{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T14:58:49Z","timestamp":1791385129076,"version":"4.3.3"},"reference-count":36,"publisher":"American Chemical Society (ACS)","issue":"10","license":[{"start":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:00:00Z","timestamp":1788480000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:00:00Z","timestamp":1788480000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:00:00Z","timestamp":1788480000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/100001003","name":"Boehringer Ingelheim","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100001003","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Mass spectrometry imaging (MSI) can complement liquid chromatography\u2013mass spectrometry (LC-MS), the gold standard for impurity assessment, by enabling spatial visualization of active pharmaceutical ingredients (APIs), byproducts, and excipients in solid formulations. With new advances in matrix-assisted laser desorption\/ionization (MALDI) MSI, critical factors such as ablated spot size, raster speed, and standardized tablet surface preparation still need to be properly addressed. This study presents an innovative sample holder and sample preparation protocol enabling reproducible up to 10-\u03bcm step size acquisition for MSI analysis of tablets. The workflow was validated by embedding several commercial tablets containing various APIs in blocks with epoxy resin, then transversally cut them to expose their surfaces. Following this, the tablet surfaces were trimmed using a cryostat and subsequently polished with lapping diamond films to achieve flat and even surfaces. The tablets were then placed in a custom metal holder for MALDI-trapped ion mobility spectrometry (TIMS)-MSI analysis using a timsTOF fleX. The optimized protocol provides high-quality sample preparation and avoids loss of laser focus, enabling high-throughput analysis with high sensitivity for tablet imaging. This robustness was essential for spatial resolution measurements using the Smartbeam 3D, where precise initial focusing is required to preserve data quality across imaging areas. Consistent high signal sensitivity was achieved for single pixels in 10 mg cetirizine or 20 mg famotidine tablets and digoxin fragments were detected in a 0.25 mg\/130 mg tablet. This approach provides an important tool for pharmaceutical development by enabling reliable, high-resolution spatial analysis of active ingredients and impurities in solid dosage forms. Collision cross section (CCS) values from reference standards and tablets, as well as MS\/MS data were used for confident identification. LC-MS-based workflows remain essential for quantitative analysis of impurity assessment, while infrared spectroscopy (IR) and nuclear magnetic resonance (NMR) can support formulation level characterization. MALDI-TIMS-MSI complements these approaches by adding direct spatial localization of APIs and API-related molecular features within the tablet matrix.<\/jats:p>","DOI":"10.1021\/jasms.6c00161","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T18:01:58Z","timestamp":1788544918000},"page":"2341-2351","source":"Crossref","is-referenced-by-count":0,"title":["MALDI MSI Workflow\nfor Pharmaceutical Tablets: Toward\na Reproducible Strategy for High-Resolution Imaging"],"prefix":"10.1021","volume":"37","author":[{"given":"Athina","family":"Lisgara","sequence":"first","affiliation":[{"name":"Yale University , , , ,","place":["New Haven, Connecticut, United States, 06510"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1719-8458","authenticated-orcid":true,"given":"Alvaro","family":"Santos-Neto","sequence":"additional","affiliation":[{"name":"Yale University , , , ,","place":["New Haven, Connecticut, United States, 06510"]},{"name":"University of Sao Paulo , , ,","place":["Sao Carlos, Brazil, 13566-590"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2302-8914","authenticated-orcid":true,"given":"Georgia","family":"Charkoftaki","sequence":"additional","affiliation":[{"name":"Yale University , , , ,","place":["New Haven, Connecticut, United States, 06510"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9167-9060","authenticated-orcid":true,"given":"Reza","family":"Aalizadeh","sequence":"additional","affiliation":[{"name":"Yale University , , , ,","place":["New Haven, Connecticut, United States, 06510"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Raikes","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharmaceuticals Inc , , ,","place":["Ridgefield, Connecticut, United States, 