A review of emerging technologies enabling improved solid oral dosage form manufacturing and processing
Emerging technologies enabling improved solid oral dosage form manufacturing and processing. [Display omitted] Tablets are the most widely utilized solid oral dosage forms because of the advantages of self-administration, stability, ease of handling, transportation, and good patient compliance. Over...
Gespeichert in:
Veröffentlicht in: | Advanced drug delivery reviews 2021-11, Vol.178, p.113840-113840, Article 113840 |
---|---|
Hauptverfasser: | , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | 113840 |
---|---|
container_issue | |
container_start_page | 113840 |
container_title | Advanced drug delivery reviews |
container_volume | 178 |
creator | Sohail Arshad, Muhammad Zafar, Saman Yousef, Bushra Alyassin, Yasmine Ali, Radeyah AlAsiri, Ali Chang, Ming-Wei Ahmad, Zeeshan Ali Elkordy, Amal Faheem, Ahmed Pitt, Kendal |
description | Emerging technologies enabling improved solid oral dosage form manufacturing and processing.
[Display omitted]
Tablets are the most widely utilized solid oral dosage forms because of the advantages of self-administration, stability, ease of handling, transportation, and good patient compliance. Over time, extensive advances have been made in tableting technology. This review aims to provide an insight about the advances in tablet excipients, manufacturing, analytical techniques and deployment of Quality by Design (QbD). Various excipients offering novel functionalities such as solubility enhancement, super-disintegration, taste masking and drug release modifications have been developed. Furthermore, co-processed multifunctional ready-to-use excipients, particularly for tablet dosage forms, have benefitted manufacturing with shorter processing times. Advances in granulation methods, including moist, thermal adhesion, steam, melt, freeze, foam, reverse wet and pneumatic dry granulation, have been proposed to improve product and process performance. Furthermore, methods for particle engineering including hot melt extrusion, extrusion-spheronization, injection molding, spray drying / congealing, co-precipitation and nanotechnology-based approaches have been employed to produce robust tablet formulations. A wide range of tableting technologies including rapidly disintegrating, matrix, tablet-in-tablet, tablet-in-capsule, multilayer tablets and multiparticulate systems have been developed to achieve customized formulation performance. In addition to conventional invasive characterization methods, novel techniques based on laser, tomography, fluorescence, spectroscopy and acoustic approaches have been developed to assess the physical–mechanical attributes of tablet formulations in a non- or minimally invasive manner. Conventional UV–Visible spectroscopy method has been improved (e.g. fiber-optic probes and UV imaging-based approaches) to efficiently record the dissolution profile of tablet formulations. Numerous modifications in tableting presses have also been made to aid machine product changeover, cleaning, and enhance efficiency and productivity. Various process analytical technologies have been employed to track the formulation properties and critical process parameters. These advances will contribute to a strategy for robust tablet dosage forms with excellent performance attributes. |
doi_str_mv | 10.1016/j.addr.2021.113840 |
format | Article |
fullrecord | <record><control><sourceid>proquest_webof</sourceid><recordid>TN_cdi_webofscience_primary_000719295100011</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0169409X21002325</els_id><sourcerecordid>2543706356</sourcerecordid><originalsourceid>FETCH-LOGICAL-c400t-a0b6bb692a4e61060a80760cf2e257a766e4f032f77b24d1558354306a12b2f33</originalsourceid><addsrcrecordid>eNqNkUuL1TAYhoMozvHoH3AhWQrS45dL0xbcDIfxAgNuFNyFNPlyzKFtxqSdwX9vSo-zFFe58LxvkieEvGZwYMDU-_PBOJcOHDg7MCZaCU_IjrUNr1reyadkV6CuktD9uCIvcj4DMN4oeE6uhGSyqYXYkdM1TXgf8IFGT3HEdArTic5of05xiKeAmeJk-mHdDeNdivfoaI5DcDQmM1AXszkh9TGNdDTT4o2dl7TSZnK08BZzLsuX5Jk3Q8ZXl3FPvn-8-Xb8XN1-_fTleH1bWQkwVwZ61feq40aiYqDAtFCubD1HXjemUQqlB8F90_RcOlbXrailAGUY77kXYk_ebr3l6F8L5lmPIVscBjNhXLLmhW5AiVoVlG-oTTHnhF7fpTCa9Fsz0KtgfdarYL0K1pvgEnpz6V_6Ed1j5K_RArzbgAfso8824GTxEQOAhnW8q1mZlco9af-fPobZzCFOx7hMc4l-2KJYdJYfTPoSdyGhnbWL4V8P-QPLQ60E</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2543706356</pqid></control><display><type>article</type><title>A review of emerging technologies enabling improved solid oral dosage form manufacturing and processing</title><source>MEDLINE</source><source>Web of Science - Science Citation Index Expanded - 2021<img src="https://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /></source><source>Access via ScienceDirect (Elsevier)</source><creator>Sohail Arshad, Muhammad ; Zafar, Saman ; Yousef, Bushra ; Alyassin, Yasmine ; Ali, Radeyah ; AlAsiri, Ali ; Chang, Ming-Wei ; Ahmad, Zeeshan ; Ali Elkordy, Amal ; Faheem, Ahmed ; Pitt, Kendal</creator><creatorcontrib>Sohail Arshad, Muhammad ; Zafar, Saman ; Yousef, Bushra ; Alyassin, Yasmine ; Ali, Radeyah ; AlAsiri, Ali ; Chang, Ming-Wei ; Ahmad, Zeeshan ; Ali Elkordy, Amal ; Faheem, Ahmed ; Pitt, Kendal</creatorcontrib><description>Emerging technologies enabling improved solid oral dosage form manufacturing and processing.
