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Leveraging Molecular Interactions to Develop a Generalized Design Framework for Coamorphous Drug-Drug Mixtures
Dani Lakshman Yarlagadda1, Kohsaku Kawakami2,3, Satyavrata Samavedi1,2
1Department of Chemical Engineering, Indian Institute of Technology Hyderabad, IITH Main Road, Near NH 65, Kandi, Sangareddy, Telangana 502285, India.
This study reveals that coamorphous mixtures (CAMs) with carboxylic acid groups show enhanced stability due to hydrogen bonding. These findings provide design rules for developing more stable drug formulations.
Area of Science:
- Pharmaceutical Science
- Materials Science
- Physical Chemistry
Background:
- Coamorphous mixtures (CAMs) offer a strategy to improve oral absorption and enable combination therapy for poorly soluble drugs.
- Enhancing the glass transition temperature (Tg) of CAMs is crucial for improving their physical stability and extending shelf life.
Purpose of the Study:
- To establish a generalized framework correlating elevated Tg values of CAMs with specific intermolecular interactions.
- To identify key functional groups and interactions responsible for Tg elevation in drug coamorphous systems.
Main Methods:
- Preparation of CAMs using quench-cooling with various drug combinations (indomethacin, ketoprofen, flurbiprofen, flufenamic acid, aripiprazole, bifonazole, clotrimazole).
- Systematic analysis of Tg deviations from Gordon-Taylor predictions.
- Investigation of intermolecular interactions including hydrogen bonding, π-π interactions, halogen bonding, and ionic bonding.
Main Results:
- CAMs containing the COOH group exhibited significant positive Tg deviations, primarily driven by COOH-associated hydrogen bonding, with synergistic effects from π-π and halogen bonding.
- Ionic bonding, favored by pKa differences, was crucial for the largest Tg deviations.
- Non-COOH hydrogen bonding, π-π interactions, and halogen bonding alone did not significantly elevate Tg.
- Continuity in Tg with varying molar ratios suggested minor stoichiometric contributions, while decreased glass transition width indicated enhanced molecular cooperativity.
Conclusions:
- COOH-associated hydrogen bonding is a primary driver for Tg elevation in CAMs.
- Ionic bonding plays a significant role in maximizing Tg enhancement when pKa values differ.
- The findings provide a basis for designing stable CAMs by understanding and controlling intermolecular interactions.
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