06877"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Pennino","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharmaceuticals Inc , , ,","place":["Ridgefield, Connecticut, United States, 06877"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John A.","family":"Smoliga","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharmaceuticals Inc , , ,","place":["Ridgefield, Connecticut, United States, 06877"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Becker","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharma GmbH & Co. KG , ,","place":["Biberach\/Riss, Germany, 55218"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Vladimir V.","family":"Papov","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharmaceuticals Inc , , ,","place":["Ridgefield, Connecticut, United States, 06877"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8944-7180","authenticated-orcid":true,"given":"Nina","family":"Gonnella","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharmaceuticals Inc , , ,","place":["Ridgefield, Connecticut, United States, 06877"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2552-3118","authenticated-orcid":true,"given":"Vasilis","family":"Vasiliou","sequence":"additional","affiliation":[{"name":"Yale University , , , ,","place":["New Haven, Connecticut, United States, 06510"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,4]]},"reference":[{"issue":"5","key":"2026100710071120100_cit1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25052591","article-title":"Identification and\nStructural Characterization of Degradation Products of Linagliptin\nby Mass Spectrometry Techniques","volume":"25","author":"Liana","year":"2024","journal-title":"Int. J. Mol.\nSci."},{"issue":"1","key":"2026100710071120100_cit2","doi-asserted-by":"publisher","DOI":"10.1038\/s41526-023-00271-6","article-title":"The effect\nof long-term spaceflight on drug potency and the risk of medication\nfailure","volume":"9","author":"Reichard","year":"2023","journal-title":"npj Microgravity"},{"issue":"1","key":"2026100710071120100_cit3","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1208\/s12249-013-0047-x","article-title":"Recent\ntrends in product development and regulatory\nissues on impurities in active pharmaceutical ingredient (API) and\ndrug products. Part 1: Predicting degradation related impurities and\nimpurity considerations for pharmaceutical dosage forms","volume":"15","author":"Alsante","year":"2014","journal-title":"AAPS PharmSciTech"},{"issue":"1","key":"2026100710071120100_cit4","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1208\/s12249-013-0061-z","article-title":"Recent\ntrends in product development and regulatory\nissues on impurities in active pharmaceutical ingredient (API) and\ndrug products. Part 2: Safety considerations of impurities in pharmaceutical\nproducts and surveying the impurity landscape","volume":"15","author":"Alsante","year":"2014","journal-title":"AAPS PharmSciTech"},{"issue":"6","key":"2026100710071120100_cit5","doi-asserted-by":"publisher","first-page":"1547","DOI":"10.1093\/jaoac\/90.6.1547","article-title":"Stability-indicating\nhigh-performance liquid chromatographic assay of atorvastatin with\nfluorescence detection","volume":"90","author":"Khedr","year":"2007","journal-title":"J. AOAC Int."},{"issue":"5","key":"2026100710071120100_cit6","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1002\/rcm.3403","article-title":"Liquid chromatography\/mass spectrometric\nstudies on atorvastatin and its stress degradation products","volume":"22","author":"Shah","year":"2008","journal-title":"Rapid Commun. Mass Spectrom."},{"key":"2026100710071120100_cit7","doi-asserted-by":"publisher","DOI":"10.1016\/j.rechem.2025.102341","article-title":"A comprehensive\nreview-current development\nin spectroscopic and chromatographic techniques for natural product\nanalysis","volume":"16","author":"Gashaw","year":"2025","journal-title":"Results Chem."},{"issue":"4","key":"2026100710071120100_cit8","doi-asserted-by":"publisher","DOI":"10.3390\/metabo6040046","article-title":"Current and Future\nPerspectives on the Structural Identification of Small Molecules in\nBiological Systems","volume":"6","author":"Dias","year":"2016","journal-title":"Metabolites"},{"issue":"20","key":"2026100710071120100_cit9","doi-asserted-by":"publisher","DOI":"10.3390\/molecules24203804","article-title":"Chemometrics Approaches\nin Forced Degradation Studies of Pharmaceutical Drugs","volume":"24","author":"de Alvarenga","year":"2019","journal-title":"Molecules"},{"issue":"1","key":"2026100710071120100_cit10","doi-asserted-by":"publisher","DOI":"10.1002\/ansa.70024","article-title":"Recent Advances\nin Liquid Chromatography-Mass Spectrometry (LC-MS) Applications in\nBiological and Applied Sciences","volume":"6","author":"Alanazi","year":"2025","journal-title":"Anal. Sci.