[Display omitted]
Tablets are the most widely utilized solid oral dosage forms because of the advantages of self-administration, stability, ease of handling, transportation, and good patient compliance. Over time, extensive advances have been made in tableting technology. This review aims to provide an insight about the advances in tablet excipients, manufacturing, analytical techniques and deployment of Quality by Design (QbD). Various excipients offering novel functionalities such as solubility enhancement, super-disintegration, taste masking and drug release modifications have been developed. Furthermore, co-processed multifunctional ready-to-use excipients, particularly for tablet dosage forms, have benefitted manufacturing with shorter processing times. Advances in granulation methods, including moist, thermal adhesion, steam, melt, freeze, foam, reverse wet and pneumatic dry granulation, have been proposed to improve product and process performance. Furthermore, methods for particle engineering including hot melt extrusion, extrusion-spheronization, injection molding, spray drying / congealing, co-precipitation and nanotechnology-based approaches have been employed to produce robust tablet formulations. A wide range of tableting technologies including rapidly disintegrating, matrix, tablet-in-tablet, tablet-in-capsule, multilayer tablets and multiparticulate systems have been developed to achieve customized formulation performance. In addition to conventional invasive characterization methods, novel techniques based on laser, tomography, fluorescence, spectroscopy and acoustic approaches have been developed to assess the physical–mechanical attributes of tablet formulations in a non- or minimally invasive manner. Conventional UV–Visible spectroscopy method has been improved (e.g. fiber-optic probes and UV imaging-based approaches) to efficiently record the dissolution profile of tablet formulations. Numerous modifications in tableting presses have also been made to aid machine product changeover, cleaning, and enhance efficiency and productivity. Various process analytical technologies have been employed to track the formulation properties and critical process parameters. These advances will contribute to a strategy for robust tablet dosage forms with excellent performance attributes.</description><identifier>ISSN: 0169-409X</identifier><identifier>EISSN: 1872-8294</identifier><identifier>DOI: 10.1016/j.addr.2021.113840</identifier><identifier>PMID: 34147533</identifier><language>eng</language><publisher>AMSTERDAM: Elsevier B.V</publisher><subject>Administration, Oral ; Capsule, analytical methodology ; Continuous manufacturing ; Drug Compounding ; Granulation ; Hot melt extrusion ; Humans ; Life Sciences & Biomedicine ; Multilayer tablets ; Nanotechnology ; Oral solid dose ; Pharmaceutical Preparations - administration & dosage ; Pharmaceutical Preparations - chemistry ; Pharmacology & Pharmacy ; Quality by design, excipients ; Science & Technology ; Tablet ; Technology, Pharmaceutical</subject><ispartof>Advanced drug delivery reviews, 2021-11, Vol.178, p.113840-113840, Article 113840</ispartof><rights>2021 Elsevier B.V.</rights><rights>Copyright © 2021 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>63</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000719295100011</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c400t-a0b6bb692a4e61060a80760cf2e257a766e4f032f77b24d1558354306a12b2f33</citedby><cites>FETCH-LOGICAL-c400t-a0b6bb692a4e61060a80760cf2e257a766e4f032f77b24d1558354306a12b2f33</cites><orcidid>0000-0002-9796-4150 ; 0000-0001-9807-5841 ; 0000-0002-0781-1127</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.addr.2021.113840$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>315,781,785,3551,27929,27930,39263,46000</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34147533$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sohail Arshad, Muhammad</creatorcontrib><creatorcontrib>Zafar, Saman</creatorcontrib><creatorcontrib>Yousef, Bushra</creatorcontrib><creatorcontrib>Alyassin, Yasmine</creatorcontrib><creatorcontrib>Ali, Radeyah</creatorcontrib><creatorcontrib>AlAsiri, Ali</creatorcontrib><creatorcontrib>Chang, Ming-Wei</creatorcontrib><creatorcontrib>Ahmad, Zeeshan</creatorcontrib><creatorcontrib>Ali Elkordy, Amal</creatorcontrib><creatorcontrib>Faheem, Ahmed</creatorcontrib><creatorcontrib>Pitt, Kendal</creatorcontrib><title>A review of emerging technologies enabling improved solid oral dosage form manufacturing and processing</title><title>Advanced drug delivery reviews</title><addtitle>ADV DRUG DELIVER REV</addtitle><addtitle>Adv Drug Deliv Rev</addtitle><description>Emerging technologies enabling improved solid oral dosage form manufacturing and processing.
