A new cocrystal and salts of itraconazole: comparison of solid-state properties, stability and dissolution behavior

Anna Shevchenko, Luis M. Bimbo, Inna Miroshnyk, Jorma Haarala, Kristýna Jelínková, Kaisa Syrjänen, Bert van Veen, Juha Kiesvaara, Hélder A. Santos, Jouko Yliruusi

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Cocrystallization and salt formation have been shown to entail substantial promise in tailoring the physicochemical properties of drug compounds, in particular, their dissolution and hygroscopicity. In this work, we report on the preparation and comparative evaluation of a new cocrystal of itraconazole and malonic acid and two new hydrochloric salts (dihydrochloride and trihydrochloride) of itraconazole. The intrinsic dissolution rate, hygroscopicity, and thermodynamic stability were determined for the obtained solid-state forms and compared to itraconazole-succinic acid (2:1) cocrystal. The results show that the solid-state forms with higher intrinsic dissolution rate are less stable. Both itraconazole salts exhibited the highest dissolution rate, but also demonstrated high hygroscopicity at relative humidity above 70%. The new cocrystal, in contrast, were found to increase the dissolution rate of the parent drug by about 5-fold without compromising the hygroscopicity and the stability. This study demonstrates that, for dissolution rate enhancement of poorly water-soluble weak bases, cocrystallization is a more suitable approach than hydrochloric salt formation.

LanguageEnglish
Pages403-409
Number of pages7
JournalInternational Journal of Pharmaceutics
Volume436
Issue number1-2
Early online date27 Jun 2012
DOIs
Publication statusPublished - 15 Oct 2012
Externally publishedYes

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Wettability
Itraconazole
Salts
Succinic Acid
Humidity
Thermodynamics
Pharmaceutical Preparations
Water

Keywords

  • antifungal agents
  • chlorides
  • crystallization
  • drug stability
  • itraconazole
  • malonates
  • powder diffraction
  • salts
  • solubility
  • x-ray diffraction

Cite this

Shevchenko, Anna ; Bimbo, Luis M. ; Miroshnyk, Inna ; Haarala, Jorma ; Jelínková, Kristýna ; Syrjänen, Kaisa ; van Veen, Bert ; Kiesvaara, Juha ; Santos, Hélder A. ; Yliruusi, Jouko. / A new cocrystal and salts of itraconazole : comparison of solid-state properties, stability and dissolution behavior. In: International Journal of Pharmaceutics. 2012 ; Vol. 436, No. 1-2. pp. 403-409.
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abstract = "Cocrystallization and salt formation have been shown to entail substantial promise in tailoring the physicochemical properties of drug compounds, in particular, their dissolution and hygroscopicity. In this work, we report on the preparation and comparative evaluation of a new cocrystal of itraconazole and malonic acid and two new hydrochloric salts (dihydrochloride and trihydrochloride) of itraconazole. The intrinsic dissolution rate, hygroscopicity, and thermodynamic stability were determined for the obtained solid-state forms and compared to itraconazole-succinic acid (2:1) cocrystal. The results show that the solid-state forms with higher intrinsic dissolution rate are less stable. Both itraconazole salts exhibited the highest dissolution rate, but also demonstrated high hygroscopicity at relative humidity above 70{\%}. The new cocrystal, in contrast, were found to increase the dissolution rate of the parent drug by about 5-fold without compromising the hygroscopicity and the stability. This study demonstrates that, for dissolution rate enhancement of poorly water-soluble weak bases, cocrystallization is a more suitable approach than hydrochloric salt formation.",
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author = "Anna Shevchenko and Bimbo, {Luis M.} and Inna Miroshnyk and Jorma Haarala and Krist{\'y}na Jel{\'i}nkov{\'a} and Kaisa Syrj{\"a}nen and {van Veen}, Bert and Juha Kiesvaara and Santos, {H{\'e}lder A.} and Jouko Yliruusi",
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year = "2012",
month = "10",
day = "15",
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Shevchenko, A, Bimbo, LM, Miroshnyk, I, Haarala, J, Jelínková, K, Syrjänen, K, van Veen, B, Kiesvaara, J, Santos, HA & Yliruusi, J 2012, 'A new cocrystal and salts of itraconazole: comparison of solid-state properties, stability and dissolution behavior' International Journal of Pharmaceutics, vol. 436, no. 1-2, pp. 403-409. https://doi.org/10.1016/j.ijpharm.2012.06.045

