More Than a Gut Feeling─A Combination of Physiologically Driven Dissolution and Pharmacokinetic Modeling as a Tool for Understanding Human Gastric Motility.

In vivo studies of formulation performance with in vitro and/or in silico simulations are often limited by significant gaps in our knowledge of the interaction between administered dosage forms and the human gastrointestinal tract. This work presents a novel approach for the investigation of gastric motility influence on dosage form performance, by combining biopredictive dissolution tests in an innovative PhysioCell apparatus with mechanistic physiology-based pharmacokinetic modeling. The methodology was based on the pharmacokinetic data from a large (n = 118) cohort of healthy volunteers who ingested a capsule containing a highly soluble and rapidly absorbed drug under fasted conditions. The developed dissolution tests included biorelevant media, varied fluid flows, and mechanical stress events of physiological timing and intensity. The dissolution results were used as inputs for pharmacokinetic modeling that led to the deduction of five patterns of gastric motility and their prevalence in the studied population. As these patterns significantly influenced the observed pharmacokinetic profiles, the proposed methodology is potentially useful to other in vitro-in vivo predictions involving immediate-release oral dosage forms.

In Vitro Simulation of the Fasted Gastric Conditions and Their Variability to Elucidate Contrasting Properties of the Marketed Dabigatran Etexilate Pellet-Filled Capsules and Loose Pellets.

Variability of the gastrointestinal tract is rarely reflected in in vitro test protocols but often turns out to be crucial for the oral dosage form performance. In this study, we present a generation method of dissolution profiles accounting for the variability of fasted gastric conditions. The workflow featured 20 biopredictive tests within the physiological variability. The experimental array was constructed with the use of the design of experiments, based on three parameters: gastric pH and timings of the intragastric stress event and gastric emptying. Then, the resulting dissolution profiles served as a training data set for the dissolution process modeling with the machine learning algorithms. This allowed us to generate individual dissolution profiles under a customizable gastric pH and motility patterns. For the first time ever, we used the method to successfully elucidate dissolution properties of two dosage forms: pellet-filled capsules and bare pellets of the marketed dabigatran etexilate product Pradaxa. We showed that the dissolution of capsules was triggered by mechanical stresses and thus was characterized by higher variability and a longer dissolution onset than observed for pellets. Hence, we proved the applicability of the method for the in vitro and in silico characterization of immediate-release dosage forms and, potentially, for the improvement of in vitro-in vivo extrapolation.

Comparative Evaluation of Dissolution Performance in a USP 2 Setup and Alternative Stirrers and Vessel Designs: A Systematic Computational Investigation.

The dissolution testing method described in the United States Pharmacopeia (USP) Chapter ⟨711⟩ is widely used for assessing the release of active pharmaceutical ingredients from solid dosage forms. However, extensive use over the years has revealed certain issues, including high experimental intervariability observed in specific formulations and the settling of particles in the dead zone of the vessel. To address these concerns and gain a comprehensive understanding of the hydrodynamic conditions within the USP 2 apparatus, computational fluid dynamic simulations have been employed in this study. The base design employed in this study is the 900 mL USP 2 vessel along with a paddle stirrer at a 50 rpm rotational speed. Additionally, alternative stirrer designs, including the hydrofoil, pitched blade, and Rushton impeller, are investigated. A comparison is also made between a flat-bottom tank and the USP round-bottom vessel of the same volume and diameter. Furthermore, this work examines the impact of various parameters, such as clearance distance (distance between the bottom of the impeller and bottom of the vessel), number of impeller blades, impeller diameter, and impeller attachment angle. The volume-average shear rate (Stv), fluid velocity (Utv), and energy dissipation rates (ϵtv) represent the key properties evaluated in this study. Comparing the USP2 design and systems with the same stirrer but flat-bottom vessel reveals more homogeneous mixing compared to the USP2 design. Analyzing fluid flow streamlines in different designs demonstrates that hydrofoil stirrers generate more suspension or upward movement of fluid compared to paddle stirrers. Therefore, when impellers are of a similar size, hydrofoil designs generate higher fluid velocities in the coning area. Furthermore, the angle of blade attachment to the hub influences the fluid velocity in the coning area in a way that the 60° angle design generates more suspension than the 45° angle design. The findings indicate that the paddle stirrer design leads to a heterogeneous shear rate and velocity distributions within the vessel compared with the other designs, suggesting suboptimal performance. These insights provide valuable guidance for the development of improved in vitro dissolution testing devices, emphasizing the importance of optimized design considerations to minimize hydrodynamic variability, enhance dissolution characterization, and reduce variability in dissolution test results. Ultimately, such advancements hold potential for improving in vitro-in vivo correlations in drug development.

