{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T11:28:03Z","timestamp":1787138883174,"version":"build-2736575974"},"reference-count":62,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100015763","name":"University of Szeged","doi-asserted-by":"publisher","award":["8981"],"award-info":[{"award-number":["8981"]}],"id":[{"id":"10.13039\/501100015763","id-type":"DOI","asserted-by":"publisher"}]},{"award":["8981"],"award-info":[{"award-number":["8981"]}],"id":[{"id":"https:\/\/ror.org\/01pnej532","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: The stability and biological safety of newly developed formulations must be established to support their therapeutic efficacy and clinical translation in pulmonary drug delivery. Therefore, this follow-up study comprehensively evaluated the short- and long-term stability and the in vitro cytotoxicity of optimized, co-spray-dried theophylline (THN) dry powders for inhalation against A549 lung epithelial cells. Methods: Two established formulations were selected: THN-RAF (raffinose\u2013leucine\u2013glycine based) and THN-TRE (trehalose\u2013leucine based). Stability was assessed under accelerated conditions (40 \u00b0C\/75% RH, 3 months) and long-term desiccator storage (25 \u00b0C, 1 year) using laser diffraction, SEM, XRPD, FTIR, DSC, TGA, and Andersen Cascade Impaction. As THN-TRE had been previously confirmed to be cytocompatible, only THN-RAF and its components were evaluated against A549 human alveolar epithelial cells using the MTT assay. Results: Under accelerated conditions, both formulations exhibited pronounced recrystallization (Xc up to 89.9%), agglomeration (D [0.9] up to 217.08 \u00b5m for THN-TRE), and deterioration in aerodynamic performance (FPF as low as 11.55%, MMAD up to 6.68 \u00b5m). By contrast, long-term desiccator storage induced substantial recrystallization (Xc up to 80.7%) while preserving thermal, chemical, and aerodynamic performance (FPF \u2248 40%; MMAD 4.99\u20135.21 \u00b5m). THN-RAF was more resistant to stress-induced agglomeration than THN-TRE. Cytotoxicity assessment confirmed cytocompatibility of THN-RAF, with cell viability exceeding 70.99% at all tested concentrations (up to 500 \u00b5g\/mL). Conclusions: These findings reveal a marked discrepancy between the outcomes of ICH accelerated testing and long-term desiccator storage. They underscore the importance of considering moisture-protective packaging configurations when designing stability protocols for amorphous inhalable formulations.<\/jats:p>","DOI":"10.3390\/pharmaceutics18081027","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T11:04:12Z","timestamp":1787137452000},"page":"1027","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comprehensive Evaluation of Storage Stability and Cytotoxicity of Co-Spray-Dried Theophylline Dry Powders for Inhalation: Follow-Up Study"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8872-2937","authenticated-orcid":false,"given":"Lomass","family":"Soliman","sequence":"first","affiliation":[{"name":"Institute of Pharmaceutical Technology and Regulatory Affairs, Faculty of Pharmacy, University of Szeged, E\u00f6tv\u00f6s utca 6, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6792-6789","authenticated-orcid":false,"given":"D\u00f3ra","family":"Par\u00f3czai","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunobiology, University of Szeged, D\u00f3m Square 10, H-6720 Szeged, Hungary"},{"name":"Department of Pulmonology, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, Tisza Lajos krt 107, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1300-2374","authenticated-orcid":false,"given":"Katalin","family":"Buri\u00e1n","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunobiology, University of Szeged, D\u00f3m Square 10, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5496-1710","authenticated-orcid":false,"given":"Rita","family":"Ambrus","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Technology and Regulatory Affairs, Faculty of Pharmacy, University of Szeged, E\u00f6tv\u00f6s utca 6, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3450","DOI":"10.21037\/jtd-23-1781","article-title":"A Narrative Review of Theophylline: Is There Still a Place for an Old Friend?","volume":"16","author":"Scurek","year":"2024","journal-title":"J. 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