Numerical Simulation of Capsule Dissolution in the USP Apparatus II

The capsule is the second most common type of drug dosage form, yet detailed research of capsule dissolution in the USP Apparatus II (a paddle dissolution apparatus that mimics the drug dissolution process in an in vivo environment) is not well reported. In this work, a mathematical model was developed that incorporates both the dissolution of the capsule shell and the slug within the capsule shell. Capsule shell dissolution was modeled with the assumption that the shell undergoes an erosion process only. The capsule slug dissolution model incorporated mass transfer principles, Markov chain theory, and the influence of hydrodynamics on capsules dissolution using computational fluid dynamics (CFD)-predicted velocity profiles. To complete the model, the mass transfer coefficients (determined experimentally and theoretically) were incorporated. The model was validated by statistically comparing the simulated profiles to the experimental data using the similarity factor. In addition, this model can provide insights into the dissolution mechanism where a drug product may either disintegrate or erode during dissolution testing. This capsule slug dissolution model has the potential to reduce substantially the number of time-consuming physical dissolution experiments and maximize the efficiency of process development

In Vivo Predictive Dissolution: Analyzing the impact of Bicarbonate Buffer and Hydrodynamics on Dissolution.

When a drug is given orally, one of the major factors that impacts safety and efficacy is dissolution rate. Two important in vivo parameters that impact dissolution that are not well accounted for in current dissolution methods are the physiological buffer species bicarbonate and hydrodynamics. This work explores important aspects of each of these. Dissolution of pure drug using rotating disk dissolution methodology was used to evaluate the accuracy of several physically realistic simultaneous diffusion and chemical reaction schemes for CO2-bicarbonate buffer. Experimental results for ibuprofen, ketoprofen, indomethacin, 2-napthoic acid, benzoic acid, and haloperidol dissolution confirmed that the CO2 hydration reaction is sufficiently slow that it plays an insignificant role in the hydrodynamic boundary layer. Therefore carbonic acid undergoes an irreversible reaction to form CO2 and H2O. Dissolution experiments were also performed in the USP 2 (paddle) apparatus using suspended ibuprofen particles and tablets to demonstrate that the CO2-bicarbonate transport analysis can be successfully applied to pharmaceutical dosage forms. This transport analysis allows for predictions of phosphate buffers that more closely simulate dissolution in vivo. In the case of weak acid and weak base BCS class 2 drugs phosphate buffer concentrations are typically 1-15mM at pH 6.5. The role of hydrodynamics on particle dissolution was studied using the USP 4 (flow through) apparatus because it provides relatively well-defined fluid velocity profiles that may simulate in vivo conditions. Experimental results showed that increasing the fluid velocity resulted in increased particle dissolution rates. The impact of fluid velocity can only be accurately predicted with knowledge of particle Reynolds number and the void space of the solid particles suspended in solution. The suspensions studied were consistent with predictions assuming a void fraction of 0.25. The impact of hydrodynamics was also studied for erodible HPMC tablets using the USP 4 apparatus. In vitro erosion studies using bulk fluid velocities that simulate average intestinal flow rates (~0.1cm/sec) resulted in erosion rates that were 2-4.5 times slower than erosion rates observed for the same formulations in humans. It was concluded that the USP 4 apparatus may not provide hydrodynamics that accurately simulate in vivo tablet erosion.PhDPharmaceutical SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/111542/1/bjkrieg_1.pd

Effects of operating and geometric variables on hydrodynamics and tablet dissolution in standard and modified dissolution testing apparatuses 2

