Jozef Al-Gousous

Background: Postprandial gastric conditions such as changed motility and increased viscosity of gastric content can interact with an ingested dosage form, such as a tablet. This can affect the mechanisms of disintegration and dissolution and result in the altered performance of the tablet. Hereby, the individual characteristics of the tablet play a crucial role, since they determine the interaction potential with hydrodynamic and physico-chemical properties of the gastric environment. Excipient properties such as solubility, swellability, or gelling tendency can have an influence. Further, tablet characteristics such as porosity or pore size can affect its breakdown by regulating water uptake or determining its physical stability. Methods: Four midodrine hydrochloride generic products with known in vivo bioequivalence, but different formulations, were used as references to improve the simulated fed-state disintegration and dissolution testing methods involving highly viscous media. The tablet samples were evaluated towards the aforementioned characteristics, estimating which parameters of the testing method influence their dissolution performance under highly viscous conditions. Hereby, different hydrodynamic and mechanical stresses were simulated by a previously presented computed numerical controlled apparatus, as well as a novel flow-through cell for viscous media. By a mechanistic biopharmaceutics modeling approach, the convoluted dissolution data were compared to in vivo plasma profiles. Results: A sequential motion method yielded similar dissolution profiles as assessed by the similarity factor (f2). Convoluted plasma profiles showed good approximation with the in vivo profiles. Conclusions: The sequential dissolution method was established as a biopredictive tool for simulating the fed state by incorporating physiologically increased postprandial chyme viscosity and hydrodynamic stress.

Fecal microbiota transplantation (FMT) is an established treatment for recurrent Clostridioides difficile infection. As a drug product, FMT is subject to pharmaceutical quality standards, including accurate quantification of viable bacteria to ensure product consistency. We developed and validated an automated fluorescence‐ and image‐based viable‐cell counting method for FMT products; total‐cell enumeration was examined secondarily. The QUANTOM Tx system (Logos Biosystems) was validated according to ICH Q2(R2) using Escherichia coli and Bacillus subtilis as reference strains. The Viable Cell Staining Kit was validated with Escherichia coli , whereas the Total Cell Staining Kit was examined in selected experiments using both strains. Applicability to complex FMT matrices was confirmed using authentic fecal samples. Viable‐cell counting showed strong linearity across a range of 9.4 × 10 ⁶ –1.2 × 10 ⁸ cells/mL, with adequate accuracy and precision. Specificity was ensured by particle‐size gating, unaffected by nonviable cells or diluent. Robustness was confirmed across operators and time points. Fecal samples showed linear quantifiability and acceptable precision; total‐cell enumeration fulfilled linearity and precision requirements. The validated method enables rapid, reproducible viable‐cell quantification suitable for Quality Control of FMT drug products, supporting formulation development, and dosing verification. Viable‐cell quantification remains the analytical focus, despite limitations in spore detection. Total‐cell enumeration provides complementary process information.

The stratum corneum represents the main barrier to transdermal drug delivery, particularly for hydrophilic and ionized compounds such as aminophylline. In

In disintegration and dissolution (D&D) testing, high media viscosity, resembling ingested food, is rarely considered for simulated fed state inves

The food-induced viscosity of the media can alter tablet disintegration and eventually the release of the drug it contains. The extent of this retardation depends on tablet formulation factors, such as the solubility of its excipients. Objectives: This research aimed to study the effect of filler solubility on the disintegration and dissolution of tablets under different testing conditions. Methods: Tablet formulations containing acetaminophen (as a model compound), mixtures of different ratios of fillers, and other excipients were directly compressed using uniform manufacturing parameters. These formulations were investigated under fasted- and fed-state conditions to determine the influence of viscosity on their disintegration, inspired by the liquid penetration ratio (LPR) theoretical framework. Disintegration and dissolution tests were performed using both compendial and novel testing apparatuses. Results: The soluble fillers in the tablets affected their disintegration and dissolution in the simulated fed-state medium, while fasted-state conditions affected the tablets only marginally. The testing devices showed partially contrasting results, which appeared to be due to the hydrodynamics of the testing media used. The novel CNC (computed numerical control) apparatus offered 3D motion and effectively exposed the tablets to the viscous testing media, unlike the compendial paddle apparatus. Conclusions: This study explored the impact of filler solubility on the disintegration and dissolution of tablets. As the LPR framework revealed, fillers with a higher solubility have positive effects on the disintegration and dissolution of tablets in viscous conditions. Additionally, the proportion of soluble filler used is also inversely correlated with the disintegration time. Further investigation of the formulation parameters, as well as the testing conditions, would provide additional insights into the effects of food on these tablets.

The food-induced viscosity of the media can alter tablet disintegration and eventually the release of the drug. The extent of this retardation depends on tablet formulation factors such as the solubility of excipients. Objectives: This research aimed to study the effect of filler solubility on the disintegration and dissolution performances of tablets in different testing conditions. Methods: Tablet formulations containing acetaminophen as a model compound, mixtures of different ratios of fillers, and other excipients were directly compressed using uniform manufacturing parameters. The formulations were investigated under simulated viscosity of fasted and fed state conditions inspired by a Liquid Penetration Ratio (LPR) theoretical framework. The disintegration and dissolution tests were performed in both compendial and novel testing apparatuses. Results: Soluble fillers in the tablets affected the disintegration and dissolution in simulated fed state media but only marginally under fasted conditions. The testing devices showed partially contrasting results based on the hydrodynamics of the testing media. The novel CNC (computed numerical control) apparatus offered 3D-motion and effectively exposed tablets to the viscous testing media, in contrast to the compendial paddle apparatus. Conclusions: This study explored the impact of filler solubility on tablet disintegration and dissolution performances. As envisaged by the LPR framework, higher filler solubility has positive effects on tablet disintegration and dissolution performance in viscous conditions. Additionally, soluble filler proportion is also inversely correlated with disintegration time. Further investigation of the formulation parameters as well as the testing conditions would provide additional insights into the food effects on the tablets.

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 (S-tv), fluid velocity (U-tv), and energy dissipation rates (& varepsilon;(tv)) 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 degrees angle design generates more suspension than the 45 degrees 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.

Several locally acting colon-targeted products to treat colonic diseases have been recently developed and marketed, taking advantage of gastrointestinal physiology to target delivery. Main mechanisms involve pH-dependent, time-controlled and/or enzymatic-triggered release. With site of action located before systemic circulation and troublesome colonic sampling, there is room for the introduction of meaningful in vitro methods for development, quality control (QC) and regulatory applications of these formulations. A one-size-fits-all method seems unrealistic, as the selection of experimental conditions should resemble the physiological features exploited to trigger the release. This article reviews the state of the art for bio-predictive dissolution testing of colon-targeted products. Compendial methods overlook physiological aspects, such as buffer molarity and fluid composition. These are critical for pH-dependent products and time-controlled systems containing ionizable drugs. Moreover, meaningful methods for enzymatic-triggered products including either bacteria or enzymes are completely ignored by pharmacopeias. Bio-predictive testing may accelerate the development of successful products, although this may require complex methodologies. However, for high-throughput routine testing (e.g., QC), simplified methods can be used where balance is struck between simplicity, robustness and transferability on one side and bio-predictivity on the other. Ultimately, bio-predictive methods can occupy a special niche in terms of supplementing plasma concentration data for regulatory approval.