{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T04:28:30Z","timestamp":1767155310240,"version":"build-2065373602"},"reference-count":86,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,10,24]],"date-time":"2024-10-24T00:00:00Z","timestamp":1729728000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NKFIH OTKA K_146148 project","award":["TKP2021-EGA"],"award-info":[{"award-number":["TKP2021-EGA"]}]},{"name":"Ministry of Innovation and Tech-nology of Hungary from the National Research, Development and Innovation Fund","award":["TKP2021-EGA"],"award-info":[{"award-number":["TKP2021-EGA"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Research on cyclodextrin-based metal-organic frameworks (CD-MOFs) is still in its infancy, but their potential for use in drug delivery\u2014expressly in the lung\u2014seems promising. We aimed to use the freeze-drying method to create a novel approach for preparing CD-MOFs. MOFs consisting of \u03b3-cyclodextrin (\u03b3CD) and potassium cations (K+) were employed to encapsulate the poorly water-soluble model drug Ibuprofen (IBU) for the treatment of cystic fibrosis (CF). Methods: Using the LeanQbD\u00ae software (v2022), we designed the experiments based on the Quality by Design (QbD) concept. According to QbD, we identified the three most critical factors, which were the molar ratio of the IBU to the \u03b3CD, incubation time, and the percentage of the organic solvent. light-, scanning electron microscope (SEM) and laser diffraction were utilized to observe the morphology and particle size of the samples. In addition, the products were characterized by Differential Scanning Calorimetry (DSC), X-ray Powder Diffraction (XRPD), Fourier Transform Infrared Spectroscopy (FT-IR) and nuclear magnetic resonance spectroscopy (NMR). Results: Based on characterizations, we concluded that a \u03b3CD-MOF\/IBU complex was also formed using the freeze-drying method. Using formulations with optimal aerodynamic properties, we achieved 38.10 \u00b1 5.06 and 47.18 \u00b1 4.18 Fine Particle Fraction% (FPF%) based on the Andersen Cascade Impactor measurement. With these formulations, we achieved a fast dissolution profile and increased IBU solubility. Conclusions: This research successfully demonstrates the innovative use of freeze-drying to produce \u03b3CD-MOFs for inhalable IBU delivery. The method enabled to modify the particle size, which was crucial for successful pulmonary intake, emphasizing the need for further investigation of these formulations as effective delivery systems.<\/jats:p>","DOI":"10.3390\/pharmaceutics16111361","type":"journal-article","created":{"date-parts":[[2024,10,25]],"date-time":"2024-10-25T03:46:04Z","timestamp":1729827964000},"page":"1361","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Preparation of Ibuprofen-Loaded Inhalable \u03b3CD-MOFs by Freeze-Drying Using the QbD Approach"],"prefix":"10.3390","volume":"16","author":[{"given":"Anett","family":"Motzwickler-N\u00e9meth","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy, Institute of Pharmaceutical Technology and Regulatory Affairs, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petra","family":"Party","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Institute of Pharmaceutical Technology and Regulatory Affairs, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7603-2406","authenticated-orcid":false,"given":"P\u00e9ter","family":"Simon","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Institute of Pharmaceutical Chemistry, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8249-5761","authenticated-orcid":false,"given":"Milena","family":"Sorrenti","sequence":"additional","affiliation":[{"name":"Department of Drug Sciences, University of Pavia, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5496-1710","authenticated-orcid":false,"given":"Rita","family":"Ambrus","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Institute of Pharmaceutical Technology and Regulatory Affairs, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0807-2781","authenticated-orcid":false,"given":"Ildik\u00f3","family":"Cs\u00f3ka","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Institute of Pharmaceutical Technology and Regulatory Affairs, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1080\/03602532.2021.1903488","article-title":"Ibuprofen-Based Advanced Therapeutics: Breaking the Inflammatory Link in Cancer, Neurodegeneration, and Diseases","volume":"53","author":"Upadhyay","year":"2021","journal-title":"Drug Metab. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1002\/ceat.201200510","article-title":"Solubility of Ibuprofen, Phytosterol, Salicylic Acid, and Naproxen in Aqueous Solutions","volume":"36","author":"Bolten","year":"2013","journal-title":"Chem. Eng. Technol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1971","DOI":"10.1007\/s10973-019-08572-3","article-title":"Ibuprofen Isobutanolammonium Salt: Synthesis, Thermal Analysis, PXRD, FTIR and Solubility Investigations","volume":"139","author":"Carvalho","year":"2020","journal-title":"J. Therm. Anal. Calorim."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1080\/03639045.2017.1391838","article-title":"Formulation and Delivery Strategies of Ibuprofen: Challenges and Opportunities","volume":"44","author":"Irvine","year":"2018","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1378\/chest.115.4.1053","article-title":"The Use of Anti-Inflammatory Medications in Cystic Fibrosis","volume":"115","author":"Oermann","year":"1999","journal-title":"Chest"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1080\/21678707.2018.1409110","article-title":"Is There a Role for Inhaled Anti-Inflammatory Drugs in Cystic Fibrosis Treatment?","volume":"6","author":"Sheikh","year":"2018","journal-title":"Expert. Opin. Orphan Drugs"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"118979","DOI":"10.1016\/j.ijpharm.2019.118979","article-title":"Functional Ibuprofen-Loaded Cationic Nanoemulsion: Development and Optimization for Dry Eye Disease Treatment","volume":"576","author":"Diebold","year":"2020","journal-title":"Int. J. Pharm."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1080\/17425247.2021.1873274","article-title":"Real-Time Quantitative Monitoring of In Vitro Nasal Drug Delivery by a Nasal Epithelial Mucosa-on-a-Chip Model","volume":"18","author":"Gholizadeh","year":"2021","journal-title":"Expert. Opin. Drug Deliv."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Party, P., Klement, M.L., Szab\u00f3-R\u00e9v\u00e9sz, P., and Ambrus, R. (2023). Preparation and Characterization of Ibuprofen Containing Nano-Embedded-Microparticles for Pulmonary Delivery. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15020545"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Sharif, S., Muneer, S., Izake, E.L., and Islam, N. (2023). Impact of Leucine and Magnesium Stearate on the Physicochemical Properties and Aerosolization Behavior of Wet Milled Inhalable Ibuprofen Microparticles for Developing Dry Powder Inhaler Formulation. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15020674"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"121242","DOI":"10.1016\/j.ijpharm.2021.121242","article-title":"Development of an Intelligent, Stimuli-Responsive Transdermal System for Efficient Delivery of Ibuprofen against Rheumatoid Arthritis","volume":"610","author":"Khan","year":"2021","journal-title":"Int. J. Pharm."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1164\/ajrccm.150.2.8049828","article-title":"Bronchoalveolar Lavage Findings in Cystic Fibrosis Patients with Stable, Clinically Mild Lung Disease Suggest Ongoing Infection and Inflammation","volume":"150","author":"Konstan","year":"1994","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1164\/ajrccm.156.4.96-11058","article-title":"Lower Airway Inflammation in Infants and Young Children with Cystic Fibrosis","volume":"156","author":"Armstrong","year":"1997","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"141","DOI":"10.2165\/11588150-000000000-00000","article-title":"Targeting Airway Inflammation in Cystic Fibrosis in Children: Past, Present, and Future","volume":"13","author":"Pressler","year":"2011","journal-title":"Pediatr. Drugs"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1002\/ppul.1144","article-title":"Early Pulmonary Infection, Inflammation, and Clinical Outcomes in Infants with Cystic Fibrosis*","volume":"32","author":"Rosenfeld","year":"2001","journal-title":"Pediatr. Pulmonol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e01574-17","DOI":"10.1128\/AAC.01574-17","article-title":"Antimicrobial Activity of Ibuprofen against Cystic Fibrosis-Associated Gram-Negative Pathogens","volume":"62","author":"Shah","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1097\/MCP.0b013e32831311e8","article-title":"Ibuprofen Therapy for Cystic Fibrosis Lung Disease: Revisited","volume":"14","author":"Konstan","year":"2008","journal-title":"Curr. Opin. Pulm. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.jpeds.2007.04.009","article-title":"High-Dose Ibuprofen in Cystic Fibrosis: Canadian Safety and Effectiveness Trial","volume":"151","author":"Lands","year":"2007","journal-title":"J. Pediatr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/S1095-6433(01)00315-4","article-title":"Alveolar Surface Forces and Lung Architecture","volume":"129","author":"Bachofen","year":"2001","journal-title":"Comp. Biochem. Physiol. Part A Mol. Integr. Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1378\/chest.83.5.725","article-title":"Clinical Studies of Measuring Extravascular Lung Water by the Thermal Dye Technique in Critically III Patients","volume":"83","author":"Sibbald","year":"1983","journal-title":"Chest"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Theilmann, R.J., Darquenne, C., Elliott, A.R., Bailey, B.A., and Conrad, D.J. (2016). Characterizing Lung Disease in Cystic Fibrosis with Magnetic Resonance Imaging and Airway Physiology. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0157177"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.ejcts.2007.04.006","article-title":"Vascular Endothelial Growth Factor Increases Pulmonary Vascular Permeability in Cystic Fibrosis Patients Undergoing Lung Transplantation","volume":"32","author":"Krenn","year":"2007","journal-title":"Eur. J. Cardio-Thorac. Surg."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.ijpharm.2012.06.055","article-title":"Cyclodextrins","volume":"453","author":"Kurkov","year":"2013","journal-title":"Int. J. Pharm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"114300","DOI":"10.1016\/j.indcrop.2021.114300","article-title":"Antibacterial Perillaldehyde\/Hydroxypropyl-\u03b3-Cyclodextrin Inclusion Complex Electrospun Polymer-Free Nanofiber: Improved Water Solubility, Thermostability, and Antioxidant Activity","volume":"176","author":"Gao","year":"2022","journal-title":"Ind. Crops Prod."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"116070","DOI":"10.1016\/j.molliq.2021.116070","article-title":"Inclusion Complexes of Cannabidiol with \u03b2-Cyclodextrin and Its Derivative: Physicochemical Properties, Water Solubility, and Antioxidant Activity","volume":"334","author":"Li","year":"2021","journal-title":"J. Mol. Liq."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4043","DOI":"10.1016\/j.cclet.2021.12.037","article-title":"Study of a Water-Soluble Supramolecular Complex of Curcumin and \u03b2-Cyclodextrin Polymer with Electrochemical Property and Potential Anti-Cancer Activity","volume":"33","author":"Zhang","year":"2022","journal-title":"Chin. Chem. Lett."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Abbas, Z.S., Sulaiman, G.M., Jabir, M.S., Mohammed, S.A.A., Khan, R.A., Mohammed, H.A., and Al-Subaiyel, A. (2022). Galangin\/\u03b2-Cyclodextrin Inclusion Complex as a Drug-Delivery System for Improved Solubility and Biocompatibility in Breast Cancer Treatment. Molecules, 27.","DOI":"10.3390\/molecules27144521"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"101413","DOI":"10.1016\/j.jddst.2019.101413","article-title":"Papain-Cyclodextrin Complexes as an Intestinal Permeation Enhancer: Permeability and in Vitro Safety Evaluation","volume":"55","author":"Corazza","year":"2020","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1080\/10837450.2020.1858319","article-title":"Sublingual Insulin Administration: Application of Hydroxypropyl Beta-Cyclodextrin and Poloxamer188 as Permeation Enhancers","volume":"26","author":"Paprikar","year":"2021","journal-title":"Pharm. Dev. Technol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Arora, P., and Dhingra, N. (2018). Cyclodextrins: Past and Present. Cyclodextrin\u2014A Versatile Ingredient, InTech.","DOI":"10.5772\/intechopen.69187"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1016\/j.ijpharm.2018.08.061","article-title":"High Dose Dry Powder Inhalers to Overcome the Challenges of Tuberculosis Treatment","volume":"550","author":"Momin","year":"2018","journal-title":"Int. J. Pharm."