Impact of Select Geometric and Operational Parameters on Hydrodynamics in Dissolution Apparatus 2 (Paddle Apparatus): A Design of Experiments Analysis Based on Computational Fluid Dynamics Simulations.

PURPOSE: A Design of Experiments (DOE) analysis driven by Computational Fluid Dynamics (CFD) simulations was used to evaluate individual and two-factor interaction effects of varying select geometric and operational parameters on the hydrodynamics in dissolution apparatus 2 (paddle apparatus). METHODS: Simulations were run with meshing controls and solution strategies retained from a mesh-independent validated baseline model. Distance between vessel and impeller bottom surfaces, impeller offset, vessel radius and impeller rotation speed were considered as input parameters. The velocity magnitudes at four locations near the vessel bottom surface were considered as output parameters. Response surfaces and Pareto charts were generated to understand individual and two-factor interaction effects of input parameters on the output parameters. RESULTS: Impeller offset has a dominating influence of a linear and quadratic nature on the output parameters and affects overall hydrodynamics. Changes to other input parameters have limited influence on velocity magnitudes at locations closest to the vessel axis and on overall hydrodynamics. However, these parameters have important influences of varying degrees on velocity magnitudes at locations away from the vessel axis. CONCLUSIONS: The hydrodynamics in Apparatus 2 is influenced differently by different parameters and their combinations. Impeller offset has a stronger influence when compared to parameters that do not alter apparatus symmetry.

Dissolution Testing in Drug Product Development: Workshop Summary Report.

This publication summarizes the proceedings and key outcomes of the first day ("Day 1") of the 3-day workshop on "Dissolution and Translational Modeling Strategies Enabling Patient-Centric Product Development." The overall aims of the workshop were to foster a productive dialog between industry and regulatory agencies and to discuss current strategies toward the development and implementation of clinically relevant dissolution specifications as an integral part of enhanced drug product understanding and effective drug product life-cycle management. The Day 1 podium presentations covered existing challenges and concerns for implementing highly valuable, yet often unique and novel experimental dissolution setups as quality control tools. In addition, several podium presentations highlighted opportunities to replace conventional dissolution testing with surrogate test methods to enable robust drug product and process understanding within the context of quality by design (QbD), new manufacturing technologies, and real-time release testing (RTRT). The topics covered on Day 1 laid the foundation for subsequent discussions which focused on the challenges related to establishing an in vitro-in vivo link and approaches for establishing clinically relevant drug product specifications which are becoming an expectation in regulatory submissions. Clarification of dissolution-related terminology used inconsistently among the scientific community, and the purpose of various testing approaches were key discussion topics of the Day 1 breakout sessions. The outcome of these discussions along with creative ways to overcome challenges related to bridging "exploratory dissolution approaches" with methods suitable for end-product control testing are captured within this report.

Evolution of Choice of Solubility and Dissolution Media After Two Decades of Biopharmaceutical Classification System.

The introduction of the biopharmaceutics drug classification system (Biopharmaceutics Classification System (BCS)), in 1995, provided a simple way to describe the biopharmaceutics behavior of a drug. Solubility and permeability are among the major parameters, which determine the fraction dose absorbed of a drug substance and consequently its chances to be bioavailable. The purpose of this review is to summarize the evolution of the media used for determining solubility and dissolution and how this can be used in modern drug development. Over the years, physiologically adapted media and buffers were introduced with the intention to better predict the in vivo solubility and dissolution of drug substances. Water, buffer solutions, compendial media, micellar solubilization media, and biorelevant media are reviewed. At this time point, there is no universal medium available which can be used to predict every drug substance's solubility or a drug product's in vivo dissolution behavior. However, there have been many improvements and additions made to media to optimize their in vivo predictability; for example, the current phosphate concentrations in buffers seem to be too high to correlate with the carbonate buffer concentrations in vivo. Biorelevant media were updated to correlate them better with the composition of human intestinal fluids. The BCS was introduced into regulatory sciences as a scientific risk management tool to waive bioequivalence studies under certain conditions. Today's different guidance documents define the dose-solubility ratio differently. As shown for amoxicillin, this can cause more confusion than certainty for globally operating companies. Harmonization of BCS guidelines is highly desirable.

