Investigation of Deteriorated Dissolution of Amorphous Itraconazole: Description of Incompatibility with Magnesium Stearate and Possible Solutions

B. Démuth, D. L. Galata, E. Szabó, B. Nagy, A. Farkas, A. Balogh, E. Hirsch, H. Pataki, Z. Rapi, L. Bezúr, T. Vigh, G. Verreck, Z. Szalay, Demeter, G. Marosi, Z. K. Nagy

Research output: Article

8 Citations (Scopus)

Abstract

Disadvantageous crystallization phenomenon of amorphous itraconazole (ITR) occurring in the course of dissolution process was investigated in this work. A perfectly amorphous form (solid dispersion) of the drug was generated by the electroblowing method (with vinylpyrrolidone-vinyl acetate copolymer), and the obtained fibers were formulated into tablets. Incomplete dissolution of the tablets was noticed under the circumstances of the standard dissolution test, after which a precipitated material could be filtered. The filtrate consisted of ITR and stearic acid since no magnesium content was detectable in it. In parallel with dissolution, ITR forms an insoluble associate, stabilized by hydrogen bonding, with stearic acid deriving from magnesium stearate. This is why dissolution curves do not have the plateaus at 100%. Two ways are viable to tackle this issue: change the lubricant (with sodium stearyl fumarate >95% dissolution can be accomplished) or alter the polymer in the solid dispersion to a type being able to form hydrogen bonds with ITR (e.g., hydroxypropyl methylcellulose). This work draws attention to one possible phenomenon that can lead to a deterioration of originally good dissolution of an amorphous solid dispersion.

Original languageEnglish
Pages (from-to)3927-3934
Number of pages8
JournalMolecular Pharmaceutics
Volume14
Issue number11
DOIs
Publication statusPublished - nov. 6 2017

Fingerprint

Itraconazole
Tablets
Lubricants
Hydrogen Bonding
Crystallization
Magnesium
Hydrogen
Polymers
stearic acid
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

Cite this

Investigation of Deteriorated Dissolution of Amorphous Itraconazole : Description of Incompatibility with Magnesium Stearate and Possible Solutions. / Démuth, B.; Galata, D. L.; Szabó, E.; Nagy, B.; Farkas, A.; Balogh, A.; Hirsch, E.; Pataki, H.; Rapi, Z.; Bezúr, L.; Vigh, T.; Verreck, G.; Szalay, Z.; Demeter, ; Marosi, G.; Nagy, Z. K.

In: Molecular Pharmaceutics, Vol. 14, No. 11, 06.11.2017, p. 3927-3934.

Research output: Article

Démuth, B, Galata, DL, Szabó, E, Nagy, B, Farkas, A, Balogh, A, Hirsch, E, Pataki, H, Rapi, Z, Bezúr, L, Vigh, T, Verreck, G, Szalay, Z, Demeter, , Marosi, G & Nagy, ZK 2017, 'Investigation of Deteriorated Dissolution of Amorphous Itraconazole: Description of Incompatibility with Magnesium Stearate and Possible Solutions', Molecular Pharmaceutics, vol. 14, no. 11, pp. 3927-3934. https://doi.org/10.1021/acs.molpharmaceut.7b00629
Démuth, B. ; Galata, D. L. ; Szabó, E. ; Nagy, B. ; Farkas, A. ; Balogh, A. ; Hirsch, E. ; Pataki, H. ; Rapi, Z. ; Bezúr, L. ; Vigh, T. ; Verreck, G. ; Szalay, Z. ; Demeter, ; Marosi, G. ; Nagy, Z. K. / Investigation of Deteriorated Dissolution of Amorphous Itraconazole : Description of Incompatibility with Magnesium Stearate and Possible Solutions. In: Molecular Pharmaceutics. 2017 ; Vol. 14, No. 11. pp. 3927-3934.
@article{3b9fac90c4014d9f9b749489f4463f83,
title = "Investigation of Deteriorated Dissolution of Amorphous Itraconazole: Description of Incompatibility with Magnesium Stearate and Possible Solutions",
abstract = "Disadvantageous crystallization phenomenon of amorphous itraconazole (ITR) occurring in the course of dissolution process was investigated in this work. A perfectly amorphous form (solid dispersion) of the drug was generated by the electroblowing method (with vinylpyrrolidone-vinyl acetate copolymer), and the obtained fibers were formulated into tablets. Incomplete dissolution of the tablets was noticed under the circumstances of the standard dissolution test, after which a precipitated material could be filtered. The filtrate consisted of ITR and stearic acid since no magnesium content was detectable in it. In parallel with dissolution, ITR forms an insoluble associate, stabilized by hydrogen bonding, with stearic acid deriving from magnesium stearate. This is why dissolution curves do not have the plateaus at 100{\%}. Two ways are viable to tackle this issue: change the lubricant (with sodium stearyl fumarate >95{\%} dissolution can be accomplished) or alter the polymer in the solid dispersion to a type being able to form hydrogen bonds with ITR (e.g., hydroxypropyl methylcellulose). This work draws attention to one possible phenomenon that can lead to a deterioration of originally good dissolution of an amorphous solid dispersion.",
keywords = "amorphous solid dispersion, crystallization, dissolution, magnesium stearate, oral delivery, tablet formulation",
author = "B. D{\'e}muth and Galata, {D. L.} and E. Szab{\'o} and B. Nagy and A. Farkas and A. Balogh and E. Hirsch and H. Pataki and Z. Rapi and L. Bez{\'u}r and T. Vigh and G. Verreck and Z. Szalay and Demeter and G. Marosi and Nagy, {Z. K.}",
year = "2017",
month = "11",
day = "6",
doi = "10.1021/acs.molpharmaceut.7b00629",
language = "English",
volume = "14",
pages = "3927--3934",
journal = "Molecular Pharmaceutics",
issn = "1543-8384",
publisher = "American Chemical Society",
number = "11",

