Insights into Nano- and Micron-Scale Phase Separation in Amorphous Solid Dispersions Using Fluorescence-Based Techniques in Combination with Solid State Nuclear Magnetic Resonance Spectroscopy
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Miscibility between the drug and the polymer in an amorphous solid dispersion (ASD) is considered to be one of the most important factors impacting the solid state stability and dissolution performance of the active pharmaceutical ingredient (API). The research described herein utilizes emerging fluorescence-based methodologies to probe (im)miscibility of itraconazole (ITZ)-hydroxypropyl methylcellulose (HPMC) ASDs.
The ASDs were prepared by solvent evaporation with varying evaporation rates and were characterized by steady-state fluorescence spectroscopy, confocal imaging, differential scanning calorimetry (DSC), and solid state nuclear magnetic resonance (ssNMR) spectroscopy.
The size of the phase separated domains for the ITZ-HPMC ASDs was affected by the solvent evaporation rate. Smaller domains (<10 nm) were observed in spray-dried ASDs, whereas larger domains (>30 nm) were found in ASDs prepared using slower evaporation rates. Confocal imaging provided visual confirmation of phase separation along with chemical specificity, achieved by selectively staining drug-rich and polymer-rich phases. ssNMR confirmed the results of fluorescence-based techniques and provided information on the size of phase separated domains.
The fluorescence-based methodologies proved to be sensitive and rapid in detecting phase separation, even at the nanoscale, in the ITZ-HPMC ASDs. Fluorescence-based methods thus show promise for miscibility evaluation of spray-dried ASDs.
KEY WORDSamorphous solid dispersion miscibility fluorescence solid state nuclear magnetic resonance
Amorphous-amorphous phase separation
Active pharmaceutical ingredient
Amorphous solid dispersion
Cross polarization magic angle spinning
Differential scanning calorimetry
Hydroxypropyl methyl cellulose
Scanning electron microscopy
Solid state nuclear magnetic resonance
Laboratory frame relaxation time
Rotating frame relaxation time
Glass transition temperature
Acknowledgments and Disclosures
Financial support to HSP from Migliaccio/Pfizer graduate fellowship is greatly acknowledged. The authors would like to thank the New Technology Review and Licensing Committee (NTRLC) at Merck & Co., Inc., Kenilworth, NJ, USA, for financial support. The authors would also like to thank Drs. Ellen C. Minnihan, Wei Xu, Anthony Leone, Timothy Rhodes, Andrew Latham and Christopher J. Welch for helpful discussions.
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