Dissolution Test System Research Articles

Validation and Demonstration of an Atmosphere-Temperature-pH-Controlled Stirred Batch Reactor System for Determination of (Nano)Material Solubility and Dissolution Kinetics in Physiological Simulant Lung Fluids.

In this study, we present a dissolution test system that allows for the testing of dissolution of nano- and micrometer size materials under highly controlled atmospheric composition (O2 and CO2), temperature, and pH. The system enables dissolution testing in physiological simulant fluids (here low-calcium Gamble’s solution and phagolysosomal simulant fluid) and derivation of the temporal dissolution rates and reactivity of test materials. The system was validated considering the initial dissolution rates and dissolution profiles using eight different materials (γ-Al2O3, TiO2 (NM-104 coated with Al2O3 and glycerin), ZnO (NM-110 and NM-113, uncoated; and NM-111 coated with triethoxycaprylsilane), SiO2 (NM-200—synthetic amorphous silica), CeO2 (NM-212), and bentonite (NM-600) showing high intra-laboratory repeatability and robustness across repeated testing (I, II, and III) in triplicate (replicate 1, 2, and 3) in low-calcium Gamble’s solution. A two-way repeated-measures ANOVA was used to determine the intra-laboratory repeatability in low-calcium Gamble’s solution, where Al2O3 (p = 0.5277), ZnO (NM-110, p = 0.6578), ZnO (NM-111, p = 0.0627), and ZnO (NM-113, p = 0.4210) showed statistical identical repeatability across repeated testing (I, II, and III). The dissolution of the materials was also tested in phagolysosomal simulant fluid to demonstrate the applicability of the ATempH SBR system in other physiological fluids. We further show the uncertainty levels at which dissolution can be determined using the ATempH SBR system.

Establishment of a Dissolution Test System for the Biorelevant Characterization of Esophageal Applied Dosage Forms

There is a high demand for drug delivery systems that enable local therapy of esophageal diseases such as eosinophilic esophagitis. For the development of such drug delivery systems, suitable in vitro test procedures are needed that allow a biorelevant characterization of dosage forms. With the help of the new test system presented in this thesis it is now possible to simulate the application site esophagus and to characterize the dissolution behavior of esophageal applied drug delivery systems under special consideration of physiological parameters like salivary flow rate, intensity of peristalsis, and posture of the patient. In this work, the dissolution of mucoadhesive films for esophageal application with the new device was investigated and compared to the results obtained with the compendial standard device (USP 2 apparatus). The results show that the novel test system is a promising tool for the early evaluation of locally applied oral formulations for esophageal application.

Prediction of Negative Food‐Effect on Drug Bioavailability by Mechanistic Biopharmaceutics Classification System (mBCS)‐guided Physiologically‐based Pharmacokinetic modeling

