Produced in Partnership with Pion IncReviewed by Maria OsipovaMay 19 2025
In this interview, Karl Box from Pion outlines the benefits of particle drift analysis using flux tools and how this can be used to enhance oral drug absorption in pharmaceutical research.
Could you start by giving us an overview of Pion’s Rainbow Dynamic Dissolution Monitor?
Pion's flagship product, the Rainbow Dynamic Dissolution Monitor, is a fiber optic UV spectrometer suitable for integration into a range of Pion’s in-house and other third-party dissolution and permeation tools.
This powerful instrument is made up of up to eight fiber optic probes that can be inserted into measurement vessels, allowing users to directly measure drugs’ dissolution, solubilization, and permeation within the vessels themselves.
Real-time insights are possible because there is no need to remove samples for offline analysis. The system generally captures data every 30 seconds, providing its users with detailed information on a sample's behavior.
How does the Rainbow Dynamic Dissolution Monitor integrate with Pion’s Dissolution-Absorption tools for the assessment of drug performance?
The Rainbow Dynamic Dissolution Monitor can be seamlessly integrated into a number of Pion’s dissolution and absorption tools.
For instance, the MicroFLUX™ system employs Rainbow probes during early development in order to measure drug permeability across a membrane separating donor and acceptor compartments.
Other tools like the MiniFLUX™, BioFLUX™, and MacroFLUX™ will be used as we later scale up to clinical development. These systems include a donor chamber with a biomimetic membrane separating this from an acceptor chamber.
The Rainbow UV probes are used to measure concentration in the donor vessel and the acceptor absorption chamber, evaluating overall Flux performance and facilitating the in-depth understanding of drug behavior across various development stages.
Could you outline the concept of particle drift and its effect on drug absorption?
A range of studies have shown that oral absorption can increase more than anticipated when an Active Pharmaceutical Ingredient (API) dose exceeds intestinal solubility limits. These studies suggest that undissolved particles have a notable effect on the absorption process in vivo, even in cases where solubility is limited.
The term ‘particle drift’ refers to cases where undissolved nanoparticles present in a drug formulation diffuse into the solution's unstirred water layer and dissolve there. This layer exists near the membrane surface, and the dissolution of these nanoparticles can lead to an increase in drug permeability, improving absorption.
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Could you explain the findings of the piroxicam case study and how this demonstrates the particle drifting effect?
This study involved using the MicroFLUX™ apparatus to study the Flux behavior of untreated piroxicam and nanosubstances of piroxicam. We worked with Nanoform in Finland during this piece of work, and the study was initially presented at the 2023 annual meeting of the Controlled Release Society.
We performed experiments in pH 5 acetate buffer at different drug loadings on the donor side, measuring Flux was across Pion’s gastrointestinal tract membrane into acceptor sink buffer in the receiver. It was observed that donor vessel loadings exceeded the solubility of piroxicam in every experiment.
The results showed that particle size had a clear impact on Flux. The piroxicam nanosuspension demonstrated a considerable increase in Flux versus the bulk suspension. It was also possible to identify the upper limit of Flux improvement occurring when the unstirred water layer becomes solubility-saturated.
Particle drift’s contribution to the total in vitro Flux was quantified. This data has wider implications and is anticipated to be beneficial when developing enabling formulations.
The study also shows that not only does reducing particle size improve dissolution rates, but this can also improve drug permeability, especially for compounds where the permeability of the unstirred water layer limits absorption.
This is a particularly important consideration for compounds exhibiting high membrane permeability and requiring high doses. In these cases, particle size reduction can enhance overall drug absorption.
How will these findings impact the field of biopharmaceutical modeling and in vivo absorption?
The findings will have a major impact on both biopharmaceutical modeling and in vivo absorption. The human intestine’s large surface area is a key factor in drug absorption, with this surface area primarily due to the presence of circular folds and villi in the wall of the intestine.
It is necessary to adjust for the difference in membrane surface area when scaling in vitro Flux results to in vivo conditions. Results must also be scaled to account for the three-dimensional nature of the villi structures and folds.
For example, the surface area provided by the villi structures could result in a twofold improvement in in vitro Flux, translating to a tenfold enhancement in in vivo absorption.
