respectively. The f2 and f1 values were ≤ 39.2 and ≥42.1 and ≤ 43.2 and ≥34.1 for basket methods and paddle methods. RSD were less than 20% at all points of dissolution profiles, and dissolution plateau were achieved in 30min at some of the tested conditions. In summary, dissolution methods based on basket and paddle can be used as a performance test for STPs.

Protocol development, validation, and troubleshooting of in-situ fiber optic bathless dissolution system (FODS) for a pharmaceutical drug testing

Currently, there is no systematic approach available for the validation, quantitative assessment, and troubleshooting for the in-situ fiber optic/bathless dissolution system (FODS). In this report, a dissolution protocol was developed and validated for a model product, chlorpheniramine maleate (CPM) 4 mg IR tablets. Dissolution runs were conducted at 37 ± 0.2 °C using a USP apparatus II, at 50 rpm in 500 mL of 0.01 N hydrochloric acid. The dissolution system was validated for linearity, accuracy, precision, specificity, and robustness analogously to an HPLC method validation. The linearity determination method was developed using five concentration levels between 25–125 % of the expected concentration, while for accuracy, 80 %, 100 %, and 120 % levels were used, and precision was determined using six runs at the 100 % level. Probe sampling depth, orientation, analytical wavelength, and paddle speed were varied to evaluate the robustness of the system tested. Method equivalence was established by comparing the dissolution results from FODS and the traditional dissolution method using UV spectrophotometry. Based on the statistics generated using the dissolution tests, the results are linear, accurate, precise, and specific. Robustness testing demonstrates that small changes in operating conditions did not significantly change the result. No significant difference in the amount dissolved at Q-timepoint was observed between FODS and traditional testing. Therefore, the FODS is a suitable alternative to traditional dissolution for CPM immediate-release tablets (many other drug products have been tested in the laboratory, and reports are in preparation).Additionally, the current work discusses problems related to media preparation, probe sensitivity, and excipient effects on data collected using FODS. The instrument-specific artifacts and data analysis problems are addressed and troubleshooting with possible solutions to eliminate or mitigate the errors. Although the FODS method was developed and evaluated using CPM in 500 mL dissolution volume, the dissolution method using a more common pharmacopoeial dissolution volume, i.e., 900 mL, was used to demonstrate the troubleshooting experiments for the drug products requiring 900 mL dissolution media.

Residence time distribution modelling and in line monitoring of drug concentration in a tablet press feed frame containing dead zones

The presence of a ‘significant dead zone’ in any continuous manufacturing equipment may affect the product quality and need to be investigated systematically. Dead zone will affect the residence time distribution (RTD) of continuous manufacturing and thus the mixing and product quality. Tablet press (feed frame) is one of unit operations that directly influence the critical quality attributes (CQA’s). However, currently no systematic methods and tools are available to characterize and model the feed frame dead zone. In this manuscript, the RTD of the tablet press feed frame containing dead zone is investigated. Step-change experiments revealed that the feed frame could be expressed as a traditional continuous stirred tank model. The volume fractions of the dead zones are determined experimentally as well as using RTD model. In addition, an in-line NIR method for drug concentration monitoring inside the feed frame is also developed. The developed NIR calibration model enables to monitor the drug concentration precisely and detect the variation immediately with the probe positioned right above the left paddle. It is also found that the feed frame paddle speed slightly affects the predictive accuracy of NIR, while the die disc speed has no significant effect.

Evaluation of dissolution techniques for orally disintegrating mini-tablets

Mini-tablets are suitable for paediatric as well as geriatric use since they may provide flexible and accurate dosing and administration. Due to the minute tablet size, there is a need for new standardized quality evaluation procedures and conventional techniques may have to be adopted. The main objective of the study was to evaluate different dissolution techniques for orally disintegrating mini-tablets. Dissolution tests using mini-paddle apparatus were compared with standard size paddle apparatus, and the effect of paddle rotation speed was evaluated. Also, the filter choice, and its impact on dissolution, was considered. Sodium salicylate was used as a model drug substance and was mixed with different size fractions of mannitol. The powder mixtures were compacted into 2 mm flat faced tablets. The mini-tablets were characterized regarding weight and content uniformity, tensile strength, friability, disintegration and dissolution. Similar dissolution profiles were obtained with both mini and standard equipment. The paddle rotation speed affected the dissolution profiles; a low paddle speed resulted in a slower dissolution. Furthermore, choosing a chemically inert filter will increase the likelihood of obtaining reliable and accurate results. An appropriately designed dissolution test using mini-paddle apparatus is required prior to further implementation in quality control procedures.