New biologically active sulfonamides as potential drugs for Alzheimer's disease.

A family of new compounds with sulfonamide and amide functional groups as potential Alzheimer's disease drugs were prepared by multistep synthesis. Thermal stability measurements recorded the initial decomposition in the range of 200-220°C, close above the melting point. The final compounds were tested for their ability to inhibit acetylcholinesterase and butyrylcholinesterase, and the in vitro dissolution behavior of selected compounds was studied through both lipophilic and hydrophilic matrix tablets. All nine tested derivatives were even more active in inhibiting acetylcholinesterase than the clinically used rivastigmine. Regression analysis of the obtained dissolution profiles was performed, and the effects of the pH and the release mechanism were determined. Some substances showed remarkable biological activity and became a subject of interest for further extensive study.

Formulation and Characterization of Buccal Films Containing Valsartan with Additional Support from Image Analysis.

The present study was aimed to the development and characterization of valsartan-containing buccal films with an introduction to a novel technique of image analysis. Visual inspection of the film provided a wealth of information that was difficult to quantify objectively. The obtained images of the films observed under the microscope were embedded in a convolutional neural network (CNN). The results were clustered according to their visual quality and on the basis of data distances. Image analysis proved to be a promising method to characterize buccal films appearance and their visual properties. The differential behavior of film composition was investigated using a reduced combinatorial experimental design. Formulation properties such as dissolution rate, moisture content, valsartan particle size distribution, film thickness, and drug assay were evaluated. In addition, more advanced methods such as Raman microscopy and image analysis were used to characterize the developed product in more detail. The results of dissolution tests using four different dissolution apparatuses showed a significant difference between the formulations containing the active ingredient in different polymorphic states. The dynamic contact angle of a water droplet on the surface of the films was measured, which correlated well with the dissolution times at 80% of the released drug (t80).

Effects of Apex Size on Dissolution Profiles in the USP II Paddle Apparatus.

The use of apex vessels may solve coning problems associated with dissolution testing. However, excessive dissolution acceleration can reduce the discriminatory power. This study aimed to clarify how different apex vessel sizes affect the dissolution behavior of cone-forming formulations. Five apex vessels with different heights, centralities, and compendial vessels were used. The paddle rotation speed at which the coning phenomenon resolved was measured using standard particles of different densities. Three model formulations-USP prednisone tablets, atorvastatin calcium hydrate tablets, and levofloxacin fine granules-were selected, and dissolution tests were conducted at 30-100 revolutions per minute (rpm). Compared to the compendial vessels, the disappearance of standard particles at the apex base at lower paddle speeds in apex vessels was observed. Standard particles tended to remain in the center of the apex vessels and disappear at rotational speeds comparable to those of the compendial vessels. Dissolution increased in an apex height-dependent manner in the model formulations, except for the atorvastatin calcium hydrate tablets at 50 rpm. For levofloxacin fine granules, dissolution was also improved by reducing the paddle agitation speed to 30 rpm in the compendial vessels. Differences in apex centrality by 3 mm did not affect the dissolution rate. Our results indicate that apex vessels with low apex heights have a mount-resolving effect, but the degree of dissolution improvement by avoiding the coning phenomenon depends on the formulation characteristics used in the dissolution tests.

PhysioCell®; - a Novel, Bio-relevant Dissolution Apparatus: Hydrodynamic Conditions and Factors Influencing the Dissolution Dynamics.

The physiologically relevant dissolution apparatuses simulate various aspects of gastrointestinal physiology and help to understand and predict the in vivo behavior of an oral dosage form. In this paper, we present and characterize for the first time a novel bio-relevant dissolution apparatus - PhysioCell®;. We evaluated the impact of several factors on the hydrodynamic conditions in the key vessel of the apparatus - the StressCell. We observed that the medium flow rate, but not the glass beads' size or amount, significantly influenced the dissolution rate. The relationship was disproportional: the increase in the flow rate from 4.6 to 9.0 mL/min reduced the dissolution time of 85% (T85) of the NaCl tablet by 46%, but from 134 to 300 mL/min decreased the T85 only by 24%. At the same time, the contractions of the StressCell's elastic walls promoted the content mixing and enhanced the dissolution rate of the paracetamol tablets: even very rare mixing contractions (1 per 10 min) decreased the T85 over twofold for the flow rate of 8 mL/min. In conclusion, the hydrodynamic conditions in the StressCell affect the dissolution of solid dosage forms and the understanding of these effects is crucial for modeling physiologically-based test conditions in the novel apparatus. Combinations of the unique PhysioCell®;features - adjustable medium flow, temperature control, controllable pH gradients and predefined mechanical agitation - can create a set of dissolution test scenarios for characterization of oral dosage forms and, in the future, making the in vitro-in vivo predictions. Graphical Abstract.

Development of stability indicating reversed-phase high-performance liquid chromatography method for determination of elobixibat in pure form and laboratory prepared tablets: Application to dissolution study.

A simple stability-indicating reversed-phase high-performance liquid chromatography method has been developed for determination of elobixibat in presence of its potential impurities and degradation products. The chromatographic separation was carried on a Thermo scientific Base Deactivated Silica BDS Hypersil-C18 (150 × 4.6 mm; 5 µm) column using a mobile phase of acetonitrile and phosphate buffer (25 mM, pH 2.5) in a ratio of (70:30, v/v). The experimental conditions were accurately investigated, and the method was validated according to ICH guidelines Q2 (R1). The drug was subjected to various stress conditions including acidic, basic, oxidative, and photolytic conditions. The method successfully separates the drug from the three reported impurities and different degradants. The method was also successfully applied for the determination of elobixibat in laboratory prepared tablets (5.0 mg). Analysis shows no interference from excipients and degradation products. The method was also applied for performing in vitro dissolution testing of elobixibat laboratory prepared tablets. Since elobixibat is recently introduced into the market, there are no previous stability studies and no reported analytical methods for its determination. Thus, this study presents a validated and selective method that can be effectively employed in routine quality control studies.

Smart UV-spectrophotometric platforms for rapid green analysis of miconazole nitrate and nystatin in their combined suppositories and in vitro dissolution testing.

Miconazole nitrate (MIC) and nystatin (NYS) combination has proven its effectiveness as a prodigious therapy to cure women's common infections; vaginal candidiasis and vaginal mycosis. Herein, six smart UV-spectrophotometric platforms depending on minimal mathematical manipulation steps were first introduced for the simultaneous green analysis of MIC and NYS in their pure forms and commercial vaginal suppositories without any preliminary separation steps. These platforms included dual-wavelength, ratio difference, mean centering of ratio spectra, first derivative ratio, ratio subtraction, and absorption correction methods. All of the aforementioned platforms could estimate MIC in a linear range of 90-900 µg/ml. While NYS was computed directly by zero-order spectrophotometry at its λmax (304 nm) in a linear range of 1-15 µg/ml without any interference by MIC even in low or high concentrations. Dual-wavelength and zero-order spectrophotometric platforms were successfully applied to study the dissolution profile of MIC and NYS in their combined formulation in compliance with FDA recommendations without excipients interference. According to ICH guidelines, all platforms were validated regarding the accuracy, precision, and selectivity producing satisfactory results within the accepted limits. Also, the suggested platforms' results were statistically compared with each other and with those of the reported HPLC platform revealing no significant difference concerning accuracy and precision at p = .05. Accordingly, all proposed platforms are regarded as economic and eco-friendly alternatives to the expensive chromatographic platforms that utilize hazardous organic solvents during the analysis of cited drugs.

