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Method Development and Applications for Reduced-Risk Products in Separation Science

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A special issue of Separations (ISSN 2297-8739). This special issue belongs to the section "Analysis of Natural Products and Pharmaceuticals".

Deadline for manuscript submissions: closed (15 January 2022) | Viewed by 45304

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Special Issue Editor

Dr. Fadi Aldeek

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Guest Editor

Center for Research & Technology, Analytical Sciences Department, Altria Client Services LLC, Richmond, Virginia, United States
Interests: tobacco harm reduction; reduced-risk products; analytical chemistry; extraction techniques; HPLC; mass spectrometry; dissolution testing; method development; method validation; chemical residues; nanomaterials; molecular biotechnology; coordinating ligands synthesis; surface chemistry; bioconjugation; spectroscopy; structural characterizations; bioanalytical assays; bacterial biofilm

Special Issue Information

Dear Colleagues,

A strong public health consensus has formed that not all tobacco products present the same risk. Public health authorities agree that there is a broad continuum of risk among tobacco products, with cigarettes at the highest end of that spectrum due to the tobacco-burning process. Noncombustible, reduced-risk products may offer a promising opportunity to reduce the harm associated with tobacco use for adults who continue to use tobacco products. These products include a variety of traditional smokeless tobacco products, modern nicotine products, heat-not-burn products, and electronic cigarettes.

Industry, academia, and public health researchers are working to develop and validate new analytical methods to extract, separate, identify, and determine a variety of analytes from potentially reduced-risk products using a wide range of chromatographic and detection techniques. These analytes include constituents, flavors, ingredients, harmful and potentially harmful constituents (HPHCs), and unknowns. The accurate identification and determination of these analytes is critical to assessing product performance and ensuring quality data for regulatory reporting.

This Special Issue invites contributions on the current advances in the development and application of analytical methods for the determination of analytes from potentially reduced-risk products.

Dr. Fadi Aldeek
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Separations is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

tobacco harm reduction
reduced-risk products
analytical chemistry
extraction techniques
sample preparation
separation techniques
chromatography
detection techniques
flavors
constituenets
HPHCs
target and non-targeted analyses
product characterizations
structural characterizations
method development
method validation
method applications

Published Papers (10 papers)

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Editorial

Jump to: Research

7 pages, 198 KiB

Open AccessEditorial

Method Development and Applications for Reduced-Risk Products

by Fadi Aldeek and Mohamadi A. Sarkar

Separations 2022, 9(3), 78; https://doi.org/10.3390/separations9030078 - 18 Mar 2022

Cited by 1 | Viewed by 2246

Abstract

Cigarette smoking remains the leading cause of preventable premature death and disease in the U [...] Full article

(This article belongs to the Special Issue Method Development and Applications for Reduced-Risk Products in Separation Science)

Research

Jump to: Editorial

15 pages, 1425 KiB

Open AccessArticle

Market Survey of Modern Oral Nicotine Products: Determination of Select HPHCs and Comparison to Traditional Smokeless Tobacco Products

by Joseph J. Jablonski, Andrew G. Cheetham and Alexandra M. Martin

Separations 2022, 9(3), 65; https://doi.org/10.3390/separations9030065 - 02 Mar 2022

Cited by 8 | Viewed by 7630

Abstract

In an effort to combat the risks associated with traditional tobacco products, tobacco product innovation has been redirected towards reducing the consumer’s potential exposure to harmful or potentially harmful constituents (HPHCs). Among these innovations are modern oral nicotine products (MONPs). This product class aims to deliver nicotine while limiting the consumer’s potential toxicant exposure. This body of work sought to investigate the potential for select HPHC exposure (tobacco-specific nitrosamines, carbonyls, benzo[a]pyrene, nitrite, and metals) from MONPs and to compare it to that from traditional tobacco products. This work expands on previously published studies both in terms of diversity of products assessed and analytes tested. In total, twenty-one unique MONPs were assessed and compared to four traditional tobacco products. We found that there was a difference in the potential exposure based on the MONP filler—plant material vs. granulate/powder. Typically, the HPHC levels observed in plant-based MONPs were higher than those observed for granulate/powder products, most notably within the metals analysis, for which the levels were occasionally greater than those seen in traditional smokeless tobacco products. Generally, the overall HPHC levels observed in MONP were at or below those levels observed in traditional tobacco products. Full article

