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Coamorphous mixtures (CAMs) prepared with two drugs have the potential to enhance the oral absorption of poorly soluble drugs and achieve combination therapy. From a practical standpoint, improving the glass transition temperature (Tg) of CAMs is desirable as it enhances stability and extends shelf life during storage. Toward the eventual goal of developing highly stable CAMs, this study establishes a generalized framework that systematically relates elevated Tg values of CAMs to intermolecular interactions based on specific functional groups. CAMs were prepared via quench-cooling using various combinations of indomethacin, ketoprofen, flurbiprofen, flufenamic acid, aripiprazole, bifonazole, and clotrimazole. CAMs prepared with drugs containing the COOH group exhibited significant positive deviations from the Tg values predicted by the Gordon–Taylor equation (i.e., ideal mixing behavior). COOH-associated hydrogen bonding was determined to be a key factor for Tg elevation, with synergistic contributions from π–π interactions and halogen bonding. In CAMs exhibiting the largest Tg deviations, contributions from ionic bonding were crucial, and were likely favored by differences in the pKa values of the constituent drugs. Continuity in Tg as a function of varying molar ratios indicated that stoichiometric pairing had a relatively minor contribution, while a decrease in the width of the glass transition suggested enhancement of molecular cooperativity as a possible mechanism for CAM stabilization. In contrast, non-COOH hydrogen bonding, π–π interactions, and halogen bonding on their own did not result in any meaningful Tg deviations from theoretical predictions. Systematic correlations between Tg deviations and molecular interactions reported in this study can lead to generalized design rules for the development of stable CAMs.

権利情報:

• In Copyright
  

  This document is the Accepted Manuscript version of a Published Work that appeared in final form in Molecular Pharmaceutics, copyright © 2025 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.molpharmaceut.5c00006.

キーワード: Co-amorphous mixture, Glass transition temperature, Gordon-Taylor equation, Molecular interaction, Amorphous drug stability, Molecular cooperativity

刊行年月日: 2025-06-02

出版者: American Chemical Society (ACS)

掲載誌:

• Molecular Pharmaceutics (ISSN: 15438384) vol. 22 issue. 6 p. 3084-3096

研究助成金:

原稿種別: 著者最終稿 (Accepted manuscript)

MDR DOI: https://doi.org/10.48505/nims.5903

公開URL: https://doi.org/10.1021/acs.molpharmaceut.5c00006

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更新時刻: 2026-04-30 12:01:11 +0900

MDRでの公開時刻: 2026-05-16 08:25:02 +0900