Sponsored Content by Pion IncReviewed by Maria OsipovaMar 31 2025
In this interview, Karl Box discusses how particle drift analysis using flux tools improves oral drug absorption in pharmaceutical research.
Can you tell us about Pion’s Rainbow Dynamic Dissolution Monitor?
The Rainbow Dynamic Dissolution Monitor is Pion's flagship product, a fiber optic UV spectrometer designed to integrate with various dissolution and permeation tools, both from Pion and other manufacturers.
It comprises up to eight fiber optic probes that can be inserted into measurement vessels. This allows us to measure the dissolution, solubilization, and permeation of drugs directly within the vessels. Eliminating the need to remove samples for offline analysis provides real-time insights. The system typically captures data every 30 seconds, offering detailed information about a sample's behavior.
How does the Rainbow Dynamic Dissolution Monitor integrate with Pion’s Dissolution-Absorption tools for assessing drug performance?
The Rainbow Dynamic Dissolution Monitor can seamlessly integrate into several of Pion’s dissolution and absorption tools. For example, in early development, the MicroFLUXTM system uses Rainbow probes to measure drug permeability across a membrane separating donor and acceptor compartments. As we scale up to clinical development, tools like the MiniFLUX, BioFLUXTM, and MacroFLUXTM come into play.
These systems feature a donor chamber separated from an acceptor chamber by a biomimetic membrane. The Rainbow UV probes measure concentration in the donor vessel and the acceptor absorption chamber, assessing the overall Flux performance and allowing for a comprehensive understanding of drug behavior across different stages of development.
Can you explain the concept of particle drift and its impact on drug absorption?
Numerous studies show that when an Active Pharmaceutical Ingredient (API) dose exceeds the intestinal solubility limits, oral absorption can increase more than expected. This suggests that undissolved particles can significantly influence the absorption process in vivo even when solubility is limited.
Particle drift refers to the phenomenon where undissolved nanoparticles in a drug formulation can diffuse into the solution's unstirred water layer that exists close to the membrane surface and dissolve there. This can lead to an increase in drug permeability, enabling enhanced absorption.

Image Credit: areeya_ann/Shutterstock.com
Could you share details about the piroxicam case study demonstrating the particle drifting effect and its findings?
The MicroFLUXTM apparatus was used to study the Flux behavior of untreated piroxicam and nanosubstances of piroxicam. This was a collaboration with Nanoform in Finland, and the work was first presented at the Controlled Release Society annual meeting in 2023.
Experiments were conducted in pH5 acetate buffer at various drug loadings on the donor side. Flux was measured across Pion’s gastrointestinal tract membrane into acceptor sink buffer in the receiver. The donor vessel loadings exceeded the solubility of piroxicam for all experiments.
The results demonstrated a clear impact of particle size on Flux. The piroxicam nanosuspension demonstrated a significant increase in Flux compared to the bulk suspension. Furthermore, we were able to identify the upper limit of Flux improvement, which occurs when the unstirred water layer becomes solubility saturated. We quantified how particle drift contributed to the total in vitro Flux, which has broader implications useful for the development of enabling formulations.
The study highlights how reducing particle size not only improves dissolution rates but can also enhance drug permeability, particularly for compounds where the unstirred water layer permeability limits absorption. This is especially important for compounds that exhibit high membrane permeability and require high doses. Particle size reduction can improve overall drug absorption in these cases.
What are the implications of these findings for biopharmaceutical modeling and in vivo absorption?
The findings have significant implications for both biopharmaceutical modeling and in vivo absorption. The human intestine’s large surface area is crucial in drug absorption. This surface area is primarily due to the circular folds and villi in the intestinal wall.
When scaling in vitro Flux results to in vivo conditions, we need to adjust for the difference in membrane surface area and scale the results to account for the three-dimensional nature of the folds and villi structures. For instance, a two-fold improvement in in vitro Flux could translate to a ten-fold enhancement in in vivo absorption due to the surface area provided by the villi structures.
In the case of nanoparticles, the particle drift effect allows penetration into the unstirred water layer, which also increases the amount of drug available for absorption. This is a game-changer because properly designed in vitro Flux assays allow scientists to estimate the relative improvement on in vivo absorption from nanosize reduction.
How does Pion’s PredictorTM software help translate in vitro results to in vivo-relevant data?
