Drug Nanocrystals: Formulation Strategies, Physicochemical Characterization, and Therapeutic Applications
Keywords:
drug nanocrystals, nanosuspensions, particle engineering, dissolution, drug delivery, long acting injectablesAbstract
Nanocrystals of the drugs can be used as an interesting method for improving the dissolution of poorly soluble drugs by achieving crystalline drug particle size smaller than one micrometre. It is the combination of crystal size, surface stabilization, dosage form and route of administration that is responsible for their value. This increased surface area can allow more of the substance to enter solution in the body, and some of the substances have poor solubility, which allows them to be 'held' in an injectable ‘depot’ for longer periods of time. Various objectives may need various formulation and evaluation strategies. Media milling, high-pressure homogenization, precipitation and combined processes are complementary production processes and each comes with its own controls and limitations. To obtain a reliable characterization, the complete size distribution, state of the solid, surface properties and chemical quality as well as the dissolution and performance after storage or re-dispersion should be measured. Rapid dissolution with both improved and unimproved exposure is demonstrated to be an unreliable guide to absorption in the oral studies. Clinical translation is demonstrated by human pharmacokinetic studies and extended-release antiretroviral studies; and numerous ocular, dermal and oncology applications continue to be based primarily on preclinical data. In order to achieve progress, we must maintain clinically meaningful properties throughout the product manufacturing and delivery and select informative comparator products and associate material properties with exposure, safety and patient benefit. The right development target is not "the lowest possible particle size", but a real product, one that can be repeated and is suited to a therapy application.
References
1. Merisko-Liversidge E, Liversidge GG, Cooper ER. Nanosizing: a formulation approach for poorly-water-soluble compounds. Eur J Pharm Sci. 2003;18(2):113-120. doi: 10.1016/s0928-0987(02)00251-8.
2. Rabinow BE. Nanosuspensions in drug delivery. Nat Rev Drug Discov. 2004;3(9):785-796. doi: 10.1038/nrd1494.
3. Shegokar R, Müller RH. Nanocrystals: industrially feasible multifunctional formulation technology for poorly soluble actives. Int J Pharm. 2010;399(1-2):129-139. doi: 10.1016/j.ijpharm.2010.07.044.
4. Möschwitzer JP. Drug nanocrystals in the commercial pharmaceutical development process. Int J Pharm. 2013;453(1):142-156. doi: 10.1016/j.ijpharm.2012.09.034.
5. Pardhi E, Vasave R, Srivastava V, Yadav R, Mehra NK. Nanocrystal technologies in biomedical science: From the bench to the clinic. Drug Discov Today. 2024;29(3):103913. doi: 10.1016/j.drudis.2024.103913.
6. Rossier B, Jordan O, Allémann E, Rodríguez-Nogales C. Nanocrystals and nanosuspensions: an exploration from classic formulations to advanced drug delivery systems. Drug Deliv Transl Res. 2024;14(12):3438-3451. doi: 10.1007/s13346-024-01559-0.
7. Noyes AA, Whitney WR. The rate of solution of solid substances in their own solutions. J Am Chem Soc. 1897;19(12):930-934. doi: 10.1021/ja02086a003.
8. Kesisoglou F, Panmai S, Wu Y. Nanosizing--oral formulation development and biopharmaceutical evaluation. Adv Drug Deliv Rev. 2007;59(7):631-644. doi: 10.1016/j.addr.2007.05.003.
9. Bonhoeffer B, Kordikowski A, John E, Juhnke M. Numerical modeling of the dissolution of drug nanocrystals and its application to industrial product development. ADMET DMPK. 2022;10(4):253-287. doi: 10.5599/admet.1437.
10. Willmann AC, Berkenfeld K, Faber T, Wachtel H, Boeck G, Wagner KG. Itraconazole Nanosuspensions via Dual Centrifugation Media Milling: Impact of Formulation and Process Parameters on Particle Size and Solid-State Conversion as Well as Storage Stability. Pharmaceutics. 2022;14(8):1528. doi: 10.3390/pharmaceutics14081528.
11. Baert L, van 't Klooster G, Dries W, François M, Wouters A, Basstanie E, et al. Development of a long-acting injectable formulation with nanoparticles of rilpivirine (TMC278) for HIV treatment. Eur J Pharm Biopharm. 2009;72(3):502-508. doi: 10.1016/j.ejpb.2009.03.006.
12. Li M, Azad M, Davé R, Bilgili E. Nanomilling of Drugs for Bioavailability Enhancement: A Holistic Formulation-Process Perspective. Pharmaceutics. 2016;8(2):17. doi: 10.3390/pharmaceutics8020017.
13. Van Eerdenbrugh B, Van den Mooter G, Augustijns P. Top-down production of drug nanocrystals: nanosuspension stabilization, miniaturization and transformation into solid products. Int J Pharm. 2008;364(1):64-75. doi: 10.1016/j.ijpharm.2008.07.023.
14. Catlin EJ, Fandiño OE, Lopez-Vidal L, Sangalli M, Donnelly RF, Palma SD, et al. A novel temperature-controlled media milling device to produce drug nanocrystals at the laboratory scale. Int J Pharm. 2024;666:124780. doi: 10.1016/j.ijpharm.2024.124780.
