Review Article


DOI :10.26650/IstanbulJPharm.2023.1005069   IUP :10.26650/IstanbulJPharm.2023.1005069    Full Text (PDF)

In vitro dissolution testing methods for inhaled drugs

Balikis FaladeCarsten Ehrhardt

Mimicking the lung environment has always been a challenge with regards to dissolution testing of inhaled drugs from dry powder inhalers (DPIs). The aim of this review is to critically appraise the literature currently available on the in vitro test methods for dissolution of orally inhaled drug particulates. Reasons for the lack of standardised testing methods are discussed. Currently, there is not one test that fully represents the situation that occurs in the lungs in vivo, and this is the reason for the lack of a dissolution test recommendation by the pharmacopoeia. The importance of dose collection as a prerequisite to dissolution testing is also discussed using the Andersen cascade impactor as an example. Moreover, a study was carried out to determine the most robust method for testing the dissolution of fluticasone. Three different testing methods were used, i.e., the Transwell system, the paddle-over-disk method and DissolvIt. The results of this study determined that the paddle-over-disk method had the fastest dissolution rate. However, the data showed that there was a lack of similarity between all three tests. This lack of similarity between dissolution methods contributes to the reason why there is no standardised recommended dissolution method listed in the pharmacopoeia. Whilst the paddle-over-disk method yielded the fastest dissolution rate, it does not mean that it is reflective of in vivo dissolution. 