Velocity Field Visualization in USP Dissolution Apparatus 3 Using Particle Image Velocimetry.

PURPOSE: The hydrodynamics in USP dissolution apparatus 3, at five different dip rates, was characterized by analyzing phase-averaged velocity fields obtained using Particle Image Velocimetry (PIV). METHODS: Phase locked 2 Component-PIV (2C-PIV) measurements were recorded on a typical dissolution apparatus 3 configuration with a black painted tablet fixed at the center of the bottom porous screen of the reciprocating cylinder. A trigger mechanism was employed to capture data over 12 phase positions for each reciprocation cycle. Data were captured over a fixed number of cycles, based on dip rate, and the resultant images were post-processed to obtain phase-averaged velocity fields at each phase. RESULTS: For all dip rates studied, the sinusoidal nature of the cylinder's reciprocating motion was evident in the images. The phase positions, in which the cylinder was completely submerged, were characterized by recirculation of liquid through the cylinder, top fitting cap, vessel-cylinder annulus, and bottom fitting cap. The direction of recirculation was opposite for phase positions during the up- and downstrokes. The end positions of the up- and downstrokes were characterized by vortices below and above the cylinder respectively. Increasing dip rates led mainly to increasing velocity magnitudes while all flow characteristics, in general, were retained. CONCLUSIONS: The hydrodynamics in typical USP dissolution apparatus 3 is characterized by cyclic phase-dependent flow fields. Specifically, the velocity field distribution within dissolution apparatus 3 is greatly influenced by the relative position of the top cap to the liquid level in the cylinder.

Effect of Four Commonly Used Dissolution Media Surfactants on Pancreatin Proteolytic Activity.

Proteolytic enzymes are often used in dissolution testing of cross-linked gelatin capsules that do not conform to the dissolution specification. Their catalytic activity, however, can be affected when they are added to a dissolution media containing solubility enhancers, such as surfactants. The aim of this study was to assess the activity of pancreatic proteases in presence of four commonly used surfactants. We found that pancreatin exhibits remarkable proteolytic activity in the presence of Tween 80, even at the concentrations as high as 250 times its critical micelle concentration (cmc) in water, whereas, Triton X-100 enhanced the proteolytic activity of pancreatin when added at concentrations above its cmc in water. Both surfactants are non-ionic surfactants. On the other hand, sodium dodecyl sulfate (SDS) and cetyltrimethylammonium bromide (CTAB), which are ionic surfactants, have a detrimental effect on the proteolytic activity of pancreatin. For example, a 50% reduction of the pancreatin activity was found in samples which contain a minor amount of SDS (0.05% w/v) in comparison to a surfactant-free reaction. Additionally, no activity was observed for the pancreatin-SDS samples which were incubated for 30 min at 40°C prior to testing. CTAB had an impact on pancreatin activity at concentrations higher than its cmc. Data from this manuscript can be used as a benchmark for optimization of the dissolution procedures that require use of both surfactants and enzymes.

Enzymatic activity in the presence of surfactants commonly used in dissolution media, Part 1: Pepsin.

The United States Pharmacopeia (USP) General Chapters Dissolution 〈711〉 and Disintegration and Dissolution of Dietary Supplements 〈2040〉 allows the use of enzymes in dissolution media when gelatin capsules do not conform to dissolution specifications due to cross linking. Possible interactions between enzymes and surfactants when used together in dissolution media could result in loss of the enzymatic activity. Pepsin is an enzyme commonly used in dissolution media, and in this work, the activity of pepsin was determined in the presence of different surfactants as usually found in case of dissolution tests of certain gelatin capsule formulations. Pepsin enzymatic activity was determined according to the Ninth Edition of the Food Chemicals Codex (FCC) 9 method, in dissolution conditions: simulated gastric fluid, 37 °C and 50 rpm. Sodium dodecyl sulfate (SDS), cetyltrimethyl ammonium bromide (CTAB), polysorbate 80 (Tween 80) and octoxynol 9 (Triton X100) in concentrations above and below their critical micellar concentrations were selected. Results showed a significant reduction in the activity of pepsin at all the concentrations of SDS assayed. On the contrary, CTAB, Tween 80, and Triton X100 did not alter the enzymatic activity at of pepsin any of the concentration assayed. This data demonstrates a rational selection of the surfactant to be used when pepsin is required in dissolution test.