\nAdv."},{"key":"2026100710071120100_cit11","first-page":"629","article-title":"Mass Spectrometry\nImaging of Pharmaceuticals: From Tablets to Tissues","volume-title":"Advances in Delivery Science and Technology","author":"Kempson","year":"2016"},{"issue":"2","key":"2026100710071120100_cit12","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/j.jconrel.2007.11.015","article-title":"Chemical imaging of drug eluting\ncoatings: combining surface analysis and confocal Raman microscopy","volume":"126","author":"Belu","year":"2008","journal-title":"J. Controlled Release"},{"issue":"1","key":"2026100710071120100_cit13","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1021\/acs.analchem.7b04733","article-title":"Mass Spectrometry Imaging:\nA Review of Emerging Advancements and Future Insights","volume":"90","author":"Buchberger","year":"2018","journal-title":"Anal. 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Mass Spectrom."},{"issue":"3","key":"2026100710071120100_cit15","doi-asserted-by":"publisher","DOI":"10.3390\/molecules26030610","article-title":"Diagnosis of Agglomeration and Crystallinity of Active\nPharmaceutical Ingredients in Over the Counter Headache Medication\nby Electrospray Laser Desorption Ionization Mass Spectrometry Imaging","volume":"26","author":"Van Meter","year":"2021","journal-title":"Molecules"},{"key":"2026100710071120100_cit16","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/j.aca.2014.01.050","article-title":"In situ\nassessment of atorvastatin impurity using MALDI mass spectrometry\nimaging (MALDI-MSI)","volume":"818","author":"Rodrigues","year":"2014","journal-title":"Anal. Chim. Acta"},{"key":"2026100710071120100_cit17","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.jpba.2014.11.047","article-title":"Application of chemometric\nalgorithms to MALDI mass spectrometry imaging of pharmaceutical tablets","volume":"105","author":"Gut","year":"2015","journal-title":"J. Pharm. Biomed. Anal."},{"key":"2026100710071120100_cit18","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2021.114760","article-title":"Advanced applications of mass spectrometry imaging\ntechnology in\nquality control and safety assessments of traditional Chinese medicines","volume":"284","author":"Jiang","year":"2022","journal-title":"J. Ethnopharmacol."},{"issue":"4","key":"2026100710071120100_cit19","doi-asserted-by":"publisher","DOI":"10.1002\/rcm.8592","article-title":"In situ analysis\nof oxytetracycline\ntablets based on matrix-assisted laser desorption\/ionization mass\nspectrometry imaging","volume":"34","author":"Xie","year":"2020","journal-title":"Rapid Commun. Mass Spectrom."},{"key":"2026100710071120100_cit20","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.copbio.2018.08.003","article-title":"Advanced MALDI\nmass spectrometry imaging in pharmaceutical research and drug development","volume":"55","author":"Schulz","year":"2019","journal-title":"Curr. Opin. Biotechnol."},{"issue":"1","key":"2026100710071120100_cit21","doi-asserted-by":"publisher","DOI":"10.1002\/ansa.70016","article-title":"Mini Review:\nHighlight of Recent\nAdvances and Applications of MALDI Mass Spectrometry Imaging in 2024","volume":"6","author":"Ngai","year":"2025","journal-title":"Anal. Sci. Adv."},{"issue":"11\u201312","key":"2026100710071120100_cit22","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1080\/14789450.2021.1876568","article-title":"Role of\nMALDI-MSI in combination\nwith 3D tissue models for early stage efficacy and safety testing\nof drugs and toxicants","volume":"17","author":"Spencer","year":"2020","journal-title":"Expert Rev. Proteomics"},{"issue":"7","key":"2026100710071120100_cit23","doi-asserted-by":"publisher","DOI":"10.1016\/j.xphs.2025.103832","article-title":"Exploring the impact of formulation\nand tablet shape\non tablet integrity: A comprehensive investigation using mechanical\nand imaging techniques","volume":"114","author":"Singhal","year":"2025","journal-title":"J. Pharm. Sci."},{"key":"2026100710071120100_cit24","unstructured":"ICH Expert Working Group.\n          . In  ICH\nGuideline Q1A (R2) Stability Testing of New Drug Substances and\nProducts, International Conference on Harmonization; ICH, 2003."