(This article belongs to the Special Issue Method Development and Applications for Reduced-Risk Products in Separation Science)

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Graphical abstract

8 pages, 1626 KiB

Open AccessArticle

Introducing a Novel Biorelevant In Vitro Dissolution Method for the Assessment of Nicotine Release from Oral Tobacco-Derived Nicotine (OTDN) and Snus Products

by Matthias M. Knopp, Nikolai K. Kiil-Nielsen, Anna E. Masser and Mikael Staaf

Separations 2022, 9(2), 52; https://doi.org/10.3390/separations9020052 - 15 Feb 2022

Cited by 2 | Viewed by 3600

Abstract

The rate at which oral tobacco-derived nicotine (OTDN) and snus pouches release nicotine into saliva is crucial to determine product performance. As no standardized method is available for this purpose, this study sought to develop a biorelevant dissolution method that could both discriminate between different products and predict in vivo behavior. Using a μDISS Profiler™ as a surrogate for the US Pharmacopoeia standard apparatuses and a custom-made sinker, nicotine release from an OTDN pouch product (ZYN^® Dry Smooth) and a snus product (General^® Pouched Snus White Portion Large) was determined in biorelevant volumes (10 mL) of artificial saliva. In addition, nicotine extraction in vivo was measured for both products. Strikingly, the method showed distinct dissolution curves for OTDN and snus pouches, and the nicotine release observed in vitro did not significantly differ from the nicotine extracted in vivo. The custom-made sinker was designed to accommodate both loose and pouched oral tobacco/nicotine products, and thus the proposed in vitro dissolution method is suitable to assess nicotine release from OTDN and snus pouches. Apart from providing individual dissolution curves, the method was also able to predict in vivo nicotine extraction. Thus, this method could serve as a (biorelevant) monograph for product equivalence studies. Full article

(This article belongs to the Special Issue Method Development and Applications for Reduced-Risk Products in Separation Science)

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15 pages, 1280 KiB

Open AccessArticle

1,2-Propylene Glycol: A Biomarker of Exposure Specific to e-Cigarette Consumption

by Therese Burkhardt, Nikola Pluym, Gerhard Scherer and Max Scherer

Separations 2021, 8(10), 180; https://doi.org/10.3390/separations8100180 - 09 Oct 2021

Cited by 7 | Viewed by 3678

Abstract

Over the past decade, new emerging tobacco and nicotine-delivery products have changed the tobacco landscape. Especially, electronic cigarettes (ECs) have been suggested to be considered for tobacco harm reduction, reinforcing the need to identify novel biomarkers of exposure (BoE) specific to the EC use as this would complement exposure assessment and product compliance monitoring. Therefore, a sensitive LC-MS/MS method for the quantification of 1,2-propylene glycol (PG) and glycerol (G), the main e-liquid constituents, was established. PG and G were analyzed in plasma and urine samples from a clinical study comparing five nicotine product user groups, users of combustible cigarettes (CC), electronic cigarettes (EC), heated tobacco products (HTP), oral tobacco (OT), and oral/dermal nicotine delivery products (used for nicotine replacement therapy, NRT) with a control group of non-users (NU). Data demonstrate significantly elevated PG levels in urine and plasma in EC users compared to users of CC, HTP, NRT, OT as well as NU. In addition, PG in plasma and urine of vapers significantly correlated with nicotine (plasma) and total nicotine equivalents (urine), biomarkers reflecting product consumption, emphasizing the high specificity of PG as a BoE for EC consumption. We therefore suggest the use of PG as BoE in urine and/or plasma in order to monitor EC use compliance in exposure assessments. Full article

