Abstract
The characterization of nanocrystalline active ingredients in multicomponent formulations for the design and manufacture of products with increased bioavailability is often challenging. The purpose of this study is to develop an atomic force microscopy (AFM) imaging method for the detailed morphological characterization of nanocrystalline active ingredients in multicomponent oral formulations. The AFM images of aprepitant and sirolimus nanoparticles in aqueous suspension show that their sizes are comparable with those measured using dynamic light scattering (DLS) analysis. The method also provides information on a wide-sized range of particles, including small particles that can often only be detected by DLS when larger particles are removed by additional filtration steps. An expected advantage of the AFM method is the ability to obtain a detailed information on particle morphology and stiffness, which allows the active pharmaceutical ingredient and excipient (titanium dioxide) particles to be distinguished. Selective imaging of particles can also be achieved by varying the surface properties of the AFM solid substrate, which allows to control the interactions between the substrate and the active pharmaceutical ingredient and excipient particles. AFM analysis in combination with other methods (e.g., DLS), should facilitate the rational development of formulations based on nanoparticles.
Similar content being viewed by others
References
Shi J, Kantoff PW, Wooster R, Farokhzad OC. Cancer nanomedicine: progress, challenges and opportunities. Nat Rev Cancer. 2017;17:20–37.
Gao L, Liu G, Ma J, Wang X, Zhou L, Li X. Drug nanocrystals: in vivo performances. J Control Release. 2012;160:418–30.
Shegokar R, Müller RH. Nanocrystals: industrially feasible multifunctional formulation technology for poorly soluble actives. Int J Pharm. 2010;399:129–39.
Muller RH, Keck CM. Challenges and solutions for the delivery of biotech drugs--a review of drug nanocrystal technology and lipid nanoparticles. J Biotechnol. 2004;113:151–70.
US Food and Drug administration: Drugs@FDA: FDA Approved Drug Products. https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed 15 Nov 2018.
Hu J, Ng WK, Dong Y, Shen S, Tan RB. Continuous and scalable process for water-redispersible nanoformulation of poorly aqueous soluble APIs by antisolvent precipitation and spray-drying. Int J Pharm. 2011;404:198–204.
Leng D, Chen H, Li G, Guo M, Zhu Z, Xu L, et al. Development and comparison of intramuscularly long-acting paliperidone palmitate nanosuspensions with different particle size. Int J Pharm. 2014;472:380–5.
Onoue S, Aoki Y, Kawabata Y, Matsui T, Yamamoto K, Sato H, et al. Development of inhalable nanocrystalline solid dispersion of tranilast for airway inflammatory diseases. J Pharm Sci. 2011;100:622–33.
Moribe K, Wanawongthai C, Shudo J, Higashi K, Yamamoto K. Morphology and surface states of colloidal probucol nanoparticles evaluated by atomic force microscopy. Chem Pharm Bull. 2008;56:878–80.
Verma S, Huey BD, Burgess DJ. Scanning probe microscopy method for nanosuspension stabilizer selection. Langmuir. 2009;25:12481–7.
Glass BD, Novak C, Brown ME. The thermal and photostability of solid pharmaceuticals—a review. J Therm Anal Calorim. 2004;77:1013–36.
Baalousha M, Lead JR. Rationalizing nanomaterial sizes measured by atomic force microscopy, flow field-flow fractionation, and dynamic light scattering: sample preparation, polydispersity, and particle structure. Environ Sci Technol. 2012;46:6134–42.
Kestens V, Roebben G, Herrmann J, Jämting Å, Coleman V, Minelli C, et al. Challenges in the size analysis of a silica nanoparticle mixture as candidate certified reference material. J Nanopart Res. 2016;18:171.
Galkina OL, Ivanov VK, Agafonov AV, Seisenbaeva GA, Kessler VG. Cellulose nanofiber–titanium nanocomposites as potential drug delivery systems for dermal applications. J Mater Chem B. 2015;3:1688–98.
Gan C, Ao M, Liu Z, Chen Y. Imaging and force measurement of LDL and HDL by AFM in air and liquid. FEBS Open Bio. 2015;5:276–82.
Domingos RF, Baalousha MA, Ju-Nam Y, Reid MM, Tufenkji N, Lead JR, et al. Characterizing manufactured nanoparticles in the environment: multimethod determination of particle sizes. Environ Sci Technol. 2009;43:7277–84.
European Medicines Agency: EMEND: EPAR-scientific discussion. https://www.ema.europa.eu/documents/scientific-discussion/emend-epar-scientific-discussion_en.pdf. Accessed 15 Nov 2018.
European Medicines Agency: Rapamune: EPAR-scientific discussion. https://www.ema.europa.eu/documents/scientific-discussion/rapamune-epar-scientific-discussion_en.pdf. Accessed 15 Nov 2018.
Shlyakhtenko LS, Gall AA, Filonov A, Cerovac Z, Lushnikov A, Lyubchenko YL. Silatrane-based surface chemistry for immobilization of DNA, protein-DNA complexes and other biological materials. Ultramicroscopy. 2003;97:279–87.
Sader JE, Chon JW, Mulvaney P. Calibration of rectangular atomic force microscope cantilevers. Rev Sci Instrum. 1999;70:3967–9.
Hutter JL, Bechhoefer J. Calibration of atomic-force microscope tips. Rev Sci Instrum. 1993;64:1868–73.
Delorme N, Fery A. Direct method to study membrane rigidity of small vesicles based on atomic force microscope force spectroscopy. Phys Rev E. 2006;74:30901.
Smolyakov G, Formosa-Dague C, Severac C, Duval RE, Dague E. High speed indentation measures by FV, QI and QNM introduce a new understanding of bionanomechanical experiments. Micron. 2016;85:8–14.
Nečas D, Klapetek P. Gwyddion: an open-source software for SPM data analysis. Cent Eur J Phys. 2012;10:181–8.
Brochu H, Vermette P. Young’s moduli of surface-bound liposomes by atomic force microscopy force measurements. Langmuir. 2008;24:2009–14.
Kalvakuntla S, Deshpande M, Attari Z, Kunnatur BK. Preparation and characterization of nanosuspension of aprepitant by H96 process. Adv Pharm Bull. 2016;6:83–90.
Hoo CM, Starostin N, West P, Mecartney ML. Comparison of atomic force microscopy (AFM) and dynamic light scattering (DLS) methods to characterize nanoparticle size distributions. J Nanopart Res. 2008;10:89–96.
DRUGBANK: Sirolimus. https://www.drugbank.ca/drugs/DB00877. Accessed 15 Nov 2018.
Egami K, Higashi K, Yamamoto K, Moribe K. Crystallization of probucol in nanoparticles revealed by AFM analysis in aqueous solution. Mol Pharm. 2015;12:2972–80.
Acknowledgments
The authors thank M. Kozaki (Kowa Company Ltd., Japan) for supplying samples of titanium dioxide and for fruitful discussions regarding the use of nanosized excipients in solid oral dosage forms.
Funding
This work was supported in part by the Research on Regulatory Harmonization and Evaluation of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics project of the Japanese Agency for Medical Research and Development (17mk0101038j0303).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Sakai-Kato, K., Nanjo, K., Takechi-Haraya, Y. et al. Detailed Morphological Characterization of Nanocrystalline Active Ingredients in Solid Oral Dosage Forms Using Atomic Force Microscopy. AAPS PharmSciTech 20, 70 (2019). https://doi.org/10.1208/s12249-018-1259-x
Received:
Accepted:
Published:
DOI: https://doi.org/10.1208/s12249-018-1259-x