Pion’s new PredictorTM software program is designed to handle data from Pion’s Rainbow instrument and enables the translation of in vitro results into in vivo-relevant predictions. These include correcting for in vivo absorption barrier properties such as unstirred water layer thickness, scaling the results based on the drug’s permeability and available intestinal surface area, accounting for dose clearance differences between in vitro and in vivo systems, and making necessary adjustments for intestinal transit time. The total mass absorbed in vivo is calculated, giving us the maximum absorbable dose. The oral fraction absorbed is then determined by dividing the total mass absorbed by the administered dose and converting it into a percentage.
Pion PredictorTM software uses the GUT framework to help model drug absorption. How can in vitro Flux be used within this framework?
The Gastrointestinal Unified Theoretical (GUT) framework, as outlined in Kiyohiko Sugano’s book “Biopharmaceutical Modelling and Simulations: Theory, Practice, Method and Applications” published by Wiley in 2012, consists of a system of equations that model key processes such as dissolution, precipitation, and absorption.
This framework requires input parameters, including specific measured physicochemical properties and constants, to make accurate predictions. These parameters calculate dissolution and precipitation rates and determine drug permeation, ultimately leading to the estimation of oral absorption.
While the equations may appear complex, an interesting aspect of this model is that in vitro Flux can serve as a surrogate for many of the dissolution and permeation processes involved. Using Flux results obtained from Pion’s Flux assays, many of the equations governing dissolution and permeation in the GUT framework can be replaced.
This makes it possible to determine the amount of a substance permeating the intestinal wall using only the Flux value, provided it is supported by solubility and dissolution behavior observed in the donor vessel. The accuracy of these predictions depends on ensuring that the experimental assay is designed to closely mimic intestinal conditions.
Another case study was conducted in collaboration with researchers at Ritsumeikan University. How do the Celecox Flux assays' results demonstrate particle drift's impact on oral drug absorption prediction?
Another study collaborated with Shiori Ishida and Kiyo Sugano at Ritsumeikan University in Japan. The primary goal was to examine the impact of particle drift on the in vitro Flux of Celecoxib formulations and use that data to predict in vivo human oral absorption.
The marketed formulation, Celecox, contains a high percentage of nanosized particles, which can influence its pharmacokinetics. Our study, initially presented at the AAPS annual meeting in 2023, explored how these nanosized particles affect drug absorption. The Celecox Flux assay results highlight how incorporating the particle drift effect into predictive models significantly improves the accuracy of oral fraction absorbed estimations.
When using the Predictor software without considering particle drift, the highest fraction absorbed is observed at the lowest administered dose, while the lowest fraction absorbed occurs at the highest dose. This outcome is primarily due to the drug being significantly limited by solubility and unstirred water layer permeability, with predicted oral absorption for the highest dose remaining below 10% over the entire intestinal transit time.
However, when the particle drift effect is accounted for in the model, the proportion of Flux arising from particle drift is scaled based on villi access, leading to a notable improvement in predicting the total oral drug fraction absorbed across all dose levels. This adjustment makes predictions more aligned with published human oral fraction absorbed data.
The comparison of predicted fraction absorbed values shows that ignoring particle drift results in increasingly inaccurate estimations at higher doses. Accounting for the particle drifting effect, more accurately aligns the in vitro predictions with the expected in vivo values. This study demonstrates that Flux data can be used to estimate the absolute in vivo fraction of drug absorbed, determine the contribution of particle drift to the total Flux value, and adjust for its impact when scaling to in vivo conditions.
In conclusion, Pion Flux assays provide valuable support in the development of enabling formulations by identifying particle drift effects, assessing bioavailability improvements due to enhanced surface access, and refining drug absorption predictions in clinical studies.
Watch webinar: Using flux tools to demonstrate the impact of the particle drift effect on oral drug absorption
About Karl Box
Karl Box was appointed as the Chief Scientific Officer (Europe) at Pion (UK) in 2020. He is involved in scientific and chemistry related functions within the company, as well as supporting commercial activities and business development. His expertise is in the field of physicochemical measurements, where he has forged a successful career in the development of new instrumentation and assays for supporting drug discovery and development.
About Pion Inc
When data matters we apply out of the box problem solving abilities to help you reach a confident conclusion on your drug characterization challenges.
Pion supports the development of lifesaving and life-enhancing drugs by providing tools for drug developers, formulations scientists, and pharmaceutical production. For early-stage drug developers, our cutting-edge analytical technologies and services enable in vitro measurements of solubility, permeability, pKa and lipophilicity, providing essential data to improve candidate selection and formulations decisions for both oral and subcutaneous dosage forms. Later in development, high-pressure homogenizers enable particle size reduction and ensure material consistency from bench- to production-scale.