Effect of Organic Acids on Molecular Mobility, Physical Stability, and Dissolution of Ternary Ketoconazole Spray-Dried Dispersions

Michelle H. Fung; Raj Suryanarayanan

doi:10.1021/acs.molpharmaceut.8b00593

Effect of Organic Acids on Molecular Mobility, Physical Stability, and Dissolution of Ternary Ketoconazole Spray-Dried Dispersions

Michelle H. Fung, Raj Suryanarayanan

Pharmaceutics

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

Abstract

In an earlier investigation, ketoconazole (KTZ)-organic acid coamorphous systems were prepared, wherein, in the solid-state, there was ionic and/or hydrogen bonding interactions between the drug and the acid (Fung, M.; Berzinš, K.; Suryanarayanan, R. Mol. Pharmaceutics, 2018, 15 (5), 1862-1869). While the coamorphous systems accelerated KTZ dissolution, the organic acids were not effective in maintaining supersaturation, and drug precipitation was observed. Ternary drug-polymer-acid amorphous solid dispersions (ASDs) were prepared with KTZ, polyvinylpyrrolidone (PVP), and each oxalic (OXA), tartaric (TAR), citric (CIT), or succinic (SUC) acid. When compared with amorphous KTZ, solid dispersions of KTZ-PVP exhibited a moderate reduction in molecular mobility and small improvement in dissolution performance. The incorporation of acid (OXA, TAR, or CIT) in PVP-KTZ solid dispersion led to orders of magnitude increase in α-relaxation times and decrease in the crystallization propensity. These ternary ASDs were stable while crystallization of the cocrystal was observed in the SUC system. Moreover, the addition of acids also dramatically improved the dissolution performance of KTZ, a result attributed to KTZ-acid interactions.

Original language	English (US)
Pages (from-to)	41-48
Number of pages	8
Journal	Molecular pharmaceutics
Volume	16
Issue number	1
DOIs	https://doi.org/10.1021/acs.molpharmaceut.8b00593
State	Published - Jan 7 2019

Bibliographical note

Funding Information:
M.H.F. was partially supported by the PhRMA Pre-Doctoral Fellowship in Pharmaceutics and the Rowell Graduate Fellowship from the University of Minnesota. This project was partially funded by the William and Mildred Peters Endowment Fund. Powder XRD work was carried out at the Characterization Facility at the University of Minnesota, a member of the NSF-funded Materials Research Facilities Network (www.mrfn.org). We thank Upsher-Smith Laboratories (Drs. Limin Shi and Howard Chen) for providing access to spray drying equipment. We thank Karlis Berziņs,̌ Jiangnan Dun, Janice Laramy, Michaela Roslawski, and Wei-Jhe Sun for their help.

Publisher Copyright:
Copyright © 2018 American Chemical Society.

Keywords

amorphous solid dispersions
coamorphous
crystallization
dissolution
molecular mobility
physical stability
Succinic Acid/chemistry
Microscopy, Electron, Scanning
Tartrates/chemistry
Drug Stability
Crystallization
Organic Chemicals/chemistry
Acids/chemistry
Povidone/chemistry
X-Ray Diffraction
Molecular Structure
Ketoconazole/chemistry
Oxalic Acid/chemistry

PubMed: MeSH publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Journal Article

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@article{345a543affa74b66a10555b0ee44726b,

title = "Effect of Organic Acids on Molecular Mobility, Physical Stability, and Dissolution of Ternary Ketoconazole Spray-Dried Dispersions",

abstract = "In an earlier investigation, ketoconazole (KTZ)-organic acid coamorphous systems were prepared, wherein, in the solid-state, there was ionic and/or hydrogen bonding interactions between the drug and the acid (Fung, M.; Berzin{\v s}, K.; Suryanarayanan, R. Mol. Pharmaceutics, 2018, 15 (5), 1862-1869). While the coamorphous systems accelerated KTZ dissolution, the organic acids were not effective in maintaining supersaturation, and drug precipitation was observed. Ternary drug-polymer-acid amorphous solid dispersions (ASDs) were prepared with KTZ, polyvinylpyrrolidone (PVP), and each oxalic (OXA), tartaric (TAR), citric (CIT), or succinic (SUC) acid. When compared with amorphous KTZ, solid dispersions of KTZ-PVP exhibited a moderate reduction in molecular mobility and small improvement in dissolution performance. The incorporation of acid (OXA, TAR, or CIT) in PVP-KTZ solid dispersion led to orders of magnitude increase in α-relaxation times and decrease in the crystallization propensity. These ternary ASDs were stable while crystallization of the cocrystal was observed in the SUC system. Moreover, the addition of acids also dramatically improved the dissolution performance of KTZ, a result attributed to KTZ-acid interactions.",

keywords = "amorphous solid dispersions, coamorphous, crystallization, dissolution, molecular mobility, physical stability, Succinic Acid/chemistry, Microscopy, Electron, Scanning, Tartrates/chemistry, Drug Stability, Crystallization, Organic Chemicals/chemistry, Acids/chemistry, Povidone/chemistry, X-Ray Diffraction, Molecular Structure, Ketoconazole/chemistry, Oxalic Acid/chemistry",

