Sponsored Content by Pion IncReviewed by Maria OsipovaMar 18 2025
What is the process of oral drug absorption, and how has the Fa equation evolved?
Oral drug absorption begins with administering a drug product, followed by a rapid disintegration process. The drug substance is then released from the formulation, dissolves in the intestinal fluid, and permeates the intestinal membrane.
The Noyes-Whitney equation describes the dissolution process, while the permeation process follows first-order kinetics. The fraction of the dose absorbed (Fa) can be calculated by integrating these equations.
The development of the Fa equation has a long history. The Noyes-Whitney equation was introduced in 1897, followed by the concept of absorption potential in 1985. In 1993, the plug-flow model was introduced by Professor Amidon's group, and in 1995, the Biopharmaceutics Classification System (BCS) was developed.
Around the same time, concepts such as maximum absorbable dose and the compartmental absorption transit model were proposed. In 1999, the absorption-limiting step classification was introduced. The Fa equation was finally established in 2009, leading to the Fa classification system in 2010, now known as FaRLS.
What is the three-bucket model of oral drug absorption, and how do dissolution rate, permeability, and solubility influence absorption?
The three-bucket model explains oral drug absorption based on different limiting factors. The first case is dissolution rate-limited absorption, where the dissolution rate is very slow while the permeation rate is fast. In this situation, oral absorption is determined by how quickly the drug dissolves.
The second case is permeability-limited absorption, where the dissolution process happens rapidly, but the permeation process is slow. As a result, drug molecules accumulate in the intestinal fluid and are gradually absorbed into the body.
The third and most important case in modern drug discovery and development is solubility-permeability limited absorption. In this case, the maximum amount of drug that can dissolve in intestinal fluid depends on its solubility, which includes both the crystalline and amorphous forms.
When a solid dispersion formulation is administered, the phase separation concentration determines the maximum drug concentration. When a crystalline drug is administered, the drug concentration is dictated by crystalline solubility.
In this case, oral drug absorption is determined by the product of solubility and permeability. Understanding the permeability component is essential for analyzing the particle drifting effect, which is key to drug absorption efficiency.
What is the Peff equation, and how does it help understand oral drug absorption?
The Peff equation describes the effective permeability of drug molecules across the intestinal wall. After dissolving in the bulk phase, drug molecules first permeate through the unstirred water layer, which is about 300 micrometers thick and located on the surface of the intestinal wall. Following this, they pass through the epithelial membrane.
Since the permeation process occurs sequentially through the unstirred water layer and the epithelial membrane, the Peff equation mathematically represents this process. It includes terms for the permeability of the unstirred water layer and the epithelial membrane, as well as Fu, the free fraction of the drug in intestinal fluids. Because intestinal fluids contain bile micelles, only the free fraction of the drug is available for permeation across the epithelial membrane.
The Peff equation is essential for understanding oral drug absorption. Combined with the Fa equation, it helps derive a decision tree to identify the rate-limiting step in drug absorption. The Fa equation incorporates the Biopharmaceutics Classification System (BCS), categorizing drugs based on their dose and permeation numbers. If the dissolution rate is very slow, absorption is considered dissolution rate-limited.
In permeability-limited absorption, the process can be further classified as either epithelial membrane-limited or unstirred water-layer-limited. Similarly, solubility-permeability limited absorption can be divided into cases where epithelial membrane permeability or unstirred water layer permeability is the limiting factor. In the latter case, the particle-drifting effect significantly influences drug absorption.
Image Credit: Pion
What is the particle drifting effect, and how was it discovered in drug development?
I first proposed the concept of the particle drifting effect in 2010 based on my real-world experience in drug discovery and development, particularly while working at Pfizer. I noticed an unexpected trend during dose titration studies, where we analyzed how different dose strengths affect absorption.
Theoretically, when we increase the dose, the absorbed dose should plateau at a value known as the maximum absorbable dose. However, in actual clinical and toxicokinetics (TK) data, the absorbed dose increased beyond this theoretical ceiling, especially when the particle size was reduced. This suggested that something was missing in our theoretical understanding of drug absorption.
In solubility-limited absorption, the absorption flux is typically determined by the drug's solubility multiplied by its permeability. However, in real in vivo studies, increasing the dose strength and reducing particle size led to a higher absorption flux, even though solubility remained unchanged.
