Computational Oral Absorption Simulation - technology
The gPROMS FormulatedProducts COAS tools are the first such tools for oral absorption constructed on Advanced Process Modelling (APM) technology. APM applies detailed, mechanistic mathematical models to provide accurate predictive information for decision support. An approach based on fundamental physics, chemistry and physiology allows the COAS tools to give unprecedented confidence in the accuracy of predictions.
Mechanistic models based on physicochemical properties
The gPROMS FormulatedProducts COAS tools are designed from the bottom up to simulate oral absorption based solely on measurable, physicochemical properties available before human, animal or even in vitro trials. Using log P, pKa, intrinsic solubility and other measurable properties, the COAS tools predict oral absorption with models that incorporate state-of-the-art APM techniques such as:
Population balance tracking of particle size distribution
As part of the The gPROMS FormulatedProducts framework, the COAS tools use a population balance approach to track particle size distribution (PSD) of each solid phase present in the drug product or formed during transit through the GI tract. The population balance approach is based on finite volumes allowing for a smooth representation of PSD rather than bins of mono-size particles. The image above shows the PSD through time in each segment of the GI tract from stomach to colon.
Kinetic co-existence of multiple solid forms
While many pharmaceuticals are formulated as salts to improve the apparent solubility of the form, the lower solubility of the resulting freeform may lead to precipitation. This lowers the amount of drug in solution, thereby partially negating the expected benefit of the more soluble form. The COAS tools can capture this phenomenon because they allow for the kinetic co-existence of multiple solid forms. The user can explore the risks and benefits of different API crystal forms.
Microclimate pH at particle surface
The gPROMS FormulatedProducts COAS tools incorporate explicit boundary layers at particle surfaces. This allows the simulation to consider the effect of the microclimate pH in the boundary layer. This provides a more realistic representation of acid and base particle dissolution.
Tracking of all species in solution
The COAS tools explicitly calculates API speciation. This allows you to investigate which species govern permeation kinetics rather than relying on a single solubility for all API species.
Classical and empirical kinetics for particle nucleation
Leveraging PSE’s experience in crystallization, the COAS tools incorporate multiple, proven models for particle nucleation. This allows the user to match the nucleation model to the level of experimental data available.
Accurate representation of dynamic physiology
The GI tract is modelled based on anatomical segments including fluid movement kinetics. Both the segment pH and segment volume are dynamic. The COAS tools include preset physiologies and the explicit values that define the physiological environment. User-defined custom physiologies allow tremendous flexibility to choose the number of segments in the GI tract and the physiological conditions in each segment.
Model framework evolves with increasing availability of experimental data
As drug development progresses, formulation scientists acquire additional experimental data that may affect the choice of an appropriate model. In the gPROMS FormulatedProducts COAS tools, users can begin with a purely theoretical model, then easily swap kinetic models to incorporate experimental results.