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"119777","DOI":"10.1016\/j.ijpharm.2020.119777","article-title":"Cyclodextrin-Based Metal-Organic Frameworks for Pulmonary Delivery of Curcumin with Improved Solubility and Fine Aerodynamic Performance","volume":"588","author":"Zhou","year":"2020","journal-title":"Int. J. Pharm."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"120825","DOI":"10.1016\/j.ijpharm.2021.120825","article-title":"Solidification of Volatile D-Limonene by Cyclodextrin Metal-Organic Framework for Pulmonary Delivery via Dry Powder Inhalers: In Vitro and In Vivo Evaluation","volume":"606","author":"Zhou","year":"2021","journal-title":"Int. J. Pharm."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"119649","DOI":"10.1016\/j.ijpharm.2020.119649","article-title":"Paeonol Loaded Cyclodextrin Metal-Organic Framework Particles for Treatment of Acute Lung Injury via Inhalation","volume":"587","author":"Li","year":"2020","journal-title":"Int. J. Pharm."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"104296","DOI":"10.1016\/j.jddst.2023.104296","article-title":"Highly Efficient Pulmonary Delivery of Levo-Tetrahydropalmatine Using \u03b3-Cyclodextrin Metal-Organic Framework as a Drug Delivery Platform","volume":"82","author":"Nie","year":"2023","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1021\/acs.cgd.1c01091","article-title":"Crystalline Rearranged CD-MOF Particles Obtained via Spray-Drying Synthesis Applied to Inhalable Formulations with High Drug Loading","volume":"22","author":"Tse","year":"2022","journal-title":"Cryst. Growth Des."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1021\/ja208224f","article-title":"Nanoporous Carbohydrate Metal\u2013Organic Frameworks","volume":"134","author":"Forgan","year":"2012","journal-title":"J. Am. Chem. Soc."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"121198","DOI":"10.1016\/j.carbpol.2023.121198","article-title":"Cyclodextrin-Based Metal-Organic Framework Materials: Classifications, Synthesis Strategies and Applications in Variegated Delivery Systems","volume":"319","author":"Zhao","year":"2023","journal-title":"Carbohydr. Polym."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2404","DOI":"10.1016\/j.apsb.2020.07.018","article-title":"A Homogenous Nanoporous Pulmonary Drug Delivery System Based on Metal-Organic Frameworks with Fine Aerosolization Performance and Good Compatibility","volume":"10","author":"Zhou","year":"2020","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"197","DOI":"10.14356\/kona.2023016","article-title":"Recent Advances in the Fabrication and Functionalization of Nanostructured Carbon Spheres for Energy Storage Applications","volume":"40","author":"Cao","year":"2023","journal-title":"KONA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"127839","DOI":"10.1016\/j.foodchem.2020.127839","article-title":"Encapsulation of Menthol into Cyclodextrin Metal-Organic Frameworks: Preparation, Structure Characterization and Evaluation of Complexing Capacity","volume":"338","author":"Hu","year":"2021","journal-title":"Food Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3887","DOI":"10.1002\/jsfa.11738","article-title":"Encapsulating Quercetin in Cyclodextrin Metal\u2013Organic Frameworks Improved Its Solubility and Bioavailability","volume":"102","author":"Wang","year":"2022","journal-title":"J. Sci. Food Agric."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Rajamohan, R., Ashokkumar, S., Murali Krishnan, M., Murugavel, K., Murugan, M., and Lee, Y.R. (2023). Adenosine\/\u03b2-Cyclodextrin-Based Metal\u2013Organic Frameworks as a Potential Material for Cancer Therapy. Biomolecules, 13.","DOI":"10.3390\/biom13071154"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"106003","DOI":"10.1016\/j.ultsonch.2022.106003","article-title":"Cyclodextrin Metal\u2013Organic Framework by Ultrasound-Assisted Rapid Synthesis for Caffeic Acid Loading and Antibacterial Application","volume":"86","author":"Shen","year":"2022","journal-title":"Ultrason. Sonochemistry"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"126496","DOI":"10.1016\/j.matchemphys.2022.126496","article-title":"Crosslinked and Biofunctionalized \u03b3-Cyclodextrin Metal Organic Framework to Enhance Cellular Binding Efficiency","volume":"289","author":"Singh","year":"2022","journal-title":"Mater. Chem. Phys."