Next Article in Journal
Docetaxel-Loaded Disulfide Cross-Linked Nanoparticles Derived from Thiolated Sodium Alginate for Colon Cancer Drug Delivery
Next Article in Special Issue
Effect of Formulation Factors and Oxygen Levels on the Stability of Aqueous Injectable Solution Containing Pemetrexed
Previous Article in Journal
Development of Level A In Vitro–Vivo Correlation for Electrosprayed Microspheres Containing Leuprolide: Physicochemical, Pharmacokinetic, and Pharmacodynamic Evaluation
Previous Article in Special Issue
Montelukast Nanocrystals for Transdermal Delivery with Improved Chemical Stability
Open AccessArticle

A Novel Testing Approach for Oxidative Degradation Dependent Incompatibility of Amine Moiety Containing Drugs with PEGs in Solid-State

1
Lek Pharmaceuticals d.d., Sandoz Development Center Slovenia, Verovškova ulica 57, SI-1526 Ljubljana, Slovenia
2
University of Ljubljana, Aškerčeva cesta 7, Faculty of Pharmacy, Chair of Medicinal Chemistry, SI-1000 Ljubljana, Slovenia
3
Department of Food Chemistry, National Institute of Chemistry, Hajdrihova 19, SI-1001 Ljubljana, Slovenia
*
Author to whom correspondence should be addressed.
Pharmaceutics 2020, 12(1), 37; https://doi.org/10.3390/pharmaceutics12010037
Received: 24 October 2019 / Revised: 3 December 2019 / Accepted: 24 December 2019 / Published: 2 January 2020
(This article belongs to the Special Issue Drug Stability and Stabilization Techniques)
Reactive impurities originating from excipients can cause drug stability issues, even at trace amounts. When produced during final dosage form storage, they are especially hard to control, and often, factors inducing their formation remain unidentified. Oxidative degradation dependent formation of formaldehyde and formic acid is responsible for N-methylation and N-formylation of amine-moiety-containing drug substances. A very popular combination of polyethylene glycols and iron oxides, used in more than two-thirds of FDA-approved tablet formulation drugs in 2018, was found to be responsible for increased concentrations of N-methyl impurity in the case of paroxetine hydrochloride. We propose a novel testing approach for early identification of potentially problematic combinations of excipients and drug substances. The polyethylene glycol 6000 degradation mechanism and kinetics in the presence of iron oxides is studied. The generality of the proposed stress test setup in view of the susceptibility of amine-moiety-containing drug substances to N-methylation and N-formylation is evaluated. View Full-Text
Keywords: reactive excipient impurities; polyethylene glycol (PEG); iron oxide (Fe2O3); compatibility studies; stress testing; N-methylation; N-formylation reactive excipient impurities; polyethylene glycol (PEG); iron oxide (Fe2O3); compatibility studies; stress testing; N-methylation; N-formylation
Show Figures

Graphical abstract

MDPI and ACS Style

Robnik, B.; Naumoska, K.; Časar, Z. A Novel Testing Approach for Oxidative Degradation Dependent Incompatibility of Amine Moiety Containing Drugs with PEGs in Solid-State. Pharmaceutics 2020, 12, 37.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop