Computational fluid dynamics modeling of the paddle dissolution apparatus: Agitation rate,mixing patterns,and fluid velocities

The purpose of this research was to further investigate the hydrodynamics of the United States Pharmacopeia (USP) paddle dissolution apparatus using a previously generated computational fluid dynamics (CFD) model. The influence of paddle rotational speed on the hydrodynamics in the dissolution vessel was simulated. The maximum velocity magnitude for axial and tangential velocities at different locations in the vessel was found to increase linearly with the paddle rotational speed. Path-lines of fluid mixing, which were examined from a central region at the base of the vessel, did not reveal a region of poor mixing between the upper cylin-drical and lower hemispherical volumes, as previously speculated. Considerable differences in the resulting flow patterns were observed for paddle rotational speeds between 25 and 150 rpm. The approximate time required to achieve complete mixing varied between 2 to 5 seconds at 150 rpm and 40 to 60 seconds at 25 rpm, although complete mixing was achievable for each speed examined. An analysis of CFD-generated velocities above the top surface of a cylindrical compact positioned at the base of the vessel, below the center of the rotating paddle, revealed that the fluid in this region was undergoing solid body rotation. An examination of the velocity boundary layers adjacent to the curved surface of the compact revealed large peaks in the shear rates for a region within∼3 mm from the base of the compact, consistent with a ‘grooving’ effect, which had been previously seen on the surface of compacts following dissolution, associated with a higher dissolution rate in this region.     

Release Characteristics of Quetiapine Fumarate Extended Release Tablets Under Biorelevant Stress Test Conditions

The aim of the present work was the investigation of robustness and reliability of drug release from 50 to 400 mg quetiapine extended release HPMC matrix tablets towards mechanical stresses of biorelevant intensity. The tests were performed under standard conditions (USP apparatus II) as well as under simulated gastrointestinal stress conditions. Mechanical stresses including pressure and agitation were applied by using the biorelevant dissolution stress test apparatus as it has been introduced recently. Test algorithms already established in previous studies were applied to simulate fasting gastrointestinal conditions. The dissolution experiments demonstrated striking differences in the product performance among standard and stress test conditions as well as dose strengths. In USP apparatus II, dissolution profiles were affected mainly by media pH. The dissolution experiments performed in biorelevant dissolution stress test device demonstrated that stress events of biorelevant intensity provoked accelerated drug release from the tablets.     

Dissolution Testing of Sublingual Tablets: A Novel <Emphasis Type="Italic">In Vitro</Emphasis> Method

In the sublingual (SL) cavity, compared with the gastrointestinal tract, tablets are subjected to minimal physiological agitation, and a limited volume of saliva is available to facilitate disintegration and dissolution. None of the official compendial dissolution apparatuses and methods simulate these SL conditions. In this study, a custom-made dissolution apparatus was constructed, and a novel in vitro method that simulates SL conditions was evaluated. Several epinephrine 40 mg SL tablet formulations under development and two commercial SL tablets, isosorbide dinitrate 5 mg and nitroglycerin 0.6 mg, were studied. The dissolution medium was 2 mL of distilled water at 25°C. Dissolution was measured at 60 and 120 s. The novel in vitro method was validated for accuracy, reproducibility, and discrimination capability, and was compared with the official US Pharmacopeia (USP) dissolution method using apparatus 2 (Paddle). The data obtained following the novel in vitro method were accurate and reproducible. This method was capable of detecting minor changes in SL formulations that could not be detected using other in vitro tests. Results from the official USP dissolution method and our novel in vitro method were significantly different (p < 0.05). Results reflecting the dissolution of rapidly disintegrating tablets using simulated SL conditions were obtained using the novel in vitro dissolution method.     