Data on rotary die filling performance of various pharmaceutical powders.

As one of critical process steps during pharmaceutical tabletting, rotary die filling is still not well understood. To address this issue, a model rotary die filling system with a paddle feeder was developed to closely mimic the industrial process. Using this model system, the performance of various pharmaceutical powders at different turret and paddle speeds was evaluated, and the dependence of fill variation on process conditions and material properties was examined. A comprehensive dataset was created and reported here to show the effects of material and process parameters on the die filling performance and the filling consistency. It is believed that the data can also be used for data-driven process modelling and for developing robust machine learning models for pharmaceutical manufacturing.

Flow behaviour of pharmaceutical powders during rotary die filling with a paddle feeder.

Rotary tabletting presses are widely used to produce tablets in the pharmaceutical industry. In the tabletting process using a rotary press, rotary die filling is one of critical process steps, as powder behaviour during die filling dictates the quality of final products, such as dosage and weight variations. It is hence of importance to understand powder flow behaviour during rotary die filling. The purpose of this study is to identify the critical process parameters and material attributes that determine the die filling performance. For this purpose, a model rotary die filling system with a paddle feeder was constructed to mimic the powder feeding process in a typical rotary press. Using this model system, the effects of powder properties, turret speed and paddle speed on die filling behaviour were investigated. Three grades of microcrystalline cellulose powders were considered. It was found that the turret speed has a more pivotal role in controlling the die filling performance than the paddle speed. In addition, it is demonstrated that powder flowability has a great impact on the fill weight variation, and a higher weight variation is induced for the powders with poorer flowability.

The Challenge of Die Filling in Rotary Presses-A Systematic Study of Material Properties and Process Parameters.

For the efficient and safe production of pharmaceutical tablets, a deep process understanding is of high importance. An essential process step during tableting is the die filling, as it is responsible for a consistent tablet weight and drug content. Furthermore, it affects the results of subsequent process steps, compaction and ejection, and thus critical quality attributes. This study focuses on understanding the influences of process parameters and material properties on die filling on a rotary tablet press. By the systematic variation in process parameters as the turret and paddle speeds as well as the fill and dosing depths, five formulations with differing properties are processed. Analysis of the normalized tablet weight, called filling yield, revealed different limitation mechanisms of the filling process, i.e., incomplete filled dies for certain parameter settings. Kinetic limitations occur due to a short residence time under the feed frame (filling time) caused by high turret speeds, which additionally induce high tablet weight variation coefficients. Characteristic maximum turret speeds at certain paddle speeds can be found to still achieve complete filling. At low turret speeds, densification of the powder inside the dies takes place, induced by two mechanisms: either high paddle speeds or high overfill ratios, or a combination of both. The challenge to fill the dies completely as well as avoid densification is dependent on material properties as the flowability. The mass discharge rate from an orifice was found to be in a linear correlation to the filling results of different formulations below complete filling.

Application of statistical design on the early development of sustained-release tablet containing ivy leaf extract

The aim of this study was to develop a sustained-release (SR) tablet of ivy leaf extract (ILE) that exhibits robust dissolution profiles unaffected by pH and mechanical stress in the gastrointestinal (GI) tract using statistical design. The response surface design was used to study the effect of type and amount of sustaining polymer on the drug release over time. The type and amount of sustaining polymers were set as factors. The percentages of dissolved hederacoside C, as an indicator substance of ILE, at 6, 12, and 24 h were set as the responses. The highest desirability value was obtained when 26.09% of HPMC K15 M (hydroxypropyl methylcellulose, 15,000 mPa s) was used among the various polymers tested. The granules and tablets prepared with this composition showed acceptable physical properties (bulk density, tapped density, angle of repose, thickness, hardness, and friability). The drug release profiles of the SR tablet exhibited non-Fickian mechanism close to zero-order release based on the Korsmeyer-Peppas model regardless of the pH of dissolution media and the paddle speed of the dissolution tester. Overall, the present study suggested a new statistical approach to the development of SR tablets containing herbal medicine and successfully developed the tablets.

