CASE STUDY

Advancing the designand optimization ofdrug formulations
with coarse-grained
molecular simulations
Scientists from AbbVie and Schrödinger gain a deep understanding of the mechanisms behind amorphoussolid dispersion (ASD) dissolution behavior at the molecular level.

Executive Summary• Evaluated dissolution profiles of different drug and polymer combinations at specified conditions• Identified interactions that are responsible for delayed release in certain formulations• Aligned with and complemented experimental data with visual and numeric insights at themolecular level• Gained insights into new excipients for drug formulations to achieve targeted dissolution behavior

Molecular dynamics
simulations

Experiment
Release proﬁle of CPV/SLP loaded with 20% drug (IBP)

100IBP (CPV)CPVIBP (SLP)
SLP% Release

8060402000204060

Time (min)*CPV, Copovidone; SLP, Soluplus; IBP, ibuprofen

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100120CHALLENGES
Formulating small molecule drugs withlow aqueous solubility in a hydrophilicpolymer matrix, also known as amorphoussolid dispersion (ASD), is one of the mostcommon approaches to achieve effective
drug delivery and, thus, bioavailability.
Producing a high-performance ASD
depends on various factors, such as thephysical stability of the drug-excipientmatrix, its interaction with polymers
during dissolution, and the rate of drug
release in an aqueous medium. Often,
researchers perform numerous designand experimental iterations to achieve thisgoal. While hypotheses about drug release
behaviors may be drawn from experimental
data, a comprehensive understanding of
the fundamental mechanisms and insights
into molecular-level occurrences remains
elusive. It’s challenging to obtain detailed
drug/polymers/water interactions throughexperiments alone. Therefore, a more
effective approach is needed to inform theselection of suitable excipients, including
polymers, for specific drugs.

Mapped atoms
onto CG sites
Divided molecules into DPD typeparticles, each representing agroup of connected atoms

Analyzed molecularsimulation results
Characterized ASD and particle
structure and evolution: drug
release, water distribution anddrug interactions with water andexcipients, particle size and radial
proﬁle of components

Approach
Scientists from AbbVie and Schrödinger worked together
to use molecular simulations to provide insights needed
to streamline time-consuming development cycles of drug
formulations. A mesoscopic simulation method, dissipative
particle dynamics (DPD), was employed to effectively model
ASD dissolution on relatively long lengths and time scales.
Two stages of the dissolution process were studied andcompared with experimental investigations: the early-stageof the dissolution process, which focuses on the breakup
and dissolution of the tablet at the ASD/water interface
with the potential for the formation of drug-excipientparticles, and the late-stage of the dissolution process
where the aqueous medium contains more mature drugexcipient particles which are important for sustained
supersaturation of the drug.
All models and simulations were performed using theSchrödinger’s Materials Science platform and the Desmondengine for molecular dynamics (MD) and coarse-grained(CG) simulations.

Built condensed systems
Determined and assigned CG
parameters and created suitable
initial simulation systems

Carried out experiments
Dissolution experiments and FTIR
spectroscopy of ASD formulations

Conducted four
early-stage dissolution
simulations
With and without IBP for both CPVand SLP

Conducted DPDsimulations on
six late-stage
dissolution systems
Drugs IBP and FFA with the polymers
CPV and SLP at two pH values*CPV, Copovidone; SLP, Soluplus; FFA, fenofibric acid; IBP, ibuprofen; PEG, polyethylene glycol

2Results
The dissolution of two poorly water-soluble drugs, ibuprofen (IBP) and fenofibric acid (FFA), in ASD
formulations with two well-known pharmaceutical polymers, copovidone (CPV) and Soluplus® (SLP),
was investigated by MD simulations and experiment. The experimental and simulation results are
consistent and complementary, demonstrating that structure−function relationships can be determinedby molecular modeling to aid formulation design. This suggests significant potential for combining
experimental and computational approaches to enhance understanding of ASD formulations andaccelerate formulation optimization.
• Molecular simulation results were consistent and provided visual explanations for experimentsfrom current and previous studies:− IBP/FFA interacts more with vinylcaprolactam in SLP than with vinylpyrrolidone in CPV− Water interacts more with vinylpyrrolidone in CPV than with vinylcaprolactam in SLP− Pure CPV dissolves faster than SLP, with water rapidly penetrating into CPV− Inclusion of IBP in CPV slows down the dissolution process− Release of IBP from SLP is slower than release from CPV• Molecular simulations provided additional insights:− CPV matrix showed more rapid hydration and breakup irrespective of drug presence, compared to theSLP matrix− Surfactant-like structures at the SLP ASD−water interface slow down water penetration into theformulation and thereby the drug release− Coherence of ASD degrades rapidly for low IBP/CPV ratios− Water distribution within the ASDs differs significantly between the two polymers− Within SLP, the PEG chain interacts more with water and less with drug molecules

Figure 1: Snapshots at different times from the late-stage dissolution simulation of the IBP/SLP system in water at pH 6.8.
The empty space in the box is occupied by water. It’s rendered transparent for better visibility of the polymer and drug molecules.

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Reference1.

Molecular-Level Examination of Amorphous Solid Dispersion Dissolution
Mohammad Atif Faiz Afzal, Kristin Lehmkemper, Ekaterina Sobich, Thomas F. Hughes, David J. Giesen, Teng Zhang,Caroline M. Krauter, Paul Winget, Matthias Degenhardt, Samuel O. Kyeremateng*, Andrea R. Browning, and John C.
Shelley* Mol. Pharmaceutics 2021, 18, 11, 3999–4014

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