Using USP I and USP IV for Discriminating Dissolution Rates of Nano- and Microparticle-Loaded Pharmaceutical Strip-Films

Recent interest in the development of drug particle-laden strip-films suggests the need for establishing standard regulatory tests for their dissolution. In this work, we consider the dissolution testing of griseofulvin (GF) particles, a poorly water-soluble compound, incorporated into a strip-film dosage form. The basket apparatus (USP I) and the flow-through cell dissolution apparatus (USP IV) were employed using 0.54% sodium dodecyl sulfate as the dissolution medium as per USP standard. Different rotational speeds and dissolution volumes were tested for the basket method while different cell patterns/strip-film position and dissolution media flow rate were tested using the flow-through cell dissolution method. The USP I was not able to discriminate dissolution of GF particles with respect to particle size. On the other hand, in the USP IV, GF nanoparticles incorporated in strip-films exhibited enhancement in dissolution rates and dissolution extent compared with GF microparticles incorporated in strip-films. Within the range of patterns and flow rates used, the optimal discrimination behavior was obtained when the strip-film was layered between glass beads and a flow rate of 16 ml/min was used. These results demonstrate the superior discriminatory power of the USP IV and suggest that it could be employed as a testing device in the development of strip-films containing drug nanoparticles.Key Words: BCS class II, dissolution, drug nanoparticles, flow-through cell, pharmaceutical strip-films     

Comparison of Three Dissolution Apparatuses for Testing Calcium Phosphate Pellets used as Ibuprofen Delivery Systems

Porous calcium phosphate pellets were produced according to two granulation processes (low and high shear wet granulations) and drug loaded with five ibuprofen contents (1.75%, 7%, 12.5%, 22%, and 36%) in order to ensure both bone defect filling and local drug delivery. The drug-release kinetics from the two types of pellets was studied using three dissolution apparatuses: paddle apparatus, reciprocating cylinder, and flow-through cell. The paper compared the three dissolution methods and considered the effect of the granulation process on the ibuprofen-release kinetics. Dissolution data were analyzed using the Weibull function as well as the difference (f1) and similarity (f2) factors. Dissolution kinetics was not influenced by the granulation process, regardless of the dissolution apparatus and of the drug content. The comparison of the three dissolution devices indicated that ibuprofen was released faster from granules loaded with 36% of drug content with the reciprocating apparatus, due to the disintegration of the granules occurring during the dissolution test. For the other drug contents, dissolution profiles were not significantly different from one apparatus to another. However, the flow-through cell seemed to be more suitable for the drug-release study of implantable materials.     

Flow modelling within a scaffold under the influence of uni-axial and bi-axial bioreactor rotation

The problem of donor scarcity has led to the recent development of tissue engineering technologies, which aim to create implantable tissue equivalents for clinical transplantation. These replacement tissues are being realised through the use of biodegradable polymer scaffolds; temporary/permanent substrates, which facilitate cell attachment, proliferation, retention and differentiated tissue function. To optimise gas transfer and nutrient delivery, as well as to mimic the fluid dynamic environment present within the body, a dynamic system might be chosen. Experiments have shown that dynamic systems enhance tissue growth, with the aid of scaffolds, as compared to static culture systems. Very often, tissue growth within scaffolds is only seen to occur at the periphery. The present study utilises the Computational Fluid Dynamics package FLUENT, to provide a better understanding of the flow phenomena in scaffolds, within our novel bioreactor system. The uni-axial and bi-axial rotational schemes are studied and compared, based on a vessel rotating speed of 35 rpm. The wall shear stresses within and without the constructs are also studied. Findings show that bi-axial rotation of the vessel results in manifold increases of fluid velocity within the constructs, relative to uni-axial rotation about the X- and Z-axes, respectively.     

Comparison of the dissolution of metaxalone tablets (Skelaxin) usingUSP apparatus 2 and 3

The purpose of this study was to evaluate the effect of pH on the dissolution behavior of metaxalone in the marketed product Skelaxin tablets. The dissolution was evaluated using United States Pharmacopeia (USP) dissolution Apparatus 2 and 3 at pHs ranging from 1.5 to 7.4 Results from these studies show that the dissolution of this product is pH dependent. At low pH (simulated gastric fluid, pH 1.5), the dissolution of metaxalone from Skelaxin tablets, was less than 10% over 75 minutes; whereas, dissolution at pH 4.5 showed greater than 90% release in the same time period. These results were consistent for both Apparatus 2 and 3. This suggests that Skelaxin Tablets should be considered a delayed release dosage form.KeyWords: Metaxalone, dissolution, pH dependence, apparatus 3     

Development of a Discriminative <Emphasis Type="Italic">In Vitro</Emphasis> Release Test for Rivastigmine Transdermal Patches Using Pharmacopeial Apparatuses: USP 5 and USP 6