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References

  • Agu, R. U., Ugwoke, M. I., Armand, M., Kinget, R. & Verbeke, N. (2001) The lung as a route for systemic delivery of therapeutic proteins and peptides. Respiratory Research, 2(4), 198-209. https:// doi.org/10.1186/rr58 google scholar
  • Alqahtani, S., Roberts, C. J., Stolnik, S. & Bosquillon, C. (2020) De-velopment of an In Vitro System to Study the Interactions of Aerosolized Drugs with Pulmonary Mucus. Pharmaceutics, 12(2), 145. https://doi.org/10.3390/pharmaceutics12020145 google scholar
  • Andersen, A. A. (1958) New sampler for the collection, sizing, and enumeration of viable airborne particles. Journal of Bacteriology, 76(5), 471-484. https://dx.doi.org/10.1128/jb.76.5.471-484.1958 google scholar
  • Arora, D., Shah, K. A., Halquist, M. S. & Sakagami, M. (2010) In Vitro Aqueous Fluid-Capacity-Limited Dissolution Testing of Respira-ble Aerosol Drug Particles Generated from Inhaler Products. Phar-maceutical Research, 27(5), 786-795. https://dx.doi.org/10.1007/ s11095-010-0070-5 google scholar
  • Backman, P,, Adelmann, H., Petersson, G. & Jones, C.B. (2014) Ad-vances in Inhaled Technologies: Understanding the Therapeutic Challenge, Predicting Clinical Performance, and Designing the Optimal Inhaled Product. Clinical Pharmacology & Therapeutics, 95(5), 509-520. https://doi.org/10.1038/clpt.2014.27 google scholar
  • Börjel, M., Selg, E. & Gerde, P. (2015) In Vitro-Ex Vivo Correlation of Fluti-casone Propionate Pharmacokinetic Profiles. Retrieved from https:// ddl-conference.com/ddl26-2015/conference-papers/vitro-ex-vivo-correlation-fluticasone-propionate-pharmacokinetic-profiles/ google scholar
  • Cingolani, E., Alqahtani, S., Sadler, R., Prime, D., Stolnik, S. & Bos-quillon, C. (2019) In vitro investigation on the impact of airway mucus on drug dissolution and absorption at the air-epithelium interface in the lungs. European Journal of Pharmaceutics and Biopharmaceutics, 141, 210-220. https://dx.doi.org/10.1016/j. ejpb.2019.05.022 google scholar
  • Deepika, B., Tasleem, J., Naga Raju, K., Sarojini, S. & Sowmya Sri, K. (2018) Dissolution: A Predictive Tool for Conventional and Novel Dosage Forms. Journal of Pharma Research, 7, 113-119. google scholar
  • Diaz, D. A., Colgan, S. T., Langer, C. S., Bandi, N. T., Likar, M. D & Van Alstine, L. (2016) Dissolution Similarity Requirements: How Similar or Dissimilar Are the Global Regulatory Expectations? AAPS Jour-nal, 18(1), 15-22. https://doi.org/10.1208/s12248-015-9830-9 google scholar
  • Dokoumetzidis, A. & Macheras, P. (2006) A century of dissolution research: From Noyes and Whitney to the Biopharmaceutics Clas-sification System. International Journal of Pharmaceutics, 321(1-2), 1-11. https://dx.doi.org/10.1016/j.ijpharm.2006.07.011 google scholar
  • Eaton, J. W., Tran, D., Hauck, W. W. & Stippler, E. S. (2012) Devel-opment of a Performance Verification Test for USP Apparatus 4. Pharmaceutical Research, 29(2), 345-351. https://doi.org/10.1007/ s11095-011-0559-6 google scholar
  • EMA. (2006, June 21) Guideline on the Pharmaceutical Quality of Inhalation and Nasal Products. Retrieved from https://www.ema. europa.eu/en/pharmaceutical-quality-inhalation-nasal-products Floroiu, A., Klein, M., Kramer, J. & Lehr, C.-M. (2018) Towards stan-dardized dissolution techniques for in vitro performance testing of dry powder inhalers. Dissolution Technologies, 25, 6-18. https:// dx.doi.org/10.14227/DT250318P6 google scholar
  • Fotaki, N. & Reppas, C. (2005) The Flow Through Cell Methodology in the Evaluation of Intralumenal Drug Release Characteristics. Dissolu-tion Technologies, 12(2), 17-21. https://doi.org/10.14227/DT120205P17 google scholar
  • Franz, T. J. (1975) Percutaneous Absorption. On the Relevance of in Vitro Data. Journal of Investigative Dermatology, 64(3), 190-195. https://dx.doi.org/10.1111/1523-1747.ep12533356 google scholar
  • Frenning, G., van der Zwaan, I., Franek, F., Fransson, R. & Tehler, U. (2020) Model for the Analysis of Membrane-Type Dissolution Tests for Inhaled Drugs. Molecular Pharmaceutics, 17, 2426-2434. https://dx.doi.org/10.1021/acs.molpharmaceut.0c00163 google scholar