[Display omitted]
Tablets are the most widely utilized solid oral dosage forms because of the advantages of self-administration, stability, ease of handling, transportation, and good patient compliance. Over time, extensive advances have been made in tableting technology. This review aims to provide an insight about the advances in tablet excipients, manufacturing, analytical techniques and deployment of Quality by Design (QbD). Various excipients offering novel functionalities such as solubility enhancement, super-disintegration, taste masking and drug release modifications have been developed. Furthermore, co-processed multifunctional ready-to-use excipients, particularly for tablet dosage forms, have benefitted manufacturing with shorter processing times. Advances in granulation methods, including moist, thermal adhesion, steam, melt, freeze, foam, reverse wet and pneumatic dry granulation, have been proposed to improve product and process performance. Furthermore, methods for particle engineering including hot melt extrusion, extrusion-spheronization, injection molding, spray drying / congealing, co-precipitation and nanotechnology-based approaches have been employed to produce robust tablet formulations. A wide range of tableting technologies including rapidly disintegrating, matrix, tablet-in-tablet, tablet-in-capsule, multilayer tablets and multiparticulate systems have been developed to achieve customized formulation performance. In addition to conventional invasive characterization methods, novel techniques based on laser, tomography, fluorescence, spectroscopy and acoustic approaches have been developed to assess the physical–mechanical attributes of tablet formulations in a non- or minimally invasive manner. Conventional UV–Visible spectroscopy method has been improved (e.g. fiber-optic probes and UV imaging-based approaches) to efficiently record the dissolution profile of tablet formulations. Numerous modifications in tableting presses have also been made to aid machine product changeover, cleaning, and enhance efficiency and productivity. Various process analytical technologies have been employed to track the formulation properties and critical process parameters. These advances will contribute to a strategy for robust tablet dosage forms with excellent performance attributes.</description><subject>Administration, Oral</subject><subject>Capsule, analytical methodology</subject><subject>Continuous manufacturing</subject><subject>Drug Compounding</subject><subject>Granulation</subject><subject>Hot melt extrusion</subject><subject>Humans</subject><subject>Life Sciences & Biomedicine</subject><subject>Multilayer tablets</subject><subject>Nanotechnology</subject><subject>Oral solid dose</subject><subject>Pharmaceutical Preparations - administration & dosage</subject><subject>Pharmaceutical Preparations - chemistry</subject><subject>Pharmacology & Pharmacy</subject><subject>Quality by design, excipients</subject><subject>Science & Technology</subject><subject>Tablet</subject><subject>Technology, Pharmaceutical</subject><issn>0169-409X</issn><issn>1872-8294</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>HGBXW</sourceid><sourceid>EIF</sourceid><recordid>eNqNkUuL1TAYhoMozvHoH3AhWQrS45dL0xbcDIfxAgNuFNyFNPlyzKFtxqSdwX9vSo-zFFe58LxvkieEvGZwYMDU-_PBOJcOHDg7MCZaCU_IjrUNr1reyadkV6CuktD9uCIvcj4DMN4oeE6uhGSyqYXYkdM1TXgf8IFGT3HEdArTic5of05xiKeAmeJk-mHdDeNdivfoaI5DcDQmM1AXszkh9TGNdDTT4o2dl7TSZnK08BZzLsuX5Jk3Q8ZXl3FPvn-8-Xb8XN1-_fTleH1bWQkwVwZ61feq40aiYqDAtFCubD1HXjemUQqlB8F90_RcOlbXrailAGUY77kXYk_ebr3l6F8L5lmPIVscBjNhXLLmhW5AiVoVlG-oTTHnhF7fpTCa9Fsz0KtgfdarYL0K1pvgEnpz6V_6Ed1j5K_RArzbgAfso8824GTxEQOAhnW8q1mZlco9af-fPobZzCFOx7hMc4l-2KJYdJYfTPoSdyGhnbWL4V8P-QPLQ60E</recordid><startdate>202111</startdate><enddate>202111</enddate><creator>Sohail