This effect was only seen when absorption was limited by the permeability of the unstirred water layer and not when it was limited by epithelial membrane permeability. This led me to conclude that the permeability of the unstirred water layer must have increased, contradicting the assumption that drug particles only exist in the bulk phase.
The key realization was that microscale drug particles could penetrate the unstirred water layer, increasing its mass transport rate. To confirm this, I looked into the literature. I found multiple studies showing that a significant portion of drug particles exist within the intervillous space, proving that microscale particles do not just stay in the bulk phase but actively move into the unstirred water layer.
How does the Peff equation predict Fa, and what role does the particle drifting effect play in improving its accuracy?
The Peff equation predicts Fa (the fraction of a dose absorbed in humans) based on key physicochemical properties such as pKa, intrinsic solubility, bile micelle binding partition coefficient, and intrinsic passive transcellular permeability (Ptrans0). The Ptrans0 value itself is predicted from the log P of compounds.
When plotting clinical Fa percentages on the horizontal axis and predicted Fa values on the vertical axis, I initially observed many underpredictions, particularly for cases involving high doses and fine particles. These discrepancies suggested that the standard model was missing an important factor.
By incorporating the particle drifting effect into the model, the accuracy of the predictions improved significantly. I published these findings in 2011 and continued to collect additional clinical data afterward. When comparing these new data points with the predicted values, the predictability remained consistent, strengthening my confidence in both the Fa and Peff equations.
However, these equations apply to simple, non-supersaturation cases. Predicting Fa in supersaturation cases—such as those involving solid-dispersion formulations, solid-form APIs, or amorphous APIs—is much more challenging. Currently, efforts are being made to improve these predictions using in vitro data, but accurate modeling of supersaturation is still difficult.
How does particle size affect solubility, and why is it important to carefully interpret solubility measurements?
Contrary to common assumptions, reducing particle size does not significantly increase solubility. Experimental data show that even when the particle size is reduced to below 200 nanometers, the relative solubility increases by only about 10%. Several well-documented studies confirm that solubility remains largely unaffected by particle size reduction, at least down to this nanometer scale.
When measuring solubility using filtration methods, careful interpretation of the data is necessary. Filtration membranes typically have pore sizes around 0.2 micrometers (200 nanometers). If only a portion of the drug particles pass through the filter, the drug concentration in the filtrate can appear artificially high, leading to an overestimation of solubility. The same caution applies when using centrifugation-based methods for solubility measurement.
Another common question is whether microscale drug particles can penetrate the unstirred water layer despite a mucus layer. A literature review on mucus structure reveals that the mucus layer's pore size is much larger than one micrometer, meaning that even microscale particles can move through it. Several experimental papers provide strong evidence supporting this conclusion, reinforcing the validity of the particle drifting effect in real biological environments.
How can the Pion MicroFlux data be extrapolated to predict human Fa while considering the particle drifting effect?
To accurately extrapolate Pion's MicroFlux data to human Fa while considering the particle drifting effect, several key structural differences between the Pion MicroFlux system and the human intestine must be accounted for. In humans, the intestinal membrane has a plicae structure (folds) and villi, significantly increasing the surface area for absorption. In contrast, the Pion microFlux membrane is flat and lacks these structural features.
The thickness of the unstirred water layer in the Pion MicroFlux system may also differ from that in the human intestine. Since the particle drifting effect influences absorption by affecting the permeability of this layer, it is crucial to adjust for any differences in unstirred water layer thickness when predicting human Fa.
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About Kiyohiko Sugano
Kiyohiko (Kiyo) Sugano is is a professor at Ritsumeikan University. He has over 20 years of experience working within the pharmaceutical industries in Japan and the UK (Chugai, Pfizer, and Asahi Kasei Pharma). He received his Bachelors's and Master’s degrees in Chemistry from Waseda University and his PhD in Pharmaceutical Sciences from Toho University. His research interests include drug oral bioavailability where his research and experiments are conducted at the molecular level on the physicochemical interaction between drugs and gastrointestinal tract components.
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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 that provide essential data to improve candidate selection and formulations decisions. Later in development, high-pressure homogenizers enable particle size reduction and ensure material consistency from bench- to production-scale.
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.