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Xiong, T., Guo, T., He, Y., Cao, Z., Xu, H., Wu, W., Wu, L., Zhu, W., and Zhang, J. (2022). Lactone Stabilized by Crosslinked Cyclodextrin Metal-Organic Frameworks to Improve Local Bioavailability of Topotecan in Lung Cancer. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15010142"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"126328","DOI":"10.1016\/j.foodchem.2020.126328","article-title":"Resveratrol-Loaded Core-Shell Nanostructured Delivery Systems: Cyclodextrin-Based Metal-Organic Nanocapsules Prepared by Ionic Gelation","volume":"317","author":"Qiu","year":"2020","journal-title":"Food Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3451","DOI":"10.1021\/acsabm.3c00162","article-title":"Drug-Facilitated Crystallization of Spray-Dried CD-MOFs with Tunable Morphology, Porosity, And Dissolution Profile","volume":"6","author":"Kadota","year":"2023","journal-title":"ACS Appl. Bio Mater."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1016\/j.ijpharm.2015.06.018","article-title":"Adaptation of the Quality by Design Concept in Early Pharmaceutical Development of an Intranasal Nanosized Formulation","volume":"491","author":"Pallagi","year":"2015","journal-title":"Int. J. Pharm."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Sipos, B., Szab\u00f3-R\u00e9v\u00e9sz, P., Cs\u00f3ka, I., Pallagi, E., Dob\u00f3, D.G., B\u00e9lteky, P., K\u00f3nya, Z., De\u00e1k, \u00c1., Janov\u00e1k, L., and Katona, G. (2020). Quality by Design Based Formulation Study of Meloxicam-Loaded Polymeric Micelles for Intranasal Administration. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12080697"},{"key":"ref_51","unstructured":"(2024, September 22). ICH Harmonised Tripartite Guideline Pharmaceutical Development Q8(R2). Available online: https:\/\/database.ich.org\/sites\/default\/files\/Q8_R2_Guideline.pdf."},{"key":"ref_52","unstructured":"(2024, September 22). ICH Harmonised Guideline Quality Risk Management Q9(R1). Available online: https:\/\/database.ich.org\/sites\/default\/files\/ICH_Q9%28R1%29_Guideline_Step4_2022_1219.pdf."},{"key":"ref_53","unstructured":"(2024, September 22). ICH Harmonised Guideline Pharmaceutical Quality System Q10. Available online: https:\/\/database.ich.org\/sites\/default\/files\/Q10%20Guideline.pdf."},{"key":"ref_54","unstructured":"(2024, September 22). ICH Harmonised Tripartite Guideline Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological\/Biological Entities) Q11. Available online: https:\/\/www.ema.europa.eu\/en\/documents\/scientific-guideline\/ich-guideline-q11-development-and-manufacture-drug-substances-chemical-entities-and-biotechnologicalbiological-entities_en.pdf."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Gyulai, O., Kov\u00e1cs, A., Sov\u00e1ny, T., Cs\u00f3ka, I., and Aigner, Z. (2018). Optimization of the Critical Parameters of the Spherical Agglomeration Crystallization Method by the Application of the Quality by Design Approach. Materials, 11.","DOI":"10.3390\/ma11040635"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"s152","DOI":"10.5530\/ijper.56.2s.86","article-title":"Box-Behnken Design Assisted Optimization and Standardization of Chromatographic Methodology for Quality Assessment of Metformin: Analytical Quality by Design Avenue","volume":"56","author":"Suryawanshi","year":"2022","journal-title":"Indian J. Pharm. Educ. Res."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Alam, P., Shakeel, F., Taleuzzaman, M., Foudah, A.I., Alqarni, M.H., Aljarba, T.M., Alshehri, S., and Ghoneim, M.M. (2022). Box-Behnken Design (BBD) Application for Optimization of Chromatographic Conditions in RP-HPLC Method Development for the Estimation of Thymoquinone in Nigella Sativa Seed Powder. Processes, 10.","DOI":"10.3390\/pr10061082"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/s40005-023-00635-w","article-title":"Recent Developments in Dry Powder Inhalation (DPI) Formulations for Lung-Targeted Drug Delivery","volume":"54","author":"Yang","year":"2024","journal-title":"J. Pharm. Investig."