  • Fröhlich, E. (2019) Biological Obstacles for Identifying In Vitro-In Vivo Correlations of Orally Inhaled Formulations. Pharmaceutics, 11(7), 316. https://dx.doi.org/10.3390/pharmaceutics11070316 google scholar
  • Gerde, P., Malmlöf, M. & Selg, E. (2021) In Vitro to ex Vivo/In Vivo Correlation (IVIVC) of dissolution kinetics from inhaled particulate solutes using air/blood barrier models: Relation between in vitro design, lung physiology and kinetic output of models. Journal of Aerosol Science, 151, 105698. https://doi.org/10.1016/j.jaero-sci.2020.105698 google scholar
  • Hassoun, M., Malmlöf, M., Scheibelhofer, O., Kumar, A., Bansal, S., Selg, E. ... Forbes, B. (2019) Use of PBPK Modeling To Evaluate the Performance of DissolvIt, a Biorelevant Dissolution Assay for Oral-ly Inhaled Drug Products. Molecular Pharmaceutics, 16(3), 12451254. https://dx.doi.org/10.1021/acs.molpharmaceut.8b01200 google scholar
  • Henning, A., Schneider, M., Nafee, N., Muijs, L., Rytting, E., Wang, X. ... Lehr, C-M. (2010) Influence of Particle Size and Material Proper-ties on Mucociliary Clearance from the Airways. Journal of Aerosol Medicine and Pulmonary Drug Delivery, 23, 233-241. https://doi. org/10.1089/jamp.2009.0806 google scholar
  • Klein, S. (2019) Advancements in Dissolution Testing of Oral and Non-oral Formulations. AAPS PharmSciTech, 20(7),266. https://doi. org/10.1208/s12249-019-1479-8 google scholar
  • Kwon, Y.-B., Kang, J.-H., Han, C.-S., Kim, D.-W. & Park, C.-W. (2020) The Effect of Particle Size and Surface Roughness of Spray-Dried Bosentan Microparticles on Aerodynamic Performance for Dry Powder Inhalation. Pharmaceutics, 12(8), 765. https://dx.doi. org/10.3390/pharmaceutics12080765 google scholar
  • Ku, M. S. (2008) Use of the Biopharmaceutical Classification Sys-tem in early drug development. AAPS Journal, 10(1), 208-212. https://doi.org/10.1208/s12248-008-9020-0 google scholar
  • Kumar, A., Terakosolphan, W., Hassoun, M., Kalliopi-Kelli, V., Novicky, A., Harvey, R.... Forbes, B. (2017) A Biocompatible Syn-thetic Lung Fluid Based on Human Respiratory Tract Lining Fluid Composition. Pharmaceutical Research, 34, 2454-2465. https:// doi.org/10.1007/s11095-017-2169-4 google scholar
  • Labiris, N. R. & Dolovich, M. B. (2003) Pulmonary drug delivery. Part I: physiological factors affecting therapeutic effectiveness of aero-solized medications. British Journal of Clinical Pharmacology, 56(6), 588-599. https://dx.doi.org/10.1046/j.1365-2125.2003.01892.x google scholar
  • Marple, V. A., Roberts, D. L., Romay, F. J., Miller, N. C., Truman, K. G., Van Oort, M Hochrainer, D. (2003) Next generation pharma-ceutical impactor (a new impactor for pharmaceutical inhaler testing). Part I: Design. Journal of Aerosol Medicine, 16(3), 283-299. https://dx.doi.org/10.1089/089426803769017659 google scholar
  • Marques, M., Löbenberg, R. & Almukainzi, M. (2011) Simulated Biological Fluids with Possible Application in Dissolution Testing. Dissolution Technologies, 18, 15-28. https://dx.doi.org/10.14227/ DT180311P15 google scholar
  • May, S., Jensen, B., Wolkenhauer, M., Schneider, M. & Lehr, C.-M. (2012) Dissolution techniques for in vitro testing of dry powders for inhalation. Pharmaceutical Research, 29(8), 2157-2166. https:// dx.doi.org/10.1007/s11095-012-0744-2 google scholar
  • May, S., Jensen, B., Weiler, C., Wolkenhauer, M., Schneider, M. & Lehr, C.-M. (2014) Dissolution testing of powders for inhalation: influence of particle deposition and modeling of dissolution pro-files. Pharmaceutical Research, 31(11), 3211-3224. https://dx.doi. org/10.1007/s11095-014-1413-4 google scholar
  • May, S., Kind, S., Jensen, B., Wolkenhauer, M., Schneider, M. & Lehr, C-M. (2015) Miniature In Vitro Dissolution Testing of Powders for Inhalation. Dissolution Technologies, 22, 40-51. https://dx.doi. org/10.14227/DT220315P40 google scholar
  • McDonnell, D., D’Arcy, D. M., Crane, L. J. & Redmond, B. (2018) A mathematical analysis of drug dissolution in the USP flow through apparatus. Heat and Mass Transfer, 54(3), :793-801. https://doi.org/10.1007/s00231-017-2151-z google scholar
  • Olejnik, A., Goscianska, J. & Nowak, I. (2012) Active Compounds Release from Semisolid Dosage Forms. Journal of Pharmaceuti-cal Sciences, 101(11), 4032-4045. https://dx.doi.org/10.1002/ jps.23289 google scholar
