title: Nanocrystal Dissolution Kinetics and Solubility Increase Prediction from Molecular Dynamics: The Case of α-, β-, and γ-Glycine.
abstract: Nanocrystals are receiving increased attention for pharmaceutical applications due to their enhanced solubility relative to their micron-sized counterpart and, in turn, potentially increased bioavailability. In this work, a computational method is proposed to predict the following: (1) polymorph specific dissolution kinetics and (2) the multiplicative increase in the polymorph specific nanocrystal solubility relative to the bulk solubility. The method uses a combination of molecular dynamics and a parametric particle size dependent mass transfer model. The method is demonstrated using a case study of α-, β-, and γ-glycine. It is shown that only the α-glycine form is predicted to have an increasing dissolution rate with decreasing particle size over the range of particle sizes simulated. On the contrary, γ-glycine shows a monotonically increasing dissolution rate with increasing particle size and dissolves at a rate 1.5 to 2 times larger than α- or β-glycine. The accelerated dissolution rate of γ-glycine relative to the other two polymorphs correlates directly with the interfacial energy ranking of γ > β > α obtained from the dissolution simulations, where γ- is predicted to have an interfacial energy roughly four times larger than either α- or β-glycine. From the interfacial energies, α- and β-glycine nanoparticles were predicted to experience modest solubility increases of up to 1.4 and 1.8 times the bulk solubility, where as γ-glycine showed upward of an 8 times amplification in the solubility. These MD simulations represent a first attempt at a computational (pre)screening method for the rational design of experiments for future engineering of nanocrystal API formulations.
authors.affiliation: School of Chemical Engineering, Purdue University , 480 West Stadium Mall, West Lafayette, Indiana 47907, United States.
authors.forename: Conor
authors.initials: C
authors.lastname: Parks
authors.affiliation: School of Chemical Engineering, Purdue University , 480 West Stadium Mall, West Lafayette, Indiana 47907, United States.
authors.forename: Andy
authors.initials: A
authors.lastname: Koswara
authors.affiliation: Process Research & Development, AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Hsien-Hsin
authors.initials: HH
authors.lastname: Tung
authors.affiliation: Process Research & Development, AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Nandkishor K
authors.initials: NK
authors.lastname: Nere
authors.affiliation: Process Research & Development, AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Shailendra
authors.initials: S
authors.lastname: Bordawekar
authors.affiliation: School of Chemical Engineering, Purdue University , 480 West Stadium Mall, West Lafayette, Indiana 47907, United States.
authors.forename: Zoltan K
authors.initials: ZK
authors.lastname: Nagy
authors.affiliation: School of Chemical Engineering, Purdue University , 480 West Stadium Mall, West Lafayette, Indiana 47907, United States.
authors.forename: Doraiswami
authors.identifier: 0000-0001-8158-5116
authors.initials: D
authors.lastname: Ramkrishna
mesh_terms: D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods; D005998:Glycine / Q000737:chemistry*; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D012995:Solubility
chemical_list: D005998:Glycine
keywords: bioavailability; dissolution rate; molecular dynamics simulation; nanocrystal; polymorph; solubility