(W1030-03-20) Predicting Drug Dissolution Performance Using Molecular Dynamics Simulations

Purpose: Drug release testing is a critical performance metric for oral solid dosage forms and is used throughout all phases of the drug development cycle. In the early stages of formulation development, candidates undergo extensive in-vitro experimental dissolution testing to define the efficacy of a given formulation. The objective of this work is to predict drug dissolution in aqueous and biorelevant environments under physiological conditions computationally using Molecular Dynamics (MD) simulations. Successful development of an accurate/validated in-silico modeling approach to dissolution screening would rapidly accelerate formulation development and bioavailability enhancement in the delivery of poorly soluble drugs minimizing experimental studies.

Methods: Two high and low solubility commercial drug compounds, Acetaminophen (ACP) and Fenofibrate (FNF), were selected for this study. For the preparation of amorphous solid dispersion (ASD) models, polyvinyl-pyrrolidone (PVP) and sodium dodecyl sulfate (SDS) were chosen based on results predicted using in-house models and available literature data. A series of 20 molecular dynamics (MD) simulations were evaluated to investigate the ASDs and their drug dissolution/release compared to crystalline API in water, fasted-state simulated intestinal fluid (FaSSIF), and fed-state simulated intestinal fluid (FeSSIF). MD simulations were performed using the NAMD software package (v.3.0b3) with CHARMM36 and CGENFF all-atom force field parameters. Models were energy-minimized, followed by a 2 ns NVT (constant number of particles, volume, and temperature) simulation gradually heating to 310 K (37 ℃). Production runs were conducted (at 310 K, 1 atm) for 200 ns, accumulating a total time of ~3 μs.

Results: Figures 1a-1e display the initial (t=0 ns) and final (t=200 ns) simulation snapshots, illustrating the drug release immediately upon contact with the aqueous dissolution medium. As shown in Figures 2a and 2c, ACP is highly soluble in aqueous media (experimental aqueous solubility of 14.3 mg/ml). However, due to its strong binding propensity with PVP, ACP exhibits slower release in ASD (ACP-PVP) compared to crystalline simulations. In Figures 2b and 2d, changes in interaction energies and the drug release profiles demonstrate the enhanced drug-media interactions and drug release of FNF in the presence of PVP and SDS. These results align with experimental observations [2,3]. Additionally, to investigate how drug interactions in various formulations affect drug release upon dispersion within the gastrointestinal (GI) tract, we conducted MD simulations of crystalline and ASDs (ACP-PVP, FNF-PVP, FNF-PVP-SDS) of ACP and FNF dispersed in water, fasted, and fed buffers. ACP is rapidly absorbed in the GI, regardless of whether it is taken with or without food. Supporting this information, the average interaction energies of the ACP crystalline and ASD in water, FaSSIF, and FeSSIF media exhibit similar drug-media interactions (Figure 3a). Due to the lipophilic nature of FNF, it is generally recommended to take it with a meal to enhance drug release and absorption. Supporting the experimental results [3], Figure 3a reveals that FNF exhibits strong interactions with FeSSIF, indicating higher miscibility in the FeSSIF when compared to the aqueous and FaSSIF phases. Moreover, FNF simulations demonstrate the formation of micellar-sized aggregates, impacting the dissolution and dispersion in the fed state (Figures 3b-c).

Conclusion: Utilizing MD simulations, we have examined the initial stages of drug dissolution in aqueous and biorelevant media. Our findings shed light on the influence of drug-drug, drug-excipient, and drug-media interactions on drug release and corroborate the experimental results. Overall, this computational study provides an understanding of the drug dissolution mechanism and presents a promising in-silico predictive approach for drug dissolution, leading to expedited drug formulation development.

References: 1. Garekani, H. A., Sadeghi, F., & Ghazi, A. (2003). Drug Development and Industrial Pharmacy, 29(2), 173–179.
2. Yousaf, A. M., Kim, D. W., Oh, Y. K., Yong, C. S., Kim, J. O., & Choi, H. G. (2015). International Journal of Nanomedicine, 10, 1819–1830.
3. Jain, D., Thakur, P. S., Thakore, S. D., Samal, S. K., & Bansal, A. K. (2020). Journal of Drug Delivery Science and Technology, 60, 102040.

Figure 1: Initial and final (200 ns) MD trajectory snapshots of a) ACP crystalline, b) ACP-PVP ASD, c) FNF crystalline, d) FNF-PVP ASD, and e) FNF-PVP-SDS ASD simulations in 0.15 M aqueous NaCl media. Coloring as follows: water (transparent blue), PVP (green), ACP (red), FNF (purple), SDS (orange), Na+ (yellow) and Cl- (cyan).

Figure 2: Per molecular interaction energy change with time a) ACP crystalline and ACP-PVP ASD and b) FNF crystalline and ASD systems. Calculated percent drug release vs time in c) ACP crystalline and ACP-PVP ASD, d) FNF crystalline, FNF-PVP ASD, and FNF-PVP-SDS ASD systems.

Figure 3: a) Drug-media interaction energy change with time in ACP crystalline, ACP-PVP ASD, FNF crystalline, FNF-PVP ASD, and FNF-PVP-SDS ASD systems. b) FNF-PVP ASD and c) FNF-PVP-SDS ASD trajectory snapshots in the FeSSIF phase demonstrate the formation of micellar-like aggregates. Coloring as follows: PVP (transparent green), FNF (purple), SDS (yellow), Na+ (yellow), Cl- (cyan) and digested forms of Glycodeoxycholate (orange, bile salt), palmitoyl lysophosphatidylcholine (light blue, phospholipids), and oleate (green, phospholipids).