Dissolution testing is routinely conducted in the pharmaceutical industry to provide critical in vitro drug release information for quality control purposes, and especially to assess batch-to-batch consistency of solid oral dosage forms such as tablets. Among the different types of apparatuses listed in the United States Pharmacopoeia (USP), the most commonly used dissolution system for solid dosage forms is the USP Dissolution Testing Apparatus 2, consisting of an unbaffled, hemispherical-bottomed vessel equipped with a 2-blade radial impeller. Despite its extensive use in industry and a large body of work, some key aspects of the hydrodynamics of Apparatus 2 have received very little attention, such as the determination of its power dissipation requirements (which controls solid-liquid mass transfer processes) and the velocity distribution under the different agitation conditions at which this system is routinely operated. In addition, the tablet dissolution performance of Apparatus 2 has been shown to be highly sensitive to a number of small geometric factors, such as the exact locations of the impeller and the dissolving tablet. Therefore, in this study, computation and experimental work was conducted to (a) quantify the roles of some key hydrodynamic variables of importance for the standard Apparatus 2 system and determine their impact on the dissolution profiles of solid dosage forms, and (b) design and test a modified Apparatus 2 that can overcome the major limitations of the standard system, and especially those related to the sensitivity of the current apparatus to tablet location. Accordingly, the hydrodynamics in the standard USP Apparatus 2 vessel was experimentally quantified using Laser-Doppler Velocimetry (LDV) and Particle Image Velocimetry (PIV). Complete experimental mapping of the velocity distribution inside the standard Apparatus 2 was obtained at three agitation intensities, i.e., 50 rpm (NRe=4939), 75 rpm (NRe= 7409) and 100 rpm (NRe= 9878). The velocity distributions from both LDV and PIV were typically found to be very similar. It was found that the overall flow pattern throughout the whole vessel was dominated by the tangential component of the velocity at all agitation speeds, whereas the magnitudes of the axial and radial velocity components were typically much smaller. In the bottom zone of the vessel, two regions were observed, i.e., a central, low-velocity inner core region, and an outer recirculation loop below the impeller, rotating around the central inner core region. This core region typically persisted, irrespective of the impeller agitation speed. Computation Fluid Dynamics (CFD) was additionally used to predict velocity profiles. Typically, the CFD predictions matched well the experimental results. The power dissipated by the impeller in Apparatus 2 was experimentally measured using a frictionless system coupled with torque measurement. CFD was additionally used to predict the power consumption, using two different approaches, one based on the integration of the local value of the energy dissipation rate, and the other based on the prediction of the pressure distribution on the impeller blade, from which the torque and the power required to rotate the impeller were predicted. The agreement between the experimental data and both types of numerical predictions was found to be quite satisfactory in most cases. The results were expressed in terms of the non- dimensional Power number, Po, which was typically found to be on the order of ~0.3. The power number was observed to decrease very gradually with increasing agitation speeds. The results of this work and of previous work with the standard USP Apparatus 2 confirm that this apparatus is very sensitive to the location of the tablet, which is typically not controlled in a typical test since the tablet is dropped into the vessel at the beginning of the test and it may rest at random locations on the vessel bottom. Therefore, in this work a modified USP Dissolution Testing Apparatus 2, in which the impeller was placed 8-mm off-center in the vessel, was designed and tested. This design eliminates the poorly mixed inner core region below the impeller observed in the standard Apparatus 2 vessel. Dissolution tests were conducted with the Modified Apparatus for different tablet locations using both disintegrating calibrator tablets (Prednisone) and non-disintegrating calibrator tablets (Salicylic Acid). The experimental data clearly showed that all dissolution profiles in the Modified Apparatus were not affected by the tablet location at the bottom of the vessel. This design can effectively eliminate artifacts generated by having the tablet settle randomly at different locations on the vessel bottom after dropping it at the beginning of a dissolution testing experiment. The hydrodynamic and mixing characteristics of the modified Apparatus 2 were studied in some detail by experimentally measuring and computationally predicting the velocity distribution, power dissipation, and mixing time in the modified system. The velocity profiles near the bottom of the vessel were found to be significantly more uniform than in the standard Apparatus 2, because of the elimination of the poorly mixed zone below the impeller. The power dissipation in the modified Apparatus 2 was typically higher than in the standard system, as expected for an non-symmetrical system, and the corresponding Power number, Po, was less dependent on Reynolds number than Po in the standard system. Finally, the mixing time in the modified system, as experimentally measured by using a decolorization method and computationally predicted through CFD simulation, was found to be shorter in the modified Apparatus 2 by 7.7 %-12.9 % as compared to Apparatus 2. It can be concluded that the modified Apparatus 2 is a more robust testing apparatus, which is capable of producing dissolution profiles that are less sensitive to small geometric factors that play a major role in the standard USP Apparatus 2

Modelling drug coatings: A parallel cellular automata model of ethylcellulose-coated microspheres