Investigating the Influence of Tablet Location Inside Dissolution Test Apparatus on Polymer Erosion and Drug Release of a Surface-Erodible Sustained-Release Tablet Using Computational Simulation Methods.

The objective of this work was to investigate the influence of tablet location along the bottom of a USP apparatus II vessel on polymer erosion and drug release of surface-erodible sustained-release tablets using computational simulation methods. Computational fluid dynamics (CFD) methods were performed to simulate the velocity distribution. A mathematical model was developed to describe polymer erosion and tablet deformation according to the mass transfer coefficient. Numerical analysis was used to simulate drug release controlled by drug diffusion and polymer erosion. The results indicated that tablets located at the off-center position deformed faster than the tablets located at the center position. However, tablet location had no profound impact on drug release rate since all drug release profiles were "similar" according to the f2 similarity values which were above 50. Hence, our simulation supported that the USP apparatus II was a reliable and robust device for the dissolution testing of surface-erodible sustained-release tablets.

Use of Drug Release Testing to Evaluate the Retention of Abuse-Deterrent Properties of Polyethylene Oxide Matrix Tablets.

Abuse-deterrent formulations (ADFs) using physical/chemical barrier approaches limit abuse by providing resistance to dosage form manipulation to limit drug extraction or altered release. Standardizing in vitro testing methods to assess the resistance to manipulation presents a number of challenges, including the variation in particle sizes resulting from the use of various tools to alter the tablet matrix (e.g., grinding, chipping, crushing). A prototype, direct-compression ADF using a sintered polyethylene oxide (PEO) matrix containing dextromethorphan, an enantiomeric form of the opioid, levorphanol, was developed to evaluate testing methodologies for retention of abuse-deterrent properties following dosage form tampering. Sintered PEO tablets were manipulated by grinding, and drug content and release were evaluated for the recovered granules. Drug content analysis revealed that higher amounts of drug were contained in the smaller size granules (< 250 µm, 190% of the theoretical amount) compared with the larger particles (> 250 µm, 55-75% of theoretical amount). Release testing was performed on various size granule fractions (> 850 µm, 500-850 µm, 250-500 µm, and < 250 µm) using USP type I (basket), type II (paddle), and type IV (flow-through) apparatus. The USP type I and type II apparatus gave highly variable release results with poor discrimination among the release rates from different size granules. The observed sticking of the hydrated granules to the baskets and paddles, agglomeration of hydrated granules within the baskets/vessels, and ongoing PEO hydration with subsequent gel formation further altered the particle size and impacted the rate of drug release. The use of a flow-through apparatus (USP type IV) resulted in improved discrimination of drug release from different size granules with less variability due to better dispersion of granules (minimal sticking and aggregation). Drug release profiles from the USP type IV apparatus showed that the larger size granules (> 500 µm) offered continued resistance to drug release following tablet manipulation, but the smaller size granules (< 500 µm) provided rapid drug release that was unhindered by the hydrated granule matrix. Since < 500-µm size particles are preferred for nasal abuse, improved direct-compression ADF formulations should minimize the formation of these smaller-sized particles following tampering to maintain the product's abuse-deterrent features.

An eco-friendly HPLC-UV method for the determination of risedronate in its bulk and tablet dosage form with application to content uniformity, dissolution and stability testing.