(This article belongs to the Special Issue Method Development and Applications for Reduced-Risk Products in Separation Science)

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Graphical abstract

15 pages, 1526 KiB

Open AccessArticle

A Sensitive LC–MS/MS Method for the Quantification of 3-Hydroxybenzo[a]pyrene in Urine-Exposure Assessment in Smokers and Users of Potentially Reduced-Risk Products

by Nadine Rögner, Heinz-Werner Hagedorn, Gerhard Scherer, Max Scherer and Nikola Pluym

Separations 2021, 8(10), 171; https://doi.org/10.3390/separations8100171 - 05 Oct 2021

Cited by 11 | Viewed by 2418

Abstract

Benzo[a]pyrene (BaP), a human carcinogen, is formed during the incomplete combustion of organic matter such as tobacco. A suitable biomarker of exposure is the monohydroxylated metabolite 3-hydroxybenzo[a]pyrene (3-OH-BaP). We developed a sensitive LC–MS/MS (liquid chromatography coupled with tandem mass spectrometry) method for the quantification of urinary 3-OH-BaP. The method was validated according to the US Food and Drug Administration (FDA) guideline for bioanalytical method validation and showed excellent results in terms of accuracy, precision, and sensitivity (lower limit of quantification (LLOQ): 50 pg/L). The method was applied to urine samples derived from a controlled clinical study to compare exposure from cigarette smoking to the use of potentially reduced-risk products. Urinary 3-OH-BaP concentrations were significantly higher in smokers of conventional cigarettes (149 pg/24 h) compared to users of potentially reduced-risk products as well as non-users (99% < LLOQ in these groups). In conclusion, 3-OH-BaP is a suitable biomarker to assess the exposure to BaP in non-occupationally exposed populations and to distinguish not only cigarette smokers from non-smokers but also from users of potentially reduced-risk products. Full article

(This article belongs to the Special Issue Method Development and Applications for Reduced-Risk Products in Separation Science)

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17 pages, 312 KiB

Open AccessArticle

Targeted Characterization of the Chemical Composition of JUUL Systems Aerosol and Comparison with 3R4F Reference Cigarettes and IQOS Heat Sticks

by Xin Chen, Patrick C. Bailey, Clarissa Yang, Bryant Hiraki, Michael J. Oldham and I. Gene Gillman

Separations 2021, 8(10), 168; https://doi.org/10.3390/separations8100168 - 03 Oct 2021

Cited by 15 | Viewed by 4048

Abstract

Aerosol constituent yields have been reported from a wide range of electronic nicotine delivery systems. No comprehensive study has been published on the aerosol constituents generated from the JUUL system. Targeted analyses of 53 aerosol constituents from the four JUUL products currently on the US market (Virginia Tobacco and Menthol flavored e-liquids in both 5.0% and 3.0% nicotine concentration by weight) was performed using non-intense and intense puffing regimens. All measurements were conducted by an ISO 17025 accredited contract research organization. JUUL product aerosol constituents were compared to published values for the 3R4F research cigarette and IQOS Regular and Menthol heated tobacco products. Across the four JUUL products and two puffing regimes, only 10/53 analytes were quantifiable, including only two carbonyls (known propylene glycol or glycerol degradants). The remaining analytes were primary ingredients, nicotine degradants and water. Average analyte reductions (excluding primary ingredients and water) for all four JUUL system aerosols tested were greater than 98% lower than 3R4F mainstream smoke, and greater than 88% lower than IQOS aerosol. In summary, chemical characterization and evaluation of JUUL product aerosols demonstrates a significant reduction in toxicants when compared to mainstream cigarette smoke from 3R4F reference cigarettes or aerosols from IQOS-heated tobacco products. Full article

(This article belongs to the Special Issue Method Development and Applications for Reduced-Risk Products in Separation Science)