Pharmaceutical companies today face a growing demand for more complex drug designs. In the past few decades, a number of probabilistic models have been developed, with the aim of improving insight on microscopic features of these complex designs. Of particular interest are models of controlled release systems, which can provide tools to study targeted dose delivery. Controlled release is achieved by using polymers with different dissolution characteristics. We present here an approach for parallelising a large-scale model of a drug delivery system based on Monte Carlo methods, as a framework for Cellular Automata mobility. The model simulates drug release in the gastro-intestinal tract, from coated ethylcellulose microspheres. The objective is high performance simulation of coated drugs for targeted delivery. The overall aim is to understand the importance of various molecular effects with respect to system evolution over time. Important underlying mechanisms of the process, such as erosion and diffusion, are described

Hydrodynamics investigation of in-vitro dissolution testing

Dissolution testing is routinely carried out in the pharmaceutical industry to determine dissolution rate of solid dosage forms. The United States Pharmacopoeia (USP) Dissolution Apparatus II is the device most commonly used for this purpose. Despite its widespread use, dissolution testing remains susceptible to significant error and test failures. Limited information is available on the hydrodynamics of this apparatus, although hydrodynamic effects can play a major role on test performance. Laser-Doppler Velocimetry (LDV) and Computational Fluid Dynamics (CFD) were used here to experimentally map and computationally predict the velocity distribution inside a standard USP Apparatus II under the typical operating conditions mandated by the dissolution test procedure. The flow in the apparatus is strongly dominated by the tangential component of the velocity, but a low recirculation zone exists in the lower part of the hemispherical vessel bottom where the tablet dissolution process takes place. The velocities in this region change significantly over short distances along the vessel bottom, implying that small variations in the location of the tablet on the vessel bottom caused by the randomness of the tablet descent through the liquid result in significantly different velocities and velocity gradients near the tablet. CFD was also used to study the hydrodynamics when the impeller was placed at four different locations, all within the limits specified by USP. Small changes in impeller location, especially off-center, produced extensive changes in the velocity profiles and shear rates. The blend time to homogenize the liquid content was also obtained for a number of operating conditions using different experimental methods, a CFD-based computational approach, and a semi-theoretical model. Excellent agreement between data and predictions was obtained. The CFD results show that blend time is inversely proportional to the agitation speed, and that blend time is some two orders of magnitude smaller than the time typically required for appreciable tablet dissolution during the typical dissolution test, implying that the contents of this device can be considered to be well mixed during the typical test. Finally, dissolution tests with prednisone and salicylic acid tablets were conducted, in which the tablets were placed at different locations in the dissolution vessel in order to study the effect of local hydrodynamics on dissolution. The results show that tablet location has a major effect, and that statistically significant differences exist in the dissolution profiles between centrally located tablets and tablets positioned off-center, at it is often the case during testing. The dissolution process was modeled using an approach based on the use of experimentally determined mass transfer coefficients, mass transfer coefficient equations, CFD-predicted velocity profiles, and mass balances. The results can satisfactorily predict the data. The hydrodynamics of dissolution testing depends strongly on small differences in equipment configurations and operating conditions, which can have a profound effect on the flow field and shear rate experienced by the oral dosage form being tested, and hence the solid-liquid mass transfer and dissolution rate

An Analysis of Drug Dissolution in Vivo

The testing of drug dissolution rates from solid dosage forms is a very important area of research within the pharmaceutical industry. The ability to produce drugs with a given dissolution rate will lead to improved performance in the treatment of patients and will be of economic benefit to the pharmaceutical industry. However, dissolution testing in laboratories, aimed at reflecting in-vivo conditions, can be both time consuming and costly. Currently, most simulations of drug dissolution take place in standardized USP (United States Pharmaceutical) apparatuses. A number of these apparatuses exist, and it is the aim of this thesis to analyse drug dissolution in both the USP Paddle Apparatus and the USP Flow Through Apparatus. The first part of this thesis examines drug dissolution from a solid dosage form (compact) in the USP Paddle Apparatus. The process is set up as a boundary layer problem for which there exists both a momentum boundary layer and a concentration boundary layer. The dominant mass transfer mechanism is that of forced convection. A semi-analytical technique is used to solve the boundary layer equations for which velocity data has been provided from computational fluid dynamic simulations. Wherever possible the results from this semi-analytical approach have been compared with that of an exact solution. The second part of the thesis concentrates on the USP Flow Through Apparatus. As the process of drug dissolution in the Flow Through Apparatus is dependent on a vertical flow, the analysis is complicated by the introduction of buoyancy effects. Chapters five to nine analyse a number of general cases for buoyancy driven flows on both flat and curved surfaces. Later, in chapter ten, these general cases are then applied to the process of drug dissolution from the surface of a compact in the USP Flow Through Apparatus. Throughout the thesis, the predicted dissolution rates from the theoretical approach are compared with those of experiment

