Determining short-lived solid forms during phase transformations using molecular dynamics

Larsen, Anders S.; Olsen, Mark A.; Moustafa, Hadeel; Larsen, Frank; Sauer, Stephan P. A.; Rantanen, Jukka; Madsen, Anders Ø.

doi:10.1039/c9ce00460b

Cited by 17 publications

(18 citation statements)

References 32 publications

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“…Solving the molecular structure of such products requires, therefore, X-ray powder diffraction (XRD). Here, MD can assist by simulating the dehydration process; the XRD pattern of the dehydrated state found in the simulation can then be compared with an experimental powder pattern to solve the structure of the new phase [442,443]. Using MD-based free-energy perturbation methods, the free energy of inclusion of a solvated molecule can be calculated, which is relevant for understanding the stability of a hydrate [444].…”

Section: Studies Of Crystalline and Amorphous Solidsmentioning

confidence: 99%

Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development

et al. 2020

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Molecular dynamics (MD) simulations have become increasingly useful in the modern drug development process. In this review, we give a broad overview of the current application possibilities of MD in drug discovery and pharmaceutical development. Starting from the target validation step of the drug development process, we give several examples of how MD studies can give important insights into the dynamics and function of identified drug targets such as sirtuins, RAS proteins, or intrinsically disordered proteins. The role of MD in antibody design is also reviewed. In the lead discovery and lead optimization phases, MD facilitates the evaluation of the binding energetics and kinetics of the ligand-receptor interactions, therefore guiding the choice of the best candidate molecules for further development. The importance of considering the biological lipid bilayer environment in the MD simulations of membrane proteins is also discussed, using G-protein coupled receptors and ion channels as well as the drug-metabolizing cytochrome P450 enzymes as relevant examples. Lastly, we discuss the emerging role of MD simulations in facilitating the pharmaceutical formulation development of drugs and candidate drugs. Specifically, we look at how MD can be used in studying the crystalline and amorphous solids, the stability of amorphous drug or drug-polymer formulations, and drug solubility. Moreover, since nanoparticle drug formulations are of great interest in the field of drug delivery research, different applications of nano-particle simulations are also briefly summarized using multiple recent studies as examples. In the future, the role of MD simulations in facilitating the drug development process is likely to grow substantially with the increasing computer power and advancements in the development of force fields and enhanced MD methodologies.

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Section: Studies Of Crystalline and Amorphous Solidsmentioning

confidence: 99%

Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development

et al. 2020

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“…Larsen et al conducted molecular dynamics simulations to provide a mechanism for FM dehydration and compared the theoretical results with PXRD and solid-state nuclear magnetic resonance experimental data. The phase transformation results showed several defects occurring in the crystalline structure until the formation of FIII, which presented disorder.…”

Section: Introductionmentioning

confidence: 99%

Understanding the Metastability of Theophylline FIII by Means of Low-Frequency Vibrational Spectroscopy

Paiva

Zaczek

et al. 2021

Mol. Pharmaceutics

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While theophylline has been extensively studied with multiple polymorphs discovered, there is still currently no conclusive structure for the metastable theophylline form III. In this present work, by combining more widely used techniques such as X-ray diffraction and thermogravimetric analysis with more emerging techniques like low-frequency Raman and terahertz time-domain spectroscopy, to analyze the structure and dynamics of a crystalline system, it was possible to provide further evidence that the form III structure has a theophylline monohydrate structure with the water molecules removed. Solid-state density functional theory simulations were paramount in proving that this proposed structure is correct and explain how vibrational modes within the crystal structures feature and govern polymorphic transitions and the metastable form III. Through the insight provided by both simulated and experimental results, it was possible to decisively conclude the elusive crystal structure of theophylline form III. It was also shown that the correct space group for theophylline monohydrate is not P21/n but, in fact, Pc.

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“…The multistep increase in f res (10-25 min) is due to the flipping of the TP MH crystal structure to the anhydrous form and this is supported by variable temperature XRD ( Supplementary Fig. 9, Supplementary Note 2) 43 . The Qs in the beginning of the experiment are linked to the softening of the particle that allows for an increased mobility of water and host molecules.…”

Section: Resultsmentioning

confidence: 65%

Single particles as resonators for thermomechanical analysis

et al. 2020

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Thermal methods are indispensable for the characterization of most materials. However, the existing methods require bulk amounts for analysis and give an averaged response of a material. This can be especially challenging in a biomedical setting, where only very limited amounts of material are initially available. Nano-and microelectromechanical systems (NEMS/MEMS) offer the possibility of conducting thermal analysis on small amounts of materials in the nano-microgram range, but cleanroom fabricated resonators are required. Here, we report the use of single drug and collagen particles as micro mechanical resonators, thereby eliminating the need for cleanroom fabrication. Furthermore, the proposed method reveals additional thermal transitions that are undetected by standard thermal methods and provide the possibility of understanding fundamental changes in the mechanical properties of the materials during thermal cycling. This method is applicable to a variety of different materials and opens the door to fundamental mechanistic insights.

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Determining short-lived solid forms during phase transformations using molecular dynamics

Abstract: We demonstrate that elusive high-energy metastable crystal structures can be determined from molecular dynamics simulations.

Cited by 17 publications

References 32 publications

Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development

Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development

Understanding the Metastability of Theophylline FIII by Means of Low-Frequency Vibrational Spectroscopy

Single particles as resonators for thermomechanical analysis

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