17 pages, 2848 KiB

Open AccessArticle

Determination of Formaldehyde Yields in E-Cigarette Aerosols: An Evaluation of the Efficiency of the DNPH Derivatization Method

by Xiaohong C. Jin, Regina M. Ballentine, William P. Gardner, Matt S. Melvin, Yezdi B. Pithawalla, Karl A. Wagner, Karen C. Avery and Mehran Sharifi

Separations 2021, 8(9), 151; https://doi.org/10.3390/separations8090151 - 13 Sep 2021

Cited by 4 | Viewed by 2935

Abstract

Recent reports have suggested that (1) formaldehyde levels (measured as a hydrazone derivative using the DNPH derivatization method) in Electronic Nicotine Delivery Systems (ENDS) products were underreported because formaldehyde may react with propylene glycol (PG) and glycerin (Gly) in the aerosol to form hemiacetals; (2) the equilibrium would shift from the hemiacetals to the acetals in the acidic DNPH trapping solution. In both cases, neither the hemiacetal nor the acetal would react with DNPH to form the target formaldehyde hydrazone, due to the lack of the carbonyl functional group, thus underreporting formaldehyde. These reports were studied in our laboratory. Our results showed that the aerosol generated from formaldehyde-fortified e-liquids provided a near-quantitative recovery of formaldehyde in the aerosol, suggesting that if any hemiacetal was formed in the aerosol, it would readily hydrolyze to free formaldehyde and, consequently, form formaldehyde hydrazone in the acidic DNPH trapping solution. We demonstrated that custom-synthesized Gly and PG hemiacetal adducts added to the DNPH trapping solution would readily hydrolyze to form the formaldehyde hydrazone. We demonstrated that acetals of PG and Gly present in e-liquid are almost completely transferred to the aerosol during aerosolization. The study results demonstrate that the DNPH derivatization method allows for an accurate measurement of formaldehyde in vapor products. Full article

(This article belongs to the Special Issue Method Development and Applications for Reduced-Risk Products in Separation Science)

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19 pages, 1369 KiB

Open AccessArticle

Non-Targeted Chemical Characterization of JUUL Virginia Tobacco Flavored Aerosols Using Liquid and Gas Chromatography

by Mark R. Crosswhite, Patrick C. Bailey, Lena N. Jeong, Anastasia Lioubomirov, Clarissa Yang, Adam Ozvald, J. Brian Jameson and I. Gene Gillman

Separations 2021, 8(9), 130; https://doi.org/10.3390/separations8090130 - 24 Aug 2021

Cited by 14 | Viewed by 4610

Abstract

The chemical constituents of JUUL Virginia Tobacco pods with 3.0% and 5.0% nicotine by weight (VT3 and VT5) were characterized by non-targeted analyses, an approach to detect chemicals that are not otherwise measured with dedicated methods or that are not known beforehand. Aerosols were generated using intense and non-intense puffing regimens and analyzed by gas chromatography electron ionization mass spectrometry and liquid chromatography electrospray ionization high resolving power mass spectrometry. All compounds above 0.7 µg/g for GC–MS analysis or above 0.5 µg/g for LC–HRMS analysis and differing from blank measurements were identified and semi-quantified. All identifications were evaluated and categorized into five groups: flavorants, harmful and potentially harmful constituents, extractables and/or leachables, reaction products, and compounds that could not be identified/rationalized. For VT3, 79 compounds were identified using an intense puffing regimen and 69 using a non-intense puffing regimen. There were 60 compounds common between both regimens. For VT5, 85 compounds were identified with an intense puffing regimen and 73 with a non-intense puffing regimen; 67 compounds were in common. For all nicotine concentrations, formulations and puffing regimens, reaction products accounted for the greatest number of compounds (ranging from 70% to 75%; 0.08% to 0.1% by mass), and flavorants comprised the second largest number of compounds (ranging from for 15% to 16%; 0.1 to 0.2% by mass). A global comparison of the compounds detected in JUUL aerosol to those catalogued in cigarette smoke indicated an approximate 50-fold decrease in chemical complexity. Both VT3 and VT5 aerosols contained 59 unique compounds not identified in cigarette smoke. Full article