}

TY - JOUR

T1 - Investigation of Deteriorated Dissolution of Amorphous Itraconazole

T2 - Description of Incompatibility with Magnesium Stearate and Possible Solutions

AU - Démuth, B.

AU - Galata, D. L.

AU - Szabó, E.

AU - Nagy, B.

AU - Farkas, A.

AU - Balogh, A.

AU - Hirsch, E.

AU - Pataki, H.

AU - Rapi, Z.

AU - Bezúr, L.

AU - Vigh, T.

AU - Verreck, G.

AU - Szalay, Z.

AU - Demeter,

AU - Marosi, G.

AU - Nagy, Z. K.

PY - 2017/11/6

Y1 - 2017/11/6

N2 - Disadvantageous crystallization phenomenon of amorphous itraconazole (ITR) occurring in the course of dissolution process was investigated in this work. A perfectly amorphous form (solid dispersion) of the drug was generated by the electroblowing method (with vinylpyrrolidone-vinyl acetate copolymer), and the obtained fibers were formulated into tablets. Incomplete dissolution of the tablets was noticed under the circumstances of the standard dissolution test, after which a precipitated material could be filtered. The filtrate consisted of ITR and stearic acid since no magnesium content was detectable in it. In parallel with dissolution, ITR forms an insoluble associate, stabilized by hydrogen bonding, with stearic acid deriving from magnesium stearate. This is why dissolution curves do not have the plateaus at 100%. Two ways are viable to tackle this issue: change the lubricant (with sodium stearyl fumarate >95% dissolution can be accomplished) or alter the polymer in the solid dispersion to a type being able to form hydrogen bonds with ITR (e.g., hydroxypropyl methylcellulose). This work draws attention to one possible phenomenon that can lead to a deterioration of originally good dissolution of an amorphous solid dispersion.

AB - Disadvantageous crystallization phenomenon of amorphous itraconazole (ITR) occurring in the course of dissolution process was investigated in this work. A perfectly amorphous form (solid dispersion) of the drug was generated by the electroblowing method (with vinylpyrrolidone-vinyl acetate copolymer), and the obtained fibers were formulated into tablets. Incomplete dissolution of the tablets was noticed under the circumstances of the standard dissolution test, after which a precipitated material could be filtered. The filtrate consisted of ITR and stearic acid since no magnesium content was detectable in it. In parallel with dissolution, ITR forms an insoluble associate, stabilized by hydrogen bonding, with stearic acid deriving from magnesium stearate. This is why dissolution curves do not have the plateaus at 100%. Two ways are viable to tackle this issue: change the lubricant (with sodium stearyl fumarate >95% dissolution can be accomplished) or alter the polymer in the solid dispersion to a type being able to form hydrogen bonds with ITR (e.g., hydroxypropyl methylcellulose). This work draws attention to one possible phenomenon that can lead to a deterioration of originally good dissolution of an amorphous solid dispersion.

KW - amorphous solid dispersion

KW - crystallization

KW - dissolution

KW - magnesium stearate

KW - oral delivery

KW - tablet formulation

UR - http://www.scopus.com/inward/record.url?scp=85033383210&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85033383210&partnerID=8YFLogxK

U2 - 10.1021/acs.molpharmaceut.7b00629

DO - 10.1021/acs.molpharmaceut.7b00629

M3 - Article

C2 - 28972782

AN - SCOPUS:85033383210

VL - 14

SP - 3927

EP - 3934

JO - Molecular Pharmaceutics

JF - Molecular Pharmaceutics

SN - 1543-8384

IS - 11

ER -