# Leveraging Molecular Interactions to Develop a Generalized Design Framework for Coamorphous Drug–Drug Mixtures Exhibiting Elevated Glass Transition Temperatures

https://mdr.nims.go.jp/datasets/77e85380-22b1-441d-8aac-51ab0facfd05

## File

- [Manuscript without highlights_2nd revision_MP.docx](https://mdr.nims.go.jp/filesets/f24d4450-24c4-4ef6-9d6d-c83396936193/download) ([Detail](https://mdr.nims.go.jp/filesets/f24d4450-24c4-4ef6-9d6d-c83396936193.md))

## Id

77e85380-22b1-441d-8aac-51ab0facfd05

## Local identifier



## Visibility

open_to_public

## State

published

## Created at

2025-11-09T18:53:14.338401Z

## Updated at

2026-04-30T03:01:11.491392Z

## Published at

2026-05-15T23:25:02.398613Z

## Doi

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

## First published url

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

## Date published

2025-06-02

## Recorded date published

2025-6-2

## Resource type

journal_article

## Manuscript type

accepted_manuscript

## Collection



## Title

- title: Leveraging Molecular Interactions to Develop a Generalized Design Framework
    for Coamorphous Drug–Drug Mixtures Exhibiting Elevated Glass Transition Temperatures
  title_type: original
  lang: en

## Description

- description: 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.
  description_type: abstract
  lang: und

## Creator

- name: Dani Lakshman Yarlagadda
  role: author
- name: Kohsaku Kawakami
  role: author
  orcid: https://orcid.org/0000-0002-3466-9365
  organization: National Institute for Materials Science
- name: Satyavrata Samavedi
  role: author
  orcid: https://orcid.org/0000-0003-1196-1598

## Contact agent



## Publisher

organization: American Chemical Society (ACS)

## Managing organization



## Keyword

- subject: Molecular cooperativity
  schema: not_defined
- subject: Co-amorphous mixture
  schema: not_defined
- subject: Glass transition temperature
  schema: not_defined
- subject: Gordon-Taylor equation
  schema: not_defined
- subject: Molecular interaction
  schema: not_defined
- subject: Amorphous drug stability
  schema: not_defined

## Rights

- description: 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.
  identifier: http://rightsstatements.org/vocab/InC/1.0/

## Other identifier(s)



## Data origin

- data_origin_type: other

## Embargo

start_date: 2025-05-16
end_date: 2026-05-17

## Journal

- title: Molecular Pharmaceutics
  issn: '15438384'
  volume: '22'
  issue: '6'
  start_page: 3084
  end_page: 3096

## Conference



## Related item



## Funding



## Instrument



## Instrument operator



## Instrument managing organization



## Measurement method



## Specimen



## Chemical composition



## Structure for specimen



## Structural feature for specimen



## Specific property for specimen



## Process for specimen treatment



## Computational method



## Energy level/transition state



## Software



## Custom property



## Fileset

- id: f24d4450-24c4-4ef6-9d6d-c83396936193
  filename: Manuscript without highlights_2nd revision_MP.docx
  content_type: application/vnd.openxmlformats-officedocument.wordprocessingml.document
  size: 2571468
  md5: 63994fdf210f2032552f368d206f1570

## Thumbnail

fileset_id: f24d4450-24c4-4ef6-9d6d-c83396936193
filename: Manuscript without highlights_2nd revision_MP.docx