Risedronate is a nitrogen-containing bisphosphonate for the treatment and prevention of postmenopausal osteoporosis. The current work aims to develop a novel green HPLC-UV method for the rapid analysis of risedronate sodium in bulk and tablet formulation. The analyzed samples were separated on Waters Atlantis dC18 (150 mm × 3.9 mm; 5 µm) column using a green mobile phase consisting of potassium phosphate buffer pH 2.9 and potassium edetate buffer pH 9.5 in a ratio of 1:2, the final pH was adjusted to 6.8 with phosphoric acid, the mobile phase was pumped at a rate of 1.0 mL/min, with column temperature set at 30 °C, eluted samples were detected at 263 nm and the chromatographic run time was 3.0 min. The method was found to be linear over the concentration range of 14-140 µg/mL with a correlation coefficient (r2) of 0.9994. Accuracy and precision were evaluated from three QC samples (LQC, MQC and HQC) together with the five calibrators where the percentage accuracy was found to be 101.84%. Processed quality control samples of risedronate sodium were tested for stability at different conditions, short term, long term and freeze- thaw stability. The current method was further extended to study the content uniformity of Actonel® tablets following United States Pharmacopoeia (USP) guidelines. The proposed method was fully validated as per ICH guidelines.

Influence of Dissolution Vessel Geometry and Dissolution Medium on In Vitro Dissolution Behaviour of Triamterene-Coated Model Stents in Different Test Setups.

The aim of this study was to investigate if the geometry of the dissolution vessel, the dissolution medium volume and composition might contribute to the variation in drug release from drug-eluting stents (DES) in different test setups, which has been observed in previous in vitro studies. Therefore, DES containing triamterene as model substance were produced via fluidised-bed technology. Dissolution testing was carried out using different incubation setups, the reciprocating holder (USP Apparatus 7) and two flow-through methods, a method similar to the USP Apparatus 4 (FTC) and the vessel-simulating flow-through cell (vFTC) equipped with a hydrogel as a second compartment simulating the blood vessel wall. The results indicate that dissolution vessel geometry and medium volume had no influence on the release behaviour and only the flow-through cell methods yielded a lower dissolution rate than the incubation setups (80.6 ± 2.0% released in the FTC after 14 days compared to > 90% for all incubation setups). The composition of the hydrogel used in the vFTC also affected the dissolution rate (53.9 ± 4.5% within 14 days with a hydrogel based on phosphate-buffered saline compared to 78.2 ± 1.2% obtained with a hydrogel based on water) possibly due to different solubility of triamterene in the release media as well as interactions between the coating polymer and the release medium. Hence, the introduction of a hydrogel as a second compartment might lead to a more biorelevant test setup.

Prediction of the Oral Pharmacokinetics and Food Effects of Gabapentin Enacarbil Extended-Release Tablets Using Biorelevant Dissolution Tests.

The purpose of this research was to establish an in vitro dissolution testing method to predict the oral pharmacokinetic (PK) profiles and food effects of gabapentin enacarbil formulated as wax matrix extended-release (ER) tablets in humans. We adopted various biorelevant dissolution methods using the United States Pharmacopeia (USP) apparatus 2, 3 and 4 under simulated fasted and fed states. Simulated PK profiles using the convolution approach were compared to published in vivo human PK data. USP apparatus 2 and 4 underestimated the in vivo performance due to slow in vitro dissolution behaviors. In contrast, biorelevant dissolution using USP apparatus 3 coupled with the convolution approach successfully predicted the oral PK profile of gabapentin enacarbil after oral administration of a Regnite® tablet under fasted state. This approach might be useful for predicting the oral PK profiles of other drugs formulated as wax matrix-type ER tablets under fasted state.

Developing a quality by design approach to model tablet dissolution testing: an industrial case study.

This study applied the concept of Quality by Design (QbD) to tablet dissolution. Its goal was to propose a quality control strategy to model dissolution testing of solid oral dose products according to International Conference on Harmonization guidelines. The methodology involved the following three steps: (1) a risk analysis to identify the material- and process-related parameters impacting the critical quality attributes of dissolution testing, (2) an experimental design to evaluate the influence of design factors (attributes and parameters selected by risk analysis) on dissolution testing, and (3) an investigation of the relationship between design factors and dissolution profiles. Results show that (a) in the case studied, the two parameters impacting dissolution kinetics are active pharmaceutical ingredient particle size distributions and tablet hardness and (b) these two parameters could be monitored with PAT tools to predict dissolution profiles. Moreover, based on the results obtained, modeling dissolution is possible. The practicality and effectiveness of the QbD approach were demonstrated through this industrial case study. Implementing such an approach systematically in industrial pharmaceutical production would reduce the need for tablet dissolution testing.