The aim of this study was to develop and validate a discriminating in vitro release test to evaluate rivastigmine transdermal patches. The Exelon® Patch was chosen as a model transdermal product. The studies of in vitro release were designed to determine the impact of the official apparatus chosen (USP apparatus 5 and USP apparatus 6), the rotation speed, and the dissolution medium characteristics on the rivastigmine release profile from transdermal patches. Patches with different drug release profiles were tested in order to evaluate the discriminating power of the in vitro release test developed and validated. Variables such as the apparatus type, the dissolution medium, and the rotation speed have a significant influence on the drug release characteristics from a transdermal patch. The in vitro release methodologies using the USP apparatus 5 at 50 rpm and USP apparatus 6 at 25 rpm using the medium phosphate-buffered saline pH 7.4 were considered discriminative and adequate to characterize the rivastigmine (RV) release from a commercial transdermal patch, Exelon® Patch.     

Regulatory Considerations for the Classification of Video Monitoring in Dissolution Testing

The goal of this article is to discuss the classification of video recordings and images when applied to dissolution testing in USP apparatus 1 and 2. Three use cases are presented. The first case presents the use and classification of video as RBE (review by exception) data under GAMP 5. The second case presents the use of video in formulation development in a research and development environment. The third case presents a feasibility study using readily available computer vision software to recognize and measure objects in the dissolution vessel, setting the groundwork for the use of image analysis as a quantitative tool. The classification of video as “electronic data”, requiring 21 CFR part 11 compliance, versus its classification as a RBE data under GAMP 5, likely depends upon its use case. Another goal of this article is to establish a position on the use of video monitoring technology as a tool for dissolution testing that is fit for purpose and compliant with regulations regarding video data management and information.Key words: computer vision, dissolution, GAMP, USP, video monitoring     

In vitro evaluation of dissolution behavior for a colon-specific drug delivery system (CODES) in multi-pH media using United States Pharmacopeia apparatus II and III

United States Pharmacopeia dissolution apparatus II (paddle) and III (reciprocating cylinder) coupled with automatic sampling devices and software were used to develop a testing procedure for acquiring release profiles of colon-specific drug delivery system (CODES^™) drug formulations in multi-pH media using acetaminophen (APAP) as a model drug. System suitability was examined. Several important instrument parameters and formulation variables were evaluated. Release profiles in artificial gastric fluid (pH 1.2), intestinal fluid (pH 6.8), and pH 5.0 buffer were determined. As expected, the percent release of APAP from coated core tablets was highly pH dependent. A release profile exhibiting a negligible release in pH 1.2 and 6.8 buffers followed by a rapid release in pH 5.0 buffer was established. The drug release in pH 5.0 buffer increased significantly with the increase in the dip or paddle speed but was inversely related to the screen mesh observed at lower dip speeds. It was interesting to note that there was a close similarity (f ₂=80.6) between the release profiles at dip speed 5 dpm and paddle speed 100 rpm. In addition, the release rate was reduced significantly with the increase in acid-soluble Eudragit E coating levels, but lactulose loading showed only a negligible effect. In conclusion, the established reciprocating cylinder method at lower agitation rates can give release profiles equivalent to those for the paddle procedure for CODES^™ drug pH-gradient release testing. Apparatus III was demonstrated to be more convenient and efficient than apparatus II by providing various programmable options in sampling times, agitation rates, and medium changes, which suggested that the apparatus II approach has better potential for in vitro evaluation of colon-specific drug delivery systems.     

Improvement and validation of a computational model of flow in the swirling well cell culture model

Effects of fluid dynamics on cells are often studied by growing the cells on the base of cylindrical wells or dishes that are swirled on the horizontal platform of an orbital shaker. The swirling culture medium applies a shear stress to the cells that varies in magnitude and directionality from the center to the edge of the vessel. Computational fluid dynamics methods are used to simulate the flow and hence calculate shear stresses at the base of the well. The shear characteristics at each radial location are then compared with cell behavior at the same position. Previous simulations have generally ignored effects of surface tension and wetting, and results have only occasionally been experimentally validated. We investigated whether such idealized simulations are sufficiently accurate, examining a commonly-used swirling well configuration. The breaking wave predicted by earlier simulations was not seen, and the edge-to-center difference in shear magnitude (but not directionality) almost disappeared, when surface tension and wetting were included. Optical measurements of fluid height and velocity agreed well only with the computational model that incorporated surface tension and wetting. These results demonstrate the importance of including accurate fluid properties in computational models of the swirling well method.     

Wall shear stresses remain elevated in mature arteriovenous fistulas: a case study

Maintaining vascular access (VA) patency continues to be the greatest challenge for dialysis patients. VA dysfunction, primarily due to venous neointimal hyperplasia development and stenotic lesion formation, is mainly attributed to complex hemodynamics within the arteriovenous fistula (AVF). The effect of VA creation and the subsequent geometrical remodeling on the hemodynamics and shear forces within a mature patient-specific AVF is investigated. A 3D reconstructed geometry of a healthy vein and a fully mature patient-specific AVF was developed from a series of 2D magnetic resonance image scans. A previously validated thresholding technique for region segmentation and lumen cross section contour creation was conducted in MIMICS 10.01, allowing for the creation of a 3D reconstructed geometry. The healthy vein and AVF computational models were built, subdivided, and meshed in GAMBIT 2.3. The computational fluid dynamic (CFD) code FLUENT 6.3.2 (Fluent Inc., Lebanon, NH) was employed as the finite volume solver to determine the hemodynamics and shear forces within the healthy vein and patient-specific AVF. Geometrical alterations were evaluated and a CFD analysis was conducted. Substantial geometrical remodeling was observed, following VA creation with an increase in cross-sectional area, out of plane curvature (maximum angle of curvature in AVF=30?deg), and angle of blood flow entry. The mean flow velocity entering the vein of the AVF is dramatically increased. These factors result in complex three-dimensional hemodynamics within VA junction (VAJ) and efferent vein of the AVF. Complex flow patterns were observed and the maximum and mean wall shear stress (WSS) magnitudes are significantly elevated. Flow reversal was found within the VAJ and efferent vein. Extensive geometrical remodeling during AVF maturation does not restore physiological hemodynamics to the VAJ and venous conduit of the AVF, and high WSS and WSS gradients, and flow reversal persist. It is theorized that the vessel remodelling and the continued non-physiological hemodynamics within the AVF compound to result in stenotic lesion development.     

Formulation and in vitro, in vivo evaluation of extended- release matrix tablet of Zidovudine: Influence of combination of hydrophilic and hydrophobic matrix formers

The aim of the present study was to prepare and characterize extended-release matrix tablets of zidovudine using hydrophilic Eudragit RLPO and RSPO alone or their combination with hydrophobic ethyl cellulose. Release kinetics was evaluated by using United States Pharmacopeia (USP)-22 type I dissolution apparatus. Scanning electron microscopy was used to visualize the effect of dissolution medium on matrix tablet surface. Furthermore, the in vitro and in vivo newly formulated sustained-release zidovudine tablets were compared with conventional marketed tablet (Zidovir, Cipla Ltd, Mumbai, India). The in-vitro drug release study revealed that either Eudragit preparation was able to sustain the drug release only for 6 hours (94.3%±4.5% release). Combining Eudragit with ethyl cellulose sustained the drug release for 12 hours (88.1%±4.1% release). Fitting the in vitro drug release data to Korsmeyer equation indicated that diffusion along with erosion could be the mechanism of drug release. In vivo investigation in rabbits showed sustained-release pharmacokinetic profile of zidovudine from the matrix tablets formulated using combination of Eudragits and ethylcellulose. In conclusion, the results suggest that the developed sustained-release tablets of zidovudine could perform therapeutically better than conventional dosage forms, leading to improve efficacy and better patient compliance. Published: January 3, 2006     

Design and evaluation of matrix-based controlled release tablets of diclofenac sodium and chondroitin sulphate