In terms of nanoparticles, the particle drift effect facilitates penetration into the unstirred water layer. This also increases the amount of drug available for absorption. This is an extremely important phenomenon, because scientists can use well-designed in vitro Flux assays to estimate the relative improvement on in vivo absorption from nanosize reduction.
How does Pion’s Predictor™ software support the translation of in vitro results to in vivo-relevant data?
Pion’s new Predictor™ software program has been developed to work with data from Pion’s Rainbow instrument, facilitating the translation of in vitro results into in vivo-relevant predictions.
This software program is able to correct for in vivo absorption barrier properties like unstirred water layer thickness.
It can also be used to scale the results based on factors like available intestinal surface area and the drug’s permeability, or it can account for dose clearance differences between in vitro and in vivo systems. The software can also be used to make required adjustments for intestinal transit time.
The maximum absorbable dose is determined by calculating the total mass absorbed in vivo. It is then possible to determine the oral fraction absorbed by dividing the total mass absorbed by the administered dose and converting this into a percentage.
Pion Predictor™ software makes use of the GUT framework to help model drug absorption. How can in vitro Flux be utilized within this framework?
The Gastrointestinal Unified Theoretical (GUT) framework was outlined in Kiyohiko Sugano’s book “Biopharmaceutical Modelling and Simulations: Theory, Practice, Method and Applications” which was published by Wiley in 2012.
This framework consists of a system of equations able to model key processes including precipitation, dissolution, and absorption.
This framework needs input parameters to make accurate predictions, including specific measured physicochemical properties and constants. These parameters determine drug permeation and calculate dissolution and precipitation rates, allowing oral absorption to be estimated.
The equations appear complex, but an interesting feature of this model is that in vitro Flux is able to act as a surrogate for a number of the dissolution and permeation processes involved.
Many of the equations governing dissolution and permeation in the GUT framework can be replaced using Flux results obtained from Pion’s Flux assays, meaning it is possible to determine the amount of a substance permeating the intestinal wall using just the Flux value.
However, these calculations need to be supported by the solubility and dissolution behavior observed in the donor vessel. The accuracy of these predictions depends on how well the experimental assay is designed to replicate intestinal conditions.
A further case study was conducted in collaboration with researchers from Ritsumeikan University. How do the Celecox Flux assays' results show the effect of particle drift on oral drug absorption prediction?
The primary goal of the study done in collaboration with Shiori Ishida and Kiyo Sugano at Ritsumeikan University in Japan was to investigate the effects of particle drift on the in vitro Flux of Celecoxib formulations.
Our aim was to use that data to predict in vivo human oral absorption, and we initially presented this study at the AAPS annual meeting in 2023.
Celecox’s marketed formulation contains a high percentage of nanosized particles, with the potential to impact its pharmacokinetics. It aimed to explore how these nanosized particles affect drug absorption.
Results from the Celecox Flux assay showed how incorporating the particle drift effect into predictive models led to major improvement in the accuracy of oral fraction absorbed estimations.
When the Predictor software is used without consideration for particle drift, the highest fraction absorbed is seen at the lowest administered dose, while the lowest fraction absorbed occurs at the highest dose.
This outcome is mainly due to the drug being heavily limited by both its solubility and permeability through the unstirred water layer, with predicted oral absorption for the highest dose remaining below 10 % throughout the entire intestinal transit time.
When the model accounts for particle drift, however, the proportion of Flux arising from particle drift is scaled based on villi access. This leads to a noteworthy improvement in predictions of total oral drug fraction absorption across all dose levels.
It was observed that this adjustment better aligns predictions with published human oral fraction absorbed data.
Comparing predicted fraction absorbed values highlighted that failure to consider particle drift leads to increasingly inaccurate estimations at higher doses. Accounting for the particle drifting effect, however, means that in vitro predictions more accurately align with anticipated in vivo values.
This study confidently showed that it is possible to use Flux data to estimate the absolute in vivo fraction of drug absorbed. It also enables the contribution of particle drift to the total Flux value to be determined, and its impact when scaling to in vivo conditions to be accommodated.
Our work confirmed that the use of Pion Flux assays is highly beneficial in the development of enabling formulations. These assays can be used to identify particle drift effects, evaluate bioavailability improvements resulting from improved surface access, and support refinements of drug absorption predictions in clinical studies.
Watch the full webinar: Using flux tools to demonstrate the impact of the particle drift effect on oral drug absorption
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.