The Effect of Excipients on the Permeability of BCS Class III Compounds and Implications for Biowaivers.

PURPOSE: Currently, the FDA allows biowaivers for Class I (high solubility and high permeability) and Class III (high solubility and low permeability) compounds of the Biopharmaceutics Classification System (BCS). Scientific evidence should be provided to support biowaivers for BCS Class I and Class III (high solubility and low permeability) compounds. METHODS: Data on the effects of excipients on drug permeability are needed to demonstrate that commonly used excipients do not affect the permeability of BCS Class III compounds, which would support the application of biowaivers to Class III compounds. This study was designed to generate such data by assessing the permeability of four BCS Class III compounds and one Class I compound in the presence and absence of five commonly used excipients. RESULTS: The permeability of each of the compounds was assessed, at three to five concentrations, with each excipient in two different models: Caco-2 cell monolayers, and in situ rat intestinal perfusion. No substantial increases in the permeability of any of the compounds were observed in the presence of any of the tested excipients in either of the models, with the exception of disruption of Caco-2 cell monolayer integrity by sodium lauryl sulfate at 0.1 mg/ml and higher. CONCLUSION: The results suggest that the absorption of these four BCS Class III compounds would not be greatly affected by the tested excipients. This may have implications in supporting biowaivers for BCS Class III compounds in general.

Computational fluid dynamics simulation of hydrodynamics in USP apparatus 3-the influence of dip rate.

PURPOSE: This study investigated the influence of dip rate on USP Apparatus 3 hydrodynamics in the presence of a solid dosage form (e.g. tablet) using Computational Fluid Dynamics (CFD) simulations. The primary variables of interest were the liquid phase velocity in the computational domain and wall shear stresses on the tablet surfaces. METHODS: Geometry building and model setup were based on a number of simplifying assumptions. Computational grid-independent solutions were achieved for dip rates ranging from 5 to 10 dips per minute (dpm). RESULTS: For all cases studied, the hydrodynamics exhibited a periodicity dictated by the dip rate. Cycle-to-cycle variations were found to be negligible. Higher velocities were predicted in the wake of the tablet and they peaked at midway positions both during the up- and downstrokes of the cylinder. Three sub-regions of velocity were identified inside the reciprocating cylinder. Results also showed localized vortices/recirculations specific to the up- and downstroke, in addition to local stagnation zones. The wall shear stresses and velocity magnitudes scaled proportionately with increasing dip rates while exhibiting qualitatively similar behavior in their spatial and temporal distributions. CONCLUSIONS: Based on the predictions of the 2D axisymmetric CFD model, the hydrodynamics in USP Apparatus 3 is characterized by complex and periodic flow structures.

Toward global standards for comparator pharmaceutical products: case studies of amoxicillin, metronidazole, and zidovudine in the Americas.

This study compared in vitro dissolution characteristics and other quality measures of different amoxicillin, metronidazole, and zidovudine products purchased in the Americas to a comparator pharmaceutical product (CPP). These three drugs are classified as Biopharmaceutics Classification System Class I drugs with the possibility that dissolution findings might be used to document bioequivalence. All investigated zidovudine products were found to be in vitro equivalent to the CPP. Only 3 of 12 tested amoxicillin products were found to be in vitro equivalent to the CPP. None of the tested metronidazole products were in vitro equivalent to the CPP. These findings suggest but do not confirm bioinequivalence where in vitro comparisons failed, given that an in vivo blood level study might have confirmed bioequivalence. At times, identifying a CPP in one of the selected markets proved difficult. The study demonstrates that products sold across national markets may not be bioequivalent. When coupled with the challenge of identifying a CPP in different countries, the results of this study suggest the value of an international CPP as well as increased use of BCS approaches as means of either documenting bioequivalence or signaling the need for further in vivo studies. Because of increased movement of medicines across national borders, practitioners and patients would benefit from these approaches.

Development of a performance verification test for USP apparatus 4.