Arshad, Muhammad</creator><creator>Zafar, Saman</creator><creator>Yousef, Bushra</creator><creator>Alyassin, Yasmine</creator><creator>Ali, Radeyah</creator><creator>AlAsiri, Ali</creator><creator>Chang, Ming-Wei</creator><creator>Ahmad, Zeeshan</creator><creator>Ali Elkordy, Amal</creator><creator>Faheem, Ahmed</creator><creator>Pitt, Kendal</creator><general>Elsevier B.V</general><general>Elsevier</general><scope>BLEPL</scope><scope>DTL</scope><scope>HGBXW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-9796-4150</orcidid><orcidid>https://orcid.org/0000-0001-9807-5841</orcidid><orcidid>https://orcid.org/0000-0002-0781-1127</orcidid></search><sort><creationdate>202111</creationdate><title>A review of emerging technologies enabling improved solid oral dosage form manufacturing and processing</title><author>Sohail Arshad, Muhammad ; Zafar, Saman ; Yousef, Bushra ; Alyassin, Yasmine ; Ali, Radeyah ; AlAsiri, Ali ; Chang, Ming-Wei ; Ahmad, Zeeshan ; Ali Elkordy, Amal ; Faheem, Ahmed ; Pitt, Kendal</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c400t-a0b6bb692a4e61060a80760cf2e257a766e4f032f77b24d1558354306a12b2f33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Administration, Oral</topic><topic>Capsule, analytical methodology</topic><topic>Continuous manufacturing</topic><topic>Drug Compounding</topic><topic>Granulation</topic><topic>Hot melt extrusion</topic><topic>Humans</topic><topic>Life Sciences & Biomedicine</topic><topic>Multilayer tablets</topic><topic>Nanotechnology</topic><topic>Oral solid dose</topic><topic>Pharmaceutical Preparations - administration & dosage</topic><topic>Pharmaceutical Preparations - chemistry</topic><topic>Pharmacology & Pharmacy</topic><topic>Quality by design, excipients</topic><topic>Science & Technology</topic><topic>Tablet</topic><topic>Technology, Pharmaceutical</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sohail Arshad, Muhammad</creatorcontrib><creatorcontrib>Zafar, Saman</creatorcontrib><creatorcontrib>Yousef, Bushra</creatorcontrib><creatorcontrib>Alyassin, Yasmine</creatorcontrib><creatorcontrib>Ali, Radeyah</creatorcontrib><creatorcontrib>AlAsiri, Ali</creatorcontrib><creatorcontrib>Chang, Ming-Wei</creatorcontrib><creatorcontrib>Ahmad, Zeeshan</creatorcontrib><creatorcontrib>Ali Elkordy, Amal</creatorcontrib><creatorcontrib>Faheem, Ahmed</creatorcontrib><creatorcontrib>Pitt, Kendal</creatorcontrib><collection>Web of Science Core Collection</collection><collection>Science Citation Index Expanded</collection><collection>Web of Science - Science Citation Index Expanded - 2021</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Advanced drug delivery reviews</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sohail Arshad, Muhammad</au><au>Zafar, Saman</au><au>Yousef, Bushra</au><au>Alyassin, Yasmine</au><au>Ali, Radeyah</au><au>AlAsiri, Ali</au><au>Chang, Ming-Wei</au><au>Ahmad, Zeeshan</au><au>Ali Elkordy, Amal</au><au>Faheem, Ahmed</au><au>Pitt, Kendal</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A review of emerging technologies enabling improved solid oral dosage form manufacturing and processing</atitle><jtitle>Advanced drug delivery reviews</jtitle><stitle>ADV DRUG DELIVER REV</stitle><addtitle>Adv Drug Deliv Rev</addtitle><date>2021-11</date><risdate>2021</risdate><volume>178</volume><spage>113840</spage><epage>113840</epage><pages>113840-113840</pages><artnum>113840</artnum><issn>0169-409X</issn><eissn>1872-8294</eissn><abstract>Emerging technologies enabling improved solid oral dosage form manufacturing and processing.