Physiological Considerations and In Vitro Strategies for Evaluating the Influence of Food on Drug Release from Extended-Release Formulations.

Food effects on oral drug bioavailability are a consequence of the complex interplay between drug, formulation and human gastrointestinal (GI) physiology. Accordingly, the prediction of the direction and the extent of food effects is often difficult. With respect to novel formulations, biorelevant in vitro methods can be extremely powerful tools to simulate the effect of food-induced changes on the physiological GI conditions on drug release and absorption. However, the selection of suitable in vitro methods should be based on a thorough understanding not only of human GI physiology but also of the drug and formulation properties. This review focuses on in vitro methods that can be applied to evaluate the effect of food intake on drug release from extended release (ER) products during preclinical formulation development. With the aid of different examples, it will be demonstrated that the combined and targeted use of various biorelevant in vitro methods can be extremely useful for understanding drug release from ER products in the fed state and to be able to forecast formulation-associated risks such as dose dumping in early stages of formulation development.

New Approach for the Application of USP Apparatus 3 in Dissolution Tests: Case Studies of Three Antihypertensive Immediate-Release Tablets.

The USP Apparatus 3 is a compendial dissolution Apparatus that has been mainly used to assess the performance of modified-release drug products. However, this Apparatus can be applied to dissolution testing of immediate-release tablets as well, with several advantages such as lower consumption of dissolution media, reduced setup time in quality control routine, and minimized hydrodynamic issues. In this work, three immediate-release (IR) tablets containing antihypertensive drugs of different Biopharmaceutic Classification System (BCS) classes were evaluated in order to assess the possible interchangeability between the official dissolution method using typical USP Apparatus 1 or 2 and the proposed methods using USP Apparatus 3. Depending on the selection of the appropriate operational conditions, such as dip rate and sieve mesh size, it was observed that USP Apparatus 3 could provide similar dissolution profiles compared to USP Apparatus 1 or 2 to the drug products tested. In addition, USP Apparatus 3 avoided conning issues related to USP Apparatus 2. The successful application of USP Apparatus 3 in dissolution tests for IR drug products depends on the definition of specific test conditions for each product, considering all the equipment variables, as well as drug and formulation characteristics.

Novel Dissolution Method for Oral Film Preparations with Modified Release Properties.

Oromucosal film preparations have gained popularity in pharmaceutical research and development. Therefore, oral films have been integrated into the monograph "oromucosal preparations" of the European Pharmacopeia in 2012. Regulatory authorities explicitly demand dissolution studies for films, but neither refer to suitable methods nor established specifications. Test methods described in the literature are often limited to immediate release formulations or not applicable to investigate the drug release of films with prolonged release profiles considering the different stages of gastrointestinal transit. The aims of this study were to develop a dissolution test method, which is suitable to investigate the drug release of film preparations with immediate as well as modified release profiles and to explore the potential of the test setup considering some physiological characteristics. Therefore, a conventional flow-through cell was equipped with in-house built sample holders. Three-dimensional printing technology was used for prototyping one of the sample holders. Four different types of films were investigated, such as ODFs with immediate (ODFIR) and prolonged release (ODFPR) characteristics as well as a double-layer film (ODFDL), produced with a water-insoluble shielding layer. Anhydrous theophylline was used as a model drug for all film types. Introducing special fixtures for oral films to a conventional flow-through cell enables successful determination of the drug release behavior of oral film preparations with immediate as well as modified release properties. Investigating ODFDL, the application of film sample holders with backing plates such as film sample holder with backing plate (FHB) and 3D printed film sample holder (FH3D) showed prolonged release profiles with 14.6 ± 1.30% theophylline dissolved within 2 h for FHB compared to 92.9 ± 3.33% for the film sample holder without backing plate (FH). This indicates their suitability to examine the integrity of the shielding layer. The application of the backing plate further decreased the drug release of ODFPR < 315 to 61.0 ± 1.69% dissolved theophylline within 2 h using FHB compared to 82.3 ± 0.74% using FH, due to a reduced ODF surface exposed to the dissolution medium. The potential of the dissolution test setup to consider physiological conditions of the human gastrointestinal transit was investigated by applying different flow rates and media compositions to simulate conditions within the oral cavity, stomach, and intestine. For the application of a low flow rate of 1 ml/min, comparable to the salivary flow within the oral cavity, decreased theophylline release was observed, while similar release profiles were obtained for flow rates between 2 and 8 ml/min. Substantial impact on the theophylline release was exerted by varying the composition of the dissolution medium. Since the drug release from ODFPR is controlled by diffusion through a water-insoluble matrix, ion species and concentration strongly affect the release behavior. In the future, IVIVC studies have to be performed to explore, whether obtained data can be used to predict drug release behavior of ODFs during the human gastrointestinal transit.