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1536","DOI":"10.1164\/ajrccm.156.5.9701098","article-title":"Regional Variability of Lung Inflammation in Cystic Fibrosis","volume":"156","author":"Meyer","year":"1997","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.jpeds.2012.12.042","article-title":"Distribution of Early Structural Lung Changes Due to Cystic Fibrosis Detected with Chest Computed Tomography","volume":"163","author":"Mott","year":"2013","journal-title":"J. Pediatr."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"121989","DOI":"10.1016\/j.ijpharm.2022.121989","article-title":"Development of Excipients Free Inhalable Co-Spray-Dried Tobramycin and Diclofenac Formulations for Cystic Fibrosis Using Two and Three Fluid Nozzles","volume":"624","author":"Marasini","year":"2022","journal-title":"Int. J. Pharm."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.jconrel.2019.10.038","article-title":"Spray-Drying of Inhalable, Multifunctional Formulations for the Treatment of Biofilms Formed in Cystic Fibrosis","volume":"314","author":"Lababidi","year":"2019","journal-title":"J. Control. Release"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/S0031-3955(16)35004-0","article-title":"The Alcohols: Ethanol, Methanol, Isopropanol, Ethylene Glycol","volume":"33","author":"Litovitz","year":"1986","journal-title":"Pediatr. Clin. N. Am."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"13193","DOI":"10.1007\/s10853-020-04937-4","article-title":"Metal\u2013Organic Frameworks Based on \u03b2-Cyclodextrin: Design and Selective Entrapment of Non-Steroidal Anti-Inflammatory Drugs","volume":"55","author":"Volkova","year":"2020","journal-title":"J. Mater. Sci."},{"key":"ref_65","first-page":"1087","article-title":"Application of Principal Component Analysis and DoE- Driven Green Analytical Chemistry Concept to Liquid Chromatographic Method for Estimation of Co- Formulated Anti-Hypertensive Drugs","volume":"106","author":"Prajapati","year":"2023","journal-title":"J. AOAC Int."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.ejps.2018.06.010","article-title":"Design and Characterization of Loratadine Nanosuspension Prepared by Ultrasonic-Assisted Precipitation","volume":"122","author":"Alshweiat","year":"2018","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_67","unstructured":"Menges, F. (2024, September 22). Spectragryph Optical Spectroscopy Software, Available online: http:\/\/spectroscopy.ninja."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"106247","DOI":"10.1016\/j.ejps.2022.106247","article-title":"Development of Extra-Fine Particles Containing Nanosized Meloxicam for Deep Pulmonary Delivery: In Vitro Aerodynamic and Cell Line Measurements","volume":"176","author":"Party","year":"2022","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1002\/jrs.2885","article-title":"Hydrogen Bonding Dynamics of Cyclodextrin\u2013Water Solutions by Depolarized Light Scattering","volume":"42","author":"Rossi","year":"2011","journal-title":"J. Raman Spectrosc."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/0378-5173(90)90132-N","article-title":"Studies of Cyclodextrin Inclusion Complexes. I. The Salbutamol-Cyclodextrin Complex as Studied by Phase Solubility and DSC","volume":"63","author":"Marques","year":"1990","journal-title":"Int. J. Pharm."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"133553","DOI":"10.1016\/j.foodchem.2022.133553","article-title":"Encapsulation of Catechin into Nano-Cyclodextrin-Metal-Organic Frameworks: Preparation, Characterization, and Evaluation of Storage Stability and Bioavailability","volume":"394","author":"Jiang","year":"2022","journal-title":"Food Chem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"108294","DOI":"10.1016\/j.foodhyd.2022.108294","article-title":"Synthesis of \u03b3-Cyclodextrin Metal-Organic Framework as Ethylene Absorber for Improving Postharvest Quality of Kiwi Fruit","volume":"136","author":"Li","year":"2023","journal-title":"Food Hydrocoll."