15. Keck CM, Müller RH. Drug nanocrystals of poorly soluble drugs produced by high pressure homogenisation. Eur J Pharm Biopharm. 2006;62(1):3-16. doi: 10.1016/j.ejpb.2005.05.009.
16. Chang S, Yang Q, Liu J, Yin L, Han J, Zong L, et al. The Increased Dissolution and Oral Absorption of Itraconazole by Nanocrystals with an Endogenous Small-Molecule Surfactant as a Stabilizer. Molecules. 2024;29(8):1769. doi: 10.3390/molecules29081769.
17. Lhaglham P, Jiramonai L, Jia Y, Huang B, Huang Y, Gao X, et al. Drug nanocrystals: Surface engineering and its applications in targeted delivery. iScience. 2024;27(11):111185. doi: 10.1016/j.isci.2024.111185.
18. Van Eerdenbrugh B, Froyen L, Van Humbeeck J, Martens JA, Augustijns P, Van den Mooter G. Drying of crystalline drug nanosuspensions-the importance of surface hydrophobicity on dissolution behavior upon redispersion. Eur J Pharm Sci. 2008;35(1-2):127-135. doi: 10.1016/j.ejps.2008.06.009.
19. Peltonen L, Strachan C. Understanding Critical Quality Attributes for Nanocrystals from Preparation to Delivery. Molecules. 2015;20(12):22286-22300. doi: 10.3390/molecules201219851.
20. Chaubal MV, Popescu C. Conversion of nanosuspensions into dry powders by spray drying: a case study. Pharm Res. 2008;25(10):2302-2308. doi: 10.1007/s11095-008-9625-0.
21. Hu J, Dong Y, Ng WK, Pastorin G. Preparation of drug nanocrystals embedded in mannitol microcrystals via liquid antisolvent precipitation followed by immediate (on-line) spray drying. Adv Powder Technol. 2018;29(4):957-963. doi: 10.1016/j.apt.2018.01.013.
22. U.S. Food and Drug Administration. Drug products, including biological products, that contain nanomaterials: guidance for industry [Internet]. Silver Spring (MD): FDA; 2022. Available from: https://www.fda.gov/media/157812/download.
23. Sarnes A, Østergaard J, Jensen SS, Aaltonen J, Rantanen J, Hirvonen J, et al. Dissolution study of nanocrystal powders of a poorly soluble drug by UV imaging and channel flow methods. Eur J Pharm Sci. 2013;50(3-4):511-519. doi: 10.1016/j.ejps.2013.08.030.
24. Liversidge GG, Cundy KC. Particle size reduction for improvement of oral bioavailability of hydrophobic drugs: I. Absolute oral bioavailability of nanocrystalline danazol in beagle dogs. Int J Pharm. 1995;125(1):91-97. doi: 10.1016/0378-5173(95)00122-y.
25. Sauron R, Wilkins M, Jessent V, Dubois A, Maillot C, Weil A. Absence of a food effect with a 145 mg nanoparticle fenofibrate tablet formulation. Int J Clin Pharmacol Ther. 2006;44(2):64-70. doi: 10.5414/CPP44064.
26. Sarnes A, Kovalainen M, Häkkinen MR, Laaksonen T, Laru J, Kiesvaara J, et al. Nanocrystal-based per-oral itraconazole delivery: superior in vitro dissolution enhancement versus Sporanox® is not realized in in vivo drug absorption. J Control Release. 2014;180:109-116. doi: 10.1016/j.jconrel.2014.02.016.
27. Swindells S, Andrade-Villanueva JF, Richmond GJ, Rizzardini G, Baumgarten A, Masiá M, et al. Long-Acting Cabotegravir and Rilpivirine for Maintenance of HIV-1 Suppression. N Engl J Med. 2020;382(12):1112-1123. doi: 10.1056/nejmoa1904398.
28. Orkin C, Arasteh K, Górgolas Hernández-Mora M, Pokrovsky V, Overton ET, Girard PM, et al. Long-Acting Cabotegravir and Rilpivirine after Oral Induction for HIV-1 Infection. N Engl J Med. 2020;382(12):1124-1135. doi: 10.1056/nejmoa1909512.
29. Schopf LR, Popov AM, Enlow EM, Bourassa JL, Ong WZ, Nowak P, et al. Topical Ocular Drug Delivery to the Back of the Eye by Mucus-Penetrating Particles. Transl Vis Sci Technol. 2015;4(3):11. doi: 10.1167/tvst.4.3.11.
30. Otake H, Ogata F, Nakazawa Y, Misra M, Tsubaki M, Kawasaki N, et al. Pharmacological Behavior of Propylene Glycol/Polyvinyl Alcohol Hydrogel Incorporating Indomethacin Nanocrystals in the Skin. Gels. 2025;11(4):251. doi: 10.3390/gels11040251.
31. Hollis CP, Weiss HL, Leggas M, Evers BM, Gemeinhart RA, Li T. Biodistribution and bioimaging studies of hybrid paclitaxel nanocrystals: lessons learned of the EPR effect and image-guided drug delivery. J Control Release. 2013;172(1):12-21. doi: 10.1016/j.jconrel.2013.06.039.
32. U.S. Food and Drug Administration. EMEND (aprepitant) capsules: prescribing information [Internet]. Silver Spring (MD): FDA; 2003. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2003/21549_Emend_lbl.pdf.
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