Investigations on hole-flanging by paddle forming and a comparison with single point incremental forming

The use of dedicated dies to carry out hole-flanging operations is costly for small batch production. As a result, hole-flanging by single point incremental forming (SPIF) was put forward because it offers advantages such as low equipment cost, high formability, and flexibility compared to conventional hole-flanging. However, drawbacks of hole-flanging by SPIF such as poor geometrical accuracy and long process times are obstacles to its industrial take-up. This paper presents a novel incremental hole-flanging method which uses paddle-shaped tools rotating at high speeds while being fed axially into the sheets to form flanges, with the aim of preserving the advantages of incremental forming while reducing the drawbacks related to process time. The results of the experiments show higher formability for the paddle forming process compared to hole-flanging by multi-stage SPIF and conventional hole-flanging. The high formability in paddle forming is attributed to the presence of shear which delays fracture. Furthermore, heat generated due to friction between the paddle and metal blanks leads to a rise in the blank temperature which enhances formability. Optical strain measurements of the formed flanges reveal that the paddle speed and feed have major influences on the forming mechanism of the process and the process borders. A maximum hole expansion ratio (HER) of 3.3 was obtained from the experiments in a process time of ∼2 s, showing that the process combines high formability and low process times.

Assessing Oil Content of Microalgae Grown in Industrial Energetic-Laden Wastewater

Industrial ammunition facilities generate wastewater containing different energetic compounds and nitrogen species. Our previous studies showed that some of these untreated wastewater streams can be mixed at a specific ratio to grow microalgae. In this study, four different untreated wastewater samples from an industrial ammunition facility were mixed and used as a culture media for microalgae, Scenedesmus obliquus ATCC®11477, in 100 L raceway reactors. The main objective of the study was to test the effect of growth parameters (light penetration, nutrient availability and retention times) on the oil content of microalgae in a semi-continuous setting. The raceway reactors were operated under 68–95 μmol/m2/s of light intensity for a 14:10 h light:dark photoperiod, and 60 rpm mixing paddle speed. Continuous monitoring of pH and temperature of the growth medium, periodic analysis of cell density and dry weight of microalgae, and analysis of the medium’s nutrient contents were performed. Biomass harvesting from the raceway reactors was conducted weekly, and the harvested algal biomass was tested for its oil content using an ethanol extraction method. Results showed that nitrogen starvation increased the oil production from 13% to 29% of oil based on the dry weight of biomass, whereas no increment in oil or biomass production was evidenced with the increase of light penetration for the two different retention times tested. This study provided significant information towards microalgae growth in energetic-laden wastewater streams. This study also showed that wastewaters from industrial ammunition facilities can be reused for culturing microalgae, which can be utilized for renewable energy production.

Generation of Electric Power Using Two-Wheelers

In the recent years power generation is also a challenging task. Mostly the power can be generated by coal mines,wind mill,etc.The proposed method involves the alternating source for generating power. Bike powered generator is a device that uses a prime mover to produce electricity in contact with a roller for charging a battery. Here an alternator is used as the electricity generator. The alternator is coupled to a pulley which is rotated by a belt and drive system. The input power is given to the paddle and final rotational speed is achieved in the alternator rotor. Therefore, mobility of equipment is of great importance. This innovation brings together the resourcefulness of power generation with the transportation feasibility of a motor bike frame.

Design and Development of a Vertical Paddle Semi Automated Garri Frying Machine

Garri frying is the most critical unit operation in the processing of cassava into garri. The quality of the final product is much dependent on this processing stage which is a combination of simultaneous cooking and drying processes. This work presents the development of a garri fryer and the performance evaluation of the machine at various operational parameters. The fryer throughput capacity, (TP)c and functional/drying efficiency, were used to evaluate the performance of the fryer. The cooking and drying performance of the developed machine accounted for throughput capacity of 20.66kg/hr and functional efficiency of 66%. In addition, a preferred final moisture content of 12.14%w.b. was achieved at 20rpm paddle speed and frying time of 23 minutes. The equipment have addressed the short coming observed in the village technique such as time-consumption, health hazard for the operator. In addition, it is user friendly as it requires no skilled labour and also uses different heat sources for convenience of the user.Keywords: Cassava, Design, Garri fryer, operational parameters, performance evaluation

Development and Validation of a Discriminatory Dissolution Method for Rifaximin Products

