Origin of Nanodroplet Formation Upon Dissolution of an Amorphous Solid Dispersion: A Mechanistic Isotope Scrambling Study.

Autor:	Indulkar AS; Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907., Waters JE; Structural Chemistry, Research and Development, AbbVie Inc., North Chicago, Illinois 60064., Mo H; Purdue Interdepartmental NMR Facility, Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907., Gao Y; Manufacturing Science & Technology (MS&T), Operations, AbbVie Inc., North Chicago, Illinois 60064., Raina SA; Manufacturing Science & Technology (MS&T), Operations, AbbVie Inc., North Chicago, Illinois 60064., Zhang GGZ; Drug Product Development, Research and Development, AbbVie Inc., North Chicago, Illinois 60064. Electronic address: Geoff.GZ.Zhang@abbvie.com., Taylor LS; Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907. Electronic address: lstaylor@purdue.edu.
Jazyk:	angličtina
Zdroj:	Journal of pharmaceutical sciences [J Pharm Sci] 2017 Aug; Vol. 106 (8), pp. 1998-2008. Date of Electronic Publication: 2017 Apr 19.
DOI:	10.1016/j.xphs.2017.04.015
Abstrakt:	It has been observed that certain amorphous solid dispersions (ASDs), upon dissolution, generate drug-rich amorphous nanodroplets. These nanodroplets, present as a dispersed phase, can potentially enhance oral bioavailability of poorly soluble drugs by serving as a drug reservoir that efficiently feeds the continuous aqueous solution phase following absorption of drug. The purpose of this study is to probe the formation mechanism of the nanodroplets. The model system studied was nifedipine (NFD) formulated as an ASD with hydroxypropyl methylcellulose E5 Premium LV or polyvinylpyrrolidone/vinyl acetate. Dissolution of ASDs prepared with proteated nifedipine (H-NFD) was carried out in a medium saturated with deuterated nifedipine (D-NFD) at the amorphous solubility. Upon dissolution, the H/D composition of NFD aqueous solution was determined using nuclear magnetic resonance spectroscopy. The results suggested that isotopic scrambling (equilibrium in the distribution of deuterated and proteated form of the drug) had occurred. Thus, as the H-NFD was brought into the aqueous solution via ASD dissolution, the drug concentration in solution exceeded the amorphous solubility. Subsequent precipitation of the drug, a process which does not differentiate H-NFD from D-NFD, generated NFD nanodroplets and resulted in redistribution of the isotopes. Thus, nanodroplets of NFD are formed due to dissolution of these homogenous ASDs followed by precipitation of the drug from aqueous solutions. (Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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