The intrinsic dissolution rate (IDR) is an important parameter in pharmaceutical science that measures the rate at which a pure crystalline active pharmaceutical ingredient dissolves in the absence of diffusion limitations. Traditional IDR measurement techniques do not capture the complex interplay between particle morphology, fluid flow, and dissolution dynamics. The dissolution rate of individual particles can differ from the population average because of factors such as particle size, surface roughness, or exposure of individual crystal facets to the dissolution medium. The aim of this work was to apply time-resolved X-ray microtomography imaging and simultaneously measure the individual dissolution characteristics of a large population of crystalline particles placed in a packed bed perfused by the dissolution medium. Using NaCl crystals in three different size fractions as a model, time-resolved microtomography made it possible to visualize the dissolution process in a custom-built flow cell. Subsequent 3D image analysis was used to evaluate changes in the shape, size, and surface area of individual particles by tracking them as they are dissolved. Information about the particle population statistics and intrabatch variability provided a deeper insight into the dissolution process that can complement established IDR measurements.

Department of Chemical Engineering University of Chemistry and Technology Prague Technická 5 Praha 166 28 Czech Republic

Paul Scherrer Institute Swiss Light Source Forschungsstrasse 111 Villigen PSI 5232 Switzerland

Zentiva k s U Kabelovny 130 Praha 10 102 00 Czech Republic

Zobrazit více v PubMed

Teleki A.; Nylander O.; Bergström C. A. S. Intrinsic Dissolution Rate Profiling of Poorly Water-Soluble Compounds in Biorelevant Dissolution Media. Pharmaceutics 2020, 12 (6), 493.10.3390/pharmaceutics12060493. PubMed DOI PMC

Tsinman K.; et al. Powder dissolution method for estimating rotating disk intrinsic dissolution rates of low solubility drugs. Pharm. Res. 2009, 26, 2093–2100. 10.1007/s11095-009-9921-3. PubMed DOI

Shekunov B.; Montgomery E. R. Theoretical Analysis of Drug Dissolution: I. Solubility and Intrinsic Dissolution Rate. J. Pharm. Sci. 2016, 105 (9), 2685–2697. 10.1016/j.xphs.2015.12.006. PubMed DOI

Novakovic D.; et al. Understanding Dissolution and Crystallization with Imaging: A Surface Point of View. Mol. Pharmaceutics 2018, 15 (11), 5361–5373. 10.1021/acs.molpharmaceut.8b00840. PubMed DOI PMC

Andersson S. B. E.; et al. Interlaboratory Validation of Small-Scale Solubility and Dissolution Measurements of Poorly Water-Soluble Drugs. J. Pharm. Sci. 2016, 105 (9), 2864–2872. 10.1016/j.xphs.2016.03.010. PubMed DOI

Tres F.; et al. Real-time Raman imaging to understand dissolution performance of amorphous solid dispersions. J. Controlled Release 2014, 188, 53–60. 10.1016/j.jconrel.2014.05.061. PubMed DOI

Karde V.; et al. Investigating sizing induced surface alterations in crystalline powders using surface energy heterogeneity determination. Powder Technol. 2022, 395, 645–651. 10.1016/j.powtec.2021.10.006. DOI

Ho R.; et al. Effect of Milling on Particle Shape and Surface Energy Heterogeneity of Needle-Shaped Crystals. Pharm. Res. 2012, 29 (10), 2806–2816. 10.1007/s11095-012-0842-1. PubMed DOI

Brown C. K.; et al. Dissolution testing of poorly soluble compounds. Pharm. Technol. 2004, 28, 56–43. 10.14227/DT110204P28. DOI

Noiriel C.; et al. Direct Determination of Dissolution Rates at Crystal Surfaces Using 3D X-ray Microtomography. ACS Earth and Space Chemistry 2019, 3 (1), 100–108. 10.1021/acsearthspacechem.8b00143. DOI

Østergaard J.; et al. Monitoring lidocaine single-crystal dissolution by ultraviolet imaging. J. Pharm. Sci. 2011, 100 (8), 3405–3410. 10.1002/jps.22532. PubMed DOI

Zeitler J. A.; Gladden L. F. In-vitro tomography and non-destructive imaging at depth of pharmaceutical solid dosage forms. Eur. J. Pharm. Biopharm. 2009, 71 (1), 2–22. 10.1016/j.ejpb.2008.08.012. PubMed DOI

Hancock B. C.; Mullarney M. P. X-ray Microtomography of Solid Dosage Forms. Pharm. Technol. 2005, 29, 92–100.