PURPOSE: To evaluate salicylic acid tablets as a candidate reference material in a Performance Verification Test (PVT) when a USP performance test for dissolution (General Chapter <711>) relies on USP Apparatus 4 (flow-through cell). METHODS: We developed a dissolution procedure relying on Apparatus 4 and salicylic acid tablets. Thereafter, a designed experiment was conducted to identify operational variables that significantly affect salicylic acid dissolution in this apparatus. RESULTS: Four variables (size of glass beads, cell temperature, flow rate, level of deaeration) and one combination effect (deaeration/bead size) were significant for mean percent dissolved. Two variables (tablet orientation, level of deaeration) were significant for standard deviation results, but these effects were less pronounced than those for mean percent dissolved results. Three variables (analyst, tester manufacturer, amount of glass beads) had no statistically significant effects on either the mean or standard deviation of the responses. CONCLUSIONS: The proposed PVT is capable of probing effects of changes in several critical operational parameters of Apparatus 4. Salicylic acid tablets were shown to be a suitable reference material for the PVT. The PVT using salicylic acid tablets satisfies important aspects of a PVT.

Validation of USP apparatus 4 method for microsphere in vitro release testing using Risperdal Consta.

The current manuscript addresses the need for a validated in vitro release testing method for controlled release parenteral microspheres. A USP apparatus 4 method was validated with the objective of possible compendial adaptation for microsphere in vitro release testing. Commercial microspheres (Risperdal Consta) were used for method validation. Accelerated and real-time release tests were conducted. The accelerated method had significantly reduced test duration and showed a good correlation with the real-time release profile (with limited number of sample analysis). Accelerated conditions were used for method validation (robustness and reproducibility). The robustness testing results revealed that release from the microspheres was not flow rate dependent and was not affected by minor variations in the method (such as cell preparation technique, amount of microspheres, flow-through cell size and size of glass beads). The significant difference in the release profile with small variations (± 0.5°C) in temperature was shown to be due to a change in risperidone catalyzed PLGA degradation in response to temperature. The accelerated method was reproducible as changing the system/equipment or the analyst did not affect the release profile. This work establishes the suitability of the modified USP apparatus 4 for possible compendial adaptation for drug release testing of microspheres.

Establishing new acceptance limits for dissolution performance verification of USPC apparatus 1 and 2 using USPC prednisone tablets reference standard.

PURPOSE: On 1 March 2010, the US Pharmacopeial Convention released into commerce Lot P1I300 of its Prednisone Tablets Reference Standard for use in periodic performance verification testing (PVT) of dissolution Apparatus 1 and 2. This report presents the collaborative study data, development of the acceptance limits, and results from supporting work for this Lot. METHODS: The collaborative study involved 25 collaborators who provided data for Apparatus 1 and 31 who provided data for Apparatus 2. These limits are for the geometric mean and percent coefficient of variation (%CV) instead of per-individual results as for prior lots. Stability of results and sensitivity to test performance parameters were also studied. RESULTS: To determine new PVT acceptance limits, the authors calculated geometric mean and variance components as percent coefficient of variation. The move to the geometric mean and %CV criteria brings the acceptance criteria in line with current accepted statistics and provides a more realistic assessment of the system's performance. Results for Apparatus 1 are stable over time, but for Apparatus 2, the mean decreases over time. Acceptance criteria are adjusted for this trend. Lot P1 demonstrates sensitivity to test performance parameters (vessels and degassing). CONCLUSIONS: Apparatus 1 results are stable over time. Those in Apparatus 2 show a decrease over time in the geometric mean but show no trend in variability. The current tablets are shown to remain sensitive to two operational parameters, degassing and vessel dimensions, not covered by mechanical calibration. The new acceptance limits for Lot P1 are based on geometric mean and %CV for Prednisone Tablets Reference Standard Lot P1I300. The limits better control variability than the prior per-individual-result limits.

Development and validation of a dissolution test method for vitamin A in dietary supplement tablets.