A new cocrystal and salts of itraconazole : comparison of solid-state properties, stability and dissolution behavior. / Shevchenko, Anna; Bimbo, Luis M.; Miroshnyk, Inna; Haarala, Jorma; Jelínková, Kristýna; Syrjänen, Kaisa; van Veen, Bert; Kiesvaara, Juha; Santos, Hélder A.; Yliruusi, Jouko.

In: International Journal of Pharmaceutics, Vol. 436, No. 1-2, 15.10.2012, p. 403-409.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A new cocrystal and salts of itraconazole

T2 - International Journal of Pharmaceutics

AU - Shevchenko, Anna

AU - Bimbo, Luis M.

AU - Miroshnyk, Inna

AU - Haarala, Jorma

AU - Jelínková, Kristýna

AU - Syrjänen, Kaisa

AU - van Veen, Bert

AU - Kiesvaara, Juha

AU - Santos, Hélder A.

AU - Yliruusi, Jouko

N1 - Copyright © 2012 Elsevier B.V. All rights reserved.

PY - 2012/10/15

Y1 - 2012/10/15

N2 - Cocrystallization and salt formation have been shown to entail substantial promise in tailoring the physicochemical properties of drug compounds, in particular, their dissolution and hygroscopicity. In this work, we report on the preparation and comparative evaluation of a new cocrystal of itraconazole and malonic acid and two new hydrochloric salts (dihydrochloride and trihydrochloride) of itraconazole. The intrinsic dissolution rate, hygroscopicity, and thermodynamic stability were determined for the obtained solid-state forms and compared to itraconazole-succinic acid (2:1) cocrystal. The results show that the solid-state forms with higher intrinsic dissolution rate are less stable. Both itraconazole salts exhibited the highest dissolution rate, but also demonstrated high hygroscopicity at relative humidity above 70%. The new cocrystal, in contrast, were found to increase the dissolution rate of the parent drug by about 5-fold without compromising the hygroscopicity and the stability. This study demonstrates that, for dissolution rate enhancement of poorly water-soluble weak bases, cocrystallization is a more suitable approach than hydrochloric salt formation.

AB - Cocrystallization and salt formation have been shown to entail substantial promise in tailoring the physicochemical properties of drug compounds, in particular, their dissolution and hygroscopicity. In this work, we report on the preparation and comparative evaluation of a new cocrystal of itraconazole and malonic acid and two new hydrochloric salts (dihydrochloride and trihydrochloride) of itraconazole. The intrinsic dissolution rate, hygroscopicity, and thermodynamic stability were determined for the obtained solid-state forms and compared to itraconazole-succinic acid (2:1) cocrystal. The results show that the solid-state forms with higher intrinsic dissolution rate are less stable. Both itraconazole salts exhibited the highest dissolution rate, but also demonstrated high hygroscopicity at relative humidity above 70%. The new cocrystal, in contrast, were found to increase the dissolution rate of the parent drug by about 5-fold without compromising the hygroscopicity and the stability. This study demonstrates that, for dissolution rate enhancement of poorly water-soluble weak bases, cocrystallization is a more suitable approach than hydrochloric salt formation.

KW - antifungal agents

KW - chlorides

KW - crystallization

KW - drug stability

KW - itraconazole

KW - malonates

KW - powder diffraction

KW - salts

KW - solubility

KW - x-ray diffraction

UR - http://www.sciencedirect.com/science/journal/03785173

U2 - 10.1016/j.ijpharm.2012.06.045

DO - 10.1016/j.ijpharm.2012.06.045

M3 - Article

VL - 436

SP - 403

EP - 409

JO - International Journal of Pharmaceutics

JF - International Journal of Pharmaceutics

SN - 0378-5173

IS - 1-2

ER -