Nanocrystal Dissolution Kinetics and Solubility Increase Prediction from Molecular Dynamics: The Case of alpha-, beta-, and gamma-Glycine

C Parks and A Koswara and HH Tung and NK Nere and S Bordawekar and ZK Nagy and D Ramkrishna, MOLECULAR PHARMACEUTICS, 14, 1023-1032 (2017).

DOI: 10.1021/acs.molpharmaceut6b00882

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 alpha-, beta-, and gamma-glycine. It is shown that only-the gamma-glycine form is predicted to have an increasing dissolution rate with decreasing particle size over the range of particle sizes:simulated. On the:contrary, gamma-glycine shows a Monotonically increasing dissolution rate with increasing particle size and dissolves at a rate 1.5 to 2 times larger than alpha- or beta-glycine. The accelerated dissolution rate of beta-glycine relative to the other two polymorphs correlates directly with the interfacial energy ranking of gamma > beta > alpha obtained from the dissolution simulations, where gamma- is predicted to have an interfacial energy roughly four times larger than either alpha- or beta-glycine. From the interfacial energies, alpha- and beta-glycine nanoparticles were predicted to experience modest solubility increases of up to 1.4 and 1.8 times the bulk solubility, where as gamma-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.

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