Drug-Excipient Interactions: Effect on Molecular Mobility and Physical Stability of Ketoconazole-Organic Acid Coamorphous Systems

Michelle H. Fung, Marla Devault, Keith T. Kuwata, Raj Suryanarayanan

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64 Scopus citations

Abstract

The use of excipients other than polymers for enhancing the physical stability of amorphous active pharmaceutical ingredients (APIs) has largely been unexplored. We investigated several organic acids (oxalic, tartaric, citric, and succinic acid) for the purpose of stabilizing a weakly basic API, ketoconazole (KTZ), in the amorphous state. Coamorphous systems with each acid, in 1:1 KTZ-Acid molar ratio, were prepared by spray drying. The interaction of KTZ with each acid was investigated by FT-IR, solid-state NMR, and quantum chemical calculations. Each acid exhibited ionic and/or hydrogen-bonding interactions with KTZ, and quantum chemical calculations provided a measure of the strength of this interaction. The α-relaxation times, a measure of molecular mobility, were determined by dielectric spectroscopy, and their crystallization propensity by variable temperature X-ray powder diffractometry. Crystallization was observed only in two systems, KTZâoxalic salt and KTZâsuccinic as a cocrystal. An increase in the strength of KTZ-Acid interaction translated to a decrease in molecular mobility. When the two systems prepared with structurally similar dicarboxylic acids (succinic and oxalic acid) were compared, the physical stability enhancement of KTZ-oxalic coamorphous system could be attributed to its lower mobility. However, the exceptional stability of KTZ-Tartaric and KTZ-citric could not be explained by mobility alone, indicating that structural factors may also contribute to stabilization. The interaction between KTZ and acid may alter the system sufficiently so that the crystallization propensity of the KTZ-Acid complex (salt or cocrystal) becomes relevant. We conclude that small molecule excipients have the potential to improve the physical stability of amorphous APIs.

Original languageEnglish (US)
Pages (from-to)1052-1061
Number of pages10
JournalMolecular pharmaceutics
Volume15
Issue number3
DOIs
StatePublished - Mar 5 2018

Bibliographical note

Funding Information:
M.H. Fung was partially supported by PhRMA Pre-Doctoral Fellowship in Pharmaceutics and the Rowell Graduate Fellowship from 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 University of Minnesota, a member of the NSF-funded Materials Research Facilities Network (www.mrfn. org). We thank: (i) Upsher-Smith Laboratories (Limin Shi and Howard Chen) for providing access to spray drying equipment, (ii) Robert Wenslow, Crystal Pharmatech, for helping in the interpretation of NMR data, and (iii) Karlis̅ Berzin̅ ̧s,̌ Subarna Samanta, Pinal Mistry, and Krishna Kumar for the helpful discussions and comments. M. DeVault received support from the Beckman Scholars Program and the computer facility of the Midwest Undergraduate Computational Chemistry Consortium housed at Hope College, established by past NSF grants CHE-0520704 and CHE-1039925.

Funding Information:
M. DeVault received support from the Beckman Scholars Program and the computer facility of the Midwest Undergraduate Computational Chemistry Consortium housed at Hope College, established by past NSF grants CHE-0520704 and CHE-1039925.

Publisher Copyright:
© Copyright 2018 American Chemical Society.

Keywords

  • amorphous
  • citric acid
  • coamorphous
  • crystallization
  • dielectric spectroscopy
  • ketoconazole
  • molecular mobility
  • oxalic acid
  • succinic acid
  • tartaric acid

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