  • Patton, J. S., Brain, J. D., Davies, L.A., Fiegel, J., Gumbleton, M., Kim, K.-J....Ehrhardt, C. (2010) The particle has landed - charac- google scholar
  • terizing the fate of inhaled pharmaceuticals. Journal of Aerosol Medicine and Pulmonary Drug Delivery, 23, 71-87. https://dx.doi. org/10.1089/jamp.2010.0836 google scholar
  • Patton, J. S. & Byron, P. R. (2007) Inhaling medicines: delivering drugs to the body through the lungs. Nature Reviews Drug Discov-ery, 6(1), 67-74. https://doi.org/10.1038/nrd2153 google scholar
  • Patton, J. S., Fishburn, C. S. & Weers, J.G. (2004) The lungs as a portal of entry for systemic drug delivery. Proceedings of the American Thoracic Society, 1(4), 338-344. https://doi.org/10.1513/ pats.200409-049TA google scholar
  • Price, R., Shur, J., Ganley, W., Farias, G., Fotaki, N., Conti, D. S.... Lee,S. (2020) Development of an Aerosol Dose Collection Apparatus for In Vitro Dissolution Measurements of Orally Inhaled Drug Products. AAPS Journal, 22(2), 47. https://doi.org/10.1208/s12248-020-0422-y google scholar
  • Radivojev, S., Zellnitz, S., Paudel, A. & Fröhlich, E. (2019) Search-ing for physiologically relevant in vitro dissolution techniques for orally inhaled drugs. International Journal of Pharmaceutics, 556, 45-56. https://dx.doi.org/10.1016/j.ijpharm.2018.11.072 google scholar
  • Riley, T., Christopher, D., Arp, J., Casazza, A., Colombani, A., Cooper, A....Lyapustina, S. (2012) Challenges with developing in vitro dis- google scholar
  • solution tests for orally inhaled products (OIPs). AAPS PharmSciTech, 13(3), 978-989. https://dx.doi.org/10.1208/s12249-012-9822-3 google scholar
  • Rohrschneider, M., Bhagwat, S., Krampe, R., Michler, V., Breit-kreutz, J. & Hochhaus, G. (2015) Evaluation of the Transwell System for Characterization of Dissolution Behavior of Inhala-tion Drugs: Effects of Membrane and Surfactant. Molecular Pharmaceutics, 12(8), 2618-2624. https://doi.org/10.1021/acs. molpharmaceut.5b00221 google scholar
  • Ruge, C. A., Kirch, J. & Lehr, C.-M. (2013) Pulmonary drug deliv-ery: from generating aerosols to overcoming biological barriers-therapeutic possibilities and technological challenges. Lancet Respiratory Medicine, 1(5), 402-413. https://dx.doi.org/10.1016/ S2213-2600(13)70072-9 google scholar
  • Shaji, J. & Shaikh, M. (2016) Current Development in the Evalu-ation Methods of Pulmonary Drug Delivery System. Indian Journal of Pharmaceutical Sciences, 78, 294-306. https://dx.doi. org/10.4172/pharmaceutical-sciences.1000118 google scholar
  • Singh, I. & Aboul-Enein, H. Y. (2006) Advantages of USP Appa-ratus IV (flow-through cell apparatus) in dissolution studies.Journal of the Iranian Chemical Society, 3(3), 220-222. https://doi. org/10.1007/BF03247211 google scholar
  • Tay, J., Liew, C. & Heng, P. (2018) Dissolution of Fine Particle Frac-tion from Truncated Anderson [sic] Cascade Impactor with an Enhancer Cell. International Journal of Pharmaceutics, 545, 45-50. https://dx.doi.org/10.1016/j.ijpharm.2018.04.048 google scholar
  • US FDA. (2018, August 9) Dissolution Testing and Acceptance Cri-teria for Immediate-Release Solid Oral Dosage Form Drug Prod-ucts Containing High Solubility Drug Substances Guidance for Industry. Retrieved from https://www.regulations.gov/docket/ FDA-2018-D-2614 google scholar
  • US Pharmacopeia. (2021) Aerosols, nasal sprays, metered dose inhalers, dry powder inhalers. Chapter 601 google scholar
  • Velaga, S. P., Djuris, J., Cvijic, S., Rozou, S., Russo, P., Colombo, G. & Rossi, A. (2018) Dry powder inhalers: An overview of the in vitro dissolution methodologies and their correlation with the bio-pharmaceutical aspects of the drug products. European Journal of Pharmaceutical Sciences, 113, 18-28. https://dx.doi.org/10.1016/j. ejps.2017.09.002 google scholar
  • Yoshida, H., Kuwana, A., Shibata, H., Izutsu, K.-I. & Goda, Y. (2017) Comparison of Aerodynamic Particle Size Distribution Between a Next Generation Impactor and a Cascade Impactor at a Range of Flow Rates. AAPS PharmSciTech, 18(3), 646-653. https://dx.doi. org/10.1208/s12249-016-0544-9 google scholar

