Design of Ternary Amorphous Solid Dispersions for Enhanced Dissolution of Drug Combinations

Jinghan Li, Nagakiran Duggirala, N. S.Krishna Kumar, Yongchao Su, Raj Suryanarayanan

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5 Scopus citations


Using sulfamethoxazole (SMZ) and trimethoprim (TMP) as model drugs, we designed amorphous solid dispersions (ASDs) for the simultaneous solubility enhancement of two active pharmaceutical ingredients (APIs) by exploiting the drug-drug and drug-polymer interactions. In order to make this approach broadly applicable and over a wide dose range, a mixture of SMZ and TMP at weight ratios of 5:1 and 1:5 (w/w) were formulated into ternary ASDs. Depending on the dose ratio of the two drugs, the polymer used was either an aminoalkyl methacrylate copolymer (Eudragit, EDE) or polyacrylic acid. The drug-drug and drug-polymer interactions were characterized to be ionic by infrared and solid-state nuclear magnetic resonance spectroscopy. The interactions resulted in a substantial reduction in molecular mobility, evident from the increase in the structural relaxation time determined by dielectric spectroscopy. The drug-drug interaction resulted in ∼3 orders of magnitude reduction in molecular mobility. The addition of a polymer led to a further decrease in molecular mobility of up to 4 orders of magnitude. The strength of intermolecular interactions was also estimated from the glass transition temperatures of the ASDs obtained by differential scanning calorimetry. The strong intermolecular interactions yielded highly stable ASDs with no evidence of crystallization, both at elevated temperatures and under accelerated storage conditions (40 °C/75% relative humidity; 6 weeks). The dissolution performances of the ASDs were evaluated using the area under the curve (AUC) obtained from the concentration-time profiles under the non-sink condition. SMZ and TMP in their ternary ASDs, when compared with their crystalline counterparts, exhibited up to 6.4- and 4.6-fold increases in AUC, respectively. Importantly, the synchronized release of the two drugs was observed, a desirable attribute in synergistic formulations. A single-phase ternary ASD, stabilized by drug-drug and drug-polymer interactions, is likely responsible for the unique release profile.

Original languageEnglish (US)
Pages (from-to)2950-2961
Number of pages12
JournalMolecular pharmaceutics
Issue number8
StatePublished - Aug 1 2022

Bibliographical note

Funding Information:
This project was supported by the William and Mildred Peters endowment fund. The authors acknowledge Drs. Dabing Chen and Li Zhong from the Material and Analytical Sciences Department, Boehringer Ingelheim, for their help with the dissolution and HPLC study.

Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.


  • amorphous solid dispersion
  • coamorphous system
  • dielectric spectroscopy
  • dissolution
  • drug combination
  • infrared spectroscopy
  • ionic interaction
  • molecular mobility
  • solid-state nuclear magnetic resonance
  • synchronized release

PubMed: MeSH publication types

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


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