Moazami Goudarzi N.; et al. Development of Flow-Through Cell Dissolution Method for In Situ Visualization of Dissolution Processes in Solid Dosage Forms Using X-ray CT. Pharmaceutics 2022, 14, 2475.10.3390/pharmaceutics14112475. PubMed DOI PMC

Datta S.; Grant D. J. W. Crystal structures of drugs: advances in determination, prediction and engineering. Nat. Rev. Drug Discovery 2004, 3 (1), 42–57. 10.1038/nrd1280. PubMed DOI

Oliveira J. M.; et al. Deformulation of a solid pharmaceutical form using computed tomography and X-ray fluorescence. J. Phys.: Conf. Ser. 2015, 630 (1), 01200210.1088/1742-6596/630/1/012002. DOI

Schomberg A. K.; et al. The use of X-ray microtomography to investigate the microstructure of pharmaceutical tablets: Potentials and comparison to common physical methods. International Journal of Pharmaceutics: X 2021, 3, 10009010.1016/j.ijpx.2021.100090. PubMed DOI PMC

Vijayakumar J.; et al. Characterization of Pharmaceutical Tablets by X-ray Tomography. Pharmaceuticals 2023, 16 (5), 733.10.3390/ph16050733. PubMed DOI PMC

Cloetens P.; et al. Phase objects in synchrotron radiation hard x-ray imaging. J. Phys. D: Appl. Phys. 1996, 29 (1), 133–146. 10.1088/0022-3727/29/1/023. DOI

Tetard L.; et al. Optical and plasmonic spectroscopy with cantilever shaped materials. J. Phys. D: Appl. Phys. 2011, 44, 44510210.1088/0022-3727/44/44/445102. DOI

Danalou S. D.; et al. Advanced 3D and 4D microstructure study of single granule formation for pharmaceutical powders using synchrotron x-ray imaging. AIChE J. 2023, 69 (5), e1804810.1002/aic.18048. DOI

Gomis V.; et al. Liquid-liquid-solid equilibria for the ternary systems water-sodium chloride or potassium chloride-1-propanol or 2-propanol. Fluid Phase Equilib. 1994, 98, 141–147. 10.1016/0378-3812(94)80113-4. DOI

Mokso R.; et al. GigaFRoST: the gigabit fast readout system for tomography. Journal of synchrotron radiation 2017, 24 (6), 1250–1259. 10.1107/S1600577517013522. PubMed DOI PMC

Paganin D.; et al. Simultaneous phase and amplitude extraction from a single defocused image of a homogeneous object. Journal of microscopy (Oxford) 2002, 206 (1), 33–40. 10.1046/j.1365-2818.2002.01010.x. PubMed DOI

Marone F.; Stampanoni M. Regridding reconstruction algorithm for real-time tomographic imaging. Journal of Synchrotron Radiation 2012, 19 (6), 1029–1037. 10.1107/S0909049512032864. PubMed DOI PMC

Rueden C. T.; et al. ImageJ2: ImageJ for the next generation of scientific image data. BMC Bioinf. 2017, 18 (1), 529.10.1186/s12859-017-1934-z. PubMed DOI PMC

Li C. H.; Tam P. K. S. An iterative algorithm for minimum cross entropy thresholding. Pattern Recognition Letters 1998, 19 (8), 771–776. 10.1016/S0167-8655(98)00057-9. DOI

Legland D.; Arganda-Carreras I.; Andrey P. MorphoLibJ: integrated library and plugins for mathematical morphology with ImageJ. Bioinformatics 2016, 32 (22), 3532–3534. 10.1093/bioinformatics/btw413. PubMed DOI

DragonFly Windows version. Comet Technologies Canada Inc.: Montreal, Canada; https://www.theobjects.com/dragonfly. 2022.

Council of Europe, European Pharmacopoeia Commission, European Directorate for the Quality of Medicines & Healthcare European pharmacopoeia, In European treaty series. 2010, Council Of Europe: European Directorate for the Quality of Medicines and Healthcare: Strasbourg. p. 294–295.

Wood J. H.; Syarto J. E.; Letterman H. Improved Holder for Intrinsic Dissolution Rate Studies. J. Pharm. Sci. 1965, 54 (7), 1068.10.1002/jps.2600540730. PubMed DOI

Viegas T.; et al. Measurement of intrinsic drug dissolution rates using two types of apparatus. Pharm. Technol. North Am. 2001, 25, 44–53.

Sonntag E.; et al. Accelerated reactive dissolution model of drug release from long-acting injectable formulations. Eur. J. Pharm. Biopharm. 2023, 189, 122–132. 10.1016/j.ejpb.2023.06.003. PubMed DOI

Godinho J. R. A.; Hassanzadeh A.; Heinig T. 3D Quantitative Mineral Characterization of Particles Using X-ray Computed Tomography. Nature Resource Research 2023, 32, 479–499. 10.1007/s11053-023-10169-5. DOI

Lo A.; Nosrati A.; Addai-Mensah J. Particle and pore dynamics under column leaching of goethitic and saprolitic nickel laterite agglomerates. Advanced Powder Technology 2016, 27, 2370–2376. 10.1016/j.apt.2016.11.009. DOI

Djukaj S.; Kolář J.; Lehocký R.; Zadražil A.; Štěpánek F. Design of particle size distribution for custom dissolution profiles by solving the inverse problem. Powder Technol. 2022, 395, 743–757. 10.1016/j.powtec.2021.10.023. DOI