AAPS PharmSciTech

, 20:34 | Cite as

On the Stability of Nano-formulations Prepared by Direct Synthesis: Simulated Ostwald Ripening of a Typical Nanocrystal Distribution Post-nucleation

  • Peter J. SkrdlaEmail author
  • Husheng Yang
Brief/Technical Note


Compared to more traditional top-down processing, the less common route to preparing drug nanocrystals through direct synthesis, e.g., starting with the nucleation of dissolved drug molecules (bottom-up processing), can offer both speed and cost advantages that makes it worthy of investigation. The current, theoretical work puts forth a technical basis and simulated results that could provide additional impetus for conducting further experimental work in this area. Specifically, an asymmetrical particle size distribution generated through the nucleation of a typical small-molecule drug, mirrored after carbamazepine hydrate based on a recent work [Skrdla PJ. J Phys Chem C 116:214–25, 2012], is subject to growth over time by a particle-coarsening mechanism using simulations of Ostwald ripening. Compared to a symmetrical, Gaussian distribution under the same conditions (fixed, relatively low concentration of free drug molecules in solution), it is found that, at longer times, the asymmetrical distribution formed through nucleation broadens more slowly. This finding could represent an additional benefit of synthetic strategies for the preparation of nano-formulations, previously unreported.


Ostwald ripening temporal evolution simulation particle size distribution 



  1. 1.
    Serajuddin ATM. Salt formation to improve drug solubility. Adv Drug Deliv Rev. 2007;59:603–16.CrossRefGoogle Scholar
  2. 2.
    Qian F, Huang J, Hussain MA. Drug-polymer solubility and miscibility: stability consideration and practical challenges in amorphous solid dispersion development. J Pharm Sci. 2010;99:2941–7.CrossRefGoogle Scholar
  3. 3.
    Fleisher D, Bong R, Stewart BH. Improved oral drug delivery: solubility limitations overcome by the use of prodrugs. Adv Drug Deliv Rev. 1996;19:115–30.CrossRefGoogle Scholar
  4. 4.
    Childs SL, Chyall LJ, Dunlap JT, Smolenskaya VN, Stahly BC, Stahly GP. Crystal engineering approach to forming cocrystals of amine hydrochlorides with organic acids. Molecular complexes of fluoxetine hydrochloride with benzoic, succinic, and fumaric acids. J Am Chem Soc. 2004;126:13335–42.CrossRefGoogle Scholar
  5. 5.
    Challa R, Ahuja A, Ali J, Khar RK. Cyclodextrins in drug delivery: an updated review. AAPS PharmSciTech. 2005;6:E329–57.CrossRefGoogle Scholar
  6. 6.
    Müller RH, Mäder K, Gohla S. Solid lipid nanoparticles (SLN) for controlled drug delivery – a review of the state of the art. Eur J Pharm Biopharm. 2000;50:161–77.CrossRefGoogle Scholar
  7. 7.
    Gao L, Zhang D, Chen M. Drug nanocrystals for the formulation of poorly soluble drugs and its application as a potential drug delivery system. J Nanopart Res. 2008;10:845–62.CrossRefGoogle Scholar
  8. 8.
    Wang M, Rutledge GC, Myerson AS, Trout BL. Production and characterization of carbamazepine nanocrystals by electrospraying for continuous pharmaceutical manufacturing. J Pharm Sci. 2012;101:1178–88.CrossRefGoogle Scholar
  9. 9.
    Strachan CJ, Howell SL, Rades T, Gordon KC. A theoretical and spectroscopic study of carbamazepine polymorphs. J Raman Spectrosc. 2004;35:401–8.CrossRefGoogle Scholar