The commercial product of rifaximin (RFX) contains α form. The α form can change to β form on exposure to high humidity that can occur during manufacturing, stability, and in-use period. It is critical to maintain α form of the drug in a drug product to avoid variability in clinical response. U.S. Food and Drug Administration dissolution method was found to be nondiscriminatory for RFX formulations containing either 100% α or β form. The objective of this study was to develop a discriminatory dissolution method that can detect low levels of α to β transformation in RFX products. Formulations containing a variable fraction of α and β forms were prepared by using direct compression method. Dissolution parameters investigated were type of dissolution medium (water and phosphate buffer), volume (500, 900, and 1000 mL), and paddle speed (50, 75, and 150 rpm). Dissolution in water with 0.2% sodium lauryl sulfate was less than 80% and nondiscriminatory. However, dissolution tested in a phosphate buffer pH 7.4 with 0.2% sodium lauryl sulfate at 50 rpm was discriminatory with more than 17.5% difference in dissolution profile between formulations containing α and β forms. The developed method can detect polymorphic transformation if there is 25% or more β form conversion.

Development of a Preconditioning System for FUTA Floating Fish Feed Extruder

The need to enhance the quality of fish feed produced in Nigeria was the major consideration in the design and development of a preconditioning system. The machine consists of two insulated cylindrical barrels, set of arranged paddles on a shaft, frame, hot water and feed mash inlet, discharge chute, chain and sprocket. It was powered by a three-phase 15 hp electric motor which transmits power to the machines shaft and set of paddles via chain and sprocket. The performance characteristics of the machine; mixing efficiency and throughput capacity were evaluated using Nigerian Institute for Oceanography and Marine Research (NIOMR) feed formulation at feed mash particle sizes of 900 µm, 550 µm, 520 µm and paired paddle rotating speed of the lower and upper chamber at (96.8; 145.2), (122.6; 183.2) and (174.5; 260.8) rpm respectively. The throughput capacity of the preconditioner is 650 kg/hr. The results showed increase in temperature and moisture content level of the particles as the machine speed decreases. The optimum mixing efficiency that gave best uniformity of mix was attained when Paired paddle speeds were (96.8; 145.2), (122.6; 183.2) with an average Biot numbers of 0.1.

Biopharmaceutic IVIVE—Mechanistic Modeling of Single- and Two-Phase In Vitro Experiments to Obtain Drug-Specific Parameters for Incorporation Into PBPK Models

The physiological relevance of single-phase (aqueous only) and 2-phase (aqueous and organic phase) in vitro dissolution experiments was compared by mechanistic modeling. For orally dosed dipyridamole, stepwise, sequential estimation/confirmation of biopharmaceutical parameters from in vitro solubility-dissolution data was followed, before applying them within a physiologically based pharmacokinetic (PBPK) model. The PBPK model predicted clinical dipyridamole luminal and plasma concentration profiles reasonably well for a range of doses only where the precipitation rate constant was derived from the 2-phase experiment. The population model predicted a distribution of maximal precipitated fractions from 0% to 45% of the 90 mg dose (mean 7.6%). Such population information cannot be obtained directly from a few in vitro experiments; however well they may represent an “average” and several extreme subjects (those with low-high luminal fluid volumes, pH, etc.) because there is no indication of outcome likelihood. For this purpose, direct input of in vitro dissolution/precipitation profiles to a PBPK model is insufficient—mechanistic modeling is required. Biopharmaceutical in vitro-in vivo extrapolation tools can also simulate the effect of key experimental parameters (dissolution volumes, pH, paddle speed, etc.) on dissolution/precipitation behavior, thereby helping to identify critical variables, which may impact the number or design of in vitro experiments.

The Effects of Feed Frame Parameters and Turret Speed on Mini-Tablet Compression

Die filling is a critical process step during tablet production as it defines the tablet weight. Achieving die fill consistency during production of mini-tablets, tablets with diameters ≤6 mm, is considerably more challenging. Although die filling in rotary presses had been studied in relation to the feed paddle design, paddle speed, and turret speed, it is unclear how these process variables could impact mini-tablet production and product properties. In this study, 1.8 and 3 mm mini-tablets were prepared using a rotary press with multiple-tip tooling using different process configurations. Mini-tablet weight variation within and across compaction cycles were determined using data from compression roller displacement and mini-tablet weight. Higher die fill densities were achieved with a flat feed wheel paddle and high paddle speed. This was attributed to better granule fluidization in the feed frame, which also increased the intercycle weight variation and reduced tensile strength. The turret speed did not impact mini-tablet properties significantly. Granule overlubrication in the feed frame potentially reduced mini-tablet tensile strength during compaction. The number of paddle passes in the die fill region was correlated to mini-tablet die fill performance. Findings from this study could provide better insights into the relationship between process variables and mini-tablet product quality.