Food can influence drug bioavailability by altering gut physiology and microenvironment. Conventional approaches such as dissolution testing and biopharmaceutics classification system (BCS) often fail to predict food effect on drug bioavailability. To address this, we proposed a mechanistic BCS (mBCS) (Figure 1) based on analysing literature data. The mBCS first classifies drugs based on if their absorption is solubility‐limited (Class I) or permeability‐limited (Class II), which are sub‐grouped based on if the food effect is predictable (IA and IIA) or not predictable (IB, IC, IIB and IIC) using the dissolution testing (Figure 1A). Finally, mBCS allows identifying the mechanisms that lead to unpredictable food‐effect on drug bioavailability. Particularly, out of 288 drugs where the food‐effect data were reported, 105 drugs exhibited negative food effect. Further evaluation suggested that the primary reason for the unpredictable negative food effect is the interplay of intestinal efflux transport and delayed gastric emptying (Figure 1B). For example, amongst all drugs that showed negative food effect, majority (58%) were substrates of GI efflux transporters (e.g., maraviroc, afatinib, furosemide, ixazomib, asciminib, and omadacycline). We thus hypothesized that since gastric emptying time in fed state is higher (>2 h) as compared to the fasting state (15 min), drug co‐administration with food results in decreased concentration gradient across intestinal wall (lumen to blood), which eventually causes desaturation of GI efflux transporters. To test this hypothesis, we developed an mBCS‐guided physiologically based pharmacokinetic (PBPK) model in MATLAB (MathWorks, Natick, MA) by incorporating the regional protein abundance and saturation kinetics (Km and Vmax) of selected drugs (maraviroc, afatinib, and furosemide). The results from maraviroc PBPK modeling are presented below. The model was successful in predicting non‐linear PK within 2‐fold at varied dose ranges (e.g., 0.5, 0.61, 0.88, 1.17, 1.07 and 1.02 folds for 30, 100, 300, 600, 900 and 1200 mg, respectively for maraviroc) in the fasted state. The model successfully captured ~37% reduction in AUC in fed state at lower clinical doses of 100 and 300 mg of maraviroc. Similarly, consistent with the observed clinical data 1, the predicted magnitude of negative food effect was significantly lower (~22 and 18% reduction in AUC) at higher doses of 900 and 1200 mg, respectively. Parameter sensitivity analysis showed that gastric emptying time and kinetic parameters of P‐gp are important mechanisms that regulate non‐linear PK and food effect for maraviroc. Therefore, the proposed mBCS‐guided PBPK modeling approach can be used for prospective prediction of negative food effect, which can also be used to justify clinical trial waiver for the food effect studies.Support or Funding InformationDepartment of Pharmaceutical Sciences, Washington State University, SpokaneMechanistic biopharmaceutics classification system (mBCS) framework (A) and proposed mechanism of interplay between GI efflux and gastric emptying in fasting and fed states for mBCS class‐IIC drugs (B).Figure 1

In Vivo-Relevant Transwell Dish-Based Dissolution Testing for Orally Inhaled Corticosteroid Products.

To establish an in vivo-relevant Transwell dish-based dissolution test system for the "respirable" aerosols of inhaled corticosteroids (ICSs) using marketed inhaler products. "Respirable" ≤ 5.8 or 6.5μm aerosols of 7 ICSs from 11 inhaler products were collected onto the filter membranes under the modified assembly of the cascade impactor. Their dissolution in 10ml of the simulated lung lining fluid (sLLF) was determined over time in the Transwell dish at 37°C and ~100% relative humidity in the presence of subsequent diffusive permeation across the Transwell's supporting membrane. While three ICSs with high-to-intermediate solubility enabled the first-order "sink" and complete dissolution in 6h, 4 ICSs with poor solubility including fluticasone propionate (FP) resulted in the pseudo-zero-order "non-sink", slow and limited dissolution. The aerosol dissolution rate constants (kdiss) were derived, well-correlated with the solubility. For FP, but not for highly-soluble flunisolide (FN), dissolution was kinetically aerosol mass-dependent. However, for a given ICS, dissolution profiles were indistinguishable between the formulations and products upon comparable aerosol mass collection. The in vivo-relevant Transwell dish-based "respirable" aerosol dissolution test system was developed, kinetically discriminative in accordance with the ICS solubility, but indistinguishable for a given ICS between the marketed products.

Simple Strategy to Protect Lactase Activity in Solid Formulation.

Lactose intolerance is characterized by the absence of the enzyme lactase (beta-galactosidase) and affects two thirds of the world adult population. Our aim was to evaluate a lactase gastro-resistant formulation to ensure increased activity in the action site of the enzyme (lumen of the small intestine). Simultaneously, we also evaluated the commercial product stability and enzyme activity, because the product containing beta-galactosidase is classified as food supplement according to the Food and Drug Administration (FDA), so it is free to pass quality testing, efficacy and stability. So, it is possible that contain some irregularities as to the content and enzymatic activity. The dissolution assay was performed using a dissolution test system and commercial product and the gastro-resistant formulation were evaluated according to a method adapted to the conditions recommended by United States Pharmacopeia (US Pharmacopeia) for gastro-resistant formulations. For the assessment of enzymatic activity throughout the dissolution test was employed the official method of lactase assay described in US Pharmacopoeia. This method is based on a colorimetric reaction which the substrate reacts with the enzyme generate a colored product further analyzed by UVVisible spectrophotometry. When carrying out dissolution test in commercial product it is noted that the existing formulation is not able to protect the enzyme from degrading action of gastric environment (a loss of 86.0 ± 0.8% of lactase activity was observed). Our proposed gastro-resistant pharmaceutical form there was no loss of activity during the acid step and the end of the dissolution test the found activity was 95 ± 1.3%. The formulations proposed in this work using hypromellose capsules ensure the enzymatic activity of lactase, preventing its contact with the acid medium. For the other side, the results of commercial tablets for lactase release indicate a significant loss of enzyme activity due to the immediate release of the enzyme in the simulated gastric fluids.