  10. 10.
    Skrdla PJ. Use of dispersive kinetic models for nucleation and denucleation to predict steady-state nanoparticle size distributions and the role of Ostwald ripening. J Phys Chem C. 2012;116:214–25.CrossRefGoogle Scholar
  11. 11.
    Ochi M, Kawachi T, Toita E, Hashimoto I, Yuminoki K, Onoue S, et al. Development of nanocrystal formulation of meloxicam with improved dissolution and pharmacokinetic behaviors. Int J Pharm. 2014;474:151–6.CrossRefGoogle Scholar
  12. 12.
    Junghanns J-UAH, Müller RH. Nanocrystal technology, drug delivery and clinical applications. Int J Nanomedicine. 2008;3:295–310.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Talapin DV. Introduction: nanoparticle chemistry. Chem Rev. 2016;116:10343–5.CrossRefGoogle Scholar
  14. 14.
    Voorhees PW. The theory of Ostwald ripening. J Stat Phys. 1985;38:231–52.CrossRefGoogle Scholar
  15. 15.
    Vekilov PG. Nucleation. Cryst Growth Des. 2010;10:5007–19.CrossRefGoogle Scholar
  16. 16.
    Atkinson JD, Murray BJ, Woodhouse MT, Whale TF, Baustian KJ, Carslaw KS, et al. The importance of feldspar for ice nucleation by mineral dust in mixed-phase clouds. Nature. 2013;498:355–8.CrossRefGoogle Scholar
  17. 17.
    Rabinow BE. Nanosuspensions in drug delivery. Nature Rev. 2004;3:785–96.Google Scholar
  18. 18.
    Peng X, Wickham J, Alivisatos P. Kinetics of II-VI and III-V colloidal semiconductor nanocrystal growth: “focusing” of size distributions. J Am Chem Soc. 1998;120:5343–4.CrossRefGoogle Scholar
  19. 19.
    Yin Y, Alivisatos P. Colloidal nanocrystal synthesis and the organic-inorganic interface. Nature. 2005;437:664–70.CrossRefGoogle Scholar
  20. 20.
    Liu Y, Kathan K, Saad W, Prud’homme RK. Ostwald ripening of β-carotene nanoparticles. Phys Rev Lett. 2007;98:036102.CrossRefGoogle Scholar
  21. 21.
    Harada M, Katagiri E. Mechanism of silver particle formation during photoreduction using in situ time-resolved SAXS analysis. Langmuir. 2010;26:17896–905.CrossRefGoogle Scholar
  22. 22.
    LaMer VK. Nucleation in phase transitions. Ind Eng Chem. 1952;44:1270–7.CrossRefGoogle Scholar
  23. 23.
    Tanh NTK, Maclean N, Mahiddine S. Mechanisms of nucleation and growth of nanoparticles in solution. Chem Rev. 2014;114:7610–30.CrossRefGoogle Scholar
  24. 24.
    Talapin DV, Rogach AL, Haase M, Weller H. Evolution of an ensemble of nanoparticles in a colloidal solution: theoretical study. J Phys Chem B. 2001;105:12278–85.CrossRefGoogle Scholar
  25. 25.
    Sugimoto T. General kinetics of Ostwald ripening of precipitates. J Colloid Interface Sci. 1978;63:16–26.CrossRefGoogle Scholar
  26. 26.
    Lovette MA, Browning AR, Griffin DW, Sizemore JP, Snyder RC, Doherty MF. Crystal shape engineering. Ind Eng Chem Res. 2008;47:9812–33.CrossRefGoogle Scholar
  27. 27.
    Niwa T, Miura S, Danjo K. Universal wet-milling technique to prepare oral nanosuspension focused on discovery and preclinical animal studies – development of particle design method. Int J Pharm. 2011;405:218–27.CrossRefGoogle Scholar
  28. 28.
    Gaumet M, Vargas A, Gurny R, Delie F. Nanoparticles for drug delivery: the need for precision in reporting particle size parameters. Eur J Pharm Biopharm. 2008;69:1–9.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  1. 1.GlaxoSmithKlineCollegevilleUSA

Personalised recommendations