{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T09:26:38Z","timestamp":1774344398433,"version":"3.50.1"},"reference-count":16,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T00:00:00Z","timestamp":1774051200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001322","name":"South African Medical Research Council","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001322","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000288","name":"Royal Society","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000288","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100011858","name":"African Academy of Sciences","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100011858","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: Bedside manipulation of adult anti-tuberculosis tablets for paediatric dosing is common in low-resource settings, yet it can compromise drug stability. This study investigated how grinding and multi-drug co-suspension affect the supramolecular organisation, thermal stability, and dissolution of isoniazid (INH). Methods: INH raw, INH branded tablets (whole and ground), and multi-drug combination mixtures (MCMs) that simulate paediatric multi-drug-resistant tuberculosis (MDR-TB) regimens were assessed. Samples were analysed as solids and aqueous suspensions using hot-stage microscopy (HSM), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), Raman spectroscopy, FTIR-ATR, USP dissolution, and HPLC (LOD 0.0015 mg mL\u22121; LOQ 0.005 mg mL\u22121). Results: Grinding and co-mixing lowered melting points and masked typical INH events. Spectroscopy revealed the broadening and shifting of OH\/NH and pyridine-ring bands, consistent with the formation of new hydrogen-bonding networks, correlative with supramolecular rearrangements. In multi-drug suspensions, INH fell below the HPLC quantification limit in both pH 1.2 and 6.8 media, despite visible residue, suggesting the formation of non-dissociable supramolecular complexes. Using a validated HPLC assay, no quantifiable INH was detected from the crushed multi-drug suspensions in either pH 1.2 or pH 6.8, whereas intact API\/tablets showed measurable release. Conclusions: Co-suspension of INH with companion tuberculosis (TB) drugs disrupts its supramolecular integrity, leading to pre-administration degradation and a loss of quantifiable drug. Dissolution testing showed minimal INH release at pH 1.2 and none at pH 6.8, contrasting with intact tablets\/API. These observations highlight that converting an immediate-release tablet into an aqueous suspension fundamentally alters its physicochemical environment and requires rational formulation design to preserve molecular stability, differentiating true resistance from formulation failure.<\/jats:p>","DOI":"10.3390\/pharmaceutics18030389","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T11:59:36Z","timestamp":1774267176000},"page":"389","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Differentiating Resistance from Formulation Failure: Isoniazid Instability and Poor Dissolution in Crushed Multi-Drug Paediatric Preparations"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9992-0282","authenticated-orcid":false,"given":"Halima","family":"Samsodien","sequence":"first","affiliation":[{"name":"Pharmaceutics Discipline, School of Pharmacy, University of the Western Cape, Robert Sobukwe Road, Bellville, Cape Town 7535, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jana","family":"Winkler","sequence":"additional","affiliation":[{"name":"Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Stellenbosch University, Tygerberg, Cape Town 8000, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2561-4458","authenticated-orcid":false,"given":"Marique","family":"Aucamp","sequence":"additional","affiliation":[{"name":"Pharmaceutics Discipline, School of Pharmacy, University of the Western Cape, Robert Sobukwe Road, Bellville, Cape Town 7535, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony J.","family":"Garcia-Prats","sequence":"additional","affiliation":[{"name":"Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Stellenbosch University, Tygerberg, Cape Town 8000, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1002\/j.2055-2335.2005.tb00333.x","article-title":"Extemporaneous isoniazid mixture: Stability implications","volume":"35","author":"Haywood","year":"2005","journal-title":"J. Pharm. Pract. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1086\/599040","article-title":"Isoniazid, rifampin, ethambutol, and pyrazinamide pharmacokinetics and treatment outcomes among a predominantly HIV-infected cohort with tuberculosis","volume":"48","author":"Chideya","year":"2009","journal-title":"Clin. Infect. Dis."},{"key":"ref_3","first-page":"61","article-title":"The rationale for recommending fixed-dose combination tablets for treatment of tuberculosis","volume":"79","author":"Blomberg","year":"2001","journal-title":"Bull. World Health Organ."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1086\/520011","article-title":"Stability of antituberculosis drugs mixed in food","volume":"45","author":"Peloquin","year":"2007","journal-title":"Clin. Infect. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"217","DOI":"10.12688\/f1000research.14088.1","article-title":"World TB Day 2018: The challenge of drug-resistant tuberculosis","volume":"7","author":"Tomlinson","year":"2018","journal-title":"F1000Research"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1080\/10408347.2017.1281098","article-title":"Isoniazid: A review of characteristics, properties and analytical methods","volume":"47","author":"Fernandes","year":"2017","journal-title":"Crit. Rev. Anal. 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Dissolution Methods Database, USP."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/3\/389\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T05:54:47Z","timestamp":1774331687000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/3\/389"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,21]]},"references-count":16,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["pharmaceutics18030389"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics18030389","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,21]]}}}