A dissolution test method and an analytical procedure by HPLC were developed and validated for evaluation of the dissolution behavior of dietary supplements tablets containing vitamin A in the forms of retinyl acetate or retinyl palmitate. Seven different commercially available products containing retinyl acetate or retinyl palmitate were selected for this study. A dissolution medium containing 1% (w/v) Octoxynol 9 (Triton X-100) and 1% (w/v) (+)-sodium alpha-ascorbate in 0.05 M phosphate buffer, pH 6.8, was found suitable to ensure sink conditions and chemical stability for both retinyl acetate and retinyl palmitate. Two rotation speeds, 50 and 75 rpm, were evaluated with USP Apparatus 2 and 900 ml dissolution medium. Dissolution profiles were generated over 120 min. Dissolution samples were analyzed with a reversed-phase HPLC method with UV detection at 325 nm. Each product was also assayed for vitamin A content according to USP 32-NF 27. The results from 45 min to the last time point of the dissolution tests performed at 75 rpm were consistent with the Assay results. The dissolution test described here could be proposed as a pharmacopeial standard to assess the performance of tablet formulations containing vitamin A as retinyl esters.

Change in criteria for USP dissolution performance verification tests.

The US Pharmacopeial Convention has been evaluating its performance verification tests (PVT) for several years. These tests help ensure the integrity of the US Pharmacopeia performance test when a dissolution procedure, as described in General Chapter Dissolution <711>, is relied upon to test a nonsolution orally administered dosage form. One result of the evaluation is a change in the PVT criterion from one based on individual tablet results to one based on the mean and variability of a set of tablets. This paper describes the new PVT and its criterion and how its acceptance limits are derived from results of a collaborative study, explains a two-stage option for the test, and presents operating characteristics.

The USP Performance Verification Test, Part I: USP Lot P Prednisone Tablets: quality attributes and experimental variables contributing to dissolution variance.

PURPOSE: Beyond instrumental qualification, proficiency testing is not usually a prerequisite for many analytical procedures, given reliance on a manufacturer's assay validation coupled with regulatory review and inspection. Given the special features of the dissolution procedure, proficiency testing was put in place initially by pharmaceutical manufacturers and carried on by USP. Proficiency testing is designed to help ensure that execution of a dissolution procedure for solid oral dosage forms adequately supports administrative and legal decisions so that measurements made at different times, by different analysts, or with different methods can be confidently compared. USP has applied metrological principles to aid practitioners in carrying out the dissolution procedure alone and in collaborative studies to facilitate understanding potential sources of variability. MATERIALS AND METHODS: The present study aimed to identify key dissolution variables associated with USP Lot P Prednisone Tablets in conjunction with the USP Performance Verification Test (PVT). Using five dissolution test assemblies from different manufacturers, at least four of six analysts determined percents prednisone dissolved on dissolution Apparatus 1 (basket) and Apparatus 2 (paddle) on each assembly. Six replicate experiments were performed on each analyst-assembly combination with a set of six to eight tablets in each experiment. RESULTS AND CONCLUSIONS: Statistical analysis demonstrated that dissolution test assemblies were the largest factor contributing to dissolution variability. Inherent tablet variability was low, and USP Lot P Prednisone Tablets did not contribute importantly to dissolution variability. Contributions from analyst and analytical procedure also were estimated to be low.

Dissolution media simulating the intralumenal composition of the small intestine: physiological issues and practical aspects.

The objective of this study was to test various aspects of dissolution media simulating the intralumenal composition of the small intestine, including the suitability of the osmolality-adjusting agents and of the buffers, the substitution of crude sodium taurocholate (from ox bile) for pure sodium taurocholate and the substitution of partially hydrolysed soybean phosphatidylcholine for egg phosphatidylcholine. It was concluded that biorelevant media should contain sodium as the major cation species to better reflect the physiology. However, the use of non-physiologically relevant buffers is inevitable, especially for simulation of the fed state in the small intestine. The buffers used may affect the solubility product of weakly basic compounds with pK(a)(s) higher than about 5, the solubility of extremely highly lipophilic compounds due to salting in/out properties of the anion of the buffer and the stability of the dissolving compound. It is prudent in relevant situations to run an additional dissolution test in a modified fed state simulated intestinal fluid (FeSSIF) (or fasted state simulated intestinal fluid (FaSSIF), where applicable) containing alternative buffer species. Although a mixture of bile salts is physiologically more relevant than pure sodium taurocholate, this issue seems to be of practical importance in only a few cases. Adequate simulations in these cases will probably require the use of a number of pure substances and could substantially increase the cost of the test. Finally, unless the drug is extremely lipophilic (ca. logP> 5), egg phosphatidylcholine can be substituted by partially hydrolysed soybean phosphatidylcholine.