Anderson, Bradley

Project : Molecular dynamics simulations of amorphous drug-excipient mixtures

Description: Amorphous formulations for enhancing bioavailability of poorly soluble drugs are increasing in importance. Amorphous dispersions are metastable and undergo relaxation with time. Physical and chemical instability may vary with aging, depending on molecular mobility and molecular interactions in the glass. Molecular dynamics (MD) simulations provide insights into atomic-level interactions and dynamic processes important for predicting such properties as water uptake and mobility, drug miscibility, physical stability, and aqueous solubility enhancement. These computational methods are highly invaluable in assessing stability of amorphous dispersions and in selecting optimal excipients for development of drug dosage forms.
In the present project, we construct various amorphous drug-excipient assemblies including various combinations of indomethacin (IMC), felodipine (FP), water, PVP, PLA, HPMC, and HPMCAS. Next we conduct MD simulations to investigate both structural and dynamic properties such as drug conformation, hydrogen bonding distributions, amorphous drug mobility, miscibility, and solubility.

Students

Names on the project: Tian-xiang Xiang and Bradley D. Anderson (PI)

Software

This project mostly uses the Amber commercial molecular dynamics simulation program package and the Gaussian commercial program package. They are both licensed and available at CCS of UK.

Collaborators

We have received and will continue to receive assistance from Dr. Michael Sheetz of CCS in implementing and running Amber and other programs.
 

Publications

2016 - 2019

1. B.D. Anderson and T.-X. Xiang, Molecular Dynamics Simulations of Amorphous Systems, in “Computational Pharmaceutical Solid State Chemistry”, Y. Abramov, ed., Wiley, ISBN: 978-1-118-70074-7, 424 pages, 2016.
2. T.-X. Xiang and B.D. Anderson, Molecular Dynamics of Amorphous Hydroxypropylmethylcellulose (HPMC) and its Mixtures with Felodipine and Water, J. Pharm. Sci., 106, 803-816 (2017)..
3. T.-X. Xiang and B.D. Anderson, Effects of molecular interactions on miscibility and mobility of ibuprofen in amorphous solid dispersions with various polymers. J. Pharm. Sci., 108, 178-186 (2019).

List of current and previous publications and grant funding that came out of the use on DLX:
1. Publication: Xiang T.-X. and Anderson B.D. Molecular Dynamics Simulation of Amorphous Indomethacin. Mol. Pharm. 10:102-114 (2013a).
2. Publication: Xiang T.-X. and Anderson B.D. Molecular Dynamics Simulation of Amorphous Indomethacin–Poly(Vinylpyrrolidone) Glasses: Solubility and Hydrogen Bonding Interactions. J. Pharm. Sci. 102:876-891 (2013b).
3. Publication: Xiang T.-X. and Anderson B.D. Explicit-Atom Molecular Dynamics Simulation of Amorphous Poly(D,L-Lactide) Solid. to be submitted.

Grants Funded:

Anderson Bradley 5R25CA153954-05 The University of KY Cancer Nanotechnology Training Center (UK CNTC) National Cancer Institute 9/3/2010 7/31/2015 $354,186
Anderson Bradley PO #565 Bendamustine HCI Form 1 Solubility Eagle Pharmaceuticals Incorporated 2/27/2014 4/30/2014 $3,911
Anderson, Bradley NO ID Multi-Industry Sponsors - Bradley Anderson Scope Multiple Industry Sponsors 2/1/2011 - 1/31/2015
Anderson, Bradley 5R25CA153954-04 SCOPE: Carry-Forward--The University of Kentucky Cancer Nanotechnology Training Center (UK CNTC) National Cancer Institute 9/3/2010 - 7/31/2015
Anderson, Bradley 1R25CA153954-01 The University of Kentucky Cancer Nanotechnology Training Center (UK CNTC) $335,580 National Cancer Institute 9/3/2010 7/31/2015
Anderson, Bradley 5R25CA153954-02 The University of KY Cancer Nanotechnology Training Center (UK CNTC) $337,229 National Cancer Institute 9/3/2010 7/31/2015
Anderson, Bradley 5R25CA153954-03 The University of KY Cancer Nanotechnology Training Center (UK CNTC) $461,300 National Cancer Institute 9/3/2010 7/31/2015
Anderson, Bradley 5R25CA153954-04 The University of Kentucky Cancer Nanotechnology Training Center (UK CNTC) $442,640 National Cancer Institute 9/3/2010 7/31/2015
Anderson, Bradley 1U01FD004892-01 Evaluation of Dissolution Methods for Complex Parenteral Liposomal Formulations $402,158 Food and Drug Administration 9/15/2013 9/14/2014

NSF I/UCRC Center for Pharmaceutical Development.
Hoffman-La Roche, Inc.