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Characterization of Grades of HPMCAS Spray Dried Dispersions of Itraconazole Based on Supersaturation Kinetics and Molecular Interactions Impacting Formulation Performance

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Abstract

Purpose

The objective was to characterize hydroxypropyl methylcellulose acetate succinate (HMPCAS) grades L, M, and H to enhance itraconazole (ITZ) release and permeation from spray dried dispersions (SDDs), and to investigate underpinning molecular ITZ-HPMCAS interactions that differentiated grade performance.

Methods

ITZ or its SDDs were subjected to solution stabilization assessment, one-dimensional proton nuclear magnetic resonance (NMR) spectroscopy, saturation transfer difference NMR studies, small volume dissolution, solid state transformation studies, and in vitro dissolution/permeation flux studies.

Results

HPMCAS-L was the best performing grade overall and exhibited greatest ITZ supersaturation concentration, small volume dissolution, and in vitro dissolution/permeation flux. Meanwhile, H grade retarded ITZ precipitation to the greatest extent in solution stabilization studies and exhibited greater hydrophobic interaction with ITZ in NMR studies. However, this apparent advantage of H grade through hydrophobic interactions between drug-polymer appeared to limit overall dissolution/permeation performance of SDD.

Conclusions

In vitro SDD studies and drug-polymer interaction studies provided insight into the performance of HPMCAS grades, as well as the relative contributions of various mechanisms that polymer can promote ITZ absorption from SDD.

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Abbreviations

1D - 1H NMR:

One dimensional proton nuclear magnetic resonance

API:

Active pharmaceutical ingredient

ASDs:

Amorphous solid dispersions

DCM:

Dichloromethane

DMSO:

Dimethyl sulfoxide

DSC:

Differential scanning calorimetry

HME:

Hot melt extrusion HME

HPMCAS:

Hydroxypropyl methylcellulose acetate succinate

ITZ:

Itraconazole

MeOH:

Methanol

SDDs:

Spray dried dispersions

SSNMR:

Solid state nuclear magnetic resonance

STD-NMR:

Saturation transfer difference nuclear magnetic resonance

Tg:

Glass transition temperature

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Acknowledgments and Disclosures

There are no conflicts of interest for these authors to declare.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, HSF2 room 623, Baltimore, Maryland, 21201, USA

    Asmita Adhikari & James E. Polli

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  1. Asmita Adhikari
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  2. James E. Polli
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Correspondence to James E. Polli.

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Adhikari, A., Polli, J.E. Characterization of Grades of HPMCAS Spray Dried Dispersions of Itraconazole Based on Supersaturation Kinetics and Molecular Interactions Impacting Formulation Performance. Pharm Res 37, 192 (2020). https://doi.org/10.1007/s11095-020-02909-6

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