Use of Activated Carbon in Packaging to Attenuate Formaldehyde-Induced and Formic Acid–Induced Degradation and Reduce Gelatin Cross-Linking in Solid Dosage Forms

Colgan, Stephen T.; Zelesky, Todd; Chen, Raymond; Likar, M. D.; MacDonald, Bruce C.; Hawkins, Joel M.; Carroll, Sophia C.; Johnson, Gail M.; Space, J. Sean; Jensen, James F.; DeMatteo, Vincent

doi:10.1016/j.xphs.2016.04.016

Cited by 5 publications

(2 citation statements)

References 12 publications

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“…Stock solutions of standards and samples were prepared in a concentration of about 1 mg/mL in methanol (paroxetine, desloratadine, vortioxetine) or in 60% methanol (varenicline and saxagliptin). Drug substance standards were further diluted with the corresponding solvent to obtain seven working solutions for plotting a calibration curve with the following concentrations (35,30,25,20,15,10, and 5 µg/mL). Standards of N-methyl and N-formyl impurities were first diluted to 25 and 10 µg/mL and, subsequently, to ten additional working solutions for plotting the calibration curves with the following concentrations (3000, 1500, 750, 375, 187.5, 93.7, 46.9, 23.4, 11.7, 5.8 ng/mL).…”

Section: Determination Of Drug Substances and N-methyl And N-formyl Dmentioning

confidence: 99%

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

2020

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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.

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Section: Determination Of Drug Substances and N-methyl And N-formyl Dmentioning

confidence: 99%

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

2020

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“…However, formaldehyde may negatively affect safety, efficacy, chemical stability, and performance of dosage forms, even in trace amounts. It can form adducts with many pharmaceuticals containing nucleophilic functional groups, especially amine and hydroxyl groups [1, 2, 4], such as gelatin [7], varenicline [8], irbesartan [9], phenylephrine [10], and GDC-0973 [11]. Some of these adducts may have toxic effects such as the degradation product of melatonine with formaldehyde [12].…”

Section: Introductionmentioning

confidence: 99%

A Robust Static Headspace GC-FID Method to Detect and Quantify Formaldehyde Impurity in Pharmaceutical Excipients

Daoudy

Al-Khayat

Karabet

et al. 2018

Journal of Analytical Methods in Chemistry

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Formaldehyde is a highly reactive impurity that can be found in many pharmaceutical excipients. Trace levels of this impurity may affect drug product stability, safety, efficacy, and performance. A static headspace gas chromatographic method was developed and validated to determine formaldehyde in pharmaceutical excipients after an effective derivatization procedure using acidified ethanol. Diethoxymethane, the derivative of formaldehyde, was then directly analyzed by GC-FID. Despite the simplicity of the developed method, however, it is characterized by its specificity, accuracy, and precision. The limits of detection and quantification of formaldehyde in the samples were of 2.44 and 8.12 µg/g, respectively. This method is characterized by using simple and economic GC-FID technique instead of MS detection, and it is successfully used to analyze formaldehyde in commonly used pharmaceutical excipients.

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Identification and structure elucidation of a new degradation impurity in the multi-component tablets of amlodipine besylate

Gibala¹,

Douša²,

Kalužíková

et al. 2019

Journal of Pharmaceutical and Biomedical Analysis

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Use of Activated Carbon in Packaging to Attenuate Formaldehyde-Induced and Formic Acid–Induced Degradation and Reduce Gelatin Cross-Linking in Solid Dosage Forms

Cited by 5 publications

References 12 publications

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

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

A Robust Static Headspace GC-FID Method to Detect and Quantify Formaldehyde Impurity in Pharmaceutical Excipients

Identification and structure elucidation of a new degradation impurity in the multi-component tablets of amlodipine besylate

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