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Improving Stability and Dissolution of Amorphous Clofazimine by Polymer Nano-Coating

  • Yue Gui
  • Yinshan Chen
  • Zhenxuan Chen
  • Karen J. Jones
  • Lian Yu
Research Paper

Abstract

Purpose

To inhibit the surface crystallization and enhance the dissolution of the basic amorphous drug clofazimine by polymer nano-coating.

Methods

The free surface of amorphous clofazimine was coated by dip coating in an alginate solution at pH 7. The stability of the coated amorphous drug against crystallization was evaluated by X-ray diffraction and light microscopy. The effect of coating on dissolution rate was measured in simulated gastric fluid in an USP-II apparatus at 37°C.

Results

At pH 7, the weak base clofazimine (pKa = 8.5) is positively charged, while the weak alginic acid (pKa = 3.5) is negatively charged, allowing coating by electrostatic deposition. Coated amorphous particles remain nearly amorphous after one year under the accelerated testing condition 40°C/75% R.H. and show faster dissolution than uncoated particles. In the first hour of dissolution, coated amorphous particles dissolve 50% faster than uncoated amorphous particles, and a factor of 3 faster than crystalline particles of the same size.

Conclusions

A pharmaceutically acceptable polymer, alginate, is coated on amorphous clofazimine by electrostatic deposition and effectively inhibits its surface crystallization and enhances its dissolution rate. This is the first time the nano-coating technique is applied to a basic drug using the principle of electrostatic deposition, demonstrating the generality of the approach.

Key Words

Amorphous pharmaceutical clofazimine crystallization dissolution polymer coating stability wetting 

Abbreviation

CFZ

Clofazimine

DSC

Differential scanning calorimetry

IMC

Indomethacin

PDDA

Poly(dimethyldiallyl ammonium)

PSS

Poly(styrenesulfonate)

PVP

Polyvinylpyrrolidone

R.H.

Relative humidity

SDS

Sodium dodecyl sulfate

SGF

Simulated gastric fluid

XRD

X-ray diffraction

Notes

Acknowledgments and Disclosures

We thank the Bill and Melinda Gates Foundation for financial support, Yuhui Li for assistance with dissolution measurements, and Mark Sacchetti, Niya Bowers, Phil Goliber, and Ellen Harrington for helpful discussions.

Supplementary material

11095_2019_2584_MOESM1_ESM.docx (488 kb)
ESM 1 (DOCX 488 kb)