The purpose of the present study was to develop and characterize an oral controlled release drug delivery system for concomitant administration of diclofenac sodium (DS) and chondroitin sulfate (CS). A hydrophilic matrix-based tablet using different concentrations of hydroxypropylmethylcellulose (HPMC) was developed using wet granulation technique to contain 100 mg of DS and 400 mg of CS. Formulations prepared were evaluated for the release of DS and CS over a period of 9 hours in pH 6.8 phosphate buffer using United States Pharmacopeia (USP) type II dissolution apparatus. Along with usual physical properties, the dynamics of water uptake and erosion degree of tablet were also investigated. The in vitro drug release study revealed that HPMC K100CR at a concentration of 40% of the dosage form weight was able to control the simultaneous release of both DS and CS for 9 hours. The release of DS matched with the marketed CR tablet of DS with similarity factor (f(2)) above 50. Water uptake and erosion study of tablets indicated that swelling followed by erosion could be the mechanism of drug release. The in vitro release data of CS and DS followed Korsmeyer-Peppas and zero-order kinetics, respectively. In conclusion, the in vitro release profile and the mathematical models indicate that release of CS and DS can be effectively controlled from a single tablet using HPMC matrix system.     

Experimental determination of mechanical shear stress about an anastomotic junction

The present study is undertaken to determine whether the elastic tube model originally developed by Kuchar and Ostrach (Biomedical Fluid Mechanics Symposium, pp. 45-69, 1966) accurately provides a first approximation of the biomechanics of the anastomotic junction. The experimental protocol involves the use of canine carotid arteries as the host vessel and several graft materials including autogenous and prosthetic substitutes. The host artery-graft combinations are perfused in vitro in a pulsatile perfusion apparatus which simulates the natural hemodynamic environment. This apparatus provides accurate dynamic measurements of radial wall motion (measured at various longitudinal increments), associated pressures and rates of fluid flow. These data are then applied to the theoretical model for calculation of anastomotic induced bending stresses. The results indicate that the predictions derived from the elastic model consistently overestimate the measured radial change adjacent to the anastomotic junction. As a result shear stresses based on elastic theory deviate from values derived from a numerical curve fit to the experimental data.     

A prediction of cell differentiation and proliferation within a collagen–glycosaminoglycan scaffold subjected to mechanical strain and perfusive fluid flow

Mesenchymal stem cell (MSC) differentiation can be influenced by biophysical stimuli imparted by the host scaffold. Yet, causal relationships linking scaffold strain magnitudes and inlet fluid velocities to specific cell responses are thus far underdeveloped. This investigation attempted to simulate cell responses in a collagen–glycosaminoglycan (CG) scaffold within a bioreactor. CG scaffold deformation was simulated using μ-computed tomography (CT) and an in-house finite element solver (FEEBE/linear). Similarly, the internal fluid velocities were simulated using the afore-mentioned μCT dataset with a computational fluid dynamics solver (ANSYS/CFX). From the ensuing cell-level mechanics, albeit octahedral shear strain or fluid velocity, the proliferation and differentiation of the representative cells were predicted from deterministic functions. Cell proliferation patterns concurred with previous experiments. MSC differentiation was dependent on the level of CG scaffold strain and the inlet fluid velocity. Furthermore, MSC differentiation patterns indicated that specific combinations of scaffold strains and inlet fluid flows cause phenotype assemblies dominated by single cell types. Further to typical laboratory procedures, this predictive methodology demonstrated loading-specific differentiation lineages and proliferation patterns. It is hoped these results will enhance in-vitro tissue engineering procedures by providing a platform from which the scaffold loading applications can be tailored to suit the desired tissue.     

FIP Position Paper on Qualification of Paddle and Basket Dissolution Apparatus

The qualification process for ensuring that a paddle or basket apparatus is suitable for its intended use is a highly debated and controversial topic. Different instrument qualification and suitability methods have been proposed by the pharmacopeias and regulatory bodies. In an effort to internationally harmonize dissolution apparatus suitability requirements, the International Pharmaceutical Federation's (FIP) Dissolution/Drug Release Special Interest Group (SIG) reviewed current instrument suitability requirements listed in the US, European, and Japanese pharmacopeias and the International Conference on Harmonization (ICH) Topic Q4B on harmonization of pharmacopoeial methods, in its Annex 7, Dissolution Test General. In addition, the SIG reviewed the Food and Drug Administration (FDA) Draft Guidance for Industry, “The Use of Mechanical Calibration of Dissolution Apparatus 1 and 2—Current Good Manufacturing Practice (CGMP)” and the related ASTM Standard E2503-07. Based on this review and several in-depth discussions, the FIP Dissolution/Drug Release SIG recommends that the qualification of a dissolution test instrument should be performed following the calibration requirements as indicated in the FDA (draft) guidance. If additional system performance information is desired, a performance verification test using US Pharmacopeia Reference Standard tablet or an established in-house reference product can be conducted. Any strict requirement on the use of a specific performance verification test tablet is not recommended at this time.     