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APA

Falade, B., & Ehrhardt, C. (2023). In vitro dissolution testing methods for inhaled drugs. İstanbul Journal of Pharmacy, 53(2), 239-250. https://doi.org/10.26650/IstanbulJPharm.2023.1005069


AMA

Falade B, Ehrhardt C. In vitro dissolution testing methods for inhaled drugs. İstanbul Journal of Pharmacy. 2023;53(2):239-250. https://doi.org/10.26650/IstanbulJPharm.2023.1005069


ABNT

Falade, B.; Ehrhardt, C. In vitro dissolution testing methods for inhaled drugs. İstanbul Journal of Pharmacy, [Publisher Location], v. 53, n. 2, p. 239-250, 2023.


Chicago: Author-Date Style

Falade, Balikis, and Carsten Ehrhardt. 2023. “In vitro dissolution testing methods for inhaled drugs.” İstanbul Journal of Pharmacy 53, no. 2: 239-250. https://doi.org/10.26650/IstanbulJPharm.2023.1005069


Chicago: Humanities Style

Falade, Balikis, and Carsten Ehrhardt. In vitro dissolution testing methods for inhaled drugs.” İstanbul Journal of Pharmacy 53, no. 2 (Dec. 2024): 239-250. https://doi.org/10.26650/IstanbulJPharm.2023.1005069


Harvard: Australian Style

Falade, B & Ehrhardt, C 2023, 'In vitro dissolution testing methods for inhaled drugs', İstanbul Journal of Pharmacy, vol. 53, no. 2, pp. 239-250, viewed 9 Dec. 2024, https://doi.org/10.26650/IstanbulJPharm.2023.1005069


Harvard: Author-Date Style

Falade, B. and Ehrhardt, C. (2023) ‘In vitro dissolution testing methods for inhaled drugs’, İstanbul Journal of Pharmacy, 53(2), pp. 239-250. https://doi.org/10.26650/IstanbulJPharm.2023.1005069 (9 Dec. 2024).


MLA

Falade, Balikis, and Carsten Ehrhardt. In vitro dissolution testing methods for inhaled drugs.” İstanbul Journal of Pharmacy, vol. 53, no. 2, 2023, pp. 239-250. [Database Container], https://doi.org/10.26650/IstanbulJPharm.2023.1005069


Vancouver

Falade B, Ehrhardt C. In vitro dissolution testing methods for inhaled drugs. İstanbul Journal of Pharmacy [Internet]. 9 Dec. 2024 [cited 9 Dec. 2024];53(2):239-250. Available from: https://doi.org/10.26650/IstanbulJPharm.2023.1005069 doi: 10.26650/IstanbulJPharm.2023.1005069


ISNAD

Falade, Balikis - Ehrhardt, Carsten. In vitro dissolution testing methods for inhaled drugs”. İstanbul Journal of Pharmacy 53/2 (Dec. 2024): 239-250. https://doi.org/10.26650/IstanbulJPharm.2023.1005069



TIMELINE


Submitted05.10.2021
Accepted17.04.2023
Published Online28.08.2023

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