Computational hydrodynamic comparison of a mini vessel and a USP 2 dissolution testing system to predict the dynamic operating conditions for similarity of dissolution performance

The hydrodynamic characteristics of a mini vessel and a USP 2 dissolution testing system were obtained and compared to predict the tablet-liquid mass transfer coefficient from velocity distributions near the tablet and establish the dynamic operating conditions under which dissolution in mini vessels could be conducted to generate concentration profiles similar to those in the USP 2. Velocity profiles were obtained experimentally using Particle Image Velocimetry (PIV). Computational Fluid Dynamics (CFD) was used to predict the velocity distribution and strain rate around a model tablet. A CFD-based mass transfer model was also developed. When plotted against strain rate, the predicted tablet-liquid mass transfer coefficient was found to be independent of the system where it was obtained, implying that a tablet would dissolve at the same rate in both systems provided that the concentration gradient between the tablet surface and the bulk is the same, the tablet surface area per unit liquid volume is identical, and the two systems are operated at the appropriate agitation speeds specified in this work. The results of this work will help dissolution scientists operate mini vessels so as to predict the dissolution profiles in the USP 2, especially during the early stages of drug development.

Monitoring Drug Release from Electrospun Fibers Using an In Situ Fiber-Optic System

Electrospun fiber mats are currently gaining attention as advanced drug delivery systems. Dissolution testing for such systems is generally performed in small vials by immersing the fiber mats in buffered solutions. Defined aliquots of dissolution medium are withdrawn at predefined time points, and the dissolved drug is quantified. However, this procedure is associated with several drawbacks. The method is not automated, and as such requires manual sampling, which potentially leads to inaccuracies particularly in frequent sampling intervals as required for characterization of rapid drug release. Further, the sheet-like fiber mats tend to partially fold upon contact with the dissolution medium, which may potentially affect the release kinetics and reproducibility of the acquired release data. In this study, we investigated the application of a fully automated fiber-optics based dissolution testing system for in situ monitoring of drug release from electrospun fiber mats. Electrospun poly (vinyl alcohol) fibers loaded with lysozyme were used as a model system. To prevent folding of the fiber mats and ensure a fixed position in the dissolution vessel throughout the experiment, a flexible adapter was developed to allow for the attachment of the fiber mats to the vessel walls. Lysozyme release from the fiber mats was compared with the release from cast films with the same composition. Even though the release processes were rather fast and differences in release kinetics of the two systems were marginal, the fiber-optics based dissolution setup allowed for the successful detection of released protein in both cases. The present study, therefore, highlights the potential for the utilization of fully automated fiber-optics based dissolution testing systems for advanced in situ monitoring of drug release from electrospun fibers.