Hydrodynamics, dissolution, and mass transfer effects in different dissolution testing apparatuses and laboratory systems

Dissolution testing apparatuses and shaker flasks agitated by shaker tables are laboratory systems routinely found in many laboratories at most companies and agencies, and especially in pharmaceutical companies. These devices are commonly used in a number of applications, from drug development to quality control. Despite their common use, these systems have not been fully investigated from an engineering perspective in order to understand their operation characteristics. For example, the hydrodynamics of many of these systems have received little attention until relatively recently, and only over the last few years have some of these systems, such as the USP dissolution testing Apparatus 2, been studied in greater detail by a few research groups, including our group at NJIT. Meanwhile, a number of modifications have been introduced in industry to simplify the practical use of these devices and to automate many of the processes in which they are utilized. This, in turn, has resulted in the introduction of variability in the way these devices are operated, with possible implication for the results that they generate in laboratory experiments and tests. Therefore, this work was aimed at studying some of these devices in order to quantify how such systems operate and what the implications for their use in the laboratory are. More specifically, the systems that were examined here included the USP Dissolution Testing Apparatus 2 with and without automatic sampling probes, dissolution testing mini vessel apparatuses, and baffled shaker flasks. In order to study all these phenomena, a number of tools were used, including Particle Image Velocimetry (PIV) and Computational Fluid Dynamics (CFD) to investigated the hydrodynamics of these systems; experimental tablet dissolutions under a number of controlled environments; and a combination of experimental, computational and modeling approaches to study mass transfer and solid suspension effects. The issues that were investigated depended on the specific apparatus. For the case of the USP Dissolution Testing Apparatus 2, the effects of the presence of different probes on the hydrodynamics in the dissolution vessel and on the dissolution profiles using solid dosage forms were investigated in this work. The results indicate that in most cases, the presence of the probe resulted in statistically significant increases in the dissolution curves with respect to the curves obtained without the probe, and that tablets at, or close to, the center of the vessel were more significantly affected by the presence of the probe, and so were tablets located immediately downstream of the probe. The hydrodynamic effects generated by the arch-shaped fiber optic probe were small but clearly measurable. The changes in velocity profiles in the dissolution vessel resulted in detectable differences in the dissolution profiles, although not high enough to cause test failures. However, these differences could contribute to amplify the difference in dissolution profiles in those cases in which tablet has an intrinsically higher release rate. In addition, the minimum agitation speed, Njs, to achieve particle suspension was investigated. A novel method to determine Njs was first developed and then applied to determine Njs as a function of different operating variables. Similarly, the hydrodynamics of smaller dissolution apparatuses termed “minivessels” were studied here and compared with the standard USP 2 system. The flow pattern in minivessels was obtained by both CFD simulations and PIV velocity measurements for four different agitation speeds in the mini vessel, and it was shown to result in flow patterns qualitatively similar to those in the standard USP 2 system. The velocity profiles were also compared on several iso-surfaces for the mini vessel system and the standard system, showing difference between two systems. In the most important zone, i.e., the inner core zone at the vessel bottom, the velocities were similar on the lowest iso-surface, especially for the axial velocity at 100rpm and 125rpm in the mini vessel compared with 100rpm in the 900mL USP 2 system. This was not clearly the case for iso-surfaces above the bottom zone. Finally, the hydrodynamics of baffled shaker flask was investigated. These baffled “trypsinizing” flasks are similar to the typical Erlenmeyer-type conical shaker flasks commonly used in biological laboratories but with a major difference, in that they are provided with vertical indentations in the glass flask so as to create vertical baffles that promote better mixing when shaken. Measurements of the velocity in the flask were obtained using PIV for seven rotation speeds of 100, 125, 150, 160, 170, 200, and 250 rpm. Two vertical cross sections were measured to obtain the velocity profiles in the flask: the one with largest diameter of the flask, and the one with the smallest diameter. The 1D energy spectra indicate nearly isotropic flow in the BF for all rotation speeds and the existence of inertial subrange, which validate the use of dimensional argument analysis for the estimation of energy dissipation rate. The results obtained in this work will contribute to increase our understanding of the performance of a number of very common and important laboratory apparatus thus contributing to a more appropriate use of all these devices in both industry and federal and state agencies