[Display omitted]
Tablets are the most widely utilized solid oral dosage forms because of the advantages of self-administration, stability, ease of handling, transportation, and good patient compliance. Over time, extensive advances have been made in tableting technology. This review aims to provide an insight about the advances in tablet excipients, manufacturing, analytical techniques and deployment of Quality by Design (QbD). Various excipients offering novel functionalities such as solubility enhancement, super-disintegration, taste masking and drug release modifications have been developed. Furthermore, co-processed multifunctional ready-to-use excipients, particularly for tablet dosage forms, have benefitted manufacturing with shorter processing times. Advances in granulation methods, including moist, thermal adhesion, steam, melt, freeze, foam, reverse wet and pneumatic dry granulation, have been proposed to improve product and process performance. Furthermore, methods for particle engineering including hot melt extrusion, extrusion-spheronization, injection molding, spray drying / congealing, co-precipitation and nanotechnology-based approaches have been employed to produce robust tablet formulations. A wide range of tableting technologies including rapidly disintegrating, matrix, tablet-in-tablet, tablet-in-capsule, multilayer tablets and multiparticulate systems have been developed to achieve customized formulation performance. In addition to conventional invasive characterization methods, novel techniques based on laser, tomography, fluorescence, spectroscopy and acoustic approaches have been developed to assess the physical–mechanical attributes of tablet formulations in a non- or minimally invasive manner. Conventional UV–Visible spectroscopy method has been improved (e.g. fiber-optic probes and UV imaging-based approaches) to efficiently record the dissolution profile of tablet formulations. Numerous modifications in tableting presses have also been made to aid machine product changeover, cleaning, and enhance efficiency and productivity. Various process analytical technologies have been employed to track the formulation properties and critical process parameters. These advances will contribute to a strategy for robust tablet dosage forms with excellent performance attributes.</abstract><cop>AMSTERDAM</cop><pub>Elsevier B.V</pub><pmid>34147533</pmid><doi>10.1016/j.addr.2021.113840</doi><tpages>28</tpages><orcidid>https://orcid.org/0000-0002-9796-4150</orcidid><orcidid>https://orcid.org/0000-0001-9807-5841</orcidid><orcidid>https://orcid.org/0000-0002-0781-1127</orcidid><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 0169-409X |
ispartof | Advanced drug delivery reviews, 2021-11, Vol.178, p.113840-113840, Article 113840 |
issn | 0169-409X 1872-8294 |
language | eng |
recordid | cdi_webofscience_primary_000719295100011 |
source | MEDLINE; Web of Science - Science Citation Index Expanded - 2021<img src="https://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" />; Access via ScienceDirect (Elsevier) |
subjects | Administration, Oral Capsule, analytical methodology Continuous manufacturing Drug Compounding Granulation Hot melt extrusion Humans Life Sciences & Biomedicine Multilayer tablets Nanotechnology Oral solid dose Pharmaceutical Preparations - administration & dosage Pharmaceutical Preparations - chemistry Pharmacology & Pharmacy Quality by design, excipients Science & Technology Tablet Technology, Pharmaceutical |
title | A review of emerging technologies enabling improved solid oral dosage form manufacturing and processing |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-12T18%3A14%3A36IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_webof&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20review%20of%20emerging%20technologies%20enabling%20improved%20solid%20oral%20dosage%20form%20manufacturing%20and%20processing&rft.jtitle=Advanced%20drug%20delivery%20reviews&rft.au=Sohail%20Arshad,%20Muhammad&rft.date=2021-11&rft.volume=178&rft.spage=113840&rft.epage=113840&rft.pages=113840-113840&rft.artnum=113840&rft.issn=0169-409X&rft.eissn=1872-8294&rft_id=info:doi/10.1016/j.addr.2021.113840&rft_dat=%3Cproquest_webof%3E2543706356%3C/proquest_webof%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2543706356&rft_id=info:pmid/34147533&rft_els_id=S0169409X21002325&rfr_iscdi=true |