Fiber-optic in situ analysis of the catalytic kinetics of the alliin/alliinase system

Abstract In this work, we studied the catalytic kinetics of the alliin/alliinase system using a fiber-optic in situ monitoring system (fiber-optic drug dissolution test system, FODT) to explore the application of a fiber-optic sensor analysis technique in the process of monitoring catalytic kinetics. According to Lambert–Beer's law and with the assistance of the computational relationship of alliin, allicin and pyruvate, we established two mathematical models, including obtaining the absorptivity of each substance in the reaction and looking at the products as a whole. According to the UV spectra of alliin, alliinase, sodium pyruvate, an allicin solution and the analyte corresponding to the allicin peak extracted from an HPLC/PDA chromatogram, an optical probe with a 5-mm gap was chosen for the measurement, and 230 nm was chosen as the detection wavelength during the catalysis reaction. Then, we determined the value of every parameter in the mathematical model at 230 nm and recorded the information into the workstation. A certain concentration of alliinase was well-mixed with a series of alliin solutions in the volume ratio 1:1, and the concentration variation of alliin was monitored in real time. The maximum reaction rates for various concentrations of the substrate were obtained using Origin 7.5 software. To this end, a double-reciprocal plot was used to calculate the parameters of the catalytic kinetics of the alliin/alliinase system, including the Michaelis constant ( K m ) and the maximum velocity ( V max ), which was compared to HPLC results.

The Effect of Probe Path Length Calibration on Dissolution Tests Performed with a Fiber-Optic In Situ Dissolution Test System

The purpose of this research was to provide a method for calibrating the path length of probes used for dissolution tests performed with a fiber-optic dissolution test system (FODT). Methods found in pharmacopeia use the absorptivity of a 60.0 µg/mL potassium dichromate solution for calibrating 10-mm cuvettes. This absorptivity should only be employed to calibrate probes with a 5-mm gap where the total path length is 10 mm, since the calibration will be inaccurate if this absorptivity is used with different path length probes. In this article, we establish a calibration method using the absorptivities of potassium dichromate solutions at concentrations of 120.0, 300.0, and 600.0 µg/mL with 5-, 2-, and 1-mm cuvettes to calibrate probes with 2.0-, 1.0-, and 0.5-mm gaps, respectively. The calibration method established here for FODT minimizes calibration inaccuracies observed with calibration of probes using the method in Appendix IVA of the Chinese Pharmacopeia.

Individualized, discrete event, simulations provide insight into inter- and intra-subject variability of extended-release, drug products

ObjectiveDevelop and validate particular, concrete, and abstract yet plausible in silico mechanistic explanations for large intra- and interindividual variability observed for eleven bioequivalence study participants. Do so in the face of considerable uncertainty about mechanisms.MethodsWe constructed an object-oriented, discrete event model called subject (we use small caps to distinguish computational objects from their biological counterparts). It maps abstractly to a dissolution test system and study subject to whom product was administered orally. A subject comprises four interconnected grid spaces and event mechanisms that map to different physiological features and processes. Drugs move within and between spaces. We followed an established, Iterative Refinement Protocol. Individualized mechanisms were made sufficiently complicated to achieve prespecified Similarity Criteria, but no more so. Within subjects, the dissolution space is linked to both a product-subject Interaction Space and the GI tract. The GI tract and Interaction Space connect to plasma, from which drug is eliminated.ResultsWe discovered parameterizations that enabled the eleven subject simulation results to achieve the most stringent Similarity Criteria. Simulated profiles closely resembled those with normal, odd, and double peaks. We observed important subject-by-formulation interactions within subjects.ConclusionWe hypothesize that there were interactions within bioequivalence study participants corresponding to the subject-by-formulation interactions within subjects. Further progress requires methods to transition currently abstract subject mechanisms iteratively and parsimoniously to be more physiologically realistic. As that objective is achieved, the approach presented is expected to become beneficial to drug development (e.g., controlled release) and to a reduction in the number of subjects needed per study plus faster regulatory review.

Effects of temperature and wavelength choice on in-situ dissolution test of Cimetidine tablets

The effects of temperature and wavelength choice on in-situ dissolution test instrument of Cimetidine were studied. Absorbance (A)<1.0 is required when using a fiber-optic dissolution test system. The detection wavelength of λmax (218nm) was replaced by 244nm to carry out this test. The absorbance of Cimetidine solution at different temperature showed an obvious change. Calibration of Cimetidine solution should be tested at the same temperature (37°C) with the test solution. A suitable wavelength with smaller tangent slope could be chosen for in-situ dissolution test of Cimetidine tablets.