In vitro and in silico Dissolution and Permeation Assessment

New chemical entities (NCEs) under development tend to be progressively more poorly water soluble. As conventional dissolution tests are not representative of in vivo conditions and thus not predictive of its in vivo behavior, formulation of these orally administered drug products is often compromised. The design of a biorelevant dissolution method reflects the physiological conditions in the gastrointestinal (GI) tract, possessing a biological discriminative power given e.g. by the increased solubilization of drug molecules by bile salts and lecithin, which is of significant importance when evaluating the dissolution behavior of poorly soluble drugs. Moreover, there has been an increasing trend in the pharmaceutical industry to use mechanistic models to complement in vitro data that are an inexpensive and fast way of assisting the formulation process. The present work aims at using a biorelevant dissolution methodology to support drug product development, employing USP Apparatus 2 and different formulations (enteric and nonenteric polymers, different binders and granule sizes) of tablets of spray dried dispersions (SDDs) of Itraconazole (ITZ), a poorly water-soluble drug. SDDs, tablets and the reference commercial product dissolution were assessed in biorelevant media and a biorelevant pH shift was performed. Also, an attempt was made to simultaneously evaluate dissolution and in vitro permeation of ITZ, using the reverse dialysis membrane methodology. Finally, an in silico model describing dissolution phenomena of amorphous active pharmaceutical compounds (APIs) was developed. Crystalline ITZ solubility in biorelevant media could not be assessed, since it was below the limit of quantification of the employed method. SDDs could not be properly tested in USP Apparatus 2 due to the characteristic poor wettability of these powders, that led to powder floating. The potential for higher bioavailability of solid oral ITZ through intestinal targeting was demonstrated via pH shift. It was not possible to quantify the molecularly dissolved ITZ through reverse dialysis method, which lacks further development and optimization. The obtained results show that the compendial dissolution methodology is not enough to evaluate poorly-soluble dosage forms performance because they can often lead to a sub or over estimation of its solubility

Particle diffusional layer thickness in a USP dissolution apparatus II: A combined function of particle size and paddle speed

This work was to investigate the effects of particle size and paddle speed on the particle diffuisonal layer thickness h app in a USP dissolution apparatus II. After the determination of the powder dissolution rates of five size fractions of fenofibrate, including <20, 20–32, 32–45, 63–75, and 90–106 µm, the present work shows that the dependence of h app on particle size follows different functions in accordance with the paddle speed. At 50 rpm, the function of h app is best described by a linear plot of $h_{{rm app}} = 9.91sqrt d - 23.31$ ( R 2  = 0.98) throughout the particle diameter, d , from 6.8 to 106 µm. In contrast, at 100 rpm a transitional particle radius, r , of 23.7 µm exists, under which linear relationship h app  = 1.59 r ( R 2  = 0.98) occurs, but above which h app becomes a constant of 43.5 µm. Thus, h app changes not only with particle size, but also with the hydrodynamics under standard USP configurations, which has been overlooked in the past. Further, the effects of particle size and paddle speed on h app were combined using dimensionless analysis. Within certain fluid velocity/particle regime, linear correlation of h app / d with the square-root of Reynolds number $(dvarpi /upsilon )^{1/2}$ , that is, $h_{{rm app}} /d = 1.5207 - 9.25 times 10^{ - 4} (dvarpi /nu )^{1/2}$ ( R 2  = 0.9875), was observed. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:4815–4829, 2008Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/61209/1/21345_ftp.pd