(713d) Nanocrystal Dissolution Kinetics and Solubility Increase from Molecular Dynamics – the Case of Alpha and Beta Glycine

Authors: 
Parks, C., Purdue
Koswara, A., Purdue University
Tung, H. H., AbbVie Inc.
Nere, N., AbbVie Inc.
Bordawekar, S., AbbVie Inc.
Nagy, Z. K., Purdue University
Ramkrishna, D., Purdue University
The physics of crystal active pharmaceutical ingredient (API) dissolution is an essential step in the ingestion of a solid oral API tablet. Poor dissolution, and hence bioavailability, can result in insufficient amount of active drug being transported to the target, resulting in suboptimal treatment for the patient. It is estimated that as high as 60% of newly discovered APIs (active pharmaceutical ingredients) possess poor aqueous solubility (<0.1g/ml). Nanocrystal API synthesis offers an intriguing method to combat this issue. Due to the increased surface area to volume ratio, nanocrystals demonstrate an increased solubility, dictated by the interfacial free energy of the nanocrystal, when compared to micron-sized particles. This solubility increase is encapsulated in the Ostwald-Freundlich equation. It is essential to understand that the parameters, most importantly the interfacial free energy , in the Ostwald-Freundlich equation are polymorph specific quantities for a given solvent. Therefore, the polymorph solubility rankings in a given solvent at bulk length scales need not apply for nanoparticles. The incorporation of the polymorph specific size dependent solubility term in classical dissolution models, and the competition between decreasing surface area (smaller particle) and solubility increase, remains largely unaddressed.

Molecular dynamics (MD) provides a first principles simulation procedure capable of simulating the dissolution process for nanoparticles on the size of a critical cluster (~2nm). In this work, a combination of first principles molecular dynamics and classical dissolution models are used to determine (1) the polymorph specific dissolution kinetics and (2) the multiplicative increase in the polymorph specific nanocrystal solubility relative to the bulk solubility for alpha and beta glycine. Alpha and beta glycine seed clusters, with varying radii, are embedded in a MD simulation domain consisting of water. This simulation set up is used to generate crystal size and polymorph specific dissolution data. The effects of the various polymorph specific model parameters (mass transfer coefficient, diffusion layer thickness, and interfacial free energy) are used to analyze the dissolution rates of the polymorphs, as well as the increase in the solubility, as a function of the particle sizes simulated.