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Synergistic effect of polymers in stabilizing amorphous pretomanid through high drug loaded amorphous solid dispersion

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Pretomanid (PTM), an oral antibiotic used in the treatment of adults with pulmonary extensively drug-resistant, nonresponsive multidrug-resistant tuberculosis (MDR-TB). It is a poor glass former, that shows high recrystallization tendency from the amorphous and supersaturated state, resulting in low aqueous solubility and suboptimal absorption through the gastrointestinal tract. The present investigation aimed to develop high drug loaded ternary amorphous solid dispersions (ASDs) of PTM with improved stability and enhanced biopharmaceutical performance by utilizing a combination of polymers. The polymers were comprehensively screened based on drug-polymer miscibility and saturation solubility analysis. A combination of Hydroxypropyl Methylcellulose Acetate Succinate (HPMCAS-HF) and Polyvinylpyrrolidone K-30 (PVP K-30) showed synergism in drug-polymer miscibility as evidenced through pronounced depression in the melting endotherm of PTM. The Powder X-ray Diffraction (P-XRD) diffractograms of 30% w/w PTM loaded ternary ASDs displayed the halo pattern, contrary to the binary ASDs. Drug-polymer interactions (hydrophobic forces) involved between PTM and polymers were detected through Fourier Transform Infrared Spectroscopy (FT-IR) and Nuclear Magnetic Resonance Spectroscopy (13C-NMR) which contributed to the synergistic enhancement in solubility and dissolution of ternary ASDs with sustained release over 12 h. Ternary ASDs demonstrated better in-vivo performance compared to the binary ASDs, showing a 4.63-fold increase in maximum plasma concentration. All ASDs remained stable and resisted phase separation during short-term stability studies for 3 months at ambient conditions. It was concluded that the hydrophobic and hydrophilic polymeric combination (HPMCAS-HF and PVP K-30, respectively) effectively prevented the crystallization and ensured sustained drug release with improved in-vivo absorption of PTM.

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Data availability

All data generated or analyzed during this study are provided in this published article and supplementary information.





Amorphous solid dispersions


Binary amorphous solid dispersion


Ternary amorphous solid dispersion


Hydroxypropyl methylcellulose acetate succinate


Hydroxypropyl methylcellulose


Hydroxypropyl methylcellulose phthalate


Polyvinyl pyrrolidone


Differential scanning calorimetry


Fourier transform infrared spectroscopy


Powder X-ray diffraction


Nuclear magnetic resonance spectroscopy


Confocal fluorescence microscopy


Scanning electron microscopy


Polarized light microscopy


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The authors would like to acknowledge Macleod’s Pharmaceuticals (Mumbai, India) for providing the gift samples. Support provided by the Director, NIPER S.A.S Nagar regarding the necessary facilities and infrastructure is also highly acknowledged.


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Authors and Affiliations



Mehak Juneja: Conceptualisation, methodology, investigation, data curation, validation, formal data analysis, manuscript writing, review and editing. Krishna Mehtre: Conceptualisation, methodology, investigation, data curation, validation. Vanshul Saini: Manuscript writing, review and editing. Ridhima Singh: Methodology and editing. Prakash Amate: Data curation. Mahesh Kashyap: Methodology (Pharmacokinetic study). Abhay T. Sangamwar: Data review, project administration, supervision, review and editing.

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Correspondence to Abhay T. Sangamwar.

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Ethical approval

All the animal handling, care and experiments are carried out in compliance with the guidelines endorsed by the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA). The animal experimental protocol (IAEC/23/03) was duly approved by the Institutional Animal Ethics Committee (NIPER, Mohali, India).

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Abhay T. Sangamwar, corresponding author for this research article, on behalf of all other respected authors (Mehak Juneja, Krishna Mehtre, Vanshul Saini, Ridhima Singh, Prakash Amate, Mahesh Kashyap) hereby affirms that this article is in original form and does not violate any copyright, this research article has not been published earlier, and not consideration in any other journal.

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Juneja, M., Mehtre, K., Saini, V. et al. Synergistic effect of polymers in stabilizing amorphous pretomanid through high drug loaded amorphous solid dispersion. Drug Deliv. and Transl. Res. (2024).

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