A Novel Off-Center Paddle Impeller (OPI) Dissolution Testing System for Reproducible Dissolution Testing of Solid Dosage Forms

Dissolution testing is routinely conducted in the pharmaceutical industry to provide in vitro drug release information for quality control purposes. The most common dissolution testing system for solid dosage forms is the United States Pharmacopeia (USP) Dissolution Testing Apparatus 2. This apparatus is very sensitive to the initial location of the tablet, which cannot be controlled because the tablet is dropped into the vessel at the beginning of the test and it may rest at random locations at the vessel's bottom. In this work, a modified Apparatus 2 in which the impeller was placed 8 mm off center in the vessel was designed and tested. This new design was termed "OPI" for "off-center paddle impeller." Dissolution tests were conducted with the OPI apparatus for nine different tablet locations using both disintegrating tablets (prednisone) and nondisintegrating tablets (salicylic acid). The dissolution profiles in the OPI apparatus were largely independent of the tablet location at the vessel's bottom, whereas those obtained in the Standard System generated statistically different profiles depending on the tablet location. The newly proposed OPI system can effectively eliminate artifacts generated by random settling of the tablet at the vessel's bottom, thus making the test more robust.

A Formulation Case Study Comparing the Dynamic Gastric Model with Conventional Dissolution Methods

Even in the 21st century, conventional compendial dissolution testing remains a key cornerstone of the drug development process and quality control testing. However, opportunities exist with respect to in vitro technology developments that provide the potential for formulation and analytical scientists to exceed the capabilities of the conventional dissolution test toward a more biorelevant testing regime. This work presents a product development case study in which bioequivalence was observed between an immediate-release (IR) innovator product and a comparative singlelayer reference product. Despite this, when the constituent granule of the comparative single-layer reference product was formulated in a bilayer formulation with a nondisintegrating second layer, bioequivalence versus the innovator was not achieved. The use of USP Apparatus 2 dissolution testing failed to predict the bioequivalence failure, and hence an investigation was undertaken to develop a mechanistic understanding of in vivo behavior. Using both USP Apparatus 4 dissolution in the open-loop configuration and the dynamic gastric model (a novel in vitro model designed to mimic the human stomach), an understanding of the dissolution and disintegration properties of the reference product was established. The insights gained using novel technology facilitated the redesign and subsequent improvement in pharmacokinetic parameters of a complex pharmaceutical dosage form. INTRODUCTION The correlation of in vitro performance to in vivo behavior is a critically important and cost-effective objective for the drug development process within the pharmaceutical industry (1). It is imperative to work toward the development of a mechanistic understanding of the conditions of the gastrointestinal environment and its influence on drug liberation phenomena from the various oral pharmaceutical dosage forms (2). While fully characterizing the complexity of the gastrointestinal tract may remain an elusive goal (3), understanding the key parameters that can facilitate the prediction of dosage form behavior in vivo may be achieved. A key contributor to developing an understanding is the development of dissolution technologies that are designed to mimic the in vivo environment more closely. The noncompendial dissolution methods have been detailed in an excellent recent review (4). These include multicompartmental models such as the artificial stomach duodenal model (ASD), which has been used to evaluate the effect of gastric emptying on drug dissolution, solubilization, and precipitation in separate duodenal compartment in several studies (5–8). In addition, models exist that are designed to simulate GI physical stress forces such as the novel stress dissolution tester (9, 10) or the modified Apparatus 2 by Burke et al. (11). Systems that mimic absorption have been described, from the simple partitioning approach using USP apparatus with organic solvents (12–14) to the more complex models like the FloVitro Dissolution Testing system provided by Rohm and Haas (15). In addition, the human gastric simulator (HGS) is a recent technological advance that has been used to study the gastric digestion of foods (16), although this has yet to be applied in the pharmaceutical development space. The next evolutionary stage of dissolution technology comprises complex systems that are multicompartmental, not only mimicking the hydrodynamics and composition of media but also incorporating mechanical processing, digestion of real food, and gastric emptying. Examples of these systems are the TNO TIM–1 system (17) and the dynamic gastric model (DGM). The DGM, developed by the Institute of Food Research in Norwich, UK, is designed to simulate the human gastric compartment of the fundus and antrum (18, 19). It is the first “dynamic” in vitro model that replicates both the complex biochemical conditions and the array of gastric hydrodynamics, critical for the prediction of digestive processes and the bioperformance of pharmaceutical agents and dosage forms. The DGM is gaining increasing utility not only as a general biopharmaceutics tool for the evaluation of dosage form disposition and drug release characteristics, but also for the evaluation of (1) food effect potential, (2) dosage form integrity (especially the propensity for dose dumping), and (3) bespoke drug–alcohol interactions. This work reports a formulation development case study that utilized noncompendial in combination with traditional in vitro tools. The study has proved useful in gaining insight into the in vivo mechanisms of success and failure of the pharmaceutical product development of a complex multilayer pharmaceutical dosage form. *Corresponding author. e-mail: james_mann@merck.com dx.doi.org/10.14227/DT190412P14

