{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T02:20:12Z","timestamp":1788142812625,"version":"build-2803163510"},"reference-count":36,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T00:00:00Z","timestamp":1788048000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001858","name":"VINNOVA","doi-asserted-by":"publisher","award":["Dnr 2019-00048"],"award-info":[{"award-number":["Dnr 2019-00048"]}],"id":[{"id":"10.13039\/501100001858","id-type":"DOI","asserted-by":"publisher"}]},{"award":["Dnr 2019-00048"],"award-info":[{"award-number":["Dnr 2019-00048"]}],"id":[{"id":"https:\/\/ror.org\/01kd5m353","id-type":"ROR","asserted-by":"publisher"}]},{"name":"AstraZeneca R&D Gothenburg"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Packing, flow, and aerosolization properties of a series of binary adhesive mixtures containing micronized or spray-dried drugs were investigated, and the relationships between these blend properties and the blend structure were studied. Methods: Micronized or spray-dried terbutaline sulfate and salbutamol sulfate were used as model drugs, and an \u03b1-lactose powder was used as the carrier. Binary mixtures with drug loads ranging from 2 to 20% were prepared. The bulk density, compressibility, permeability, and shearing properties of the carrier powder and mixtures were determined, along with the in vitro aerosolization propensity of the mixtures using two types of inhalers. Imaging of the mixtures was used to assess the blend structure. Conclusions: The particle engineering method gave differences in particle crystallinity and morphology. The development of the adhesive layer with drug load was broadly consistent with the blend state concept. Spray-dried particles, however, exhibited a higher propensity to localize within surface cavities on the carrier and produced a more voluminous enveloped adhesive layer. The spray-dried particles gave a higher bulk density, a lower Hausner ratio, comparable shear strength, and a lower angle of internal friction. Aerosolization performance, including metrics such as fine particle fraction (FPF), depended on inhaler design; nevertheless, for both inhalers, aerosolization behavior was influenced by blend state and physicochemical properties of the drug. At low drug loads, spray-dried particles dispersed to a lower degree, while at high drug loads, the dispersion performance of the two particle types converged. For example, at an intermediate drug load of 7.4%, the FPF was about 20% for the spray-dried drugs and about 30% for the micronized drugs using the Screenhaler device, while the corresponding FPF:s were about 25% and 50% for spray-dried drugs and 40% and 55% for crystalline drugs using the Monodose inhaler. Overall, the physical characteristics of the drug particles were found to influence the structural evolution of the blends, as well as their mechanical and aerosolization properties.<\/jats:p>","DOI":"10.3390\/pharmaceutics18091092","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T02:08:58Z","timestamp":1788142138000},"page":"1092","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Packing, Flow and Aerosolization Properties of Binary Adhesive Mixtures Containing Micronized and Spray-Dried Drugs"],"prefix":"10.3390","volume":"18","author":[{"given":"Anna","family":"Simonsson","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Biosciences and the Swedish Drug Delivery Center, Uppsala University, P.O. Box 591, SE-751 24 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6795-1310","authenticated-orcid":false,"given":"Nicklas Bunta","family":"Sundin","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Biosciences and the Swedish Drug Delivery Center, Uppsala University, P.O. Box 591, SE-751 24 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Bramer","sequence":"additional","affiliation":[{"name":"Global Product Development, Pharmaceutical Technology & Development, AstraZeneca Gothenburg, SE-431 53 M\u00f6lndal, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Wimbush","sequence":"additional","affiliation":[{"name":"Sustainable Innovation and Transformational Excellence, Pharmaceutical Technology & Development, AstraZeneca Gothenburg, SE-431 53 M\u00f6lndal, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00f6ran","family":"Alderborn","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Biosciences and the Swedish Drug Delivery Center, Uppsala University, P.O. Box 591, SE-751 24 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ijpharm.2010.03.017","article-title":"Formulation strategy and use of excipients in pulmonary drug delivery","volume":"392","author":"Pilcer","year":"2010","journal-title":"Int. J. Pharm."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"120568","DOI":"10.1016\/j.ijpharm.2021.120568","article-title":"A quantitative approach to predicting lung deposition profiles of pharmaceutical powder aerosols","volume":"602","author":"Yaqoubi","year":"2021","journal-title":"Int. J. Pharm."