},{"key":"2026100710071120100_cit25","first-page":"1","article-title":"How to approach\na forced degradation study","volume":"31","author":"Brummer","year":"2011","journal-title":"Life Sci. Technol.\nBull."},{"key":"2026100710071120100_cit26","first-page":"32","article-title":"Regulatory\nconsiderations and implementation","volume":"18","author":"Kats","year":"2005","journal-title":"BioPharm\nInternational"},{"issue":"11","key":"2026100710071120100_cit27","doi-asserted-by":"publisher","first-page":"2460","DOI":"10.1021\/jasms.5c00211","article-title":"Investigating\nthe Quantitative Structure\u2013Ionization Efficiency Relationship\nof Small Molecules and Lipids in the Presence of Ammonium Fluoride\nin MALDI-TIMS-QTOF Mass Spectrometry Imaging","volume":"36","author":"Nikolopoulou","year":"2025","journal-title":"J. Am. Soc. Mass Spectrom."},{"issue":"5","key":"2026100710071120100_cit29","doi-asserted-by":"publisher","first-page":"1275","DOI":"10.1007\/s00216-013-7478-9","article-title":"critical\nevaluation of the current\nstate-of-the-art in quantitative imaging mass spectrometry","volume":"406","author":"Ellis","year":"2014","journal-title":"Anal. Bioanal. Chem."},{"issue":"18","key":"2026100710071120100_cit30","doi-asserted-by":"publisher","first-page":"6448","DOI":"10.1021\/ac060788p","article-title":"Direct Molecular\nAnalysis of Whole-Body Animal Tissue\nSections by Imaging MALDI Mass Spectrometry","volume":"78","author":"Khatib-Shahidi","year":"2006","journal-title":"Anal. Chem."},{"issue":"2","key":"2026100710071120100_cit31","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1016\/0731-7085(94)90033-7","article-title":"Pharmaceutical application of LC-MS.\n1 \u2500 Characterization of a famotidine degradates in a package\nscreening study by LC-APCI MS","volume":"12","author":"Qin","year":"1994","journal-title":"J. Pharm. Biomed.\nAnal."},{"key":"2026100710071120100_cit32","doi-asserted-by":"publisher","DOI":"10.1186\/s13321-016-0115-9","article-title":"MetFrag relaunched: incorporating strategies beyond\nin silico fragmentation","volume":"8","author":"Ruttkies","year":"2016","journal-title":"J. Cheminf."},{"issue":"4","key":"2026100710071120100_cit33","doi-asserted-by":"publisher","first-page":"2097","DOI":"10.1021\/es5002105","article-title":"Identifying\nSmall Molecules via High\nResolution Mass Spectrometry: Communicating Confidence","volume":"48","author":"Schymanski","year":"2014","journal-title":"Environ. Sci. Technol."},{"issue":"4","key":"2026100710071120100_cit34","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1023\/A:1016222501079","article-title":"Isothermal\nand nonisothermal decomposition of famotidine\nin aqueous solution","volume":"12","author":"Junnarkar","year":"1995","journal-title":"Pharm. Res."},{"key":"2026100710071120100_cit35","doi-asserted-by":"publisher","first-page":"1409","DOI":"10.1080\/02772241003636505","article-title":"Study on degradation\nprocess of famotidine\nhydrochloride in aqueous samples","volume":"92","author":"Karpin\u0301ska","year":"2010","journal-title":"Toxicol. Environ.\nChem."},{"key":"2026100710071120100_cit36","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-8-105","article-title":"Seven Golden Rules\nfor heuristic filtering of molecular formulas\nobtained by accurate mass spectrometry","volume":"8","author":"Kind","year":"2007","journal-title":"BMC\nBioinf."},{"issue":"3","key":"2026100710071120100_cit37","doi-asserted-by":"publisher","first-page":"1437","DOI":"10.1021\/ac504734s","article-title":"Mass Spectrometry\nImaging in Drug\nDevelopment","volume":"87","author":"Nilsson","year":"2015","journal-title":"Anal. Chem."}],"container-title":["Journal of the American\nSociety for Mass Spectrometry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/jasms.6c00161","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jamsef\/article-pdf\/37\/10\/2341\/68384140\/jasms.6c00161.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jamsef\/article-pdf\/37\/10\/2341\/68384140\/jasms.6c00161.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T14:25:19Z","timestamp":1791383119000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jamsef\/article\/37\/10\/2341\/5421194\/MALDI-MSI-Workflow-for-Pharmaceutical-Tablets"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,4]]},"references-count":36,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,9,4]]},"published-print":{"date-parts":[[2026,10,7]]}},"URL":"https:\/\/doi.org\/10.1021\/jasms.6c00161","relation":{},"ISSN":["1044-0305","1879-1123"],"issn-type":[{"value":"1044-0305","type":"print"},{"value":"1879-1123","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,4]]}}}