Development and Validation of a Discriminative Dissolution Test for Betamethasone Sodium Phosphate and Betamethasone Dipropionate Intramuscular Injectable Suspension

The intramuscular administration of the injectable suspension betamethasone sodium phosphate (BSP) and betamethasone dipropionate (BD) has immediate therapeutic activity due to solubilized BSP and prolonged activity resulting from the slow release of BD micro-crystals. The purpose of this study was to develop and validate a dissolution method for BD in intramuscular injectable suspensions with detection by high-performance liquid chromatography (HPLC) method. Five commercial products presented a distribution of particle sizes, ranging between 7.43 and 40.25 μm as measured by laser diffraction. It was also found that particle sizes differed between batches of the same product. The different products were tested using the paddle apparatus, with stirring speeds of 25 and 50 rpm in 300 mL of phosphate buffer; simulated body fluid, muscle fluid, and synovial fluid were used as biorelevant dissolution media at 37 ± 0.5°C. It was verified that not only does average particle size affect the dissolution rate, but also the mode and the polydispersity index of the particles. Discriminatory power was obtained using the in vitro dissolution method with 0.1 M sodium phosphate buffer pH 7.4 containing 0.1% sodium lauryl sulfate and a stirring speed of 50 rpm. The HPLC-method is linear, precise, selective, and accurate for the quantification of BSP and BD in dissolution profile testing. This dissolution method can be utilized as a method to control the quality of these injectable suspensions.Key words: dipropionate betamethasone, dissolution test, intramuscular injectable suspensions, simulated muscular fluid, sodium phosphate betamethasone     

Challenges with Developing In Vitro Dissolution Tests for Orally Inhaled Products (OIPs)

The purpose of this article is to review the suitability of the analytical and statistical techniques that have thus far been developed to assess the dissolution behavior of particles in the respirable aerodynamic size range, as generated by orally inhaled products (OIPs) such as metered-dose inhalers and dry powder inhalers. The review encompasses all analytical techniques publicized to date, namely, those using paddle-over-disk USP 2 dissolution apparatus, flow-through cell dissolution apparatus, and diffusion cell apparatus. The available techniques may have research value for both industry and academia, especially when developing modified-release formulations. The choice of a method should be guided by the question(s) that the research strives to answer, as well as by the strengths and weaknesses of the available techniques. There is still insufficient knowledge, however, for translating the dissolution data into statements about quality, performance, safety, or efficacy of OIPs in general. Any attempts to standardize a dissolution method for compendial inclusion or compendial use would therefore be premature. This review reinforces and expands on the 2008 stimulus article of the USP Inhalation Ad Hoc Advisory Panel, which "could not find compelling evidence suggesting that such dissolution testing is kinetically and/or clinically crucial for currently approved inhalation drug products."     

Bio-Dis and the Paddle Dissolution Apparatuses Applied to the Release Characterization of Ketoprofen from Hypromellose Matrices

The purposes of this work were: (1) to comparatively evaluate the effects of hypromellose viscosity grade and content on ketoprofen release from matrix tablets, using Bio-Dis and the paddle apparatuses, (2) to investigate the influence of the pH of the dissolution medium on drug release. Furthermore, since direct compression had not shown to be appropriate to obtain the matrices under study, it was also an objective (3) to evaluate the impact of granulation on drug release process. Six formulations of ketoprofen matrix tablets were obtained by compression, with or without previous granulation, varying the content and viscosity grade of hypromellose. Dissolution tests were carried out at a fixed pH, in each experiment, with the paddle method (pH 4.5, 6.0, 6.8, or 7.2), while a pH gradient was used in Bio-Dis (pH 1.2 to 7.2). The higher the hypromellose viscosity grade and content were, the lower the amount of ketoprofen released was in both apparatuses, the content effect being more expressive. Drug dissolution enhanced with the increase of the pH of the medium due to its pH-dependent solubility. Granulation caused an increase in drug dissolution and modified the mechanism of the release process.Key words: apparatus 3, Bio-Dis, dissolution, hypromellose matrix, ketoprofen