Delaying the First Nucleation Event of Amorphous Solid Dispersions Above the Polymer Overlap Concentration (c*): PVP and PVPVA in Posaconazole

Sichen Song; Xin Yao; Chenguang Wang; Changquan Calvin Sun; Ronald A Siegel

doi:10.1016/j.xphs.2024.04.026

Delaying the First Nucleation Event of Amorphous Solid Dispersions Above the Polymer Overlap Concentration (c*): PVP and PVPVA in Posaconazole

J Pharm Sci. 2024 Apr 28:S0022-3549(24)00154-0. doi: 10.1016/j.xphs.2024.04.026. Online ahead of print.

Authors

Sichen Song¹, Xin Yao², Chenguang Wang³, Changquan Calvin Sun³, Ronald A Siegel⁴

Affiliations

¹ Department of Pharmaceutics, University of Minnesota, Minneapolis, MN, 55455, United States; School of Mathematics, University of Minnesota, Minneapolis, MN, 55455, United States.
² School of Pharmacy, University of Wisconsin-Madison, Madison, WI, 53705, United States; Research and Development, AbbVie Inc., North Chicago, IL, 60064, United States.
³ Department of Pharmaceutics, University of Minnesota, Minneapolis, MN, 55455, United States.
⁴ Department of Pharmaceutics, University of Minnesota, Minneapolis, MN, 55455, United States; Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, 55455, United States. Electronic address: siege017@umn.edu.

PMID: 38685452
DOI: 10.1016/j.xphs.2024.04.026

Abstract

A thorough understanding of effects of polymers on crystallization of amorphous drugs is essential for rational design of robust amorphous solid dispersion (ASD), since crystallization of the amorphous drug negates their solubility advantage. In this work, we measured the first nucleation time (t₀, time to form the first critical nucleus in fresh liquid/glass) in posaconazole (POS)/polyvinylpyrrolidone vinyl acetate (PVPVA) and POS/polyvinylpyrrolidone (PVP K25) ASDs and showed that the polymer overlap concentration (c*, concentration above which adjacent polymer chains begin to contact) is critical in controlling crystallization of ASDs. When polymer concentration c < c*, t₀ of POS ASDs is approximately equal to that of the neat amorphous POS, but it increases significantly when c > c*. This observation supports the view that the effective inhibitory effect of crystallization in ASDs above c* is primarily correlated with delay in the first nucleation event. Our finding is useful in efficient polymer selection and performance prediction of high drug loaded ASD formulations.

Keywords: Amorphous solid dispersion (ASD); Crystal growth; Crystal nucleation; Physical stability; Polymer overlap concentration (c*).