author = "Fung, \{Michelle H.\} and Raj Suryanarayanan",

note = "Funding Information: M.H.F. was partially supported by the PhRMA Pre-Doctoral Fellowship in Pharmaceutics and the Rowell Graduate Fellowship from the University of Minnesota. This project was partially funded by the William and Mildred Peters Endowment Fund. Powder XRD work was carried out at the Characterization Facility at the University of Minnesota, a member of the NSF-funded Materials Research Facilities Network (www.mrfn.org). We thank Upsher-Smith Laboratories (Drs. Limin Shi and Howard Chen) for providing access to spray drying equipment. We thank Karlis Berziņs{\v ,} Jiangnan Dun, Janice Laramy, Michaela Roslawski, and Wei-Jhe Sun for their help. Publisher Copyright: Copyright {\textcopyright} 2018 American Chemical Society.",

year = "2019",

month = jan,

day = "7",

doi = "10.1021/acs.molpharmaceut.8b00593",

language = "English (US)",

volume = "16",

pages = "41--48",

journal = "Molecular pharmaceutics",

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TY - JOUR

T1 - Effect of Organic Acids on Molecular Mobility, Physical Stability, and Dissolution of Ternary Ketoconazole Spray-Dried Dispersions

AU - Fung, Michelle H.

AU - Suryanarayanan, Raj

N1 - Funding Information: M.H.F. was partially supported by the PhRMA Pre-Doctoral Fellowship in Pharmaceutics and the Rowell Graduate Fellowship from the University of Minnesota. This project was partially funded by the William and Mildred Peters Endowment Fund. Powder XRD work was carried out at the Characterization Facility at the University of Minnesota, a member of the NSF-funded Materials Research Facilities Network (www.mrfn.org). We thank Upsher-Smith Laboratories (Drs. Limin Shi and Howard Chen) for providing access to spray drying equipment. We thank Karlis Berziņs,̌ Jiangnan Dun, Janice Laramy, Michaela Roslawski, and Wei-Jhe Sun for their help. Publisher Copyright: Copyright © 2018 American Chemical Society.

PY - 2019/1/7

Y1 - 2019/1/7

N2 - In an earlier investigation, ketoconazole (KTZ)-organic acid coamorphous systems were prepared, wherein, in the solid-state, there was ionic and/or hydrogen bonding interactions between the drug and the acid (Fung, M.; Berzinš, K.; Suryanarayanan, R. Mol. Pharmaceutics, 2018, 15 (5), 1862-1869). While the coamorphous systems accelerated KTZ dissolution, the organic acids were not effective in maintaining supersaturation, and drug precipitation was observed. Ternary drug-polymer-acid amorphous solid dispersions (ASDs) were prepared with KTZ, polyvinylpyrrolidone (PVP), and each oxalic (OXA), tartaric (TAR), citric (CIT), or succinic (SUC) acid. When compared with amorphous KTZ, solid dispersions of KTZ-PVP exhibited a moderate reduction in molecular mobility and small improvement in dissolution performance. The incorporation of acid (OXA, TAR, or CIT) in PVP-KTZ solid dispersion led to orders of magnitude increase in α-relaxation times and decrease in the crystallization propensity. These ternary ASDs were stable while crystallization of the cocrystal was observed in the SUC system. Moreover, the addition of acids also dramatically improved the dissolution performance of KTZ, a result attributed to KTZ-acid interactions.

AB - In an earlier investigation, ketoconazole (KTZ)-organic acid coamorphous systems were prepared, wherein, in the solid-state, there was ionic and/or hydrogen bonding interactions between the drug and the acid (Fung, M.; Berzinš, K.; Suryanarayanan, R. Mol. Pharmaceutics, 2018, 15 (5), 1862-1869). While the coamorphous systems accelerated KTZ dissolution, the organic acids were not effective in maintaining supersaturation, and drug precipitation was observed. Ternary drug-polymer-acid amorphous solid dispersions (ASDs) were prepared with KTZ, polyvinylpyrrolidone (PVP), and each oxalic (OXA), tartaric (TAR), citric (CIT), or succinic (SUC) acid. When compared with amorphous KTZ, solid dispersions of KTZ-PVP exhibited a moderate reduction in molecular mobility and small improvement in dissolution performance. The incorporation of acid (OXA, TAR, or CIT) in PVP-KTZ solid dispersion led to orders of magnitude increase in α-relaxation times and decrease in the crystallization propensity. These ternary ASDs were stable while crystallization of the cocrystal was observed in the SUC system. Moreover, the addition of acids also dramatically improved the dissolution performance of KTZ, a result attributed to KTZ-acid interactions.

KW - amorphous solid dispersions

KW - coamorphous

KW - crystallization

KW - dissolution

KW - molecular mobility

KW - physical stability

KW - Succinic Acid/chemistry

KW - Microscopy, Electron, Scanning

KW - Tartrates/chemistry

KW - Drug Stability

KW - Crystallization

KW - Organic Chemicals/chemistry

KW - Acids/chemistry

KW - Povidone/chemistry

KW - X-Ray Diffraction

KW - Molecular Structure

KW - Ketoconazole/chemistry

KW - Oxalic Acid/chemistry

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U2 - 10.1021/acs.molpharmaceut.8b00593

DO - 10.1021/acs.molpharmaceut.8b00593

M3 - Article

C2 - 30359037

AN - SCOPUS:85057534702

SN - 1543-8384

VL - 16

SP - 41

EP - 48

JO - Molecular pharmaceutics

JF - Molecular pharmaceutics

IS - 1

ER -

Effect of Organic Acids on Molecular Mobility, Physical Stability, and Dissolution of Ternary Ketoconazole Spray-Dried Dispersions

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

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