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"45","DOI":"10.17344\/acsi.2016.2772","article-title":"Infrared Spectroscopy for Analysis of Co-Processed Ibuprofen and Magnesium Trisilicate at Milling and Freeze Drying","volume":"64","author":"Acharya","year":"2017","journal-title":"ACSi"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/S0378-5173(00)00569-X","article-title":"Inertial Sizing of Aerosol Inhaled from Two Dry Powder Inhalers with Realistic Breath Patterns versus Constant Flow Rates","volume":"210","author":"Finlay","year":"2000","journal-title":"Int. J. Pharm."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ijpharm.2010.12.040","article-title":"Influence of Particle Size on Regional Lung Deposition\u2014What Evidence Is There?","volume":"406","author":"Carvalho","year":"2011","journal-title":"Int. J. Pharm."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.ijpharm.2019.01.034","article-title":"Formulation and Comparison of Spray Dried Non-Porous and Large Porous Particles Containing Meloxicam for Pulmonary Drug Delivery","volume":"559","author":"Chvatal","year":"2019","journal-title":"Int. J. Pharm."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.ijpharm.2016.01.066","article-title":"Development of a Novel Dry Powder Inhalation Formulation for the Delivery of Rivastigmine Hydrogen Tartrate","volume":"501","author":"Simon","year":"2016","journal-title":"Int. J. Pharm."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"121223","DOI":"10.1016\/j.ijpharm.2021.121223","article-title":"Effects of L-Leucine on the Properties of Spray-Dried Swellable Microparticles with Wrinkled Surfaces for Inhalation Therapy of Pulmonary Fibrosis","volume":"610","author":"Wang","year":"2021","journal-title":"Int. J. Pharm."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Huang, Y., Tang, H., Meng, X., Liu, D., Liu, Y., Chen, B., and Zou, Z. (2024). \u03b3-Cyclodextrin Metal-Organic Frameworks as the Promising Carrier for Pulmonary Delivery of Cyclosporine A. Biomed. Pharmacother., 171.","DOI":"10.1016\/j.biopha.2024.116174"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"19268","DOI":"10.1073\/pnas.0905998106","article-title":"Biodegradable Polymer Nanoparticles That Rapidly Penetrate the Human Mucus Barrier","volume":"106","author":"Tang","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"365","DOI":"10.2217\/nnm.10.123","article-title":"Rapid Transport of Muco-Inert Nanoparticles in Cystic Fibrosis Sputum Treated with N-Acetyl Cysteine","volume":"6","author":"Suk","year":"2011","journal-title":"Nanomedicine"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"113504","DOI":"10.1016\/j.fluid.2022.113504","article-title":"Phase Behaviour and pH-Solubility Profile Prediction of Aqueous Buffered Solutions of Ibuprofen and Ketoprofen","volume":"560","author":"Wehbe","year":"2022","journal-title":"Fluid. Phase Equilibria"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.ddtec.2018.03.002","article-title":"Modifying the Physicochemical Properties of NSAIDs for Nasal and Pulmonary Administration","volume":"27","year":"2018","journal-title":"Drug Discov. Today Technol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.1021\/acs.molpharmaceut.7b00168","article-title":"Encapsulation of Ibuprofen in CD-MOF and Related Bioavailability Studies","volume":"14","author":"Hartlieb","year":"2017","journal-title":"Mol. Pharm."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1007\/s10953-009-9394-3","article-title":"Isothermal Titration Calorimetry and Theoretical Studies on Host-Guest Interaction of Ibuprofen with \u03b1-, \u03b2- and \u03b3-Cyclodextrin","volume":"38","author":"Xing","year":"2009","journal-title":"J. Solut. Chem."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/j.jpba.2011.02.022","article-title":"Solubilization of Ibuprofen with \u03b2-Cyclodextrin Derivatives: Energetic and Structural Studies","volume":"55","author":"Stein","year":"2011","journal-title":"J. Pharm. Biomed. Anal."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/16\/11\/1361\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:19:57Z","timestamp":1760113197000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/16\/11\/1361"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,24]]},"references-count":86,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["pharmaceutics16111361"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics16111361","relation":{},"ISSN":["1999-4923"],"issn-type":[{"type":"electronic","value":"1999-4923"}],"subject":[],"published":{"date-parts":[[2024,10,24]]}}}