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"104553","DOI":"10.1016\/j.jddst.2023.104553","article-title":"A comprehensive overview of dry powder inhalers for pulmonary drug delivery: Challenges, advances, optimization techniques, and applications","volume":"84","author":"Shahin","year":"2023","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/j.rmed.2012.12.007","article-title":"Inhaler devices\u2014From theory to practice","volume":"107","author":"Sanchis","year":"2013","journal-title":"Respir. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"123966","DOI":"10.1016\/j.ijpharm.2024.123966","article-title":"Critical attributes of fine excipient materials in carrier-based dry powder inhalation formulations: The particle shape and surface properties","volume":"655","author":"Elsayed","year":"2024","journal-title":"Int. J. Pharm."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"114527","DOI":"10.1016\/j.addr.2022.114527","article-title":"Recent developments in lactose blend formulations for carrier-based dry powder inhalation","volume":"189","author":"Hebbink","year":"2022","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.ijpharm.2016.05.057","article-title":"From single excipients to dual excipient platforms in dry powder inhaler products","volume":"514","author":"Shur","year":"2016","journal-title":"Int. J. Pharm."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"124549","DOI":"10.1016\/j.ijpharm.2024.124549","article-title":"New theory to explain the effect of lactose fines on the performance of adhesive mixtures for inhalation","volume":"663","author":"Thalberg","year":"2024","journal-title":"Int. J. Pharm."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.ijpharm.2011.06.020","article-title":"The influence of drug loading on formulation structure and aerosol performance in carrier based dry powder inhalers","volume":"416","author":"Young","year":"2011","journal-title":"Int. J. Pharm."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.ijpharm.2019.02.038","article-title":"Linking carrier morphology to the powder mechanics of adhesive mixtures for dry powder inhalers via a blend-state model","volume":"561","author":"Frenning","year":"2019","journal-title":"Int. J. Pharm."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"124122","DOI":"10.1016\/j.ijpharm.2024.124122","article-title":"Effect of drug load on the aerosolisation propensity of binary adhesive mixtures for inhalation","volume":"657","author":"Simonsson","year":"2024","journal-title":"Int. J. Pharm."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Grasmeijer, F., Hagedoorn, P., Frijlink, H.W., and de Boer, A.H. (2013). Drug content effects on the dispersion performance of adhesive mixtures for inhalation. PLoS ONE, 8.","DOI":"10.1371\/annotation\/7302762a-a6fe-4fcd-8656-36d8b7c259a5"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.ijpharm.2007.06.041","article-title":"Influence of fine lactose and magnesium stearate on low dose dry powder inhaler formulations","volume":"348","author":"Guchardi","year":"2008","journal-title":"Int. J. Pharm."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/S0378-5173(99)00021-6","article-title":"Effects of particle size and adding sequence of fine lactose on the deposition of salbutamol sulphate from a dry powder formulation","volume":"182","author":"Zeng","year":"1999","journal-title":"Int. J. Pharm."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1208\/s12249-015-0317-x","article-title":"Devices for dry powder drug delivery to the lung","volume":"16","author":"Berkenfeld","year":"2015","journal-title":"AAPS PharmSciTech"},{"key":"ref_16","first-page":"100069","article-title":"On the relationship between blend state and dispersibility of adhesive mixtures containing active pharmaceutical ingredients","volume":"3","author":"Frenning","year":"2021","journal-title":"Int. J. Pharm. X"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"121590","DOI":"10.1016\/j.ijpharm.2022.121590","article-title":"Effect of pressure drop on the in vitro dispersion of adhesive mixtures of different blend states for inhalation","volume":"617","author":"Frenning","year":"2022","journal-title":"Int. J. Pharm."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.ejpb.2023.04.006","article-title":"Segregation in inhalable powders: Quantification of the effect of vibration on adhesive mixtures","volume":"187","author":"Sarangi","year":"2023","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_19","first-page":"100358","article-title":"Packing and flow performance of binary adhesive mixtures for inhalation of different drug loads and their relationships to aerosolisation","volume":"10","author":"Simonsson","year":"2025","journal-title":"Int. J. Pharm. X"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.powtec.2021.02.031","article-title":"Designing enhanced spray dried particles for inhalation: A review of the impact of excipients and processing parameters on particle properties","volume":"384","author":"Alhajj","year":"2021","journal-title":"Powder Technol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3047","DOI":"10.1007\/s11095-022-03363-2","article-title":"Advancements in particle engineering for inhalation delivery of small molecules and biotherapeutics","volume":"39","author":"Chang","year":"2022","journal-title":"Pharm. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1016\/j.jddst.2018.10.014","article-title":"Insights into the processability and performance of adhesive blends of inhalable jet-milled and spray dried salbutamol sulphate at different drug loads","volume":"48","author":"Pinto","year":"2018","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1656","DOI":"10.1007\/s11095-013-1270-6","article-title":"Effect of crystallinity on electrostatic charging in dry powder inhaler formulations","volume":"31","author":"Wong","year":"2014","journal-title":"Pharm. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"118709","DOI":"10.1016\/j.powtec.2023.118709","article-title":"Elucidation of the using condition and working mechanism of tertiary lactose in dry powder formulations for inhalation","volume":"427","author":"Ye","year":"2023","journal-title":"Powder Technol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"122702","DOI":"10.1016\/j.ijpharm.2023.122702","article-title":"Role of dispersion enhancer in the development of novel tratinterol hydrochloride dry powder inhalation formulation","volume":"635","author":"Liu","year":"2023","journal-title":"Int. J. Pharm."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.ijpharm.2016.03.004","article-title":"Dispersibility of lactose fines as compared to API in dry powders for inhalation","volume":"504","author":"Thalberg","year":"2016","journal-title":"Int. J. Pharm."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1021\/cg700840j","article-title":"Characterization of polymorphs and solvates of terbutaline sulfate","volume":"8","author":"Harris","year":"2008","journal-title":"Cryst. Growth Des."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.ijpharm.2015.04.079","article-title":"Crystallization speed of salbutamol as a function of relative humidity and temperature","volume":"489","author":"Zellnitz","year":"2015","journal-title":"Int. J. Pharm."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1089\/jamp.2021.29056.spn","article-title":"Fine particle fraction: The good and the bad","volume":"35","author":"Newman","year":"2022","journal-title":"J. Aerosol Med. Pulm. Drug Deliv."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.ijpharm.2018.07.008","article-title":"Challenges for pulmonary delivery of high powder doses","volume":"548","author":"Sibum","year":"2018","journal-title":"Int. J. Pharm."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Son, Y.-J., Miller, D.P., and Weers, J.G. (2021). Optimizing spray-dried porous particles for high-dose delivery with a portable dry powder inhaler. Pharmaceutics, 13.","DOI":"10.20944\/preprints202107.0641.v1"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Ding, L., Brunaugh, A.D., Stegemann, S., Jermain, S.V., Herpin, M.J., Kalafat, J., and Smyth, H.D.C. (2021). A quality by design framework for capsule-based dry powder inhalers. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13081213"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"122871","DOI":"10.1016\/j.ijpharm.2023.122871","article-title":"Effects of the mouthpiece and chamber of Turbuhaler\u00ae on the aerosolization of API-only powder formulations","volume":"637","author":"Zhu","year":"2023","journal-title":"Int. J. Pharm."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"122359","DOI":"10.1016\/j.ijpharm.2022.122359","article-title":"Elucidation of the effect of added fines on the performance of dry powder inhalation formulations","volume":"629","author":"Radivojev","year":"2022","journal-title":"Int. J. Pharm."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"121407","DOI":"10.1016\/j.ijpharm.2021.121407","article-title":"Insights into the potential of rheological measurements in development of dry powder inhalation formulations","volume":"614","author":"Almansour","year":"2022","journal-title":"Int. J. Pharm."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/S0928-0987(99)00025-1","article-title":"Relationships between the effective interparticulate contact area and the tensile strength of tablets of amorphous and crystalline lactose of varying particle size","volume":"8","author":"Sebhatu","year":"1999","journal-title":"Eur. J. Pharm. Sci."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/9\/1092\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T02:11:30Z","timestamp":1788142290000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/9\/1092"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,30]]},"references-count":36,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["pharmaceutics18091092"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics18091092","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,30]]}}}