(This article belongs to the Special Issue Method Development and Applications for Reduced-Risk Products in Separation Science)

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10 pages, 266 KiB

Open AccessArticle

Determination of Nicotine-Related Impurities in Nicotine Pouches and Tobacco-Containing Products by Liquid Chromatography–Tandem Mass Spectrometry

by Rozanna Avagyan, Maya Spasova and Johan Lindholm

Separations 2021, 8(6), 77; https://doi.org/10.3390/separations8060077 - 03 Jun 2021

Cited by 8 | Viewed by 4774

Abstract

Smokeless tobacco products and nicotine-containing tobacco-free oral pouches have increased in popularity in recent years. They are associated with far fewer health hazards compared to cigarettes. Nicotine pouches are filled with non-tobacco filler and nicotine. The nicotine used in nicotine pouches usually comes from the extraction of tobacco; thus, related alkaloids may be found as impurities at low levels. Moreover, nicotine degradation products are formed because of microbial action, flavor oxidation, exposure to high temperatures etc. Currently, there are no published or recommended methods for the analysis of nicotine degradants in nicotine pouches. Here, we present a sensitive and selective liquid chromatography–tandem mass spectrometry method for the simultaneous determination of seven nicotine-related impurities. All seven analytes and corresponding deuterated internal standards were separated within 3.5 min, including 1 min equilibration. The method was fully validated, showing good linearity with correlation coefficients >0.996 for all analytes, good extraction yields ranging from 78% to 110%, limits of detection between 0.08 and 0.56 µg/g and limits of quantification between 0.27 and 2.04 µg/g. Although the method was mainly developed to determine the degradants of nicotine in nicotine pouches, it was validated and performed well on a broader range of tobacco-containing products. Full article

(This article belongs to the Special Issue Method Development and Applications for Reduced-Risk Products in Separation Science)

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13 pages, 2151 KiB

Open AccessArticle

Dissolution Testing of Nicotine Release from OTDN Pouches: Product Characterization and Product-to-Product Comparison

by Fadi Aldeek, Nicholas McCutcheon, Cameron Smith, John H. Miller and Timothy L. Danielson

Separations 2021, 8(1), 7; https://doi.org/10.3390/separations8010007 - 07 Jan 2021

Cited by 15 | Viewed by 7028

Abstract

In recent years, oral tobacco-derived nicotine (OTDN) pouches have emerged as a new oral tobacco product category. They are available in a variety of flavors and do not contain cut or ground tobacco leaf. The on!^® nicotine pouches fall within this category of OTDN products and are currently marketed in seven (7) flavors with five (5) different nicotine levels. Evaluation of the nicotine release from these products is valuable for product assessment and product-to-product comparisons. In this work, we characterized the in vitro release profiles of nicotine from the 35 varieties of on!^® nicotine pouches using a fit-for-purpose dissolution method, employing the U.S. Pharmacopeia flow-through cell dissolution apparatus 4 (USP-4). The nicotine release profiles were compared using the FDA’s Guidance for Industry: Dissolution Testing of Immediate Release Solid Oral Dosage Forms. The cumulative release profiles of nicotine show a dose dependent response for all nicotine levels. The on!^® nicotine pouches exhibit equivalent percent nicotine release rates for each flavor variant across all nicotine levels. Furthermore, the nicotine release profiles from on!^® nicotine pouches were compared to a variety of other commercially available OTDN pouches and traditional pouched smokeless tobacco products. The percent nicotine release rates were found to be dependent on the product characteristics, showing similarities and differences in the nicotine release profiles between the on!^® nicotine pouches and other compared products. Full article

(This article belongs to the Special Issue Method Development and Applications for Reduced-Risk Products in Separation Science)

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