PHYSICOCHEMICAL CHARACTERIZATION OF CAPSTONE DEPLETED URANIUM AEROSOLS IV: IN VITRO SOLUBILITY ANALYSIS

As part of the Capstone Depleted Uranium (DU) Aerosol Study, the solubility of selected aerosol samples was measured using an accepted in vitro dissolution test system. This static system was employed along with a SUF (synthetic ultrafiltrate) solvent, which is designed to mimic the physiological chemistry of extracellular fluid. Using sequentially obtained solvent samples, the dissolution behavior over a 46-d test period was evaluated by fitting the measurement data to two- or three-component negative exponential functions. These functions were then compared with Type M and S absorption taken from the International Commission on Radiological Protection Publication 66 Human Respiratory Tract Model. The results indicated that there was a substantial variability in solubility of the aerosols, which in part depended on the type of armor being impacted by the DU penetrator and the particle size fraction being tested. Although some trends were suggested, the variability noted leads to uncertainties in predicting the solubility of other DU-based aerosols. Nevertheless, these data provide a useful experimental basis for modeling the intake-dose relationships for inhaled DU aerosols arising from penetrator impact on armored vehicles.

Monitoring Ambroxol Hydrochloride Sustained-Release Tablets Release by Fiber-Optic Drug Dissolution In Situ Test System

The purpose of this research was to monitor in situ the drug release of ambroxol hydrochloride sustained-release tablets using a fiber-optic dissolution test system. A control experiment with a UV-vis spectrophotometer was performed simultaneously. Within 4 h, a real-time drug release profile was obtained. The average drug release at 60 min, 120 min, and 240 min was 23.1%, 52.2%, and 87.6%, respectively, using the fiber-optic in situ system. There were no significant differences between the two methods. The drug release of sustained-release tablets can be monitored by a fiber-optic drug dissolution in situ test system. Information about the whole dissolution process can be produced by the real-time dissolution profile.

Monitoring Dissolution Rate of Amiodarone Tablets by a Multiple Fiber-Optic Sensor System

Afiber-optic dissolution testing (FODT) system for solid pharmaceutical formulations has been constructed. The system is based on a charge-coupled device (CCD) detector and includes six fiber-optic probes. Light is produced by a small deuterium arc lamp illuminating an optical fiber bundle. Six fiber-optic dipping probes were constructed with reflection geometry. The light passes back and forth through the flow-through cuvette backed by a coated aluminum mirror. The sampling interval was typically 30 sec for all probes. The system was tested for different tablet and capsule formulations. Amiodarone is a Class III anti-arrhythmic agent. It is used for treatment of many ventricular and supraventricular arrhythmias, including arterial fibrillation. It is a highly hydrophobic drug, and factors of its formulation, including constitutional heterogeneity, surface membrane, and production technology, influence its absorption. The dissolution of marketed amiodarone tablets was tested by the system, and dissolution parameters were directly obtained from the dissolution curves. It was found that there were significant differences in the dissolution of these products.

In Situ Measurement of Solvent-Mediated Phase Transformations During Dissolution Testing

In this study, solvent-mediated phase transformations of theophylline (TP) and nitrofurantoin (NF) were measured in a channel flow intrinsic dissolution test system. The test set-up comprised simultaneous measurement of drug concentration in the dissolution medium (with UV-Vis spectrophotometry) and measurement of the solid-state form of the dissolving solid (in situ with Raman spectroscopy). The solid phase transformations were also investigated off-line with scanning electron microscopy. TP anhydrate underwent a transformation to TP monohydrate, and NF anhydrate (form β) to NF monohydrate (form II). Transformation of TP anhydrate to TP monohydrate resulted in a clear decrease in the dissolution rate, while the transformation of NF anhydrate (form β) to NF monohydrate (form II) could not be linked as clearly to changes in the dissolution rate. The transformation of TP was an order of magnitude faster than that of NF. The presence of a water absorbing excipient, microcrystalline cellulose, was found to delay the onset of the transformation of TP anhydrate. Combining the measurement of drug concentration in the dissolution medium with the solid phase measurement offers a deeper understanding of the solvent-mediated phase transformation phenomena during dissolution.

Quantitative Assessment of Probe and Spectrometer Performance for a Multi-Channel CCD-based Fiber Optic Dissolution Testing System

Quantitative Assessment of Probe and Spectrometer Performance for a Multi-Channel CCD-based Fiber Optic Dissolution Testing System

General solution for diffusion‐controlled dissolution of spherical particles. 2. Evaluation of experimental data

Our general particle dissolution model unified three traditional particle dissolution models and predicted that dissolution rates depend on surface curvature. Spherical benzocaine particles were prepared with a hot‐melt dispersion method and physicochemically characterized. Their dissolution behavior was studied to evaluate the general dissolution model. A flow‐through dissolution test system was used which employed an HPLC pump, an HPLC UV detector, a cylindrical‐shaped dissolution cell, and a data collection system. Single benzocaine particle dissolution profiles were determined at ambient temperature (22–23°C) in water at a constant flow rate. Dissolution rate normalized by surface area was found to be particle radius‐dependent and fitted well by the general particle dissolution model with a diffusion layer thickness of 110 μm and benzocaine diffusion coefficient of 1.4 × 10−5 cm2/s. Analysis of literature particle dissolution data also supported this general model. Our general model accounts for literature reports of apparent diffusion layer thicknesses being smaller for small particles compared with large particles. This study supports the applicability of the general particle dissolution model for a flow‐through dissolution test system.

Combination of flow injection with capillary electrophoresis: Part 4. Automated multicomponent monitoring of drug dissolution

The combined flow injection–capillary electrophoresis (FI–CE) system, described previously in this series, was used in connection with a drug dissolution testing system to automatically monitor the dissolution process of multicomponents. Samples from the dissolution medium were withdrawn at fixed intervals through an on-line membrane filter to load the sample loop of an injection valve, from which 25 μl samples were injected into a carrier buffer and transported into a split–flow interface coupling the FI and CE systems. Trimethoprim (TMP) and sulphamethoxazole (SMZ), the two active components in a sulphatrim tablet formulation dissolved in 0.1 mol l −1 HCl, were introduced into a short silica separation capillary of 14.5 cm effective length by electrokinetic means, separated at a constant voltage of 1.0 kV by capillary zone electrophoresis, using a phosphate running buffer (pH 6.5), and the separated constituents recorded continuously, using an UV detector at 224 nm. The signals were recorded within a testing period of 65 min. By partially overlapping the separation zones of neighboring samples, a high sample throughput of 60 h −1 was achieved with single-vessel dissolution and 48 (24 duplicates) h −1 with dual-vessel dissolution. The reproducibility of the FI–CE system, obtained using TMP and SMZ standards within the testing period was 1.6 and 0.8% relative standard deviation (RSD) with peak height evaluation, and 2.0 and 1.1% RSD ( n=72), respectively, for peak area. Good agreement of results was obtained between those using the reported method and a standard liquid chromatography method.