Pharmaceutical profiling and molecular dynamics simulations reveal crystallization effects in amorphous formulations

Edueng, Khadijah; Kabedev, Aleksei; Ekdahl, Alyssa; Mahlin, Denny; Baumann, John M.; Mudie, Deanna M.; Bergström, Christel A. S.

doi:10.1016/j.ijpharm.2021.121360

Cited by 9 publications

(3 citation statements)

References 64 publications

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“…Self-aggregation of the APIs within the micelles may also be insufficient for recrystallization. In a study by Edueng et al clustering of probucol molecules in an amorphous solid dispersion did not lead to crystal formation [73]. Thus, multiple factors together define the fate of a drug solubilized in intestinal fluid colloids, many of which can potentially be addressed with MD simulations.…”

Section: Discussionmentioning

confidence: 99%

Molecular dynamics study on micelle-small molecule interactions: developing a strategy for an extensive comparison

Kabedev,

Bergström,

Larsson

2023

J Comput Aided Mol Des

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Theoretical predictions of the solubilizing capacity of micelles and vesicles present in intestinal fluid are important for the development of new delivery techniques and bioavailability improvement. A balance between accuracy and computational cost is a key factor for an extensive study of numerous compounds in diverse environments. In this study, we aimed to determine an optimal molecular dynamics (MD) protocol to evaluate small-molecule interactions with micelles composed of bile salts and phospholipids. MD simulations were used to produce free energy profiles for three drug molecules (danazol, probucol, and prednisolone) and one surfactant molecule (sodium caprate) as a function of the distance from the colloid center of mass. To address the challenges associated with such tasks, we compared different simulation setups, including freely assembled colloids versus pre-organized spherical micelles, full free energy profiles versus only a few points of interest, and a coarse-grained model versus an all-atom model. Our findings demonstrate that combining these techniques is advantageous for achieving optimal performance and accuracy when evaluating the solubilization capacity of micelles. Graphical abstract All-atom (AA) and coarse-grained (CG) umbrella sampling (US) simulations and point-wise free energy (FE) calculations were compared to their efficiency to computationally analyze the solubilization of active pharmaceutical ingredients in intestinal fluid colloids.

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Section: Discussionmentioning

confidence: 99%

Molecular dynamics study on micelle-small molecule interactions: developing a strategy for an extensive comparison

Kabedev,

Bergström,

Larsson

2023

J Comput Aided Mol Des

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“…Experimental techniques often cannot approach the resolution at a scale of nanometers or nano- and micro-seconds. Computer simulations, and molecular dynamics (MD) in particular, can then serve as a useful tool to provide molecular-level information about drug–excipient interactions. , Wide spectra of MD simulations, ranging from all-atom resolution and up to significantly coarse-grained models, allows for studying miscibility, mobility, solubility, hydrogen-bond formation, effect of surfactants, and dynamics of the entire system. − Such knowledge can then facilitate optimization of the current ASDs and development of new formulations. Among other advantages of MD, there is an ability to a better system control in the simulations than during the experiment, including moisture, temperature, and other factors that could have an effect on the experiment.…”

Section: Introductionmentioning

confidence: 99%

“… 13 , 14 Wide spectra of MD simulations, ranging from all-atom resolution and up to significantly coarse-grained models, allows for studying miscibility, mobility, solubility, hydrogen-bond formation, effect of surfactants, and dynamics of the entire system. 15 − 17 Such knowledge can then facilitate optimization of the current ASDs and development of new formulations. Among other advantages of MD, there is an ability to a better system control in the simulations than during the experiment, including moisture, temperature, and other factors that could have an effect on the experiment.…”

Section: Introductionmentioning

confidence: 99%

Stabilizing Mechanisms of β-Lactoglobulin in Amorphous Solid Dispersions of Indomethacin

Kabedev

Zhuo

Leng³

et al. 2022

Mol. Pharmaceutics

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Proteins, and in particular whey proteins, have recently been introduced as a promising excipient class for stabilizing amorphous solid dispersions. However, despite the efficacy of the approach, the molecular mechanisms behind the stabilization of the drug in the amorphous form are not yet understood. To investigate these, we used experimental and computational techniques to study the impact of drug loading on the stability of protein-stabilized amorphous formulations. β-Lactoglobulin, a major component of whey, was chosen as a model protein and indomethacin as a model drug. Samples, prepared by either ball milling or spray drying, formed single-phase amorphous solid dispersions with one glass transition temperature at drug loadings lower than 40−50%; however, a second glass transition temperature appeared at drug loadings higher than 40−50%. Using molecular dynamics simulations, we found that a drug-rich phase occurred at a loading of 40−50% and higher, in agreement with the experimental data. The simulations revealed that the mechanisms of the indomethacin stabilization by β-lactoglobulin were a combination of (a) reduced mobility of the drug molecules in the first drug shell and (b) hydrogen-bond networks. These networks, formed mostly by glutamic and aspartic acids, are situated at the β-lactoglobulin surface, and dependent on the drug loading (>40%), propagated into the second and subsequent drug layers. The simulations indicate that the reduced mobility dominates at low (<40%) drug loadings, whereas hydrogen-bond networks dominate at loadings up to 75%. The computer simulation results agreed with the experimental physical stability data, which showed a significant stabilization effect up to a drug fraction of 70% under dry storage. However, under humid conditions, stabilization was only sufficient for drug loadings up to 50%, confirming the detrimental effect of humidity on the stability of protein-stabilized amorphous formulations.

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Evaluation and comparison of the mechanism of two bioactive materials in vital pulp therapy: a molecular dynamics simulation approach

Karrari,

Afarideh,

Kermanshah

et al. 2024

Bull Mater Sci

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Pharmaceutical profiling and molecular dynamics simulations reveal crystallization effects in amorphous formulations

Cited by 9 publications

References 64 publications

Molecular dynamics study on micelle-small molecule interactions: developing a strategy for an extensive comparison

Molecular dynamics study on micelle-small molecule interactions: developing a strategy for an extensive comparison

Stabilizing Mechanisms of β-Lactoglobulin in Amorphous Solid Dispersions of Indomethacin

Evaluation and comparison of the mechanism of two bioactive materials in vital pulp therapy: a molecular dynamics simulation approach

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