References

  1. 1.
    Crowley KJ, Zografi G. The effect of low concentrations of molecularly dispersed poly(vinylpyrrolidone) on indomethacin crystallization from the amorphous state. Pharm Res. 2003;20:1417–22.CrossRefGoogle Scholar
  2. 2.
    Huang C, Powell CT, Sun Y, Cai T, Yu L. Effect of low-concentration polymers on crystal growth in molecular glasses: a controlling role for polymer segmental mobility relative to host dynamics. J Phys Chem B. 2017;121:1963–71.CrossRefGoogle Scholar
  3. 3.
    Wu T, Sun Y, Li N, de Villiers MM, Yu L. Inhibiting surface crystallization of amorphous indomethacin by nanocoating. Langmuir. 2007;23:5148–53.CrossRefGoogle Scholar
  4. 4.
    Li Y, Yu J, Hu S, Chen Z, Sacchetti M, Sun CC, et al. Polymer nanocoating of amorphous drugs for improving stability, dissolution, powder flow, and tabletability: the case of chitosan-coated indomethacin. Mol Pharm. 2019;16:1305−11.CrossRefGoogle Scholar
  5. 5.
    Zhu L, Brian CW, Swallen SF, Straus PT, Ediger MD, Yu L. Surface self-diffusion of an organic glass. Phys Rev Lett. 2011;106:256103.CrossRefGoogle Scholar
  6. 6.
    Huang C, Ruan S, Cai T, Yu L. Fast surface diffusion and crystallization of amorphous griseofulvin. J Phys Chem B. 2017;121:9463–8.CrossRefGoogle Scholar
  7. 7.
    Wu T, Yu L. Surface crystallization of indomethacin below T g. Pharm Res. 2006;23:2350–5.CrossRefGoogle Scholar
  8. 8.
    Sun Y, Zhu L, Kearns KL, Ediger MD, Yu L. Glasses crystallize rapidly at surfaces by growing crystals upward. Proc Natl Acad Sci U S A. 2011;108:5990–5.CrossRefGoogle Scholar
  9. 9.
    Cai T, Zhu L, Yu L. Crystallization of organic glasses: effect of polymer additives on bulk and surface crystal growth in amorphous nifedipine. Pharm Res. 2011;28:2458–66.CrossRefGoogle Scholar
  10. 10.
    Hasebe M, Musumeci D, Yu L. Fast surface crystallization of molecular glasses: creation of depletion zones by surface diffusion and crystallization flux. J Phys Chem B. 2015;119:3304–11.CrossRefGoogle Scholar
  11. 11.
    Quigley JM, Blake JM, Bonner FJ. The effect of ionization on the partitioning of clofazimine in the 2,2,4-trimetylpentane-water system. Int J Pharm. 1989;54:155–9.CrossRefGoogle Scholar
  12. 12.
    Teerakapibal R, Gui Y, Yu L. Gelatin nano-coating for inhibiting surface crystallization of amorphous drugs. Pharm Res. 2018;35:23–9.CrossRefGoogle Scholar
  13. 13.
    Zhu L, Wong L, Yu L. Surface-enhanced crystallization of amorphous nifedipine. Mol Pharm. 2008;5:921–6.CrossRefGoogle Scholar
  14. 14.
    Bannigan P, Zeglinski J, Lusi M, O’Brien J, Hudson SP. Investigation into the solid and solution properties of known and novel polymorphs of the antimicrobial molecule clofazimine. Cryst Growth Des. 2016;16:7240–50.CrossRefGoogle Scholar
  15. 15.
    Valetti S, Xia X, Costa-Gouveia J, Brodin P, Bernet-Camard M-F, Andersson M, et al. Clofazimine encapsulation in nanoporous silica particles for the oral treatment of antibiotic-resistant mycobacterium tuberculosis infections. Nanomedicine. 2017;12:831–44.CrossRefGoogle Scholar
  16. 16.
    Decher G. Fuzzy nanoassemblies: toward layered polymeric multicomposites. Science. 1997;277:1232–7.CrossRefGoogle Scholar
  17. 17.
    Powell CT, Cai T, Hasebe M, Gunn EM, Gao P, Zhang G, et al. Low-concentration polymers inhibit and accelerate crystal growth in organic glasses in correlation with segmental mobility. J Phys Chem B. 2013;117:10334–41.CrossRefGoogle Scholar
  18. 18.
    Rychlewska U, Broom MBH, Effleston DS, Hodgson DJ. Antileprosy dihydrophenazines. Structural characterization of two crystal forms of clofazimine and of isoclofazimine, B.3857. J Am Chem Soc. 1985;107:4768–72.CrossRefGoogle Scholar
  19. 19.
    Hancock BC, Parks M. What is the true solubility advantage for amorphous pharmaceuticals? Pharm Res. 2000;17:397–404.CrossRefGoogle Scholar
  20. 20.
    Quigley JM, Fahelelhom MS, Timoney RF, Corrigan OI. Temperature dependence and thermodynamics of partitioning of clofazimine analogues in the n-octanol/water system. Int J Pharm. 1990;58:107–13.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.School of PharmacyUniversity of Wisconsin-MadisonMadisonUSA
  2. 2.Zeeh Pharmaceutical Experiment Station, School of PharmacyUniversity of Wisconsin-Madison,MadisonUSA
  3. 3.Department of ChemistryUniversity of Wisconsin-MadisonMadisonUSA

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