Micellar HPLC method for the simultaneous determination of three anticonvulsant drugs in dosage forms and biological fluids. Application to dissolution-rate testing.

This work describes a micellar liquid chromatographic method which was developed and validated to determine simultaneously three structurally-related antiepileptic drugs; namely carbamazepine (CMZ), oxcarbazepine (OCZ) and eslicarbazepine acetate (ECZ). The analysis was achieved using a phenyl column (250mm×4.6mm i.d., 5µm particle size), a mobile phase consisting of a mixture of 0.3% triethylamine and 10% n-butanol in a solution of 0.05M sodium dodecyl sulphate adjusted to pH 7.0 using 0.02M orthophosphoric acid. The mobile phase was pumped at a flow rate of 1.5mLmin-1 and detection was adjusted at 215nm. The method showed good linearity (r2>0.998) over the concentration ranges of 0.1-10 for CMZ and OCZ and 0.2-20µgmL-1 for ECZ. The suggested method was successfully applied for the analysis of the studied drugs in their dosage forms and for the determination of CMZ and OCZ in spiked human urine and plasma without prior extraction. The proposed method was further extended to the analysis of real samples of plasma and urine of volunteers receiving therapy of CMZ and OCZ. Furthermore, the method was successfully applied to tablets dissolution-rate testing, and the results were satisfactory.

Validation of Dissolution Testing with Biorelevant Media: An OrBiTo Study.

Dissolution testing with biorelevant media has become widespread in the pharmaceutical industry as a means of better understanding how drugs and formulations behave in the gastrointestinal tract. Until now, however, there have been few attempts to gauge the reproducibility of results obtained with these methods. The aim of this study was to determine the interlaboratory reproducibility of biorelevant dissolution testing, using the paddle apparatus (USP 2). Thirteen industrial and three academic laboratories participated in this study. All laboratories were provided with standard protocols for running the tests: dissolution in FaSSGF to simulate release in the stomach, dissolution in a single intestinal medium, FaSSIF, to simulate release in the small intestine, and a "transfer" (two-stage) protocol to simulate the concentration profile when conditions are changed from the gastric to the intestinal environment. The test products chosen were commercially available ibuprofen tablets and zafirlukast tablets. The biorelevant dissolution tests showed a high degree of reproducibility among the participating laboratories, even though several different batches of the commercially available medium preparation powder were used. Likewise, results were almost identicalbetween the commercial biorelevant media and those produced in-house. Comparing results to previous ring studies, including those performed with USP calibrator tablets or commercially available pharmaceutical products in a single medium, the results for the biorelevant studies were highly reproducible on an interlaboratory basis. Interlaboratory reproducibility with the two-stage test was also acceptable, although the variability was somewhat greater than with the single medium tests. Biorelevant dissolution testing is highly reproducible among laboratories and can be relied upon for cross-laboratory comparisons.